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Causes 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: Oct 2013. | This topic last updated: Nov 4, 2013. INTRODUCTION Hyponatremia is commonly defined as a serum sodium concentration below 135 meq/L but can vary to a small degree in different clinical laboratories [1]. The dilutional fall in serum sodium is in most patients associated with a proportional reduction in the serum osmolality (ie, to a level below 275 mosmol/kg), but there are some exceptions. (See 'Hyponatremia with a high or normal serum osmolality' below.) In virtually all patients, hyponatremia results from the intake (either oral or intravenous) and subsequent retention of water [2]. A water load will, in normal individuals, be rapidly excreted as the dilutional fall in serum osmolality suppresses the release of antidiuretic hormone (ADH, also called vasopressin) (figure 1), thereby allowing excretion of the excess water in a dilute urine. The maximum attainable urine volume in normal individuals on a regular diet is over 10 L/day. This provides an enormous range of protection against the development of hyponatremia since the daily fluid intake in most healthy individuals is less than 2 to 2.5 L/day. In contrast to the response in normal individuals, patients who develop hyponatremia typically have an impairment in renal water excretion, most often due to an inability to suppress ADH secretion. An uncommon exception occurs in patients with primary polydipsia who can become hyponatremic because they rapidly drink such large quantities of fluid that they overwhelm the excretory capacity of the kidney even though ADH release is appropriately suppressed. An overview of the causes of hyponatremia will be presented here (table 1). Most of the individual causes of hyponatremia are discussed in detail separately, as are issues related to the diagnosis and treatment of hyponatremia [2,3]. (See "Evaluation of the patient with hyponatremia" and "Overview of the treatment of hyponatremia".) DETERMINANTS OF THE SERUM SODIUM CONCENTRATION Understanding the factors that determine the serum sodium concentration is required to appreciate the factors that promote the development of hyponatremia and what the composition of intravenous fluids must be to correct the hyponatremia. In the following discussion, the term "tonicity" (also called the effective plasma osmolality) refers to the osmotic activity of solutes that do not easily cross cell membranes and therefore determine the transcellular distribution of water. The extracellular and intracellular fluids are in osmotic equilibrium since water moves freely across most cell membranes. As a result, plasma tonicity is equal to the effective intracellular osmolality and to the effective osmolality of the total body water (TBW). These relationships can be summarized by the Section Editor Michael Emmett, MD Deputy Editor John P Forman, MD, MSc

following equation: Plasma tonicity = (Extracellular solute + Intracellular solute) TBW Exchangeable sodium salts (Nae) are the primary effective extracellular solute and exchangeable potassium (Ke) and its associated intracellular anions are the primary intracellular solutes; these solutes are the major determinants of the effective plasma osmolality. Glucose, the other major extracellular solute is, in the absence of marked hyperglycemia, present in a much lower molar concentration than sodium (eg, 5 mmol/L [90 mg/dL] versus 140 mmol/L). Approximately 30 percent of total body sodium and a smaller fraction of total body potassium are bound in areas such as bone where they are "nonexchangeable" and therefore not osmotically active. In addition, urea is considered an ineffective osmole since it freely equilibrates across the cell membranes. When the plasma concentration of an ineffective osmole changes, the solute rapidly moves into or out of cells to equalize the concentrations. Thus, there is little or no water shift into or out of the cells as occurs with changes in the plasma sodium concentration. Thus, plasma tonicity (effective plasma osmolality) can be expressed as: Plasma tonicity (2 x Nae + 2 x Ke) TBW The multiplier 2 accounts for the osmotic contributions of the anions accompanying sodium and potassium. In the absence of marked hyperglycemia or the administration of mannitol, the above equation can be simplified to: 2 x plasma Na (2 x Nae + 2 x Ke) TBW and then to: Plasma Na (Nae + Ke) TBW As shown in the figure, this relationship applies over a wide range of plasma or serum sodium concentrations (figure 2) [4]. Application to hyponatremia The importance of considering the effect of potassium on the plasma sodium concentration in patients with hyponatremia can be illustrated by the following examples: In patients with hyponatremia induced by thiazide diuretics, the sodium plus potassium concentration in the urine may exceed that in the plasma, which will directly lower the plasma sodium concentration independent of fluid intake. (See 'Diuretic-induced hyponatremia' below.) In a patient who has both severe hyponatremia and severe hypokalemia (due, for example, to diuretic therapy or vomiting), treatment with large

amounts of potassium in addition to isotonic or hypertonic saline may lead to overly rapid correction of the hyponatremia and possible brain injury due to osmotic demyelination syndrome. (See "Overview of the treatment of hyponatremia", section on 'Effect of potassium' and "Overview of the treatment of hyponatremia", section on 'Avoid overly rapid correction'.) CLASSIFICATION At least two classification systems have been used for the etiology of hyponatremia with a low serum osmolality (defined as a serum osmolality less than 275 mosmol/kg): one stratifies patients according to whether circulating antidiuretic hormone (ADH) levels are inappropriately elevated or appropriately suppressed [2], and the other stratifies patients according to volume status (hypovolemia, normovolemia, or hypervolemia) [5,6]. In either case, the development of hyponatremia requires the intake of water that cannot be excreted. The individual causes of hyponatremia are described below in the appropriate sections. According to serum ADH levels Urinary excretion of a water load requires the suppression of ADH release, which is mediated by the reduction in serum osmolality (figure 1). An inability to suppress ADH release is the most common cause of hyponatremia and can be seen in the following settings: True volume depletion, which can be due to gastrointestinal losses (eg, vomiting or diarrhea) or renal losses (most often thiazide rather than loop diuretics) Decreased tissue perfusion (also called effective arterial volume depletion) due to reduced cardiac output in heart failure or to systemic vasodilation in cirrhosis A primary (ie, not hypovolemic) increase in ADH release in the syndrome of inappropriate ADH secretion (SIADH), including an infrequent variant characterized by resetting of the osmostat. There are also disorders in which hyponatremia occurs despite appropriate suppression of ADH secretion. These include primary polydipsia, a low dietary solute intake, and advanced renal failure. According to volume status The causes of hyponatremia can also be stratified by volume status [5,6]: Hypovolemia due to gastrointestinal losses (eg, vomiting or diarrhea) or renal losses (most often thiazide rather than loop diuretics) Normovolemia, which is most often associated with the SIADH but can also be seen with primary polydipsia and a low dietary solute intake Hypervolemia due to heart failure or cirrhosis Hyponatremia can also occur in patients with advanced renal failure. These patients may appear either euvolemic or, if they also retain salt and develop edema, hypervolemic. HYPONATREMIA WITH A LOW SERUM OSMOLALITY The serum osmolality (Sosm) can be calculated by the concentration in millimoles per liter of the major serum solutes according to the following equation: Sosm (mmol/kg) = (2 x serum [Na]) + (serum [glucose]/18) + (blood urea nitrogen/2.8) The serum sodium concentration is multiplied by two to account for the accompanying anions (mostly chloride and bicarbonate) that provide electroneutrality, and the corrections in the glucose concentration and blood urea nitrogen (BUN) are to convert mg/dL into mmol/L. These corrections in glucose and BUN do not need to be made when standard units are used.

