Hyponatremia, defined as a serum [Na⁺] 135 mEq/L, occurs in 2030% of patients with acute decompensated heart failure (HF)13 and has been independently associated with a poor prognosis. In clinical trials of acute decompensated HF, the reported mean serum sodium is often normal or near normal, but a significant proportion of study subjects can have serum sodium values that approach 130 mEq/L or lower.3 However, despite the association between hyponatremia and clinical outcomes like hospitalization and mortality, data from studies are sparse about the impact of drug or device interventions in the hyponatremic cohort, since patients are generally not stratified at the time of randomization by the value of baseline serum sodium.

HYPONATREMIA AND PROGNOSIS

Hyponatremia has long been recognized as a potential prognostic marker in heart failure, highlighted by Packer and Lee in 1986.4 Subsequently, a wealth of data derived from clinical trials, registries, and observational databases support the concept that hyponatremia is an independent predictor of both short‐ and long‐term outcomes.13, 511 As reviewed by Jao and Chiong,3 this relationship holds in patients on optimal evidence‐based medical therapy, including treatment with antagonists of the renin‐angiotensin system and beta blockers. In the Organized Program To Initiate Lifesaving Treatment In Hospitalized Patients With Heart Failure (OPTIMIZE)2 HF Registry of nearly 50,000 patients, in‐hospital and 60‐day mortality rates were higher in patients with lower serum sodium levels on admission (cut‐off point of 135 mEq/L). In‐hospital death and the combined endpoint of death or re‐hospitalization increased significantly for each 3 mEq/L decrease in serum [Na⁺] below 140 mEq/L. Patients with hyponatremia were more likely to have lower systolic blood pressures and receive intravenous inotropic agents; lengths of stay were also longer.

Similar findings were reported in the Evaluation Study of Congestive Heart Failure and Pulmonary Acute and Chronic Therapeutic Impact of a Vasopressin 2 Antagonist (Tolvaptan) in Congestive Heart Failure (ACTIV in CHF)10 trial.11 For example, in the former, Gheorghiade and colleagues tracked serum sodium levels in 433 hospitalized patients who had acute decompensated HF and examined the proportion free from a major event (defined as death and/or HF hospitalization).1 There was a clear association between the event rate and serum sodium level. Patients whose hyponatremia persisted from hospital admission to discharge were at higher risk relative to those whose hyponatremia was corrected during the hospital stay.

However, whether the way in which the serum sodium improvement is achieved has a bearing on outcomes is not known. In the studies comparing outcomes in patients with heart failure and hyponatremia versus normonatremia, no mention is made about how the patient arrived at either state. Despite this limitation, the findings are incontrovertibly consistent. Hyponatremia on discharge (prior to or after the adoption of renin‐angiotensin‐aldosterone system (RAAS) antagonists or beta blockers) is a marker for poorer outcomes, as is another laboratory abnormality frequently observed in patients hospitalized with heart failure: an elevated creatinine.

Additionally, serum sodium obtained shortly after hospitalization is a potent predictor of re‐hospitalization12 and persistently poor health‐related quality‐of‐life.13 The impact on longer‐term outcomes can also be demonstrated in multiple prognostic models6, 8, 9 in which serum sodium is a risk factor for adverse outcomes. For example, using the Seattle Heart Failure Model, overall prognosis worsens for each 1 mEq decline in serum sodium when all other variables are kept constant.8 This observation suggests that, in terms of prognosis, the value of serum sodium functions as a continuous not a binary variable.

HYPONATREMIA AND HF PATHOPHYSIOLOGY

The reasons underlying hyponatremia in heart failure are complex, but a key component is the non‐osmotic release of arginine vasopressin (AVP) in response to stimulation of carotid baroreceptors. This phenomenon occurs as a result of arterial underfilling (both lower blood pressure and lower cardiac output). AVP is one member of a family of neurohormones and cytokines that are upregulated in heart failure (eg, norepinephrine, renin, angiotensin, aldosterone, endothelin, and tumor necrosis factor‐alpha). Levels of AVP are increased most markedly in patients with advanced symptoms (ie, New York Heart Association Class III and IV),14 and this leads to impaired free water handling in the renal tubules and a hypervolemic form of hyponatremia. The reasons underlying the upregulation are debated, but likely reflect a short‐term hemodynamic adaptation that is designed to augment cardiac output by increasing circulating volume. In addition, multiple neurohormones have been shown to promote progressive ventricular dilation, referred to as remodeling. For example, chronic elevations of norepinephrine contribute to a multitude of genotypic and phenotypic changes at the level of the myocyte. The short‐term benefits of neurohormonal upregulation are offset by maladaptive responses in the long term, and this observation likely explains a major part of the clinical benefits seen with drugs such as angiotensin converting enzyme inhibitors, aldosterone antagonists, and beta blockers.

It is also clear that the development and management of patients with hyponatremia and heart failure are frequently complicated by the presence of other factors that impact sodium and water handling. Heart failure often occurs in older patients with renal dysfunction who are on medications that can exacerbate hyponatremia, such as diuretics, non‐steroidal anti‐inflammatory agents, antidepressants, and opiate derivatives. In addition, other conditions like hypothyroidism may coexist and contribute to the hyponatremic state. It is therefore crucial for the clinician to consider these possibilities when a patient with heart failure presents with or develops hyponatremia, and in particular to critically evaluate the potential role of concomitant medications that can cause a syndrome of inappropriate antidiuretic hormone secretion (SIADH)‐like picture.

HYPONATREMIA AND RESOURCE USE

As with other markers of poor outcome in heart failure, such as worsening renal insufficiency, chronic obstructive lung disease, and other comorbidities, hyponatremia is associated with longer lengths of stay (LOS) and cost. In an analysis of approximately 116,000 patients hospitalized with HF and grouped at admission by serum [Na⁺], risk‐adjusted mortality, LOS, and attributable cost were highest for patients with severe hyponatremia compared to patients with normonatremia.15 In addition, Amin and colleagues recently demonstrated that length of stay in the intensive care unit and associated costs were greater (21% and 23%, respectively) in patients who had an International Classification of Diseases, 9th revision, Clinical Modification (ICD‐9‐CM) code for hyponatremia compared to those that did not.16

CONSIDERATIONS FOR PATIENTS HOSPITALIZED WITH HEART FAILURE WITH AND WITHOUT HYPONATREMIA

A number of significant management challenges exist during the hospitalization phase of acute decompensated heart failure. Among other tasks, the clinician should evaluate the potential cause of the decompensation (eg, medication noncompliance, dietary noncompliance, increased metabolic demand from pneumonia or other infection, worsening renal failure, diuretic resistance, iatrogenic fluid overload) and decide whether the patient is fluid overloaded, in a low cardiac output state contributing to end‐organ perfusion, or both. Manifestations of worsening heart failure other than dyspnea may be present. For example, mental status changes in an elderly patient may reflect fluid overload with or without low cardiac output, but the differential diagnosis also includes impaired clearance of drugs due to liver congestion or worsening renal function (eg, digoxin toxicity), hyponatremia (potentially mediated through cerebral edema), low cardiac output, occult infection, cerebrovascular accident, and other complications of coronary heart disease.

Key components of the physical exam include the presence of jugular venous distention,17 a more sensitive and specific finding than pulmonary rales in chronic or acute‐on‐chronic heart failure. While the mainstay of therapy for fluid overload remains diuretic therapy, we have only recently learned in a definitive way from the Diuretic Optimization Strategies Evaluation (DOSE)18 study that the method of administration (bolus vs continuous intravenous infusion and high dose vs low dose) matters, albeit slightly. Patients who receive high doses of loop diuretic have greater dyspnea relief and weight loss but are at greater risk for developing worsening renal function.

Certain key clinical markers, when present on admission, place the patient in an at‐risk group for a longer length of stay (Table 1). In addition to new or established hyponatremia, these include a creatinine value above baseline, marked antecedent weight gain, and hypotension. During the hospitalization, development of new hyponatremia or worsening of established hyponatremia, worsening renal function (often simply defined by an increase in baseline creatinine by 0.3 mg/dL or more), lack of dyspnea relief, and lack of weight loss, increase the complexity of decision‐making. A proportion of these higher‐risk patients may benefit from the initiation of intravenous vasoactive therapy, mechanical fluid removal (eg, with ultrafiltration), or the use of a vaptan (or aquaretic), depending on the particular presentation and profile. Occasionally, mechanical support will be needed but this option only applies to a limited subgroup.19 However, aside from ventricular assist devices, none of these options have been associated with improved survival.

Despite this limitation, the immediate goal of care in the acute setting is symptom relief. Thus, although neither intravenous dobutamine nor milrinone have been shown to decrease mortality, both are recognized as palliative options in patients with advanced or end‐stage symptoms20, 21; for example, milrinone, due to its inodilator characteristics, may improve symptoms and end‐organ perfusion while mitigating against an increase in pulmonary vascular resistance. However routine use in the management of acute decompensated heart failure is discouraged, based on the Outcome of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME‐CHF)2 Trial.22 Similarly, the routine use of nesiritide cannot be recommended, based on the neutral findings of the recently published Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND‐HF)23 study, though subsets of patients may still be candidates for this therapy.

Ultrafiltration appears to function well as an adjunct to fluid and salt removal as demonstrated in the Ultrafiltration versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure (UNLOAD)24 study, though a number of limitations have been cited.25 It should be strongly considered for patients who have developed refractory fluid overload and anasarca, especially if responsiveness to loop diuretics is blunted.

For hypervolemic hyponatremia, the standard approach has been fluid restriction, but this can require a prolonged and at times uncomfortable prescription for patients to follow. Hypertonic saline is contraindicated in most cases, given the salt load and risk of exacerbating fluid overload. Data for demeclocycline are sparse.26 The vaptan class is an interesting option, in large part because of the significant free water loss that can be achieved through the competitive antagonism of V₂ receptors in renal tubules. Competitive binding to this receptor leads to a reduction in the deposition of new water channels (or aquaporins) on the luminal side of the tubule, resulting in a marked reduction in water reuptake from the urine.27 Indeed, data for tolvaptan, an orally available vaptan, suggest that short‐term treatment can increase urine output, weight loss, and serum sodium level.28 In both the Acute and Chronic Therapeutic Impact of a Vasopressin 2 Antagonist (Tolvaptan) in Congestive Heart Failure (ACTIV) and Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan (EVEREST)29 studies,28 a number of favorable short‐term effects were seen such as dyspnea relief and weight loss, but in the latter study, the trial did not meet 1 of its 2 prespecified co‐primary endpoints (change on a visual analog scale) in an embedded analysis of acute treatment effects. Further, EVEREST failed to show any meaningful impact on posthospitalization morbidity and mortality when tolvaptan was administered chronically.30 It is also noteworthy that in both trials, inclusion criteria required the presence of symptomatic heart failure rather than hyponatremia; in fact, in EVEREST only 11.5% of patients had a serum sodium level less than 135 mEq/L. To date, there are no long‐term prospectively collected data on the impact of the vaptan class in heart failure accompanied by hyponatremia.

Despite these caveats, the judicious use of vaptans may have a role in heart failure; at the very least, serum sodium increases by, on average, 5.2 mEq/L.31 Fluid restriction should be liberalized and serum sodium should be monitored frequently in the first few days of therapy to avoid rapid correction of serum sodium, which can lead to an unusual neurological complication (osmotic demyelination syndrome).32

OUTPATIENT MANAGEMENT CONSIDERATIONS

Patients who have chronic hyponatremia or who are at risk for worsening of preexisting hyponatremia should be closely monitored during the early postdischarge period, in part to detect further decreases in the serum sodium level and deterioration in overall clinical status. Worsening of hyponatremia may occur in the outpatient setting due to intentional or unintentional increased free water intake, initiation of new medications, exacerbation of the underlying condition, infection, or related conditions. Similar to the inpatient setting, the outpatient management of patients with fluid overload and hyponatremia can be difficult. Further study is required and clinical trials are needed to assess whether the chronic administration of a vaptan in this particular patient population will impact prognosis relative to fluid restriction alone.

Regardless of serum sodium, a frequently advocated intervention in long‐term management is daily weight monitoring which has become a gold standard, especially for patients with advanced symptoms. As shown in EVEREST, lean body weight increases prior to re‐hospitalization for HF were 1.96, 2.07, and 1.97 kg, compared with 0.74, 0.90, and 1.04 kg, respectively, in patients who were not re‐hospitalized (P < 0.001 for all groups).33 Recently, use of invasive hemodynamic monitoring, largely on the basis of the CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION)34 trial, has been advocated as a potential breakthrough in outpatient management because increased right‐sided pressures, rather than weight gain, may precede a heart failure exacerbation.35, 36 It is, however, worthwhile to emphasize that routine hemodynamic monitoring with pulmonary artery catheterization has not been shown to be effective in the inpatient setting,37 despite the attractiveness of knowing the numbers. Additionally, the data supporting the use of serial measurements of biomarkers (in particular, brain natriuretic peptide or its precursor) as a surrogate for filling pressures are conflicting, and therefore this approach is not at present considered standard of care.38

Studies also suggest that postdischarge adherence and the intensity of follow‐up for patients recently admitted for HF may be critical to ensure optimal outcomes. From a practical standpoint, the presence of defined risk factors should lead clinicians to adopt a selective approach to postdischarge monitoring. For those patients deemed to be at risk, reasonable options include outpatient medication titration, more frequent nurse contact, and focused efforts at increasing patient self‐efficacy, all of which can be targeted in the context of a HF disease management program or HF clinic.39, 40 A recent consensus paper outlines the components that should be considered in the establishment of a clinic devoted to the care of patients with heart failure.40 Given increasing reimbursement pressures, these clinics may provide a mechanism to increase quality of care in the outpatient setting while decreasing risk of readmission for preventable heart failure exacerbations. However, other nonphysiological factors influence readmission rates, and not all of these factors can be easily addressed in a traditional medical model.41

SUMMARY

Hyponatremia, in addition to declining renal function, persistent dyspnea, and weight gain, is a major clinical concern during and following hospitalizations for acute decompensated heart failure. Low serum sodium (especially below 130 mEq/L) can contribute to symptoms, complicate diagnostic and therapeutic decision‐making, and significantly prolong length of stay and associated costs. Early recognition of the underlying etiologies, aggressive fluid restriction, and removal of medications that might exacerbate hyponatremia are key steps. The vaptan class is now a useful adjunct in select patients with hyponatremia and fluid overload who do not respond to standard approaches such as fluid restriction.

Hyponatremia, defined as a serum [Na⁺] 135 mEq/L, occurs in 2030% of patients with acute decompensated heart failure (HF)13 and has been independently associated with a poor prognosis. In clinical trials of acute decompensated HF, the reported mean serum sodium is often normal or near normal, but a significant proportion of study subjects can have serum sodium values that approach 130 mEq/L or lower.3 However, despite the association between hyponatremia and clinical outcomes like hospitalization and mortality, data from studies are sparse about the impact of drug or device interventions in the hyponatremic cohort, since patients are generally not stratified at the time of randomization by the value of baseline serum sodium.

