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Overview of the treatment of hyponatremia

Official reprint from UpToDate www.uptodate.com 2014 UpToDate

Overview of the treatment of hyponatremia Author Richard H Sterns, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Feb 2014. | This topic last updated: may 29, 2013. 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 reduced effective arterial blood volume, the syndrome of inappropriate ADH secretion (SIADH), thiazide diuretics, adrenal insufficiency, or hypothyroidism. (See "Causes of hyponatremia in adults".) 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 120 meq/L). In this setting, initial therapy usually consists of hypertonic saline with or without vasopressin receptor antagonists. The following issues are reviewed in this topic: 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 sometimes irreversible neurologic disorder called osmotic demyelination syndrome. 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 syndrome 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
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Section Editor Michael Emmett, MD

Deputy Editor John P Forman, MD, MSc

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Overview of the treatment of hyponatremia

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 in adults".) 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 longacting drugs. (See "Causes of hyponatremia in adults", section on '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 indicated for the treatment of symptomatic or severe hyponatremia in edematous states (such as heart failure and cirrhosis), the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and advanced renal failure. Restriction to 50 to 60 percent of daily fluid requirements may be required to achieve the goal of inducing negative water balance [4]. In general, fluid intake should be less than 800 mL/day. In patients with a highly concentrated urine (eg, 500 mosmol/kg or higher), fluid restriction alone may be insufficient to correct hyponatremia. (See "Hyponatremia in patients with heart failure", section on 'Fluid restriction' and "Hyponatremia in patients with cirrhosis", section on 'Fluid restriction' and "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Fluid restriction'.) Fluid restriction is also warranted in hyponatremic patients with primary polydipsia in whom increased fluid intake is the primary problem. (See "Causes of hyponatremia in adults", section on 'Primary polydipsia'.) Sodium chloride administration Sodium chloride, usually as isotonic saline or increased dietary salt, is given to hyponatremic patients with true volume depletion and/or adrenal insufficiency and to some patients with SIADH. Salt administration is generally contraindicated for chronic therapy 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,
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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 (eg, diarrhea, vomiting, diuretic therapy), 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 correcting the hypovolemia, 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 some patients, overly rapid correction of hyponatremia can lead to a severe neurologic disorder called osmotic demyelination [6,7]. The management of such patients is discussed separately. (See "Osmotic demyelination syndrome and overly rapid correction of hyponatremia", section on 'Relowering the serum sodium if overly rapid correction has occurred'.) Equation to estimate efficacy of initial therapy The degree to which one liter of a given solution would be expected to initially raise the serum sodium concentration (SNa) in a hyponatremic patient, absent any water or sodium losses in the urine, is often estimated from the Adrogu-Madias formula [4], although for various reasons we do not use this equation (see 'The "sodium deficit" and its limitations' below): 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). The TBW rather than extracellular fluid volume is used in this equation since, although the administered sodium will stay in the extracellular space, water moves from the intracellular to extracellular space in response to the administered sodium to equalize the osmolality of the two fluid compartments. Potassium added to the solution should be included in the formula (ie, "Infusate [Na + K]" rather than "Infusate [Na]") since potassium is as osmotically active as sodium and will therefore contribute to the elevation in serum sodium. (See 'Effect of potassium' below.) This formula can be used to identify unexpected urinary water losses that are contributing to the increase in SNa. Suppose, for example, that one liter of isotonic saline (containing 154 meq/L of sodium) is given to a 60 kg woman with a serum sodium concentration of 110 meq/L and an estimated TBW of 30 L (50 percent of lean body weight). As long as there are no water losses in the urine, the saline solution would be expected to initially 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 If the serum sodium increases more than predicted, one should suspect that an increase in water excretion occurred, caused by restored euvolemia and appropriate suppression of ADH secretion. It should be emphasized that the Adrogu-Madias formula cannot be used as the sole guide to therapy; monitoring of the serum sodium concentration is essential in all cases. In particular, 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 '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