The contributions of glucose and BUN to the serum osmolality are normally small, except in conditions such as diabetes mellitus and renal failure. Thus, the serum osmolality can be estimated in most patients by doubling the serum sodium concentration. (See "General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)", section on 'Plasma osmolality'.) The two most common causes of hyponatremia with a low serum osmolality are effective arterial blood volume depletion and the syndrome of inappropriate antidiuretic hormone (ADH) secretion, both of which are associated with persistent ADH release [5-7]. Most patients with hyponatremia have a single cause but, in some patients, multiple factors contribute to the fall in serum sodium. Symptomatic infection with human immunodeficiency virus (HIV) is an example of this phenomenon, as volume depletion, the syndrome of inappropriate ADH secretion, and adrenal insufficiency all may be present. (See "Electrolyte disturbances with HIV infection".) Effective arterial blood volume depletion The term effective arterial blood volume (also called effective circulating volume) refers to the volume of arterial blood that is perfusing the tissues. Effective arterial blood volume depletion can occur by two mechanisms: true volume depletion; and edematous patients with heart failure or cirrhosis in whom tissue perfusion is reduced because of a low cardiac output or arterial vasodilation, respectively. The reduction in tissue perfusion is sensed by baroreceptors at three sites: in the carotid sinus and aortic arch that regulate sympathetic activity and, with significant volume depletion, the release of antidiuretic hormone; in the glomerular afferent arterioles that regulate the activity of the renin-angiotensin system; and in the atria and ventricles that regulate the release of natriuretic peptides. (See "General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)", section on 'Effective arterial blood volume'.) Regardless of the mechanism, significantly decreased tissue perfusion is a potent stimulus to the secretion of ADH (figure 3). This response is mediated by baroreceptors in the carotid sinus, which sense a reduction in pressure or stretch, and can overcome the inhibitory effect of hyponatremia on ADH secretion. Thus, water retention and hyponatremia can develop in patients with any disorder causing effective arterial blood volume depletion. True volume depletion True volume depletion can be caused by the loss of sodium and water from the gastrointestinal tract (eg, vomiting or diarrhea), in the urine (most often due to diuretic therapy), or bleeding. Such patients may also have hypokalemia and, if enough fluid is lost, azotemia due to decreased renal perfusion. The replacement of severe diarrhea losses due to cholera (which is associated with a sodium concentration in stool of 120 to 140 meq/L) with an oral rehydration solution with reduced osmolality (ie, more free water) may result in an increased incidence of hyponatremia as compared to replacement with standard oral rehydration therapy, which has a higher sodium concentration [8]. (See "Oral rehydration therapy".) Diuretic-induced hyponatremia Hyponatremia, which can be severe, is an occasional complication of therapy with thiazide diuretics. It typically begins soon after the onset of thiazide therapy. In contrast, hyponatremia is only rarely induced by loop diuretics since the inhibition of sodium chloride transport in the loop of Henle prevents the generation of the countercurrent gradient and therefore limits the ability of ADH to promote water retention. The following discussion will briefly review the mechanisms involved in thiazide-induced hyponatremia. A more complete discussion is presented elsewhere. (See "Diuretic-induced hyponatremia", section on 'Pathogenesis'.) Although hypovolemia can contribute to thiazide-induced hyponatremia, most patients appear clinically euvolemic and several other factors appear to play a role in the development of hyponatremia:

 An underlying tendency to increased water intake. A reduction in diluting ability and therefore impaired water excretion, which is a direct effect of reduced sodium chloride reabsorption without water in the distal tubule. The sodium plus potassium concentration in the urine may exceed that in the plasma, which will directly lower the plasma sodium concentration (see 'Determinants of the serum sodium concentration' above). As an example, in a study of five patients with recent onset of severe thiazide-induced hyponatremia (mean serum sodium 105 meq/L), the urine sodium plus potassium concentration was 156 meq/L [9]. Heart failure and cirrhosis Even though the plasma and extracellular volumes may be markedly increased in heart failure and cirrhosis, the pressure sensed at the carotid sinus baroreceptors is generally reduced due to the fall in cardiac output in heart failure and to arterial vasodilatation in cirrhosis [2,10]. Thus, serum ADH levels tend to reflect the severity of the underlying disease, making the development of hyponatremia an important prognostic sign. A stable serum sodium below 130 meq/L is a marker of near end-stage liver or heart disease (figure 4). (See "Hyponatremia in patients with heart failure" and "Hyponatremia in patients with cirrhosis".) In contrast, hyponatremia is an uncommon finding in patients with the nephrotic syndrome in the absence of concurrent renal failure. Most such patients have relatively normal tissue perfusion and effective arterial volume and therefore do not have a clinically important stimulus to ADH secretion. (See "Pathophysiology and treatment of edema in patients with the nephrotic syndrome", section on 'Volume regulatory hormones'.) Syndrome of inappropriate ADH secretion Persistent ADH release and water retention can be seen in a variety of disorders that are not associated with hypovolemia, a condition called syndrome of inappropriate ADH secretion (SIADH). Major causes include central nervous system disease, malignancy, certain drugs, and recent surgery. (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)", section on 'Etiology'.) Endocrine disorders The original definition of SIADH excluded patients with glucocorticoid deficiency or hypothyroidism [11,12]. However, hyponatremia with features that are identical to those found in patients meeting the classical definition of SIADH (ie, euvolemia with a high urine osmolality and urine sodium) can also occur in patients with hypothyroidism or secondary adrenal insufficiency (not primary adrenal insufficiency, in which hyponatremia is associated with hypovolemia). Because these endocrine disorders are not always clinically apparent when patients first present with unexplained hyponatremia, some authors include endocrine disorders in the differential diagnosis of SIADH. Hypothyroidism Hyponatremia is sometimes associated with moderate to severe hypothyroidism, particularly in patients with primary hypothyroidism and myxedema [13-17]. Thus, thyroid function should be evaluated in any patient with an otherwise unexplained reduction in the plasma sodium concentration. However, because hypothyroidism and hyponatremia are common findings in hospitalized patients, their coexistence may not necessarily be causal; other explanations for hyponatremia should still be sought unless hypothyroidism is severe. The mechanism by which hypothyroidism induces hyponatremia is incompletely understood. Patients with hypothyroidism have a diminished ability to excrete free water and fail to achieve maximally dilute urine after a water load. Some but not all studies have reported elevated levels of ADH in patients who have hyponatremia associated with hypothyroidism [13-15]. This may be due in part to a reduced cardiac output, which can lead to the release of ADH via the carotid sinus baroreceptors [14,15,18]. However, some patients fulfill criteria for SIADH since the urine sodium is not low as would be expected if a reduced cardiac output were responsible [19]. The glomerular filtration rate is also decreased in hypothyroidism. This can directly diminish free water excretion by diminishing water delivery to the

