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Overview of the treatment of hyponatremia
Last literature review version 18.3: September 2010 | This topic last updated: June 10, 2010 (More)

INTRODUCTION — Hyponatremia represents a relative excess of water in relation to sodium. It can be induced by a marked increase in water intake (primary polydipsia) or, in the great majority of cases, by impaired water excretion resulting from advanced renal failure or from persistent release of antidiuretic hormone (ADH) induced by effective volume depletion, the syndrome of inappropriate ADH secretion (SIADH), thiazide diuretics, adrenal insufficiency, or hypothyroidism. (See "Causes of hyponatremia".)

Most patients with hyponatremia have chronic (ie, gradual onset) hyponatremia, a serum sodium concentration above 120 meq/L, and appear asymptomatic, although subtle neurologic abnormalities may be present when the serum sodium is between 120 and 130 meq/L. (See 'Necessity for therapy' below.)

Initial treatment in such patients typically consists of slow correction of the hyponatremia via fluid restriction or, if volume depletion is present, the administration of isotonic saline (or oral salt tablets) [1-3]. Vasopressin receptor antagonists also may be helpful. Among patients with SIADH, isotonic saline may worsen the hyponatremia. (See 'SIADH' below.)

More aggressive therapy is indicated in patients who have symptomatic or severe hyponatremia (serum sodium concentration below 110 to 115 meq/L). In this setting, initial therapy usually consists of hypertonic saline with or without vasopressin receptor antagonists.

When considering the treatment of patients with hyponatremia, the following issues will be reviewed here:

  • The optimal method of raising the serum sodium concentration, which varies with the cause of hyponatremia
  • Estimation of the sodium deficit if sodium is to be given
  • The optimal rate of correction

The rate of correction is important because overly rapid correction of severe hyponatremia can lead to a severe and usually irreversible neurologic disorder called osmotic demyelination. One group that is probably not at risk for this complication is patients with hyperacute hyponatremia that develops over a few hours due to a marked increase in water intake as may be seen in marathon runners, psychotic patients, and users of ecstasy. Issues related to osmotic demyelination are discussed separately. (See "Osmotic demyelination syndrome and overly rapid correction of hyponatremia".)

METHODS OF RAISING THE SERUM SODIUM — The serum sodium concentration can be raised in hyponatremic patients by one or more of the following approaches [1-5]:

  • Treat the underlying disease, if possible.
  • Fluid restriction.
  • Oral or intravenous sodium chloride in patients with true volume depletion. Sodium chloride administration is also effective in patients the syndrome of inappropriate antidiuretic hormone secretion (SIADH) using either oral salt tablets or hypertonic saline. In contrast, isotonic saline is often not effective and may worsen the hyponatremia in SIADH. (See 'SIADH' below.)
  • Administration of a vasopressin receptor antagonist.

These approaches will be discussed in detail in the following sections. In addition, initial therapy with hypertonic saline is warranted in patients with neurologic symptoms attributable to hyponatremia, particularly if severe. (See 'Choice of therapy' below.)

Treat the underlying disease — In addition to the specific therapies described below that are aimed at correcting the hyponatremia, therapy should also be directed at the underlying disease. (See "Causes of hyponatremia".)

There are several circumstances in which the underlying disease can be corrected quickly, possibly leading to overly rapid correction of the hyponatremia (see 'Avoid overly rapid correction' below):

  • The administration of saline to patients with true volume depletion. In this setting, restoration of euvolemia will suppress the release of ADH (which has a half-life of only 15 to 20 minutes), thereby allowing rapid excretion of the excess water. (See 'True volume depletion' below.)
  • The administration of glucocorticoids to patients with adrenal insufficiency, which will directly suppress the release of ADH. (See "Hyponatremia and hyperkalemia in adrenal insufficiency".)
  • Relatively rapid reversal of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). This can occur with self-limited disease (eg, nausea, pain, surgery) and with cessation of therapy with certain drugs that cause SIADH such as desmopressin and selective serotonin reuptake inhibitors (eg, fluoxetine, sertraline).

There are a number of other causes of hyponatremia that can be corrected in which the serum sodium rises more slowly. This is most often seen with thyroid hormone replacement in patients with hypothyroidism and by gradually reversing the cause of SIADH by, for example, the treatment of tuberculosis or meningitis or the cessation of long-acting drugs. (See "Hyponatremia in hypothyroidism" and "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)", section on 'Etiology'.)

Fluid restriction — Fluid restriction to below the level of urine output is the primary therapy for hyponatremia in edematous states (such as heart failure and cirrhosis), the syndrome of inappropriate antidiuretic hormone secretion (SIADH), primary polydipsia, and advanced renal failure. Hyponatremia develops gradually in these settings and is not usually associated with overt symptoms. Restriction to 50 to 60 percent of daily fluid requirements may be required to achieve the goal of inducing negative water balance [4,6]. In general, fluid intake should be less than 800 mL/day. (See "Hyponatremia in patients with heart failure" and "Hyponatremia in patients with cirrhosis" and "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat".)

Sodium chloride administration — Sodium chloride, usually as isotonic saline or increased dietary salt, is given to patients with true volume depletion and/or adrenal insufficiency, and to some patients with SIADH. Salt therapy is generally contraindicated in edematous patients (eg, heart failure, cirrhosis, renal failure) since it will lead to exacerbation of the edema.

