Hyponatremia

Etiology

The etiology of hyponatremia can be classified according to extracellular fluid volume status. As mentioned earlier, sodium (Na) is the primary solute of extracellular fluid. Based on extracellular volume, a patient can be classified as hypovolemic, euvolemic, or hypervolemic.[7] To understand sodium and water movement in the kidney, it is essential to understand the roles of the different nephron segments.

Under normal physiologic conditions, the kidney filters free water, and about 70% and 20% of filtered water are reabsorbed in the proximal tubule and thin descending loop of Henle, respectively. Both segments express aquaporin-1, a water channel located on the apical and basolateral tubular membranes. In the proximal tubule, water can also diffuse paracellularly, accounting for about 30% of this segment's water transport.[8] The thin descending loop of Henle is permeable to water but impermeable to solutes, allowing urine concentration mediated by the countercurrent multiplier.

Conversely, the ascending loop of Henle and the distal convoluted tubule are impermeable to water and are also known as the diluting segments. The sodium-potassium-2 chloride cotransporter, located on the apical side of the thick ascending loop of Henle, is essential for creating the medullary gradient via active transport. Therefore, the descending loop of Henle helps concentrate urine, while the ascending loop helps dilute urine.[9]

Active regulation of water absorption occurs in the more distal nephron segments. Arginine vasopressin (AVP), also known as antidiuretic hormone, is the primary regulator. The distal convoluted tubule begins after the macula densa segment of the nephron. The distal convoluted tubule absorbs about 5% to 10% of filtered sodium. Absorption of sodium in this segment is primarily mediated through the sodium-chloride cotransporter, which is also the site of action for thiazide-like diuretics. The distal convoluted tubule can be divided into early and late segments (ie, distal convoluted tubule segment 1 and distal convoluted tubule segment 2).

In addition to the sodium-chloride cotransporter, the latter segment of the distal convoluted tubule contains epithelial sodium channels, which help create a negative transmural potential difference in the tubular lumen. Epithelial sodium channels are the site of action for potassium-sparing diuretics (eg, amiloride and triamterene). Potassium-sparing diuretics can be used in conjunction with thiazide-type diuretics for additional diuresis. Mineralocorticoid receptors for aldosterone are present throughout the distal convoluted tubule, but the latter segment is more sensitive to aldosterone. Mineralocorticoid receptors are the site of action for mineralocorticoid receptor antagonists (ie, finerenone, spironolactone, and eplerenone). Several distal convoluted tubules converge to form the collecting ducts.[10][11]

The collecting duct is impermeable to water in the absence of external factors, thereby regulating water absorption and serum osmolality. Arginine vasopressin is the major hormone regulating sodium and water reabsorption. Arginine vasopressin binds to vasopressin 1 and vasopressin 2 receptors; vasopressin 1 receptors mediate the vasoconstrictive effects of arginine vasopressin, and vasopressin 2 receptors cause aquaporin-2 water channels to translocate to the apical collecting duct tubular membrane.

Aquaporin-3 and aquaporin-4 are constitutively expressed in the basolateral membrane, allowing water to be reabsorbed in the collecting duct of the nephron during transport from urine to the interstitium.[8][9] In addition, the connecting tubule and the outer cortical and medullary parts of the collecting duct are impermeable to water. In the presence of arginine vasopressin, the inner medullary collecting duct becomes permeable to urea through the urea transporter A1 and urea transporter A3 channels.[9] Other hormones affecting the collecting duct include renin and endothelin.[12]

Physiological stimuli that trigger vasopressin release, along with increased fluid intake, can lead to hyponatremia. Stimuli for vasopressin release include loss of intravascular volume (hypovolemic hyponatremia), loss of effective intravascular volume (hypervolemic hyponatremia), drugs, and syndrome of inappropriate antidiuretic hormone (SIADH). Please see StatPearls' companion reference, "Syndrome of Inappropriate Diuretic Hormone," for further information.

Causes of Hypovolemic Hyponatremia

In hypovolemic hyponatremia, the total body water decreases less than the total body sodium. Causes include:

• Gastrointestinal tract fluid loss (eg, diarrhea or vomiting)
• Fluid sequestration (pancreatitis, hypoalbuminemia, small bowel obstruction), which causes relative intravascular depletion
• Diuretics
• Osmotic diuresis (glucose, mannitol)
• Salt-wasting nephropathies
• Cerebral salt-wasting syndrome (urinary salt wasting, possibly caused by increased brain natriuretic peptide). For further information, please see StatPearls companion reference, "Cerebral Salt Wasting Syndrome," for further information [13]
• Mineralocorticoid deficiency

Causes of Hypervolemic Hyponatremia

In hypervolemic hyponatremia, the total body water increases more than the total body sodium. Causes include:

• Renal causes (eg, acute renal failure, chronic renal failure, nephrotic syndrome)
• Extrarenal causes (eg, congestive heart failure, cirrhosis)
• Iatrogenic causes [14][15]

Causes of Euvolemic Hyponatremia

In euvolemic hyponatremia, the total body water increases while the total body sodium remains stable. Nonosmotic, pathologic vasopressin release may occur in the setting of normal volume status, as with euvolemic hyponatremia. Causes of euvolemic hyponatremia include the following:

• Drugs (listed below)
• Syndrome of inappropriate antidiuretic hormone 
• Addison disease
• Hypothyroidism
• High fluid intake in conditions such as primary polydipsia or potomania, caused by a low intake of solutes and relatively high fluid intake
• Medical testing related to excessive fluids, such as a colonoscopy or cardiac catheterization [16][17][18]
• Iatrogenic causes [19][16][17][18]

Many drugs cause hyponatremia, and the most common include:

• Vasopressin analogs such as desmopressin and oxytocin
• Medications that stimulate vasopressin release or potentiate the effects of vasopressin, such as selective serotonin-reuptake inhibitors and other antidepressants, morphine, and other opioids
• Medications that impair urinary dilution, such as thiazide diuretics
• Medications that cause hyponatremia, such as carbamazepine or its analogs, vincristine, nicotine, antipsychotics, chlorpropamide, cyclophosphamide, and nonsteroidal anti-inflammatory drugs
• Illicit drugs, such as methylenedioxymethamphetamine (MDMA, also known as ecstasy)[16]

Epidemiology

Hyponatremia is the most common electrolyte disorder, with a prevalence of 20% to 35% among patients in the hospital. The incidence of hyponatremia is high among critically ill patients in the intensive care unit and after surgical procedures. Hyponatremia is more common in older adults because of multiple comorbidities, multiple medications, and a lack of access to food and drinks.[20] In the community, an estimated 5% of the population has this condition.[6][20] Results from a study found that 2% to 10% of patients presenting to the emergency department had hyponatremia.[21]

Pathophysiology

Thirst stimulation, arginine vasopressin secretion, and renal handling of filtered sodium maintain serum sodium concentration and osmolality. To maintain serum osmolality within the reference range, water intake should equal water excretion, which depends on the ability of the kidneys to excrete urine of varying osmolality. Additionally, insensible fluid losses through the skin and respiratory tract can total up to 1000 mL daily.

An imbalance between water intake and excretion causes hyponatremia or hypernatremia. The kidneys filter about 180 L of water daily and usually excrete between 1 and 2 L of urine daily, depending on fluid intake. The minimum urine osmolality is 50 to 100 mOsm/kg, and the maximum urine osmolality is 1200 mOsm/kg.[8] Patients with normal renal function can excrete up to 20 L of water per day.[22][23] Results from one study found that the most common causes of hyponatremia are SIADH, diuretics, polydipsia, adrenal insufficiency, and heart and liver failure.[7] 

Water intake is regulated by the thirst mechanism, in which osmoreceptors in the hypothalamus trigger thirst when body osmolality reaches about 295 mOsm/kg. Some of the sensory pathways mediating thirst involve the tongue acid-sensing receptor cells, the hypothalamic median preoptic nucleus, the subfornical organ, and the organum vasculosum.[8][24][25] Water excretion is tightly regulated by AVP, which is synthesized by the hypothalamic magnocellular neurons and stored in the posterior pituitary gland.

Changes in tonicity can enhance or suppress AVP secretion. Baroreceptors in the carotid sinus and renal arteries can also stimulate AVP secretion, but they are less sensitive than the osmoreceptors. Baroreceptors trigger AVP secretion in response to decreased effective circulating volume, nausea, pain, stress, and certain drugs.[26] Increased AVP secretion promotes water reabsorption in the kidneys, whereas decreased AVP secretion has the opposite effect.

Baroreceptors in the carotid sinus and renal arteries can also stimulate AVP secretion, but they are less sensitive than the osmoreceptors. Baroreceptors trigger AVP secretion in response to decreased effective circulating volume, nausea, pain, stress, and certain drugs.[26] In patients with normal renal function, urine can be diluted to a minimum osmolality of 50 mOsm/kg; urine osmolality less than 100 mOsm/kg suggests AVP suppression.