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(TBW). The term exchangeable cation in the following equations refers to the body content of osmotically active sodium and potassium ions, not sodium and potassium present in bone. Thus, in this 60 kg woman with a serum sodium of 110 meq/L: Total body exchangeable cation = TBW x SNa = 30 x 110 = 3300 meq Assuming that the extracellular fluid (ECF) is approximately 33 percent (10 L) and the intracellular fluid is approximately 67 percent (20 L) of the total body water [8]: Extracellular exchangeable 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 exchangeable cation to 3454 meq and since all of the sodium chloride will stay in the ECF, the extracellular exchangeable cation to 1254 meq. Thus: New SNa = Total exchangeable cation TBW = 3454 31 = 111.4 meq/L New ECF volume = Total ECF exchangeable cation SNa = 1254 111.4 = 11.3 L The ECF volume has increased by 1.3 L. This is more than the 1 L of saline given because the rise in serum sodium concentration and plasma osmolality results in osmotic water movement from the cells into the extracellular fluid. 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 In contrast to hypovolemia, the response to administered isotonic saline is different in a hyponatremic patient with SIADH. Assuming the patient is euvolemic, the administered sodium is excreted in the urine because the response to aldosterone and atrial natriuretic peptide are normal. However, the water is retained because of the persistent action of ADH. Thus, when one liter of isotonic saline is administered to a patient with SIADH, the sodium is excreted in the urine while some of the water is retained, worsening the hyponatremia. A few simple calculations can illustrate this point. Suppose a patient with SIADH and hyponatremia has a high, relatively fixed urine osmolality and a urine cation concentration (urine [Na] + urine [K]) of 308 meq/L, which is twice the cation concentration of isotonic saline. If 1000 mL of isotonic saline is given (containing 154 meq of sodium), all of the NaCl will be excreted (because sodium handling is intact) but in only 500 mL of water (154 meq of urinary sodium in 500 mL equals 308 meq/L). 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 will temporarily increase because the isotonic saline is hypertonic to the patient. Using the hypothetical 60 kg woman with a serum sodium of 110 meq/L and the equations that were presented in the preceding section (see 'Equation to estimate efficacy of initial therapy' above), the effect of 500 mL of retained will be: New SNa = Total exchangeable cation 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 modest volumes of only isotonic saline or near-isotonic Ringer's lactate [9]. At 24 hours after induction of anesthesia, the serum sodium fell by a mean of 4.2 meq/L. Fatalities from severe hyponatremia have been reported following the administration of large volumes of isotonic fluid after surgery [9]. In contrast, hypertonic saline contains 513 meq of sodium per liter. If 1000 mL of this solution is given, all of the
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NaCl will again be excreted but now in a larger volume of urine. If, as in the above example, the patient with SIADH has a urine cation concentration of 308 meq/L, the 513 meq of administered sodium is excreted in 1665 mL of urine (513 308 meq/L). 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 665 mL of water: New SNa = Total exchangeable cations TBW = 3300 (same as baseline) 29.3 (665 mL loss) = 113 meq/L Treatment of SIADH begins with fluid restriction. The effectiveness of fluid restriction alone can be predicted by the urine to serum electrolyte ratio (the concentration of the urine cations, sodium and potassium, to the serum sodium concentration) [10]. A ratio less than 0.5 suggests that the serum sodium concentration will rise with fluid restriction, while a ratio greater than 1 indicates that it will not. Similarly, if fluid must be given or the serum sodium concentration must be raised quickly because of symptomatic hyponatremia, the cation concentration of the administered fluid must exceed the cation concentration of the urine. Isotonic saline has a limited role in correction of the hyponatremia in SIADH, and hypertonic saline must be given when an urgent increase in serum sodium is required. 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 who have a high urine to serum electrolyte ratio. By inhibiting sodium chloride reabsorption in the thick ascending limb of the loop of Henle, furosemide interferes with the countercurrent mechanism and induces a state of ADH resistance, resulting in the excretion of a less concentrated urine and increased water loss. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Salt plus a loop diuretic'.) Chronic therapy of SIADH is discussed elsewhere. (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 [7,11-14]. 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 and anticipating the rate of correction of the hyponatremia. This relationship becomes clinically important in the patient with severe diuretic or vomiting-induced hyponatremia who is also hypokalemic. Suppose, for example, that a patient with hyponatremia has a serum potassium concentration of 2 meq/L and that 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). Using the equations presented above, the administered potassium will raise the serum sodium concentration by about 10 meq/L, which exceeds the upper limit for the rate of safe correction. Thus, giving potassium chloride alone will correct both the hyponatremia and the hypokalemia [7,11]. Giving additional sodium may lead to an overly rapid elevation in the serum sodium concentration and potentially cause the osmotic demyelination syndrome [13]. (See 'Rate of correction' below.)
