Hypernatremia: Comprehensive Overview for Provider Theory Examination

Definition and Classification

Hypernatremia is defined as a plasma sodium concentration greater than 145 mmol/L, representing a disorder of water balance where there is either absolute or relative water deficit compared to sodium content. 1, 2

Classification Systems

By Duration:

Acute hypernatremia: <24-48 hours duration, allowing for rapid correction without significant neurological risk 1, 3
Chronic hypernatremia: >48 hours duration, requiring slow correction (maximum 10-15 mmol/L per 24 hours or 0.4 mmol/L/hour) to prevent cerebral edema, seizures, and neurological injury 4, 1, 3

By Severity:

Mild: 146-149 mmol/L 1
Moderate: 150-159 mmol/L 1
Severe/Threatening: ≥160 mmol/L 1

By Volume Status and Pathogenesis:

Hypervolemic hypernatremia: Excess total body sodium with relatively less water excess 1, 2
Euvolemic hypernatremia: Normal total body sodium with water deficit 1, 2
Hypovolemic hypernatremia: Deficit of both water and sodium, with proportionally greater water loss 1, 2, 5

Pathophysiology and Biochemistry

Normal Water Homeostasis

Total body water and tonicity are tightly regulated through four integrated mechanisms: 6

Antidiuretic hormone (ADH/vasopressin): Released from the posterior pituitary in response to increased plasma osmolality (>295 mOsm/kg) or decreased effective circulating volume, promoting water reabsorption in the collecting ducts 6
Renin-angiotensin-aldosterone system (RAAS): Regulates sodium reabsorption and indirectly affects water balance 6
Thirst mechanism: Stimulated at plasma osmolality >295 mOsm/kg, providing behavioral drive for water intake 6
Norepinephrine: Contributes to volume regulation 6

Mechanisms of Hypernatremia Development

Hypernatremia fundamentally reflects an imbalance where water loss exceeds sodium loss, or sodium gain exceeds water gain. 1, 5 The disorder rarely results from excessive sodium intake alone but rather from:

Impaired access to water: Patients with altered mental status, mechanical ventilation, physical restraints, or institutionalization cannot respond to thirst 2, 6
Impaired thirst mechanism: Hypothalamic lesions, advanced age, or osmoreceptor dysfunction 2, 6
Excessive water losses: Renal or extrarenal routes exceeding intake 2, 5
Iatrogenic causes: Hypertonic saline administration, sodium bicarbonate infusions, or inadequate free water provision 1, 2

Cellular Consequences

Acute hypernatremia causes cellular dehydration through osmotic water shift from intracellular to extracellular compartments, particularly affecting brain cells. 1 This leads to:

Brain cell shrinkage and potential vascular rupture
Risk of intracerebral and subarachnoid hemorrhage
Central nervous system dysfunction 1, 3

Chronic hypernatremia triggers adaptive mechanisms: Brain cells generate organic osmolytes (idiogenic osmoles) including taurine, glutamine, and myoinositol to restore cell volume over 24-48 hours. 1 This adaptation explains why rapid correction of chronic hypernatremia is dangerous—it creates a relative hypotonic state causing cerebral edema. 4, 3

Etiology

Hypervolemic Hypernatremia (Sodium Excess)

Acute causes:

Hypertonic saline (3% NaCl) administration 1
Sodium bicarbonate infusions 1
Salt poisoning or ingestion 1

Chronic causes:

Primary hyperaldosteronism (Conn's syndrome) 1
Cushing's syndrome 1

Euvolemic Hypernatremia (Pure Water Deficit)

Central (Neurogenic) Diabetes Insipidus:

Traumatic: Head injury, neurosurgery 1
Vascular: Subarachnoid hemorrhage, Sheehan syndrome 1
Infectious: Meningitis, encephalitis 1
Neoplastic: Craniopharyngioma, metastases 1
Infiltrative: Sarcoidosis, histiocytosis X 1
Idiopathic: Autoimmune destruction 1

Nephrogenic Diabetes Insipidus:

Pharmacological: Lithium (most common), demeclocycline, foscarnet, amphotericin B 1
Metabolic: Hypokalemia, hypercalcemia 1
Congenital: AVPR2 or AQP2 gene mutations 7
Chronic kidney disease: Medullary damage 1

Insensible water losses:

Fever (increases by ~10% per degree Celsius above 37°C) 2
Tachypnea 2
Burns 2

Hypovolemic Hypernatremia (Water Loss > Sodium Loss)

Renal losses (urine sodium typically >20 mmol/L):

Osmotic diuresis (hyperglycemia, mannitol, urea) 2, 5
Loop diuretics 2, 5
Post-obstructive diuresis 2
Intrinsic renal disease 2