diluting segments [16,17]. Decreased delivery may be particularly important in those cases in which hyponatremia develops despite appropriate suppression of ADH release [20,21]. Regardless of the mechanism, the net effect of the impairment in water excretion is the retention of ingested water and a reduction in the plasma sodium concentration by dilution. Some have questioned whether hypothyroidism deserves its traditional listing as a cause of hyponatremia [22]. As an example, a study that compared 999 ambulatory patients with newly diagnosed hypothyroidism with 4875 euthyroid controls found no difference in serum sodium concentrations [23]. In addition, none of the hypothyroid patients had a serum sodium concentration <120 mmol/L, while two controls had hyponatremia of this severity. Although there was a statistical correlation between higher TSH levels and lower serum sodium concentrations, the slope of the relationship was clinically negligible. In contrast, symptomatic hyponatremia (with serum sodium concentrations ranging from 121 to 110 meq/L) was reported in five patients with metastatic thyroid carcinoma after withdrawal of thyroid hormone replacement (withdrawn prior to administration of radioactive iodine) [24]. The serum sodium returned to normal after thyroid replacement was restarted. However, four of the five patients had known lung or cerebral metastases, which may have contributed to hyponatremia. Adrenal insufficiency The hypersecretion of ADH seen with cortisol deficiency may be in part due to the reductions in systemic blood pressure and cardiac output (via an unknown mechanism) and the interruption of a negative feedback loop in which cortisol suppresses ADH release. In primary adrenal insufficiency (Addison disease), hypovolemia induced ADH secretion resulting from aldosterone deficiency also contributes. Secondary adrenal insufficiency (hypopituitarism), presents with euvolemic hyponatremia with biochemical features of SIADH. These issues are discussed in detail elsewhere. (See "Hyponatremia and hyperkalemia in adrenal insufficiency".) Pregnancy The release of human chorionic gonadotropin during pregnancy may be responsible for a mild resetting of the osmostat downward that is responsible for a fall in the serum sodium concentration of about 5 meq/L [25]. (See "Renal and urinary tract physiology in normal pregnancy".) Ectopic ANP Although SIADH is more common, ectopic atrial natriuretic peptide production may be rarely associated with hyponatremia in some patients with small cell lung cancer [26-28]. Exercise-associated hyponatremia Marathon and ultramarathon runners can develop potentially severe hyponatremia that is primarily due to excessive water intake combined, in many cases, with impaired water excretion due to persistent ADH secretion. A similar sequence can occur during military operations and desert hikes. (See "Exercise-associated hyponatremia".) Ecstasy (MDMA) intoxication Symptomatic and potentially fatal hyponatremia has been described after ingestion of the designer amphetamine ecstasy (methylenedioxymethamphetamine or MDMA) [29-39]. Two factors appear to be of primary importance in the development of hyponatremia: a marked increase in water intake [29,30,33], as occurs with primary polydipsia; and drug-induced inappropriate secretion of ADH, which limits water excretion [29,30,32-35,37]. (See 'Primary polydipsia' below.) Hyponatremia is a major cause of death related to ecstasy use [39]. As with other causes of hyponatremia [40], young women with ecstasy-induced hyponatremia are more likely than men to develop severe neurologic complications such as coma and death [36,38]. Women are also more likely than men to develop ecstasy-induced hyponatremia [41,42]. In a study of 63 ecstasy users and 44 non-users attending a commercial "rave" party, mild hyponatremia (defined as a serum sodium less than 136 meq/L) was significantly more common among ecstasy users (14 versus 0 percent), and among female as opposed to male ecstasy users (27 versus 3 percent) [41]. No cases of symptomatic hyponatremia were identified in this small series, and those with hyponatremia had serum sodium concentrations ranging between 133 and 135 meq/L. (See "Manifestations of hyponatremia and hypernatremia", section on 'Susceptibility of premenopausal women' and "MDMA (ecstasy) intoxication".)

