Why is SIADH Important to Hospitalists?

Disorders of body fluids, and particularly hyponatremia, are among the most commonly encountered problems in clinical medicine, affecting up to 30% of hospitalized patients. In a study of 303,577 laboratory samples collected from 120,137 patients, the prevalence of hyponatremia (serum [Na⁺] 135 mmol/L) on initial presentation to a healthcare provider was 28.2% among those treated in an acute hospital care setting, 21% among those treated in an ambulatory hospital care setting, and 7.2% in community care centers.1 Numerous other studies have corroborated a high prevalence of hyponatremia in hospitalized patients,2 which reflects the increased vulnerability of this patient population to disruptions of body fluid homeostasis. Recognizing the many possible causes of hyponatremia in hospitalized patients and implementing appropriate treatment strategies therefore are critical steps toward optimizing care and improving outcomes in hospitalized patients with hyponatremia.

In addition to its frequency, hyponatremia is also important because it has been associated with worse clinical outcomes across the entire range of inpatient care, from the general hospital population to those treated in the intensive care unit (ICU). In a study of 4123 patients age 65 years or older who were admitted to a community hospital, 3.5% had clinically significant hyponatremia (serum [Na⁺] 130 mmol/L) at admission. Compared with nonhyponatremic patients, those with hyponatremia were twice as likely to die during their hospital stay (relative risk [RR], 1.95; P 0.05).3 In another study of 2188 patients admitted to a medical ICU over a 5‐year period, 13.7% had hyponatremia. The overall rate of in‐hospital mortality among all ICU patients was high at 37.7%. However, severe hyponatremia (serum [Na⁺] 125 mmol/L) more than doubled the risk of in‐hospital mortality (RR, 2.10; P 0.001).4 In addition to the general hospital population, in virtually every disease ever studied, the presence of hyponatremia has been found to be an independent risk factor for increased mortality, from congestive heart failure to tuberculosis to liver failure.2

What Causes Hyponatremia in Patients with SIADH?

Hyponatremia can be caused by 1 of 2 potential disruptions in fluid balance: dilution from retained water, or depletion from electrolyte losses in excess of water. Dilutional hyponatremias are associated with either a normal (euvolemic) or an increased (hypervolemic) extracellular fluid (ECF) volume, whereas depletional hyponatremias generally are associated with a decreased ECF volume (hypovolemic). Dilutional hyponatremia can arise from a primary defect in osmoregulation, such as in SIADH, or as a result of ECF volume expansion, as seen in conditions associated with concomitant secondary hyperaldosteronism such as heart failure, hepatic cirrhosis, or nephrotic syndrome. Among some hospitalized patient groups, euvolemic hyponatremia is the most common presentation of abnormally low serum [Na⁺]. In a study of patients who developed clinically significant postoperative hyponatremia (defined as a serum [Na⁺] 130 mmol/L) in a large teaching hospital, only 8% were hypovolemic, whereas 42% were euvolemic and 21% were hypervolemic.5

Euvolemic hyponatremia results from an increase in total body water, but with normal or near‐normal total body sodium. As a result, there is an absence of clinical manifestations of ECF volume expansion, such as subcutaneous edema or ascites. It is important to recognize that although SIADH clearly represents a state of volume expansion due to water retention, it rarely causes clinically recognizable hypervolemia since the retained water is distributed across the intracellular fluid (ICF) as well as the ECF, and because volume regulatory processes act to decrease the actual degree of ECF volume expansion.6 Euvolemic hyponatremia can accompany a wide variety of pathological processes, but the most common cause by far is SIADH. Normally, increased plasma osmolality activates osmoreceptors located in the anterior hypothalamus and stimulates the secretion of arginine vasopressin (AVP), also called antidiuretic hormone (ADH), a key neurohormone that regulates fluid homeostasis. In patients with euvolemic hyponatremia due to SIADH, plasma AVP levels are not suppressed despite normal or decreased plasma osmolality.7 This can be a result of ectopic production of AVP by tumors, or stimulation of endogenous pituitary AVP secretion as a result of nonosmotic stimuli that also stimulate vasopressinergic neurons, which include hypovolemia, hypotension, angiotensin II, nausea, hypoxia, hypercarbia, hypoglycemia, stress, and physical activity. Nonsuppressed AVP levels have been documented in the majority of hyponatremic patients, including those with SIADH8 and heart failure.9

SIADH can develop as the result of many different disease processes that disrupt the normal mechanisms that regulate AVP secretion, including pneumonias and other lung infections, thoracic and extrathoracic tumors, a variety of different central nervous system disorders, the postoperative state, human immunodeficiency virus (HIV), and many different drugs (Figure 1). Given the multiplicity of disorders and drugs that can cause disrupted AVP secretion, it is not surprising that hyponatremia is the most common electrolyte abnormality seen in clinical practice.

Figure 1

What Symptoms are Associated With SIADH?

Symptoms of hyponatremia correlate both with the degree of decrease in the serum [Na⁺] and with the chronicity of the hyponatremia. Acute hyponatremia, defined as 48 hours in duration, is often associated with life‐threatening clinical features such as obtundation, seizures, coma, and respiratory arrest. These symptoms can occur abruptly, sometimes with little warning.10 In the most severe cases, death can occur as a result of cerebral edema with tentorial herniation. Hypoxia secondary to neurogenic pulmonary edema can increase the severity of brain swelling.11

In contrast, chronic hyponatremia is much less symptomatic, and the reason for the profound differences between the symptoms of acute and chronic hyponatremia is now well understood to be due to the process of brain volume regulation.12 It is essential that this process be understood in order to understand the full spectrum of hyponatremic symptoms. As the ECF [Na⁺] decreases, regardless of whether due to a loss of sodium or a gain of water, there is an obligate movement of water into the brain along osmotic gradients. That water shift causes swelling of the brain, or cerebral edema. If the increased brain water reaches approximately 8% in adults, it exceeds the capacity of the skull to accommodate brain expansion, leading to tentorial herniation and death from respiratory arrest and/or ischemic brain damage. However, if the patient survives the initial hyponatremia, a very strong volume regulatory process follows, consisting of loss of electrolytes and small organic molecules called osmolytes from brain cells into brain ECF, and eventually the peripheral ECF.12, 13 As the solute content of the brain decreases, the water content is allowed to normalize, eventually reaching a state in which brain edema is virtually absent, and as a result symptoms are markedly less than with acute hyponatremia. Although the time required for the brain to acieve a volume‐regulated state varies across patients, this process is completed within 48 hours in experinmental animal studies, and probably follows a similar time course in humans.

Despite this powerful adaptation process, chronic hyponatremia is frequently associated with neurological symptomatology, albeit milder and more subtle in nature. A recent report found a fairly high incidence of symptoms in 223 patients with chronic hyponatremia as a result of thiazide administration: 49% had malaise/lethargy, 47% had dizzy spells, 35% had vomiting, 17% had confusion/obtundation, 17% experienced falls, 6% had headaches, and 0.9% had seizures.14 Although dizziness can potentially be attributed to a diuretic‐induced hypovolemia, symptoms such as confusion, obtundation and seizures are more consistent with hyponatremic symptomatology. Because thiazide‐induced hyponatremia can be readily corrected by stopping the thiazide and/or administering sodium, this represents an ideal situation in which to assess improvement in hyponatremia symptomatology with normalization of the serum [Na⁺]; in this study, all of these symptoms improved with correction of the hyponatremia. This represents one of the best examples demonstrating reversal of the symptoms associated with chronic hyponatremia by correction of the hyponatremia, because the patients in this study did not in general have severe underlying comorbidities that might complicate interpretation of their symptoms, as is often the case in patients with SIADH.

What Is Required for Making a Diagnosis of SIADH in Hospitalized Patients?

In patients with hypotonic hypoosmolality, ascertainment of their ECF volume status (ie, hypovolemic, euvolemic, or hypervolemic) is an essential first step, as this will segregate patients into different treatment paradigms. For example, in patients who are truly clinically hypovolemic with a decreased ECF volume by clinical parameters, treatment would generally consist of solute repletion with sodium, generally isotonic saline infusion with or without potassium, until the sodium levels normalize. In patients who are hypervolemic, treatment should focus first on the underlying disease rather than addressing the serum [Na⁺] directly. In patients with clinical euvolemia, the standard diagnostic pathway should be followed to confirm a diagnosis of SIADH as described below.

Assessing ECF volume status can be difficult, even for the most experienced clinicians. Physical signs such as orthostatic decreases in blood pressure and increases in pulse rate, dry mucus membranes, and skin tenting indicate hypovolemic hyponatremia, while signs such as subcutaneous edema, ascites, or anasarca indicate hypervolemic hyponatremia. Patients without any of these findings are generally considered to be euvolemic. However, in any situation these signs are only applicable if there are no other reasons to suspect an altered ECF volume. Along with a complete history and physical examination that includes a careful neurological evaluation, several laboratory tests can help to assess the etiology of the hyponatremia, once serum sodium concentrations have been shown to be below normal ([Na⁺] 135 mmol/L):

• Urine osmolality. A urine osmolality (U_osm) less than 100 mOsm/kg H₂O can indicate low dietary solute intake, primary polydipsia, or a reset osmostat after suppression of AVP release by a decrease in plasma osmolality below the osmotic threshold for AVP secretion, usually as a result of increased water loading.

• Urine sodium concentration. Excretion of sodium, as measured by a spot urine [Na⁺] (U_Na), can indicate depletional hyponatremia if the concentration is less than 30 mmol/L.15 A low U_Na reflects a volume depleted state unless the patient has secondary hyperaldosteronism from heart failure or cirrhosis. Patients with a low U_Na are more likely to respond to isotonic saline. Euvolemic patients who have a normal dietary sodium intake will generally have spot U_Na 30 mmol/L and will not benefit from isotonic saline administration.15 In fact, in SIADH, these patients may respond to isotonic saline with a worsening of hyponatremia, since the sodium from the isotonic saline will be excreted in a concentrated urine while the free water is reabsorbed in the kidney collecting ducts. If the patient is on diuretic therapy, urine sodium values cannot always be accurately interpreted, since a U_Na 30 mmol/L may reflect the natriuretic effect of the diuretic and not a volume replete state.

• Blood tests. Additional indicators of volume status include serum blood nitrogen (BUN) and uric acid levels. A BUN 10 mg/dL and uric acid 4 mg/dL are generally consistent with a euvolemic state, particularly when there is glomerular hyperfiltration, which is often present in SIADH. Elevated serum BUN and uric acid levels (BUN >20 mg/dL and uric acid >6 mg/dL), especially if prior values are available for comparison, can also help to establish whether ineffective vascular volume status may be contributing to the pathophysiology of the hyponatremia. In certain clinical scenarios, the B‐type natriuretic protein (BNP) can be helpful to support a clinical impression of congestive heart failure.

The criteria necessary for a diagnosis of SIADH remain essentially as defined by Bartter and Schwartz16 in 1967 (Table 1), but several points deserve emphasis.17 First, true ECF hypoosmolality must be present and hyponatremia secondary to pseudohyponatremia or hyperglycemia excluded. Second, urinary osmolality must be inappropriate for plasma hypoosmolality (P_osm). This does not require a U_osm>P_osm, but simply that the urine osmolality is greater than maximally dilute (ie, U_osm>100 mOsm/kg H₂O in adults). Furthermore, urine osmolality need not be inappropriately elevated at all levels of P_osm but simply at some level under 275 mOsm/kg H₂O, since in patients with a reset osmostat, AVP secretion can be suppressed at some level of osmolality resulting in maximal urinary dilution and free water excretion at plasma osmolalities below this level.18 Although some consider a reset osmostat to be a separate disorder rather than a variant of SIADH, such cases nonetheless illustrate that some hypoosmolar patients can exhibit an appropriately dilute urine at some, though not all, plasma osmolalities. Third, clinical euvolemia must be present to diagnose SIADH, and this diagnosis cannot be made in a hypovolemic or edematous patient. Importantly, this does not mean that patients with SIADH cannot become hypovolemic for other reasons, but in such cases it is impossible to diagnose the underlying SIADH until the patient is rendered euvolemic. The fourth criterion, renal salt wasting, has probably caused the most confusion in the diagnosis of SIADH. As noted above, the importance of this criterion lies in its usefulness in differentiating hypoosmolality caused by a decreased effective intravascular volume with high aldosterone levels in which case renal Na⁺ conservation occurs, from dilutional disorders in which urine Na⁺ excretion is normal or increased due to ECF volume expansion and a suppressed renin‐angiotensin‐aldosterone system. However, U_Na can also be high in renal causes of solute depletion such as diuretic use or Addison's disease, and conversely patients with SIADH can have a low U_Na if they subsequently become hypovolemic or solute depleted, conditions sometimes produced by imposed salt and water restriction. Consequently, although high urinary Na⁺ excretion is generally the rule in most patients with SIADH, its presence does not necessarily confirm this diagnosis, nor does its absence rule out the diagnosis. The final criterion emphasizes that SIADH remains a diagnosis of exclusion, and the absence of other potential causes of hypoosmolality must always be verified. Glucocorticoid deficiency and SIADH can be especially difficult to distinguish, since both primary and secondary hypocortisolism can cause elevated plasma AVP levels in addition to direct renal effects that prevent maximal urinary dilution.19 Therefore, no patient with chronic hyponatremia should be diagnosed as having SIADH without a thorough evaluation of adrenal function, preferably via a rapid adrenocorticotropic hormone (ACTH) stimulation test. Acute hyponatremia of obvious etiology, such as postoperatively or in association with pneumonitis, may be treated without adrenal testing as long as there are no other clinical signs or symptoms suggestive of adrenal dysfunction.20

Hyponatremia is a particularly common complication in elderly hospitalized patients, increasing in prevalence from approximately 7% in the general older population to 18% to 22% among elderly patients in chronic care facilities.21 Despite the many known causes of SIADH (Figure 1), hyponatremia is often associated with idiopathic SIADH in the elderly population. In a study of 119 nursing home residents aged 60 to 103 years, 53% had at least 1 episode of hyponatremia during the previous 12 months.22 Of these patients, 26% were diagnosed with idiopathic SIADH. In another study of elderly patients with hyponatremia and SIADH, 60% were diagnosed with idiopathic SIADH. Among remaining patients, the 2 main causes identified were pneumonia (9 cases/18%) and medications (6 cases/12%).23 Therefore, more than half of elderly patients who present with hyponatremia due to SIADH may have an idiopathic form, with no detectable underlying treatable disease.

