Hyponatremia

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Practice Essentials

Hyponatremia—defined as a serum sodium concentration of less than 135 mEq/L—is the most commonly encountered and important electrolyte imbalance that can be seen in isolation or, as is most often the case, as a complication of other medical illnesses (eg, heart failure, liver failure, kidney failure, pneumonia, cancer).[1]  The normal serum sodium concentration is 135-145 mEq/L. Hyponatremia is classified in adults according to serum sodium concentration, as follows[2] :

Correction of hyponatremia varies according to its source, its severity, and its duration. In patients whose hyponatremia has a known duration of > 48 hours, treatment must be calibrated to avoid osmotic demyelination syndrome (ODS), which may result from overly rapid correction.[3]

Signs and symptoms

Symptoms range from nausea and malaise, in persons with mild reduction in the serum sodium, to lethargy, decreased level of consciousness, headache, and (with severe hyponatremia) seizures and coma. Overt neurologic symptoms most often are due to very low serum sodium levels (usually < 115 mEq/L), resulting in intracerebral osmotic fluid shifts and brain edema.

Hyponatremia can be classified according to effective osmolality, as follows:

Hypotonic hyponatremia can be further subclassified according to volume status, as follows:

See Presentation for more detail.

Diagnosis

Three laboratory tests are essential in the evaluation of patients with hyponatremia: serum osmolality, urine osmolality, and urinary sodium concentration. Together with the history and the physical examination, those tests help to establish the primary underlying etiologic mechanism in an algorithmic fashion.

Serum osmolality

Serum osmolality readily differentiates true hyponatremia (hypotonic hyponatremia) from pseudohyponatremia. The latter may be secondary to hyperlipidemia or hyperproteinemia (isotonic hyponatremia), or may be hypertonic hyponatremia associated with elevated levels of glucose, mannitol, glycine (posturologic or postgynecologic procedure), sucrose, or maltose (contained in IgG formulations).

Urine osmolality

Urine osmolality helps differentiate between conditions associated with the presence or absence of antidiuretic hormone (ADH), also called arginine vasopressin (AVP). A dilute urine (urine osmolality < 100 mOsm/kg) and hypotonic hyponatremia generally results from conditions that overwhelm the kidney’s capacity to excrete free water (as in primary polydipsia) or conditions that truncate the amount of free water that can be excreted, typically due to low solute load (as in tea and toast diet). A urine osmolality greater than 100 mOsm/kg indicates impaired ability of the kidneys to dilute the urine, usually due to physiologic or non-physiologic secretion of ADH. Some uncommon conditions may result in either low or high urinary osmolality, depending on the treatment initiated.

Urinary sodium concentration

Urinary sodium concentration helps to differentiate hyponatremia secondary to hypovolemia or ineffective intravascular volume status from syndrome of inappropriate antidiuretic hormone secretion (SIADH). In SIADH and salt-wasting syndrome the urine sodium is greater than 20-40 mEq/L. In hypovolemia or ineffective intravascular volume status, the urine sodium typically measures less than 20 mEq/L. However, if sodium intake in a patient with SIADH or salt-wasting happens to be low, then urine sodium may fall below 20 mEq/L.

See Workup for more detail.

Management

Hypotonic hyponatremia accounts for most clinical cases of hyponatremia and requires free water restriction. The treatment of hypertonic hyponatremia and pseudo-hyponatremia is directed at the underlying disorder, in the absence of symptoms.

Acute hyponatremia (duration < 48 hours) can be safely corrected more quickly than chronic hyponatremia. The rate of correction for chronic hyponatremia (duration of > 48 hours or unknown) should be tailored according to the severity of the hyponatremia so as to avoid overcorrection and risk of ODS, but should be limited to 4-8 mEq/L per 24 hours.

Intravenous fluids and water restriction

Patients with overt symptoms (eg, seizures, severe neurologic deficits) and generally those with severe hyponatremia should be treated with a hypertonic (3%) saline bolus to increase serum sodium concentration and mitigate their symptoms. In patients with moderate symptoms, a slow infusion of hypertonic saline can be considered. Patients who are asymptomatic or have mild symptoms will rarely require hypertonic saline.

Administer isotonic saline to patients who are hypovolemic to replace the contracted intravascular volume. Patients with hypovolemia secondary to diuretics may also need potassium repletion. Note that potassium, like sodium, is osmotically active.

Treat patients who are hypervolemic with fluid restriction, with or without loop diuretics, and correction of the underlying condition. The use of a vasopressin V2 receptor antagonist may be considered as second-line therapy.

For asymptomatic patients with euvolemic hyponatremia, free-water restriction is generally the treatment of choice. There is no role for hypertonic saline in these patients.

Pharmacologic treatment

Two vasopressin receptor antagonists, tolvaptan (Samsca) and conivaptan (Vaprisol), are approved for treatment of euvolemic and hypervolemic hyponatremia.

Tolvaptan, an orally administered selective vasopressin V2 receptor antagonist, is indicated for hypervolemic and euvolemic hyponatremia. It can be used for hyponatremia associated with congestive heart failure and SIADH and must be initiated or reinitiated in the hospital.

Conivaptan, an intravenously administered V1A and V2 vasopressin receptor antagonist, is currently unavailable in the United States due to a shortage. It is approved for use in the hospital setting for euvolemic and hypervolemic hyponatremia. It is contraindicated in hypovolemic patients.

Additional options include the following:

See Treatment and Medication for more detail.

Pathophysiology

Hypo-osmolality (serum osmolality < 275 mOsm/kg) always indicates excess total body water relative to body solutes or excess water relative to solute in the extracellular fluid (ECF), as water moves freely between the intracellular and the extracellular compartments. This imbalance can be due to solute depletion, solute dilution, or a combination of both.

Under normal conditions, renal handling of water is sufficient to excrete as much as 15-20 L of free water per day. Further, the body's response to a decreased osmolality is decreased thirst. Thus, hyponatremia can occur only when some condition impairs normal free-water excretion.

Generally, hyponatremia is of clinical significance when it reflects a drop in the serum osmolality (ie, hypotonic hyponatremia), which is measured directly via osmometry or is calculated as 2(Na) mEq/L + serum glucose (mg/dL)/18 + BUN (mg/dL)/2.8. Note that urea is not an ineffective osmole, so when the urea levels are very high (as in azotemia), the measured osmolality should be corrected for the contribution of urea (measured serum osmolality – BUN (mg/dL)/2.8).

The recommendations for treatment of hyponatremia rely on the current understanding of central nervous system (CNS) adaptation to an altered serum osmolality.[4]  In the setting of an acute drop in the serum osmolality, neuronal cell swelling occurs due to the water shift from the extracellular space to the intracellular space (ie, Starling forces). Swelling of the brain cells elicits the following two osmoregulatory responses:

Therefore, correction of hyponatremia must take into account the chronicity of the condition. Acute hyponatremia (duration < 48 h) can be corrected more quickly than chronic hyponatremia. Most individuals who present with symptomatic hyponatremia (as opposed to those who develop hyponatremia in an inpatient setting) have had hyponatremia for some time, so their condition is chronic, and correction should proceed accordingly. Overly rapid correction of serum sodium levels in these individuals can precipitate a severe neurologic complication, ODS. Consequently, when the duration of hyponatremia is uncertain, the condition should be considered chronic.