Hyponatremia despite appropriate suppression of ADH There are several conditions in which hyponatremia can occur despite suppression of ADH release: advanced renal failure, primary polydipsia, and low dietary solute intake. Advanced renal failure The relative ability to excrete free water (free water excretion divided by the glomerular filtration rate) is not significantly impaired in patients with mild to moderate renal failure [43]. Thus, normonatremia is usually maintained. In contrast, in advanced renal failure, the minimum urine osmolality rises to as high as 200 to 250 mosmol/kg despite the appropriate suppression of ADH [44]. The osmotic diuresis induced by increased solute excretion per functioning nephron is thought to be responsible for the inability to dilute the urine. The impairment in free water excretion in advanced renal failure can lead to the retention of ingested water and the development of hyponatremia. Although the water retention will also lower the serum osmolality, this will be offset at least in part by the elevation in blood urea nitrogen (BUN). As a result, the measured serum osmolality may be normal or even increased, a finding that can also be seen in some other disorders. (See 'Hyponatremia with a high or normal serum osmolality' below.) However, there is a difference between the measured serum osmolality and the effective serum osmolality. Urea is an ineffective osmole since it can freely cross cell membranes and therefore does not obligate water movement out of the cells. Thus, patients with hyponatremia and renal failure have a low effective serum osmolality (Sosm) that becomes apparent if the measured Sosm is corrected for the effect of urea: Corrected Sosm = Measured Sosm - (BUN 2.8) Dividing the BUN by 2.8 converts mg/dL into mmol/L, which is required when estimating its contribution to osmolality. If the blood urea is measured in units of mmol/L, the formula is: Corrected Sosm = Measured Sosm - blood urea concentration Primary polydipsia Primary polydipsia, a disorder in which there is a primary increase in thirst, is most often seen in patients with psychiatric illnesses [45-50]. As an example, one study of 239 hospitalized patients with mental illness found that 6.6 percent had a history compatible with compulsive water drinking and that one-half of these had intermittent symptoms of hyponatremia due to transient water retention [51]. It is presumed that a central defect in thirst regulation plays an important role in the pathogenesis of polydipsia [48,52]. In some cases, for example, the osmotic threshold for thirst is reduced below the threshold for the release of ADH [53]. In contrast to normal subjects in whom the thirst threshold is roughly equal to or a few mosmol/kg higher than the threshold for ADH [54], these patients will continue to drink until the plasma osmolality is less than the threshold level. This may be difficult to achieve, however, since ADH secretion will be suppressed by the fall in plasma osmolality, resulting in rapid excretion of the excess water and continued stimulation of thirst. The mechanism responsible for abnormal thirst regulation in patients with primary polydipsia is unclear. Normal subjects can excrete more than 400 to 600 mL of urine per hour, a response that is mediated by suppression of ADH secretion and the subsequent formation of a dilute urine with a minimum osmolality between 40 and 100 mosmol/kg. If ADH regulation were intact, primary polydipsia should not lead to clinically important disturbances in the plasma sodium concentration unless intake were massively increased. Thus, the serum sodium concentration is usually normal or only slightly reduced in primary polydipsia since the excess water is readily excreted [46]. These patients may be asymptomatic or present with complaints of polydipsia and polyuria. (See "Diagnosis of polyuria and diabetes insipidus".) Water intake may occasionally exceed 400 to 600 mL per hour, particularly in institutionalized patients with severe psychosis [50], and may produce fatal

hyponatremia even though the urine is maximally dilute with an osmolality below 100 mosmol/kg [55,56]. Symptomatic hyponatremia can also be induced with an acute 3- to 4-liter water load. This is sometimes seen in anxious patients preparing for a radiologic examination or in those attempting to dilute their urine to avoid a positive urine drug test [57]. However, some patients with polydipsia who become hyponatremic have a higher urine osmolality than polydipsic patients who remain normonatremic, indicating a concurrent increase in ADH release and/or response [45,52,58,59]. A number of different abnormalities in ADH regulation have been identified in psychotic patients, each of which can impair water excretion. Studies in patients who have had at least one episode of hyponatremia have revealed the following defects [52]: Transient stimulation of ADH release during acute psychotic episodes, producing the syndrome of inappropriate ADH secretion (SIADH) [58,60]. An increase in the net renal response to ADH so that, at the same plasma ADH levels, psychotic patients have a higher urine osmolality and therefore a lower rate of free water excretion than healthy controls [52]. How this occurs is not known. Antipsychotic or antidepressant drugs (such as fluoxetine) may also produce SIADH in a few patients. As examples, carbamazepine and fluoxetine can produce hyponatremia with a SIADH-like clinical picture [61,62]. A downward resetting of the osmostat regulating ADH release. As a result, a lower-than-normal plasma sodium concentration is required to completely suppress ADH release and excrete a water load. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat".) Transient ADH release due to nausea [50]. The net effect is that some modestly hyponatremic patients with primary polydipsia do not have a maximally dilute urine as would be expected if ADH were appropriately suppressed by the fall in plasma osmolality and there were not increased sensitivity to ADH [52]. The likelihood of developing hyponatremia will be increased further if some other cause for enhanced ADH release is present, such as nausea, stress, or concurrent diuretic therapy [57,63]. Primary polydipsia can also occur with hypothalamic lesions that affect the thirst center, as can be seen with infiltrative diseases such as sarcoidosis [64]. Low dietary solute intake can contribute to the development of hyponatremia by limiting water excretion even if the secretion of ADH is appropriately suppressed. (See 'Low dietary solute intake' below.) As in any patient with polydipsia and polyuria, the possibility of diabetes insipidus should be considered in patients with psychiatric illness who present with these symptoms in the absence of hyponatremia. If compliance is possible, we recommend a water restriction test. An alternative in the uncooperative patient is to increase the plasma osmolality via a slow infusion of hypertonic saline. (See "Diagnosis of polyuria and diabetes insipidus".) Measuring the urine osmolality is also important in polydipsic patients who are hyponatremic. Pure primary polydipsia should be associated with appropriate suppression of ADH release and a urine osmolality below 100 mosmol/kg. A higher urine osmolality, which is often present, suggests at least a contributory role for increased ADH release or responsiveness [45,52,59]. (See "Evaluation of the patient with hyponatremia".) There is no proven specific therapy for primary polydipsia with or without hyponatremia in psychotic patients. Acutely, limiting water intake will rapidly raise the plasma sodium concentration as the excess water is readily excreted in a dilute urine. The risk of inducing osmotic demyelination in this setting is unclear [65,66].