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Thus, when calculating the impact of a particular regimen on the serum sodium concentration, one must consider the sodium plus potassium concentration of the solution, not simply 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 and sodium chloride administration in patients with hyponatremia is the use of an ADH receptor antagonist [15]. 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 adrenocorticotropic hormone (ACTH) release, respectively [3,5]. The vasopressin receptor antagonists produce a selective water diuresis (also called aquaresis) 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 [5,16]. Some oral formulations, such as tolvaptan, mozavaptan, 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. Tolvaptan should not be used in any patient for longer than 30 days and should not be given at all to patients with liver disease (including cirrhosis). (See 'Limitations' below.) 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 in patients with cirrhosis 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 in patients with cirrhosis 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: SIADH (see "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Vasopressin receptor antagonists'). Heart failure (see "Hyponatremia in patients with heart failure" and "Possibly effective emerging therapies for heart failure", section on 'Vasopressin receptor antagonists'). Cirrhosis (see "Hyponatremia in patients with cirrhosis", section on 'Vasopressin receptor antagonists' and "Hepatorenal syndrome", section on 'Terlipressin plus albumin where available'). 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 [16]. 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 [17]. 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
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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: Concerns about the safety of tolvaptan were raised by a multicenter trial (TEMPO 3:4) that examined its effect on the progression of kidney disease in polycystic kidney disease [18,19]. A greater than 2.5-fold increase in liver enzymes was more common among patients who received tolvaptan compared with placebo. Based upon these data, the US FDA initially issued a safety warning regarding the use of tolvaptan [20], recommending that liver function tests be promptly performed among patients who report symptoms that suggest liver injury, including fatigue, anorexia, right upper quadrant discomfort, dark urine, or jaundice. However, the FDA subsequently determined that tolvaptan should not be used in any patient for longer than 30 days or at all in patients with liver disease (including cirrhosis) because it may potentially lead to liver failure or death [21]. (See "Course and treatment of autosomal dominant polycystic kidney disease", section on 'Vasopressin receptor antagonists'.) 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 [16]. However, we now recommend that the serum sodium be raised by no more than 8 meq/L, not 12 meq/L, in any 24hour period. 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.) Increased thirst, which may limit the rise in serum sodium [16]. Another important limiting factor is the prohibitive cost of tolvaptan, which is as high as $300 per tablet in some areas. THE "SODIUM DEFICIT" AND ITS LIMITATIONS 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. If saline is given to a patient with SIADH, a hypertonic solution is typically required. The mechanisms responsible for these conclusions are described above. (See 'Sodium chloride administration' above.) Formulas have been proposed to estimate both the sodium deficit and the direct effect of a given fluid (eg, hypertonic saline) on the serum sodium (SNa) concentration, for example: Sodium deficit = Total body water (TBW) x (desired SNa actual SNa) Increase in SNa = (Infusate [Na] SNa) (TBW + 1) However, these formulas have a number of limitations and cannot be used to accurately predict the magnitude of change in serum sodium. When hypertonic saline is given, the increase in serum sodium is often greater than that predicted by the formula [22,23]. As an example, in a series of 62 patients with a baseline serum sodium of 112 meq/L who were treated with hypertonic saline, 74 percent had a rise in serum sodium greater than expected from the above formula. In addition, the maximum recommended rate of correction at 24 and 48 hours was exceeded in 11 and 10 percent, respectively [22]. Inadvertent overcorrection was due to a water diuresis in 40 percent of patients which, as mentioned above, can occur when saline therapy corrects hypovolemia, thereby removing the hypovolemic stimulus to the release of antidiuretic hormone and permitting rapid excretion of the excess water. These limitations are discussed in detail elsewhere. (See "Estimation of the sodium deficit in patients with hyponatremia".) RATE OF CORRECTION General issues There are several general issues that must be addressed before discussing specific therapies:
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Is the hyponatremia acute or chronic? Does the patient have severe symptoms or intracranial pathology? 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 if there is overly rapid correction of the hyponatremia [24,25]. (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 that are thought to be due to the hyponatremia and by the cause of the hyponatremia. Symptomatic versus asymptomatic hyponatremia Severe symptoms are most likely to occur with an acute (especially less than 24 hours) and marked reduction in the serum sodium concentration. Without time for the brain adaptation to occur, 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) [26-29]. 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 'Mild to moderate symptoms' below.) Avoid overly rapid correction Overly rapid correction of severe hyponatremia (serum sodium concentration almost always less than 120 meq/L and usually less than 115 meq/L) can lead to a severe and sometimes irreversible neurologic disorder called the osmotic demyelination syndrome. This disorder was formerly called central pontine myelinolysis (CPM), but the name was changed because demyelination may be more diffuse and does not necessarily involve the pons, because not all patients with post-treatment neurological symptoms have demonstrable anatomic lesions, and because not all patients with CPM have experienced a rapid increase in serum sodium (figure 1) [30]. (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, patients with primary polydipsia, 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
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administration of hypertonic saline or from elimination of the cause of impaired water excretion, such as the administration of saline to patients with true volume depletion and glucocorticoid therapy in adrenal insufficiency. (See 'Treat the underlying disease' above.) Goals of therapy Most cases of osmotic demyelination syndrome have occurred in patients with severe hyponatremia in whom the serum sodium concentration increased by more than 10 to 12 meq/L within 24 hours or more than 18 meq/L within 48 hours [27,31]. However, a few cases have been reported after slower correction rates of 9 meq/L in 24 hours [32]. Because a 4 to 6 meq/L increase in serum sodium concentration appears to be sufficient to reverse the most severe manifestations of acute hyponatremia and because actual correction often exceeds what is intended, an increase of 4 to 6 meq/L in 24 hours is a reasonable therapeutic goal for all patients [33]. Thus, the goal of therapy is to raise the serum sodium concentration by 4 to 6 meq/L in a 24-hour period. Every effort should be made so that the increase in serum sodium is less than 9 meq/L in any 24-hour period [1,3,32,33]. For patients with severe symptoms, the first day's goal may be achieved in the first few hours since the daily rate rather than the hourly rate of correction is associated with osmotic demyelination. 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 'Relowering the serum sodium if overly rapid correction has occurred'.) 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 following specific causes is discussed in detail separately: SIADH The mainstay of chronic therapy is fluid restriction. Sometimes, oral salt tablets and, if the urine to serum electrolyte ratio is greater than 1, a loop diuretic may be required to reach the serum sodium goal. Vasopressin receptor antagonists are occasionally used, but these drugs have serious limitations. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat" and 'Limitations' above.). Heart failure and cirrhosis Serum sodium concentrations below 130 meq/L are typically associated with close to end-stage disease. (See "Hyponatremia in patients with heart failure", section on 'Treatment' and "Hyponatremia in patients with cirrhosis", section on 'Treatment'.) Transurethral resection or hysteroscopy. (See "Hyponatremia following transurethral resection or hysteroscopy".) 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 (including impaired mental status) or with symptomatic hyponatremia in patients with intracerebral diseases that have been associated with brain herniation [27,28,30,31,34,35].