Administration of hypertonic saline is primarily limited to patients with symptomatic or severe hyponatremia or, occasionally, to patients with SIADH and a highly concentrated urine. (See 'Severe symptoms' below and 'SIADH' below.)

The degree to which isotonic saline will raise the serum sodium concentration in hyponatremic patients varies with the cause of the hyponatremia. As illustrated by the following discussion, the response to isotonic saline differs in volume depletion and SIADH.

True volume depletion — In states of true volume depletion, the administered sodium and water will initially be retained. In this setting, isotonic saline corrects the hyponatremia by two mechanisms:

  • It slowly raises the serum sodium by approximately 1 meq/L for every liter of fluid infused, since isotonic saline has a higher sodium concentration (154 meq/L) than the hyponatremic plasma.
  • By eventually causing volume repletion, it removes the stimulus to ADH release, thereby allowing the excess water to be excreted in a dilute urine. At this time, the serum sodium concentration may return rapidly toward normal; in selected patients, overly rapid correction of hyponatremia can lead to a severe neurologic disorder called osmotic demyelination [7,8]. The management of such patients is discussed separately. (See "Osmotic demyelination syndrome and overly rapid correction of hyponatremia", section on 'Prevention and treatment of overly rapid correction'.)

The degree to which one liter of a given solution will initially raise the serum sodium concentration (SNa) can be estimated from the following formula [4]:

  Increase in SNa = (Infusate [Na] - SNa) ÷ (TBW + 1)

where TBW is the estimated total body water (lean body weight times 0.5 for women, 0.6 for men).

Thus, the administration of one liter of isotonic saline (containing 154 meq/L of sodium) in a 60 kg women with a serum sodium of 110 meq/L and an estimated TBW of 30 L (50 percent of lean body weight) should raise the serum sodium by approximately 1.4 meq/L to 111.4 meq/L:

  Increase in SNa = (154 - 110) ÷ 31 = 1.4 meq/L

There are two limitations to use of this formula in patients with true volume depletion: it does not provide information on shifts in body water, and it does not take into account the increase in water excretion that will occur when euvolemia is restored and ADH release is suppressed. In addition, any potassium added to the infused solution must be considered as sodium. The formula cannot be used to predict the increase in serum sodium in patients with SIADH, since the administered sodium will be excreted in the urine and some of the water retained, possibly worsening the hyponatremia. (See 'Effect of potassium' below and 'SIADH' below.)

A more complete understanding of the effect on serum sodium and total body water is provided by the following approach. Since the osmolality in the cells (where potassium is the primary solute) is the same as that in the extracellular fluid, the effect of the serum sodium concentration (SNa) is distributed through the total body water (TBW). The term effective cation in the following equations refers to cations that are osmotically active, not, for example, sodium or potassium bound in bone.

Thus, in this 60 kg woman with a serum sodium of 110 meq/L:

  Total body effective cation = TBW x SNa = 30 x 110 = 3300 meq

Assuming that the extracellular fluid (ECF) is 33 percent (10 L) and the intracellular fluid is 67 percent (20 L) of the total body water [9]:

  Extracellular effective cation = 10 x 110 = 1100 meq

The administration and retention of 1000 mL of isotonic saline containing 154 meq of sodium will raise the TBW to 31 L, the total body effective cation to 3454 meq, and, since all of the sodium chloride will stay in the ECF, the extracellular effective cation to 1254 meq. Thus:

  New SNa = total effective solute ÷ TBW

      =  3454  ÷  31  =  111.4 meq/L

  New ECF volume = total ECF solute ÷ SNa

      =  1254  ÷  111.4  =  11.3 L

The ECF volume has increased by 1.3 L, which is more than the 1.0 L given because the rise in the serum sodium concentration pulls water out of the cells.

These calculations illustrate the relatively limited direct effect of isotonic saline to correct hyponatremia. In the hypovolemic patient; the much more important effect is restoration of euvolemia with subsequent suppression of ADH release.

SIADH — The response to isotonic saline is different in SIADH. Whereas both the sodium and water are retained in hypovolemia, sodium balance is normal in SIADH since it is regulated by aldosterone and atrial natriuretic peptide not ADH. Thus, the administered sodium will be excreted in the urine, while some of the water may be retained, leading to possible worsening of the hyponatremia.

A few simple calculations can illustrate this point. Suppose a patient with SIADH and hyponatremia has a urine osmolality that is relatively fixed at 600 mosmol/kg. If 1000 mL of isotonic saline is given (containing 150 meq each of Na and Cl or 300 mosmol), all of the NaCl will be excreted (because sodium handling is intact) but in only 500 mL of water (300 mosmol in 500 mL of water equals 600 mosmol/kg). The retention of one-half of the administered water will lead to a further reduction in the serum sodium concentration even though the serum sodium concentration may initially rise because the isotonic saline is hypertonic to the patient.