Urine sodium levels less than 20 mmol/L suggest decreased renal perfusion, while urine sodium levels greater than 40 mmol/L suggest SIADH.[27] Acute and chronic hyponatremia are typically differentiated by a 48-hour threshold. Accurate classification is important when correcting hyponatremia because rapid correction of chronic hyponatremia is associated with osmotic demyelination.[7]

Hypertonic Hyponatremia

Serum osmolality: Greater than 295 mOsm/kg. Causes include:

• Hyperglycemia
• Exogenous osmoles
  • Mannitol
  • Maltose 
  • Radiocontrast 
  • Sucrose [7][28][29]

Isotonic Hyponatremia

Serum osmolality: Between 275 mOsm/kg and 295 mOsm/kg

• Pseudohyponatremia is a laboratory artifact. Pseudohyponatremia is usually caused by hypertriglyceridemia, lipoprotein X (associated with cholestasis, genetic conditions, or liver disease), or hyperproteinemia (associated with monoclonal gammopathy or intravenous immunoglobulin therapy). The large amount of protein reduces the plasma's aqueous portion, and indirect ion-selective electrodes assume a normal plasma volume; therefore, the measured sodium concentration will be low. Two-thirds of clinical laboratories still use indirect ion-selective electrode technology; therefore, the problem persists. However, intravenous immunoglobulin therapy can also contain maltose, dextrose, or sucrose, which can cause hypertonicity as described earlier.[29][30]
• Transurethral resection of the prostate syndrome occurs when hypotonic fluids, such as glycine, sorbitol, mannitol, and urea, are used for irrigation. In addition, glycine can cause toxicity because it is metabolized to ammonia, causing further impairment. The degree of hyponatremia depends on the volume of fluid administered and the duration of the procedure. Isotonic fluids are increasingly used.[31][32]

Hypotonic Hyponatremia

Serum osmolality: Less than 275 mOsm/kg

Hypotonic hyponatremia represents an excess of free water. Two mechanisms can cause excess free water: 

1. Excessive free water intake occurs when a patient drinks a large volume of free water, usually more than 18 L/d or greater than 750 mL/h, overwhelming the kidneys' capacity to excrete water. Examples include psychogenic polydipsia, marathon running, water-drinking competitions, and drugs such as methylenedioxymethamphetamine, also known as ecstasy.
2. Decreased free water excretion results from the kidneys' inability to excrete water.

Three main mechanisms contribute to the inability of the kidneys to excrete water:

1. High AVP activity: Decreased effective arterial blood volume increases AVP release. AVP is released when effective arterial blood volume decreases by 15% or more. A reduction in effective arterial blood volume occurs with hypovolemia (eg, vomiting, diarrhea), decreased cardiac output (eg, heart failure), or vasodilation (eg, cirrhosis).
2. SIADH: ADH is secreted autonomously in SIADH. Four general causes of this are brain disorders, lung disorders, drugs (eg, selective serotonin reuptake inhibitors), and miscellaneous (eg, nausea and pain).
   • Cortisol deficiency: Cortisol inhibits AVP release. When cortisol levels are decreased, AVP is released in large amounts. Adrenal insufficiency underlies this mechanism.[33]
   • Reduced glomerular filtration rate (GFR):  A reduced GFR can impair the kidneys' ability to excrete water. Typical examples are acute kidney injury, chronic kidney disease, and end-stage renal disease.
3. Low solute intake
   • Patients following a regular diet consume 600 to 900 mOsm of solute per day. Solutes are defined as substances that are freely filtered by the glomeruli but have relative or absolute difficulty being reabsorbed by the tubules compared with water.
   • The primary solutes are urea (produced by protein metabolism) and electrolytes (eg, salt). Carbohydrates do not contribute to solute load. In steady-state conditions, solute intake equals urine solute load. Therefore, patients are expected to excrete 600 to 900 mOsm of solute in the urine.
   • Urine volume, and hence water excretion, is dependent on the urine solute load. Patients who need to excrete more solute must produce a larger urine volume. Conversely, patients who need to excrete less solute produce a smaller urine volume.
   • Patients who consume a low-solute diet, such as 200 mOsm/d, under steady-state conditions will still excrete a low amount of solute in the urine, resulting in a smaller urine volume. The reduced urine volume limits the kidneys' capacity to excrete water.
   • Typical examples include beer potomania and the tea-and-toast diet. Much rarer causes of potomania include ingestion of diet sodas or soy-based drinks, which are low-solute beverages. Carbohydrates do not contribute to osmolarity.[2][34] Alcohol itself can also be associated with SIADH, hypovolemia, malnutrition, and liver cirrhosis. Beer is particularly associated with this condition because, in addition to its higher volume intake compared with other forms of alcohol, it is high in carbohydrates.