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Severe symptoms of hyponatremia are most likely to occur in the following settings: Exercise-associated hyponatremia, as in marathon runners (see "Exercise-associated hyponatremia", section on 'Use of hypertonic saline'). Hyponatremia associated with the use of ecstasy (see "MDMA (ecstasy) intoxication", section on 'Hyponatremia' and "MDMA (ecstasy) intoxication", section on 'Seizures') Self-induced water intoxication in primary polydipsia (see "Causes of hyponatremia in adults", section on 'Primary polydipsia'). Postoperative hyponatremia due to SIADH in patients with known intracerebral pathology (eg, meningitis, stroke, or brain tumor) and in premenopausal women, who may be at increased risk of neurologic complications as compared with postmenopausal women and men. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat" and "Manifestations of hyponatremia and hypernatremia", section on 'Susceptibility of premenopausal women'.) The primary problem in patients who have seizures or other severe neurologic abnormalities is cerebral edema. Treatment of the hyponatremia must take into account two potential problems that can be associated with persistent neurologic deficits or death: Failure to adequately raise the serum sodium concentration [36,37]. Overly rapid correction of the hyponatremia. (See 'Rate of correction' above and 'Avoid overly rapid correction' above.) 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 and outcomes in patients with severe symptomatic hyponatremia [1,3,38-41]. A small dose of 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'.) We suggest a regimen that was first suggested for the treatment of 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 severe 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 [1,42,43]. 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 [1,4,44-46]. (See "Exercise-associated hyponatremia", section on 'Use of hypertonic saline'.) The usual goal for the overall 24-hour rate of correction is to raise the serum sodium by 4 to 6 meq/L and by less than 9 meq/L. In patients with severe symptoms, this goal of increasing the serum sodium by 4 to 6 meq/L can be achieved in the first six hours; the serum sodium can thereafter be maintained at a constant level for the remainder of the 24-hour period to avoid overly rapid correction. (See 'Goals of therapy' above and 'Acute versus chronic hyponatremia' above.) The treatment of symptomatic hyponatremia due to SIADH is complicated by the fact that, in patients with a high urine cation concentration, the initial elevation in the 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 above and elsewhere. (See 'SIADH' above and "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Intravenous saline'.)
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Hyponatremia developing in marathon runners, ecstasy users, or patients with primary polydipsia is associated with marked increases in fluid intake and, often, 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 (9 meq/L in any 24-hour period) 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.) In addition, desmopressin should not be given to these patients with self-induced water intoxication as a means to slow or reverse overcorrection. Despite careful observation in the inpatient setting, such patients may covertly ingest large amounts of water that cannot be excreted because of the antidiuretic effect of desmopressin. This can produce recurrent severe hyponatremia. 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 of 0.5 to 1 meq/L per hour may be justified in the first four hours. This can generally be achieved by administering hypertonic (3 percent) saline at an initial 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. Alternatively, therapy can begin with a 50 mL bolus of 3 percent saline followed by a slower rate of infusion. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Mild to moderate symptoms'.) The total elevation in serum sodium during the first 24 hours should be 4 to 6 meq/L, and the same rate of increase should be continued on subsequent days. The concurrent use of both hypertonic saline and desmopressin may help achieve this goal while avoiding overly rapid correction. This was shown in a retrospective study of 25 symptomatic patients with severe hyponatremia (serum sodium less than 120 meq/L) who were treated with hypertonic saline plus desmopressin (1 to 2 mcg intravenously or subcutaneously every 8 hours for 24 to 48 hours) [47]. The mean increase in serum sodium was 6 meq/L in the first 24 hours and 4 meq/L in the second 24 hours; one patient corrected by 11 meq/L in the first 24 hours, but there were no other instances of overly rapid correction. With this approach, desmopressin is given to eliminate the potential for urinary water losses, in essence creating a state of iatrogenic SIADH that can be managed more predictably with hypertonic saline. 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.
