What are the definition, etiologies, pathophysiology, and treatment of hypernatremia?

Hypernatremia: Definition, Causes, and Pathophysiology

Definition

Hypernatremia is defined as a plasma sodium concentration greater than 145 mmol/L 1, 2, 3. This electrolyte disorder fundamentally reflects an imbalance in water homeostasis rather than a primary sodium problem 4.

Pathophysiology

Normal Protective Mechanisms

The body maintains plasma osmolality between 280-295 mOsm/kg through three integrated mechanisms 3:

• Thirst mechanism: When plasma sodium rises above 145 mmol/L, hypothalamic osmoreceptors stimulate thirst, driving water ingestion 1
• Arginine Vasopressin (AVP) release: Hypothalamic osmoreceptors trigger synthesis and release of antidiuretic hormone 1, 3
• Renal response to AVP: Normal kidneys respond by increasing water reabsorption, preventing further water loss 1

Why Hypernatremia Persists

Persistent hypernatremia implies either inability to sense thirst or lack of access to water, since water ingestion alone can prevent significant hypernatremia even without AVP or renal response 1. Dysfunction of all three protective factors—AVP, thirst, and renal AVP response—can cause hypernatremia 3.

Classification and Causes

By Volume Status

Hypovolemic Hypernatremia (Most Common)

This results from water loss exceeding sodium loss 2, 4:

Renal losses 2, 4:

• Osmotic diuresis (hyperglycemia, mannitol)
• Loop diuretics
• Post-obstructive diuresis

Extrarenal losses 2, 4:

• Gastrointestinal (diarrhea, vomiting)
• Skin (burns, excessive sweating)
• Respiratory (hyperventilation)

Euvolemic Hypernatremia

This occurs in diabetes insipidus 2:

Central (neurogenic) diabetes insipidus 2:

• Traumatic brain injury
• Neurosurgery
• Vascular events (subarachnoid hemorrhage)
• Infectious causes (meningitis, encephalitis)
• Tumors affecting hypothalamus/pituitary

Nephrogenic diabetes insipidus 2:

• Lithium toxicity (most common pharmacological cause)
• Hypokalemia
• Hypercalcemia
• Chronic kidney disease
• Congenital forms

Hypervolemic Hypernatremia (Rare)

This results from sodium gain 2, 4:

Acute hypervolemic hypernatremia 2:

• Hypertonic saline administration
• Sodium bicarbonate infusions
• Salt poisoning

Chronic hypervolemic hypernatremia 2:

• Primary hyperaldosteronism
• Cushing syndrome

By Duration

Acute hypernatremia (< 24-48 hours) 5, 2, 6:

• Allows for rapid correction without significant neurological risk
• Often iatrogenic in hospitalized patients

Chronic hypernatremia (> 48 hours) 5, 2, 6:

• Requires slow correction (maximum 10-15 mmol/L per 24 hours) to avoid cerebral edema
• Brain cells have adapted by generating organic osmolytes

By Severity

• Mild: 146-149 mmol/L 2
• Moderate: 150-159 mmol/L 2
• Severe/Threatening: ≥160 mmol/L 2

High-Risk Populations

Elderly Patients

Elderly persons are at markedly increased risk due to diminished thirst perception 1:

• Decreased thirst response leads to inadequate water intake
• Hospitalized elderly and nursing home residents depend on others for water needs
• Frail elderly cannot access water independently 1

Critical Care Patients

Hospitalized patients face multiple risk factors 5:

• Impaired thirst or inability to communicate thirst
• Lack of access to water (intubated, sedated, altered mental status)
• Excessive fluid losses (fever, mechanical ventilation, osmotic diuresis)
• Iatrogenic causes (inadequate free water prescription, hypertonic solutions)

Neonates

Very low birth weight neonates are vulnerable 5:

• Immature renal concentrating ability
• High insensible water losses
• Dependence on prescribed fluids

Cellular Pathophysiology

Acute Hypernatremia

When plasma sodium rises acutely, water shifts from intracellular to extracellular compartments, causing cellular dehydration 2, 6. This is particularly dangerous in the brain, where cellular shrinkage can cause:

• Tearing of cerebral vessels
• Intracerebral hemorrhage
• Subarachnoid hemorrhage
• Permanent neurological damage

Chronic Hypernatremia

Over 24-48 hours, brain cells adapt by generating organic osmolytes (idiogenic osmoles) to restore cell volume 6. This adaptation explains why:

• Chronic hypernatremia is better tolerated clinically
• Rapid correction causes cerebral edema (water rushes into cells with elevated osmolyte content)
• Slow correction (≤10-15 mmol/L per 24 hours) is mandatory 5, 6

Clinical Significance

Hypernatremia is associated with increased morbidity and mortality 4, 3. The mortality rate is unappreciated but high, particularly in hospitalized patients 3. Treatment should be initiated promptly once identified 4.

The primary goal of treatment is restoration of plasma tonicity, with correction speed determined by duration of hypernatremia 5, 2. Identifying and treating the underlying cause is crucial 5.