Which Hospital Patients With SIADH are Candidates for Treatment of Hyponatremia?

Correction of hyponatremia is associated with markedly improved neurological outcomes in patients with severely symptomatic hyponatremia. In a retrospective review of patients who presented with severe neurological symptoms and serum [Na⁺] 125 mmol/L, prompt therapy with isotonic or hypertonic saline resulted in a correction in the range of 20 mmol/L over several days and neurological recovery in almost all cases. In contrast, in patients who were treated with fluid restriction alone, there was very little correction over the study period (5 mmol/L over 72 hours), and the neurological outcomes were much worse, with most of these patients either dying or entering a persistently vegetative state.24 Consequently, prompt therapy to rapidly increase the serum [Na⁺] represents the standard‐of‐care for treatment of patients presenting with severe life‐threatening symptoms of hyponatremia.

As discussed earlier, chronic hyponatremia is much less symptomatic as a result of the process of brain volume regulation. Because of this adaptation process, chronic hyponatremia is arguably a condition that clinicians feel they may not need to be as concerned about, and in some publications this has been called asymptomatic hyponatremia. However, such patients often do have neurological symptoms, even if milder and more subtle in nature, including headaches, nausea, mood disturbances, depression, difficulty concentrating, slowed reaction times, unstable gait, increased falls, confusion, and disorientation. Consequently, any patient with hyponatremia secondary to SIADH who manifests any neurological symptoms that could be related to the hyponatremia should be considered as appropriate candidates for treatment of the hyponatremia, regardless of the chronicity of the hyponatremia or the level of serum [Na⁺].

What Therapies are Currently Available to Manage SIADH in Hospitalized Patients?

Conventional management strategies for euvolemic hyponatremia range from saline infusion and fluid restriction to pharmacologic adjustment of fluid balance. Consideration of treatment options should include an evaluation of the benefits as well as the potential toxicities of any therapy (Table 2). Sometimes, simply stopping treatment with an agent that is associated with hyponatremia is sufficient to reverse a low serum [Na⁺].

Why is SIADH Important to Hospitalists?

Disorders of body fluids, and particularly hyponatremia, are among the most commonly encountered problems in clinical medicine, affecting up to 30% of hospitalized patients. In a study of 303,577 laboratory samples collected from 120,137 patients, the prevalence of hyponatremia (serum [Na⁺] 135 mmol/L) on initial presentation to a healthcare provider was 28.2% among those treated in an acute hospital care setting, 21% among those treated in an ambulatory hospital care setting, and 7.2% in community care centers.1 Numerous other studies have corroborated a high prevalence of hyponatremia in hospitalized patients,2 which reflects the increased vulnerability of this patient population to disruptions of body fluid homeostasis. Recognizing the many possible causes of hyponatremia in hospitalized patients and implementing appropriate treatment strategies therefore are critical steps toward optimizing care and improving outcomes in hospitalized patients with hyponatremia.

In addition to its frequency, hyponatremia is also important because it has been associated with worse clinical outcomes across the entire range of inpatient care, from the general hospital population to those treated in the intensive care unit (ICU). In a study of 4123 patients age 65 years or older who were admitted to a community hospital, 3.5% had clinically significant hyponatremia (serum [Na⁺] 130 mmol/L) at admission. Compared with nonhyponatremic patients, those with hyponatremia were twice as likely to die during their hospital stay (relative risk [RR], 1.95; P 0.05).3 In another study of 2188 patients admitted to a medical ICU over a 5‐year period, 13.7% had hyponatremia. The overall rate of in‐hospital mortality among all ICU patients was high at 37.7%. However, severe hyponatremia (serum [Na⁺] 125 mmol/L) more than doubled the risk of in‐hospital mortality (RR, 2.10; P 0.001).4 In addition to the general hospital population, in virtually every disease ever studied, the presence of hyponatremia has been found to be an independent risk factor for increased mortality, from congestive heart failure to tuberculosis to liver failure.2

What Causes Hyponatremia in Patients with SIADH?

Hyponatremia can be caused by 1 of 2 potential disruptions in fluid balance: dilution from retained water, or depletion from electrolyte losses in excess of water. Dilutional hyponatremias are associated with either a normal (euvolemic) or an increased (hypervolemic) extracellular fluid (ECF) volume, whereas depletional hyponatremias generally are associated with a decreased ECF volume (hypovolemic). Dilutional hyponatremia can arise from a primary defect in osmoregulation, such as in SIADH, or as a result of ECF volume expansion, as seen in conditions associated with concomitant secondary hyperaldosteronism such as heart failure, hepatic cirrhosis, or nephrotic syndrome. Among some hospitalized patient groups, euvolemic hyponatremia is the most common presentation of abnormally low serum [Na⁺]. In a study of patients who developed clinically significant postoperative hyponatremia (defined as a serum [Na⁺] 130 mmol/L) in a large teaching hospital, only 8% were hypovolemic, whereas 42% were euvolemic and 21% were hypervolemic.5

Euvolemic hyponatremia results from an increase in total body water, but with normal or near‐normal total body sodium. As a result, there is an absence of clinical manifestations of ECF volume expansion, such as subcutaneous edema or ascites. It is important to recognize that although SIADH clearly represents a state of volume expansion due to water retention, it rarely causes clinically recognizable hypervolemia since the retained water is distributed across the intracellular fluid (ICF) as well as the ECF, and because volume regulatory processes act to decrease the actual degree of ECF volume expansion.6 Euvolemic hyponatremia can accompany a wide variety of pathological processes, but the most common cause by far is SIADH. Normally, increased plasma osmolality activates osmoreceptors located in the anterior hypothalamus and stimulates the secretion of arginine vasopressin (AVP), also called antidiuretic hormone (ADH), a key neurohormone that regulates fluid homeostasis. In patients with euvolemic hyponatremia due to SIADH, plasma AVP levels are not suppressed despite normal or decreased plasma osmolality.7 This can be a result of ectopic production of AVP by tumors, or stimulation of endogenous pituitary AVP secretion as a result of nonosmotic stimuli that also stimulate vasopressinergic neurons, which include hypovolemia, hypotension, angiotensin II, nausea, hypoxia, hypercarbia, hypoglycemia, stress, and physical activity. Nonsuppressed AVP levels have been documented in the majority of hyponatremic patients, including those with SIADH8 and heart failure.9

SIADH can develop as the result of many different disease processes that disrupt the normal mechanisms that regulate AVP secretion, including pneumonias and other lung infections, thoracic and extrathoracic tumors, a variety of different central nervous system disorders, the postoperative state, human immunodeficiency virus (HIV), and many different drugs (Figure 1). Given the multiplicity of disorders and drugs that can cause disrupted AVP secretion, it is not surprising that hyponatremia is the most common electrolyte abnormality seen in clinical practice.

Figure 1

What Symptoms are Associated With SIADH?

Symptoms of hyponatremia correlate both with the degree of decrease in the serum [Na⁺] and with the chronicity of the hyponatremia. Acute hyponatremia, defined as 48 hours in duration, is often associated with life‐threatening clinical features such as obtundation, seizures, coma, and respiratory arrest. These symptoms can occur abruptly, sometimes with little warning.10 In the most severe cases, death can occur as a result of cerebral edema with tentorial herniation. Hypoxia secondary to neurogenic pulmonary edema can increase the severity of brain swelling.11

In contrast, chronic hyponatremia is much less symptomatic, and the reason for the profound differences between the symptoms of acute and chronic hyponatremia is now well understood to be due to the process of brain volume regulation.12 It is essential that this process be understood in order to understand the full spectrum of hyponatremic symptoms. As the ECF [Na⁺] decreases, regardless of whether due to a loss of sodium or a gain of water, there is an obligate movement of water into the brain along osmotic gradients. That water shift causes swelling of the brain, or cerebral edema. If the increased brain water reaches approximately 8% in adults, it exceeds the capacity of the skull to accommodate brain expansion, leading to tentorial herniation and death from respiratory arrest and/or ischemic brain damage. However, if the patient survives the initial hyponatremia, a very strong volume regulatory process follows, consisting of loss of electrolytes and small organic molecules called osmolytes from brain cells into brain ECF, and eventually the peripheral ECF.12, 13 As the solute content of the brain decreases, the water content is allowed to normalize, eventually reaching a state in which brain edema is virtually absent, and as a result symptoms are markedly less than with acute hyponatremia. Although the time required for the brain to acieve a volume‐regulated state varies across patients, this process is completed within 48 hours in experinmental animal studies, and probably follows a similar time course in humans.

Despite this powerful adaptation process, chronic hyponatremia is frequently associated with neurological symptomatology, albeit milder and more subtle in nature. A recent report found a fairly high incidence of symptoms in 223 patients with chronic hyponatremia as a result of thiazide administration: 49% had malaise/lethargy, 47% had dizzy spells, 35% had vomiting, 17% had confusion/obtundation, 17% experienced falls, 6% had headaches, and 0.9% had seizures.14 Although dizziness can potentially be attributed to a diuretic‐induced hypovolemia, symptoms such as confusion, obtundation and seizures are more consistent with hyponatremic symptomatology. Because thiazide‐induced hyponatremia can be readily corrected by stopping the thiazide and/or administering sodium, this represents an ideal situation in which to assess improvement in hyponatremia symptomatology with normalization of the serum [Na⁺]; in this study, all of these symptoms improved with correction of the hyponatremia. This represents one of the best examples demonstrating reversal of the symptoms associated with chronic hyponatremia by correction of the hyponatremia, because the patients in this study did not in general have severe underlying comorbidities that might complicate interpretation of their symptoms, as is often the case in patients with SIADH.

What Is Required for Making a Diagnosis of SIADH in Hospitalized Patients?

In patients with hypotonic hypoosmolality, ascertainment of their ECF volume status (ie, hypovolemic, euvolemic, or hypervolemic) is an essential first step, as this will segregate patients into different treatment paradigms. For example, in patients who are truly clinically hypovolemic with a decreased ECF volume by clinical parameters, treatment would generally consist of solute repletion with sodium, generally isotonic saline infusion with or without potassium, until the sodium levels normalize. In patients who are hypervolemic, treatment should focus first on the underlying disease rather than addressing the serum [Na⁺] directly. In patients with clinical euvolemia, the standard diagnostic pathway should be followed to confirm a diagnosis of SIADH as described below.

Assessing ECF volume status can be difficult, even for the most experienced clinicians. Physical signs such as orthostatic decreases in blood pressure and increases in pulse rate, dry mucus membranes, and skin tenting indicate hypovolemic hyponatremia, while signs such as subcutaneous edema, ascites, or anasarca indicate hypervolemic hyponatremia. Patients without any of these findings are generally considered to be euvolemic. However, in any situation these signs are only applicable if there are no other reasons to suspect an altered ECF volume. Along with a complete history and physical examination that includes a careful neurological evaluation, several laboratory tests can help to assess the etiology of the hyponatremia, once serum sodium concentrations have been shown to be below normal ([Na⁺] 135 mmol/L):

• Urine osmolality. A urine osmolality (U_osm) less than 100 mOsm/kg H₂O can indicate low dietary solute intake, primary polydipsia, or a reset osmostat after suppression of AVP release by a decrease in plasma osmolality below the osmotic threshold for AVP secretion, usually as a result of increased water loading.