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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 concentration below 120 meq/L might be at risk for overly rapid correction and possible osmotic demyelination. In such patients, if the serum sodium concentration has already increased by 4 to 6 meq/L but less than 9 meq/L in the previous 24 hours, administration of dextrose in water to match urinary water losses will be required. Desmopressin can also be administered to diminish urinary water losses, making the administration of dextrose in water unnecessary. If, despite these efforts, overcorrection occurs, administration of desmopressin with dextrose in water to relower the serum sodium may be needed. (See "Osmotic demyelination syndrome and overly rapid correction of hyponatremia", section on 'Relowering the serum sodium if overly rapid correction has occurred'.) Mild or absent symptoms Patients with SIADH or hypovolemia who have only mild symptoms (eg, dizziness, forgetfulness, gait disturbance) and a serum sodium above 120 meq/L should be treated with less aggressive therapy, such as fluid restriction and oral salt tablets or, in patients with hypovolemia, isotonic saline and treatment of the cause of fluid loss. If fluid restriction and salt tablets are not sufficient and the urine cation concentration is very high, subsequent therapy includes a loop diuretic or a vasopressin antagonist. (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 with placebo in patients with chronic hyponatremia due to SIADH, heart failure, or cirrhosis [16]. 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 concentration [48]. (See "Manifestations of hyponatremia and hypernatremia", section on 'Subtle manifestations in mild to moderate chronic hyponatremia'.) 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
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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", section on 'Predictor of adverse prognosis' and "Hyponatremia in patients with cirrhosis", section on 'Predictor of adverse prognosis'.) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient information: Hyponatremia (The Basics)") 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 indicated 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.) If the serum sodium is 120 meq/L or less, or if a patient with hyponatremia has a comorbidity such as alcoholism, liver disease, malnutrition, or severe hypokalemia, then the risk of osmotic demyelination is increased (patients with acute self-induced water intoxication are exceptions). For these high-risk patients, we recommend that the serum sodium concentration be raised by a goal of 4 to 6 meq/L per 24 hours, and by less than 9 meq/L in any 24-hour period (Grade 1B). Serial measurements of the serum sodium concentration are required to assess the impact of therapy. These measurements should occur initially every two to three hours following initiation of active treatment, and then every three to four hours while active treatment is continued. (See 'Avoid overly rapid correction' above.) In patients with the severe symptoms (eg, seizures, severe neurologic abnormalities), the goal of increasing the serum sodium concentration by 4 to 6 meq/L can be achieved over a relatively short period of time
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(approximately six hours). (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 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 with the goal of achieving a correction rate of 4 to 6 meq/L per day (and by less than 9 meq/L within any 24-hour period). (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 or absent 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 if the urine to serum electrolyte ratio is less than 0.5 (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 with a urine to serum electrolyte ratio greater than 1, in whom fluid restriction will not be sufficient to achieve the desired goal, additional therapy includes salt tablets and, if necessary, a loop diuretic. An alternative approach is the initiation of a vasopressin antagonist without fluid restriction. 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 'Symptomatic versus asymptomatic hyponatremia' above.)