Etiology

Although the differential diagnosis is quite broad, most hyponatremia can be classified as hypertonic, normotonic, or hypotonic in origin.

Hypertonic hyponatremia

Patients with hypertonic hyponatremia often have normal total body sodium levels but a dilutional drop in the measured serum sodium due to the presence of osmotically active molecules in the serum, which causes a water shift from the intracellular compartment to the extracellular compartment.

Glucose reduces the serum sodium level by 1.6 mEq/L for each 100 mg/dL of serum glucose greater than 100 mg/dL. This relationship is nonlinear, with greater reduction in plasma sodium concentrations with glucose concentrations over 400 mg/dL, so a 2.4 mEq/L reduction in sodium for each 100 mg/dL increase in glucose over 100 mg/dL is a more accurate correction factor when the glucose is greater than 400 mg/dL.[6]

Other examples of osmotically active molecules include mannitol (often used to treat brain edema) or maltose (used with intravenous immunoglobulin administration).

Normotonic hyponatremia

Severe hyperlipidemia and paraproteinemia can lead to low measured serum sodium concentrations with normal serum osmolality. Normally, water comprises 92-94% of plasma volume. The plasma water fraction falls with an increase in fats and proteins. The measured sodium concentration in the total plasma volume is respectively reduced, although the plasma sodium concentration and plasma osmolality are unchanged. This artifactual low sodium (so-called pseudohyponatremia) is secondary to measurement by flame photometry. It can be avoided by direct ion-selective electrode measurement. Another cause of pseudohyponatremia is seen in patients with cholestatic jaundice secondary to the presence of low-density lipoprotein, lipoprotein X, which can be detected by lipoprotein electrophoresis.[7]

Hyponatremia after transurethral resection of the prostate (TURP) or hysteroscopy is caused by absorption of glycine, sorbitol, or mannitol contained in nonconductive flushing solutions used for those procedures. The degree of hyponatremia is related to the quantity and rate of fluid absorbed. The plasma osmolality is also variable and changes over time. The presence of a relatively large osmolal gap due to excess organic solute is diagnostic in the appropriate clinical setting.

Hemodialysis, which will correct the hyponatremia and remove glycine and its toxic metabolites, can be used in patients with end-stage renal disease. Use of isotonic saline as an irrigant instead of glycine with the new bipolar resectoscope for TURP in high-risk patients (those with large prostates that require lengthy resection) can avoid this complication, making this disorder more a diagnosis of the past.[8]

Hypotonic hyponatremia

Hypotonic hyponatremia always reflects the inability of the kidneys to handle the excretion of free water to match the intake. Hypotonic hyponatremia with a urinary osmolality > 100 mOsm/kg (due to presence of inappropriate ADH) can be divided pathophysiologically into the following categories, according to the effective intravascular volume: hypervolemic, euvolemic, and hypovolemic. These clinically relevant groupings aid in determination of likely underlying etiology and guide treatment.

Hypervolemic hypotonic hyponatremia

This is characterized by clinically detectable edema or ascites that signifies an increase in total body water and sodium. Paradoxically, however, a decrease in the effective circulating volume, critical for tissue perfusion, stimulates the same pathophysiologic mechanism of impaired water excretion by the kidney that is observed in hypovolemic hypotonic hyponatremia. Commonly encountered examples include liver cirrhosis, congestive heart failure, nephrotic syndrome, and severe hypoproteinemia (albumin level < 1.5-2 g/dL).

Normovolemic (euvolemic) hypotonic hyponatremia

This is a very common cause of hyponatremia in hospitalized patients. It is associated with non-osmotic and non–volume-related ADH secretion (ie, SIADH) secondary to a variety of clinical conditions, including the following:

Some of the common medications associated with SIADH are as follows:

In those circumstances, the ability of the kidney to dilute urine in the setting of serum hypotonicity is reduced.

Hyponatremia is a relatively common adverse effect of desmopressin, a vasopressin analogue that acts as a pure V2 agonist and is used in the treatment of central diabetes insipidus, von Willebrand disease, nocturia in adults, and enuresis in children. Patients receiving desmopressin require regular monitoring of serum sodium levels.[12]

The diagnostic criteria for SIADH are as follows:

Urinary sodium concentrations are also typically greater than 20 mEq/L on a normal salt diet, as sodium excretion will reflect dietary sodium intake. Serum uric acid levels are generally reduced; this is due to reduced tubular uric acid reabsorption, which parallels the decrease in proximal tubular sodium reabsorption associated with central volume expansion. These findings are also found in a renal salt-wasting process. This similarity makes the differentiation between salt wasting and SIADH difficult except that in renal salt wasting, one would expect to find a hypovolemic state and possibly hypotension.

Reset osmostat is another important, but rare, cause of normovolemic hypotonic hyponatremia. This may occur in the elderly and during pregnancy. These patients regulate their serum osmolality around a reduced set point; however, in contrast to patients with SIADH (who also have a downward resetting of the osmotic threshold for thirst),[13]  they are able to dilute their urine in response to a water load to keep the serum osmolality around the preset low point.

Severe hypothyroidism (unknown mechanism, possibly secondary to low cardiac output and glomerular filtration rate) and adrenal insufficiency are also associated with non-osmotic vasopressin release and impaired sodium reabsorption, leading to hypotonic hyponatremia. Hyponatremia associated with cortisol deficiency, such as primary or secondary hypoadrenalism, commonly presents subtly and may go undiagnosed. A random cortisol level check, especially in acute illness, can be misleading if the level is normal (when it should be high). Testing for adrenal insufficiency and hypothyroidism should be part of the hyponatremia workup, as the disorders respond promptly to hormone replacement.

Hospitalized patients who are infected with human immunodeficiency virus (HIV) have a high incidence of hyponatremia.[14]  In these cases, hyponatremia is usually due to disorders associated with an increased ADH level:

Hypovolemic hypotonic hyponatremia

This usually indicates concomitant solute depletion, with patients presenting with orthostatic symptoms. The pathophysiology underlying hypovolemic hypotonic hyponatremia is complex and involves the interplay of carotid baroreceptors, the sympathetic nervous system, the renin-angiotensin system, antidiuretic hormone (ADH; vasopressin) secretion, and renal tubular function. In the setting of decreased intravascular volume (eg, severe hemorrhage or severe volume depletion secondary to GI or renal loss or diuretic use) owing to a decreased stretch on the baroreceptors in the great veins, aortic arch, and carotid bodies, an increased sympathetic tone to maintain systemic blood pressure generally occurs.

This increased sympathetic tone, along with decreased renal perfusion secondary to intravascular volume depletion, results in increased renin and angiotensin secretion. This, in turn, results in increased sodium absorption in the proximal tubules of the kidney via angiotensin II and consequent decreased delivery of solutes to distal diluting segments, causing an impairment of renal free water excretion. There also is a concomitant increase in serum ADH production that further impairs free water excretion. Because angiotensin is also a very potent stimulant of thirst, free water intake is increased inappropriately at the same time, when water excretion is limited. Together, these changes lead to hyponatremia.