Extrarenal losses (urine sodium typically <20 mmol/L):

Gastrointestinal: Diarrhea, vomiting (particularly in infants and elderly) 2, 5
Cutaneous: Excessive sweating, burns 2, 5
Respiratory: Hyperventilation 2

Clinical Manifestations

Central Nervous System Symptoms (Predominant)

The clinical presentation is primarily characterized by CNS dysfunction due to brain cell dehydration: 3

Altered mental status: Confusion, lethargy, obtundation progressing to coma 3, 2
Seizures: Particularly in severe or rapidly developing hypernatremia 4, 3
Focal neurological deficits: May mimic stroke 2
Irritability and restlessness: Especially in children 2
Muscle weakness and hyperreflexia: From cellular dysfunction 2

Thirst and Volume Status

Intense thirst (polydipsia): Present in conscious patients with intact thirst mechanism 3, 2
Volume depletion signs (in hypovolemic hypernatremia): Orthostatic hypotension, tachycardia, dry mucous membranes, decreased skin turgor, sunken eyes 2
Volume overload signs (in hypervolemic hypernatremia): Edema, hypertension, jugular venous distension 2

Severe Complications

Intracerebral hemorrhage: From vascular rupture due to brain shrinkage 1
Subarachnoid hemorrhage: Particularly in acute severe hypernatremia 1
Rhabdomyolysis: From severe cellular dehydration 2
Increased mortality: Hypernatremia is associated with significantly increased hospital mortality 6

Diagnostic Approach

Eight-Step Diagnostic Algorithm 2

Step 1: Exclude Pseudohypernatremia

Rule out laboratory error or severe hyperlipidemia/hyperproteinemia (rare with modern ion-selective electrodes) 2

Step 2: Confirm Glucose-Corrected Sodium

Correct for hyperglycemia: Add 1.6 mmol/L to measured sodium for every 100 mg/dL (5.6 mmol/L) glucose above 100 mg/dL 2
This distinguishes true hypernatremia from translocational hyponatremia 2

Step 3: Determine Extracellular Volume Status

Hypovolemic: Orthostatic hypotension, tachycardia, dry mucous membranes, decreased skin turgor, flat neck veins 2
Euvolemic: Normal blood pressure, no edema, normal jugular venous pressure 2
Hypervolemic: Edema, hypertension, elevated jugular venous pressure 2

Step 4: Measure Urine Sodium Levels

Urine Na+ <20 mmol/L: Suggests extrarenal losses (GI, skin, respiratory) 2
Urine Na+ >20 mmol/L: Suggests renal losses or sodium excess 2

Step 5: Measure Urine Volume and Osmolality

Urine osmolality >800 mOsm/kg: Appropriate renal response to hypernatremia; suggests extrarenal losses or sodium excess 2
Urine osmolality <300 mOsm/kg: Inappropriate dilute urine; suggests diabetes insipidus 2
Polyuria (>3 L/day): Strongly suggests diabetes insipidus 7, 2

Step 6: Check Ongoing Urinary Electrolyte-Free Water Clearance

Calculate free water clearance to quantify ongoing losses 2
Formula: CH₂O = Urine volume × [1 - (Urine Na + Urine K)/Plasma Na] 2

Step 7: Determine Arginine Vasopressin/Copeptin Levels

Low/undetectable copeptin with polyuria: Central diabetes insipidus 2
Elevated copeptin with polyuria: Nephrogenic diabetes insipidus 2
Note: Copeptin is a stable surrogate marker for ADH 2

Step 8: Assess Other Electrolyte Disorders

Hypokalemia: Can cause nephrogenic diabetes insipidus 1, 2
Hypercalcemia: Can cause nephrogenic diabetes insipidus 1, 2

Key Laboratory Tests

Essential initial workup:

Serum sodium, potassium, chloride, bicarbonate 2
Blood urea nitrogen and creatinine 2
Serum glucose 2
Serum osmolality 2
Urine osmolality and sodium 2
Urine volume (24-hour or timed collection) 2

Additional tests based on clinical suspicion:

Serum calcium and potassium (if diabetes insipidus suspected) 2
Copeptin or ADH levels (if diabetes insipidus suspected) 2
Brain imaging (if central diabetes insipidus suspected) 1

Water Deprivation Test (for Diabetes Insipidus Diagnosis)

Indications: Polyuria with inappropriately dilute urine 7

Procedure:

Withhold fluids under close supervision 7
Monitor weight, vital signs, serum and urine osmolality hourly 7
Central DI: Urine osmolality remains <300 mOsm/kg; increases >50% after desmopressin administration 7
Nephrogenic DI: Urine osmolality remains <300 mOsm/kg; minimal response (<10% increase) to desmopressin 7
Primary polydipsia: Urine osmolality increases appropriately (>600 mOsm/kg) with dehydration 7

Treatment

Six-Step Management Algorithm 2

Step 1: Identify and Treat Underlying Causes

Discontinue offending medications: Lithium, diuretics 1, 2
Treat diabetes insipidus: Desmopressin for central DI 7, 3
Correct electrolyte abnormalities: Hypokalemia, hypercalcemia 1, 2
Restore access to water: For patients with impaired access 2
Treat infections or other precipitants: Address underlying pathology 2

Step 2: Distinguish Acute from Chronic Hypernatremia

This is the most critical decision point determining correction rate: 4, 1, 3

Acute (<24-48 hours): Rapid correction is safe and prevents cellular dehydration complications; can correct at 1 mmol/L/hour 1, 3
Chronic (>48 hours) or unknown duration: Slow correction mandatory (maximum 10-15 mmol/L per 24 hours or 0.4 mmol/L/hour) to prevent cerebral edema 4, 1, 3

Step 3: Calculate Water Deficit and Determine Rate

Water deficit formula: 2

Water deficit (L) = Total body water × [(Current Na/140) - 1]
Total body water = 0.6 × body weight (kg) in men; 0.5 × body weight (kg) in women

Correction rate guidelines:

Acute hypernatremia: Can correct rapidly, up to 1 mmol/L/hour 1, 3
Chronic hypernatremia: Maximum 10-15 mmol/L per 24 hours (0.4-0.6 mmol/L/hour) 4, 1, 3
Conservative approach: Target 8-10 mmol/L per 24 hours for chronic cases 3

Step 4: Select Type of Replacement Solution

For hypervolemic hypernatremia:

Avoid hypotonic fluids initially 2
Loop diuretics (furosemide) to promote sodium excretion 2
Then hypotonic fluids (0.45% NaCl or D5W) once euvolemic 2

For euvolemic hypernatremia:

Hypotonic fluids: 0.45% NaCl (half-normal saline) or D5W (5% dextrose in water) 2
D5W preferred if no glucose intolerance 2
Oral water if patient can tolerate (safest route) 2

For hypovolemic hypernatremia:

Initial resuscitation: 0.9% normal saline to restore hemodynamic stability 2, 5
Then switch to hypotonic fluids (0.45% NaCl or D5W) once hemodynamically stable 2, 5

Special consideration for nephrogenic diabetes insipidus:

Avoid isotonic saline (0.9% NaCl): The tonicity (~~300 mOsm/kg) exceeds typical urine osmolality in NDI (~~100 mOsm/kg) by 3-fold, requiring ~3 L urine to excrete the osmotic load from 1 L isotonic fluid, risking serious hypernatremia 7
Use 5% dextrose with no renal osmotic load 7
Calculate maintenance rate: Children: first 10 kg at 100 mL/kg/24h; 10-20 kg at 50 mL/kg/24h; remaining at 20 mL/kg/24h; Adults: 25-30 mL/kg/24h 7

Step 5: Account for Ongoing Losses

Add to calculated deficit: 2

Insensible losses: ~500-1000 mL/day (increases with fever, tachypnea) 2
Ongoing urine losses: Measure and replace, especially in diabetes insipidus 2
GI losses: If diarrhea or vomiting present 2

Step 6: Adjust Treatment Schedule with Frequent Monitoring

Monitoring frequency:

Severe hypernatremia (>160 mmol/L): Check serum sodium every 2-4 hours initially 2
Moderate hypernatremia: Check every 4-6 hours 2
Mild hypernatremia: Check every 6-12 hours 2

Adjust infusion rate based on actual sodium change versus target 2

Specific Treatment for Diabetes Insipidus

Central Diabetes Insipidus:

Desmopressin (DDAVP): 1-4 mcg subcutaneous/IV or 10-20 mcg intranasal twice daily 7, 3
Titrate to control polyuria while avoiding hyponatremia 7

Nephrogenic Diabetes Insipidus (Congenital):

Dietary management: 7

Low sodium intake (≤6 g/day): Reduces osmotic load and urine volume 7
Low protein diet (<1 g/kg/day): Reduces urea-mediated osmotic diuresis 7
Dietetic counseling essential 7

Pharmacological therapy: 7

Thiazide diuretics (hydrochlorothiazide): Impair urinary dilution in distal tubule, enhance proximal water reabsorption via volume depletion; efficacy may decrease with age 7
Amiloride: Impairs urinary dilution in collecting duct; used in combination with thiazides, particularly for lithium-induced NDI 7
Prostaglandin synthesis inhibitors: Enhance collecting duct water permeability; risk of GI ulcers 7
Celecoxib (selective COX-2 inhibitor): Reduces GI bleeding risk compared to non-selective COX inhibitors 7