HYPONATREMIA AND PROGNOSIS

Hyponatremia has long been recognized as a potential prognostic marker in heart failure, highlighted by Packer and Lee in 1986.4 Subsequently, a wealth of data derived from clinical trials, registries, and observational databases support the concept that hyponatremia is an independent predictor of both short‐ and long‐term outcomes.13, 511 As reviewed by Jao and Chiong,3 this relationship holds in patients on optimal evidence‐based medical therapy, including treatment with antagonists of the renin‐angiotensin system and beta blockers. In the Organized Program To Initiate Lifesaving Treatment In Hospitalized Patients With Heart Failure (OPTIMIZE)2 HF Registry of nearly 50,000 patients, in‐hospital and 60‐day mortality rates were higher in patients with lower serum sodium levels on admission (cut‐off point of 135 mEq/L). In‐hospital death and the combined endpoint of death or re‐hospitalization increased significantly for each 3 mEq/L decrease in serum [Na⁺] below 140 mEq/L. Patients with hyponatremia were more likely to have lower systolic blood pressures and receive intravenous inotropic agents; lengths of stay were also longer.

Similar findings were reported in the Evaluation Study of Congestive Heart Failure and Pulmonary Acute and Chronic Therapeutic Impact of a Vasopressin 2 Antagonist (Tolvaptan) in Congestive Heart Failure (ACTIV in CHF)10 trial.11 For example, in the former, Gheorghiade and colleagues tracked serum sodium levels in 433 hospitalized patients who had acute decompensated HF and examined the proportion free from a major event (defined as death and/or HF hospitalization).1 There was a clear association between the event rate and serum sodium level. Patients whose hyponatremia persisted from hospital admission to discharge were at higher risk relative to those whose hyponatremia was corrected during the hospital stay.

However, whether the way in which the serum sodium improvement is achieved has a bearing on outcomes is not known. In the studies comparing outcomes in patients with heart failure and hyponatremia versus normonatremia, no mention is made about how the patient arrived at either state. Despite this limitation, the findings are incontrovertibly consistent. Hyponatremia on discharge (prior to or after the adoption of renin‐angiotensin‐aldosterone system (RAAS) antagonists or beta blockers) is a marker for poorer outcomes, as is another laboratory abnormality frequently observed in patients hospitalized with heart failure: an elevated creatinine.

Additionally, serum sodium obtained shortly after hospitalization is a potent predictor of re‐hospitalization12 and persistently poor health‐related quality‐of‐life.13 The impact on longer‐term outcomes can also be demonstrated in multiple prognostic models6, 8, 9 in which serum sodium is a risk factor for adverse outcomes. For example, using the Seattle Heart Failure Model, overall prognosis worsens for each 1 mEq decline in serum sodium when all other variables are kept constant.8 This observation suggests that, in terms of prognosis, the value of serum sodium functions as a continuous not a binary variable.

HYPONATREMIA AND HF PATHOPHYSIOLOGY

The reasons underlying hyponatremia in heart failure are complex, but a key component is the non‐osmotic release of arginine vasopressin (AVP) in response to stimulation of carotid baroreceptors. This phenomenon occurs as a result of arterial underfilling (both lower blood pressure and lower cardiac output). AVP is one member of a family of neurohormones and cytokines that are upregulated in heart failure (eg, norepinephrine, renin, angiotensin, aldosterone, endothelin, and tumor necrosis factor‐alpha). Levels of AVP are increased most markedly in patients with advanced symptoms (ie, New York Heart Association Class III and IV),14 and this leads to impaired free water handling in the renal tubules and a hypervolemic form of hyponatremia. The reasons underlying the upregulation are debated, but likely reflect a short‐term hemodynamic adaptation that is designed to augment cardiac output by increasing circulating volume. In addition, multiple neurohormones have been shown to promote progressive ventricular dilation, referred to as remodeling. For example, chronic elevations of norepinephrine contribute to a multitude of genotypic and phenotypic changes at the level of the myocyte. The short‐term benefits of neurohormonal upregulation are offset by maladaptive responses in the long term, and this observation likely explains a major part of the clinical benefits seen with drugs such as angiotensin converting enzyme inhibitors, aldosterone antagonists, and beta blockers.

It is also clear that the development and management of patients with hyponatremia and heart failure are frequently complicated by the presence of other factors that impact sodium and water handling. Heart failure often occurs in older patients with renal dysfunction who are on medications that can exacerbate hyponatremia, such as diuretics, non‐steroidal anti‐inflammatory agents, antidepressants, and opiate derivatives. In addition, other conditions like hypothyroidism may coexist and contribute to the hyponatremic state. It is therefore crucial for the clinician to consider these possibilities when a patient with heart failure presents with or develops hyponatremia, and in particular to critically evaluate the potential role of concomitant medications that can cause a syndrome of inappropriate antidiuretic hormone secretion (SIADH)‐like picture.

HYPONATREMIA AND RESOURCE USE

As with other markers of poor outcome in heart failure, such as worsening renal insufficiency, chronic obstructive lung disease, and other comorbidities, hyponatremia is associated with longer lengths of stay (LOS) and cost. In an analysis of approximately 116,000 patients hospitalized with HF and grouped at admission by serum [Na⁺], risk‐adjusted mortality, LOS, and attributable cost were highest for patients with severe hyponatremia compared to patients with normonatremia.15 In addition, Amin and colleagues recently demonstrated that length of stay in the intensive care unit and associated costs were greater (21% and 23%, respectively) in patients who had an International Classification of Diseases, 9th revision, Clinical Modification (ICD‐9‐CM) code for hyponatremia compared to those that did not.16

CONSIDERATIONS FOR PATIENTS HOSPITALIZED WITH HEART FAILURE WITH AND WITHOUT HYPONATREMIA

A number of significant management challenges exist during the hospitalization phase of acute decompensated heart failure. Among other tasks, the clinician should evaluate the potential cause of the decompensation (eg, medication noncompliance, dietary noncompliance, increased metabolic demand from pneumonia or other infection, worsening renal failure, diuretic resistance, iatrogenic fluid overload) and decide whether the patient is fluid overloaded, in a low cardiac output state contributing to end‐organ perfusion, or both. Manifestations of worsening heart failure other than dyspnea may be present. For example, mental status changes in an elderly patient may reflect fluid overload with or without low cardiac output, but the differential diagnosis also includes impaired clearance of drugs due to liver congestion or worsening renal function (eg, digoxin toxicity), hyponatremia (potentially mediated through cerebral edema), low cardiac output, occult infection, cerebrovascular accident, and other complications of coronary heart disease.

Key components of the physical exam include the presence of jugular venous distention,17 a more sensitive and specific finding than pulmonary rales in chronic or acute‐on‐chronic heart failure. While the mainstay of therapy for fluid overload remains diuretic therapy, we have only recently learned in a definitive way from the Diuretic Optimization Strategies Evaluation (DOSE)18 study that the method of administration (bolus vs continuous intravenous infusion and high dose vs low dose) matters, albeit slightly. Patients who receive high doses of loop diuretic have greater dyspnea relief and weight loss but are at greater risk for developing worsening renal function.

Certain key clinical markers, when present on admission, place the patient in an at‐risk group for a longer length of stay (Table 1). In addition to new or established hyponatremia, these include a creatinine value above baseline, marked antecedent weight gain, and hypotension. During the hospitalization, development of new hyponatremia or worsening of established hyponatremia, worsening renal function (often simply defined by an increase in baseline creatinine by 0.3 mg/dL or more), lack of dyspnea relief, and lack of weight loss, increase the complexity of decision‐making. A proportion of these higher‐risk patients may benefit from the initiation of intravenous vasoactive therapy, mechanical fluid removal (eg, with ultrafiltration), or the use of a vaptan (or aquaretic), depending on the particular presentation and profile. Occasionally, mechanical support will be needed but this option only applies to a limited subgroup.19 However, aside from ventricular assist devices, none of these options have been associated with improved survival.

Despite this limitation, the immediate goal of care in the acute setting is symptom relief. Thus, although neither intravenous dobutamine nor milrinone have been shown to decrease mortality, both are recognized as palliative options in patients with advanced or end‐stage symptoms20, 21; for example, milrinone, due to its inodilator characteristics, may improve symptoms and end‐organ perfusion while mitigating against an increase in pulmonary vascular resistance. However routine use in the management of acute decompensated heart failure is discouraged, based on the Outcome of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME‐CHF)2 Trial.22 Similarly, the routine use of nesiritide cannot be recommended, based on the neutral findings of the recently published Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND‐HF)23 study, though subsets of patients may still be candidates for this therapy.

Ultrafiltration appears to function well as an adjunct to fluid and salt removal as demonstrated in the Ultrafiltration versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure (UNLOAD)24 study, though a number of limitations have been cited.25 It should be strongly considered for patients who have developed refractory fluid overload and anasarca, especially if responsiveness to loop diuretics is blunted.

For hypervolemic hyponatremia, the standard approach has been fluid restriction, but this can require a prolonged and at times uncomfortable prescription for patients to follow. Hypertonic saline is contraindicated in most cases, given the salt load and risk of exacerbating fluid overload. Data for demeclocycline are sparse.26 The vaptan class is an interesting option, in large part because of the significant free water loss that can be achieved through the competitive antagonism of V₂ receptors in renal tubules. Competitive binding to this receptor leads to a reduction in the deposition of new water channels (or aquaporins) on the luminal side of the tubule, resulting in a marked reduction in water reuptake from the urine.27 Indeed, data for tolvaptan, an orally available vaptan, suggest that short‐term treatment can increase urine output, weight loss, and serum sodium level.28 In both the Acute and Chronic Therapeutic Impact of a Vasopressin 2 Antagonist (Tolvaptan) in Congestive Heart Failure (ACTIV) and Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan (EVEREST)29 studies,28 a number of favorable short‐term effects were seen such as dyspnea relief and weight loss, but in the latter study, the trial did not meet 1 of its 2 prespecified co‐primary endpoints (change on a visual analog scale) in an embedded analysis of acute treatment effects. Further, EVEREST failed to show any meaningful impact on posthospitalization morbidity and mortality when tolvaptan was administered chronically.30 It is also noteworthy that in both trials, inclusion criteria required the presence of symptomatic heart failure rather than hyponatremia; in fact, in EVEREST only 11.5% of patients had a serum sodium level less than 135 mEq/L. To date, there are no long‐term prospectively collected data on the impact of the vaptan class in heart failure accompanied by hyponatremia.

Despite these caveats, the judicious use of vaptans may have a role in heart failure; at the very least, serum sodium increases by, on average, 5.2 mEq/L.31 Fluid restriction should be liberalized and serum sodium should be monitored frequently in the first few days of therapy to avoid rapid correction of serum sodium, which can lead to an unusual neurological complication (osmotic demyelination syndrome).32

OUTPATIENT MANAGEMENT CONSIDERATIONS

Patients who have chronic hyponatremia or who are at risk for worsening of preexisting hyponatremia should be closely monitored during the early postdischarge period, in part to detect further decreases in the serum sodium level and deterioration in overall clinical status. Worsening of hyponatremia may occur in the outpatient setting due to intentional or unintentional increased free water intake, initiation of new medications, exacerbation of the underlying condition, infection, or related conditions. Similar to the inpatient setting, the outpatient management of patients with fluid overload and hyponatremia can be difficult. Further study is required and clinical trials are needed to assess whether the chronic administration of a vaptan in this particular patient population will impact prognosis relative to fluid restriction alone.

Regardless of serum sodium, a frequently advocated intervention in long‐term management is daily weight monitoring which has become a gold standard, especially for patients with advanced symptoms. As shown in EVEREST, lean body weight increases prior to re‐hospitalization for HF were 1.96, 2.07, and 1.97 kg, compared with 0.74, 0.90, and 1.04 kg, respectively, in patients who were not re‐hospitalized (P < 0.001 for all groups).33 Recently, use of invasive hemodynamic monitoring, largely on the basis of the CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION)34 trial, has been advocated as a potential breakthrough in outpatient management because increased right‐sided pressures, rather than weight gain, may precede a heart failure exacerbation.35, 36 It is, however, worthwhile to emphasize that routine hemodynamic monitoring with pulmonary artery catheterization has not been shown to be effective in the inpatient setting,37 despite the attractiveness of knowing the numbers. Additionally, the data supporting the use of serial measurements of biomarkers (in particular, brain natriuretic peptide or its precursor) as a surrogate for filling pressures are conflicting, and therefore this approach is not at present considered standard of care.38

Studies also suggest that postdischarge adherence and the intensity of follow‐up for patients recently admitted for HF may be critical to ensure optimal outcomes. From a practical standpoint, the presence of defined risk factors should lead clinicians to adopt a selective approach to postdischarge monitoring. For those patients deemed to be at risk, reasonable options include outpatient medication titration, more frequent nurse contact, and focused efforts at increasing patient self‐efficacy, all of which can be targeted in the context of a HF disease management program or HF clinic.39, 40 A recent consensus paper outlines the components that should be considered in the establishment of a clinic devoted to the care of patients with heart failure.40 Given increasing reimbursement pressures, these clinics may provide a mechanism to increase quality of care in the outpatient setting while decreasing risk of readmission for preventable heart failure exacerbations. However, other nonphysiological factors influence readmission rates, and not all of these factors can be easily addressed in a traditional medical model.41

SUMMARY

Hyponatremia, in addition to declining renal function, persistent dyspnea, and weight gain, is a major clinical concern during and following hospitalizations for acute decompensated heart failure. Low serum sodium (especially below 130 mEq/L) can contribute to symptoms, complicate diagnostic and therapeutic decision‐making, and significantly prolong length of stay and associated costs. Early recognition of the underlying etiologies, aggressive fluid restriction, and removal of medications that might exacerbate hyponatremia are key steps. The vaptan class is now a useful adjunct in select patients with hyponatremia and fluid overload who do not respond to standard approaches such as fluid restriction.

Hyponatremia, defined as a serum [Na⁺] 135 mEq/L, occurs in 2030% of patients with acute decompensated heart failure (HF)13 and has been independently associated with a poor prognosis. In clinical trials of acute decompensated HF, the reported mean serum sodium is often normal or near normal, but a significant proportion of study subjects can have serum sodium values that approach 130 mEq/L or lower.3 However, despite the association between hyponatremia and clinical outcomes like hospitalization and mortality, data from studies are sparse about the impact of drug or device interventions in the hyponatremic cohort, since patients are generally not stratified at the time of randomization by the value of baseline serum sodium.

