Hyponatremia

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.[4]

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 seen 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.[5]  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:

• It inhibits both arginine vasopressin secretion from neurons in the hypothalamus and hypothalamic thirst center. This leads to excess water elimination as dilute urine.
• There is an immediate cellular adaptation with loss of electrolytes, and over the next few days, a more gradual loss of organic intracellular osmolytes. ^[6]

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, versus individuals 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.

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.[7]

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 alcoholics, the mortality is over 50%.[8]

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.[9] In hospitalized survivors of acute MI, the presence of hyponatremia at discharge is an independent predictor of 12-month mortality.[10]

Similarly, cirrhotic patients with persistent ascites and a low serum sodium level who are awaiting transplant 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.[11, 12, 13]

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.[14]

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.

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,[15, 16]  liver failure,[13] kidney failure,[14]  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.[17]

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,[18]  antiepileptic drugs,[19]  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.

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.

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.[20]

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 water 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 factitious hyponatremia is seen in patients with cholestatic jaundice secondary to presence of low-density lipoprotein, lipoprotein-X, which can be detected by lipoma protein electrophoresis.[21]

Hyponatremia after transurethral resection of the prostate (TURP) or hysteroscopy is caused by absorption of irrigants, 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 (with large prostates that require lengthy resection) could avoid this complication, making this disorder a diagnosis of the past.[22]

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:

• CNS disturbances (eg, hypopituitarism) ^[23]
• Major surgery
• Trauma
• Pulmonary tumors
• Infection
• Stress
• Certain medications
• Uncontrolled pain and nausea
• Idiopathic  ^[24]

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

• Chlorpropamide (potentiates the renal action of ADH)
• Carbamazepine (possesses antidiuretic property)
• Cyclophosphamide (marked water retention secondary to SIADH and potentially fatal hyponatremia may ensue in selected cases; use of isotonic saline rather than free water to maintain a high urine output to prevent hemorrhagic cystitis can minimize the risk)
• Vincristine
• Vinblastine
• Amitriptyline
• Haloperidol
• Selective serotonin reuptake inhibitors (particularly in elderly patients)
• Monoamine oxidase inhibitor (MAOI) antidepressants
• NSAIDs (inhibit prostaglandin, which has inhibitory effect on ADH)

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.[25]

The diagnostic criteria for SIADH are as follows:

• Normal liver, kidney, and heart function - clinical euvolemia (absence of intravascular volume depletion)
• Normal thyroid and adrenal function
• Hypotonic hyponatremia
• Urine osmolality greater than 100 mOsm/kg, generally greater than 400-500 mOsm/kg with normal kidney function

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.

Reset osmostat is another important, but rare, cause of normovolemic hypotonic hyponatremia. This may occur in elderly patients 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),[26]  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.[27]  In these cases, hyponatremia is usually due to disorders associated with an increased ADH level:

• Increased release of ADH due to malignancy, occult or symptomatic infection of the central nervous system, or pneumonia resulting from infection with Pneumocystis jirovecii or other organisms.
• Effective volume depletion secondary to fluid loss from the gastrointestinal tract, primarily due to infectious diarrhea. 
• Adrenal insufficiency often due to an adrenalitis, an abnormality that may be infectious in origin, perhaps being induced by cytomegalovirus, Mycobacterium avium-intracellulare, or HIV itself. Affected patients have a high risk of morbidity and mortality

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, and metastatic carcinoma, but especially after neurologic procedures.[28] 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.[29]  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.[30]

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.[31]  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.[32]  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.[33]

Acute hyponatremia is not an uncommon occurrence in ultra-endurance athletes and marathon runners, with women being at higher risk.[34] The strongest single predictor of hyponatremia in these cases is weight gain during the race correlating with excessive fluid intake. Longer race time and 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,[35]  making blanket recommendations difficult. However, fluid intake to the point of weight gain should be avoided.[36]  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.[37]

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.[38]

Symptomatic and potentially fatal hyponatremia can develop with rapid onset after ingestion of the designer drug ecstasy (methylenedioxymethamphetamine, or MDMA), an amphetamine.[39]  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 anti-diuresis (or 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 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 an osmotic diuresis.[40]