Over the long term, limiting the use of drugs that cause dry mouth, restricting fluid intake, and frequent weighing (to detect water retention) all may be helpful. Some physicians have tried the tetracycline derivative demeclocycline, which induces reversible ADH resistance; however, this agent has not generally been effective [67]. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat".) Low dietary solute intake Beer drinkers or other malnourished patients (including those with low-protein, high water intake diets; ie, the "tea and toast syndrome") may have a marked reduction in water excretory capacity that is directly mediated by poor dietary intake [68-70]. Ingestion of a normal diet results in the generation and excretion of 600 to 900 mosmol of solute per day (primarily sodium and potassium salts and urea). Thus, if the minimum urine osmolality is 60 mosmol/kg, the maximum urine output will be 10 to 15 L/day (eg, 900 mosmol/day 60 mosmol/kg = 15 L). In contrast, beer contains little or no sodium, potassium, or protein to generate solutes for excretion. In addition, the alcohol and carbohydrate load from beer will suppress endogenous protein breakdown and therefore urea excretion. As a result, daily solute excretion may fall below 250 mosmol, leading to a reduction in the maximum urine output to below 4 L/day even though the urine is maximally dilute. Hyponatremia will ensue if more than this amount of fluid is taken in. HYPONATREMIA WITH A HIGH OR NORMAL SERUM OSMOLALITY Although hyponatremia is typically associated with a proportional reduction in serum osmolality (to a level below 275 mosmol/kg), some patients have a high (ie, greater than 295 mosmol/kg) or normal serum osmolality. One example, advanced renal failure, was described above. In that disorder, the associated elevation in blood urea nitrogen can counteract the fall in serum osmolality induced by hyponatremia. However, the effective serum osmolality is reduced in proportion to the hyponatremia in this setting since urea is an ineffective osmole. (See 'Advanced renal failure' above.) In the following sections on high and normal serum osmolality, the development of hyponatremia may be linked to the factor that affects the serum osmolality. It is also possible that the factor that raises the serum osmolality is independent of the development of hyponatremia. One example of such an effect is alcohol ingestion [71]. Alcohol is an ineffective osmole (like urea) and will therefore not cause hyponatremia; however, alcohol will increase osmolality. Thus, in patients who are hyponatremic, significant alcohol ingestion can raise the serum osmolality to normal or high values. (See "Serum osmolal gap", section on 'Ethanol intoxication'.) High serum osmolality Hyponatremia with a high serum osmolality is most often due to marked hyperglycemia in patients with diabetic ketoacidosis or hyperosmolar hyperglycemic state (also known as nonketotic hyperglycemia). Less common causes include the administration and subsequent retention of hypertonic mannitol or of maltose or sucrose when intravenous immune globulin is given in a maltose or sucrose solution to patients with renal failure. (See "Complications of mannitol therapy" and "General principles in the use of immune globulin".) The rise in serum osmolality induced by hyperglycemia, mannitol, maltose, or sucrose pulls water out of the cells, thereby lowering the serum sodium concentration by dilution. Marked hyperglycemia The changes that can occur in patients with marked hyperglycemia are discussed in detail elsewhere but will be briefly reviewed here. (See "Clinical features and diagnosis of diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults", section on 'Serum sodium'.) Physiologic calculations suggest that the serum sodium concentration should fall by 1.6 meq/L for every 100 mg/dL (5.5 mmol/L) rise in the serum glucose concentration [72]. However, this standard correction factor was not verified experimentally. In an attempt to address this issue, hyperglycemia was induced in six healthy subjects by the administration of both somatostatin (to block endogenous

insulin secretion) and a hypertonic dextrose solution [73]. A nonlinear relationship was observed between the changes in the glucose and sodium concentrations: The 1.6:100 ratio applied when the serum glucose concentration was less than 400 mg/dL (22.2 mmol/L). At higher glucose concentrations, there was a greater reduction in the serum sodium concentration (1:25 ratio, ie, a 4 meq/L reduction in serum sodium per 100 mg/dL further increase in serum glucose). These calculations are idealized since they do not account for the osmotic diuresis typically induced by glucose excretion in the urine. The loss of water in excess of sodium and potassium will raise the serum sodium concentration. Some patients with uncontrolled diabetes have such a marked osmotic diuresis that, at presentation, the serum sodium concentration is increased and the serum osmolality is markedly elevated. The calculations are best used to estimate how much the serum sodium concentration will rise as the hyperglycemia is corrected. The administration of insulin drives glucose and water into the cells, reversing the initial direction of water movement and raising the serum sodium concentration. Normal serum osmolality Nonconductive irrigation solutions Isosmotic hyponatremia can be produced by the addition of an isosmotic (or near isosmotic) but non-sodiumcontaining fluid to the extracellular space. This problem primarily results from the absorption of variable quantities of nonconductive glycine or sorbitol irrigation solutions during transurethral resection of the prostate or bladder (called the transurethral resection syndrome) or during hysteroscopy or laparoscopic surgery. These patients may develop marked hyponatremia (below 110 meq/L) and neurologic symptoms. Multiple factors can contribute to the neurologic symptoms, including the very low serum sodium concentration itself, glycine toxicity, and the accumulation of ammonia, serine, or glyoxylate from the metabolism of glycine. (See "Hyponatremia following transurethral resection or hysteroscopy", section on 'Pathogenesis of neurologic symptoms' and "Hysteroscopy: Managing fluid and gas distending media".) Pseudohyponatremia Pseudohyponatremia, which is associated with a normal serum osmolality, refers to those disorders in which marked elevations in serum lipids or proteins result in a reduction in the fraction of serum that is water and an artificially low serum sodium concentration [2,74,75]. In normal subjects, the plasma water is approximately 93 percent of the plasma volume, with fats and proteins accounting for the remaining 7 percent. Thus, a normal plasma sodium concentration of 142 meq/L (measured per liter of plasma) actually represents a concentration in the physiologically important plasma water of 153 meq/L (142 0.93 = 153). However, the plasma water fraction may fall below 80 percent in patients with marked hyperlipidemia (as with lactescent serum in uncontrolled diabetes mellitus) or hyperproteinemia (as in multiple myeloma). In these settings, the plasma water sodium concentration and plasma osmolality are unchanged, but the measured sodium concentration in the total plasma volume will be reduced since the specimen contains less plasma water. This specific artifact is dependent upon the method used for electrolyte measurement. Thus, it is a prominent artifact when flame photometry or indirect potentiometry is utilized but does not occur when with direct potentiometry. The diagnosis and impact of pseudohyponatremia is discussed separately. (See "Evaluation of the patient with hyponatremia", section on 'Serum osmolality'.) 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 Although the definition may vary slightly among clinical laboratories, hyponatremia is commonly defined as a serum sodium concentration below 135 meq/L. In virtually all patients, hyponatremia is due to the intake (either oral or intravenous) of water that cannot be excreted. This is usually accompanied by a proportional fall in serum osmolality (to a level below 275 mosmol/kg) but there are settings in the which the serum osmolality is high (greater than 295 mosmol/kg) or normal. (See 'Introduction' above.) At least two classification systems have been used for the etiology of hyponatremia with a low serum osmolality: one stratifies patients according to whether circulating antidiuretic hormone (ADH) levels are inappropriately elevated or appropriately suppressed, and the other stratifies patients according to volume status (hypovolemia, normovolemia, or hypervolemia). (See 'Classification' above.) There are two major causes of hyponatremia with a low serum osmolality, both of which are associated with elevated serum ADH levels (see 'Hyponatremia with a low serum osmolality' above): Effective arterial blood volume depletion, which may be associated with true volume depletion (due, for example, to gastrointestinal or renal losses, as with thiazide diuretics) or with hypervolemia in patients with heart failure or cirrhosis. (See 'Effective arterial blood volume depletion' above.) Heart failure and cirrhosis cause hyponatremia despite increased plasma volume because the pressure sensed at the carotid sinus baroreceptors is reduced due to the fall in cardiac output in heart failure and to peripheral vasodilatation in cirrhosis. The rise in serum ADH levels varies with the severity of the disease, making the development of hyponatremia an important adverse prognostic sign. (See 'Heart failure and cirrhosis' above.) Normovolemia in the syndrome of inappropriate antidiuretic hormone secretion (SIADH). (See 'Syndrome of inappropriate ADH secretion' above.) Hyponatremia with a low serum osmolality can also occur in a number of other settings: In association with hormonal changes, such adrenal insufficiency, hypothyroidism, the release of human chorionic gonadotropin during pregnancy, and ectopic production of atrial natriuretic peptide. (See 'Endocrine disorders' above.) In marathon and ultramarathon runners due to excessive water intake combined with impaired water excretion due to persistent ADH secretion. A similar sequence can occur during military operations and desert hikes. (See 'Exercise-associated hyponatremia' above.) Despite appropriate suppression of ADH release in patients with advanced renal failure, primary polydipsia, and low dietary solute intake. (See