HYPONATREMIA AND PROGNOSIS

Hyponatremia has long been recognized as a potential prognostic marker in heart failure, highlighted by Packer and Lee in 1986.4 Subsequently, a wealth of data derived from clinical trials, registries, and observational databases support the concept that hyponatremia is an independent predictor of both short‐ and long‐term outcomes.13, 511 As reviewed by Jao and Chiong,3 this relationship holds in patients on optimal evidence‐based medical therapy, including treatment with antagonists of the renin‐angiotensin system and beta blockers. In the Organized Program To Initiate Lifesaving Treatment In Hospitalized Patients With Heart Failure (OPTIMIZE)2 HF Registry of nearly 50,000 patients, in‐hospital and 60‐day mortality rates were higher in patients with lower serum sodium levels on admission (cut‐off point of 135 mEq/L). In‐hospital death and the combined endpoint of death or re‐hospitalization increased significantly for each 3 mEq/L decrease in serum [Na⁺] below 140 mEq/L. Patients with hyponatremia were more likely to have lower systolic blood pressures and receive intravenous inotropic agents; lengths of stay were also longer.

Similar findings were reported in the Evaluation Study of Congestive Heart Failure and Pulmonary Acute and Chronic Therapeutic Impact of a Vasopressin 2 Antagonist (Tolvaptan) in Congestive Heart Failure (ACTIV in CHF)10 trial.11 For example, in the former, Gheorghiade and colleagues tracked serum sodium levels in 433 hospitalized patients who had acute decompensated HF and examined the proportion free from a major event (defined as death and/or HF hospitalization).1 There was a clear association between the event rate and serum sodium level. Patients whose hyponatremia persisted from hospital admission to discharge were at higher risk relative to those whose hyponatremia was corrected during the hospital stay.

However, whether the way in which the serum sodium improvement is achieved has a bearing on outcomes is not known. In the studies comparing outcomes in patients with heart failure and hyponatremia versus normonatremia, no mention is made about how the patient arrived at either state. Despite this limitation, the findings are incontrovertibly consistent. Hyponatremia on discharge (prior to or after the adoption of renin‐angiotensin‐aldosterone system (RAAS) antagonists or beta blockers) is a marker for poorer outcomes, as is another laboratory abnormality frequently observed in patients hospitalized with heart failure: an elevated creatinine.

Additionally, serum sodium obtained shortly after hospitalization is a potent predictor of re‐hospitalization12 and persistently poor health‐related quality‐of‐life.13 The impact on longer‐term outcomes can also be demonstrated in multiple prognostic models6, 8, 9 in which serum sodium is a risk factor for adverse outcomes. For example, using the Seattle Heart Failure Model, overall prognosis worsens for each 1 mEq decline in serum sodium when all other variables are kept constant.8 This observation suggests that, in terms of prognosis, the value of serum sodium functions as a continuous not a binary variable.

HYPONATREMIA AND HF PATHOPHYSIOLOGY

The reasons underlying hyponatremia in heart failure are complex, but a key component is the non‐osmotic release of arginine vasopressin (AVP) in response to stimulation of carotid baroreceptors. This phenomenon occurs as a result of arterial underfilling (both lower blood pressure and lower cardiac output). AVP is one member of a family of neurohormones and cytokines that are upregulated in heart failure (eg, norepinephrine, renin, angiotensin, aldosterone, endothelin, and tumor necrosis factor‐alpha). Levels of AVP are increased most markedly in patients with advanced symptoms (ie, New York Heart Association Class III and IV),14 and this leads to impaired free water handling in the renal tubules and a hypervolemic form of hyponatremia. The reasons underlying the upregulation are debated, but likely reflect a short‐term hemodynamic adaptation that is designed to augment cardiac output by increasing circulating volume. In addition, multiple neurohormones have been shown to promote progressive ventricular dilation, referred to as remodeling. For example, chronic elevations of norepinephrine contribute to a multitude of genotypic and phenotypic changes at the level of the myocyte. The short‐term benefits of neurohormonal upregulation are offset by maladaptive responses in the long term, and this observation likely explains a major part of the clinical benefits seen with drugs such as angiotensin converting enzyme inhibitors, aldosterone antagonists, and beta blockers.

It is also clear that the development and management of patients with hyponatremia and heart failure are frequently complicated by the presence of other factors that impact sodium and water handling. Heart failure often occurs in older patients with renal dysfunction who are on medications that can exacerbate hyponatremia, such as diuretics, non‐steroidal anti‐inflammatory agents, antidepressants, and opiate derivatives. In addition, other conditions like hypothyroidism may coexist and contribute to the hyponatremic state. It is therefore crucial for the clinician to consider these possibilities when a patient with heart failure presents with or develops hyponatremia, and in particular to critically evaluate the potential role of concomitant medications that can cause a syndrome of inappropriate antidiuretic hormone secretion (SIADH)‐like picture.

HYPONATREMIA AND RESOURCE USE

As with other markers of poor outcome in heart failure, such as worsening renal insufficiency, chronic obstructive lung disease, and other comorbidities, hyponatremia is associated with longer lengths of stay (LOS) and cost. In an analysis of approximately 116,000 patients hospitalized with HF and grouped at admission by serum [Na⁺], risk‐adjusted mortality, LOS, and attributable cost were highest for patients with severe hyponatremia compared to patients with normonatremia.15 In addition, Amin and colleagues recently demonstrated that length of stay in the intensive care unit and associated costs were greater (21% and 23%, respectively) in patients who had an International Classification of Diseases, 9th revision, Clinical Modification (ICD‐9‐CM) code for hyponatremia compared to those that did not.16

CONSIDERATIONS FOR PATIENTS HOSPITALIZED WITH HEART FAILURE WITH AND WITHOUT HYPONATREMIA

A number of significant management challenges exist during the hospitalization phase of acute decompensated heart failure. Among other tasks, the clinician should evaluate the potential cause of the decompensation (eg, medication noncompliance, dietary noncompliance, increased metabolic demand from pneumonia or other infection, worsening renal failure, diuretic resistance, iatrogenic fluid overload) and decide whether the patient is fluid overloaded, in a low cardiac output state contributing to end‐organ perfusion, or both. Manifestations of worsening heart failure other than dyspnea may be present. For example, mental status changes in an elderly patient may reflect fluid overload with or without low cardiac output, but the differential diagnosis also includes impaired clearance of drugs due to liver congestion or worsening renal function (eg, digoxin toxicity), hyponatremia (potentially mediated through cerebral edema), low cardiac output, occult infection, cerebrovascular accident, and other complications of coronary heart disease.

Key components of the physical exam include the presence of jugular venous distention,17 a more sensitive and specific finding than pulmonary rales in chronic or acute‐on‐chronic heart failure. While the mainstay of therapy for fluid overload remains diuretic therapy, we have only recently learned in a definitive way from the Diuretic Optimization Strategies Evaluation (DOSE)18 study that the method of administration (bolus vs continuous intravenous infusion and high dose vs low dose) matters, albeit slightly. Patients who receive high doses of loop diuretic have greater dyspnea relief and weight loss but are at greater risk for developing worsening renal function.

Certain key clinical markers, when present on admission, place the patient in an at‐risk group for a longer length of stay (Table 1). In addition to new or established hyponatremia, these include a creatinine value above baseline, marked antecedent weight gain, and hypotension. During the hospitalization, development of new hyponatremia or worsening of established hyponatremia, worsening renal function (often simply defined by an increase in baseline creatinine by 0.3 mg/dL or more), lack of dyspnea relief, and lack of weight loss, increase the complexity of decision‐making. A proportion of these higher‐risk patients may benefit from the initiation of intravenous vasoactive therapy, mechanical fluid removal (eg, with ultrafiltration), or the use of a vaptan (or aquaretic), depending on the particular presentation and profile. Occasionally, mechanical support will be needed but this option only applies to a limited subgroup.19 However, aside from ventricular assist devices, none of these options have been associated with improved survival.

Despite this limitation, the immediate goal of care in the acute setting is symptom relief. Thus, although neither intravenous dobutamine nor milrinone have been shown to decrease mortality, both are recognized as palliative options in patients with advanced or end‐stage symptoms20, 21; for example, milrinone, due to its inodilator characteristics, may improve symptoms and end‐organ perfusion while mitigating against an increase in pulmonary vascular resistance. However routine use in the management of acute decompensated heart failure is discouraged, based on the Outcome of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME‐CHF)2 Trial.22 Similarly, the routine use of nesiritide cannot be recommended, based on the neutral findings of the recently published Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND‐HF)23 study, though subsets of patients may still be candidates for this therapy.

Ultrafiltration appears to function well as an adjunct to fluid and salt removal as demonstrated in the Ultrafiltration versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure (UNLOAD)24 study, though a number of limitations have been cited.25 It should be strongly considered for patients who have developed refractory fluid overload and anasarca, especially if responsiveness to loop diuretics is blunted.

For hypervolemic hyponatremia, the standard approach has been fluid restriction, but this can require a prolonged and at times uncomfortable prescription for patients to follow. Hypertonic saline is contraindicated in most cases, given the salt load and risk of exacerbating fluid overload. Data for demeclocycline are sparse.26 The vaptan class is an interesting option, in large part because of the significant free water loss that can be achieved through the competitive antagonism of V₂ receptors in renal tubules. Competitive binding to this receptor leads to a reduction in the deposition of new water channels (or aquaporins) on the luminal side of the tubule, resulting in a marked reduction in water reuptake from the urine.27 Indeed, data for tolvaptan, an orally available vaptan, suggest that short‐term treatment can increase urine output, weight loss, and serum sodium level.28 In both the Acute and Chronic Therapeutic Impact of a Vasopressin 2 Antagonist (Tolvaptan) in Congestive Heart Failure (ACTIV) and Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan (EVEREST)29 studies,28 a number of favorable short‐term effects were seen such as dyspnea relief and weight loss, but in the latter study, the trial did not meet 1 of its 2 prespecified co‐primary endpoints (change on a visual analog scale) in an embedded analysis of acute treatment effects. Further, EVEREST failed to show any meaningful impact on posthospitalization morbidity and mortality when tolvaptan was administered chronically.30 It is also noteworthy that in both trials, inclusion criteria required the presence of symptomatic heart failure rather than hyponatremia; in fact, in EVEREST only 11.5% of patients had a serum sodium level less than 135 mEq/L. To date, there are no long‐term prospectively collected data on the impact of the vaptan class in heart failure accompanied by hyponatremia.

Despite these caveats, the judicious use of vaptans may have a role in heart failure; at the very least, serum sodium increases by, on average, 5.2 mEq/L.31 Fluid restriction should be liberalized and serum sodium should be monitored frequently in the first few days of therapy to avoid rapid correction of serum sodium, which can lead to an unusual neurological complication (osmotic demyelination syndrome).32

OUTPATIENT MANAGEMENT CONSIDERATIONS

Patients who have chronic hyponatremia or who are at risk for worsening of preexisting hyponatremia should be closely monitored during the early postdischarge period, in part to detect further decreases in the serum sodium level and deterioration in overall clinical status. Worsening of hyponatremia may occur in the outpatient setting due to intentional or unintentional increased free water intake, initiation of new medications, exacerbation of the underlying condition, infection, or related conditions. Similar to the inpatient setting, the outpatient management of patients with fluid overload and hyponatremia can be difficult. Further study is required and clinical trials are needed to assess whether the chronic administration of a vaptan in this particular patient population will impact prognosis relative to fluid restriction alone.

Regardless of serum sodium, a frequently advocated intervention in long‐term management is daily weight monitoring which has become a gold standard, especially for patients with advanced symptoms. As shown in EVEREST, lean body weight increases prior to re‐hospitalization for HF were 1.96, 2.07, and 1.97 kg, compared with 0.74, 0.90, and 1.04 kg, respectively, in patients who were not re‐hospitalized (P < 0.001 for all groups).33 Recently, use of invasive hemodynamic monitoring, largely on the basis of the CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION)34 trial, has been advocated as a potential breakthrough in outpatient management because increased right‐sided pressures, rather than weight gain, may precede a heart failure exacerbation.35, 36 It is, however, worthwhile to emphasize that routine hemodynamic monitoring with pulmonary artery catheterization has not been shown to be effective in the inpatient setting,37 despite the attractiveness of knowing the numbers. Additionally, the data supporting the use of serial measurements of biomarkers (in particular, brain natriuretic peptide or its precursor) as a surrogate for filling pressures are conflicting, and therefore this approach is not at present considered standard of care.38

Studies also suggest that postdischarge adherence and the intensity of follow‐up for patients recently admitted for HF may be critical to ensure optimal outcomes. From a practical standpoint, the presence of defined risk factors should lead clinicians to adopt a selective approach to postdischarge monitoring. For those patients deemed to be at risk, reasonable options include outpatient medication titration, more frequent nurse contact, and focused efforts at increasing patient self‐efficacy, all of which can be targeted in the context of a HF disease management program or HF clinic.39, 40 A recent consensus paper outlines the components that should be considered in the establishment of a clinic devoted to the care of patients with heart failure.40 Given increasing reimbursement pressures, these clinics may provide a mechanism to increase quality of care in the outpatient setting while decreasing risk of readmission for preventable heart failure exacerbations. However, other nonphysiological factors influence readmission rates, and not all of these factors can be easily addressed in a traditional medical model.41

SUMMARY

Hyponatremia, in addition to declining renal function, persistent dyspnea, and weight gain, is a major clinical concern during and following hospitalizations for acute decompensated heart failure. Low serum sodium (especially below 130 mEq/L) can contribute to symptoms, complicate diagnostic and therapeutic decision‐making, and significantly prolong length of stay and associated costs. Early recognition of the underlying etiologies, aggressive fluid restriction, and removal of medications that might exacerbate hyponatremia are key steps. The vaptan class is now a useful adjunct in select patients with hyponatremia and fluid overload who do not respond to standard approaches such as fluid restriction.

M.C. is an 82‐year‐old female resident of a skilled nursing facility with a past medical history of moderate dementia, hypertension, type 2 diabetes, and stage 3 chronic kidney disease (baseline creatinine, 1.4 mg/dL; creatinine clearance, 33 mL/min). Her serum sodium concentration ([Na⁺]) is normal (range, 136139 mEq/L) at baseline. She is brought to the emergency department with a 2‐day history of fever, productive cough, and altered mental status from baseline. She is febrile (38.7C), and has tachycardia (114 bpm), normal blood pressure (128/76 mmHg), and hypoxemia (89% on 2 L). Physical examination suggests euvolemia. Notable laboratory values include: serum [Na⁺], 127 mEq/L; serum potassium, 4.1 mEq/L; blood urea nitrogen, 14 mg/dL; serum creatinine, 1.5 mg/dL; glucose, 110 mg/dL; plasma osmolality, 253 mOsm/kg; urine [Na⁺], 92 mEq/L; and urine osmolality, 480 mOsm/kg. Chest radiography shows a right lower lobe infiltrate with prominent air‐bronchograms. The patient is started on intravenous (IV) antibiotics and normal saline (75 mL/hr), and is admitted to the medical service for management of healthcare‐associated pneumonia.