Cerebral salt wasting (CSW) is seen with intracranial disorders, such as subarachnoid hemorrhage, carcinomatous or infectious meningitis, metastatic carcinoma,  traumatic brain injury, and pituitary disorders, but especially after neurologic procedures.[15, 16] Disruption of sympathetic neural input into the kidney, which normally promotes salt and water reabsorption in the proximal nephron segment through various indirect and direct mechanisms, might cause renal salt wasting, resulting in reduced plasma volume.

Plasma renin and aldosterone levels fail to rise appropriately in patients with CSW despite a reduced plasma volume because of disruption of the sympathetic nervous system. In addition, the release of one or more natriuretic factors could also play a role in the renal salt wasting seen in CSW. Volume depletion leads to an elevation of plasma vasopressin levels and impaired free water excretion.

Distinguishing between CSW and SIADH can be challenging, because there is considerable overlap in the clinical presentation.[17]  Vigorous salt replacement is required in patients with CSW, whereas fluid restriction is the treatment of choice in patients with SIADH. Infusion of isotonic saline to correct the volume depletion is usually effective in reversing the hyponatremia in CSW, since euvolemia will suppress the release of ADH. The disorder is usually transient, with resolution occurring within 3-4 weeks of disease onset.

Salt-wasting nephropathy causing hypovolemic hyponatremia may rarely develop in a range of renal disorders (eg, interstitial nephropathy, medullary cystic disease, polycystic kidney disease, partial urinary obstruction) with low salt intake.

Another rare cause of hypovolemic hyponatremia secondary to solute loss in body fluid is high biliary fluid loss due to external biliary drainage—for example, in the setting of acalculous cholecystitis.The drained biliary fluid has a high sodium concentration, ranging between 122-164 mmol/L. The significant sodium loss in bile fluid results in hypotension and renal free-water retention in response to increased ADH secretion.[18]

Diuretics may induce hypovolemic hyponatremia. Note that thiazide diuretics, in contrast to loop diuretics, impair the diluting mechanism without limiting the concentrating mechanism, thereby impairing the ability to excrete a free-water load. Thus, thiazides are more prone to causing hyponatremia than are loop diuretics. This is particularly so in elderly persons, who already have impaired diluting ability.

Other causes

There are other causes that do not fit in any of the above categories and may or may not be associated with elevated levels of ADH or may simply overwhelm the capacity of the kidneys to properly excrete excess water.

The most common precipitant of hyponatremia in patients after surgery is the iatrogenic infusion of hypotonic fluids.[19]  Inappropriate administration of hypotonic intravenous fluids after surgery increases the risk of hyponatremia in these vulnerable patients, who retain water due to non-osmotic release of ADH, which can be elevated for a few days after most surgical procedures.

In severely malnourished individuals with a low-protein but high-water diet, diminished intake of solutes limits the ability of the kidney to handle free water. This is similar to the known condition of beer potomania, which occurs in individuals whose main source of calories is alcohol.[20]  In these patients, the urinary osmolality will typically be < 100 mOsm/kg.

Compulsive intake of large amounts of water exceeding the diluting capacity of the kidneys (> 20 L/d), despite a normal solute intake of 600-900 mOsm/d can result in hyponatremia. These patients will have a maximally dilute urine (urinary osmolality < 100 mOsm/kg), unlike those with SIADH. In primary polydipsia, there is a defect in thirst regulation due to a psychiatric illness, with different abnormalities in ADH regulation identified in psychotic patients. Transient stimulation of ADH release during acute psychotic episodes, an increase in the net renal response to ADH, downward resetting of the osmostat, and antipsychotic medication may contribute. Limiting water intake will rapidly raise the plasma sodium concentration as the excess water is readily excreted in dilute urine.[21]

Acute hyponatremia is not an uncommon occurrence in ultra-endurance athletes and marathon runners, with women being at higher risk.[22] The strongest single predictor of hyponatremia in these cases is weight gain during the race correlating with excessive fluid intake. Longer race time and lower body mass index extremes are also associated with hyponatremia, whereas the composition of fluids consumed (plain water rather than sports drinks containing electrolytes) is not. Oxidization of glycogen and triglyceride during a race is associated with the production of "bound" water, which then becomes an endogenous, electrolyte-free water infusion contributing to hyponatremia induced by water ingestion in excess of water losses.

It should be noted that some runners who collapse during a race are normonatremic or even hypernatremic,[23]  making blanket recommendations difficult. However, fluid intake to the point of weight gain should be avoided.[24]  Athletes should rely on thirst as their guide for fluid replacement and avoid global recommendations for water intake. Symptomatic patients with documented hyponatremia should receive 100 mL of 3% sodium chloride over 10 minutes in the field before transportation to hospital. This maneuver should raise the plasma sodium concentration an average of 2-3 mEq/L.[25]

By inhibiting prostaglandin formation, NSAID use may increase the risk of hyponatremia developing during strenuous exercise. Prostaglandins have a natriuretic effect. Prostaglandin depletion increases NaCl reabsorption in the thick ascending limb of Henle (ultimately increasing medullary tonicity) whereby ADH action in the collecting duct can lead to increased free water retention.[26]

Symptomatic and potentially fatal hyponatremia can develop with rapid onset after ingestion of the amphetamine derivative methylenedioxymethamphetamine (MDMA; ecstasy, Molly).[27]  A marked increase in water intake via direct thirst stimulation, as well as inappropriate secretion of ADH, contributes to the hyponatremia seen with even a low dose of this drug.

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is an SIADH-like clinical and laboratory picture seen in male infants who present with neurologic symptoms secondary to hyponatremia in the setting of undetectable plasma arginine vasopressin (AVP) levels. This hereditary disorder is secondary to a gain-of-function mutation in the V2 vasopressin receptor, resulting in constitutive activation of the receptor with elevated cyclic adenosine monophosphate (cAMP) production in the collecting duct principal cells.

Treatment of NSIAD poses a challenge. Water restriction improves serum sodium levels and osmolality in infants, but it limits calorie intake in formula-fed infants. The use of demeclocycline or lithium is potentially limited due to their adverse effects. The current therapy of choice is fluid restriction and the use of oral urea to induce obligatory free water excretion via osmotic diuresis.[28]

Hyponatremic-hypertensive syndrome, a rare condition, consists of severe hypertension associated with renal artery stenosis, hyponatremia, hypokalemia, severe thirst, and kidney dysfunction characterized by natriuresis, hypercalciuria, renal glycosuria, and proteinuria. Angiotensin-mediated thirst coupled with non-osmotic release of vasopressin provoked by angiotensin II and/or hypertensive encephalopathy are likely mechanisms for this syndrome. Sodium depletion due to pressure natriuresis and potassium depletion due to hyperaldosteronism with high plasma renin activity are also likely to play a role in the pathogenesis of hyponatremia. The abnormalities resolve with correction of the renal artery stenosis.[29]

Epidemiology

United States

The incidence of hyponatremia depends largely on the patient population and the criteria used to establish the diagnosis. Among hospitalized patients, 15-20% have a serum sodium level of < 135 mEq/L, while only 1-4% have a serum sodium level of less than 130 mEq/L. The prevalence of hyponatremia is lower in the ambulatory setting.