• Urine sodium concentration. Excretion of sodium, as measured by a spot urine [Na⁺] (U_Na), can indicate depletional hyponatremia if the concentration is less than 30 mmol/L.15 A low U_Na reflects a volume depleted state unless the patient has secondary hyperaldosteronism from heart failure or cirrhosis. Patients with a low U_Na are more likely to respond to isotonic saline. Euvolemic patients who have a normal dietary sodium intake will generally have spot U_Na 30 mmol/L and will not benefit from isotonic saline administration.15 In fact, in SIADH, these patients may respond to isotonic saline with a worsening of hyponatremia, since the sodium from the isotonic saline will be excreted in a concentrated urine while the free water is reabsorbed in the kidney collecting ducts. If the patient is on diuretic therapy, urine sodium values cannot always be accurately interpreted, since a U_Na 30 mmol/L may reflect the natriuretic effect of the diuretic and not a volume replete state.

• Blood tests. Additional indicators of volume status include serum blood nitrogen (BUN) and uric acid levels. A BUN 10 mg/dL and uric acid 4 mg/dL are generally consistent with a euvolemic state, particularly when there is glomerular hyperfiltration, which is often present in SIADH. Elevated serum BUN and uric acid levels (BUN >20 mg/dL and uric acid >6 mg/dL), especially if prior values are available for comparison, can also help to establish whether ineffective vascular volume status may be contributing to the pathophysiology of the hyponatremia. In certain clinical scenarios, the B‐type natriuretic protein (BNP) can be helpful to support a clinical impression of congestive heart failure.

The criteria necessary for a diagnosis of SIADH remain essentially as defined by Bartter and Schwartz16 in 1967 (Table 1), but several points deserve emphasis.17 First, true ECF hypoosmolality must be present and hyponatremia secondary to pseudohyponatremia or hyperglycemia excluded. Second, urinary osmolality must be inappropriate for plasma hypoosmolality (P_osm). This does not require a U_osm>P_osm, but simply that the urine osmolality is greater than maximally dilute (ie, U_osm>100 mOsm/kg H₂O in adults). Furthermore, urine osmolality need not be inappropriately elevated at all levels of P_osm but simply at some level under 275 mOsm/kg H₂O, since in patients with a reset osmostat, AVP secretion can be suppressed at some level of osmolality resulting in maximal urinary dilution and free water excretion at plasma osmolalities below this level.18 Although some consider a reset osmostat to be a separate disorder rather than a variant of SIADH, such cases nonetheless illustrate that some hypoosmolar patients can exhibit an appropriately dilute urine at some, though not all, plasma osmolalities. Third, clinical euvolemia must be present to diagnose SIADH, and this diagnosis cannot be made in a hypovolemic or edematous patient. Importantly, this does not mean that patients with SIADH cannot become hypovolemic for other reasons, but in such cases it is impossible to diagnose the underlying SIADH until the patient is rendered euvolemic. The fourth criterion, renal salt wasting, has probably caused the most confusion in the diagnosis of SIADH. As noted above, the importance of this criterion lies in its usefulness in differentiating hypoosmolality caused by a decreased effective intravascular volume with high aldosterone levels in which case renal Na⁺ conservation occurs, from dilutional disorders in which urine Na⁺ excretion is normal or increased due to ECF volume expansion and a suppressed renin‐angiotensin‐aldosterone system. However, U_Na can also be high in renal causes of solute depletion such as diuretic use or Addison's disease, and conversely patients with SIADH can have a low U_Na if they subsequently become hypovolemic or solute depleted, conditions sometimes produced by imposed salt and water restriction. Consequently, although high urinary Na⁺ excretion is generally the rule in most patients with SIADH, its presence does not necessarily confirm this diagnosis, nor does its absence rule out the diagnosis. The final criterion emphasizes that SIADH remains a diagnosis of exclusion, and the absence of other potential causes of hypoosmolality must always be verified. Glucocorticoid deficiency and SIADH can be especially difficult to distinguish, since both primary and secondary hypocortisolism can cause elevated plasma AVP levels in addition to direct renal effects that prevent maximal urinary dilution.19 Therefore, no patient with chronic hyponatremia should be diagnosed as having SIADH without a thorough evaluation of adrenal function, preferably via a rapid adrenocorticotropic hormone (ACTH) stimulation test. Acute hyponatremia of obvious etiology, such as postoperatively or in association with pneumonitis, may be treated without adrenal testing as long as there are no other clinical signs or symptoms suggestive of adrenal dysfunction.20

Hyponatremia is a particularly common complication in elderly hospitalized patients, increasing in prevalence from approximately 7% in the general older population to 18% to 22% among elderly patients in chronic care facilities.21 Despite the many known causes of SIADH (Figure 1), hyponatremia is often associated with idiopathic SIADH in the elderly population. In a study of 119 nursing home residents aged 60 to 103 years, 53% had at least 1 episode of hyponatremia during the previous 12 months.22 Of these patients, 26% were diagnosed with idiopathic SIADH. In another study of elderly patients with hyponatremia and SIADH, 60% were diagnosed with idiopathic SIADH. Among remaining patients, the 2 main causes identified were pneumonia (9 cases/18%) and medications (6 cases/12%).23 Therefore, more than half of elderly patients who present with hyponatremia due to SIADH may have an idiopathic form, with no detectable underlying treatable disease.

Which Hospital Patients With SIADH are Candidates for Treatment of Hyponatremia?

Correction of hyponatremia is associated with markedly improved neurological outcomes in patients with severely symptomatic hyponatremia. In a retrospective review of patients who presented with severe neurological symptoms and serum [Na⁺] 125 mmol/L, prompt therapy with isotonic or hypertonic saline resulted in a correction in the range of 20 mmol/L over several days and neurological recovery in almost all cases. In contrast, in patients who were treated with fluid restriction alone, there was very little correction over the study period (5 mmol/L over 72 hours), and the neurological outcomes were much worse, with most of these patients either dying or entering a persistently vegetative state.24 Consequently, prompt therapy to rapidly increase the serum [Na⁺] represents the standard‐of‐care for treatment of patients presenting with severe life‐threatening symptoms of hyponatremia.

As discussed earlier, chronic hyponatremia is much less symptomatic as a result of the process of brain volume regulation. Because of this adaptation process, chronic hyponatremia is arguably a condition that clinicians feel they may not need to be as concerned about, and in some publications this has been called asymptomatic hyponatremia. However, such patients often do have neurological symptoms, even if milder and more subtle in nature, including headaches, nausea, mood disturbances, depression, difficulty concentrating, slowed reaction times, unstable gait, increased falls, confusion, and disorientation. Consequently, any patient with hyponatremia secondary to SIADH who manifests any neurological symptoms that could be related to the hyponatremia should be considered as appropriate candidates for treatment of the hyponatremia, regardless of the chronicity of the hyponatremia or the level of serum [Na⁺].

What Therapies are Currently Available to Manage SIADH in Hospitalized Patients?

Conventional management strategies for euvolemic hyponatremia range from saline infusion and fluid restriction to pharmacologic adjustment of fluid balance. Consideration of treatment options should include an evaluation of the benefits as well as the potential toxicities of any therapy (Table 2). Sometimes, simply stopping treatment with an agent that is associated with hyponatremia is sufficient to reverse a low serum [Na⁺].

Why is SIADH Important to Hospitalists?

Disorders of body fluids, and particularly hyponatremia, are among the most commonly encountered problems in clinical medicine, affecting up to 30% of hospitalized patients. In a study of 303,577 laboratory samples collected from 120,137 patients, the prevalence of hyponatremia (serum [Na⁺] 135 mmol/L) on initial presentation to a healthcare provider was 28.2% among those treated in an acute hospital care setting, 21% among those treated in an ambulatory hospital care setting, and 7.2% in community care centers.1 Numerous other studies have corroborated a high prevalence of hyponatremia in hospitalized patients,2 which reflects the increased vulnerability of this patient population to disruptions of body fluid homeostasis. Recognizing the many possible causes of hyponatremia in hospitalized patients and implementing appropriate treatment strategies therefore are critical steps toward optimizing care and improving outcomes in hospitalized patients with hyponatremia.

In addition to its frequency, hyponatremia is also important because it has been associated with worse clinical outcomes across the entire range of inpatient care, from the general hospital population to those treated in the intensive care unit (ICU). In a study of 4123 patients age 65 years or older who were admitted to a community hospital, 3.5% had clinically significant hyponatremia (serum [Na⁺] 130 mmol/L) at admission. Compared with nonhyponatremic patients, those with hyponatremia were twice as likely to die during their hospital stay (relative risk [RR], 1.95; P 0.05).3 In another study of 2188 patients admitted to a medical ICU over a 5‐year period, 13.7% had hyponatremia. The overall rate of in‐hospital mortality among all ICU patients was high at 37.7%. However, severe hyponatremia (serum [Na⁺] 125 mmol/L) more than doubled the risk of in‐hospital mortality (RR, 2.10; P 0.001).4 In addition to the general hospital population, in virtually every disease ever studied, the presence of hyponatremia has been found to be an independent risk factor for increased mortality, from congestive heart failure to tuberculosis to liver failure.2

What Causes Hyponatremia in Patients with SIADH?

Hyponatremia can be caused by 1 of 2 potential disruptions in fluid balance: dilution from retained water, or depletion from electrolyte losses in excess of water. Dilutional hyponatremias are associated with either a normal (euvolemic) or an increased (hypervolemic) extracellular fluid (ECF) volume, whereas depletional hyponatremias generally are associated with a decreased ECF volume (hypovolemic). Dilutional hyponatremia can arise from a primary defect in osmoregulation, such as in SIADH, or as a result of ECF volume expansion, as seen in conditions associated with concomitant secondary hyperaldosteronism such as heart failure, hepatic cirrhosis, or nephrotic syndrome. Among some hospitalized patient groups, euvolemic hyponatremia is the most common presentation of abnormally low serum [Na⁺]. In a study of patients who developed clinically significant postoperative hyponatremia (defined as a serum [Na⁺] 130 mmol/L) in a large teaching hospital, only 8% were hypovolemic, whereas 42% were euvolemic and 21% were hypervolemic.5

Euvolemic hyponatremia results from an increase in total body water, but with normal or near‐normal total body sodium. As a result, there is an absence of clinical manifestations of ECF volume expansion, such as subcutaneous edema or ascites. It is important to recognize that although SIADH clearly represents a state of volume expansion due to water retention, it rarely causes clinically recognizable hypervolemia since the retained water is distributed across the intracellular fluid (ICF) as well as the ECF, and because volume regulatory processes act to decrease the actual degree of ECF volume expansion.6 Euvolemic hyponatremia can accompany a wide variety of pathological processes, but the most common cause by far is SIADH. Normally, increased plasma osmolality activates osmoreceptors located in the anterior hypothalamus and stimulates the secretion of arginine vasopressin (AVP), also called antidiuretic hormone (ADH), a key neurohormone that regulates fluid homeostasis. In patients with euvolemic hyponatremia due to SIADH, plasma AVP levels are not suppressed despite normal or decreased plasma osmolality.7 This can be a result of ectopic production of AVP by tumors, or stimulation of endogenous pituitary AVP secretion as a result of nonosmotic stimuli that also stimulate vasopressinergic neurons, which include hypovolemia, hypotension, angiotensin II, nausea, hypoxia, hypercarbia, hypoglycemia, stress, and physical activity. Nonsuppressed AVP levels have been documented in the majority of hyponatremic patients, including those with SIADH8 and heart failure.9

SIADH can develop as the result of many different disease processes that disrupt the normal mechanisms that regulate AVP secretion, including pneumonias and other lung infections, thoracic and extrathoracic tumors, a variety of different central nervous system disorders, the postoperative state, human immunodeficiency virus (HIV), and many different drugs (Figure 1). Given the multiplicity of disorders and drugs that can cause disrupted AVP secretion, it is not surprising that hyponatremia is the most common electrolyte abnormality seen in clinical practice.

Figure 1

What Symptoms are Associated With SIADH?