Emergency management of hypernatremic dehydration in NDI:

Avoid salt-containing solutions (0.9% NaCl): Will worsen hypernatremia due to high osmotic load relative to dilute urine 7
Use 5% dextrose at maintenance rate 7
Low threshold for IV rehydration if oral failed 7

Hemodialysis for Severe Acute Hypernatremia

Indications: 3

Acute hypernatremia (<24 hours) with severe elevation (>160-170 mmol/L) 3
Hypernatremia with acute kidney injury requiring dialysis 3
Allows rapid, controlled correction 3

Caution: When starting renal replacement therapy in chronic hypernatremia, use dialysate with higher sodium concentration to avoid rapid sodium drop 3

Recent Advances and Evidence

Copeptin as Diagnostic Biomarker

Copeptin (C-terminal pro-vasopressin) is a stable surrogate marker for ADH that can be measured reliably, unlike ADH itself. 2 This represents a significant diagnostic advance:

Low copeptin with polyuria: Confirms central diabetes insipidus 2
High copeptin with polyuria: Confirms nephrogenic diabetes insipidus 2
May replace water deprivation test in many cases 2

Congenital Nephrogenic Diabetes Insipidus Management

The 2025 international expert consensus statement provides comprehensive management guidelines for congenital NDI: 7

Combination therapy with thiazides, amiloride, and COX-2 inhibitors more effective than monotherapy 7
Importance of low sodium and protein diet emphasized 7
Surveillance imaging (renal ultrasound every 2 years) to detect hydronephrosis from voluntary urine retention 7
Recognition of CKD risk in NDI patients requiring closer monitoring 7

Correction Rate Controversies

Recent evidence emphasizes the critical importance of distinguishing acute from chronic hypernatremia: 4, 1, 3

Acute hypernatremia: Rapid correction is safe and beneficial, preventing cellular dehydration complications 1, 3
Chronic hypernatremia: Slow correction (10-15 mmol/L per 24 hours maximum) is mandatory to prevent cerebral edema 4, 1, 3
When duration unknown: Treat as chronic to err on side of safety 4, 3

Mortality and Morbidity Data

Hypernatremia is associated with increased morbidity and mortality, making prompt treatment essential: 6, 5

Hospital-acquired hypernatremia carries worse prognosis than community-acquired 5
Both undercorrection and overcorrection associated with poor outcomes 4
Frequent monitoring essential to optimize correction rate 4, 2

Common Pitfalls and How to Avoid Them

Pitfall 1: Too rapid correction of chronic hypernatremia

Consequence: Cerebral edema, seizures, neurological injury, death 4, 3
Avoidance: Always assume chronic if duration unknown; limit correction to 10-15 mmol/L per 24 hours; check sodium every 2-4 hours initially 4, 3, 2

Pitfall 2: Using isotonic saline in nephrogenic diabetes insipidus

Consequence: Worsening hypernatremia due to high osmotic load relative to dilute urine 7
Avoidance: Use 5% dextrose or hypotonic solutions in NDI 7

Pitfall 3: Inadequate monitoring during correction

Consequence: Overcorrection or undercorrection 4, 2
Avoidance: Check sodium every 2-4 hours in severe cases; adjust infusion rate based on actual response 2

Pitfall 4: Failing to account for ongoing losses

Consequence: Persistent hypernatremia despite calculated replacement 2
Avoidance: Add insensible losses (~500-1000 mL/day) and ongoing measured losses to calculated deficit 2

Pitfall 5: Using hypotonic fluids before volume resuscitation in hypovolemic hypernatremia

Consequence: Hemodynamic instability, inadequate tissue perfusion 2, 5
Avoidance: Restore hemodynamic stability with isotonic saline first, then switch to hypotonic fluids 2, 5

Pitfall 6: Not correcting hyperglycemia-induced pseudohypernatremia

Consequence: Misdiagnosis and inappropriate treatment 2
Avoidance: Always correct sodium for glucose: add 1.6 mmol/L per 100 mg/dL glucose above 100 mg/dL 2

Pitfall 7: Ignoring underlying cause

Consequence: Recurrent hypernatremia, treatment failure 2
Avoidance: Always identify and treat underlying etiology (discontinue lithium, treat diabetes insipidus, restore water access) 1, 2

What is hypernatremia, including its pathophysiology, etiology, clinical manifestations, diagnostic approach, treatment, and recent advances?

Help us tailor your experience