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.[41]

Using a retrospective case note analysis, an Irish study examined the incidence of hyponatremia in a variety of neurologic conditions.[42]  The investigators found that the occurrence of hyponatremia was greater in persons with subarachnoid hemorrhage (62 out of 316 patients, or 19.6%; P< 0.001), intracranial neoplasm (56 out of 355 patients, or 15.8%; P< 0.001), traumatic brain injury (44 out of 457 patients, or 9.6%; P< 0.001), and pituitary disorders (5 out of 81 patients, or 6.25%; P = 0.004) than it was in patients with spinal disorders (4 out of 489 patients, or 0.81%). The investigators also determined that the median hospital stay for patients with hyponatremia was 19 days, compared with a median stay of 12 days for the study's other patients.

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.[43, 44]

These tests are as follows

• Serum osmolality
• Urine osmolality
• Urinary sodium concentration

Serum osmolality readily differentiates between true hyponatremia and pseudo-hyponatremia secondary to hyperlipidemia, hyperproteinemia, or hypertonic hyponatremia. Sources of hypertonic hyponatremia include elevations of the following: Glucose, Mannitol, Glycine (after urologic or gynecologic procedures)[45] , Sucrose, Maltose (contained in IgG formulations)

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 intact kidney function). 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 vasopressin (antidiuretic hormone; ADH) levels, which can be physiologic or non-physiologic.

Urinary sodium concentration helps to differentiate between hyponatremia secondary to hypovolemia and the 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.

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) can help evaluate patients suspected of ODS but, if MRI is unavailable, CT of the brain can be done.

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 pseudo-hyponatremia is directed at the underlying disorder in the absence of symptoms.

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

• Degree and severity of clinical symptoms
• Duration and magnitude of the hyponatremia
• Patient's volume status

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.[3]  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.[46]

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.[3, 46]  The treatment of chronic hyponatremia focuses on avoiding overcorrection to reduce the risk of osmotic demyelination syndrome (ODS). Noting the higher risk of ODS for some patients would lower the limit on the daily correction rate.[47]  Addition of desmopressin should be discussed with an expert, particularly if the patients are at high risk of developing ODS (those with a serum sodium concentration ≤105 mmol/L or those with significant hypokalemia, alcoholism, malnutrition, and advanced liver disease), have a lower baseline starting serum sodium concentration, or have undergone overly rapid correction of hyponatremia ( > 6-8 mmol/L at 24 hours or > 18 mmol/L at 48 hours).

Table. Guidelines for Management of Hyponatremia (Open Table in a new window)

 

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: [48]

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.[49]  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.[47]

For patients with the 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.[3]  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 combined treatment of low-dose loop diuretics and oral sodium chloride.[46]  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 the asymptomatic patient, the treatment options below may be of use.

Hypovolemic hyponatremia: For patients with reduced circulating volume, extracellular volume should be restored 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 demopressin may need to be administered (see the table in Approach Considerations for guideline recommendations).[50]

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.[51]  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 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 is limited and exact benefits have yet to be determined. 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.[52, 53, 54]  The first agent to be approved was conivaptan, a V1A and V2 vasopressin receptor antagonist. It is available only for intravenous use and is approved for use in the hospital setting for euvolemic and hypervolemic hyponatremia. It is contraindicated in hypovolemic patients.

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.[55]

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. New 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 pseudo-hyponatremia.

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[3, 46] :

• Mild: serum sodium concentration 130–135 mmol/L 
• Moderate: serum sodium concentration 125–129 mmol/L
• Severe: serum sodium concentration < 125 mmol/L
• Acute: documented as lasting < 48 h
• Chronic: documented as lasting ≥48 h, or duration cannot be classified

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:

• If urine osmolality is ≤100 mOsm/kg, consider this maximally dilute urine with relative excess water intake or low solute intake (such as in polydipsia or beer potomania)
• If urine osmolality is >100 mOsm/kg, consider the presence of ADH (physiologic or non-physiologic)
• Check the urine sodium concentration on a spot urine sample taken simultaneously with a blood sample to help differentiate further
• If urine sodium concentration is < 20 mmol/L, it suggest a low effective arterial volume as a cause
• If urine sodium concentration is >30 mmol/L, assess extracellular fluid status and use of diuretics to further differentiate likely causes of hyponatremia
• Measuring vasopressin for confirming the diagnosis of SIADH is not suggested.