Symptoms of hyponatremia correlate both with the degree of decrease in the serum [Na⁺] and with the chronicity of the hyponatremia. Acute hyponatremia, defined as 48 hours in duration, is often associated with life‐threatening clinical features such as obtundation, seizures, coma, and respiratory arrest. These symptoms can occur abruptly, sometimes with little warning.10 In the most severe cases, death can occur as a result of cerebral edema with tentorial herniation. Hypoxia secondary to neurogenic pulmonary edema can increase the severity of brain swelling.11

In contrast, chronic hyponatremia is much less symptomatic, and the reason for the profound differences between the symptoms of acute and chronic hyponatremia is now well understood to be due to the process of brain volume regulation.12 It is essential that this process be understood in order to understand the full spectrum of hyponatremic symptoms. As the ECF [Na⁺] decreases, regardless of whether due to a loss of sodium or a gain of water, there is an obligate movement of water into the brain along osmotic gradients. That water shift causes swelling of the brain, or cerebral edema. If the increased brain water reaches approximately 8% in adults, it exceeds the capacity of the skull to accommodate brain expansion, leading to tentorial herniation and death from respiratory arrest and/or ischemic brain damage. However, if the patient survives the initial hyponatremia, a very strong volume regulatory process follows, consisting of loss of electrolytes and small organic molecules called osmolytes from brain cells into brain ECF, and eventually the peripheral ECF.12, 13 As the solute content of the brain decreases, the water content is allowed to normalize, eventually reaching a state in which brain edema is virtually absent, and as a result symptoms are markedly less than with acute hyponatremia. Although the time required for the brain to acieve a volume‐regulated state varies across patients, this process is completed within 48 hours in experinmental animal studies, and probably follows a similar time course in humans.

Despite this powerful adaptation process, chronic hyponatremia is frequently associated with neurological symptomatology, albeit milder and more subtle in nature. A recent report found a fairly high incidence of symptoms in 223 patients with chronic hyponatremia as a result of thiazide administration: 49% had malaise/lethargy, 47% had dizzy spells, 35% had vomiting, 17% had confusion/obtundation, 17% experienced falls, 6% had headaches, and 0.9% had seizures.14 Although dizziness can potentially be attributed to a diuretic‐induced hypovolemia, symptoms such as confusion, obtundation and seizures are more consistent with hyponatremic symptomatology. Because thiazide‐induced hyponatremia can be readily corrected by stopping the thiazide and/or administering sodium, this represents an ideal situation in which to assess improvement in hyponatremia symptomatology with normalization of the serum [Na⁺]; in this study, all of these symptoms improved with correction of the hyponatremia. This represents one of the best examples demonstrating reversal of the symptoms associated with chronic hyponatremia by correction of the hyponatremia, because the patients in this study did not in general have severe underlying comorbidities that might complicate interpretation of their symptoms, as is often the case in patients with SIADH.

What Is Required for Making a Diagnosis of SIADH in Hospitalized Patients?

In patients with hypotonic hypoosmolality, ascertainment of their ECF volume status (ie, hypovolemic, euvolemic, or hypervolemic) is an essential first step, as this will segregate patients into different treatment paradigms. For example, in patients who are truly clinically hypovolemic with a decreased ECF volume by clinical parameters, treatment would generally consist of solute repletion with sodium, generally isotonic saline infusion with or without potassium, until the sodium levels normalize. In patients who are hypervolemic, treatment should focus first on the underlying disease rather than addressing the serum [Na⁺] directly. In patients with clinical euvolemia, the standard diagnostic pathway should be followed to confirm a diagnosis of SIADH as described below.

Assessing ECF volume status can be difficult, even for the most experienced clinicians. Physical signs such as orthostatic decreases in blood pressure and increases in pulse rate, dry mucus membranes, and skin tenting indicate hypovolemic hyponatremia, while signs such as subcutaneous edema, ascites, or anasarca indicate hypervolemic hyponatremia. Patients without any of these findings are generally considered to be euvolemic. However, in any situation these signs are only applicable if there are no other reasons to suspect an altered ECF volume. Along with a complete history and physical examination that includes a careful neurological evaluation, several laboratory tests can help to assess the etiology of the hyponatremia, once serum sodium concentrations have been shown to be below normal ([Na⁺] 135 mmol/L):

• Urine osmolality. A urine osmolality (U_osm) less than 100 mOsm/kg H₂O can indicate low dietary solute intake, primary polydipsia, or a reset osmostat after suppression of AVP release by a decrease in plasma osmolality below the osmotic threshold for AVP secretion, usually as a result of increased water loading.

• Urine sodium concentration. Excretion of sodium, as measured by a spot urine [Na⁺] (U_Na), can indicate depletional hyponatremia if the concentration is less than 30 mmol/L.15 A low U_Na reflects a volume depleted state unless the patient has secondary hyperaldosteronism from heart failure or cirrhosis. Patients with a low U_Na are more likely to respond to isotonic saline. Euvolemic patients who have a normal dietary sodium intake will generally have spot U_Na 30 mmol/L and will not benefit from isotonic saline administration.15 In fact, in SIADH, these patients may respond to isotonic saline with a worsening of hyponatremia, since the sodium from the isotonic saline will be excreted in a concentrated urine while the free water is reabsorbed in the kidney collecting ducts. If the patient is on diuretic therapy, urine sodium values cannot always be accurately interpreted, since a U_Na 30 mmol/L may reflect the natriuretic effect of the diuretic and not a volume replete state.

• Blood tests. Additional indicators of volume status include serum blood nitrogen (BUN) and uric acid levels. A BUN 10 mg/dL and uric acid 4 mg/dL are generally consistent with a euvolemic state, particularly when there is glomerular hyperfiltration, which is often present in SIADH. Elevated serum BUN and uric acid levels (BUN >20 mg/dL and uric acid >6 mg/dL), especially if prior values are available for comparison, can also help to establish whether ineffective vascular volume status may be contributing to the pathophysiology of the hyponatremia. In certain clinical scenarios, the B‐type natriuretic protein (BNP) can be helpful to support a clinical impression of congestive heart failure.

The criteria necessary for a diagnosis of SIADH remain essentially as defined by Bartter and Schwartz16 in 1967 (Table 1), but several points deserve emphasis.17 First, true ECF hypoosmolality must be present and hyponatremia secondary to pseudohyponatremia or hyperglycemia excluded. Second, urinary osmolality must be inappropriate for plasma hypoosmolality (P_osm). This does not require a U_osm>P_osm, but simply that the urine osmolality is greater than maximally dilute (ie, U_osm>100 mOsm/kg H₂O in adults). Furthermore, urine osmolality need not be inappropriately elevated at all levels of P_osm but simply at some level under 275 mOsm/kg H₂O, since in patients with a reset osmostat, AVP secretion can be suppressed at some level of osmolality resulting in maximal urinary dilution and free water excretion at plasma osmolalities below this level.18 Although some consider a reset osmostat to be a separate disorder rather than a variant of SIADH, such cases nonetheless illustrate that some hypoosmolar patients can exhibit an appropriately dilute urine at some, though not all, plasma osmolalities. Third, clinical euvolemia must be present to diagnose SIADH, and this diagnosis cannot be made in a hypovolemic or edematous patient. Importantly, this does not mean that patients with SIADH cannot become hypovolemic for other reasons, but in such cases it is impossible to diagnose the underlying SIADH until the patient is rendered euvolemic. The fourth criterion, renal salt wasting, has probably caused the most confusion in the diagnosis of SIADH. As noted above, the importance of this criterion lies in its usefulness in differentiating hypoosmolality caused by a decreased effective intravascular volume with high aldosterone levels in which case renal Na⁺ conservation occurs, from dilutional disorders in which urine Na⁺ excretion is normal or increased due to ECF volume expansion and a suppressed renin‐angiotensin‐aldosterone system. However, U_Na can also be high in renal causes of solute depletion such as diuretic use or Addison's disease, and conversely patients with SIADH can have a low U_Na if they subsequently become hypovolemic or solute depleted, conditions sometimes produced by imposed salt and water restriction. Consequently, although high urinary Na⁺ excretion is generally the rule in most patients with SIADH, its presence does not necessarily confirm this diagnosis, nor does its absence rule out the diagnosis. The final criterion emphasizes that SIADH remains a diagnosis of exclusion, and the absence of other potential causes of hypoosmolality must always be verified. Glucocorticoid deficiency and SIADH can be especially difficult to distinguish, since both primary and secondary hypocortisolism can cause elevated plasma AVP levels in addition to direct renal effects that prevent maximal urinary dilution.19 Therefore, no patient with chronic hyponatremia should be diagnosed as having SIADH without a thorough evaluation of adrenal function, preferably via a rapid adrenocorticotropic hormone (ACTH) stimulation test. Acute hyponatremia of obvious etiology, such as postoperatively or in association with pneumonitis, may be treated without adrenal testing as long as there are no other clinical signs or symptoms suggestive of adrenal dysfunction.20

Hyponatremia is a particularly common complication in elderly hospitalized patients, increasing in prevalence from approximately 7% in the general older population to 18% to 22% among elderly patients in chronic care facilities.21 Despite the many known causes of SIADH (Figure 1), hyponatremia is often associated with idiopathic SIADH in the elderly population. In a study of 119 nursing home residents aged 60 to 103 years, 53% had at least 1 episode of hyponatremia during the previous 12 months.22 Of these patients, 26% were diagnosed with idiopathic SIADH. In another study of elderly patients with hyponatremia and SIADH, 60% were diagnosed with idiopathic SIADH. Among remaining patients, the 2 main causes identified were pneumonia (9 cases/18%) and medications (6 cases/12%).23 Therefore, more than half of elderly patients who present with hyponatremia due to SIADH may have an idiopathic form, with no detectable underlying treatable disease.

Which Hospital Patients With SIADH are Candidates for Treatment of Hyponatremia?

Correction of hyponatremia is associated with markedly improved neurological outcomes in patients with severely symptomatic hyponatremia. In a retrospective review of patients who presented with severe neurological symptoms and serum [Na⁺] 125 mmol/L, prompt therapy with isotonic or hypertonic saline resulted in a correction in the range of 20 mmol/L over several days and neurological recovery in almost all cases. In contrast, in patients who were treated with fluid restriction alone, there was very little correction over the study period (5 mmol/L over 72 hours), and the neurological outcomes were much worse, with most of these patients either dying or entering a persistently vegetative state.24 Consequently, prompt therapy to rapidly increase the serum [Na⁺] represents the standard‐of‐care for treatment of patients presenting with severe life‐threatening symptoms of hyponatremia.

As discussed earlier, chronic hyponatremia is much less symptomatic as a result of the process of brain volume regulation. Because of this adaptation process, chronic hyponatremia is arguably a condition that clinicians feel they may not need to be as concerned about, and in some publications this has been called asymptomatic hyponatremia. However, such patients often do have neurological symptoms, even if milder and more subtle in nature, including headaches, nausea, mood disturbances, depression, difficulty concentrating, slowed reaction times, unstable gait, increased falls, confusion, and disorientation. Consequently, any patient with hyponatremia secondary to SIADH who manifests any neurological symptoms that could be related to the hyponatremia should be considered as appropriate candidates for treatment of the hyponatremia, regardless of the chronicity of the hyponatremia or the level of serum [Na⁺].

What Therapies are Currently Available to Manage SIADH in Hospitalized Patients?

Conventional management strategies for euvolemic hyponatremia range from saline infusion and fluid restriction to pharmacologic adjustment of fluid balance. Consideration of treatment options should include an evaluation of the benefits as well as the potential toxicities of any therapy (Table 2). Sometimes, simply stopping treatment with an agent that is associated with hyponatremia is sufficient to reverse a low serum [Na⁺].

Under normal circumstances, there is a balance between water intake and water excretion such that plasma osmolality and the serum sodium (Na⁺) concentration remain relatively constant. The principal mechanism responsible for prevention of hyponatremia and hyposmolality is renal water excretion. In all hyponatremic patients, water intake exceeds renal water excretion.

Excretion of water by the kidney is dependent on 3 factors. First, there must be adequate delivery of filtrate to the tip of the loop of Henle. Second, solute absorption in the ascending limb and the distal nephron must be preserved so that the tubular fluid will be diluted. Lastly, arginine vasopressin (AVP) levels must be low in the plasma. Of these 3 requirements for water excretion, the one which is most important in the genesis of hyponatremia is the failure to maximally suppress AVP levels. Given the central role of AVP in limiting renal water excretion, AVP receptor antagonists represent a physiologic and rational method to increase renal water excretion.

AVP in Regulation of Plasma Osmolality

AVP is synthesized in the supraoptic and paraventricular nucleus of the hypothalamus and then stored in the neurohypophysis (reviewed in the article Diagnostic Approach and Management of Inpatient Hyponatremia in this supplement). The release of AVP is exquisitely sensitive to changes in plasma osmolality. AVP is not detectable in the plasma at an osmolality below approximately 280 mOsm/kg but increases in a nearly linear fashion beginning with as little as a 2% to 3% increase in osmolality above this value. The extreme sensitivity of this system allows for plasma osmolality to be maintained within a narrow range.