Using the calculations in the preceding section on true volume depletion in a woman with a baseline serum sodium (SNa) of 110 meq/L:

  New SNa = total effective solute ÷ total body water (TBW)

      =  3300 meq (same as baseline)  ÷  30.5 L (500 mL increase)
      =  108 meq/L

Support for possible harm from isotonic saline was provided in a report of 22 women who underwent uncomplicated gynecologic surgery and had been treated with only isotonic saline or near-isotonic Ringer's lactate [10]. At 24 hours after induction of anesthesia, the serum sodium fell a mean of 4.2 meq/L.

In contrast, hypertonic saline contains 1026 mosmol per liter (513 mosmol each of sodium and chloride). If 1000 mL of this solution is given, all of the NaCl will again be excreted but now in a larger volume of 1700 mL. Thus, after the administration of hypertonic saline, there will be an initial large rise in the serum sodium concentration followed by reduction toward baseline after the administered sodium has been excreted. At this time, the rise in the serum sodium is entirely due to the net loss of 700 mL of water:

  New SNa = total effective solute ÷ TBW

      =  3300 (same as baseline)  ÷  29.3  =  112.6 meq/L

Treatment of SIADH begins with fluid restriction. If fluid must be given or the serum sodium concentration must be raised quickly because of symptomatic hyponatremia, the effective osmolality (two times the sodium plus potassium concentration) of the fluid given must exceed the osmolality of the urine. Since the urine osmolality is usually above 300 mosmol/kg in SIADH, isotonic saline has a limited role in correction of the hyponatremia and hypertonic saline must be given. Whenever this is done, careful monitoring of the serum sodium is essential to prevent overly rapid correction. (See 'Rate of correction' below.)

Concurrent use of a loop diuretic may be beneficial in patients with SIADH since, by inhibiting sodium chloride reabsorption in the thick ascending limb of the loop of Henle, it interferes with the countercurrent mechanism and induces a state of ADH resistance and a more dilute urine is excreted.

Chronic therapy of SIADH is discussed separately. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat".)

Effect of potassium — Potassium is as osmotically active as sodium. As a result, giving potassium (usually for concurrent hypokalemia) can raise the serum sodium concentration and osmolality in hyponatremic patients [7,8,11,12]. Since most of the excess potassium enters the cells, electroneutrality is maintained in one of three ways, each of which will raise the serum sodium concentration:

  • Intracellular sodium moves into the extracellular fluid.
  • Extracellular chloride moves into the cells with potassium; the increase in cell osmolality promotes free water entry into the cells.
  • Intracellular hydrogen moves into the extracellular fluid. These hydrogen ions are buffered by extracellular bicarbonate and to a much lesser degree plasma proteins. This buffering renders the hydrogen ions osmotically inactive; the ensuing fall in extracellular osmolality leads to water movement into the cells.

The net effect is that concurrent administration of potassium must be taken into account when estimating the sodium deficit. This relationship becomes clinically important in the patient with severe diuretic or vomiting-induced hyponatremia who is also hypokalemic.

Suppose, for example, that the serum potassium concentration is 2 meq/L and it is decided to give 400 meq of potassium during the first day. If the patient is a 70 kg man, the total body water will be approximately 40 liters (60 percent of body weight). In this setting, 800 milliosmoles of osmotically active potassium chloride (400 milliosmoles of each) distributed through 40 liters will raise the serum osmolality by 20 mosmol/kg and the serum sodium concentration by roughly 10 meq/L, which is at the limit for safe correction. Thus, giving potassium chloride alone will correct both the hyponatremia and the hypokalemia [8]. Giving additional sodium may lead to an overly rapid elevation in the serum sodium concentration. (See 'Rate of correction' below.)

Thus, when calculating the impact of a particular regimen on the serum sodium concentration, one must use two times the sodium plus potassium concentration of the solution, not simply two times the sodium concentration. Similar considerations apply to calculating the impact of fluid losses induced by vomiting, diarrhea, or diuretic therapy.

Vasopressin receptor antagonists — An alternative or possible addition to fluid restriction or sodium chloride administration in patients with hyponatremia is the use of an ADH receptor antagonist. There are multiple receptors for vasopressin (ADH): the V1a, V1b, and V2 receptors. The V2 receptors primarily mediate the antidiuretic response, while V1a and V1b receptors principally cause vasoconstriction and mediate adrenocorticotropin release, respectively [3,5].

The vasopressin receptor antagonists produce a selective water diuresis without affecting sodium and potassium excretion. The ensuing loss of free water will tend to correct the hyponatremia. However, thirst increases significantly with these agents, which may limit the rise in serum sodium [5,13].

Some oral formulations — tolvaptan, satavaptan, and lixivaptan — are selective for the V2 receptor, while an intravenous agent, conivaptan, blocks both the V2 and V1a receptors. Only tolvaptan and conivaptan are currently available in the United States. Both drugs are approved for the management of patients with euvolemic hyponatremia, mostly due to the syndrome of inappropriate ADH secretion (SIADH).

Tolvaptan is also approved for use in patients with heart failure or cirrhosis. With respect to conivaptan, there are concerns that the concurrent V1a receptor blockade might lower the blood pressure and increase the risk of variceal bleeding, since vasopressin is used to treat active bleeding in such patients (a V1a effect). There is also a concern that V1a receptor blockade might worsen renal function since terlipressin, a V1a receptor agonist, has been used to treat hepatorenal syndrome.