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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. There are important limitations to the use of oral tolvaptan and conivaptan (see 'Vasopressin receptor antagonists' above): Because of potential hepatotoxicity, tolvaptan should not be used for longer than 30 days and should not be given to patients with liver disease (including cirrhosis). Vasopressin receptor antagonists should not be used in hyponatremic patients who are volume depleted in whom volume repletion is the primary therapy. Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Sterns RH, Nigwekar SU, Hix JK. The treatment of hyponatremia. Semin Nephrol 2009; 29:282. 2. Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York 2001. p.716. 3. Verbalis JG, Goldsmith SR, Greenberg A, et al. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med 2007; 120:S1. 4. Adrogu HJ, Madias NE. Hyponatremia. N Engl J Med 2000; 342:1581. 5. Greenberg A, Verbalis JG. Vasopressin receptor antagonists. Kidney Int 2006; 69:2124. 6. Oh MS, Uribarri J, Barrido D, et al. Danger of central pontine myelinolysis in hypotonic dehydration and recommendation for treatment. Am J Med Sci 1989; 298:41. 7. Kamel KS, Bear RA. Treatment of hyponatremia: a quantitative analysis. Am J Kidney Dis 1993; 21:439. 8. EDELMAN IS, LEIBMAN J. Anatomy of body water and electrolytes. Am J Med 1959; 27:256. 9. Steele A, Gowrishankar M, Abrahamson S, et al. Postoperative hyponatremia despite near-isotonic saline infusion: a phenomenon of desalination. Ann Intern Med 1997; 126:20. 10. Furst H, Hallows KR, Post J, et al. The urine/plasma electrolyte ratio: a predictive guide to water restriction. Am J Med Sci 2000; 319:240. 11. LARAGH JH. The effect of potassium chloride on hyponatremia. J Clin Invest 1954; 33:807. 12. Fichman MP, Vorherr H, Kleeman CR, Telfer N. Diuretic-induced hyponatremia. Ann Intern Med 1971; 75:853. 13. Berl T, Rastegar A. A patient with severe hyponatremia and hypokalemia: osmotic demyelination following potassium repletion. Am J Kidney Dis 2010; 55:742. 14. Rose BD. New approach to disturbances in the plasma sodium concentration. Am J Med 1986; 81:1033. 15. Jovanovich AJ, Berl T. Where vaptans do and do not fit in the treatment of hyponatremia. Kidney Int 2013; 83:563. 16. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006; 355:2099. 17. Berl T, Quittnat-Pelletier F, Verbalis JG, et al. Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol 2010; 21:705.
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18. Higashihara E, Torres VE, Chapman AB, et al. Tolvaptan in autosomal dominant polycystic kidney disease: three years' experience. Clin J Am Soc Nephrol 2011; 6:2499. 19. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012; 367:2407. 20. Samsca (tolvaptan): Drug Warning - Potential Risk of Liver Injury. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm336669.ht m?source=govdelivery (Accessed on January 28, 2013). 21. Samsca (Tolvaptan): Drug Safety Communication - FDA Limits Duration and Usage Due To Possible Liver Injury Leading to Organ Transplant or Death. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350185.ht m (Accessed on May 20, 2013). 22. Mohmand HK, Issa D, Ahmad Z, et al. Hypertonic saline for hyponatremia: risk of inadvertent overcorrection. Clin J Am Soc Nephrol 2007; 2:1110. 23. Berl T. The Adrogue-Madias formula revisited. Clin J Am Soc Nephrol 2007; 2:1098. 24. Mount DB. The brain in hyponatremia: both culprit and victim. Semin Nephrol 2009; 29:196. 25. Sterns RH, Silver SM. Brain volume regulation in response to hypo-osmolality and its correction. Am J Med 2006; 119:S12. 26. Chow KM, Kwan BC, Szeto CC. Clinical studies of thiazide-induced hyponatremia. J Natl Med Assoc 2004; 96:1305. 