A second major determinant of AVP release is the effective arterial blood volume. While AVP levels are very sensitive to plasma osmolality, small changes of 10% in blood pressure or blood volume have no effect on AVP levels. However, once decreases in volume or pressure exceed this value, baroreceptor‐mediated signals provide persistent stimuli for AVP secretion. Baroreceptor‐mediated AVP release will continue even when plasma osmolality falls below 280 mOsm/kg. Teleologically, this system can be viewed as an emergency mechanism to defend blood pressure. Thus, small decreases in blood volume and blood pressure will cause the body to retain NaCl which will raise osmolality and lead to water retention. However, if NaCl is not available and if blood pressure and volume are becoming dangerously low (down 10%), the body behaves as if defense of blood pressure is more important than defense of osmolality, and AVP is secreted.1 The specific compartment whose volume is sensed in order to determine AVP secretion in this setting is the effective arterial volume. This overriding effect of volume explains the persistence of high AVP levels in hyponatremic patients with conditions such as heart failure and cirrhosis.

Other stimuli for the release of AVP include pain, nausea, and hypoxia. Inappropriate release of AVP can occur with a variety of central nervous system and pulmonary diseases as well as with drugs, particularly those that act within the central nervous system.2 Certain tumors can synthesize and release AVP.

AVP exerts its effects on cells through 3 receptors (Table 1). The V_1A receptor is expressed in a variety of tissues but is primarily found on vascular smooth muscle cells. Stimulation of this receptor results in vasoconstriction, platelet aggregation, inotropic stimulation and myocardial protein synthesis. The V_1B receptor is expressed in cells of the anterior pituitary and throughout the brain. Stimulation of this receptor results in release of adrenocorticotropin stimulating hormone (ACTH). Stimulation of the V_1A and V_1B receptors activate phospholipase C leading to increases in inositol trisphosphate and diacylglycerol with secondary increases in cell calcium and activation of protein kinase C.

The V₂ receptor is found on the basolateral surface of the renal collecting duct and vascular endothelium where it mediates the antidiuretic effects of AVP and stimulates the release of von Willebrand factor respectively. Unlike the V_1A and V_1B receptors, binding of AVP to the V₂ receptor activates the G_S‐coupled adenyl cyclase system causing increased intracellular levels of cyclic adenosine monophosphate (cAMP). In the kidney, generation of cAMP stimulates protein kinase A which then phosphorylates preformed aquaporin‐2 water channels causing trafficking and insertion of the channels into the luminal membrane of the tubular cells.3 The insertion of the aquaporin‐2 protein renders the collecting duct selectively permeable to water, which is then reabsorbed from the tubular lumen into the blood driven by the osmotic driving force of the hypertonic interstitium. In the absence of AVP, aquaporin membrane insertion and apical membrane water permeability are dramatically reduced.

Under normal circumstances, there is a balance between water intake and water excretion such that plasma osmolality and the serum sodium (Na⁺) concentration remain relatively constant. The principal mechanism responsible for prevention of hyponatremia and hyposmolality is renal water excretion. In all hyponatremic patients, water intake exceeds renal water excretion.

Excretion of water by the kidney is dependent on 3 factors. First, there must be adequate delivery of filtrate to the tip of the loop of Henle. Second, solute absorption in the ascending limb and the distal nephron must be preserved so that the tubular fluid will be diluted. Lastly, arginine vasopressin (AVP) levels must be low in the plasma. Of these 3 requirements for water excretion, the one which is most important in the genesis of hyponatremia is the failure to maximally suppress AVP levels. Given the central role of AVP in limiting renal water excretion, AVP receptor antagonists represent a physiologic and rational method to increase renal water excretion.

AVP in Regulation of Plasma Osmolality

AVP is synthesized in the supraoptic and paraventricular nucleus of the hypothalamus and then stored in the neurohypophysis (reviewed in the article Diagnostic Approach and Management of Inpatient Hyponatremia in this supplement). The release of AVP is exquisitely sensitive to changes in plasma osmolality. AVP is not detectable in the plasma at an osmolality below approximately 280 mOsm/kg but increases in a nearly linear fashion beginning with as little as a 2% to 3% increase in osmolality above this value. The extreme sensitivity of this system allows for plasma osmolality to be maintained within a narrow range.

A second major determinant of AVP release is the effective arterial blood volume. While AVP levels are very sensitive to plasma osmolality, small changes of 10% in blood pressure or blood volume have no effect on AVP levels. However, once decreases in volume or pressure exceed this value, baroreceptor‐mediated signals provide persistent stimuli for AVP secretion. Baroreceptor‐mediated AVP release will continue even when plasma osmolality falls below 280 mOsm/kg. Teleologically, this system can be viewed as an emergency mechanism to defend blood pressure. Thus, small decreases in blood volume and blood pressure will cause the body to retain NaCl which will raise osmolality and lead to water retention. However, if NaCl is not available and if blood pressure and volume are becoming dangerously low (down 10%), the body behaves as if defense of blood pressure is more important than defense of osmolality, and AVP is secreted.1 The specific compartment whose volume is sensed in order to determine AVP secretion in this setting is the effective arterial volume. This overriding effect of volume explains the persistence of high AVP levels in hyponatremic patients with conditions such as heart failure and cirrhosis.

Other stimuli for the release of AVP include pain, nausea, and hypoxia. Inappropriate release of AVP can occur with a variety of central nervous system and pulmonary diseases as well as with drugs, particularly those that act within the central nervous system.2 Certain tumors can synthesize and release AVP.

AVP exerts its effects on cells through 3 receptors (Table 1). The V_1A receptor is expressed in a variety of tissues but is primarily found on vascular smooth muscle cells. Stimulation of this receptor results in vasoconstriction, platelet aggregation, inotropic stimulation and myocardial protein synthesis. The V_1B receptor is expressed in cells of the anterior pituitary and throughout the brain. Stimulation of this receptor results in release of adrenocorticotropin stimulating hormone (ACTH). Stimulation of the V_1A and V_1B receptors activate phospholipase C leading to increases in inositol trisphosphate and diacylglycerol with secondary increases in cell calcium and activation of protein kinase C.

The V₂ receptor is found on the basolateral surface of the renal collecting duct and vascular endothelium where it mediates the antidiuretic effects of AVP and stimulates the release of von Willebrand factor respectively. Unlike the V_1A and V_1B receptors, binding of AVP to the V₂ receptor activates the G_S‐coupled adenyl cyclase system causing increased intracellular levels of cyclic adenosine monophosphate (cAMP). In the kidney, generation of cAMP stimulates protein kinase A which then phosphorylates preformed aquaporin‐2 water channels causing trafficking and insertion of the channels into the luminal membrane of the tubular cells.3 The insertion of the aquaporin‐2 protein renders the collecting duct selectively permeable to water, which is then reabsorbed from the tubular lumen into the blood driven by the osmotic driving force of the hypertonic interstitium. In the absence of AVP, aquaporin membrane insertion and apical membrane water permeability are dramatically reduced.

Under normal circumstances, there is a balance between water intake and water excretion such that plasma osmolality and the serum sodium (Na⁺) concentration remain relatively constant. The principal mechanism responsible for prevention of hyponatremia and hyposmolality is renal water excretion. In all hyponatremic patients, water intake exceeds renal water excretion.

Excretion of water by the kidney is dependent on 3 factors. First, there must be adequate delivery of filtrate to the tip of the loop of Henle. Second, solute absorption in the ascending limb and the distal nephron must be preserved so that the tubular fluid will be diluted. Lastly, arginine vasopressin (AVP) levels must be low in the plasma. Of these 3 requirements for water excretion, the one which is most important in the genesis of hyponatremia is the failure to maximally suppress AVP levels. Given the central role of AVP in limiting renal water excretion, AVP receptor antagonists represent a physiologic and rational method to increase renal water excretion.

AVP in Regulation of Plasma Osmolality

AVP is synthesized in the supraoptic and paraventricular nucleus of the hypothalamus and then stored in the neurohypophysis (reviewed in the article Diagnostic Approach and Management of Inpatient Hyponatremia in this supplement). The release of AVP is exquisitely sensitive to changes in plasma osmolality. AVP is not detectable in the plasma at an osmolality below approximately 280 mOsm/kg but increases in a nearly linear fashion beginning with as little as a 2% to 3% increase in osmolality above this value. The extreme sensitivity of this system allows for plasma osmolality to be maintained within a narrow range.

A second major determinant of AVP release is the effective arterial blood volume. While AVP levels are very sensitive to plasma osmolality, small changes of 10% in blood pressure or blood volume have no effect on AVP levels. However, once decreases in volume or pressure exceed this value, baroreceptor‐mediated signals provide persistent stimuli for AVP secretion. Baroreceptor‐mediated AVP release will continue even when plasma osmolality falls below 280 mOsm/kg. Teleologically, this system can be viewed as an emergency mechanism to defend blood pressure. Thus, small decreases in blood volume and blood pressure will cause the body to retain NaCl which will raise osmolality and lead to water retention. However, if NaCl is not available and if blood pressure and volume are becoming dangerously low (down 10%), the body behaves as if defense of blood pressure is more important than defense of osmolality, and AVP is secreted.1 The specific compartment whose volume is sensed in order to determine AVP secretion in this setting is the effective arterial volume. This overriding effect of volume explains the persistence of high AVP levels in hyponatremic patients with conditions such as heart failure and cirrhosis.

Other stimuli for the release of AVP include pain, nausea, and hypoxia. Inappropriate release of AVP can occur with a variety of central nervous system and pulmonary diseases as well as with drugs, particularly those that act within the central nervous system.2 Certain tumors can synthesize and release AVP.

AVP exerts its effects on cells through 3 receptors (Table 1). The V_1A receptor is expressed in a variety of tissues but is primarily found on vascular smooth muscle cells. Stimulation of this receptor results in vasoconstriction, platelet aggregation, inotropic stimulation and myocardial protein synthesis. The V_1B receptor is expressed in cells of the anterior pituitary and throughout the brain. Stimulation of this receptor results in release of adrenocorticotropin stimulating hormone (ACTH). Stimulation of the V_1A and V_1B receptors activate phospholipase C leading to increases in inositol trisphosphate and diacylglycerol with secondary increases in cell calcium and activation of protein kinase C.

The V₂ receptor is found on the basolateral surface of the renal collecting duct and vascular endothelium where it mediates the antidiuretic effects of AVP and stimulates the release of von Willebrand factor respectively. Unlike the V_1A and V_1B receptors, binding of AVP to the V₂ receptor activates the G_S‐coupled adenyl cyclase system causing increased intracellular levels of cyclic adenosine monophosphate (cAMP). In the kidney, generation of cAMP stimulates protein kinase A which then phosphorylates preformed aquaporin‐2 water channels causing trafficking and insertion of the channels into the luminal membrane of the tubular cells.3 The insertion of the aquaporin‐2 protein renders the collecting duct selectively permeable to water, which is then reabsorbed from the tubular lumen into the blood driven by the osmotic driving force of the hypertonic interstitium. In the absence of AVP, aquaporin membrane insertion and apical membrane water permeability are dramatically reduced.