The studies that have evaluated the use of vasopressin receptor antagonists in the different settings in which hyponatremia occurs are presented elsewhere:

An example of the potential efficacy of these drugs was provided in a combined report of oral tolvaptan in two randomized, double-blind, placebo-controlled multicenter trials (SALT-1 and SALT-2) in 448 patients with hyponatremia (mean serum sodium 129 meq/L) caused by SIADH, heart failure, or cirrhosis [13]. Compared with placebo, tolvaptan significantly increased the serum sodium concentration at day 4 (134 to 135 meq/L versus 130 meq/L) and day 30 (136 versus 131 meq/L). Among patients with a serum sodium below 130 meq/L at baseline, tolvaptan was also associated with a statistically significant improvement in mental status scores. However, the difference was usually not clinically significant and long-term efficacy is uncertain since the duration of follow-up was only 30 days.

In an open-label extension (called SALTWATER), 111 patients were treated with tolvaptan for a mean follow-up of almost two years [14]. The mean serum sodium was maintained at more than 135 meq/L compared to 131 meq/L at baseline. The responses were similar in SIADH and heart failure, and more modest in cirrhosis. The main adverse effects were abnormally frequent urination, thirst, dry mouth, fatigue, polyuria, and polydipsia. Adverse effects that were possibly or probably related to tolvaptan led to discontinuation of therapy in six patients (5.4 percent).

Vasopressin receptor antagonists should not be used in hyponatremic patients who are volume depleted in whom volume repletion with saline is the primary therapy. (See 'True volume depletion' above.)

Limitations — There are two major potential adverse effects associated with oral V2 receptor antagonists:

  • Increased thirst, which may limit the rise in serum sodium [13].
  • Overly rapid correction of the hyponatremia, which can lead to irreversible neurologic injury. In the SALT trials, 1.8 percent of patients exceeded the study goal of limiting daily correction to 12 meq/L [13]. However, more recent recommendations have suggested a maximum rate of correction of hyponatremia of less than 10 meq/L, not ≤12 meq/L, in the first 24 hours. Thus, it is almost certain that more than 1.8 percent of treated patients exceeded the currently recommended rate of correction. Because of this risk, hospitalization is required for the initiation or reinitiation of therapy. (See 'Avoid overly rapid correction' below.)

Another limiting factor is the prohibitive cost of tolvaptan, which is as high as $300 per tablet in some areas.

ESTIMATION OF THE SODIUM DEFICIT — Patients with true volume depletion and some with SIADH require saline administration to raise the serum sodium. Isotonic saline is typically sufficient in true volume depletion but ineffective in SIADH where, if saline is given, a hypertonic solution is typically required. The mechanisms responsible for these conclusions are described above. (See 'Sodium chloride administration' above.)

Formulas are available to estimate both the sodium deficit and the direct effect of a given fluid (eg, hypertonic saline) on the serum concentration (the Adrogue-Madias formula) [4]:

  • Sodium deficit = TBW x (desired serum Na - actual serum Na)

Although sodium itself is restricted to the extracellular fluid, changes in the serum sodium concentration reflect changes in osmolality and are distributed through the total body water. TBW is estimated as lean body weight times 0.5 for women and 0.6 for men.

  • Change in serum Na = (Infusate minus serum Na) / (TBW + 1)

However, these formulas have a number of limitations and often do not accurately predict the magnitude of change in serum sodium [15]. These limitations are discussed in detail elsewhere. (See "Estimation of the sodium deficit in patients with hyponatremia".)

The main use of the sodium deficit formula is to estimate the initial rate of sodium administration. Serial measurements of the serum sodium concentration are required to assess the impact of therapy, beginning at two to three hours and then every three to four hours while active treatment is being given.

Use of the sodium deficit formula to determine initial therapy can be illustrated by the following example. A nonedematous, mildly symptomatic woman who weighs 60 kg (approximately 50 percent of which is water) has a serum sodium concentration of 116 meq/L. The goal is to raise the serum sodium concentration by 8 meq/L in the first 24 hours. (See 'Rate of correction' below.)

The sodium deficit (in meq) for initial therapy can be estimated from the above formula:

  Sodium deficit  =   TBW (0.5  x  60 L)  x  desired change in serum sodium (124 - 116)  =   240 meq

The 240 meq of sodium can be given as 480 mL of hypertonic (3 percent) saline, which contains approximately 500 meq of sodium per liter, or 1 meq of sodium per 2 mL. This volume of hypertonic saline can be given at an initial rate of 20 mL/h, which would be expected to raise the serum sodium concentration at close to the desired rate of 8 meq/L during the first 24 hours which, as noted above, should be confirmed by serial measurements of the serum sodium.

RATE OF CORRECTION

General issues — There are several general issues that must be addressed before discussing specific therapies:

  • Is the hyponatremia acute or chronic?
  • Is the patient symptomatic or asymptomatic?
  • What is the optimal rate of correction?