The US armed forces reported 1579 incident diagnoses of exertional hyponatremia among active service members from 2003 through 2018, for a crude overall incidence rate of 7.2 cases per 100,000 person-years. Cases occurred both in training facilities and theaters of war. Diagnosis and treatment without hospitalization was accomplished in 86.3% of cases.[30]

Mortality/morbidity

Severe hyponatremia (< 125 mEq/L) has a high mortality rate. In patients whose serum sodium level falls below 105 mEq/L, and especially in persons with alcohol use disorder, the mortality is over 50%.[31]

In patients with acute ST-elevation myocardial infarction (MI), the presence of hyponatremia on admission or early development of hyponatremia is an independent predictor of 30-day mortality, and the prognosis worsens with the severity of hyponatremia.[32] In hospitalized survivors of acute MI, the presence of hyponatremia at discharge is an independent predictor of 12-month mortality.[33]

Similarly, cirrhotic patients with persistent ascites and a low serum sodium level who are awaiting liver transplantation have a high mortality risk despite low- severity Model for End-Stage Liver Disease (MELD) scores (see the MELD Score calculator). The independent predictors—ascites and hyponatremia—are findings indicative of hemodynamic decompensation.[34, 35, 36]

In patients with chronic kidney disease, hyponatremia and hypernatremia are associated with an increased risk for all-cause mortality and for deaths unrelated to cardiovascular problems or malignancy. Hyponatremia is also linked to an increased risk for cardiovascular- and malignancy-related mortality in these patients.[37]

Race-, sex-, and age-related demographics

Hyponatremia affects all races.

No sexual predilection exists for hyponatremia. However, symptoms are more likely to occur in young women than in men. Hyponatremia is more common in elderly persons partially because of higher rate of comorbid conditions (eg, heart, liver, or kidney failure) that can lead to hyponatremia.

Prognosis

The prognosis for patients with hyponatremia is predicated upon the underlying etiology. Hyponatremia in patients with cancer is associated with extended hospital stays and higher mortality rates; however, whether long-term correction of hyponatremia would improve these outcomes is unclear.[38]

In patients with end-stage renal disease who are receiving hemodialysis or peritoneal dialysis, evidence suggests that the risk of death rises with incrementally lower sodium levels. Causes of hyponatremia-related mortality in the dialysis population remain uncertain, but possibilities include central nervous system toxicity, falls and fractures, infection-related complications, and impaired cardiac function.[39]

A meta-analysis of 15 studies encompassing 13,816 patients found that any improvement in hyponatremia was associated with a reduced risk of overall mortality (odds ratio [OR]=0.57). With the eight studies that reported a threshold for serum sodium improvement to > 130 mmol/L, the association was even stronger (OR=0.51). The reduction in mortality risk persisted at 12-month follow-up (OR=0.55). Reduced mortality was more evident in older patients and in patients with lower serum sodium levels at enrollment.[40]

Patient Education

Patients who are to be treated with fluid restriction often require education regarding the free-water content of foods and an explanation of the need to limit the intake of liquids to a predetermined level.

History

Patients may present to medical attention with symptoms related to low serum sodium concentrations. However, many patients present due to manifestations of other medical comorbidities, with hyponatremia being recognized only secondarily. In many cases, therefore, the recognition is entirely incidental. Clinical symptoms may result from the underlying cause of hyponatremia or the hyponatremia itself.

Many medical illnesses, such as chronic heart failure,[41, 42]  liver failure,[36] kidney failure,[37]  or pneumonia, may be associated with hyponatremia. These patients frequently present because of their primary disease (eg, with dyspnea, jaundice, uremia, cough).

Exercise-associated hyponatremia (EAH), which develops during or immediately after physical activity, was first reported in athletes participating in long-duration and high-intensity exercise (eg, ultramarathons) particularly in hot weather. But it has also been described in otherwise healthy participants in a variety of sporting and recreational activities, including team sports and yoga classes. EAH results from drinking hypotonic fluids (water or sports drinks) beyond thirst and in excess of sweat, urine, and insensible water losses.[43]

Symptoms of hyponatremia range from nausea and malaise, which occur with mild reduction in the serum sodium, to lethargy, decreased level of consciousness, headache, and (with severe hyponatremia) seizures and coma. Overt neurologic symptoms most often are due to very low serum sodium levels (usually < 115 mEq/L), resulting in intracerebral osmotic fluid shifts and brain edema. This neurologic symptom complex can lead to tentorial herniation with subsequent brain stem compression and respiratory arrest, resulting in death in the most severe cases.

The severity of neurologic symptoms correlates well with the rate, degree, and duration of the drop in serum sodium. A gradual drop in serum sodium, even to very low levels, may be tolerated well if it occurs over several days or weeks, because of neuronal adaptation. The presence of an underlying neurologic disease, such a seizure disorder, or non-neurologic metabolic abnormalities, such as hypoxia, hypercapnia, or acidosis, also affects the severity of neurologic symptoms.

A detailed medication history, including information on over-the-counter (OTC) drugs the patient has been using, is an important aspect of the patient interview because many medications may precipitate hyponatremia, including antipsychotic medications, antidepressants,[44]  antiepileptic drugs,[45]  diuretics, and nonsteroidal anti-inflammatory drugs (NSAIDs). A dietary history with reference to salt, protein, and water intake is useful, as well. For patients who are hospitalized, reviewing the records of parenteral fluids administered is crucial.

Physical Examination

Examination should include measurement of orthostatic vital signs, and an accurate assessment of volume status. This determination (ie, whether the patient is hypervolemic, euvolemic, or hypovolemic) often guides diagnostic and treatment decisions.

A full assessment for medical comorbidities is also essential, with particular attention paid to cardiopulmonary and neurologic components of the examination.

Laboratory Studies

There are three essential laboratory tests in the evaluation of patients with hyponatremia that, together with the history and the physical examination, help to establish the primary underlying etiologic mechanism. In general, the etiology of the hyponatremia directs its management.[46, 47]

These tests, ideally to be obtained at the same time, are as follows

Serum osmolality readily differentiates true hyponatremia from pseudohyponatremia secondary to hyperlipidemia, hyperproteinemia, or hypertonic hyponatremia. Sources of hypertonic hyponatremia include elevations of the following:

Urine osmolality helps to differentiate between conditions associated with impaired free water excretion and primary polydipsia (or malnutrition), in which water excretion should be normal (provided that kidney function is intact). With primary polydipsia, as with malnutrition (severe decreased solute intake) and a reset osmostat, the urine osmolality is maximally dilute, generally less than 100 mOsm/kg. A urine osmolality greater than 100 mOsm/kg indicates impaired ability of the kidneys to dilute the urine. This usually is secondary to elevated levels of vasopressin (antidiuretic hormone; ADH), which can be physiologic or non-physiologic.