The serum sodium (Na) level is the major determinant of serum osmolality. In normal physiologic states is tightly regulated between 135 mEq/L to 145 mEq/L despite variable intake of water and solute through the interaction of osmoreceptors in the hypothalamus where arginine vasopressin (AVP) is synthesized and then released by the posterior pituitary and the binding of AVP with V2 AVP receptors on the basolateral surface of the principal cells within the collecting duct of the kidney. Binding of AVP to the V2 receptors promotes the translocation and fusion of cytoplasmic vesicles which carry the water channel protein aquaporin 2 (AQP2) to the apical membrane of the cell and, in this manner, increases water permeability and absorption.1, 2, 3

Patients with hyponatremia, defined by a serum Na level 135 mEq/L, can be broadly classified by their volume status into those who are euvolemic, hypervolemic, and hypovolemic (Table 1). In patients with euvolemic hyponatremia such as those with Syndrome of Inappropriate Antidiuretic Hormone (SIADH), total body Na is nearly normal, but total body water is increased. In patients with hypervolemic hyponatremia, both total body Na and water are increased, but water to a much greater degree. These patients typically have increased extracellular fluid such as edema and/or ascites. The most common conditions associated with this condition are cirrhosis, congestive heart failure (CHF), and renal failure. In contrast, hypovolemic hyponatremia is associated with a reduction in both total body Na and water, but Na to a greater degree. This condition is encountered in patients with excessive fluid losses such as those with over‐diuresis, excessive gastrointestinal losses, burns, and pancreatitis.4

Hyponatremia is the most common electrolyte abnormality seen in general hospital patients.5 In a database of over 120,000 patients, a serum sodium level of 136mEq/L was observed in 28.2%.6 Hyponatremia is associated with selected medical conditions (especially cirrhosis and CHF), the extremes of age, and those receiving selected medications, including several that are commonly administered to cirrhotic patients (diuretics, selective serotonin reuptake inhibitors, opiates, proton‐pump inhibitors).7, 8 Hyponatremia is associated with increased total costs per hospital admission.5, 9 In an analysis of the effect of hyponatremia on length of stay in a retrospective cohort study of hospitalized patients derived from a large administrative database of 198,281 discharges from 39 US hospitals, mean length of stay was significantly greater among patients with hyponatremia than those with normal Na levels (8.6 8.0 vs. 7.2 8.2 days). After adjusting for confounders that may be associated with more severe disease and hyponatremia (age, gender, race, geographic region, teaching status of the hospital, admission source, principal payer, comorbidity index score and primary diagnosis), the presence of hyponatremia contributed an increase in length of stay of 1.0 day. Patients with hyponatremia are more frequently admitted to the intensive care unit (ICU) and require mechanical ventilation. In patients with CHF, the presence of hyponatremia at discharge is associated with increased risk for early mortality and rehospitalization.10

Although frequently asymptomatic, hyponatremia may be associated with a range of findings, from subtle and non‐specific complaints, including headache, fatigue, confusion, malaise, to severe and life‐threatening manifestations with lethargy, seizures, brainstem herniation, respiratory arrest and death.11 The most important complications are neurologic consequences related to cerebral edema. However, there is increased morbidity even in hyponatremic patients considered to be asymptomatic. Patients with low serum sodium have attention deficients, and falls are common. In a study of 122 patients who were considered to have chronic asymptomatic hyponatremia, the incidence of falls was significantly higher at 21.3% compared to only 5.3% in a control population.12

In hyponatremia, water enters into the cells to attain osmotic balance, resulting in cellular swelling.4 To avoid cerebral edema, the brain is capable of adapting to hyponatremia by regulating its volume to avoid swelling, especially when hyponatremia is chronic. In acute hyponatremia, astrocytes and neurons adapt through osmoregulatory mechanisms by extruding intracellular electrolytes such as potassium.13 Chronically, adaption occurs through the loss of low‐molecular weight organic compounds termed organic osmolytes including myoinsoitol, glutamine, choline and taurine. As a result, both the severity and the rate of its development are critical factors in determining the neurologic manifestation of hyponatremia in a given patient.14

Dilutional Hyponatremia and Cirrhosis

Patients with hyponatremia who are either euvolemic or hypervolemic are considered to have dilutional hyponatremia (DH). Management of these patients is distinct from those who are hypovolemic in whom appropriate therapy consists of the administration of normal saline. The remainder of this article addresses the pathogenesis, management and treatment of cirrhotic patients with DH.

Pathogenesis

The development of hyponatremia in cirrhosis is intimately related to the pathophysiology of portal hypertension and the non‐osmotic release of AVP3, 15 (Figure 1). In the early phases of cirrhosis, portal hypertension is the result of an increase in intrahepatic resistance. With the development of porto‐systemic collaterals, a hyperdynamic splanchnic circulation develops as a result of splanchnic arterial vasodilatation and increased vascular capacity. Nitric oxide, an endothelial derived relaxing factor, is the critical mediator of this process, and upregulation of its expression is pivotal in the pathogenesis of portal hypertension.

Figure 1

Multiple factors are related to the development of DH in cirrhosis. A reduction of effective central blood volume due to the development of porto‐venous collaterals and arterial splanchnic vasodilation, leading to baroreceptor‐mediated nonosmotic release of AVP, is considered the initiating and most important factor. Patients with cirrhosis and DH have higher plasma and urine vasopressin levels, higher plasma renin activity, and decreased plasma levels of atrial natriuretic factor than those with normal serum sodium concentrations, findings consistent with the presence of a decreased effective plasma volume.16 Arterial underfilling is sensed by baroreceptors located in the left ventricle, aortic arch, carotid sinus and renal afferent arterioles. Decreased activation leads to neurohumoral compensatory responses which include non‐osmotic release of vasopressin from the neurohypophysis and increased levels. Impaired catabolism of AVP that has been correlated with the severity of liver dysfunction may further contribute to increased levels.17 Initially, the increased AVP maintains arterial circulatory integrity by inducing splanchnic, peripheral and renal arterial vasoconstriction through its action on the V1a receptors and expansion of blood volume through renal water retention by its action on the V2 receptors located on the collecting ducts.

The initial adaptive response which leads to increased central blood volume can chronically result in detrimental effects, including the development of fluid overload with ascites, edema, and hyponatremia.16, 18 Additional factors that contribute to hyponatremia include decreased glomerular filtration rate (GFR) and/or increased proximal reabsorption of sodium (that reduce the distal delivery of filtrate and the potential for water reabsorption) and decreased cardiac function that further impairs effective central blood volume.19 In addition, urinary levels of AQP2 are increased in cirrhotic patients, especially those with decompensated disease with higher Child‐Pugh scores and ascites, and provide another potential mechanism to increase water reabsorption.20

Prevalence and Prognostic Significance

Hyponatremia in cirrhosis is a common finding. In a survey of 997 cirrhotic patients with ascites from 28 centers in Europe, North and South America, the prevalence of serum sodium concentration 135, 130, 125, 120 meq/L were 49.4%, 21.6%, 5.7%, and 1.2%, respectively.21 In a retrospective analysis of 188 inpatients, the prevalence of DH of 135, 130, and 125 were 20.8%, 14.9%, and 12.2%, respectively.22 The development of hyponatremia is a manifestation of increasing portal hypertension. In a natural history study of 263 patients hospitalized for first episode of significant ascites, 74 patients developed DH (Na level 130 mEq/L), including 11 patients in whom it appeared during the first episode and 63 cases during follow‐up (mean period of 40 3 months) with a 5‐year incidence of 37.1%.23

The presence of hyponatremia carries significant adverse prognostic significance. It is strongly associated with severity of liver function impairment as assessed by Child‐Pugh and model for end‐stage liver disease (MELD) scores.22 Even mild hyponatremia is associated with severe complications such as massive ascites, severe hepatic encephalopathy, spontaneous bacterial peritonitis (SBP), and hepatic hydrothorax, and the severity of hyponatremia is directly related to the severity of these complications.21, 22 (Figure 2). In a natural history study of patients presenting with large volume ascites, 1‐year survival after its development was reduced to only 25.6%.230

Figure 2

Figure 3

Hyponatremia is an especially poor prognostic sign for a hospitalized cirrhotic patient. In a retrospective analysis of 156 cirrhotic patients, hyponatremiapresent in 57 (29.8%) of admissionswas associated with increased hospital mortality (26.3% vs. 8.9% among those with normal Na levels), and the mortality rate was even higher (48%) among the 25 patients who developed severe hyponatremia during the hospital stay.24 In hospitalized patients, hyponatremia is predictive of the development of acute renal failure which is associated with substantially increased mortality (73% vs. 13%).25 Similarly, a low serum sodium level in critically ill cirrhotic patients admitted to the ICU is associated with complications, in‐hospital mortality, and poor short‐term prognosis.26

Whether hyponatremia should impact liver transplant prioritization remains an area of controversy. The United Network for Organ Sharing (UNOS) contracted by the Organ Procurement and Transplant Network (OPTN) to optimize the efficient use of deceased organs through fair and timely allocation, currently uses the MELD score, a formula that calculates the risk of death within three months from the bilirubin, creatinine, and International Normalized Ratio (INR) levels. Hyponatremia is an earlier and more sensitive marker than serum creatinine to detect renal impairment and/or circulatory dysfunction in patients with advanced cirrhosis and adds to MELD in predicting waitlist mortality.2729 In patients with a MELD score of 21, only low serum sodium and persistent ascites are independent predictors of mortality.28 To account for the importance of hyponatremia on survival, both modification of the MELD score in which the Na level is incorporated (MELD‐Na model) and the MELD to serum sodium ratio (MESO) have been developed. Adding hyponatremia to the MELD score is a better predictor of death than MELD alone, particularly in patients with low MELD scores.27, 2931 The OPTN/UNOS Liver and Intestinal Organ Transplantation Committee has discussed updating the liver allocation system to include the Na level. However, it was concluded that implementation of MELD‐Na would change the allocation status of only 4% of candidates. Further, based on the concerns about the ability to manipulate serum sodium levels and the utility of employing resources to change the system for a relatively small number of patients, it was decided to defer incorporating the Na level pending further analysis (Report of the OPTN/UNOS Liver and Intestinal Organ Transplantation Committee To the Board of Directors, Los Angeles, California, September 17‐18, 2007). At this time, the use of Na is a regional decision.32 However, the OPTN/UNOS Liver and Intestinal Organ Transplantation Committee has recently solicited feedback from the transplant community about including Na in allocation for review at a forum in April 2010.

Management of the Hospitalized Cirrhotic Patient With Hyponatremia: Recommendations

Hyponatremia in hospitalized cirrhotic patients is a marker for severe disease and high risk of hospital mortality.24 As a result, prompt evaluation and treatment is imperative. The availability of tolvaptan potentially revolutionizes the manner in which these patients are treated. In the SALT trials, only clinically stable patients were enrolled. In this last section, a guideline for the evaluation and treatment of acutely ill, hospitalized cirrhotic patients with DH is presented.

Unanswered Questions

The vaptans provide an important opportunity to clarify the role that hyponatremia plays in the pathogenesis of cirrhosis. In the past, DH in a cirrhotic patient represented a sign of advanced disease. With the availability of safe and effective therapy, we can now determine whether it also plays an important role in the pathophysiology of end‐stage liver disease and whether its treatment will have a beneficial effect on patient outcomes.

Specific clinical questions that will inevitably be addressed over the next few years to determine whether DH is only a marker for advanced disease or whether it plays a direct but modifiable role in the pathophysiology of cirrhosis will include:

• 1

  Role of vaptans in the management of ascites: In a 14‐day randomized, trial of a satavaptan, another selective vasopressin V(2) receptor antagonist, vs. placebo with spironolactone, combination therapy was associated with improved control of ascites and improvements in serum sodium levels in hyponatremic patients with ascites.59 If future similar studies demonstrate more prolonged benefits, this would constitute an important advance in the treatment of ascites in cirrhosis.

• 2

  Effect on renal function: Prolonged use of tolvaptan leads to a compensatory increase in endogenous levels of AVP and, potentially, increased stimulation of V1a receptors, which might be helpful in the setting of portal hypertension. In patients with hepatorenal syndrome, vasopressin stimulation of splanchnic V1a receptors leads to improved renal function, presumably by decreasing splanchnic blood flow and improving central blood volume.60 As a result, tolvaptan may indirectly improve kidney function in patients with advanced cirrhosis and refractory ascites. Whether long‐term tolvaptan therapy will help to prevent hepatorenal syndrome through this mechanism remains to be determined but is an exciting possibility.61

• 3

  Effect on hepatic encephalopathy: Hepatic encephalopathy is associated with poor quality of life in patients with cirrhosis. Although hepatic encephalopathy was not directly assessed in the SALT trials, the mean mental component summary of the Short Form General Health Survey, a quality of life measure, improved in cirrhotic patients receiving tolvaptan to a greater degree that those receiving placebo.62 A possible explanation for this finding is a beneficial effect of tolvaptan on hepatic encephalopathy. Confirmation of this hypothesis, however, will require prospective studies in which hepatic encephalopathy is directly assessed.

• 4

  Effect on medical economics: Based on retrospective reviews, hyponatremia has an adverse impact on length of stay and outcomes following liver transplantation. It will be important to demonstrate in prospective studies that correction of hyponatremia with tolvaptan reduces length of stay, complications, and costs.