Therefore, beer intake prevents protein catabolism, thereby reducing urine urea levels and osmolality.[22][35] Beer potomania has traditionally been associated with low urine osmolality values and low urine sodium levels. However, results from one study showed a wide range of urine osmolality and sodium levels.[36] Patients with this condition are at very high risk of overly rapid correction of sodium levels. Clinicians should closely monitor these patients in an intensive care setting with frequent sodium level measurements and neurologic evaluations.[37]

Results from case reports described hyponatremia related to bowel preparation for colonoscopies in the setting of rapid fluid intake without solute intake. A similar situation arises in patients who participate in extreme exercise such as marathons. Both situations also involve nonosmotic AVP release.[38][39] In exercise-induced hyponatremia, increased water intake, solute loss through sweating, and sympathetic stimulation of AVP can lead to hyponatremia. For more information, please see StatPearls companion review, "Exercise-Associated Hyponatremia," for further information.

Syndrome of Inappropriate Antidiuretic Hormone Secretion

Syndrome of inappropriate antidiuretic hormone secretion is characterized by inappropriate secretion of AVP despite normal or increased plasma volume. Increased AVP secretion impairs renal water excretion, leading to hyponatremia. SIADH is a diagnosis of exclusion because no single test confirms it. Patients are usually hyponatremic and euvolemic.[40][41]

Causes of SIADH include the following: 

• Any central nervous system disorder
• Ectopic production of AVP (most commonly small cell carcinoma of the lung)
• Drugs (carbamazepine, oxcarbazepine, chlorpropamide, and multiple other drugs)
• HIV
• Pulmonary diseases (pneumonia, tuberculosis)
• Postoperative pain
• Reset osmostat, which occurs when AVP is released at a lower sodium threshold, leading to chronic hyponatremia. Unlike typical SIADH, the nephron has normal diluting capacity. Reset osmostat can occur in physiologic states such as pregnancy, older age, severe illness, malignant neoplasms, cerebral hemorrhage, and other conditions.[42][43]

SIADH is evaluated using a water-loading test. Treatment of SIADH, aside from resetting the osmostat, includes fluid restriction and vasopressin 2 receptor antagonists.[33][44]

Pseudohyponatremia 

Pseudohyponatremia is a rare laboratory artifact causing spuriously low measured sodium levels in the setting of serum osmolality within the reference range (280 to 300 mOsm/kg) due to replacement of the water compartment with nonaqueous components, most commonly lipids or proteins, which usually comprise about 7% of plasma volume. Sodium can be measured by direct or indirect methods. Point-of-care direct ion-selective electrodes measure sodium directly and are therefore not affected by additional components; however, most larger laboratories use indirect ion-selective electrodes due to their greater testing capacity. Indirect ion-selective electrodes calculate sodium levels based on a presumed normal water component. The indirect method for measuring serum sodium is accurate and valid under standard physiological conditions. However, when additional solid components are abnormally elevated, the ratio of solid components to water in plasma becomes unpredictably altered, resulting in inaccurate sodium ion measurements.[45] Previously, flame emission spectrophotometry was used, but this method is currently not in common use. Patients with pseudohyponatremia do not have clinical signs of hyponatremia because no water movement occurs; therefore, pseudohyponatremia requires no treatment. However, clinicians must recognize pseudohyponatremia as a potential confounding factor to avoid inappropriate and harmful treatments.[46]

Markedly elevated lipid levels are the primary cause and can result from conditions such as hyperlipidemia, lipoprotein X accumulation (typically secondary to biliary obstruction or cholestasis, such as primary biliary cirrhosis), and familial hypercholesterolemia.[45][47][48] Furthermore, abnormally high protein levels, including native or exogenous immunoglobulins, can lead to pseudohyponatremia, in part because hyperviscosity prevents sodium-containing serum from reaching the sensing electrode relative to the sodium-free diluent.[46] Notable examples include chronic infectious disease states, such as hepatitis C virus infection or HIV, [47] malignant monoclonal gammopathies, such as multiple myeloma, polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes syndrome, and Waldenstrom macroglobulinemia,[48] malignant neoplasms, particularly malignant lymphoproliferative disorders,[45][49] myelodysplastic syndromes, heavy- and light-chain diseases, immunoglobulin deposition diseases, such as amyloidosis, and intravenous immunoglobulin therapy.[50]

Pseudohyponatremia may be suggested if a sample is obviously lipemic, but lipemia is often not visually apparent. An osmolar gap should be calculated using the true sodium concentration measured with a direct ion-selective electrode, because pseudohyponatremia can coexist with hypoosmolar or hyperosmolar hyponatremia. Results from case reports also described hyperkalemic hyponatremia, with proposed mechanisms including defective cell membranes or cell lysis that cause hyperkalemia and subsequent sodium influx into cells, but this is exceedingly rare.[46] 

History and Physical

A detailed history, including pulmonary and neurologic disorders; all prescribed and over-the-counter medications; drug and alcohol use; exercise and eating habits; urinary symptoms, such as polyuria or oliguria; and excessive thirst, is important. Symptoms depend on the degree and chronicity of hyponatremia and do not necessarily correlate with the absolute plasma sodium concentration. Patients with mild to moderate hyponatremia (greater than 125 mEq/L) or a gradual decrease in sodium levels over more than 48 hours generally have minimal symptoms.