HYPONATREMIA AND PNEUMONIA

The association of hyponatremia with respiratory illness has been recognized for more than 70 years. Winkler and Crankshaw first reported low serum [Na⁺] in patients with pulmonary tuberculosis in 1938.1 Roughly 25 years later, reports of hyponatremia in patients with pneumonia began to surface in the literature.2 The prevalence of hyponatremia (serum [Na⁺] <135 mEq/L) is up to 29% of patients with pneumonia.3 Low serum [Na⁺] is associated with worse outcomes in such patients.36 In a large retrospective cohort (n = 7965), Zilberberg and colleagues found that pneumonia patients with hyponatremia (serum [Na⁺] <135 mEq/L) had statistically higher rates of intensive care unit (ICU) admission (10.0% vs 6.3%, P < 0.001), mechanical ventilation (3.9% vs 2.3%, P = 0.01), longer ICU (6.3 vs 5.3 days, P = 0.07) and hospital lengths of stay (7.6 vs 7.0 days, P < 0.001), and a trend toward higher hospital mortality (5.4% vs 4.0%, P = 0.1) as compared with those with normal serum [Na⁺].4 Hyponatremia is also associated with higher illness severity in a variety of other patient populations. The underlying nature of these associations, however, remains obscure.

The mechanism of hyponatremia in pneumonia is incompletely understood. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is most often implicated.7 Patients with pneumonia often present with several factors that are associated with nonosmotic stimulation of antidiuretic hormone (ADH), most notably inflammatory cytokines such as interleukin‐6,8 stress, nausea, and hypoxemia.9, 10 Others implicate a reset osmostat, citing evidence for this mechanism in other infectious conditions (ie, tuberculosis and malaria).11, 12 Patients with pneumonia may also have concomitant hypovolemia due to factors such as inadequate oral intake, systemic vasodilation, and extrarenal sodium losses from vomiting and diarrhea.13 In contrast to SIADH, hypovolemia is a potent stimulus for appropriate ADH secretion through activation of the carotid baroreceptors.

CASE STUDY REVISITED

M.C.'s initial laboratory assessment would suggest SIADH. Additional testing rules out endocrinopathy (thyroid‐stimulating hormone, 2.2 mIU/L; _AM serum cortisol, 16 g/dL). After 3 days of normal saline infusion (75 mL/hr) and IV vancomycin, cefepime, and levofloxacin, her serum [Na⁺] has dropped to 125 mEq/L. Her vital signs have normalized and she is now saturating well on ambient air. She remains euvolemic. Notable laboratory values on hospital day 4 include serum [Na⁺], 125 mEq/L; serum creatinine, 1.3 mg/dL; plasma osmolality, 261 mOsm/kg; urine [Na⁺], 103 mEq/L; urine potassium, 58 mEq/L; and urine osmolality, 518 mOsm/kg. Her provider invokes a diagnosis of SIADH and appropriately discontinues the normal saline. A fluid restriction of 500 mL/day is then instituted based on her average daily urine volume (1.7 L) and urine/plasma electrolyte ratio (electrolyte‐free water clearance = urine volume {1 [(U_Na + U_K)/P_Na].14 After 48 hours, her serum [Na⁺] has improved to 128 mEq/L, yet she notes extreme thirst. A trial of increased dietary salt is offered, but she refuses, stating that her primary care physician has advised her for years to avoid salt due to her blood pressure. At this point, the nephrology service is consulted for consideration of a vasopressin receptor antagonist.

MANAGEMENT OF HYPONATREMIA IN PATIENTS WITH PNEUMONIA

As mentioned above, hyponatremia has been identified as a marker of increased disease severity in patients with pneumonia, and as such should serve as a reminder to implement the appropriate level of monitoring and vigilance so as to minimize unfavorable outcomes.

Pneumonia patients with hyponatremia often have concomitant hypovolemia. Administering isotonic fluids at admission is appropriate to treat volume depletion, as well as reduce the risk of hyponatremia developing during hospitalization.3 Nair and colleagues reported that 10.5% of the pneumonia patients with normal serum [Na⁺] levels at admission developed hyponatremia during their hospital stay.3 The choice of initial IV fluid treatment influenced this risk significantly: 3.9% of patients given isotonic saline developed hyponatremia compared with 14.5% of those given hypotonic fluids and 13.5% given no IV fluids. Volume status must be followed closely in pneumonia patients who are given isotonic fluids such as normal saline. If hyponatremia persists once euvolemia is achieved, isotonic fluids should be discontinued or used with caution in patients with other indications for IV fluids. Although patients with SIADH have impaired free water excretion, their ability to excrete sodium remains intact.15 Therefore, giving normal saline to euvolemic patients with SIADH can lead to free water retention and downward pressure on the serum [Na⁺].

Once euvolemia is established in this patient group, treatment mirrors the general management principles for SIADH. Many approaches exist to managing this condition, yet the majority of options have significant drawbacks. Although fluid restriction has been promoted for years, the level of restriction must generally be significant and ongoing to be effective. A goal intake of <800 mL/day is usually required to maintain the negative water balance necessary to treat hyponatremia and maintain a normal serum [Na⁺].16 Patients on such a fluid restriction experience thirst, a fundamentally strong impulse that is difficult to manage. As a result, long‐term compliance is extremely challenging.1719 Diets high in solute (sodium and/or protein) have also been used to manage SIADH. Unfortunately, there are no guidelines to follow, and such diets are generally contraindicated in patients with comorbidities such as heart failure and kidney disease. Demeclocycline has been used successfully to treat hyponatremia, but its effects are variable and it can be nephrotoxic.20 Urea induces an osmotic diuresis and concomitant free water excretion. However, its use is very limited by an unpleasant bitter taste and the lack of availability in many countries.20 Vasopressin receptor antagonists (also known as vaptans) have a US Food and Drug Administration (FDA) indication for the treatment of clinically significant hypervolemic or euvolemic hyponatremia (associated with heart failure, cirrhosis or SIADH) with either a serum [Na⁺] level <125 mEq/L or less marked hyponatremia that is symptomatic and resistant to fluid restriction. The use of vaptans in patients with pneumonia has not been studied specifically or extensively (unlike patients with heart failure or cirrhosis), and therefore should be used with extra caution in this group, under the supervision of a nephrologist. Additional studies are needed to evaluate long‐term clinical outcomes and cost/benefit ratios for the use of vaptans in patients with SIADH.

SUMMARY

The presence of hyponatremia in patients admitted with pneumonia should be recognized and actively managed. Isotonic fluids are generally appropriate initially to address underlying volume depletion and reduce the risk of hyponatremia developing during hospitalization. If hyponatremia persists once euvolemia is achieved, patients are traditionally then managed with fluid restriction, increased dietary solute, or demeclocycline, each of which has significant limitations. Vasopressin receptor antagonists represent a new option for managing these patients, but must be used carefully under the supervision of a nephrologist.

M.C. is an 82‐year‐old female resident of a skilled nursing facility with a past medical history of moderate dementia, hypertension, type 2 diabetes, and stage 3 chronic kidney disease (baseline creatinine, 1.4 mg/dL; creatinine clearance, 33 mL/min). Her serum sodium concentration ([Na⁺]) is normal (range, 136139 mEq/L) at baseline. She is brought to the emergency department with a 2‐day history of fever, productive cough, and altered mental status from baseline. She is febrile (38.7C), and has tachycardia (114 bpm), normal blood pressure (128/76 mmHg), and hypoxemia (89% on 2 L). Physical examination suggests euvolemia. Notable laboratory values include: serum [Na⁺], 127 mEq/L; serum potassium, 4.1 mEq/L; blood urea nitrogen, 14 mg/dL; serum creatinine, 1.5 mg/dL; glucose, 110 mg/dL; plasma osmolality, 253 mOsm/kg; urine [Na⁺], 92 mEq/L; and urine osmolality, 480 mOsm/kg. Chest radiography shows a right lower lobe infiltrate with prominent air‐bronchograms. The patient is started on intravenous (IV) antibiotics and normal saline (75 mL/hr), and is admitted to the medical service for management of healthcare‐associated pneumonia.

HYPONATREMIA AND PNEUMONIA

The association of hyponatremia with respiratory illness has been recognized for more than 70 years. Winkler and Crankshaw first reported low serum [Na⁺] in patients with pulmonary tuberculosis in 1938.1 Roughly 25 years later, reports of hyponatremia in patients with pneumonia began to surface in the literature.2 The prevalence of hyponatremia (serum [Na⁺] <135 mEq/L) is up to 29% of patients with pneumonia.3 Low serum [Na⁺] is associated with worse outcomes in such patients.36 In a large retrospective cohort (n = 7965), Zilberberg and colleagues found that pneumonia patients with hyponatremia (serum [Na⁺] <135 mEq/L) had statistically higher rates of intensive care unit (ICU) admission (10.0% vs 6.3%, P < 0.001), mechanical ventilation (3.9% vs 2.3%, P = 0.01), longer ICU (6.3 vs 5.3 days, P = 0.07) and hospital lengths of stay (7.6 vs 7.0 days, P < 0.001), and a trend toward higher hospital mortality (5.4% vs 4.0%, P = 0.1) as compared with those with normal serum [Na⁺].4 Hyponatremia is also associated with higher illness severity in a variety of other patient populations. The underlying nature of these associations, however, remains obscure.

The mechanism of hyponatremia in pneumonia is incompletely understood. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is most often implicated.7 Patients with pneumonia often present with several factors that are associated with nonosmotic stimulation of antidiuretic hormone (ADH), most notably inflammatory cytokines such as interleukin‐6,8 stress, nausea, and hypoxemia.9, 10 Others implicate a reset osmostat, citing evidence for this mechanism in other infectious conditions (ie, tuberculosis and malaria).11, 12 Patients with pneumonia may also have concomitant hypovolemia due to factors such as inadequate oral intake, systemic vasodilation, and extrarenal sodium losses from vomiting and diarrhea.13 In contrast to SIADH, hypovolemia is a potent stimulus for appropriate ADH secretion through activation of the carotid baroreceptors.

CASE STUDY REVISITED

M.C.'s initial laboratory assessment would suggest SIADH. Additional testing rules out endocrinopathy (thyroid‐stimulating hormone, 2.2 mIU/L; _AM serum cortisol, 16 g/dL). After 3 days of normal saline infusion (75 mL/hr) and IV vancomycin, cefepime, and levofloxacin, her serum [Na⁺] has dropped to 125 mEq/L. Her vital signs have normalized and she is now saturating well on ambient air. She remains euvolemic. Notable laboratory values on hospital day 4 include serum [Na⁺], 125 mEq/L; serum creatinine, 1.3 mg/dL; plasma osmolality, 261 mOsm/kg; urine [Na⁺], 103 mEq/L; urine potassium, 58 mEq/L; and urine osmolality, 518 mOsm/kg. Her provider invokes a diagnosis of SIADH and appropriately discontinues the normal saline. A fluid restriction of 500 mL/day is then instituted based on her average daily urine volume (1.7 L) and urine/plasma electrolyte ratio (electrolyte‐free water clearance = urine volume {1 [(U_Na + U_K)/P_Na].14 After 48 hours, her serum [Na⁺] has improved to 128 mEq/L, yet she notes extreme thirst. A trial of increased dietary salt is offered, but she refuses, stating that her primary care physician has advised her for years to avoid salt due to her blood pressure. At this point, the nephrology service is consulted for consideration of a vasopressin receptor antagonist.

MANAGEMENT OF HYPONATREMIA IN PATIENTS WITH PNEUMONIA

As mentioned above, hyponatremia has been identified as a marker of increased disease severity in patients with pneumonia, and as such should serve as a reminder to implement the appropriate level of monitoring and vigilance so as to minimize unfavorable outcomes.

Pneumonia patients with hyponatremia often have concomitant hypovolemia. Administering isotonic fluids at admission is appropriate to treat volume depletion, as well as reduce the risk of hyponatremia developing during hospitalization.3 Nair and colleagues reported that 10.5% of the pneumonia patients with normal serum [Na⁺] levels at admission developed hyponatremia during their hospital stay.3 The choice of initial IV fluid treatment influenced this risk significantly: 3.9% of patients given isotonic saline developed hyponatremia compared with 14.5% of those given hypotonic fluids and 13.5% given no IV fluids. Volume status must be followed closely in pneumonia patients who are given isotonic fluids such as normal saline. If hyponatremia persists once euvolemia is achieved, isotonic fluids should be discontinued or used with caution in patients with other indications for IV fluids. Although patients with SIADH have impaired free water excretion, their ability to excrete sodium remains intact.15 Therefore, giving normal saline to euvolemic patients with SIADH can lead to free water retention and downward pressure on the serum [Na⁺].

Once euvolemia is established in this patient group, treatment mirrors the general management principles for SIADH. Many approaches exist to managing this condition, yet the majority of options have significant drawbacks. Although fluid restriction has been promoted for years, the level of restriction must generally be significant and ongoing to be effective. A goal intake of <800 mL/day is usually required to maintain the negative water balance necessary to treat hyponatremia and maintain a normal serum [Na⁺].16 Patients on such a fluid restriction experience thirst, a fundamentally strong impulse that is difficult to manage. As a result, long‐term compliance is extremely challenging.1719 Diets high in solute (sodium and/or protein) have also been used to manage SIADH. Unfortunately, there are no guidelines to follow, and such diets are generally contraindicated in patients with comorbidities such as heart failure and kidney disease. Demeclocycline has been used successfully to treat hyponatremia, but its effects are variable and it can be nephrotoxic.20 Urea induces an osmotic diuresis and concomitant free water excretion. However, its use is very limited by an unpleasant bitter taste and the lack of availability in many countries.20 Vasopressin receptor antagonists (also known as vaptans) have a US Food and Drug Administration (FDA) indication for the treatment of clinically significant hypervolemic or euvolemic hyponatremia (associated with heart failure, cirrhosis or SIADH) with either a serum [Na⁺] level <125 mEq/L or less marked hyponatremia that is symptomatic and resistant to fluid restriction. The use of vaptans in patients with pneumonia has not been studied specifically or extensively (unlike patients with heart failure or cirrhosis), and therefore should be used with extra caution in this group, under the supervision of a nephrologist. Additional studies are needed to evaluate long‐term clinical outcomes and cost/benefit ratios for the use of vaptans in patients with SIADH.

SUMMARY

The presence of hyponatremia in patients admitted with pneumonia should be recognized and actively managed. Isotonic fluids are generally appropriate initially to address underlying volume depletion and reduce the risk of hyponatremia developing during hospitalization. If hyponatremia persists once euvolemia is achieved, patients are traditionally then managed with fluid restriction, increased dietary solute, or demeclocycline, each of which has significant limitations. Vasopressin receptor antagonists represent a new option for managing these patients, but must be used carefully under the supervision of a nephrologist.