Acute versus chronic hyponatremia — Patients with acute hyponatremia are more likely to develop neurologic symptoms resulting from cerebral edema induced by water movement into the brain. However, the brain has a protective response that reduces the degree of cerebral edema; this response begins on the first day and is complete within several days. The net effect of this adaptation is that the clinical manifestations of hyponatremia are reduced, with the potential disadvantage of increasing the susceptibility to osmotic demyelination with overly rapid correction of the hyponatremia [16,17]. (See 'Symptomatic versus asymptomatic hyponatremia' below and "Manifestations of hyponatremia and hypernatremia", section on 'Osmolytes and cerebral adaptation to hyponatremia'.)

Some have suggested that hyponatremia developing over two or more days should be considered "chronic." In practice, however, the duration of hyponatremia is often unknown, and patients with chronic hyponatremia may develop acute reductions in the serum sodium concentration. Thus, while the terms "acute" and "chronic" may be helpful conceptually, the clinical approach to the patient should be primarily determined by the severity of symptoms and the cause of the hyponatremia.

Symptomatic versus asymptomatic hyponatremia — Symptoms are most likely to occur with an acute (within 24 to 48 hours) and marked reduction in the serum sodium concentration. Without time for the brain adaptation noted in the previous section, affected patients can develop severe neurologic manifestations, including seizures, impaired mental status or coma, and death (figure 1). These patients are typically treated initially with hypertonic saline. (See 'Severe symptoms' below.)

Because of the brain adaptation that occurs over a few days, some patients with a serum sodium concentration below 120 meq/L have less severe neurologic symptoms (eg, fatigue, nausea, dizziness, gait disturbances, forgetfulness, confusion, lethargy, and muscle cramps) [18-21]. These findings are not usually associated with impending herniation (as with acute severe hyponatremia) and do not mandate the urgent therapy recommended for patients with severe symptoms. (See "Manifestations of hyponatremia and hypernatremia" and 'Mild to moderate symptoms' below.)

In contrast to symptomatic patients, patients with chronic moderate hyponatremia (serum sodium concentration 120 to 130 meq/L) have generally been considered to be at low risk for neurologic symptoms because of the less marked reduction in serum sodium concentration and the protective cerebral adaptation. However, some "asymptomatic" patients with moderate hyponatremia have subtle neurologic symptoms that may improve following elevation of the serum sodium concentration. (See 'Asymptomatic hyponatremia' below.)

Avoid overly rapid correction — Overly rapid correction of severe hyponatremia (serum sodium concentration usually less than 110 to 115 meq/L) can lead to a severe and usually irreversible neurologic disorder called the osmotic demyelination syndrome (also called central pontine myelinolysis, although demyelination may be more diffuse and does not necessarily involve the pons). Premenopausal women appear to be at greatest risk (figure 1) [22]. (See "Osmotic demyelination syndrome and overly rapid correction of hyponatremia" and "Manifestations of hyponatremia and hypernatremia", section on 'Susceptibility of premenopausal women'.)

One group that is probably not at risk for this complication is patients with hyperacute hyponatremia that developed over a few hours due to a marked increase in water intake (as can occur in marathon runners, psychotic patients, and users of ecstasy). These patients have not had time for the brain adaptations that reduce the severity of brain swelling but also increase the risk of harm from rapid correction of the hyponatremia. (See 'Acute versus chronic hyponatremia' above.)

Overly rapid correction of severe and more chronic hyponatremia can result from the too rapid or excessive administration of hypertonic saline or rapid correction of the underlying disease, such as the administration of saline to patients with true volume depletion and glucocorticoid therapy in adrenal insufficiency. (See 'Treat the underlying disease' above.)

Osmotic demyelination typically occurs in patients in whom the serum sodium concentration increases more than 10 to 12 meq/L in the first 24 hours or more than 18 meq/L in the first 48 hours. However, some patients with severe hyponatremia develop neurologic symptoms from osmotic demyelination when the serum sodium is increased by 10 to 12 meq/L in the first day [19,23].

Thus, the goals of therapy are to raise the serum sodium concentration by less than 10 meq/L in the first 24 hours and less than 18 meq/L in the first 48 hours [1,3,20,24]. Studies in experimental animals suggest that the rate of correction over the first 24 hours is more important than the maximum rate in any given hour or several hour period [21,25].

Issues related to the osmotic demyelination syndrome, including prevention and treatment with possible relowering of the serum sodium in patients who correct too rapidly, are discussed in detail elsewhere. (See "Osmotic demyelination syndrome and overly rapid correction of hyponatremia", section on 'Prevention and treatment of overly rapid correction'.)

CHOICE OF THERAPY

General principles — As described above, there are a variety of modalities used in the treatment of hyponatremia. The choice among them varies with the severity and underlying cause of the hyponatremia. (See 'Methods of raising the serum sodium' above.)

With true volume depletion, the administration of saline can correct the hypovolemia, thereby removing the stimulus to the release of antidiuretic hormone (ADH) and allowing the excess water to be excreted in the urine. Correction of the underlying disorder can also be achieved with certain causes of SIADH (eg, glucocorticoids for adrenal insufficiency or the cessation of offending drugs). (See 'Treat the underlying disease' above.)