Patients with severe hyponatremia (less than 125 mEq/L) or a rapid reduction in sodium levels may exhibit a wide range of symptoms.[51] The physical examination begins with vital signs and an assessment of volume status. Patients may have different physical signs depending on the cause of hyponatremia. For example, patients with liver cirrhosis may have ascites and anasarca.[5] 

Symptoms

The symptoms of hyponatremia are variable and often correlate with the severity of the condition.

Mild hyponatremia:

Mild hyponatremia is defined as a sodium level of 130 to 134 mEq/L. Symptoms include:

• Fatigue
• Weakness
• Neurologic symptoms
  • Cognitive dysfunction may include problems with attention and memory. The degree of dysfunction appears to correlate directly with sodium levels.
  • Cerebral edema is a common finding in hyponatremia.
  • An unexplained headache could be a sign of cerebral edema. 
  • Loss of osmolytes, including neurotransmitters, may further worsen neurologic dysfunction.
  • Gait abnormalities are also prevalent.[6][52][53] 
• Falls
• Bone fractures
  • Osteoporosis is directly associated with hyponatremia.
  • Vasopressin 1 (V1) and V2 receptors can be found on osteoclasts and osteoblasts and may increase osteoclast activity relative to osteoblasts.

Moderate hyponatremia: 

Moderate hyponatremia is defined as a sodium level of 125 to 129 mEq/L. Symptoms include:

• Increased fatigue and drowsiness
• Neurologic symptoms, including decreased alertness, memory, attention, and increased gait abnormalities
• Muscle cramps
• Nausea and vomiting [54][55]

Severe hyponatremia:

Severe hyponatremia is defined by a sodium level of less than 125 mEq/L (some institutions define severe hyponatremia as a sodium level of less than 120 mEq/L or 125 mEq/L or less, accompanied by symptoms). Symptoms include:

• Somnolence
• Confusion and disorientation
• Decreased consciousness
• Muscle weakness
• Falls
• Seizures
• Nausea and vomiting
• Cardiorespiratory collapse [6][21]

Evaluation

The following steps may be performed during the evaluation of a patient with suspected hyponatremia. As noted above, clinical volume status is the most critical part of the physical examination, although assessment may lack sensitivity in patients with multiple comorbid conditions:

Step 1: Plasma Osmolality (Reference Range, 275 to 295 mOsm/kg)

Plasma osmolality can help differentiate between hypertonic, isotonic, and hypotonic hyponatremia.[7][56] Of note, this step is not always necessary when the patient has a clinically apparent cause of hypervolemia or hypovolemia. Most patients with hyponatremia have hypotonic hyponatremia. Osmolality is expressed as osmoles/kg H2O, whereas osmolarity is expressed as osmoles/L H2O. The density of water is 1 kg/L; therefore, these values are usually similar under physiologic conditions, although osmolarity can be temperature-dependent. Serum osmolality is calculated as follows:

Serum Osmolality = 2(Na) + (Blood Urea Nitrogen)/2.8 + (Glucose)/18,

An osmolar gap greater than 10 should raise suspicion for unmeasured osmoles (eg, alcohols, sugars, pseudohyponatremia). Please see StatPearls' companion reference, "Physiology, Plasma Osmolality and Oncotic Pressure," for further information.[56][57] Pseudohyponatremia can be ruled out by measuring serum glucose and lipid levels. If hypotonic hyponatremia is diagnosed, proceed to step 2.

Step 2: Urine Osmolality

Urine osmolality less than 100 mOsm/kg usually indicates primary polydipsia, reset osmostat, or potomania. As noted above, a reset osmostat is a diagnosis of exclusion.[42] Urine osmolality greater than 100 mOsm/kg usually indicates a high AVP state. A high AVP state is generally due to low effective arterial blood volume (eg, heart or liver failure), hypovolemia (eg, diarrhea, vomiting, drugs), or SIADH.[27]

