Updated: Aug 24, 2016
  • Author: Ivo Lukitsch, MD; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Hypernatremia is a common electrolyte problem that is defined as a rise in serum sodium concentration to a value exceeding 145 mmol/L. [1, 2, 3] It is strictly defined as a hyperosmolar condition caused by a decrease in total body water (TBW) [4] relative to electrolyte content. Hypernatremia is a “water problem,” not a problem of sodium homeostasis.

Patients developing hypernatremia outside of the hospital are generally elderly people who are mentally and physically impaired, often with an acute infection. Patients who develop hypernatremia during the course of hospitalization have an age distribution similar to that of the general hospital population. In both patient groups, hypernatremia is caused by impaired thirst and/or restricted access to water, often exacerbated by pathologic conditions with increased fluid loss.

The development of hyperosmolality from the water loss can lead to neuronal cell shrinkage and resultant brain injury. Loss of volume can lead to circulatory problems (eg, tachycardia, hypotension). Rapid free-water replacement can cause cerebral edema.



Hypernatremia results when there is a net water loss or a sodium gain, and it reflects too little water in relation to total body sodium and potassium. In a simplified view, the serum sodium concentration (Na+) can be seen as a function of the total exchangeable sodium and potassium in the body and the total body water. [5] The formula is expressed below:

Na+ = Na+ total body + K+ total body/total body water

Consequently, hypernatremia can only develop as a result of either a loss of free water or a gain of sodium or a combination of both. Hypernatremia by definition is a state of hyperosmolality, because sodium is the dominant extracellular cation and solute. [6]

The normal plasma osmolality (Posm) lies between 275 and 290 mOsm/kg and is primarily determined by the concentration of sodium salts. (Calculated plasma osmolality: 2(Na) mEq/L + serum glucose (mg/dL)/18 + BUN (mg/dL)/2.8). Regulation of the Posm and the plasma sodium concentration is mediated by changes in water intake and water excretion. This occurs via two mechanisms:

  • Urinary concentration (via pituitary secretion and renal effects of the antidiuretic hormone arginine vasopressin [AVP]) [7, 8]
  • Thirst [9]

In a healthy individual, thirst and AVP release are stimulated by an increase in body fluid osmolality above a certain osmotic threshold, which is approximately 280-290 mOsm/L and is considered to be similar if not identical for both thirst and AVP release. An increased osmolality draws water from cells into the blood, thus dehydrating specific neurons in the brain that serve as osmoreceptors or “tonicity receptors.” It is postulated that the deformation of the neuron size activates these cells (thus acting like mechanoreceptors). On stimulation, they signal to other parts of the brain to initiate thirst and AVP release, resulting in increased water ingestion and urinary concentration, rapidly correcting the hypernatremic state.

Urinary concentration - AVP and the kidney  [10]

Conservation and excretion of water by the kidney depends on the normal secretion and action of AVP and is very tightly regulated. The stimulus for AVP secretion is an activation of hypothalamic osmoreceptors, which occurs when the plasma osmolality reaches a certain threshold (approximately 280 mOsm/kg). At plasma osmolalities below this threshold level, AVP secretion is suppressed to low or undetectable levels. Other afferent stimuli, such as a decrease in effective arterial blood volume, pain, nausea, anxiety, and numerous drugs, can also cause a release of AVP.

AVP is synthesized in specialized magnocellular neurons whose cell bodies are located in the supraoptic and paraventricular nuclei of the hypothalamus. The prohormone is processed and transported down the axon, which terminates in the posterior pituitary gland. From there, it is secreted as active AVP hormone into the circulation in response to an appropriate stimulus (hyperosmolality, hypovolemia).

AVP binds to the V2 receptor located on the basolateral membrane of the principal cells of the renal collection ducts. The binding to this G-protein coupled receptor initiates a signal transduction cascade, leading to phosphorylation of aquaporin-2 and its translocation and insertion into the apical (luminal) membrane, creating "water channels" that enable the absorption of free water in this otherwise water-impermeable segment of the tubular system


Thirst is the body’s mechanism to increase water consumption in response to detected deficits in body fluid. As with AVP secretion, thirst is mediated by an increase in effective plasma osmolality of only 2-3%. Thirst is thought to be mediated by osmoreceptors located in the anteroventral hypothalamus. The osmotic thirst threshold averages approximately 288-295 mOsm/kg. This mechanism is so effective that even in pathologic states in which patients are unable to concentrate their urine (diabetes insipidus) and excrete excessive amounts of urine (10-15 L/d), hypernatremia does not develop because thirst is stimulated and body fluid osmolality is maintained at the expense of profound secondary polydipsia.

Developing hypernatremia is virtually impossible if the thirst response is intact and water available. Thus, sustained hypernatremia can occur only when the thirst mechanism is impaired and water intake does not increase in response to hyperosmolality or when water ingestion is restricted.

Significant hypovolemia stimulates AVP secretion and thirst. Blood pressure decreases of 20-30% result in AVP levels many times those required for maximal antidiuresis.

Hypernatremic states can be classified as isolated water deficits (which are generally not associated with intravascular volume changes), hypotonic fluid deficits, and hypertonic sodium gain.