'Hyponatremia despite appropriate suppression of ADH' above.) Hyponatremia can also occur in patients with a high or normal serum osmolality; in addition to the following disorders which cause both hyponatremia and a high or normal serum osmolality, ethanol ingestion can raise the serum osmolality in patients who are hyponatremic for some other reason (see 'Hyponatremia with a high or normal serum osmolality' above): Hyponatremia with a high serum osmolality can be seen with hyperglycemia, advanced renal failure, or, less often, in association with the administration of hypertonic mannitol or maltose. In advanced renal failure, the associated elevation in blood urea nitrogen can counteract the fall in serum osmolality induced by hyponatremia. However, the effective serum osmolality is appropriately reduced in this setting since urea is an ineffective osmole. (See 'Advanced renal failure' above.) Hyponatremia with a normal (or near-normal) serum osmolality can result from the addition of an isosmotic but non-sodium-containing fluid to the extracellular space, as occurs with the use of nonconductive glycine or sorbitol flushing solutions during transurethral resection of the prostate or bladder. (See 'Nonconductive irrigation solutions' above.) Pseudohyponatremia is defined as an artificially low serum sodium concentration associated with a normal serum osmolality due to marked elevations in lipids or proteins, resulting in a reduction in the water-containing fraction of serum. (See 'Pseudohyponatremia' above.) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Adrogu HJ, Madias NE. Hyponatremia. N Engl J Med 2000; 342:1581. 2. Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York 2001. p.699. 3. Clayton JA, Le Jeune IR, Hall IP. Severe hyponatraemia in medical in-patients: aetiology, assessment and outcome. QJM 2006; 99:505. 4. EDELMAN IS, LEIBMAN J, O'MEARA MP, BIRKENFELD LW. Interrelations between serum sodium concentration, serum osmolarity and total exchangeable sodium, total exchangeable potassium and total body water. J Clin Invest 1958; 37:1236. 5. Anderson RJ, Chung HM, Kluge R, Schrier RW. Hyponatremia: a prospective analysis of its epidemiology and the pathogenetic role of vasopressin. Ann Intern Med 1985; 102:164. 6. Chung HM, Kluge R, Schrier RW, Anderson RJ. Clinical assessment of extracellular fluid volume in hyponatremia. Am J Med 1987; 83:905. 7. Pham PC, Pham PM, Pham PT. Vasopressin excess and hyponatremia. Am J Kidney Dis 2006; 47:727. 8. Alam NH, Majumder RN, Fuchs GJ. Efficacy and safety of oral rehydration solution with reduced osmolarity in adults with cholera: a randomised double-blind clinical trial. CHOICE study group. Lancet 1999; 354:296. 9. Ashraf N, Locksley R, Arieff AI. Thiazide-induced hyponatremia associated with death or neurologic damage in outpatients. Am J Med 1981; 70:1163. 10. Schrier RW. An odyssey into the milieu intrieur: pondering the enigmas. J Am Soc Nephrol 1992; 2:1549. 11. Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med 2007; 356:2064.