M.C. is an 82‐year‐old female resident of a skilled nursing facility with a past medical history of moderate dementia, hypertension, type 2 diabetes, and stage 3 chronic kidney disease (baseline creatinine, 1.4 mg/dL; creatinine clearance, 33 mL/min). Her serum sodium concentration ([Na⁺]) is normal (range, 136139 mEq/L) at baseline. She is brought to the emergency department with a 2‐day history of fever, productive cough, and altered mental status from baseline. She is febrile (38.7C), and has tachycardia (114 bpm), normal blood pressure (128/76 mmHg), and hypoxemia (89% on 2 L). Physical examination suggests euvolemia. Notable laboratory values include: serum [Na⁺], 127 mEq/L; serum potassium, 4.1 mEq/L; blood urea nitrogen, 14 mg/dL; serum creatinine, 1.5 mg/dL; glucose, 110 mg/dL; plasma osmolality, 253 mOsm/kg; urine [Na⁺], 92 mEq/L; and urine osmolality, 480 mOsm/kg. Chest radiography shows a right lower lobe infiltrate with prominent air‐bronchograms. The patient is started on intravenous (IV) antibiotics and normal saline (75 mL/hr), and is admitted to the medical service for management of healthcare‐associated pneumonia.

HYPONATREMIA AND PNEUMONIA

The association of hyponatremia with respiratory illness has been recognized for more than 70 years. Winkler and Crankshaw first reported low serum [Na⁺] in patients with pulmonary tuberculosis in 1938.1 Roughly 25 years later, reports of hyponatremia in patients with pneumonia began to surface in the literature.2 The prevalence of hyponatremia (serum [Na⁺] <135 mEq/L) is up to 29% of patients with pneumonia.3 Low serum [Na⁺] is associated with worse outcomes in such patients.36 In a large retrospective cohort (n = 7965), Zilberberg and colleagues found that pneumonia patients with hyponatremia (serum [Na⁺] <135 mEq/L) had statistically higher rates of intensive care unit (ICU) admission (10.0% vs 6.3%, P < 0.001), mechanical ventilation (3.9% vs 2.3%, P = 0.01), longer ICU (6.3 vs 5.3 days, P = 0.07) and hospital lengths of stay (7.6 vs 7.0 days, P < 0.001), and a trend toward higher hospital mortality (5.4% vs 4.0%, P = 0.1) as compared with those with normal serum [Na⁺].4 Hyponatremia is also associated with higher illness severity in a variety of other patient populations. The underlying nature of these associations, however, remains obscure.

The mechanism of hyponatremia in pneumonia is incompletely understood. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is most often implicated.7 Patients with pneumonia often present with several factors that are associated with nonosmotic stimulation of antidiuretic hormone (ADH), most notably inflammatory cytokines such as interleukin‐6,8 stress, nausea, and hypoxemia.9, 10 Others implicate a reset osmostat, citing evidence for this mechanism in other infectious conditions (ie, tuberculosis and malaria).11, 12 Patients with pneumonia may also have concomitant hypovolemia due to factors such as inadequate oral intake, systemic vasodilation, and extrarenal sodium losses from vomiting and diarrhea.13 In contrast to SIADH, hypovolemia is a potent stimulus for appropriate ADH secretion through activation of the carotid baroreceptors.

CASE STUDY REVISITED

M.C.'s initial laboratory assessment would suggest SIADH. Additional testing rules out endocrinopathy (thyroid‐stimulating hormone, 2.2 mIU/L; _AM serum cortisol, 16 g/dL). After 3 days of normal saline infusion (75 mL/hr) and IV vancomycin, cefepime, and levofloxacin, her serum [Na⁺] has dropped to 125 mEq/L. Her vital signs have normalized and she is now saturating well on ambient air. She remains euvolemic. Notable laboratory values on hospital day 4 include serum [Na⁺], 125 mEq/L; serum creatinine, 1.3 mg/dL; plasma osmolality, 261 mOsm/kg; urine [Na⁺], 103 mEq/L; urine potassium, 58 mEq/L; and urine osmolality, 518 mOsm/kg. Her provider invokes a diagnosis of SIADH and appropriately discontinues the normal saline. A fluid restriction of 500 mL/day is then instituted based on her average daily urine volume (1.7 L) and urine/plasma electrolyte ratio (electrolyte‐free water clearance = urine volume {1 [(U_Na + U_K)/P_Na].14 After 48 hours, her serum [Na⁺] has improved to 128 mEq/L, yet she notes extreme thirst. A trial of increased dietary salt is offered, but she refuses, stating that her primary care physician has advised her for years to avoid salt due to her blood pressure. At this point, the nephrology service is consulted for consideration of a vasopressin receptor antagonist.

MANAGEMENT OF HYPONATREMIA IN PATIENTS WITH PNEUMONIA

As mentioned above, hyponatremia has been identified as a marker of increased disease severity in patients with pneumonia, and as such should serve as a reminder to implement the appropriate level of monitoring and vigilance so as to minimize unfavorable outcomes.

Pneumonia patients with hyponatremia often have concomitant hypovolemia. Administering isotonic fluids at admission is appropriate to treat volume depletion, as well as reduce the risk of hyponatremia developing during hospitalization.3 Nair and colleagues reported that 10.5% of the pneumonia patients with normal serum [Na⁺] levels at admission developed hyponatremia during their hospital stay.3 The choice of initial IV fluid treatment influenced this risk significantly: 3.9% of patients given isotonic saline developed hyponatremia compared with 14.5% of those given hypotonic fluids and 13.5% given no IV fluids. Volume status must be followed closely in pneumonia patients who are given isotonic fluids such as normal saline. If hyponatremia persists once euvolemia is achieved, isotonic fluids should be discontinued or used with caution in patients with other indications for IV fluids. Although patients with SIADH have impaired free water excretion, their ability to excrete sodium remains intact.15 Therefore, giving normal saline to euvolemic patients with SIADH can lead to free water retention and downward pressure on the serum [Na⁺].

Once euvolemia is established in this patient group, treatment mirrors the general management principles for SIADH. Many approaches exist to managing this condition, yet the majority of options have significant drawbacks. Although fluid restriction has been promoted for years, the level of restriction must generally be significant and ongoing to be effective. A goal intake of <800 mL/day is usually required to maintain the negative water balance necessary to treat hyponatremia and maintain a normal serum [Na⁺].16 Patients on such a fluid restriction experience thirst, a fundamentally strong impulse that is difficult to manage. As a result, long‐term compliance is extremely challenging.1719 Diets high in solute (sodium and/or protein) have also been used to manage SIADH. Unfortunately, there are no guidelines to follow, and such diets are generally contraindicated in patients with comorbidities such as heart failure and kidney disease. Demeclocycline has been used successfully to treat hyponatremia, but its effects are variable and it can be nephrotoxic.20 Urea induces an osmotic diuresis and concomitant free water excretion. However, its use is very limited by an unpleasant bitter taste and the lack of availability in many countries.20 Vasopressin receptor antagonists (also known as vaptans) have a US Food and Drug Administration (FDA) indication for the treatment of clinically significant hypervolemic or euvolemic hyponatremia (associated with heart failure, cirrhosis or SIADH) with either a serum [Na⁺] level <125 mEq/L or less marked hyponatremia that is symptomatic and resistant to fluid restriction. The use of vaptans in patients with pneumonia has not been studied specifically or extensively (unlike patients with heart failure or cirrhosis), and therefore should be used with extra caution in this group, under the supervision of a nephrologist. Additional studies are needed to evaluate long‐term clinical outcomes and cost/benefit ratios for the use of vaptans in patients with SIADH.

SUMMARY

The presence of hyponatremia in patients admitted with pneumonia should be recognized and actively managed. Isotonic fluids are generally appropriate initially to address underlying volume depletion and reduce the risk of hyponatremia developing during hospitalization. If hyponatremia persists once euvolemia is achieved, patients are traditionally then managed with fluid restriction, increased dietary solute, or demeclocycline, each of which has significant limitations. Vasopressin receptor antagonists represent a new option for managing these patients, but must be used carefully under the supervision of a nephrologist.

Cirrhosis is one of the main causes of hypervolemic hyponatremia, a dilutional form of hyponatremia that occurs when there is an increase in total body water but a relatively smaller increase in total serum sodium. Portal hypertension is the main precipitating factor in fluid retention that leads to the development of cirrhotic hyponatremia. In cirrhosis, portal hypertension is determined by 2 main factors: increased intrahepatic resistance and increased spanchnic blood flow. The increased intrahepatic resistance is due to both structural (fibrosis, conversion of low resistance fenestrated sinusoids into capillaries) and dynamic (vasoconstriction due to endothelial cell dysfunction) changes.1

The hepatic circulation normally is able to accommodate an increase in portal blood flow associated with postprandial hyperemia. The elevated intrahepatic resistance in cirrhosis results in an inability to accommodate the normal increase in portal blood flow that occurs in the postprandial hyperemia state.3 As a result, portal pressure increases during postprandial hyperemia, leading to reflex vasoconstriction, which creates a shear stress and increases splanchnic nitric oxide (NO) production.4 NO, one of the most important vasodilators in the splanchnic circulation, increases splanchnic blood flow and portal pressures. When this happens repeatedly, it leads to a progressive dilation of preexisting portosystemic vascular channels and the development of varices.5 At the same time, levels of vascular endothelial growth factor rise; this is a very important mediator for angiogenesis because it increases NO, further increasing splanchnic vasodilation.6

Progressive splanchnic vasodilation and increased blood flow into the splanchnic circulation leads to central hypovolemia, arterial underfilling, and decreased blood flow in renal afferent arterioles. Vasoconstrictor norepinephrine and antinatriuretic mechanisms are subsequently activated in an attempt to normalize renal perfusion pressures. Baroreceptor‐mediated nonosmotic release of arginine vasopressin (AVP) is triggered and renin angiotensin‐aldosterone system activity is increased, which increases sodium reabsorption and activates the stellate cells, causing fibrosis, vasoconstriction, and increased portal pressures.6, 7

AVP acts at vasopression‐1A (V_1A) receptors to increase arterial vasoconstriction, and at V₂ receptors in renal tubule cells for solute‐free water retention.1 The increased sodium and water reabsorption leads to fluid retention, increased central blood volume, venous return to the heart, and an increase in cardiac output to maintain arterial perfusion and create the hyperdynamic circulation that is characteristic of cirrhosis with advanced portal hypertension. Dilutional hyponatremia develops when free water retention is more pronounced than that of sodium retention.

CLINICAL FACTORS ASSOCIATED WITH CIRRHOTIC HYPONATREMIA

Diuretics lead to hyponatremia through several mechanisms.8 First, they induce a contraction of the central blood volume, leading to the nonosmotic release of AVP. In advanced cirrhosis, there is activation of the renin‐angiotensin system in addition to the nonosmotic release of AVP, leading to sodium and free water reabsorption. Diuretics block the sodium reabsorption. However, the water‐retaining effects persist, further contributing to dilutional hyponatremia.8 This cycle is made worse by low sodium intake and frequent thirst experienced by these patients.8 Other medications (eg, non‐steroidal anti‐inflammatory drugs, proton pump inhibitors, and selective serotonin reuptake inhibitors) commonly prescribed for cirrhotic patients may also contribute to the development or worsening of dilutional hyponatremia.8

Increased intrathoracic pressure in patients with tense ascites can also contribute to dilutional hyponatremia by increasing baroreceptor‐mediated release of AVP.9 Large volume paracentesis without the oncotic influence of albumin, an intervention commonly required in patients with cirrhosis and recurrent ascites, may also lead to significant increases in plasma renin activity and plasma aldosterone, which further worsen these pathophysiologic mechanisms, resulting in reduced serum sodium concentration.10 Following removal of excess peritoneal fluid, blood flow to the kidneys is initially improved, but ascitic fluid reaccumulates and the patient becomes intravascularly depleted.10

Infection is an important clinical mediator for the development of both portal hypertension as well as hyponatremia. Bacterial translocation leads to endotoxemia and increased tumor necrosis factor (TNF)‐alpha, resulting in increased splanchnic NO and splanchnic arterial vasodilatation. This process reduces cardiac output, which leads to increased AVP secretion.11, 12 Endotoxin‐mediated splanchnic vasodilatation, especially with spontaneous bacterial peritonitis (SBP), can adversely affect central blood volume status, especially in the presence of severe ascites.1 Clinicians providing care for patients with cirrhosis should be aware of these factors and closely monitor at‐risk patients for the onset or worsening of hyponatremia.1

PROGNOSTIC SIGNIFICANCE OF HYPONATREMIA IN CIRRHOSIS

Hyponatremia has several important clinical implications for patients with cirrhosis.13 Hyponatremia is associated with refractory ascites, greater fluid accumulation, the need for paracentesis, and, importantly, impaired renal function. In patients with ascites and cirrhosis, approximately 50% have some degree of hyponatremia.2 Moreover, the severity of hyponatremia associated with advanced cirrhosis correlates with the degree of cirrhosis complications, especially hyponatremia associated with hepatorenal syndrome, encephalopathy, and SBP (Table 1).2

Similarly, hyponatremia is strongly associated with increasing Child‐Pugh and Model for End‐Stage Liver Disease (MELD) scores.14 In an analysis of data among candidates for liver transplantation from the Organ Procurement and Transplantation Network, the combination of MELD score and serum sodium concentration was a better predictor of death than the MELD score alone.14 In addition, the effect of hyponatremia on clinical outcomes was greater in patients with a low MELD score than those with a relatively high MELD score.. These results suggest that combining serum sodium concentrations with MELD scores to assign transplantation priority might reduce mortality among patients on the waiting list.14

Hyponatremia is also a marker for the development of overt hepatic encephalopathy in patients with cirrhosis.13 One of the proposed mechanisms for encephalopathy is low‐grade cerebral edema. This leads to the conversion of glutamate to glutamine by ammonia, which accumulates within astrocytes, causing astrocyte swelling and dysfunction. Because hyponatremia complicates the management of fluid overload, it increases the risk of developing or exacerbating hepatic encephalopathy.13

Hyponatremia is intimately involved with the development of renal failure in the patient with cirrhosis. It is an earlier and more sensitive marker of renal impairment and/or circulatory dysfunction than serum creatinine.15 It is often the precursor to the development of hepatorenal syndrome.16, 17

Hyponatremia is more common in hospitalized versus ambulatory patients with cirrhosis.1 In a study of 126 patients with cirrhosis admitted to an intensive care unit, patients with serum [Na⁺] 135 mEq/L had a greater frequency of ascites, illness severity scores, hepatic encephalopathy, sepsis, renal failure, and in‐hospital mortality than normonatremic patients (73.1% vs 55.9%).18 Persistent ascites and low serum sodium identified cirrhotic patients with a high mortality risk, despite low MELD scores, in a study of 507 veterans in the United States with cirrhosis.19 In a retrospective review of 127 patients, hyponatremia was predictive of the development of acute renal failure during hospitalization; among patients with hyponatremia who developed renal failure in the hospital, 72% died.20

Clinical assessment of a patient with cirrhosis who has hyponatremia can be difficult.1 These patients have too much salt and water in the wrong spaces (ie, in the peritoneal cavity and peripheral tissue). As a result, it is possible to have fluid overload with intravascular depletion. A further complication is that dilutional hyponatremia is associated with hepatorenal syndrome. Because these patients have elevated blood urea nitrogen (BUN) and creatinine, and decreased urine output and urine sodium concentration, they appear to be indistinguishable from a patient with prerenal azotemia prior to volume expansion.1 Many of these factors and concerns are illustrated in the following case we handled several years ago.

