eMedicine Specialties > Nephrology > Acid-Base, Fluid, and Electrolyte Disorders

Hypernatremia

Author: Ivo Lukitsch, MD, Faculty, Department of Internal Medicine, Section of Nephrology, Tulane University School of Medicine
Coauthor(s): Trung Q Pham, MD, Consulting Staff, Department of Internal Medicine, Kayenta Health Center
Contributor Information and Disclosures

Updated: Apr 27, 2009

Introduction

Background

• 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 and Image 1.)

• 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.

Pathophysiology

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 kidney⁷

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; it is illustrated in Image 1.

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.

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%.

Race

• No race predilection exists for hypernatremia.

Sex

• No sex predilection exists for hypernatremia.¹⁰

Age

• The groups most commonly affected by hypernatremia are elderly people and children.¹⁰

Clinical

History

Patients developing hypernatremia outside of the hospital setting are generally elderly and debilitated, and often present with an intercurrent acute (febrile) illness. Hospital-acquired hypernatremia affects patients of all ages.

The history should be used to discover why the patient was unable to prevent hypernatremia with adequate oral fluid intake; eg, it should be determined whether the patient is suffering from an altered mental status or whether there are any factors causing increased fluid excretion (eg, the use of diuretic therapy, the existence of diabetes mellitus, or the occurrence of fever, diarrhea, and vomiting). The history should also cover the symptoms and causes of possible diabetes insipidus (eg, the presence of preexisting polydipsia or polyuria, a history of cerebral pathology, or medication use [lithium]).

It is important to find out if the hypernatremia developed acutely or over time, because this will guide treatment decisions.

Risk factors for hypernatremia include the following:

• Advanced age
• Mental or physical impairment
• Uncontrolled diabetes (solute diuresis)
• Underlying polyuria disorders
• Diuretic therapy
• Residency in nursing home, inadequate nursing care
• Hospitalization
  • Decreased baseline levels of consciousness
  • Tube feeding
  • Hypertonic infusions
  • Osmotic diuresis
  • Lactulose
  • Mechanical ventilation
  • Medication (eg, diuretics, sedatives)

Physical

The examination should include an accurate assessment of volume status and cognitive function. Symptoms can be related to volume deficit and/or hypertonicity and shrinkage of brain cells.

The worsening symptoms associated with hypernatremia may go unnoticed in elderly patients who have a preexisting impairment of their mental status and decreased access to water.

Table 1. Characteristics and symptoms of hypernatremia

Open table in new window

In a prospective, case-control, multicenter study, Chassagne and colleagues looked at the symptoms associated with hypernatremia in 150 geriatric patients.¹¹ The likelihood that patients with hypernatremia would have low blood pressure, tachycardia, dry oral mucosa, abnormal skin turgor, and a recent change in consciousness was significantly greater than that of the controls. The only clinical findings to occur in at least 60% of patients with hypernatremia were orthostatic blood pressure and abnormal subclavicular and forearm skin turgor (poor specificity and sensitivity for all physical findings).

Causes

Several risk factors exist for hypernatremia. The greatest risk factor is age older than 65 years. In addition, mental or physical disability may result in impaired thirst sensation, an impaired ability to express thirst, and/or decreased access to water.¹²

Hypernatremia often is the result of several concurrent factors. The most prominent is poor fluid intake. Normally, an increase in osmolality of just 1-2% stimulates thirst, as do hypovolemia and hypotension. For clinical purposes, hypernatremia can, in a simplified view, be classified on the basis of the concurrent water loss or electrolyte gain and on corresponding changes in extracellular fluid volume:

• Hypotonic fluid deficits (loss of water and electrolytes)
• Nearly pure-water deficits
• Hypertonic sodium gain (gain of electrolytes in excess of water).

Loss of hypotonic fluid (loss of water in excess of electrolytes)

Patients who lose hypotonic fluid have a deficit in free water and electrolytes (low total body sodium and potassium) and have decreased extracellular volume. In these patients, hypovolemia may be more life threatening than hypertonicity. When physical evidence of hypovolemia is present, fluid resuscitation with normal saline is the first step in therapy.