12. SCHWARTZ WB, BENNETT W, CURELOP S, BARTTER FC. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med 1957; 23:529. 13. Schrier RW. Body water homeostasis: clinical disorders of urinary dilution and concentration. J Am Soc Nephrol 2006; 17:1820. 14. Derubertis FR Jr, Michelis MF, Bloom ME, et al. Impaired water excretion in myxedema. Am J Med 1971; 51:41. 15. Hanna FW, Scanlon MF. Hyponatraemia, hypothyroidism, and role of arginine-vasopressin. Lancet 1997; 350:755. 16. Schrier RW, Bichet DG. Osmotic and nonosmotic control of vasopressin release and the pathogenesis of impaired water excretion in adrenal, thyroid, and edematous disorders. J Lab Clin Med 1981; 98:1. 17. Skowsky WR, Kikuchi TA. The role of vasopressin in the impaired water excretion of myxedema. Am J Med 1978; 64:613. 18. Kreisman SH, Hennessey JV. Consistent reversible elevations of serum creatinine levels in severe hypothyroidism. Arch Intern Med 1999; 159:79. 19. Archambeaud-Mouveroux F, Dejax C, Jadaud JM, et al. [Myxedema coma with hypervasopressinism. 2 cases]. Ann Med Interne (Paris) 1987; 138:114. 20. Iwasaki Y, Oiso Y, Yamauchi K, et al. Osmoregulation of plasma vasopressin in myxedema. J Clin Endocrinol Metab 1990; 70:534. 21. Schmitz PH, de Meijer PH, Meinders AE. Hyponatremia due to hypothyroidism: a pure renal mechanism. Neth J Med 2001; 58:143. 22. Kilpatrick ES. Disorders of sodium balance: hypothyroidism and hyponatraemia: an old wives' tale? BMJ 2006; 332:854. 23. Warner MH, Holding S, Kilpatrick ES. The effect of newly diagnosed hypothyroidism on serum sodium concentrations: a retrospective study. Clin Endocrinol (Oxf) 2006; 64:598. 24. Shakir MK, Krook LS, Schraml FV, et al. Symptomatic hyponatremia in association with a low-iodine diet and levothyroxine withdrawal prior to I131 in patients with metastatic thyroid carcinoma. Thyroid 2008; 18:787. 25. Davison JM, Shiells EA, Philips PR, Lindheimer MD. Influence of humoral and volume factors on altered osmoregulation of normal human pregnancy. Am J Physiol 1990; 258:F900. 26. Johnson BE, Chute JP, Rushin J, et al. A prospective study of patients with lung cancer and hyponatremia of malignancy. Am J Respir Crit Care Med 1997; 156:1669. 27. Chute JP, Taylor E, Williams J, et al. A metabolic study of patients with lung cancer and hyponatremia of malignancy. Clin Cancer Res 2006; 12:888. 28. Johnson BE, Damodaran A, Rushin J, et al. Ectopic production and processing of atrial natriuretic peptide in a small cell lung carcinoma cell line and tumor from a patient with hyponatremia. Cancer 1997; 79:35. 29. Campbell GA, Rosner MH. The agony of ecstasy: MDMA (3,4-methylenedioxymethamphetamine) and the kidney. Clin J Am Soc Nephrol 2008; 3:1852. 30. Hartung TK, Schofield E, Short AI, et al. Hyponatraemic states following 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') ingestion. QJM 2002; 95:431. 31. Holmes SB, Banerjee AK, Alexander WD. Hyponatraemia and seizures after ecstasy use. Postgrad Med J 1999; 75:32. 32. Holden R, Jackson MA. Near-fatal hyponatraemic coma due to vasopressin over-secretion after "ecstasy" (3,4-MDMA). Lancet 1996; 347:1052. 33. Cherney DZ, Davids MR, Halperin ML. Acute hyponatraemia and 'ecstasy': insights from a quantitative and integrative analysis. QJM 2002; 95:475. 34. Henry JA, Fallon JK, Kicman AT, et al. Low-dose MDMA ("ecstasy") induces vasopressin secretion. Lancet 1998; 351:1784.

35. Wolff K, Tsapakis EM, Winstock AR, et al. Vasopressin and oxytocin secretion in response to the consumption of ecstasy in a clubbing population. J Psychopharmacol 2006; 20:400. 36. Rosenson J, Smollin C, Sporer KA, et al. Patterns of ecstasy-associated hyponatremia in California. Ann Emerg Med 2007; 49:164. 37. Farah R, Farah R. Ecstasy (3,4-methylenedioxymethamphetamine)-induced inappropriate antidiuretic hormone secretion. Pediatr Emerg Care 2008; 24:615. 38. Budisavljevic MN, Stewart L, Sahn SA, Ploth DW. Hyponatremia associated with 3,4-methylenedioxymethylamphetamine ("Ecstasy") abuse. Am J Med Sci 2003; 326:89. 39. Rogers G, Elston J, Garside R, et al. The harmful health effects of recreational ecstasy: a systematic review of observational evidence. Health Technol Assess 2009; 13:iii. 40. Ayus JC, Wheeler JM, Arieff AI. Postoperative hyponatremic encephalopathy in menstruant women. Ann Intern Med 1992; 117:891. 41. van Dijken GD, Blom RE, Hen RJ, et al. High incidence of mild hyponatraemia in females using ecstasy at a rave party. Nephrol Dial Transplant 2013; 28:2277. 42. Moritz ML, Kalantar-Zadeh K, Ayus JC. Ecstacy-associated hyponatremia: why are women at risk? Nephrol Dial Transplant 2013; 28:2206. 43. KLEEMAN CR, ADAMS DA, MAXWELL MH. An evaluation of maximal water diuresis in chronic renal disease. I. Normal solute intake. J Lab Clin Med 1961; 58:169. 44. Tannen RL, Regal EM, Dunn MJ, Schrier RW. Vasopressin-resistant hyposthenuria in advanced chronic renal disease. N Engl J Med 1969; 280:1135. 45. Hariprasad MK, Eisinger RP, Nadler IM, et al. Hyponatremia in psychogenic polydipsia. Arch Intern Med 1980; 140:1639. 46. BARLOW ED, DE WARDENER HE. Compulsive water drinking. Q J Med 1959; 28:235. 47. Rao KJ, Miller M, Moses A. Water intoxication and thioridazine (Mellaril). Ann Intern Med 1975; 82:61. 48. Illowsky BP, Kirch DG. Polydipsia and hyponatremia in psychiatric patients. Am J Psychiatry 1988; 145:675. 49. de Leon J. Polydipsia--a study in a long-term psychiatric unit. Eur Arch Psychiatry Clin Neurosci 2003; 253:37. 50. Kawai N, Baba A, Suzuki T, Shiraishi H. Roles of arginine vasopressin and atrial natriuretic peptide in polydipsia-hyponatremia of schizophrenic patients. Psychiatry Res 2001; 101:39. 51. Jose CJ, Perez-Cruet J. Incidence and morbidity of self-induced water intoxication in state mental hospital patients. Am J Psychiatry 1979; 136:221. 52. Goldman MB, Luchins DJ, Robertson GL. Mechanisms of altered water metabolism in psychotic patients with polydipsia and hyponatremia. N Engl J Med 1988; 318:397. 53. Thompson CJ, Edwards CR, Baylis PH. Osmotic and non-osmotic regulation of thirst and vasopressin secretion in patients with compulsive water drinking. Clin Endocrinol (Oxf) 1991; 35:221. 54. Thompson CJ, Selby P, Baylis PH. Reproducibility of osmotic and nonosmotic tests of vasopressin secretion in men. Am J Physiol 1991; 260:R533. 55. LANGGARD H, SMITH WO. Self-induced water intoxication without predisposing illness. N Engl J Med 1962; 266:378. 56. Gillum DM, Linas SL. Water intoxication in a psychotic patient with normal renal water excretion. Am J Med 1984; 77:773. 57. Klonoff DC, Jurow AH. Acute water intoxication as a complication of urine drug testing in the workplace. JAMA 1991; 265:84. 58. Dubovsky SL, Grabon S, Berl T, Schrier RW. Syndrome of inappropriate secretion of antidiuretic hormone with exacerbated psychosis. Ann Intern