A 70‐YEAR‐OLD WOMAN WITH CIRRHOSIS

K.R. is a 70‐year‐old white woman recently discharged from the hospital following treatment of recurrent cellulitis. Her past medical history is positive for cirrhosis secondary to active alcohol use, chronic autoimmune hepatitis, and iron overload. Her hospital course was notable for tense ascites, asterixis, and a serum [Na⁺] of 126 mEq/L at admission. K.R. was managed with large volume paracentesis with 25% salt‐poor albumin, elevation of her lower extremities, discontinuation of diuretics, and 1 L fluid restriction. Her serum [Na⁺] increased to 128 mEq/L. Although her cellulitis and edema both improved, both persisted. In addition, her mental status also improved, but asterixis persisted. At this point in the hospitalization, effective management of the cellulitis was hindered by the persistent edema, and its treatment with diuretics was limited by the hyponatremia and hepatic encephalopathy.

Today, we have better treatment options for managing this patient. To effectively correct the hyponatremia and facilitate treatment of the other complications of cirrhosis, we can now initiate therapy with one of the vaptans currently available.

TREATMENT OF MILD ASYMPTOMATIC HYPERVOLEMIC HYPONATREMIA

The initial approach to treatment of patients with mild asymptomatic, hypervolemic hyponatremia consists of fluid restriction and a sodium‐restricted diet.1 Fluid restriction, however, has limited efficacy and is often not well tolerated by patients. For patients with severe or progressive hyponatremia, diuretics should be minimized or discontinued to avoid intravascular volume depletion. If patients have severe dilutional hyponatremia and tense ascites, therapeutic paracentesis with plasma expanders is safe.1

The pharmacologic approach to treating hyponatremia has advanced with the discovery of vaptans, drugs that inhibit V₂ receptors in cells of the collecting ducts.21 In contrast to conventional diuretics, vaptans do not increase natriuresis. Administration of a vaptan agent for 1 to 2 weeks has been shown to significantly improve low serum sodium levels in patients with hyponatremia, and promote aquaresis without significantly altering renal or circulatory function or activity of the renin‐angiotensin‐aldosterone system. The most frequent side effect of vaptan therapy is thirst.21

Two vaptan agents are currently approved for use in the United States: conivaptan and tolvaptan. Conivaptan is administered intravenously, and is a nonselective vasopressin inhibitor, blocking both V_1A and V₂ receptors. The course of therapy for conivaptan is 4 days. Tolvaptan, on the other hand, selectively blocks V₂ receptors, and is a once‐daily oral vaptan that can be given long‐term.21

The efficacy of tolvaptan was evaluated in the Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2 (SALT‐1 and SALT‐2).22 In these multicenter, prospective, randomized, placebo‐controlled trials, patients with dilutional hyponatremia (serum [Na⁺] <135 mEq/L) associated with cirrhosis (22.4% in SALT‐1, 30.5% in SALT‐2), heart failure, or syndrome of inappropriate antidiuretic hormone (ADH) hypersecretion, and who were hospitalized and clinically stable, received tolvaptan 15 mg daily or placebo. Repeat serum sodium levels were obtained at 8 hours, 2, 3, and 4 days, and then weekly at days 11, 18, 25, and 30. The study drug was discontinued on day 30, with follow‐up serum sodium levels taken 7 days later. (In patients with persistent hyponatremia, the tolvaptan dose was adjusted to 30 mg and then 60 mg with the goal of achieving a serum [Na⁺] <135 mEq/L.) Increases in serum sodium concentration were seen as early as 8 hours after the first administration of tolvaptan and persisted throughout the study period. After tolvaptan was discontinued, serum sodium levels decreased to baseline within 1 week.22 Tolvaptan was well tolerated, with the most common side effects being increased thirst, dry mouth, and increased urination.22

Longer‐term administration of tolvaptan was shown to maintain a higher serum sodium concentration with an acceptable safety profile in SALTWATER, the open‐label extension of the SALT‐1 and SALT‐2 trials.23 The study included 111 patients with hyponatremia who received oral tolvaptan for a mean follow‐up of 701 days. The most common adverse effects potentially related to tolvaptan were thirst, dry mouth, polydipsia, and polyuria.22, 23 Overall, there were 9 possible and 1 probable serious adverse events, which represents an acceptable safety profile over 77,369 patient‐days of exposure. Over time, 64 patients discontinued tolvaptan, 30 due to adverse reactions or death.22 The results of SALTWATER indicated that most patients received benefit from treatment with tolvaptan, with a decreased need for fluid restriction.23

PATIENT CHARACTERISTICS FOR TOLVAPTAN

In the SALT trials, tolvaptan was administered to clinically stable patients. Based on recommendations by the US Food and Drug Administration (FDA), tolvaptan should be initiated or reinitiated in a hospital setting.1 Patients with severe neurologic symptoms due to hyponatremia should be treated with normal saline instead of tolvaptan; combination therapy with tolvaptan and normal saline should be avoided due to the potential for a too‐rapid correction of hyponatremia and the potential for central pontine myelinolysis. Saline should be discontinued and persistent hyponatremia confirmed before beginning tolvaptan therapy.1

Several additional factors should be considered before patients begin tolvaptan. First, tolvaptan increases thirst, as well as the frequency and volume of urination. Therefore, patients must be able to respond appropriately to thirst with increased water intake. Patients should not be fluid‐restricted during the first day of tolvaptan therapy; instead, they should be instructed to respond to their thirst with increased water ingestion. Because of these factors, caution should be exercised in administering tolvaptan to a confused, restrained patient. In addition, patients should have adequate toileting aids, such as a bedside urinal or commode.1

As with most new drugs, acquisition costs for tolvaptan should be considered in light of the clinical benefits of treatment outcomes. In a retrospective review, median hospital costs for patients with moderate‐to‐severe ($16,606) and mild‐to‐moderate hyponatremia ($14,266) were higher than matched patients without hyponatremia ($13,066).24 In the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial, in which patients with severe congestive heart failure (including those with and without hyponatremia) were randomized to tolvaptan or placebo, the adjusted mean length of hospital stay for those with hyponatremia at baseline who received tolvaptan was 1.72 days shorter than those who received placebo.25 Although tolvaptan is somewhat expensive, the cost compares favorably with the daily cost of hospitalization.

SUMMARY

Portal hypertension plays a pivotal role in the development of hyponatremia in patients with cirrhosis. Reflex vasodilation in the splanchnic circulation compromises the effective central blood volume, triggering compensatory vasoconstrictor and antinatriuretic mechanisms. The net effect is greater free water accumulation than sodium retention, creating dilutional hyponatremia.

The severity of hyponatremia correlates with the severity of cirrhosis complications, such as hepatorenal syndrome, encephalopathy, SBP, and renal failure. The presence of hyponatremia is a marker for poor outcomes and shortened survival, regardless of MELD scores.

In a hospitalized, acutely ill patient with cirrhosis, such as the person in this case, therapy may involve discontinuation of diuretics, evaluation and treatment of infection, volume expansion with salt‐poor albumin, and tolvaptan for treatment of hyponatremia. Regarding tolvaptan, early morning administration is recommended. At initiation of therapy, fluid restriction should be discontinued, and off‐floor testing should be avoided. Concomitant medications should be reviewed to avoid potentially harmful interactions.

Cirrhosis is one of the main causes of hypervolemic hyponatremia, a dilutional form of hyponatremia that occurs when there is an increase in total body water but a relatively smaller increase in total serum sodium. Portal hypertension is the main precipitating factor in fluid retention that leads to the development of cirrhotic hyponatremia. In cirrhosis, portal hypertension is determined by 2 main factors: increased intrahepatic resistance and increased spanchnic blood flow. The increased intrahepatic resistance is due to both structural (fibrosis, conversion of low resistance fenestrated sinusoids into capillaries) and dynamic (vasoconstriction due to endothelial cell dysfunction) changes.1

The hepatic circulation normally is able to accommodate an increase in portal blood flow associated with postprandial hyperemia. The elevated intrahepatic resistance in cirrhosis results in an inability to accommodate the normal increase in portal blood flow that occurs in the postprandial hyperemia state.3 As a result, portal pressure increases during postprandial hyperemia, leading to reflex vasoconstriction, which creates a shear stress and increases splanchnic nitric oxide (NO) production.4 NO, one of the most important vasodilators in the splanchnic circulation, increases splanchnic blood flow and portal pressures. When this happens repeatedly, it leads to a progressive dilation of preexisting portosystemic vascular channels and the development of varices.5 At the same time, levels of vascular endothelial growth factor rise; this is a very important mediator for angiogenesis because it increases NO, further increasing splanchnic vasodilation.6

Progressive splanchnic vasodilation and increased blood flow into the splanchnic circulation leads to central hypovolemia, arterial underfilling, and decreased blood flow in renal afferent arterioles. Vasoconstrictor norepinephrine and antinatriuretic mechanisms are subsequently activated in an attempt to normalize renal perfusion pressures. Baroreceptor‐mediated nonosmotic release of arginine vasopressin (AVP) is triggered and renin angiotensin‐aldosterone system activity is increased, which increases sodium reabsorption and activates the stellate cells, causing fibrosis, vasoconstriction, and increased portal pressures.6, 7

AVP acts at vasopression‐1A (V_1A) receptors to increase arterial vasoconstriction, and at V₂ receptors in renal tubule cells for solute‐free water retention.1 The increased sodium and water reabsorption leads to fluid retention, increased central blood volume, venous return to the heart, and an increase in cardiac output to maintain arterial perfusion and create the hyperdynamic circulation that is characteristic of cirrhosis with advanced portal hypertension. Dilutional hyponatremia develops when free water retention is more pronounced than that of sodium retention.

CLINICAL FACTORS ASSOCIATED WITH CIRRHOTIC HYPONATREMIA

Diuretics lead to hyponatremia through several mechanisms.8 First, they induce a contraction of the central blood volume, leading to the nonosmotic release of AVP. In advanced cirrhosis, there is activation of the renin‐angiotensin system in addition to the nonosmotic release of AVP, leading to sodium and free water reabsorption. Diuretics block the sodium reabsorption. However, the water‐retaining effects persist, further contributing to dilutional hyponatremia.8 This cycle is made worse by low sodium intake and frequent thirst experienced by these patients.8 Other medications (eg, non‐steroidal anti‐inflammatory drugs, proton pump inhibitors, and selective serotonin reuptake inhibitors) commonly prescribed for cirrhotic patients may also contribute to the development or worsening of dilutional hyponatremia.8

Increased intrathoracic pressure in patients with tense ascites can also contribute to dilutional hyponatremia by increasing baroreceptor‐mediated release of AVP.9 Large volume paracentesis without the oncotic influence of albumin, an intervention commonly required in patients with cirrhosis and recurrent ascites, may also lead to significant increases in plasma renin activity and plasma aldosterone, which further worsen these pathophysiologic mechanisms, resulting in reduced serum sodium concentration.10 Following removal of excess peritoneal fluid, blood flow to the kidneys is initially improved, but ascitic fluid reaccumulates and the patient becomes intravascularly depleted.10

Infection is an important clinical mediator for the development of both portal hypertension as well as hyponatremia. Bacterial translocation leads to endotoxemia and increased tumor necrosis factor (TNF)‐alpha, resulting in increased splanchnic NO and splanchnic arterial vasodilatation. This process reduces cardiac output, which leads to increased AVP secretion.11, 12 Endotoxin‐mediated splanchnic vasodilatation, especially with spontaneous bacterial peritonitis (SBP), can adversely affect central blood volume status, especially in the presence of severe ascites.1 Clinicians providing care for patients with cirrhosis should be aware of these factors and closely monitor at‐risk patients for the onset or worsening of hyponatremia.1

PROGNOSTIC SIGNIFICANCE OF HYPONATREMIA IN CIRRHOSIS

Hyponatremia has several important clinical implications for patients with cirrhosis.13 Hyponatremia is associated with refractory ascites, greater fluid accumulation, the need for paracentesis, and, importantly, impaired renal function. In patients with ascites and cirrhosis, approximately 50% have some degree of hyponatremia.2 Moreover, the severity of hyponatremia associated with advanced cirrhosis correlates with the degree of cirrhosis complications, especially hyponatremia associated with hepatorenal syndrome, encephalopathy, and SBP (Table 1).2

Similarly, hyponatremia is strongly associated with increasing Child‐Pugh and Model for End‐Stage Liver Disease (MELD) scores.14 In an analysis of data among candidates for liver transplantation from the Organ Procurement and Transplantation Network, the combination of MELD score and serum sodium concentration was a better predictor of death than the MELD score alone.14 In addition, the effect of hyponatremia on clinical outcomes was greater in patients with a low MELD score than those with a relatively high MELD score.. These results suggest that combining serum sodium concentrations with MELD scores to assign transplantation priority might reduce mortality among patients on the waiting list.14

Hyponatremia is also a marker for the development of overt hepatic encephalopathy in patients with cirrhosis.13 One of the proposed mechanisms for encephalopathy is low‐grade cerebral edema. This leads to the conversion of glutamate to glutamine by ammonia, which accumulates within astrocytes, causing astrocyte swelling and dysfunction. Because hyponatremia complicates the management of fluid overload, it increases the risk of developing or exacerbating hepatic encephalopathy.13

Hyponatremia is intimately involved with the development of renal failure in the patient with cirrhosis. It is an earlier and more sensitive marker of renal impairment and/or circulatory dysfunction than serum creatinine.15 It is often the precursor to the development of hepatorenal syndrome.16, 17

Hyponatremia is more common in hospitalized versus ambulatory patients with cirrhosis.1 In a study of 126 patients with cirrhosis admitted to an intensive care unit, patients with serum [Na⁺] 135 mEq/L had a greater frequency of ascites, illness severity scores, hepatic encephalopathy, sepsis, renal failure, and in‐hospital mortality than normonatremic patients (73.1% vs 55.9%).18 Persistent ascites and low serum sodium identified cirrhotic patients with a high mortality risk, despite low MELD scores, in a study of 507 veterans in the United States with cirrhosis.19 In a retrospective review of 127 patients, hyponatremia was predictive of the development of acute renal failure during hospitalization; among patients with hyponatremia who developed renal failure in the hospital, 72% died.20

Clinical assessment of a patient with cirrhosis who has hyponatremia can be difficult.1 These patients have too much salt and water in the wrong spaces (ie, in the peritoneal cavity and peripheral tissue). As a result, it is possible to have fluid overload with intravascular depletion. A further complication is that dilutional hyponatremia is associated with hepatorenal syndrome. Because these patients have elevated blood urea nitrogen (BUN) and creatinine, and decreased urine output and urine sodium concentration, they appear to be indistinguishable from a patient with prerenal azotemia prior to volume expansion.1 Many of these factors and concerns are illustrated in the following case we handled several years ago.