Step 3: Urine Sodium Concentration 

Urine sodium levels less than 30 mEq/L suggest low intravascular volume. Hypervolemic states may indicate heart or liver failure or nephrotic syndrome. Hypovolemic states may result from diarrhea, vomiting, fluid sequestration, or decreased salt or water intake. Urine sodium levels greater than 30 mEq/L can be related to diuretics, which must always be considered (diuretics are sometimes sold as weight-loss supplements). Hypovolemic states may reflect renal salt wasting, cerebral salt wasting, or primary adrenal insufficiency. Primary adrenal insufficiency causes hypovolemia due to loss of glucocorticoid and mineralocorticoid activity. Euvolemic states may include SIADH, secondary adrenal insufficiency, or hypothyroidism, although hypothyroidism is a rare cause. In secondary adrenal insufficiency, mineralocorticoid activity is preserved through the renin-angiotensin-aldosterone system.[7][53]

Other Considerations:

In patients taking diuretics, urine sodium levels may be unreliable; therefore, clinicians often assess the fractional excretion of urea or uric acid. Fractional excretion of urea greater than 55% or fractional excretion of uric acid greater than 10% indicates concentrated urine.[27] Thyroid function testing may also be useful. Low thyroid hormone levels can cause low cardiac output and elevated AVP levels, but this association is usually observed with markedly abnormal thyroid function results, and other symptoms typically present first.[58]

Other tests that might help in differentiating the causes include the following:

• Serum adrenocorticotropic hormone levels should be measured, and corticotropin-releasing hormone levels can be measured if secondary adrenal insufficiency is suspected.
• Liver function tests are used to evaluate for cirrhosis and hypoalbuminemia.
• Serum protein electrophoresis can be conducted if paraproteinemia is suspected.
• Chest radiography or a CT scan of the chest can be performed to evaluate for a malignant neoplasm.
• A CT scan of the head can be performed to evaluate for central nervous system causes.

Treatment / Management

Treatment depends on the degree of hyponatremia, its duration, symptom severity, and volume status. Traditional recommendations limited sodium correction to a maximum of 10 to 12 mEq/L within 24 hours.[7] More recent guidelines in the US and Europe recommend treating severely symptomatic hyponatremia with a bolus of hypertonic saline to reverse hyponatremic encephalopathy by increasing the serum sodium level by 4 to 6 mEq/L within 1 to 2 hours, but by no more than 10 mEq/L (correction limit) within the first 24 hours. Regardless of the initial sodium level, increasing it by 6 mEq/L should reduce the severity of neurologic symptoms. However, this treatment approach exceeds the correction limit in about 4.5% to 28% of patients. The main concern with rapid overcorrection is osmotic demyelination syndrome, a rare complication that can cause parkinsonian symptoms, quadriparesis, or death.[6][59]

However, patients with neurologic symptoms and signs caused by hyponatremia require prompt treatment to prevent permanent neurologic damage and cerebral herniation.[60] Results from a recent review of 16 studies involving patients with severe hyponatremia found that slower rates of correction led to higher mortality. Correction rates of 8 to 10 mEq/L or higher over 24 hours were associated with lower mortality and shorter lengths of stay than slow correction rates of less than 8 mEq/L over 24 hours. The association was dose-dependent; specifically, lower correction rates were associated with higher mortality. Results from the review did not identify a significant increase in osmotic demyelination with more rapid correction.[61] (A1)

A key feature of treatment is determining the acuity of hyponatremia. Acute hyponatremia (less than 48 hours) causes cerebral edema because cells have less time to adapt to a hypotonic environment. Chronic hyponatremia (more than 48 hours) allows cells to adapt by expelling other osmoles, and rapid correction increases the risk of osmotic demyelination syndrome. Serum sodium changes in hypovolemic hyponatremia may be challenging to predict due to water diuresis after correcting the hypovolemia. If the duration of hyponatremia is unclear and no concerning neurologic symptoms are present, slower correction goals should be followed.[59] Treatment should be based on clinical presentation and laboratory values.[7] No single set of guidelines for sodium correction exists, but general principles are as follows: 

Acute Symptomatic Hyponatremia

Severely symptomatic hyponatremia: For patients with severe symptoms (eg, seizures, obtundation, delirium), 3% sodium chloride can be administered in 100-mL intravenous boluses over 10 min as needed, with a goal correction rate of 4 to 6 mEq/L in the first 4 hours of treatment. The US Expert Panel Recommendations do not set an upper limit for sodium correction, whereas the European Clinical Practice Guidelines set an upper limit of 10 mEq/L. Results from multiple studies showed that bolus treatment is associated with fewer complications than hypertonic saline infusion.[53]

Mild to moderately symptomatic hyponatremia: For patients with milder symptoms (eg, fatigue, somnolence, nausea, weakness), 3% sodium chloride can be administered by a slow infusion using the sodium deficit formula to calculate the infusion rate. Clinicians should frequently recalculate the deficit and monitor sodium levels. Some experts suggest monitoring sodium levels hourly or every 4 to 6 hours, depending on the clinical scenario.