Med 1973; 79:551. 59. Goldman MB, Robertson GL, Luchins DJ, Hedeker D. The influence of polydipsia on water excretion in hyponatremic, polydipsic, schizophrenic patients. J Clin Endocrinol Metab 1996; 81:1465. 60. Goldman MB, Robertson GL, Luchins DJ, et al. Psychotic exacerbations and enhanced vasopressin secretion in schizophrenic patients with hyponatremia and polydipsia. Arch Gen Psychiatry 1997; 54:443. 61. Flegel KM, Cole CH. Inappropriate antidiuresis during carbamazepine treatment. Ann Intern Med 1977; 87:722. 62. Cohen BJ, Mahelsky M, Adler L. More cases of SIADH with fluoxetine. Am J Psychiatry 1990; 147:948. 63. Levine S, McManus BM, Blackbourne BD, Roberts WC. Fatal water intoxication, schizophrenia, and diuretic therapy for systemic hypertension. Am J Med 1987; 82:153. 64. Stuart CA, Neelon FA, Lebovitz HE. Disordered control of thirst in hypothalamic-pituitary sarcoidosis. N Engl J Med 1980; 303:1078. 65. Cheng JC, Zikos D, Skopicki HA, et al. Long-term neurologic outcome in psychogenic water drinkers with severe symptomatic hyponatremia: the effect of rapid correction. Am J Med 1990; 88:561. 66. Tanneau RS, Henry A, Rouhart F, et al. High incidence of neurologic complications following rapid correction of severe hyponatremia in polydipsic patients. J Clin Psychiatry 1994; 55:349. 67. Alexander RC, Karp BI, Thompson S, et al. A double blind, placebo-controlled trial of demeclocycline treatment of polydipsia-hyponatremia in chronically psychotic patients. Biol Psychiatry 1991; 30:417. 68. Hilden T, Svendsen TL. Electrolyte disturbances in beer drinkers. A specific "hypo-osmolality syndrome". Lancet 1975; 2:245. 69. Thaler SM, Teitelbaum I, Berl T. "Beer potomania" in non-beer drinkers: effect of low dietary solute intake. Am J Kidney Dis 1998; 31:1028. 70. Fox BD. Crash diet potomania. Lancet 2002; 359:942. 71. Purssell RA, Pudek M, Brubacher J, Abu-Laban RB. Derivation and validation of a formula to calculate the contribution of ethanol to the osmolal gap. Ann Emerg Med 2001; 38:653. 72. Katz MA. Hyperglycemia-induced hyponatremia--calculation of expected serum sodium depression. N Engl J Med 1973; 289:843. 73. Hillier TA, Abbott RD, Barrett EJ. Hyponatremia: evaluating the correction factor for hyperglycemia. Am J Med 1999; 106:399. 74. Weisberg LS. Pseudohyponatremia: a reappraisal. Am J Med 1989; 86:315. 75. Turchin A, Seifter JL, Seely EW. Clinical problem-solving. Mind the gap. N Engl J Med 2003; 349:1465. Topic 2374 Version 18.0

GRAPHICS Osmotic regulation of ADH release and thirst

Relation between plasma antidiuretic hormone (ADH) concentration and plasma osmolality in normal humans in whom the plasma osmolality was changed by varying the state of hydration. The osmotic threshold for thirst is a few mosmol/kg higher than that for ADH.
Data from Robertson GL, Aycinena P, Zerbe RL. Am J Med 1982; 72:339.

Major causes of hyponatremia

Disorders in which ADH levels are elevated
Effective circulating volume depletion
True volume depletion Heart failure C irrhosis Thiazide diuretics

Syndrome of inappropriate ADH secretion, including reset osmostat pattern Hormonal changes
Adrenal insufficiency Hypothyroidism Pregnancy

Disorders in which ADH levels may be appropriately suppressed

Advanced renal failure Primary polydipsia Beer drinker's potomania

Hyponatremia with normal or elevated plasma osmolality

High plasma osmolality (effective osmols)
Hyperglycemia Mannitol

High plasma osmolality (ineffective osmols)

Renal failure Alcohol intoxication with an elevated serum alcohol concentration

Normal plasma osmolality

Pseudohyponatremia (laboratory artifact) High triglycerides C holestatic and obstructive jaundice (lipoprotein X)

Multiple myeloma Absorption of irrigant solutions Glycine Sorbitol Mannitol

Determinants of the plasma sodium concentration

Among both normal subjects and patients with a variety of diseases, there is a very close correlation between the plasma water sodium concentration and the ratio of total body exchangeable solutes (primarily Na salts in the extracellular fluid + K salts in the cells) to the total body water (TBW). The exchangeable portion is used since about 30 percent of the body Na and a smaller fraction of the body K are bound in areas such as bone where they are "nonexchangeable" and therefore osmotically inactive.
Adapted from Edelman I, Leibman J, O'Meara MP, et al. J Clin Invest 1958; 37:1236, by copyright permission of the American Society for Clinical Investigation.

Hypovolemic stimulus to ADH release

Relationship of plasma antidiuretic hormone (ADH) concentrations to isosmotic changes in blood volume in the rat. Much higher ADH levels can occur with hypovolemia than with hyperosmolality, although a relatively large fall in blood volume is required before this response is initiated.
Data from Dunn FL, Brennan TJ, Nelson AE, et al. J Clin Invest 1973; 52:3212.

Hyponatremia associated with reduced survival in patients with severe chronic heart failure

Survival over time in patients with severe chronic heart failure and a left ventricular ejection fraction less than 30 percent who, at study entry, had either a normal plasma sodium concentration (greater than 137 meq/L, solid line) or hyponatremia (plasma sodium less than or equal to 137 meq/L, dashed line). Survival was significantly reduced in the patients with hyponatremia. The survival rate was very low (approximately 15 percent at 12 months) in those with a baseline plasma sodium concentration less than or equal to 130 meq/L.
Data from: Lee WH, Packer M. Circulation 1986; 73:257.