Urinary sodium concentration helps to differentiate between hyponatremia secondary to hypovolemia and the syndrome of inappropriate antidiuretic hormone secretion (SIADH). With SIADH (and salt-wasting syndrome), the urine sodium is greater than 20-40 mEq/L. With hypovolemia, the urine sodium typically measures less than 20 mEq/L. However, if sodium intake in a patient with SIADH (or salt wasting) happens to be low, then urine sodium may be low as well.

Ancillary tests

Serum uric acid levels can be important supportive information; they are typically reduced in SIADH and in salt wasting. After correction of hyponatremia, the hypouricemia corrects in SIADH but remains with a salt-wasting process.

Thyroid-stimulating hormone (TSH) and serum cortisol levels should be measured if hypothyroidism or hypoadrenalism is suspected.

Serum albumin, triglycerides, and serum protein electrophoresis are indicated for patients with iso-osmolar hyponatremia.

Imaging Studies

Head computed tomography (CT) scanning and chest radiography can be used to assess for an underlying etiology in select patients with suspected SIADH or cerebral salt wasting.

A diffusion-weighted magnetic resonance imaging (MRI) scan can help evaluate patients suspected of osmotic demyelination syndrome (ODS). Iif MRI is unavailable, CT of the brain can be done. Of note, however, is that the appearance of central pontine and extrapontine myelinolysis on conventional CT and MRI scans typically lags behind the clinical manifestations by 2-4 weeks.[49]

Approach Considerations

When faced with a patient with hyponatremia, the first decision is what type of fluid, if any, should be given. The treatment of hypertonic and pseudohyponatremia is directed at the underlying disorder, in the absence of symptoms.

Hypotonic hyponatremia accounts for most clinical cases of hyponatremia. The first step in these cases is to determine whether emergency therapy is warranted. The following three factors guide treatment:

The recommendations for treatment of hyponatremia rely on the current understanding of the central nervous system (CNS) adaptation to an alteration in serum osmolality. In the setting of an acute fall in the serum osmolality, neuronal cell swelling occurs due to the water shift from the extracellular space to the intracellular space (ie, Starling forces). Therefore, correction of hyponatremia should take into account the limited capacity of this adaptation mechanism to respond to acute alteration in the serum tonicity, because the degree of brain edema and consequent neurologic symptoms depend as much on the rate and duration of hypotonicity as they do on its magnitude.

A panel of United States experts on hyponatremia issued guidelines on the diagnosis, evaluation, and treatment of hyponatremia in 2007; the guidelines were updated in 2013.[2]  Additionally, in 2014, the European Society of Intensive Care Medicine, the European Society of Endocrinology, and the European Renal Association–European Dialysis and Transplant Association released guidelines on the diagnosis, classification, and treatment of true hypotonic hyponatremia.[50]

Although not completely uniform in their recommendations (see the table below), the guideline have a common aim of acute treatment of moderately and severely symptomatic patients with the goal of increasing the serum sodium concentration by about 4-6 mmol/L in the first few hours, to prevent brain herniation and neurologic damage from cerebral ischemia.[2, 50]  The treatment of chronic hyponatremia focuses on avoiding overcorrection to reduce the risk of osmotic demyelination syndrome (ODS). The higher risk of ODS in some patients would lower the limit on the daily correction rate.[51]  Addition of desmopressin should be discussed with an expert, particularly in patients at high risk of developing ODS. Risk factors for ODS are as follows:

Table. Guidelines for Management of Hyponatremia



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See Table

 

Medical Care

When treating patients with overtly symptomatic hyponatremia (eg, seizures, severe neurologic deficits), hypertonic (3%) saline should be used. There is no place in the initial treatment for free-water restriction or other treatment options. Note that normal saline can exacerbate hyponatremia in patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH), who may excrete the sodium and retain the water. A liter of normal saline contains 154 mEq sodium chloride (NaCl) and 3% saline has 513 mEq NaCl. Management decisions should also factor in ongoing renal free water and solute losses. During therapy, close monitoring of serum electrolytes (ie, every 2-4 h) to avoid overcorrection is essential.

The following equation helps to estimate an expected change in serum sodium (Na) with respect to characteristics of infusate used[52] :

Change in serum Na = [(infusate Na + infusate K) - serum Na] / [Total body water +1]

Acute hyponatremia (duration < 48 h) can be safely corrected more quickly than chronic hyponatremia. A severely symptomatic patient with acute hyponatremia is in danger from brain edema. In contrast, a symptomatic patient with chronic hyponatremia is more at risk from rapid correction of hyponatremia. Overly rapid correction of serum sodium can precipitate severe neurologic complications, such as ODS, which can produce spastic quadriparesis, swallowing dysfunction, pseudobulbar palsy, and mutism. A symptomatic patient with unknown duration of hyponatremia is the most challenging, warranting a prompt but controlled and limited correction of hyponatremia until symptoms resolve. However, fear of ODS should not deter prompt and definitive treatment of symptomatic patient.

In patients with symptomatic acute hyponatremia (duration < 48 h, such as after surgery), the treatment goal is to increase the serum sodium level by approximately 4-6 mEq/L/h to prevent brain herniation or until the neurologic symptoms subside.[53]  In contrast, in chronic symptomatic hyponatremia, the rate of correction should not exceed 4-6 or 4-8 mEq/L/d, depending on the ODS risk. Guidelines recommend no more than 18 mEq/L in the first 48 h. The sodium concentration must be corrected to a safe range (usually to no greater than 120 mEq/L) rather than to a normal value. As noted before, spontaneous diuresis secondary to ADH suppression with intravascular volume repletion could lead to unintended overcorrection.

Overly rapid correction of chronic hyponatremia (> 48 hours) could result in ODS. Although extremely rare in patients with plasma sodium > 120 mEq/L, the incidence may be as high as 50% in patients with plasma sodium < 105 mEq/L. It is the magnitude of daily plasma sodium rise rather than the hourly correction rate that is critical for the development of demyelination. In a large cohort of patients, overcorrection of > 8 mEq/L over a 24-hour period) was associated with the development of ODS.[51]

For patients with SIADH, the United States guidelines recommend fluid restriction (with a goal of 500 mL/d below the 24-hour urine volume) as the general first-line therapy, but pharmacologic treatment should be strongly considered if the patient's urinary parameters indicate low renal electrolyte-free water excretion or if the serum sodium concentration does not correct after 24-48 hours of fluid restriction. Pharmacologic options include demeclocycline (off-label use), urea, and vasopressin receptor antagonists (vaptans). Vaptans should not be used in hypovolemic hyponatremia, or in conjunction with other treatments for hyponatremia.[2]  If vaptans are used, maintain ad libitum fluid intake during the first 24-48 hours of treatment.

Similarly, the European guidelines recommend that the first-line treatment for patients with SIADH and moderate or profound hyponatremia should be fluid restriction; second-line treatments should include increasing solute intake with 0.25–0.50 g/kg per day of urea or combination treatment with low-dose loop diuretics and oral sodium chloride.[50]  In contrast to US guidelines, the European guidelines do not recommend demeclocycline or vaptans for treatment of patients with SIADH.