The following discussion will provide an overview of the approach to therapy according to the presence or absence of symptoms that are attributable to the hyponatremia. The treatment of hyponatremia due to specific causes is discussed in detail separately:

Severe symptoms — Hypertonic saline is warranted in patients with severe and often acute hyponatremia (serum sodium usually below 120 meq/L) who present with seizures or other severe neurologic abnormalities or with symptomatic hyponatremia in patients with intracerebral diseases that have been associated with brain herniation [19,20,22,23,26,27].

Severe symptoms of hyponatremia are most likely to occur in the following settings:

The primary problem in such patients who have seizures or other severe neurologic abnormalities is cerebral edema, and the risk of delayed therapy (eg, brain herniation) is greater than the potential risk of overly rapid correction.

Based upon broad clinical experience, the administration of hypertonic saline is the only rapid way to raise the serum sodium concentration and improve neurologic manifestations in patients with severe symptomatic hyponatremia [28]. Hypertonic saline may also be given to selected symptomatic patients who develop hyponatremia and hypoosmolality during transurethral resection of the prostate or bladder or hysteroscopy. In this setting, the serum osmolality is not reduced to the same degree as the serum sodium due to the accumulation of glycine, sorbitol, or mannitol irrigation fluids. (See "Hyponatremia following transurethral resection or hysteroscopy", section on 'Role of hypertonic saline'.)

One hypertonic saline regimen that we have used was initially described in hyponatremic athletes participating in endurance events such as marathon races. It consists of 100 mL of 3 percent saline given as an intravenous bolus, which should acutely raise the serum sodium concentration by 2 to 3 meq/L, thereby reducing the degree of cerebral edema; if neurologic symptoms persist or worsen, a 100 mL bolus of 3 percent saline can be repeated one or two more times at 10 minute intervals [1,29,30]. The rationale for this approach is that, in patients with symptomatic hyponatremia, rapid increases in serum sodium of approximately 4 to 6 meq/L can reverse severe symptoms such as seizures [1,4,31-33]. (See "Exercise-associated hyponatremia", section on 'Use of hypertonic saline'.)

The usual goals for the overall rate of correction are to raise the serum sodium less than 10 meq/L in the first 24 hours and less than 18 meq/L in the first 48 hours. Faster rates of correction may lead to osmotic demyelination, with premenopausal women being at greatest risk (figure 1). (See 'Acute versus chronic hyponatremia' above.)

The treatment of symptomatic hyponatremia due to SIADH is complicated by the fact that, in patients with a highly concentrated urine (eg, greater than 500 to 600 mosmol/kg), the initial elevation in serum sodium induced by hypertonic saline will fall back toward baseline as the administered sodium is excreted in the urine. Why this occurs and recommendations for further therapy are discussed elsewhere. (See 'SIADH' above and "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Intravenous saline'.)

Hyponatremia developing in marathon runners, ecstasy users, or patients with primary polydipsia is associated with marked increases in fluid intake and, with exercise and ecstasy use, frequent failure to completely suppress ADH release. The net effect is acute hyponatremia that can develop over a period of several hours.

Avoidance of overly rapid correction (≥10 meq/L in the first 24 hours) is often difficult in patients with primary polydipsia. These patients tend to autocorrect since ADH is physiologically suppressed, permitting rapid excretion of large volumes of free water. Autocorrection can also occur in patients with exercise-associated hyponatremia or ecstasy use. Fortunately, the acute onset of hyponatremia in these disorders is associated with a low risk of osmotic demyelination due to overly rapid correction. (See 'Avoid overly rapid correction' above.)

Mild to moderate symptoms — Less severe neurologic symptoms that are attributable to hyponatremia (eg, dizziness, gait disturbances, forgetfulness, confusion, and lethargy) can be seen in patients with a serum sodium concentration below 120 meq/L that develops over more than 48 hours, in patients with a lesser degree of hyponatremia that develops over less than 48 hours, and in patients with chronic moderate hyponatremia (serum sodium 120 to 129 meq/L).

The following discussion primarily applies to hyponatremia in patients with SIADH or volume depletion. Although mild to moderate symptoms due to hyponatremia can also occur in patients with heart failure or cirrhosis, serum sodium concentrations below 130 meq/L are typically associated with close to end-stage disease. (See "Hyponatremia in patients with heart failure" and "Hyponatremia in patients with cirrhosis".)

Moderate symptoms — For the purposes of this discussion, moderate symptoms are defined as confusion and/or lethargy. Some of these patients, particularly those with SIADH, may benefit from hypertonic saline, but do not require the aggressive approach suggested in the preceding section for those with severe neurologic symptoms. (See 'Severe symptoms' above.)

In patients with SIADH and moderate symptoms, initial hypertonic saline therapy to raise the serum sodium at rates up to 1 meq/L per hour may be justified in the first three to four hours. This can generally be achieved by administering hypertonic (3 percent) saline at a rate of 1 mL/kg lean body weight per hour. Such calculations are only estimates and the serum sodium should be measured at two to three hours. The total elevation in serum sodium in the first 24 hours should be less than 10 meq/L. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Mild to moderate symptoms'.)

The choice of initial therapy in patients with moderate symptoms of hyponatremia who are volume depleted is more difficult. Isotonic saline will not rapidly raise the serum sodium until near euvolemia is attained and ADH secretion is suppressed. Hypertonic saline will raise the serum sodium immediately but, in some patients (particularly the elderly), the neurologic manifestations may not be clearly attributable to the hyponatremia. The optimal therapy in such patients must be made on an individual basis. Isotonic saline should be used in the vast majority of patients.

