Hypernatremia 

• Hypernatremia is a common electrolyte problem and is defined as a rise in serum sodium concentration to a value exceeding 145 mmol/L.^{[1, 2]}
• Hypernatremia is strictly defined as a hyperosmolar condition caused by a decrease in total body water (TBW)^[3] relative to electrolyte content. Hypernatremia is a “water-problem,” not a problem of sodium homeostasis. (See image below) 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.
• 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 hypertonic sodium gain and reflects too little water in relation to total body sodium and potassium. Hypernatremia by definition is a state of hyperosmolality, because sodium is the dominant extracellular cation and solute.^[4]

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 2 mechanisms:

• Urinary concentration (via pituitary secretion and renal effects of the antidiuretic hormone arginine vasopressin [AVP])^{[5, 6]}
• Thirst

In the normal individual, thirst is stimulated by an increase in body fluid osmolality above a certain threshold and results in increased water ingestion, rapidly correcting the hypernatremic state.

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 liters per day), hypernatremia will not develop, because thirst is stimulated and body fluid osmolality is maintained at the expense of profound secondary polydipsia.

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.

Urinary concentration - AVP and the kidney ^[7]

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.

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

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.

Of physiologic significance is the fact that this level lies above the osmotic threshold for AVP release and approximates the plasma osmolality at which maximal urine concentration is normally achieved. Thus, under normal physiological conditions, AVP accounts for the regulation of plasma osmolality within narrow limits and adjusts water excretion to small changes in osmolality. Only when unregulated water intake (beverages) is not enough in the presence of maximal AVP secretion to maintain plasma osmolality will the perceived desire for water (thirst) become crucial.

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.

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. The accumulation of intracellular solutes bears the risk for cerebral edema during rehydration. The brain cell response to hypernatremia is critical.

Frequency

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. The prevalence in intensive care units (ICUs) appears to be much higher. Hypernatremia is most prevalent in the geriatric population.

International

• 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.^{[8, 9]}
• A Canadian study of 8000 adult patients identified ICU-acquired hyponatremia in 11% of them and ICU-acquired hypernatremia in 26% of these patients.^[9] 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.
• 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 hours 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.^[10]

Mortality/Morbidity

• Morbidity and mortality estimates in hypernatremic adults range from 42% to more than 70%, with the highest rates being found in the geriatric age group.
• The mortality rate for chronic hypernatremia is approximately 10%, while the mortality rate for severe acute hypernatremia in the ICU setting is as high as 75%.^{[10, 11]}

Race

• No race predilection exists for hypernatremia.

Sex

• No sex predilection exists for hypernatremia.^[12]

Age

• The groups most commonly affected by hypernatremia are elderly people and children.^[12]