Consultation with either a nephrologist or a critical care specialist is often of considerable value in managing patients with symptomatic, refractory hyponatremia or overcorrection of chronic hyponatremia.

For asymptomatic patients, the treatment options below may be of use.

Hypovolemic hyponatremia: For patients with reduced circulating volume, restore intravascular volume with an intravenous infusion of 0.9% saline or a balanced crystalloid solution at 0.5 to 1.0 mL/kg per hour to suppress the cause of physiologic vasopressin release. Patients with hypovolemia secondary to diuretics may also need potassium repletion; potassium, like sodium, is osmotically active. Correction of volume repletion turns off the stimulus to ADH secretion, so a large water diuresis may ensue, leading to a more rapid correction of hyponatremia than desired. If so, electrolyte-free water orally or as an infusion (dextrose 5% in water [D5W]) with or without desmopressin may need to be administered (see the table in Approach Considerations for guideline recommendations).[54]

Hypervolemic hyponatremia: Treat patients who are hypervolemic with fluid restriction plus loop diuretics, and correction of the underlying condition. Alternatively, the combination of intravenous normal saline and diuresis with a loop diuretic (eg, furosemide) will also elevate the serum sodium concentration. This latter approach is often useful for patients with high urine osmolality, because the loop diuretic acts to reduce urine osmolality. Concomitant use of loop diuretics increases free-water excretion and decreases the risk of fluid overload. The use of a vaptan may be considered (see table for guidelines).

For normovolemic (euvolemic) asymptomatic hyponatremic patients, free-water restriction is generally the treatment of choice. There is no role for hypertonic saline in these patients. Base the volume of restriction on the patient's renal diluting capacity. For instance, fluid restriction to 1 L/d, which is enough to raise the serum sodium in some patients, may exceed the renal free-water excretion capacity in others, necessitating more severe restriction. This approach is recommended as initial treatment for patients with asymptomatic SIADH. However, many patients will not adhere to fluid restriction.

The addition of oral sodium chloride and loop diuretic to fluid restriction has been suggested as a second-line treatment option but this combination does not seem to be any more effective than fluid restriction alone.[55]  Further, the definition of asymptomatic is changing due to the recognition that subtle but significant deficits, such as in gait, may be present, which could possibly increase the risk of falls and hip fractures. Therefore, pharmacologic treatment may be considered.

Pharmacologic treatment

Pharmacologic agents can be used in some cases of more refractory SIADH, allowing more liberal fluid intake. Demeclocycline can increase the diluting capacity of the kidneys, by achieving vasopressin antagonism and a functional nephrogenic diabetes insipidus. This treatment requires 3-4 days for maximal effect. Demeclocycline is contraindicated in cirrhotic patients. Other agents, such as lithium, have been used with variable success. Lithium is also associated with several untoward effects, including thyroid dysfunction, interstitial kidney disease, and, in overdosage, CNS dysfunction, which make its use problematic.

Aquaretics

The use of vaptans in appropriate setting can be beneficial, though limited. AVP receptor antagonists, designed specifically to promote aquaresis (ie, electrolyte-sparing excretion of free water), has been evaluated in clinical trials for the treatment of hyponatremia.[56, 57, 58]  The first agent to be approved was conivaptan, an intravenously administered V1A and V2 vasopressin receptor antagonist. It is approved for use in the hospital setting for euvolemic and hypervolemic hyponatremia. It is contraindicated in hypovolemic patients. However, conivaptin is currently unavailable in the United States due to a shortage.

Most of the clinical experience with conivaptan has been in heart failure. It is effective in raising serum sodium levels; however, conivaptan has not been shown to improve heart failure per se. Close monitoring of the rate of correction is needed and conivaptan is approved for treatment for only 4 days. In addition, the effects in patients with kidney and liver impairment have not been well studied, so caution is advised with use in this population. There are several drug interactions that need close monitoring and the use of conivaptan with CYP3A4 inhibitors is contraindicated.

Tolvaptan, a selective V2 receptor antagonist, can be taken orally and has been approved for use in the treatment of euvolemic and hypervolemic hyponatremia, including cases associated with cirrhosis and heart failure. Tolvaptan treatment must be initiated in the hospital to avoid the possibility of rapid correction. Because of the requirement for hospitalization for initiation or reintroduction and the expense of the drug, its use is limited. It also interacts with CYP3A inhibitors and use with such drugs is contraindicated. In 2013, the FDA limited use of tolvaptan to no more than 30 days and indicated that it should not be used in patients with underlying liver disease. This decision was based on reports of liver injury, including those potentially leading to the need for liver transplantation or to death.[59]

Diet

Free water restriction often is appropriate for patients with normovolemic hypotonic hyponatremia.

Individuals who are undernourished need to maintain an appropriate solute intake, because a high protein diet increases the urinary solute excretion and respectively the obligatory urinary free water excretion. An oral urea formula can be used to achieve the same effect.

Patients with hyperglycemia or hyperlipidemia should receive appropriate nutritional counseling in the setting of pseudohyponatremia.

Complications

Overly rapid correction of hyponatremia may result in permanent neurologic impairment due to central pontine myelinolysis and extrapontine myelinolysis. The clinical course of these patients features initial encephalopathy secondary to hyponatremia, then improvement as the plasma sodium concentration increases, and finally deterioration several days later. The disorder can resolve completely or result in permanent disability or death.

This typical clinical course has been called osmotic demyelination syndrome (ODS). The clinical neurologic picture may be confusing, as it may include a variety of findings from psychiatric, behavioral, and movement disorders, such as dysphagia and flaccid or spastic quadriparesis, depending on the involvement of extrapontine or central pontine myelinolysis. Disruption of the blood-brain barrier is presumed to play an important role in the pathogenesis of ODS.

An increased susceptibility to osmotic demyelination is also observed in cirrhotic patients. In this setting, myoinositol, the most abundant organic osmolyte, is depleted because of glutamine- and hyponatremia-induced brain cell swelling. Central pontine myelinolysis is a common and often fatal complication of orthotopic liver transplantation, affecting up to 10% of patients who are hyponatremic prior to transplant.[60]

Guidelines Summary

Two clinical practice guidelines on the diagnosis and treatment of hyponatremia, one from a United States expert panel and one a joint venture of three European societies, define hyponatremia as follows[2, 50] :

The guidelines recommend that in case of hypertonic and isotonic hyponatremia, address the underlying cause. The European guidelines state that hyponatremia with a measured osmolality < 275 mOsm/kg always reflects hypotonic hyponatremia.

To differentiate the cause of hypotonic hyponatremia, the guidelines recommend interpreting the osmolality of a spot urine sample as the next step, followed by urine sodium check:

Treatment

For comparison of the US and European guideline treatment recommendations, see the table in Treatment/Approach Considerations.