A 70‐YEAR‐OLD WOMAN WITH CIRRHOSIS

K.R. is a 70‐year‐old white woman recently discharged from the hospital following treatment of recurrent cellulitis. Her past medical history is positive for cirrhosis secondary to active alcohol use, chronic autoimmune hepatitis, and iron overload. Her hospital course was notable for tense ascites, asterixis, and a serum [Na⁺] of 126 mEq/L at admission. K.R. was managed with large volume paracentesis with 25% salt‐poor albumin, elevation of her lower extremities, discontinuation of diuretics, and 1 L fluid restriction. Her serum [Na⁺] increased to 128 mEq/L. Although her cellulitis and edema both improved, both persisted. In addition, her mental status also improved, but asterixis persisted. At this point in the hospitalization, effective management of the cellulitis was hindered by the persistent edema, and its treatment with diuretics was limited by the hyponatremia and hepatic encephalopathy.

Today, we have better treatment options for managing this patient. To effectively correct the hyponatremia and facilitate treatment of the other complications of cirrhosis, we can now initiate therapy with one of the vaptans currently available.

TREATMENT OF MILD ASYMPTOMATIC HYPERVOLEMIC HYPONATREMIA

The initial approach to treatment of patients with mild asymptomatic, hypervolemic hyponatremia consists of fluid restriction and a sodium‐restricted diet.1 Fluid restriction, however, has limited efficacy and is often not well tolerated by patients. For patients with severe or progressive hyponatremia, diuretics should be minimized or discontinued to avoid intravascular volume depletion. If patients have severe dilutional hyponatremia and tense ascites, therapeutic paracentesis with plasma expanders is safe.1

The pharmacologic approach to treating hyponatremia has advanced with the discovery of vaptans, drugs that inhibit V₂ receptors in cells of the collecting ducts.21 In contrast to conventional diuretics, vaptans do not increase natriuresis. Administration of a vaptan agent for 1 to 2 weeks has been shown to significantly improve low serum sodium levels in patients with hyponatremia, and promote aquaresis without significantly altering renal or circulatory function or activity of the renin‐angiotensin‐aldosterone system. The most frequent side effect of vaptan therapy is thirst.21

Two vaptan agents are currently approved for use in the United States: conivaptan and tolvaptan. Conivaptan is administered intravenously, and is a nonselective vasopressin inhibitor, blocking both V_1A and V₂ receptors. The course of therapy for conivaptan is 4 days. Tolvaptan, on the other hand, selectively blocks V₂ receptors, and is a once‐daily oral vaptan that can be given long‐term.21

The efficacy of tolvaptan was evaluated in the Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2 (SALT‐1 and SALT‐2).22 In these multicenter, prospective, randomized, placebo‐controlled trials, patients with dilutional hyponatremia (serum [Na⁺] <135 mEq/L) associated with cirrhosis (22.4% in SALT‐1, 30.5% in SALT‐2), heart failure, or syndrome of inappropriate antidiuretic hormone (ADH) hypersecretion, and who were hospitalized and clinically stable, received tolvaptan 15 mg daily or placebo. Repeat serum sodium levels were obtained at 8 hours, 2, 3, and 4 days, and then weekly at days 11, 18, 25, and 30. The study drug was discontinued on day 30, with follow‐up serum sodium levels taken 7 days later. (In patients with persistent hyponatremia, the tolvaptan dose was adjusted to 30 mg and then 60 mg with the goal of achieving a serum [Na⁺] <135 mEq/L.) Increases in serum sodium concentration were seen as early as 8 hours after the first administration of tolvaptan and persisted throughout the study period. After tolvaptan was discontinued, serum sodium levels decreased to baseline within 1 week.22 Tolvaptan was well tolerated, with the most common side effects being increased thirst, dry mouth, and increased urination.22

Longer‐term administration of tolvaptan was shown to maintain a higher serum sodium concentration with an acceptable safety profile in SALTWATER, the open‐label extension of the SALT‐1 and SALT‐2 trials.23 The study included 111 patients with hyponatremia who received oral tolvaptan for a mean follow‐up of 701 days. The most common adverse effects potentially related to tolvaptan were thirst, dry mouth, polydipsia, and polyuria.22, 23 Overall, there were 9 possible and 1 probable serious adverse events, which represents an acceptable safety profile over 77,369 patient‐days of exposure. Over time, 64 patients discontinued tolvaptan, 30 due to adverse reactions or death.22 The results of SALTWATER indicated that most patients received benefit from treatment with tolvaptan, with a decreased need for fluid restriction.23

PATIENT CHARACTERISTICS FOR TOLVAPTAN

In the SALT trials, tolvaptan was administered to clinically stable patients. Based on recommendations by the US Food and Drug Administration (FDA), tolvaptan should be initiated or reinitiated in a hospital setting.1 Patients with severe neurologic symptoms due to hyponatremia should be treated with normal saline instead of tolvaptan; combination therapy with tolvaptan and normal saline should be avoided due to the potential for a too‐rapid correction of hyponatremia and the potential for central pontine myelinolysis. Saline should be discontinued and persistent hyponatremia confirmed before beginning tolvaptan therapy.1

Several additional factors should be considered before patients begin tolvaptan. First, tolvaptan increases thirst, as well as the frequency and volume of urination. Therefore, patients must be able to respond appropriately to thirst with increased water intake. Patients should not be fluid‐restricted during the first day of tolvaptan therapy; instead, they should be instructed to respond to their thirst with increased water ingestion. Because of these factors, caution should be exercised in administering tolvaptan to a confused, restrained patient. In addition, patients should have adequate toileting aids, such as a bedside urinal or commode.1

As with most new drugs, acquisition costs for tolvaptan should be considered in light of the clinical benefits of treatment outcomes. In a retrospective review, median hospital costs for patients with moderate‐to‐severe ($16,606) and mild‐to‐moderate hyponatremia ($14,266) were higher than matched patients without hyponatremia ($13,066).24 In the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial, in which patients with severe congestive heart failure (including those with and without hyponatremia) were randomized to tolvaptan or placebo, the adjusted mean length of hospital stay for those with hyponatremia at baseline who received tolvaptan was 1.72 days shorter than those who received placebo.25 Although tolvaptan is somewhat expensive, the cost compares favorably with the daily cost of hospitalization.

SUMMARY

Portal hypertension plays a pivotal role in the development of hyponatremia in patients with cirrhosis. Reflex vasodilation in the splanchnic circulation compromises the effective central blood volume, triggering compensatory vasoconstrictor and antinatriuretic mechanisms. The net effect is greater free water accumulation than sodium retention, creating dilutional hyponatremia.

The severity of hyponatremia correlates with the severity of cirrhosis complications, such as hepatorenal syndrome, encephalopathy, SBP, and renal failure. The presence of hyponatremia is a marker for poor outcomes and shortened survival, regardless of MELD scores.

In a hospitalized, acutely ill patient with cirrhosis, such as the person in this case, therapy may involve discontinuation of diuretics, evaluation and treatment of infection, volume expansion with salt‐poor albumin, and tolvaptan for treatment of hyponatremia. Regarding tolvaptan, early morning administration is recommended. At initiation of therapy, fluid restriction should be discontinued, and off‐floor testing should be avoided. Concomitant medications should be reviewed to avoid potentially harmful interactions.

Cirrhosis is one of the main causes of hypervolemic hyponatremia, a dilutional form of hyponatremia that occurs when there is an increase in total body water but a relatively smaller increase in total serum sodium. Portal hypertension is the main precipitating factor in fluid retention that leads to the development of cirrhotic hyponatremia. In cirrhosis, portal hypertension is determined by 2 main factors: increased intrahepatic resistance and increased spanchnic blood flow. The increased intrahepatic resistance is due to both structural (fibrosis, conversion of low resistance fenestrated sinusoids into capillaries) and dynamic (vasoconstriction due to endothelial cell dysfunction) changes.1

The hepatic circulation normally is able to accommodate an increase in portal blood flow associated with postprandial hyperemia. The elevated intrahepatic resistance in cirrhosis results in an inability to accommodate the normal increase in portal blood flow that occurs in the postprandial hyperemia state.3 As a result, portal pressure increases during postprandial hyperemia, leading to reflex vasoconstriction, which creates a shear stress and increases splanchnic nitric oxide (NO) production.4 NO, one of the most important vasodilators in the splanchnic circulation, increases splanchnic blood flow and portal pressures. When this happens repeatedly, it leads to a progressive dilation of preexisting portosystemic vascular channels and the development of varices.5 At the same time, levels of vascular endothelial growth factor rise; this is a very important mediator for angiogenesis because it increases NO, further increasing splanchnic vasodilation.6

Progressive splanchnic vasodilation and increased blood flow into the splanchnic circulation leads to central hypovolemia, arterial underfilling, and decreased blood flow in renal afferent arterioles. Vasoconstrictor norepinephrine and antinatriuretic mechanisms are subsequently activated in an attempt to normalize renal perfusion pressures. Baroreceptor‐mediated nonosmotic release of arginine vasopressin (AVP) is triggered and renin angiotensin‐aldosterone system activity is increased, which increases sodium reabsorption and activates the stellate cells, causing fibrosis, vasoconstriction, and increased portal pressures.6, 7

AVP acts at vasopression‐1A (V_1A) receptors to increase arterial vasoconstriction, and at V₂ receptors in renal tubule cells for solute‐free water retention.1 The increased sodium and water reabsorption leads to fluid retention, increased central blood volume, venous return to the heart, and an increase in cardiac output to maintain arterial perfusion and create the hyperdynamic circulation that is characteristic of cirrhosis with advanced portal hypertension. Dilutional hyponatremia develops when free water retention is more pronounced than that of sodium retention.

CLINICAL FACTORS ASSOCIATED WITH CIRRHOTIC HYPONATREMIA

Diuretics lead to hyponatremia through several mechanisms.8 First, they induce a contraction of the central blood volume, leading to the nonosmotic release of AVP. In advanced cirrhosis, there is activation of the renin‐angiotensin system in addition to the nonosmotic release of AVP, leading to sodium and free water reabsorption. Diuretics block the sodium reabsorption. However, the water‐retaining effects persist, further contributing to dilutional hyponatremia.8 This cycle is made worse by low sodium intake and frequent thirst experienced by these patients.8 Other medications (eg, non‐steroidal anti‐inflammatory drugs, proton pump inhibitors, and selective serotonin reuptake inhibitors) commonly prescribed for cirrhotic patients may also contribute to the development or worsening of dilutional hyponatremia.8

Increased intrathoracic pressure in patients with tense ascites can also contribute to dilutional hyponatremia by increasing baroreceptor‐mediated release of AVP.9 Large volume paracentesis without the oncotic influence of albumin, an intervention commonly required in patients with cirrhosis and recurrent ascites, may also lead to significant increases in plasma renin activity and plasma aldosterone, which further worsen these pathophysiologic mechanisms, resulting in reduced serum sodium concentration.10 Following removal of excess peritoneal fluid, blood flow to the kidneys is initially improved, but ascitic fluid reaccumulates and the patient becomes intravascularly depleted.10

Infection is an important clinical mediator for the development of both portal hypertension as well as hyponatremia. Bacterial translocation leads to endotoxemia and increased tumor necrosis factor (TNF)‐alpha, resulting in increased splanchnic NO and splanchnic arterial vasodilatation. This process reduces cardiac output, which leads to increased AVP secretion.11, 12 Endotoxin‐mediated splanchnic vasodilatation, especially with spontaneous bacterial peritonitis (SBP), can adversely affect central blood volume status, especially in the presence of severe ascites.1 Clinicians providing care for patients with cirrhosis should be aware of these factors and closely monitor at‐risk patients for the onset or worsening of hyponatremia.1

PROGNOSTIC SIGNIFICANCE OF HYPONATREMIA IN CIRRHOSIS

Hyponatremia has several important clinical implications for patients with cirrhosis.13 Hyponatremia is associated with refractory ascites, greater fluid accumulation, the need for paracentesis, and, importantly, impaired renal function. In patients with ascites and cirrhosis, approximately 50% have some degree of hyponatremia.2 Moreover, the severity of hyponatremia associated with advanced cirrhosis correlates with the degree of cirrhosis complications, especially hyponatremia associated with hepatorenal syndrome, encephalopathy, and SBP (Table 1).2

Similarly, hyponatremia is strongly associated with increasing Child‐Pugh and Model for End‐Stage Liver Disease (MELD) scores.14 In an analysis of data among candidates for liver transplantation from the Organ Procurement and Transplantation Network, the combination of MELD score and serum sodium concentration was a better predictor of death than the MELD score alone.14 In addition, the effect of hyponatremia on clinical outcomes was greater in patients with a low MELD score than those with a relatively high MELD score.. These results suggest that combining serum sodium concentrations with MELD scores to assign transplantation priority might reduce mortality among patients on the waiting list.14

Hyponatremia is also a marker for the development of overt hepatic encephalopathy in patients with cirrhosis.13 One of the proposed mechanisms for encephalopathy is low‐grade cerebral edema. This leads to the conversion of glutamate to glutamine by ammonia, which accumulates within astrocytes, causing astrocyte swelling and dysfunction. Because hyponatremia complicates the management of fluid overload, it increases the risk of developing or exacerbating hepatic encephalopathy.13

Hyponatremia is intimately involved with the development of renal failure in the patient with cirrhosis. It is an earlier and more sensitive marker of renal impairment and/or circulatory dysfunction than serum creatinine.15 It is often the precursor to the development of hepatorenal syndrome.16, 17

Hyponatremia is more common in hospitalized versus ambulatory patients with cirrhosis.1 In a study of 126 patients with cirrhosis admitted to an intensive care unit, patients with serum [Na⁺] 135 mEq/L had a greater frequency of ascites, illness severity scores, hepatic encephalopathy, sepsis, renal failure, and in‐hospital mortality than normonatremic patients (73.1% vs 55.9%).18 Persistent ascites and low serum sodium identified cirrhotic patients with a high mortality risk, despite low MELD scores, in a study of 507 veterans in the United States with cirrhosis.19 In a retrospective review of 127 patients, hyponatremia was predictive of the development of acute renal failure during hospitalization; among patients with hyponatremia who developed renal failure in the hospital, 72% died.20

Clinical assessment of a patient with cirrhosis who has hyponatremia can be difficult.1 These patients have too much salt and water in the wrong spaces (ie, in the peritoneal cavity and peripheral tissue). As a result, it is possible to have fluid overload with intravascular depletion. A further complication is that dilutional hyponatremia is associated with hepatorenal syndrome. Because these patients have elevated blood urea nitrogen (BUN) and creatinine, and decreased urine output and urine sodium concentration, they appear to be indistinguishable from a patient with prerenal azotemia prior to volume expansion.1 Many of these factors and concerns are illustrated in the following case we handled several years ago.