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:

• Avoid further hypertonic 3% saline.
• Start a diagnosis-specific treatment if available, aiming at least to stabilize the sodium concentration.
• Limit the increase in serum sodium concentration, as outlined in the table during the first 24 hours and during every 24 hours thereafter if hyponatremia is not true acute hyponatremia.

Treatment of patients with moderately severe symptoms

• For hyponatremia with moderate symptoms consider hypertonic 3% saline
• Start prompt diagnostic assessment and provide cause-specific treatment.
• Limit the increase in serum sodium concentration to avoid potential harm and risk of ODS in the chronic hyponatremia
• If possible, stop fluids, medications, and other factors that can contribute to or provoke hyponatremia.

Treatment of patients without severe or moderately severe symptoms

• Make sure that the serum sodium concentration has been measured using the same technique used for the previous measurement and that no administrative errors in sample handling have occurred.
• If possible, stop non-essential fluids, medications, and other factors that can contribute to or provoke hyponatremia.
• Start prompt diagnostic assessment.
• Provide cause-specific treatment.
• Monitor clinical picture and serum sodium concentration closely.
• Avoid an increase in serum sodium concentration above the limits outlined in the table in the setting of chronic hyponatremia.

Correcting overcorrection

If hyponatremia is corrected too rapidly, do the following:

• Promptly initiate electrolyte free water, as outlined in the table, to re-lower the serum sodium concentration
• Discontinue the ongoing active treatment. 
• Consult an expert to discuss whether it is appropriate to add IV desmopressin

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),[53, 54] or urea[56] ; less commonly, salt tablets, or demeclocycline are used.

Furosemide (Lasix)

Loop diuretics can increase renal free water excretion. It 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. 

Class Summary

Certain antibiotics may affect renal ADH action.

Demeclocycline (Declomycin)

Demeclocycline (Declomycin) 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, cause nausea, vomiting, and photosensitivity. 

Class Summary

V2 receptor antagonism of AVP in the renal collecting duct results in aquaresis (excretion of free water).[53, 54, 55, 57, 58]

Conivaptan (Vaprisol)

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.

Tolvaptan (Samsca)

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.water). 

Sodium chloride

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 (e.g. heart failure).

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. [50, 59]  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

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

Patients with hyponatremia from any cause require close attention to their electrolyte and fluid status.

Patients with symptomatic hyponatremia who are being actively treated often require several daily measurements of serum sodium to avoid a rate of correction that is too rapid.

After acute treatment, follow-up generally is dictated by the underlying etiology of the hyponatremia.

Clinical manifestations include clouding of consciousness, confusion, stupor, or coma. Seizures commonly occur with rapid reductions in serum sodium or with serum sodium concentrations of less than 115-120 mEq/L.

For unknown reasons, premenopausal women seem to have a less efficient osmotic adaptation. This increases their susceptibility to severe hyponatremia and rapid progression from minimal symptoms (eg, headache, nausea) to respiratory arrest. Cerebral edema and herniation have been found at autopsy.[60]

Correction of hyponatremia that is too rapid may cause permanent neurologic impairment. Central pontine myelinolysis (CPM) and extrapontine myelinolysis (EPM), complications of excessive correction of chronic hyponatremia, are now diagnosed by diffusion-weighted magnetic resonance imaging (MRI). Of note is that conventional computed tomography and MRI scan findings typically lag behind the clinical manifestations of myelinosis by 2-4 weeks.[61]

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. CPM is a common and often fatal complication of orthotopic liver transplantation, affecting up to 10% of patients who are hyponatremic prior to transplant.[62]

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.[63]

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.[64]

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.[65]

 

 

For patient education information, see Hyponatremia (Low Sodium). Patients to be treated with a 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.