27. Sterns RH. Severe symptomatic hyponatremia: treatment and outcome. A study of 64 cases. Ann Intern Med 1987; 107:656. 28. Sterns RH, Cappuccio JD, Silver SM, Cohen EP. Neurologic sequelae after treatment of severe hyponatremia: a multicenter perspective. J Am Soc Nephrol 1994; 4:1522. 29. Soupart A, Penninckx R, Stenuit A, et al. Treatment of chronic hyponatremia in rats by intravenous saline: comparison of rate versus magnitude of correction. Kidney Int 1992; 41:1662. 30. Ayus JC, Wheeler JM, Arieff AI. Postoperative hyponatremic encephalopathy in menstruant women. Ann Intern Med 1992; 117:891. 31. Karp BI, Laureno R. Pontine and extrapontine myelinolysis: a neurologic disorder following rapid correction of hyponatremia. Medicine (Baltimore) 1993; 72:359. 32. Adrogu HJ, Madias NE. The challenge of hyponatremia. J Am Soc Nephrol 2012; 23:1140. 33. Sterns RH, Hix JK, Silver S. Treatment of hyponatremia. Curr Opin Nephrol Hypertens 2010; 19:493. 34. Moritz ML, Ayus JC. The pathophysiology and treatment of hyponatraemic encephalopathy: an update. Nephrol Dial Transplant 2003; 18:2486. 35. Berl T. Treating hyponatremia: damned if we do and damned if we don't. Kidney Int 1990; 37:1006. 36. Ayus JC, Arieff AI. Chronic hyponatremic encephalopathy in postmenopausal women: association of therapies with morbidity and mortality. JAMA 1999; 281:2299. 37. Nzerue CM, Baffoe-Bonnie H, You W, et al. Predictors of outcome in hospitalized patients with severe hyponatremia. J Natl Med Assoc 2003; 95:335. 38. Soupart A, Decaux G. Therapeutic recommendations for management of severe hyponatremia: current concepts on pathogenesis and prevention of neurologic complications. Clin Nephrol 1996; 46:149. 39. Ayus JC, Krothapalli RK, Arieff AI. Changing concepts in treatment of severe symptomatic hyponatremia. Rapid correction and possible relation to central pontine myelinolysis. Am J Med 1985; 78:897. 40. Gross P, Reimann D, Neidel J, et al. The treatment of severe hyponatremia. Kidney Int Suppl 1998; 64:S6. 41. Arieff AI, Ayus JC. Endometrial ablation complicated by fatal hyponatremic encephalopathy. JAMA 1993; 270:1230. 42. Ayus JC, Arieff A, Moritz ML. Hyponatremia in marathon runners. N Engl J Med 2005; 353:427. 43. Hew-Butler T, Ayus JC, Kipps C, et al. Statement of the Second International Exercise-Associated
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Hyponatremia Consensus Development Conference, New Zealand, 2007. Clin J Sport Med 2008; 18:111. 44. Sarnaik AP, Meert K, Hackbarth R, Fleischmann L. Management of hyponatremic seizures in children with hypertonic saline: a safe and effective strategy. Crit Care Med 1991; 19:758. 45. Worthley LI, Thomas PD. Treatment of hyponatraemic seizures with intravenous 29.2% saline. Br Med J (Clin Res Ed) 1986; 292:168. 46. Siegel AJ, Verbalis JG, Clement S, et al. Hyponatremia in marathon runners due to inappropriate arginine vasopressin secretion. Am J Med 2007; 120:461.e11. 47. Sood L, Sterns RH, Hix JK, et al. Hypertonic saline and desmopressin: a simple strategy for safe correction of severe hyponatremia. Am J Kidney Dis 2013; 61:571. 48. Renneboog B, Musch W, Vandemergel X, et al. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med 2006; 119:71.e1. Topic 2350 Version 12.0

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GRAPHICS Course of osmotic demyelination in hyponatremia

Clinical course in seven previously healthy women show developed postoperative hyponatremia and seizures presumably due to cerebral edema. Rapid correction of the plasma sodium concentration was associated with late deterioration into coma or a permanent vegetative state that may have been due to osmotic demyelination.
Data from: Arieff AI. N Engl J Med 1986; 314:1529. Graphic 76471 Version 2.0

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