• Renal hypotonic fluid loss - Results from anything that will interfere with the ability of the kidney to concentrate the urine or osmotic diuresis
  • Diuretic drugs (loop and thiazide diuretics)
  • Osmotic diuresis (hyperglycemia, mannitol, urea [tube feeding])
  • Renal salt wasting
  • Postobstructive diuresis
  • Diuretic phase of acute tubular necrosis
• Nonrenal hypotonic fluid loss
  • Gastrointestinal - Vomiting, diarrhea, lactulose, cathartics, nasogastric suction, gastrointestinal fluid drains, and fistulas
  • Cutaneous - Sweating (extreme sports, marathon runs), burn injuries

Pure-water deficits

Patients with pure-water deficits in the majority of cases have a normal extracellular volume with normal total body sodium and potassium. This condition most commonly develops when impaired intake is combined with increased insensible (eg, respiratory) or renal water losses.

Free-water loss will also result from an inability of the kidney to concentrate the urine. The cause of that can be either from failure of the hypothalamic-pituitary axis to synthesize or release adequate amounts of AVP (central diabetes insipidus) or a lack of responsiveness of the kidney to AVP (nephrogenic diabetes insipidus). Patients with diabetes insipidus and intact thirst mechanisms most often present with normal plasma osmolality and serum NA ⁺, but with symptoms of polyuria and polydipsia.

• Water intake less than insensible losses
  • Lack of access to water (through incarceration, restraints, intubation, immobilization)
  • Altered mental status (through medications, disease)
  • Neurologic disease (dementia, impaired motor function)
  • Abnormal thirst
    • Geriatric hypodipsia  
    • “Essential” hypernatremia with osmoreceptor dysfunction (reset of the osmotic threshold).
    • Injury to the thirst centers by any lesions to the hypothalamus, including from metastasis, granulomatous diseases, vascular abnormalities, and trauma.
  • Loss of pure water through the respiratory tract

Vasopressin (AVP) deficiency (diabetes insipidus)

Central diabetes insipidus¹³ can be caused by any pathologic process that destroys the anatomic structures of the hypothalamic-pituitary axis involved in AVP production and secretion. Such processes include the following:

• Pituitary injury - Posttraumatic, neurosurgical, hemorrhage, ischemia (Sheehan’s), idiopathic-autoimmune
• Tumors - Craniopharyngioma, pinealoma, meningioma, germinoma, lymphoma, metastatic disease, cysts
• Aneurysms - Particularly anterior communicating
• Inflammatory states and granulomatous disease - Acute meningitis/encephalitis, Langerhans cell histiocytosis, neurosarcoidosis, tuberculosis
• Drugs - Ethanol (transient), phenytoin
• Genetic - Neurophysin-AVP gene defect  

Nephrogenic diabetes insipidus (decreased responsiveness of the kidney to vasopressin)

• Genetic - V2-receptor defects, aquaporin defects (AQP2 and AQP1)
• Structural - Urinary tract obstruction, papillary necrosis, sickle-cell nephropathy
• Tubulointerstitial disease - Medullary cystic disease, polycystic kidney disease, nephrocalcinosis, Sj ö gren’s syndrome, lupus, analgesic-abuse nephropathy, sarcoidosis, M-protein disease
• Electrolyte disorders - Hypercalcemia, hypokalemia
• Any prolonged state of severe polyuria - By washing out the renal medullary- intramedullary concentration gradient needed for urinary concentration, and by down-regulating kidney AQP2 water channels
• Medications that induce nephrogenic diabetes insipidus
  • Lithium
  • Amphotericin B
  • Demeclocycline
  • Dopamine
  • Ofloxacin
  • Orlistat
  • Ifosfamide
• Medications that possibly cause nephrogenic diabetes insipidus
  • Contrast agents
  • Cyclophosphamide
  • Cidofovir
  • Ethanol
  • Foscarnet
  • Indinavir
  • Libenzapril
  • Mesalazine
  • Methoxyflurane
  • Pimozide
  • Rifampin
  • Streptozocin
  • Tenofir
  • Triamterene hydrochloride
  • Cholchicine

Gestational diabetes insipidus

In this form of diabetes insipidus, AVP is rapidly degraded by a high circulating level of oxytocinase/vasopressinase. It is a rare condition, because increased AVP secretion will compensate for the increased rate of degradation. Gestational diabetes insipidus occurs only in combination with impaired AVP production.

Hypertonic sodium gain

Patients with hypertonic sodium gain have a high total-body sodium and an extracellular volume overload (rare, mostly iatrogenic). When thirst and renal function are intact, this condition is transient.

• Administration of hypertonic electrolyte solutions - Eg, sodium bicarbonate solutions, hypertonic alimentation solutions
• Sodium ingestion - NaCl tablets, seawater ingestion
• Sodium modeling in hemodialysis

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