Treatment of patients with severe symptoms

For severe symptomatic hyponatremia prompt infusion of hypertonic 3% saline in the first-hour of management is recommended. It is recommended to monitor patients in an environment where close clinical monitoring can be provide with the serum sodium concentration checked in short intervals while repeating an infusion of hypertonic 3% saline

For patients whose symptoms improve after a 4-6  mmol/L increase in serum sodium concentration in the first hour, guideline statements include the following:

Treatment of patients with moderately severe symptoms

Treatment of patients without severe or moderately severe symptoms

Correcting overcorrection

If hyponatremia is corrected too rapidly, do the following:

Guideline controversy

A retrospective analysis of hospital administrative data that included 22,858 hospitalizations with hyponatremia reported that rapid correction of serum sodium was performed in 17.7% of patients but ODS occurred in only 0.05%, and more than half of patients who developed ODS had not had rapid correction of serum sodium.[61]  An accompanying editorial suggested that guideline recommendations for limiting the rate of correction and closely monitoring the serum sodium concentration may be overly cautious.[62]  In response, a multinational expert group has criticized those conclusions as "unwarranted and potentially dangerous" and strongly supported current guideline recommendations.[3]

Medication Summary

The primary treatments used in the management of hyponatremic patients rely on the use of intravenous sodium-containing fluids (normal saline or hypertonic saline) and fluid restriction. This is followed by use of loop diuretics (eg, furosemide), arginine vasopressin (AVP) receptor antagonists (eg, tolvaptan, conivaptan),[57] or urea[63] ; less commonly, salt tablets, or demeclocycline are used.

Oral salt tablets in conjunction with loop diuretics can be used to help excrete urinary free water. Sodium chloride tablets (1 gram) are osmotically active and ingesting 9 grams of sodium chloride in one day equals the addition of an extra 154 mEq each of sodium and chloride. Salt tablets should be avoided in the treatment of hypervolemic hyponatremia (eg, heart failure).

Furosemide (Furoscix, Lasix)

Clinical Context:  Furosemide inhibits sodium/potassium/chloride cotransport system, thereby increasing solute delivery to distal renal tubules, which acts to increase free water excretion. Elderly patients may have greater sensitivity to effects of loop diuretics. 

Demeclocycline (Declomycin)

Clinical Context:  Demeclocycline can cause insensitivity of distal renal tubules to the action of ADH and produce a nephrogenic diabetes insipidus. Effects are seen within 5 days and are reversed within 2-6 days following cessation of therapy. Demeclocycline can be nephrotoxic and cause nausea, vomiting, and photosensitivity. 

Class Summary

Certain antibiotics may affect renal ADH action.

Conivaptan (Vaprisol)

Clinical Context:  Arginine vasopressin antagonist (V1A, V2), indicated for euvolemic (dilutional) and hypervolemic hyponatremia, increases urine output of mostly free water, with little electrolyte loss. Over 80% of conivaptan is excreted in feces and the rest in urine. Conivaptan is an intravenous injection that can be administered for up to 4 days. Conivaptan is currently unavailable in the United States due to a shortage.

Tolvaptan (Samsca)

Clinical Context:  Selective vasopressin V2-receptor antagonist is indicated for euvolemic or hypervolemic hyponatremia, associated with SIADH or congestive heart failure. Initiate or reinitiate in hospital environment only. Tolvaptan can cause serious and potentially fatal liver injury; hence, duration of use is limited to 30 days to minimize risk of liver injury. 

Class Summary

V2 receptor antagonism of AVP in the renal collecting duct results in aquaresis (excretion of free water).

Class Summary

Oral urea is an osmotic agent that increases urinary free water excretion. It is effective, safe, well tolerated and cost effective for treatment of SIADH associated hyponatremia. A modest but expected elevation of BUN is the result of normal urea metabolism and should not be interpreted as a reduction in kidney function. Urea has been shown to have a direct antinatriuretic effect and free water excretion leading to increased serum sodium levels.[54, 64]  The use of urea is contraindicated in patients with hypovolemic hyponatremia. Furthermore, urea is relatively contraindicated in patients with cirrhosis, due to potential metabolization into ammonium by urease-producing bacteria in the colon, which can lead to hyperammonemia.

Desmopressin (DDAVP, Minirin, Nocdurna)

Clinical Context:  Desmopressin (DDAVP), a synthetic analogue of the antidiuretic hormone arginine vasopressin, increases cyclic adenosine monophosphate (cAMP), in a dose-dependent manner, in renal tubular cells. This increases water permeability, resulting in decreased urine volume and increased urine osmolality.

What is hyponatremia?How is hyponatremia categorized?What are symptoms of hyponatremia?What lab tests are used in the evaluation of hyponatremia?How is urine osmolality used in the diagnosis of hyponatremia?How is serum osmolality used in the diagnosis of hyponatremia?How is urinary sodium concentration used in the diagnosis of hyponatremia?How is hyponatremia treated?How should IV fluids be used and water restricted in patients with hyponatremia?What pharmacologic treatment is available for patients with hyponatremia?What is the pathophysiology of hyponatremia?At what level of serum osmolality is hyponatremia clinically significant?How are hyponatremia treatment decisions and recommendations made?What is the incidence of hyponatremia in the US?What is the mortality rate for patients with severe hyponatremia?How does hyponatremia affect the mortality rates of patients with acute myocardial infarction?How does hyponatremia affect the mortality rates of patients with cirrhosis?How does hyponatremia affect mortality rates in patients with chronic kidney disease?How does the prevalence of hyponatremia differ by race, age, and sex?How does hyponatremia typically come to medical attention?What is exercise-associated hyponatremia (EAH)?What are symptoms of hyponatremia?What affects the severity of neurologic symptoms in hyponatremia?What history should be obtained for patients who present with hyponatremia?What physical exam is conducted for patients with hyponatremia?What causes hyponatremia?How does hypertonic hyponatremia present?What causes pseudohyponatremia and how is it avoided?What causes hyponatremia after transurethral resection of the prostate or hysteroscopy?What is the treatment for patients with a large osmolal gap due to excess organic solute?When is hemodialysis used in the treatment of hyponatremia?What is hypotonic hyponatremia and how is it categorized?What is the pathophysiology of hypovolemic hypotonic hyponatremia?What is the pathophysiology of cerebral salt wasting?How can syndrome of inappropriate ADH secretion (SIADH) be differentiated from cerebral salt wasting?What are possible renal complications of hypovolemic hyponatremia caused by salt wasting nephropathy?Can diuretics cause hypovolemic hyponatremia?How is hypervolemic hypotonic hyponatremia characterized?What are the causes of normovolemic (euvolemic) hypotonic hyponatremia?What medications are associated with syndrome of inappropriate ADH secretion (SIADH)?Is hyponatremia an adverse effect of desmopressin?What is the diagnostic criteria for syndrome of inappropriate ADH secretion (SIADH)?How does reset osmostat cause normovolemic hypotonic hyponatremia?How does hypothyroidism and adrenal insufficiency cause hyponatremia?What causes hyponatremia in patients with HIV infection?Are there causes of hyponatremia other than normovolemic (euvolemic) hypotonic hyponatremia, hypervolemic hypotonic hyponatremia, and hypovolemic hypotonic hyponatremia?What is the most common cause of hyponatremia following surgery?What dietary factors can induce hyponatremia?How does hyponatremia affect athletes and marathon runners and how can it be avoided?How does ecstasy, or MDMA, induce hyponatremia?What is nephrogenic syndrome of inappropriate antidiuresis (NSIAD) and how is it treated?What is hyponatremic hypertensive syndrome?What is the incidence of hyponatremia in different neurologic conditions?What should be considered in the differential diagnoses (DDx) of hyponatremia?What are the differential diagnoses for Hyponatremia?What lab tests are used to evaluate hyponatremia?What does urine osmolality indicate regarding hyponatremia?What does serum osmolality indicate regarding hyponatremia?What does urinary sodium concentration indicate regarding hyponatremia?What ancillary tests are helpful in the evaluation of hyponatremia?What imaging studies are helpful in the evaluation of hyponatremia?What should be taken into account before making recommendations on the treatment of hyponatremia?What are the guidelines regarding treatment of symptomatic patients with acute hyponatremia?What are the guidelines regarding treatment of chronic hyponatremia?What are the guidelines regarding the treatment of hyponatremia with inappropriate antidiuretic hormone secretion (SIADH)?What are the guidelines regarding the treatment of true hypotonic hyponatremia?What is the first step in treating patients with hyponatremia?How common is hypotonic hyponatremia and what factors guide its treatment?What are the treatment options for an asymptomatic hyponatremic patient?What are the treatment recommendations for normovolemic (euvolemic), asymptomatic hyponatremia?What are the treatment recommendations for patients with overtly symptomatic hyponatremia?What is the equation used to estimate the expected change in serum sodium (Na) with respect to characteristics of infusates?How is symptomatic acute hyponatremia treated differently than chronic hyponatremia?What is the goal of treatment for acutely symptomatic hyponatremia?What is the goal of treatment for chronic, severe symptomatic hyponatremia?Which pharmacologic agents can be used to treat hyponatremia?What is the role of aquaretics in the treatment of hyponatremia?What diet recommendations are suggested for patients with hyponatremia?What are the European clinical practice guidelines on the diagnosis and treatment of hyponatremia?What are the treatment guidelines for hyponatremia?What treatments are used in the management of hyponatremiaWhich medications in the drug class Arginine Vasopressin Antagonists are used in the treatment of Hyponatremia?Which medications in the drug class Antibiotics are used in the treatment of Hyponatremia?Which medications in the drug class Diuretics are used in the treatment of Hyponatremia?