Although hyponatremia is initially corrected slowly with isotonic saline in hypovolemic patients, ADH release will be appropriately suppressed once near euvolemia is restored. This will lead to a marked water diuresis and patients with an initial serum sodium below 120 meq/L might be at risk for overly rapid correction and possible osmotic demyelination. In such patients, desmopressin with or without dextrose in water may be considered to either prevent or treat overly rapidly correction. (See "Osmotic demyelination syndrome and overly rapid correction of hyponatremia", section on 'Prevention and treatment of overly rapid correction'.)

Mild symptoms — Patients with SIADH or hypovolemia who have only mild symptoms (eg, dizziness, forgetfulness, gait disturbance) should be treated with less aggressive therapy, such as fluid restriction and oral salt tablets in SIADH or, with hypovolemia, isotonic saline and treatment of the cause of fluid loss.

Asymptomatic hyponatremia — Patients who have asymptomatic hyponatremia should be corrected slowly, since rapid correction is not necessary and may be harmful. (See 'Avoid overly rapid correction' above.)

Treatment varies with the underlying disease. Among patients with SIADH, isotonic saline may, via a mechanism described above, lower the serum sodium when the urine osmolality is well above 300 mosmol/kg. Thus, if fluid restriction is not sufficient, subsequent therapy includes salt tablets and, if necessary, a loop diuretic if the urine osmolality is more than twice that of the plasma. (See 'SIADH' above and "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Intravenous saline'.)

Among patients who are hypovolemic, either intravenous isotonic saline or oral salt tablets may be effective in combination with treatment of the cause of hypovolemia.

The treatment of asymptomatic hyponatremia in patients with heart failure and cirrhosis is discussed separately. (See "Hyponatremia in patients with heart failure" and "Hyponatremia in patients with cirrhosis".)

Necessity for therapy — Patients with chronic moderate hyponatremia (serum sodium 120 to 129 meq/L) are typically asymptomatic on routine history. Such patients have often been treated only with fluid restriction if the underlying disease (SIADH, heart failure, cirrhosis) cannot be corrected.

However, some of these patients have subtle neurologic symptoms that can be improved by raising the serum sodium concentration. As an example, the SALT trials described above evaluated the effect of the vasopressin receptor antagonist tolvaptan compared to placebo in patients with chronic hyponatremia due to SIADH, heart failure, or cirrhosis [13]. None of the patients had clinically apparent neurologic symptoms from hyponatremia and almost all had a serum sodium concentration of 120 meq/L or higher.

Raising the serum sodium with tolvaptan resulted in statistically significant improvement on the Mental Component of the Medical Outcomes Study Short-Form General Health Survey at one month, a benefit that was significant only in patients with a serum sodium concentration between 120 and 129 meq/L and was not seen in the placebo group. However, the benefit was usually not clinically significant and long-term efficacy is uncertain since the duration of follow-up was only 30 days. (See 'Vasopressin receptor antagonists' above.)

In addition to subtle impairments in mentation, an increased incidence of falls due to impairments in gait and attention have been described in elderly patients with a serum sodium between 120 and 129 meq/L; these manifestations may be improved by raising the serum sodium [34]. (See "Manifestations of hyponatremia and hypernatremia", section on 'Manifestations in apparently asymptomatic patients'.)

These observations suggest that some and perhaps many apparently asymptomatic patients with moderate chronic hyponatremia (serum sodium 120 to 129 meq/L) have subtle neurologic manifestations and that aiming for a goal serum sodium of 130 meq/L or higher might be beneficial. Such an approach would apply only to patients with SIADH. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Asymptomatic hyponatremia'.)

Little benefit would be provided in patients with hyponatremia due to heart failure or cirrhosis in whom a serum sodium concentration persistently below 130 meq/L is a marker of end-stage disease and a poor prognosis unless transplantation or some equivalent intervention is performed. (See "Hyponatremia in patients with heart failure" and "Hyponatremia in patients with cirrhosis".)

SUMMARY AND RECOMMENDATIONS

  • Hyponatremia represents a relative excess of water in relation to sodium. It can be induced by an increase in water intake (primary polydipsia) or impaired water excretion. Impaired water excretion results from advanced renal failure or persistent release of antidiuretic hormone (ADH). ADH may be induced by effective volume depletion, the syndrome of inappropriate ADH secretion (SIADH), thiazide diuretics, adrenal insufficiency, or hypothyroidism. (See 'Introduction' above.)
  • The serum sodium concentration can be raised in hyponatremic patients by treating the underlying disease, restricting water intake, giving oral or intravenous sodium chloride, or by giving a vasopressin receptor antagonist. The choice of therapy is governed by the cause and severity of the hyponatremia and the presence or absence of neurologic symptoms. (See 'Methods of raising the serum sodium' above.)
  • Fluid restriction to below the level of urine output is the primary therapy for hyponatremia in edematous states (such as heart failure and cirrhosis), the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and advanced renal failure. In general, fluid intake should be less than 800 mL/day. (See 'Fluid restriction' above.)
  • Sodium chloride, usually as isotonic saline or oral salt tablets, is given to patients with true volume depletion. The administered sodium and water initially corrects the hyponatremia (by approximately 1 meq/L for every liter of isotonic saline infused) and then, once volume repletion is attained, by removing the stimulus to ADH release and allowing the excess water to be excreted. Salt therapy is generally contraindicated in edematous patients. (See 'Sodium chloride administration' above.)
  • Administration of hypertonic saline is limited to patients with symptomatic or severe hyponatremia. The rate of correction of hyponatremia is important, since overly rapid correction of severe hyponatremia can lead to the osmotic demyelination syndrome. To help prevent osmotic demyelination, we recommend that among all patients with hyponatremia, the goal increase in serum sodium concentration is by less than 10 meq/L in the first 24 hours and less than 18 meq/L in the first 48 hours (Grade 1B). Serial measurements of the serum sodium concentration are required to assess the impact of therapy, beginning at two to three hours and then every three to four hours while active treatment is being given. (See 'Avoid overly rapid correction' above.)