The equation used to calculate the sodium deficit is as follows:

Sodium Deficit (mEq/L) = Total Body Water × (Desired Sodium Level − Current Sodium Level),

Total body water (TBW) is calculated as follows:

Total Body Water = Weight (kg) × 0.6 for men and children or 0.5 for women and older adults.

Chronic Asymptomatic Hyponatremia  

• Hypovolemic hyponatremia is usually treated with isotonic fluid administration, treatment of nausea and vomiting, and withholding diuretics.
• Hypervolemic hyponatremia is usually treated by addressing the underlying condition, restricting salt and fluids, and administering loop diuretics.
• Euvolemic hyponatremia is usually treated with fluid restriction to less than 1 L/d.[62]
• Patients with chronic hyponatremia are at much higher risk of osmotic demyelination syndrome than patients with acute hyponatremia.
• Risk factors for osmotic demyelination syndrome include hypokalemia, liver disease, malnutrition, and alcohol use.
• Desmopressin or free water can be given if the rate of correction is too rapid to avoid osmotic demyelination.[62] Please see StatPearls' companion reference, "Central Pontine Myelinolysis," for further information
(A1)

Vasopressin Receptor Agonists (Vaptans)

Selective vasopressin 2 receptor antagonists have been widely used for hypervolemic and euvolemic hyponatremia (especially congestive heart failure and SIADH). Vaptans block the effects of AVP on the renal collecting duct, increasing water excretion without affecting sodium excretion and thereby increasing serum sodium levels. Results from the Study of Ascending Levels of Tolvaptan in Hyponatremia (SALT-1 and SALT-2) trials showed that tolvaptan effectively treats SIADH and hypervolemic hyponatremia (excluding cirrhosis). However, many experts consider the tested dose of 15 mg too high because overcorrection was observed at doses as low as 3.75 mg. Patients with severe hyponatremia require intensive inpatient monitoring when treated with vaptans.[53][63] 

Conivaptan is a dual vasopressin 1 and vasopressin 2 receptor antagonist and is US Food and Drug Administration–approved for inpatient treatment of euvolemic and hypervolemic hyponatremia. US guidelines recommend treating SIADH with vaptans if fluid restriction is ineffective, whereas European guidelines do not recommend their use. Vaptans carry a risk of rapid correction, but higher rates of osmotic demyelination syndrome have not been noted.[53][63][64] Results from several trials also showed that vaptans are effective at improving neurocognition in patients with mild-to-moderate hyponatremia.[9][65] (A1)

Urea

Urea has been used as an inexpensive method to increase solute intake, increase urine volume, and induce osmotic diuresis. Spot urine samples can identify patients with low urine osmolality and urine output, and these patients may benefit from oral solute administration rather than free-water restriction. Results from several randomized controlled trials found that oral urea is a safe and effective treatment.[66][67][68] 

Oral urea has been used in Europe and Australia for many years and recently became available in the US as a powdered formulation. The powder is mixed with water or juice and is considered a dietary supplement; therefore, a prescription is not required. Doses range from 15 to 60 g/d, and because of the bitter taste, clinicians should advise patients to mix the powder with a sweet-tasting liquid.

Although blood urea nitrogen levels may increase, the increase is an expected effect of urea metabolism and does not reflect decreased kidney function. In addition, study results showed that urine sodium loss decreases with oral urea administration, further potentiating its effects on hyponatremia. Results from some studies showed that oral urea is as effective as vaptans without the adverse effects of severe thirst or sodium overcorrection.

In addition, urea offers a significant cost benefit: 1 dose of urea costs about US $4, while 1 dose of tolvaptan costs about US $400. Urea should not be used in patients with hypovolemic hyponatremia, drug-related SIADH, or adrenal insufficiency. Urea is also contraindicated in patients with liver cirrhosis because it may cause hyperammonemia.[53][64][68] (A1)

Results from some studies also showed that 90 g/d of protein supplementation can induce osmotic diuresis. Unlike sodium, urea has minimal tubular reabsorption, further supporting its effectiveness as a treatment. Although the adverse effects of urea appear minimal and the risk of overly rapid correction appears low, no randomized controlled trials have been conducted to date.[59]

Sodium Chloride Tablets

Sodium chloride tablets have also been prescribed to increase solute intake and promote diuresis; however, their efficacy is limited. These tablets are prescribed in conjunction with fluid restriction and diuretics, which frequently reduce adherence due to excessive thirst. Oral urea allows for more liberal fluid intake (1.5 to 1.8 L) and likely improves patient adherence. In addition, a large number of sodium chloride tablets may be required to achieve the same solute load, because these tablets are about 60% chloride and 40% sodium by weight, given their molecular weights. Comparatively, a 600-mg tablet of sodium chloride provides 21 mOsm, while 15 g of urea provides 250 mOsm of solute.[59][68]

Sodium-Glucose Cotransporter 2 Inhibitors

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are oral medications approved for the treatment of type 2 diabetes, chronic heart failure, and chronic kidney disease. These medications inhibit glucose reabsorption in the early proximal tubule via SGLT2, which accounts for about 90% of tubular glucose reabsorption. Sodium-glucose cotransporter 1 reabsorbs the rest of the urinary glucose in the more distal segments of the proximal tubule.