Author

Seyed Mehrdad Hamrahian, MD, Associate Professor of Medicine (Nephrology), Sidney Kimmel Medical College of Thomas Jefferson University; Director of American Society of Hypertension-Designated Jefferson Hypertension Center; Medical Director, Jefferson Nephrology Outpatient Clinic; Medical Director, Jefferson Home Hemodialysis Program; Medical Director of Chronic Dialysis Unit, DaVita City Line Dialysis

Disclosure: Nothing to disclose.

Coauthor(s)

Eric E Simon, MD, Professor of Medicine, Chief, Section of Nephrology and Hypertension, Tulane University School of Medicine; Director, Nephrology Training, Medical Director, Dialysis Clinic, Inc, Canal Street

Disclosure: Nothing to disclose.

Federico J Teran, MD, Assistant Professor of Clinical Medicine, Section of Nephrology and Hypertension, Tulane University School of Medicine; Chief of Nephrology, VA Southeast Louisiana Healthcare System

Disclosure: Nothing to disclose.

Omar H Maarouf, MD, Associate Professor of Medicine, Director of Renal Course, Division of Nephrology, Sidney Kimmel Medical College of Thomas Jefferson University; Director of Acute Dialysis Unit, Associate Program Director of Renal Fellowship, Jefferson Renal Associates, Thomas Jefferson University Hospital

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Eleanor Lederer, MD, FASN, Professor of Medicine, Chief, Nephrology Division, Director, Nephrology Training Program, Director, Metabolic Stone Clinic, Kidney Disease Program, University of Louisville School of Medicine; Consulting Staff, Louisville Veterans Affairs Hospital

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: American Society of Nephrology<br/>Received income in an amount equal to or greater than $250 from: Healthcare Quality Strategies, Inc.

Chief Editor

Vecihi Batuman, MD, FASN, Professor of Medicine, Section of Nephrology-Hypertension, Deming Department of Medicine, Tulane University School of Medicine

Disclosure: Nothing to disclose.

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  United States Guidelines European Guidelines
Symptomatic Acute Hyponatremia (< 24-48 hours)
Urgent correction goal, with aim of preventing brain herniationIncrease serum Na+ by 4-6 mmol/LIncrease serum Na+ by 5 mmol/L
Treatment based on symptoms   
Severe symptomsBolus 100 mL of 3% NaCl over 10 minutes × 3 as neededBolus 150 mL of 3% NaCl over 20 minutes, 2- 3 times as needed, checking Na every 20 minutes



(First-hour management, regardless of acute or chronic condition)



Moderate symptoms with low risk of herniationContinuous infusion of 3% NaCl at 0.5-2 mL/kg/hBolus 150 mL 3% NaCl over 20 minutes, × 1 to prevent further decrease in Na
Limit not to exceedNone in true acute hyponatremiaNone in true acute hyponatremia
Chronic Hyponatremia (> 48 hours)
Correction rate in symptomatic patients using hypertonic saline4-8 mmol/L/d if low risk for ODS



4-6 mmol/L/d if high risk of ODS



For patients with severe symptoms, the first day’s increase can be accomplished during first 6 h



Avoid: > 10 mmol/L in the first 24 h



          > 8 mmol/l during every 24 h thereafter



Limit to avoid potential harm in asymptomatic patients10-12 mmol/L/d, but max 18 mmol in 48 h if at low risk for ODS



8 mmol/L/d if at high risk of ODS



10 mmol/L in the first 24 h



and 8 mmol/l during every 24 h thereafter



Managing Overcorrection of Chronic Hyponatremia
 Baseline serum Na+ ≥ 120 mmol/L: Intervention probably unnecessaryStart once above mentioned limits are exceeded
 Baseline serum Na+ < 120 mmol/L: Replace water orally or as D5W at 3 mL/kg/h with or without desmopressin (2-4 µg every 8 h parenterally)



Withhold any vasopressin receptor antagonists (vaptans) used



Consider dexamethasone, 4 mg every 6 hr for 24 hr following excessive correction



Consult an expert to discuss infusion containing electrolyte-free water (10 mL/kg) over 1 h with or without 2 µg desmopressin IV every 8 h
Other Treatment Options   
Hypovolemic hyponatremia Isotonic salineIsotonic saline or balanced solution at 0.5-1.0 mL/kg/h
Euvolemic hyponatremia (SIADH) Fluid restriction of 500 mL/d below the 24-h urine volume (first-line treatment)



Urea, vaptan, or demeclocycline (second-line treatment)



Fluid restriction (first-line)



Urea or loop diuretics + oral NaCl (second-line)



Do not recommend vaptans



Recommend against lithium or demeclocycline



Hypervolemic hyponatremia Fluid restriction, loop diuretic



Vaptans



Fluid restriction



Recommend against vaptans and demeclocycine