The choice of initial therapy in patients with hyponatremia varies with the severity and cause of hyponatremia and the presence or absence of symptoms:

  • Among patients with severe symptomatic hyponatremia who present with seizures or other severe neurologic abnormalities or with symptomatic hyponatremia in patients with intracerebral diseases, we recommend urgent intervention with hypertonic saline rather than other therapies (Grade 1A). An effective regimen is 100 mL of 3 percent saline given as an intravenous bolus, which should raise the serum sodium concentration by approximately 1.5 meq/L in men and 2.0 meq/L in women, thereby reducing the degree of cerebral edema. If neurologic symptoms persist or worsen, a 100 mL bolus of 3 percent saline can be repeated one or two more times at ten minute intervals. (See 'Severe symptoms' above.)
  • Less severe neurologic symptoms that are attributable to hyponatremia (eg, dizziness, gait disturbances, forgetfulness, confusion, and lethargy) can be seen in patients with a serum sodium concentration below 120 meq/L that develops over more than 48 hours, in patients with a lesser degree of hyponatremia that develops over less than 48 hours, and in patients with chronic moderate hyponatremia (serum sodium 120 to 129 meq/L). The approach varies with the severity of symptoms and the underlying cause of the hyponatremia:
  • Among patients with SIADH who have moderate symptoms such as confusion and lethargy, we recommend the initial administration of hypertonic saline therapy to raise the serum sodium (Grade 1B). The goal is to raise the serum sodium 1 meq/L per hour for three to four hours. The serum sodium should be measured at two to three hours and subsequent infusion rate should be adjusted to achieve a rate of correction of less than 10 meq/L at 24 hours and less than 18 meq/L at 48 hours. (See 'Moderate symptoms' above.)
  • Among patients with moderate symptoms of hyponatremia who are volume depleted, the vast majority of patients should be treated with isotonic saline. Once most of the volume deficit has been repaired, ADH release will be appropriately suppressed, leading to the potential for overly rapid correction. (See 'Moderate symptoms' above.)
  • Patients with hypovolemia or SIADH who have only mild symptoms (eg, dizziness, forgetfulness, gait disturbance) should be treated with less aggressive therapy, such as isotonic saline in hypovolemia and, in SIADH, fluid restriction with, if necessary, the addition of oral salt tablets and, if the urine osmolality is more than twice the plasma osmolality and the serum sodium concentration is below goal, a loop diuretic. (See 'Mild symptoms' above.)
  • Among asymptomatic patients with moderate hyponatremia, the treatment varies with the underlying cause of the hyponatremia.

  • For asymptomatic patients with moderate chronic hyponatremia (serum sodium 120 to 129 meq/L) resulting from SIADH, we suggest initiating treatment with fluid restriction (Grade 2B). (See 'Necessity for therapy' above.) Most patients will respond to fluid restriction of 800 mL/day. We aim for a goal serum sodium of 130 meq/L or higher. Among patients in whom fluid restriction is not sufficient to achieve the desired goal, subsequent therapy includes salt tablets and, if necessary, a loop diuretic if the urine osmolality is more than twice that of the plasma.
  • Among asymptomatic patients who are hypovolemic, either intravenous isotonic saline or oral salt tablets may be effective in combination with treatment of the cause of hypovolemia. (See 'Asymptomatic hyponatremia' above.)
  • The treatment of asymptomatic hyponatremia in patients with heart failure and cirrhosis is discussed separately. (See "Hyponatremia in patients with heart failure" and "Hyponatremia in patients with cirrhosis".)

  • Vasopressin receptor antagonists are an alternative or possible addition to fluid restriction or sodium chloride administration in patients with hyponatremia. Only tolvaptan (oral) and conivaptan (intravenous) are currently available in the United States. Both drugs are approved for the management of patients with euvolemic hyponatremia, mostly due to SIADH. Tolvaptan is also approved for use in patients with heart failure or cirrhosis. There are important limitations to the use of oral tolvaptan and conivaptan should not be used in patients with cirrhosis. (See 'Vasopressin receptor antagonists' above.)

  • Vasopressin receptor antagonists should not be used in hyponatremic patients who are volume depleted in whom volume repletion is the primary therapy.
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