The serum sodium (Na) level is the major determinant of serum osmolality. In normal physiologic states is tightly regulated between 135 mEq/L to 145 mEq/L despite variable intake of water and solute through the interaction of osmoreceptors in the hypothalamus where arginine vasopressin (AVP) is synthesized and then released by the posterior pituitary and the binding of AVP with V2 AVP receptors on the basolateral surface of the principal cells within the collecting duct of the kidney. Binding of AVP to the V2 receptors promotes the translocation and fusion of cytoplasmic vesicles which carry the water channel protein aquaporin 2 (AQP2) to the apical membrane of the cell and, in this manner, increases water permeability and absorption.1, 2, 3

Patients with hyponatremia, defined by a serum Na level 135 mEq/L, can be broadly classified by their volume status into those who are euvolemic, hypervolemic, and hypovolemic (Table 1). In patients with euvolemic hyponatremia such as those with Syndrome of Inappropriate Antidiuretic Hormone (SIADH), total body Na is nearly normal, but total body water is increased. In patients with hypervolemic hyponatremia, both total body Na and water are increased, but water to a much greater degree. These patients typically have increased extracellular fluid such as edema and/or ascites. The most common conditions associated with this condition are cirrhosis, congestive heart failure (CHF), and renal failure. In contrast, hypovolemic hyponatremia is associated with a reduction in both total body Na and water, but Na to a greater degree. This condition is encountered in patients with excessive fluid losses such as those with over‐diuresis, excessive gastrointestinal losses, burns, and pancreatitis.4

Hyponatremia is the most common electrolyte abnormality seen in general hospital patients.5 In a database of over 120,000 patients, a serum sodium level of 136mEq/L was observed in 28.2%.6 Hyponatremia is associated with selected medical conditions (especially cirrhosis and CHF), the extremes of age, and those receiving selected medications, including several that are commonly administered to cirrhotic patients (diuretics, selective serotonin reuptake inhibitors, opiates, proton‐pump inhibitors).7, 8 Hyponatremia is associated with increased total costs per hospital admission.5, 9 In an analysis of the effect of hyponatremia on length of stay in a retrospective cohort study of hospitalized patients derived from a large administrative database of 198,281 discharges from 39 US hospitals, mean length of stay was significantly greater among patients with hyponatremia than those with normal Na levels (8.6 8.0 vs. 7.2 8.2 days). After adjusting for confounders that may be associated with more severe disease and hyponatremia (age, gender, race, geographic region, teaching status of the hospital, admission source, principal payer, comorbidity index score and primary diagnosis), the presence of hyponatremia contributed an increase in length of stay of 1.0 day. Patients with hyponatremia are more frequently admitted to the intensive care unit (ICU) and require mechanical ventilation. In patients with CHF, the presence of hyponatremia at discharge is associated with increased risk for early mortality and rehospitalization.10

Although frequently asymptomatic, hyponatremia may be associated with a range of findings, from subtle and non‐specific complaints, including headache, fatigue, confusion, malaise, to severe and life‐threatening manifestations with lethargy, seizures, brainstem herniation, respiratory arrest and death.11 The most important complications are neurologic consequences related to cerebral edema. However, there is increased morbidity even in hyponatremic patients considered to be asymptomatic. Patients with low serum sodium have attention deficients, and falls are common. In a study of 122 patients who were considered to have chronic asymptomatic hyponatremia, the incidence of falls was significantly higher at 21.3% compared to only 5.3% in a control population.12

In hyponatremia, water enters into the cells to attain osmotic balance, resulting in cellular swelling.4 To avoid cerebral edema, the brain is capable of adapting to hyponatremia by regulating its volume to avoid swelling, especially when hyponatremia is chronic. In acute hyponatremia, astrocytes and neurons adapt through osmoregulatory mechanisms by extruding intracellular electrolytes such as potassium.13 Chronically, adaption occurs through the loss of low‐molecular weight organic compounds termed organic osmolytes including myoinsoitol, glutamine, choline and taurine. As a result, both the severity and the rate of its development are critical factors in determining the neurologic manifestation of hyponatremia in a given patient.14

Dilutional Hyponatremia and Cirrhosis

Patients with hyponatremia who are either euvolemic or hypervolemic are considered to have dilutional hyponatremia (DH). Management of these patients is distinct from those who are hypovolemic in whom appropriate therapy consists of the administration of normal saline. The remainder of this article addresses the pathogenesis, management and treatment of cirrhotic patients with DH.

Pathogenesis

The development of hyponatremia in cirrhosis is intimately related to the pathophysiology of portal hypertension and the non‐osmotic release of AVP3, 15 (Figure 1). In the early phases of cirrhosis, portal hypertension is the result of an increase in intrahepatic resistance. With the development of porto‐systemic collaterals, a hyperdynamic splanchnic circulation develops as a result of splanchnic arterial vasodilatation and increased vascular capacity. Nitric oxide, an endothelial derived relaxing factor, is the critical mediator of this process, and upregulation of its expression is pivotal in the pathogenesis of portal hypertension.

Figure 1

Multiple factors are related to the development of DH in cirrhosis. A reduction of effective central blood volume due to the development of porto‐venous collaterals and arterial splanchnic vasodilation, leading to baroreceptor‐mediated nonosmotic release of AVP, is considered the initiating and most important factor. Patients with cirrhosis and DH have higher plasma and urine vasopressin levels, higher plasma renin activity, and decreased plasma levels of atrial natriuretic factor than those with normal serum sodium concentrations, findings consistent with the presence of a decreased effective plasma volume.16 Arterial underfilling is sensed by baroreceptors located in the left ventricle, aortic arch, carotid sinus and renal afferent arterioles. Decreased activation leads to neurohumoral compensatory responses which include non‐osmotic release of vasopressin from the neurohypophysis and increased levels. Impaired catabolism of AVP that has been correlated with the severity of liver dysfunction may further contribute to increased levels.17 Initially, the increased AVP maintains arterial circulatory integrity by inducing splanchnic, peripheral and renal arterial vasoconstriction through its action on the V1a receptors and expansion of blood volume through renal water retention by its action on the V2 receptors located on the collecting ducts.

The initial adaptive response which leads to increased central blood volume can chronically result in detrimental effects, including the development of fluid overload with ascites, edema, and hyponatremia.16, 18 Additional factors that contribute to hyponatremia include decreased glomerular filtration rate (GFR) and/or increased proximal reabsorption of sodium (that reduce the distal delivery of filtrate and the potential for water reabsorption) and decreased cardiac function that further impairs effective central blood volume.19 In addition, urinary levels of AQP2 are increased in cirrhotic patients, especially those with decompensated disease with higher Child‐Pugh scores and ascites, and provide another potential mechanism to increase water reabsorption.20

Prevalence and Prognostic Significance

Hyponatremia in cirrhosis is a common finding. In a survey of 997 cirrhotic patients with ascites from 28 centers in Europe, North and South America, the prevalence of serum sodium concentration 135, 130, 125, 120 meq/L were 49.4%, 21.6%, 5.7%, and 1.2%, respectively.21 In a retrospective analysis of 188 inpatients, the prevalence of DH of 135, 130, and 125 were 20.8%, 14.9%, and 12.2%, respectively.22 The development of hyponatremia is a manifestation of increasing portal hypertension. In a natural history study of 263 patients hospitalized for first episode of significant ascites, 74 patients developed DH (Na level 130 mEq/L), including 11 patients in whom it appeared during the first episode and 63 cases during follow‐up (mean period of 40 3 months) with a 5‐year incidence of 37.1%.23

The presence of hyponatremia carries significant adverse prognostic significance. It is strongly associated with severity of liver function impairment as assessed by Child‐Pugh and model for end‐stage liver disease (MELD) scores.22 Even mild hyponatremia is associated with severe complications such as massive ascites, severe hepatic encephalopathy, spontaneous bacterial peritonitis (SBP), and hepatic hydrothorax, and the severity of hyponatremia is directly related to the severity of these complications.21, 22 (Figure 2). In a natural history study of patients presenting with large volume ascites, 1‐year survival after its development was reduced to only 25.6%.230

Figure 2

Figure 3

Hyponatremia is an especially poor prognostic sign for a hospitalized cirrhotic patient. In a retrospective analysis of 156 cirrhotic patients, hyponatremiapresent in 57 (29.8%) of admissionswas associated with increased hospital mortality (26.3% vs. 8.9% among those with normal Na levels), and the mortality rate was even higher (48%) among the 25 patients who developed severe hyponatremia during the hospital stay.24 In hospitalized patients, hyponatremia is predictive of the development of acute renal failure which is associated with substantially increased mortality (73% vs. 13%).25 Similarly, a low serum sodium level in critically ill cirrhotic patients admitted to the ICU is associated with complications, in‐hospital mortality, and poor short‐term prognosis.26

Whether hyponatremia should impact liver transplant prioritization remains an area of controversy. The United Network for Organ Sharing (UNOS) contracted by the Organ Procurement and Transplant Network (OPTN) to optimize the efficient use of deceased organs through fair and timely allocation, currently uses the MELD score, a formula that calculates the risk of death within three months from the bilirubin, creatinine, and International Normalized Ratio (INR) levels. Hyponatremia is an earlier and more sensitive marker than serum creatinine to detect renal impairment and/or circulatory dysfunction in patients with advanced cirrhosis and adds to MELD in predicting waitlist mortality.2729 In patients with a MELD score of 21, only low serum sodium and persistent ascites are independent predictors of mortality.28 To account for the importance of hyponatremia on survival, both modification of the MELD score in which the Na level is incorporated (MELD‐Na model) and the MELD to serum sodium ratio (MESO) have been developed. Adding hyponatremia to the MELD score is a better predictor of death than MELD alone, particularly in patients with low MELD scores.27, 2931 The OPTN/UNOS Liver and Intestinal Organ Transplantation Committee has discussed updating the liver allocation system to include the Na level. However, it was concluded that implementation of MELD‐Na would change the allocation status of only 4% of candidates. Further, based on the concerns about the ability to manipulate serum sodium levels and the utility of employing resources to change the system for a relatively small number of patients, it was decided to defer incorporating the Na level pending further analysis (Report of the OPTN/UNOS Liver and Intestinal Organ Transplantation Committee To the Board of Directors, Los Angeles, California, September 17‐18, 2007). At this time, the use of Na is a regional decision.32 However, the OPTN/UNOS Liver and Intestinal Organ Transplantation Committee has recently solicited feedback from the transplant community about including Na in allocation for review at a forum in April 2010.

Management of the Hospitalized Cirrhotic Patient With Hyponatremia: Recommendations

Hyponatremia in hospitalized cirrhotic patients is a marker for severe disease and high risk of hospital mortality.24 As a result, prompt evaluation and treatment is imperative. The availability of tolvaptan potentially revolutionizes the manner in which these patients are treated. In the SALT trials, only clinically stable patients were enrolled. In this last section, a guideline for the evaluation and treatment of acutely ill, hospitalized cirrhotic patients with DH is presented.

Unanswered Questions

The vaptans provide an important opportunity to clarify the role that hyponatremia plays in the pathogenesis of cirrhosis. In the past, DH in a cirrhotic patient represented a sign of advanced disease. With the availability of safe and effective therapy, we can now determine whether it also plays an important role in the pathophysiology of end‐stage liver disease and whether its treatment will have a beneficial effect on patient outcomes.

Specific clinical questions that will inevitably be addressed over the next few years to determine whether DH is only a marker for advanced disease or whether it plays a direct but modifiable role in the pathophysiology of cirrhosis will include:

• 1

  Role of vaptans in the management of ascites: In a 14‐day randomized, trial of a satavaptan, another selective vasopressin V(2) receptor antagonist, vs. placebo with spironolactone, combination therapy was associated with improved control of ascites and improvements in serum sodium levels in hyponatremic patients with ascites.59 If future similar studies demonstrate more prolonged benefits, this would constitute an important advance in the treatment of ascites in cirrhosis.

• 2

  Effect on renal function: Prolonged use of tolvaptan leads to a compensatory increase in endogenous levels of AVP and, potentially, increased stimulation of V1a receptors, which might be helpful in the setting of portal hypertension. In patients with hepatorenal syndrome, vasopressin stimulation of splanchnic V1a receptors leads to improved renal function, presumably by decreasing splanchnic blood flow and improving central blood volume.60 As a result, tolvaptan may indirectly improve kidney function in patients with advanced cirrhosis and refractory ascites. Whether long‐term tolvaptan therapy will help to prevent hepatorenal syndrome through this mechanism remains to be determined but is an exciting possibility.61

• 3

  Effect on hepatic encephalopathy: Hepatic encephalopathy is associated with poor quality of life in patients with cirrhosis. Although hepatic encephalopathy was not directly assessed in the SALT trials, the mean mental component summary of the Short Form General Health Survey, a quality of life measure, improved in cirrhotic patients receiving tolvaptan to a greater degree that those receiving placebo.62 A possible explanation for this finding is a beneficial effect of tolvaptan on hepatic encephalopathy. Confirmation of this hypothesis, however, will require prospective studies in which hepatic encephalopathy is directly assessed.

• 4

  Effect on medical economics: Based on retrospective reviews, hyponatremia has an adverse impact on length of stay and outcomes following liver transplantation. It will be important to demonstrate in prospective studies that correction of hyponatremia with tolvaptan reduces length of stay, complications, and costs.