Regulation of brain cell volume

Acute hypernatremia is associated with a rapid decrease in intracellular water content and brain volume caused by an osmotic shift of free water out of the cells. Within 24 hours, electrolyte uptake into the intracellular compartment results in partial restoration of brain volume. A second phase of adaptation, characterized by an increase in intracellular organic solute content (accumulation of amino acids, polyols, and methylamines), restores brain volume to normal. Some patients complete this adaptive response in less than 48 hours. The accumulation of intracellular solutes bears the risk for cerebral edema during rehydration. The brain cell response to hypernatremia is critical. See the image below.

Figure A: Normal cell. Figure B: Cell initially re Figure A: Normal cell. Figure B: Cell initially responds to extracellular hypertonicity through passive osmosis of water extracellularly, resulting in cell shrinkage. Figure C: Cell actively responds to extracellular hypertonicity and cell shrinkage in order to limit water loss through transport of organic osmolytes across the cell membrane, as well as through intracellular production of these osmolytes. Figure D: Rapid correction of extracellular hypertonicity results in passive movement of water molecules into the relatively hypertonic intracellular space, causing cellular swelling, damage, and ultimately death.



United States

The overall incidence of hospitalized patients with hypernatremia ranges from 0.3-5.5%. The incidence of patients who have hypernatremia on admission to the hospital is very low, being estimated at 0.12-1.4%. Over 60% of hypernatremia cases are hospital acquired. Considerably higher prevalences of 9-26% are seen in critically ill patients, in whom major risk factors for hypernatremia include mechanical ventilation, coma, and sedation. [11] Hypernatremia is most prevalent in the geriatric population.


A retrospective, single-center study from Europe, which included 981 patients, found a 9% incidence of hypernatremia at the center's intensive care unit (ICU). However, it was also found that among those patients with hypernatremia, only 23% already had the condition when admitted to the ICU. [12, 13]

A Canadian study of 8000 adult patients identified ICU-acquired hyponatremia in 11% of them and ICU-acquired hypernatremia in 26% of these patients. [13] The report found that the mortality rate in patients with ICU-acquired hyponatremia or hypernatremia was greater than that of study patients with normal serum sodium levels, being 28% versus 16%, p < 0.001, and 34% versus 16%, p <0.001, respectively.


Mortality rates of 30-48% have been shown in patients in ICUs who have serum sodium levels exceeding 150 mmol/L. [11, 14] A review of 256 patients presenting to a Turkish emergency department with severe hypernatremia (serum sodium >160 mmol/L) determined that the following factors were independently associated with mortality [15] :

  • Low systolic blood pressure
  • Low pH
  • Serum sodium >166 mmol/L
  • Increased plasma osmolarity
  • Mean sodium reduction rate of 0.134 mmol/L/h or less
  • Dehydration
  • Pneumonia

Darmon et al sought to determine the prevalence of ICU-acquired hypernatremia and whether this condition can affect patient outcomes. Of 8140 patients reviewed in the retrospective study, 1245 were found to have had ICU-acquired hypernatremia (defined in the study as hypernatremia acquired 24 h or more after ICU admission); this included 901 patients (11.1%) with mild hypernatremia and 344 patients (4.2%) with moderate-to-severe hypernatremia. Comparing hospital mortality rates for the patients without hypernatremia with those for cohort members with the condition, the authors determined that the subdistribution hazard ratio for mortality from ICU-acquired hypernatremia was 2.03 for the mild form of the condition and 2.67 for moderate–to-severe hypernatremia. [11] However, whether the association of ICU-acquired hypernatremia with an increased risk for death reflects a direct effect of hypernatremia is uncertain or is a marker for suboptimal quality of care.

One study confirmed that maximum daily sodium amount is a significant risk factor for the development of acute kidney injury in patients with subarachnoid hemorrhage (SAH) who are receiving hypertonic saline therapy. Such therapy is often used to control intracranial hypertension and manage symptomatic hyponatremia. Of 736 patients in one study, 9% (64) developed acute kidney injury. For each 1 mEq/L increase in the running maximum daily serum sodium rate, the risk of developing acute kidney injury increased by 5.4 %, and the risk of death was more than twofold greater for patients who developed acute kidney injury. [16]

Early acquired hypernatremia in the ICU has been found to be a frequent complication in patients with severe sepsis and is associated with the volume of 0.9% saline received during the first 48 hours of admission in the ICU. In one study, of 95 patients with severe sepsis, 29 (31%) developed hypernatremia within 5 days. For every 50 ml/kg increase in 0.9% saline intake during the first 48 hours, the odds of hypernatremia increased by 1.61 times. Patients who developed hypernatremia had increased duration of mechanical ventilation and increased mortality. [17]

According to a study by Leung et al, preoperative hypernatremia is associated with increased perioperative 30-day morbidity and mortality. In their study, 20,029 patients with preoperative hypernatremia (>144 mmol/L) were compared with 888,840 patients with a normal baseline sodium (135-144 mmol/L). The odds of morbidity and mortality increased according to the severity of hypernatremia (P < .001 for pairwise comparison for mild [145-148 mmol/L] vs severe [>148 mmol/L] categories). Hypernatremia, versus normal baseline sodium, was associated with a greater odds for perioperative major coronary events (1.6% vs 0.7%), pneumonia (3.4% vs 1.5%), and venous thromboembolism (1.8% vs 0.9%). [18]


The groups most commonly affected by hypernatremia are elderly people and children. [19] Breastfeeding-associated neonatal hypernatremia has been recognized in infants ≤ 21 days of age who have lost ≥10% of birth weight. [20]