As implied by the name, sodium, chloride, and water are also reabsorbed along with glucose. When these molecules remain in the urine, fluid and sodium chloride are sensed by the macula densa, triggering tubuloglomerular feedback and reducing glomerular capillary pressure and the hyperfiltration associated with diabetic nephropathy. Tubuloglomerular feedback also reduces the GFR and intraglomerular pressure. Reduced sodium chloride reabsorption also reduces oxygen consumption in the proximal tubule. Increased urinary glucose, sodium, and chloride levels also cause osmotic diuresis. Sodium-glucose cotransporter 2 inhibitors are particularly effective in SIADH, which is often identified by an elevated fractional excretion of urea (except in reset osmostat).[64] (A1)

However, SGLT2 inhibitors are contraindicated in patients with type 1 diabetes due to the risk of diabetic ketoacidosis and should not be used when the GFR is less than 30 mL/min. Other risks include genital infections caused by glucosuria, Fournier gangrene, and volume depletion. Sodium-glucose cotransporter 2 inhibitors are also not recommended during pregnancy. Results from the Canagliflozin Cardiovascular Assessment Study (CANVAS) trial showed that canagliflozin may be associated with a higher risk of foot amputation. Patients with heavy alcohol use or those following a ketogenic diet may also be predisposed to diabetic ketoacidosis.[69]

Results from multiple studies have shown that SGLT2 inhibitors are renoprotective in patients with and without diabetes.[69] Results from some studies showed a decrease in estimated GFR of up to 30% after treatment initiation, but this decrease is renoprotective through the mechanisms described above. In addition to their nephroprotective effects, initial studies showed neuroprotective effects on cognition and gait, not only in patients with hyponatremia but also in those with normal sodium levels.[59][64] Sodium-glucose cotransporter 2 inhibitors likely improve adherence compared with fluid restriction, which is often unsuccessful, especially in patients with high urine osmolality values (greater than 500 mOsm/L). This medication class is also relatively affordable at approximately US $4 per pill, especially when compared with vaptans.[64][70](A1)

Differential Diagnosis

True hyponatremia is associated with hypoosmolality. Conditions causing hyperosmolar hyponatremia and isoosmolar hyponatremia (pseudohyponatremia) should first be differentiated and include the following:

• Hyperglycemia
• Mannitol administration
• Hyperlipidemia
• Hyperproteinemia [71]

Differential Diagnosis for Hypoosmolar Hyponatremia

• Gastroenteritis
• Diuretic use
• Congestive heart failure
• Liver failure
• Psychogenic polydipsia
• Renal causes
• SIADH
• Adrenal crisis
• Hypothyroidism

Prognosis

The prognosis for patients with hyponatremia depends on the severity of the condition and its underlying cause. Patients with severe hyponatremia or acute hyponatremia and older adults have a poor prognosis.[72] Patients with euvolemic hyponatremia have a better prognosis than patients with other types of hyponatremia.[15] Chronic hyponatremia is also associated with increased morbidity and mortality. Complications, particularly among older adults, include chronic osteoporosis and neuromuscular and cognitive impairment.[5] 

Complications

If left untreated or inadequately treated, hyponatremia can cause rhabdomyolysis, altered mental status, seizures, and coma. Rapid correction of chronic hyponatremia can lead to osmotic demyelination syndrome. Osmotic demyelination syndrome, formerly known as central pontine myelinolysis, is a complication of rapid correction of sodium levels in patients with chronic hyponatremia.[73] In patients with hyponatremia, the brain adapts to a fall in serum sodium levels without developing cerebral edema within about 48 hours. Consequently, patients with chronic hyponatremia are often asymptomatic. Once the brain adapts to low serum sodium levels, rapid correction can lead to osmotic demyelination syndrome. Clinical manifestations are typically delayed by a few days and include several irreversible neurologic symptoms, including seizures, disorientation, and coma. Locked-in syndrome occurs in severely affected patients. Affected patients are awake but unable to move and can communicate only with their eyes.[74] Finally, hyponatremia is strongly associated with osteoporosis, likely due to increased osteoclast activity. Normalization of sodium levels has been associated with decreased osteoclast activity.[75]