The serum sodium (Na) level is the major determinant of serum osmolality. In normal physiologic states is tightly regulated between 135 mEq/L to 145 mEq/L despite variable intake of water and solute through the interaction of osmoreceptors in the hypothalamus where arginine vasopressin (AVP) is synthesized and then released by the posterior pituitary and the binding of AVP with V2 AVP receptors on the basolateral surface of the principal cells within the collecting duct of the kidney. Binding of AVP to the V2 receptors promotes the translocation and fusion of cytoplasmic vesicles which carry the water channel protein aquaporin 2 (AQP2) to the apical membrane of the cell and, in this manner, increases water permeability and absorption.1, 2, 3

Patients with hyponatremia, defined by a serum Na level 135 mEq/L, can be broadly classified by their volume status into those who are euvolemic, hypervolemic, and hypovolemic (Table 1). In patients with euvolemic hyponatremia such as those with Syndrome of Inappropriate Antidiuretic Hormone (SIADH), total body Na is nearly normal, but total body water is increased. In patients with hypervolemic hyponatremia, both total body Na and water are increased, but water to a much greater degree. These patients typically have increased extracellular fluid such as edema and/or ascites. The most common conditions associated with this condition are cirrhosis, congestive heart failure (CHF), and renal failure. In contrast, hypovolemic hyponatremia is associated with a reduction in both total body Na and water, but Na to a greater degree. This condition is encountered in patients with excessive fluid losses such as those with over‐diuresis, excessive gastrointestinal losses, burns, and pancreatitis.4

Hyponatremia is the most common electrolyte abnormality seen in general hospital patients.5 In a database of over 120,000 patients, a serum sodium level of 136mEq/L was observed in 28.2%.6 Hyponatremia is associated with selected medical conditions (especially cirrhosis and CHF), the extremes of age, and those receiving selected medications, including several that are commonly administered to cirrhotic patients (diuretics, selective serotonin reuptake inhibitors, opiates, proton‐pump inhibitors).7, 8 Hyponatremia is associated with increased total costs per hospital admission.5, 9 In an analysis of the effect of hyponatremia on length of stay in a retrospective cohort study of hospitalized patients derived from a large administrative database of 198,281 discharges from 39 US hospitals, mean length of stay was significantly greater among patients with hyponatremia than those with normal Na levels (8.6 8.0 vs. 7.2 8.2 days). After adjusting for confounders that may be associated with more severe disease and hyponatremia (age, gender, race, geographic region, teaching status of the hospital, admission source, principal payer, comorbidity index score and primary diagnosis), the presence of hyponatremia contributed an increase in length of stay of 1.0 day. Patients with hyponatremia are more frequently admitted to the intensive care unit (ICU) and require mechanical ventilation. In patients with CHF, the presence of hyponatremia at discharge is associated with increased risk for early mortality and rehospitalization.10

Although frequently asymptomatic, hyponatremia may be associated with a range of findings, from subtle and non‐specific complaints, including headache, fatigue, confusion, malaise, to severe and life‐threatening manifestations with lethargy, seizures, brainstem herniation, respiratory arrest and death.11 The most important complications are neurologic consequences related to cerebral edema. However, there is increased morbidity even in hyponatremic patients considered to be asymptomatic. Patients with low serum sodium have attention deficients, and falls are common. In a study of 122 patients who were considered to have chronic asymptomatic hyponatremia, the incidence of falls was significantly higher at 21.3% compared to only 5.3% in a control population.12

In hyponatremia, water enters into the cells to attain osmotic balance, resulting in cellular swelling.4 To avoid cerebral edema, the brain is capable of adapting to hyponatremia by regulating its volume to avoid swelling, especially when hyponatremia is chronic. In acute hyponatremia, astrocytes and neurons adapt through osmoregulatory mechanisms by extruding intracellular electrolytes such as potassium.13 Chronically, adaption occurs through the loss of low‐molecular weight organic compounds termed organic osmolytes including myoinsoitol, glutamine, choline and taurine. As a result, both the severity and the rate of its development are critical factors in determining the neurologic manifestation of hyponatremia in a given patient.14

Dilutional Hyponatremia and Cirrhosis

Patients with hyponatremia who are either euvolemic or hypervolemic are considered to have dilutional hyponatremia (DH). Management of these patients is distinct from those who are hypovolemic in whom appropriate therapy consists of the administration of normal saline. The remainder of this article addresses the pathogenesis, management and treatment of cirrhotic patients with DH.

Pathogenesis

The development of hyponatremia in cirrhosis is intimately related to the pathophysiology of portal hypertension and the non‐osmotic release of AVP3, 15 (Figure 1). In the early phases of cirrhosis, portal hypertension is the result of an increase in intrahepatic resistance. With the development of porto‐systemic collaterals, a hyperdynamic splanchnic circulation develops as a result of splanchnic arterial vasodilatation and increased vascular capacity. Nitric oxide, an endothelial derived relaxing factor, is the critical mediator of this process, and upregulation of its expression is pivotal in the pathogenesis of portal hypertension.

Figure 1

Multiple factors are related to the development of DH in cirrhosis. A reduction of effective central blood volume due to the development of porto‐venous collaterals and arterial splanchnic vasodilation, leading to baroreceptor‐mediated nonosmotic release of AVP, is considered the initiating and most important factor. Patients with cirrhosis and DH have higher plasma and urine vasopressin levels, higher plasma renin activity, and decreased plasma levels of atrial natriuretic factor than those with normal serum sodium concentrations, findings consistent with the presence of a decreased effective plasma volume.16 Arterial underfilling is sensed by baroreceptors located in the left ventricle, aortic arch, carotid sinus and renal afferent arterioles. Decreased activation leads to neurohumoral compensatory responses which include non‐osmotic release of vasopressin from the neurohypophysis and increased levels. Impaired catabolism of AVP that has been correlated with the severity of liver dysfunction may further contribute to increased levels.17 Initially, the increased AVP maintains arterial circulatory integrity by inducing splanchnic, peripheral and renal arterial vasoconstriction through its action on the V1a receptors and expansion of blood volume through renal water retention by its action on the V2 receptors located on the collecting ducts.

The initial adaptive response which leads to increased central blood volume can chronically result in detrimental effects, including the development of fluid overload with ascites, edema, and hyponatremia.16, 18 Additional factors that contribute to hyponatremia include decreased glomerular filtration rate (GFR) and/or increased proximal reabsorption of sodium (that reduce the distal delivery of filtrate and the potential for water reabsorption) and decreased cardiac function that further impairs effective central blood volume.19 In addition, urinary levels of AQP2 are increased in cirrhotic patients, especially those with decompensated disease with higher Child‐Pugh scores and ascites, and provide another potential mechanism to increase water reabsorption.20

Prevalence and Prognostic Significance

Hyponatremia in cirrhosis is a common finding. In a survey of 997 cirrhotic patients with ascites from 28 centers in Europe, North and South America, the prevalence of serum sodium concentration 135, 130, 125, 120 meq/L were 49.4%, 21.6%, 5.7%, and 1.2%, respectively.21 In a retrospective analysis of 188 inpatients, the prevalence of DH of 135, 130, and 125 were 20.8%, 14.9%, and 12.2%, respectively.22 The development of hyponatremia is a manifestation of increasing portal hypertension. In a natural history study of 263 patients hospitalized for first episode of significant ascites, 74 patients developed DH (Na level 130 mEq/L), including 11 patients in whom it appeared during the first episode and 63 cases during follow‐up (mean period of 40 3 months) with a 5‐year incidence of 37.1%.23

The presence of hyponatremia carries significant adverse prognostic significance. It is strongly associated with severity of liver function impairment as assessed by Child‐Pugh and model for end‐stage liver disease (MELD) scores.22 Even mild hyponatremia is associated with severe complications such as massive ascites, severe hepatic encephalopathy, spontaneous bacterial peritonitis (SBP), and hepatic hydrothorax, and the severity of hyponatremia is directly related to the severity of these complications.21, 22 (Figure 2). In a natural history study of patients presenting with large volume ascites, 1‐year survival after its development was reduced to only 25.6%.230

Figure 2

Figure 3

Hyponatremia is an especially poor prognostic sign for a hospitalized cirrhotic patient. In a retrospective analysis of 156 cirrhotic patients, hyponatremiapresent in 57 (29.8%) of admissionswas associated with increased hospital mortality (26.3% vs. 8.9% among those with normal Na levels), and the mortality rate was even higher (48%) among the 25 patients who developed severe hyponatremia during the hospital stay.24 In hospitalized patients, hyponatremia is predictive of the development of acute renal failure which is associated with substantially increased mortality (73% vs. 13%).25 Similarly, a low serum sodium level in critically ill cirrhotic patients admitted to the ICU is associated with complications, in‐hospital mortality, and poor short‐term prognosis.26

Whether hyponatremia should impact liver transplant prioritization remains an area of controversy. The United Network for Organ Sharing (UNOS) contracted by the Organ Procurement and Transplant Network (OPTN) to optimize the efficient use of deceased organs through fair and timely allocation, currently uses the MELD score, a formula that calculates the risk of death within three months from the bilirubin, creatinine, and International Normalized Ratio (INR) levels. Hyponatremia is an earlier and more sensitive marker than serum creatinine to detect renal impairment and/or circulatory dysfunction in patients with advanced cirrhosis and adds to MELD in predicting waitlist mortality.2729 In patients with a MELD score of 21, only low serum sodium and persistent ascites are independent predictors of mortality.28 To account for the importance of hyponatremia on survival, both modification of the MELD score in which the Na level is incorporated (MELD‐Na model) and the MELD to serum sodium ratio (MESO) have been developed. Adding hyponatremia to the MELD score is a better predictor of death than MELD alone, particularly in patients with low MELD scores.27, 2931 The OPTN/UNOS Liver and Intestinal Organ Transplantation Committee has discussed updating the liver allocation system to include the Na level. However, it was concluded that implementation of MELD‐Na would change the allocation status of only 4% of candidates. Further, based on the concerns about the ability to manipulate serum sodium levels and the utility of employing resources to change the system for a relatively small number of patients, it was decided to defer incorporating the Na level pending further analysis (Report of the OPTN/UNOS Liver and Intestinal Organ Transplantation Committee To the Board of Directors, Los Angeles, California, September 17‐18, 2007). At this time, the use of Na is a regional decision.32 However, the OPTN/UNOS Liver and Intestinal Organ Transplantation Committee has recently solicited feedback from the transplant community about including Na in allocation for review at a forum in April 2010.

Management of the Hospitalized Cirrhotic Patient With Hyponatremia: Recommendations

Hyponatremia in hospitalized cirrhotic patients is a marker for severe disease and high risk of hospital mortality.24 As a result, prompt evaluation and treatment is imperative. The availability of tolvaptan potentially revolutionizes the manner in which these patients are treated. In the SALT trials, only clinically stable patients were enrolled. In this last section, a guideline for the evaluation and treatment of acutely ill, hospitalized cirrhotic patients with DH is presented.

Unanswered Questions

The vaptans provide an important opportunity to clarify the role that hyponatremia plays in the pathogenesis of cirrhosis. In the past, DH in a cirrhotic patient represented a sign of advanced disease. With the availability of safe and effective therapy, we can now determine whether it also plays an important role in the pathophysiology of end‐stage liver disease and whether its treatment will have a beneficial effect on patient outcomes.

Specific clinical questions that will inevitably be addressed over the next few years to determine whether DH is only a marker for advanced disease or whether it plays a direct but modifiable role in the pathophysiology of cirrhosis will include:

• 1

  Role of vaptans in the management of ascites: In a 14‐day randomized, trial of a satavaptan, another selective vasopressin V(2) receptor antagonist, vs. placebo with spironolactone, combination therapy was associated with improved control of ascites and improvements in serum sodium levels in hyponatremic patients with ascites.59 If future similar studies demonstrate more prolonged benefits, this would constitute an important advance in the treatment of ascites in cirrhosis.

• 2

  Effect on renal function: Prolonged use of tolvaptan leads to a compensatory increase in endogenous levels of AVP and, potentially, increased stimulation of V1a receptors, which might be helpful in the setting of portal hypertension. In patients with hepatorenal syndrome, vasopressin stimulation of splanchnic V1a receptors leads to improved renal function, presumably by decreasing splanchnic blood flow and improving central blood volume.60 As a result, tolvaptan may indirectly improve kidney function in patients with advanced cirrhosis and refractory ascites. Whether long‐term tolvaptan therapy will help to prevent hepatorenal syndrome through this mechanism remains to be determined but is an exciting possibility.61

• 3

  Effect on hepatic encephalopathy: Hepatic encephalopathy is associated with poor quality of life in patients with cirrhosis. Although hepatic encephalopathy was not directly assessed in the SALT trials, the mean mental component summary of the Short Form General Health Survey, a quality of life measure, improved in cirrhotic patients receiving tolvaptan to a greater degree that those receiving placebo.62 A possible explanation for this finding is a beneficial effect of tolvaptan on hepatic encephalopathy. Confirmation of this hypothesis, however, will require prospective studies in which hepatic encephalopathy is directly assessed.

• 4

  Effect on medical economics: Based on retrospective reviews, hyponatremia has an adverse impact on length of stay and outcomes following liver transplantation. It will be important to demonstrate in prospective studies that correction of hyponatremia with tolvaptan reduces length of stay, complications, and costs.