A 70‐YEAR‐OLD WOMAN WITH CIRRHOSIS

K.R. is a 70‐year‐old white woman recently discharged from the hospital following treatment of recurrent cellulitis. Her past medical history is positive for cirrhosis secondary to active alcohol use, chronic autoimmune hepatitis, and iron overload. Her hospital course was notable for tense ascites, asterixis, and a serum [Na⁺] of 126 mEq/L at admission. K.R. was managed with large volume paracentesis with 25% salt‐poor albumin, elevation of her lower extremities, discontinuation of diuretics, and 1 L fluid restriction. Her serum [Na⁺] increased to 128 mEq/L. Although her cellulitis and edema both improved, both persisted. In addition, her mental status also improved, but asterixis persisted. At this point in the hospitalization, effective management of the cellulitis was hindered by the persistent edema, and its treatment with diuretics was limited by the hyponatremia and hepatic encephalopathy.

Today, we have better treatment options for managing this patient. To effectively correct the hyponatremia and facilitate treatment of the other complications of cirrhosis, we can now initiate therapy with one of the vaptans currently available.

TREATMENT OF MILD ASYMPTOMATIC HYPERVOLEMIC HYPONATREMIA

The initial approach to treatment of patients with mild asymptomatic, hypervolemic hyponatremia consists of fluid restriction and a sodium‐restricted diet.1 Fluid restriction, however, has limited efficacy and is often not well tolerated by patients. For patients with severe or progressive hyponatremia, diuretics should be minimized or discontinued to avoid intravascular volume depletion. If patients have severe dilutional hyponatremia and tense ascites, therapeutic paracentesis with plasma expanders is safe.1

The pharmacologic approach to treating hyponatremia has advanced with the discovery of vaptans, drugs that inhibit V₂ receptors in cells of the collecting ducts.21 In contrast to conventional diuretics, vaptans do not increase natriuresis. Administration of a vaptan agent for 1 to 2 weeks has been shown to significantly improve low serum sodium levels in patients with hyponatremia, and promote aquaresis without significantly altering renal or circulatory function or activity of the renin‐angiotensin‐aldosterone system. The most frequent side effect of vaptan therapy is thirst.21

Two vaptan agents are currently approved for use in the United States: conivaptan and tolvaptan. Conivaptan is administered intravenously, and is a nonselective vasopressin inhibitor, blocking both V_1A and V₂ receptors. The course of therapy for conivaptan is 4 days. Tolvaptan, on the other hand, selectively blocks V₂ receptors, and is a once‐daily oral vaptan that can be given long‐term.21

The efficacy of tolvaptan was evaluated in the Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2 (SALT‐1 and SALT‐2).22 In these multicenter, prospective, randomized, placebo‐controlled trials, patients with dilutional hyponatremia (serum [Na⁺] <135 mEq/L) associated with cirrhosis (22.4% in SALT‐1, 30.5% in SALT‐2), heart failure, or syndrome of inappropriate antidiuretic hormone (ADH) hypersecretion, and who were hospitalized and clinically stable, received tolvaptan 15 mg daily or placebo. Repeat serum sodium levels were obtained at 8 hours, 2, 3, and 4 days, and then weekly at days 11, 18, 25, and 30. The study drug was discontinued on day 30, with follow‐up serum sodium levels taken 7 days later. (In patients with persistent hyponatremia, the tolvaptan dose was adjusted to 30 mg and then 60 mg with the goal of achieving a serum [Na⁺] <135 mEq/L.) Increases in serum sodium concentration were seen as early as 8 hours after the first administration of tolvaptan and persisted throughout the study period. After tolvaptan was discontinued, serum sodium levels decreased to baseline within 1 week.22 Tolvaptan was well tolerated, with the most common side effects being increased thirst, dry mouth, and increased urination.22

Longer‐term administration of tolvaptan was shown to maintain a higher serum sodium concentration with an acceptable safety profile in SALTWATER, the open‐label extension of the SALT‐1 and SALT‐2 trials.23 The study included 111 patients with hyponatremia who received oral tolvaptan for a mean follow‐up of 701 days. The most common adverse effects potentially related to tolvaptan were thirst, dry mouth, polydipsia, and polyuria.22, 23 Overall, there were 9 possible and 1 probable serious adverse events, which represents an acceptable safety profile over 77,369 patient‐days of exposure. Over time, 64 patients discontinued tolvaptan, 30 due to adverse reactions or death.22 The results of SALTWATER indicated that most patients received benefit from treatment with tolvaptan, with a decreased need for fluid restriction.23

PATIENT CHARACTERISTICS FOR TOLVAPTAN

In the SALT trials, tolvaptan was administered to clinically stable patients. Based on recommendations by the US Food and Drug Administration (FDA), tolvaptan should be initiated or reinitiated in a hospital setting.1 Patients with severe neurologic symptoms due to hyponatremia should be treated with normal saline instead of tolvaptan; combination therapy with tolvaptan and normal saline should be avoided due to the potential for a too‐rapid correction of hyponatremia and the potential for central pontine myelinolysis. Saline should be discontinued and persistent hyponatremia confirmed before beginning tolvaptan therapy.1

Several additional factors should be considered before patients begin tolvaptan. First, tolvaptan increases thirst, as well as the frequency and volume of urination. Therefore, patients must be able to respond appropriately to thirst with increased water intake. Patients should not be fluid‐restricted during the first day of tolvaptan therapy; instead, they should be instructed to respond to their thirst with increased water ingestion. Because of these factors, caution should be exercised in administering tolvaptan to a confused, restrained patient. In addition, patients should have adequate toileting aids, such as a bedside urinal or commode.1

As with most new drugs, acquisition costs for tolvaptan should be considered in light of the clinical benefits of treatment outcomes. In a retrospective review, median hospital costs for patients with moderate‐to‐severe ($16,606) and mild‐to‐moderate hyponatremia ($14,266) were higher than matched patients without hyponatremia ($13,066).24 In the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial, in which patients with severe congestive heart failure (including those with and without hyponatremia) were randomized to tolvaptan or placebo, the adjusted mean length of hospital stay for those with hyponatremia at baseline who received tolvaptan was 1.72 days shorter than those who received placebo.25 Although tolvaptan is somewhat expensive, the cost compares favorably with the daily cost of hospitalization.

SUMMARY

Portal hypertension plays a pivotal role in the development of hyponatremia in patients with cirrhosis. Reflex vasodilation in the splanchnic circulation compromises the effective central blood volume, triggering compensatory vasoconstrictor and antinatriuretic mechanisms. The net effect is greater free water accumulation than sodium retention, creating dilutional hyponatremia.

The severity of hyponatremia correlates with the severity of cirrhosis complications, such as hepatorenal syndrome, encephalopathy, SBP, and renal failure. The presence of hyponatremia is a marker for poor outcomes and shortened survival, regardless of MELD scores.

In a hospitalized, acutely ill patient with cirrhosis, such as the person in this case, therapy may involve discontinuation of diuretics, evaluation and treatment of infection, volume expansion with salt‐poor albumin, and tolvaptan for treatment of hyponatremia. Regarding tolvaptan, early morning administration is recommended. At initiation of therapy, fluid restriction should be discontinued, and off‐floor testing should be avoided. Concomitant medications should be reviewed to avoid potentially harmful interactions.

The high prevalence of hyponatremia in hospitalized patients has been recognized for decades. Published reports dating back to the 1960s indicate that serum sodium concentrations ([Na⁺]) tend to be lower in hospitalized patients than in outpatients in the community.1 Current estimates for the prevalence of hyponatremia in hospitalized patients range from 15% to nearly 40%.2, 3 Several factors account for this wide range. While most studies estimate the presence of hyponatremia based on International Classification of Diseases, Ninth Revision (ICD‐9) codes, accurate reporting varies widely from institution to institution.4 Furthermore, the definition of hyponatremia depends entirely on the cut‐off value of [Na⁺] used (generally, <136 mEq/L).3 In addition to patients who have hyponatremia present on admission, a significant proportion develop the condition during their hospital stay.3 Deficits in water excretion can develop or worsen during hospitalization as a result of several factors, combined with intake of hypotonic fluid.3 In a study of hyponatremia in intensive care unit (ICU) patients, as many as 80% demonstrated impaired urinary dilution during their ICU course.5

The prevalence of hyponatremia is significant in patients hospitalized for heart failure (HF), cirrhosis, and pneumonia.6 The prevalence of hyponatremiadefined as serum sodium <135 mEq/Lranges from 18% to 25% in patients admitted for congestive heart failure.79 Rates of hyponatremia in patients admitted with cirrhosis are even higher on average, ranging between 18% and 49%.1012 Hyponatremia is also common in patients with community‐acquired pneumonia (CAP), with prevalence estimates ranging from 8% to 28%.1315

Overall, hyponatremia in each of these disease states portends worse outcome.16 In a retrospective study of 71 adults with pneumonia, admission serum [Na⁺] <135 mEq/L was a risk factor for in‐hospital mortality.13 In each of these conditions, hyponatremia is associated with the need for ICU care and mechanical ventilation, increased hospital length of stay (LOS), and higher costs of care.17, 18

PATHOPHYSIOLOGY OF HYPONATREMIA

There are 2 primary stimuli for the secretion of antidiuretic hormone (ADH), otherwise known as arginine vasopressin (AVP). Osmoreceptors in the hypothalamus measure the osmolality of the plasma.19 When osmolality increases, AVP is secreted; alternatively, when plasma osmolality drops, secretion of AVP under normal circumstances will diminish. The other stimulus results from baroreceptors throughout the body. Decreased intravascular volume (manifested by lower blood pressure) causes activation of the renin‐angiotensin‐aldosterone system, the sympathetic nervous system, as well as AVP secretion.16, 20 In turn, AVP acts on vasopressin V₂ receptors in the kidney to encourage water reapsorption, therefore impairing the patient's ability to excrete dilute urine.6

The mechanism by which hyponatremia develops varies according to disease state. Whereas neurohormonal activation predominates in those with HF and cirrhosis, inappropriate AVP secretion (and in some cases, a resetting of the osmostat) occurs in patients with CAP.10, 13, 17 In both HF and cirrhosis, the degree of neurohormonal activation correlates with the degree of hyponatremia.17

In healthy individuals, the mechanism for free water excretion is AVP suppression caused by a fall in plasma osmolality. Patients with hyponatremia, however, are unable to suppress AVP due to true volume depletion (eg, as a result of inadequate oral intake, gastrointestinal fluids loss from vomiting/diarrhea, or use of thiazide diuretics), effective volume depletion (reduced cardiac output in HF patients vs vasodilation in patients with cirrhosis), or an inappropriate increase in AVP secretion.19, 21, 22

RISK FACTORS

The risk factors for hyponatremia are numerous.2, 22 The ability to excrete water declines with increasing age and is exacerbated by chronic illness. Other risk factors include low body weight, low sodium diets, and residence in a chronic care facility.22, 23 Patients with a low baseline serum sodium concentration also appear to be at increased risk of developing hyponatremia. Although the mechanisms by which such patients develop hyponatremia are not always clear, they generally involve an impaired ability to excrete free water due to an inability to appropriately suppress AVP secretion. Medications commonly associated with the syndrome of inappropriate ADH secretion (SIADH) include selective serotonin reuptake inhibitors (SSRIs), psychotropic drugs, non‐steroidal anti‐inflammatory drugs (NSAIDs), opiates, proton pump inhibitors, as well as certain chemotherapeutics.21, 22 Other risk factors associated with SIADH include major abdominal or thoracic surgery, pain, nausea, and excessive administration of hypotonic intravenous fluids. Finally, diuretic use (in particular thiazides) places patients at risk to develop hyponatremia by increasing total urine volume and solute excretion without an appreciable increase in free water excretion.24

MORBIDITY

The morbidities associated with hyponatremia vary widely in severity. Serious sequelae may occur as a result of hyponatremia itself, as well as from complications that occur due to the challenging nature of effective management. Much of the symptomatology relates to the central nervous system (CNS). Patients presenting with extremely low serum [Na⁺] levels (eg, <115 mEq/L) often have severe neurologic symptoms, while those with lesser degrees of hyponatremia may be asymptomatic, or present with milder nonspecific symptoms, such as confusion.25, 26 It is important to note that the clinical presentation of hyponatremia very much depends on whether it is acute (occurring over 2448 hours) or chronic (>48 hours).

Water shifts between the intracellular and extracellular fluid compartments are the primary means by which the body equalizes osmolality. When serum sodium changes, the ability of the brain to compensate is limited, and may result in various forms of neurologic impairment due to cerebral edema.25, 26 Such patients may become disoriented, restless, unable to attend, or unable to process information cognitively. There may also be peripheral neurologic dysfunction, such as muscle weakness, blunted neuromuscular reflexes, and impaired gait. Such impairments can lead to delirium, falls, and fractures.25, 27

HYPONATREMIA AND COGNITIVE IMPAIRMENT

Renneboog and colleagues performed a case‐control study to assess the impact of mild chronic asymptomatic hyponatremia (mean serum [Na⁺] 126 5 mEq/L) in 122 patients compared with 244 matched controls (mean age 72 13 years).28 Hyponatremic patients had significantly longer mean response times on concentration tests. Interestingly, the changes in cognitive function in hyponatremic patients were similar to healthy volunteers purposefully intoxicated with alcohol.28 Patients with hyponatremia have also been shown to score lower on the mental component summary of the 36‐item Short‐Form (SF‐36) survey.29 With treatment aimed at improving serum sodium, these same patients demonstrated improved cognitive function,29 suggesting that treating even mild forms of hyponatremia can improve patient outcomes.30

HYPONATREMIA AND FALLS/FRACTURES

Renneboog and colleagues also demonstrated a markedly increased risk of falls in their patients with chronic hyponatremia compared to controls.28 Hyponatremia increases not only the risk of falls, but also the risk of fracture following a fall. In another recent case‐control study of 513 patients, the adjusted odds ratio for fracture after a fall in a patient with hyponatremia was 4.16 compared with an age‐matched control with normal serum sodium who sustained a similar fall.27 Of note, hyponatremia was mild and asymptomatic in all patients studied. Medications (36% diuretics, 17% SSRIs) were the most common precipitating cause of hyponatremia in this study, which is notable because such risk factors should be recognized and addressed.

Although falls and fractures lead to obvious increases in morbidity and cost, delirium has also been identified as a risk factor for increased hospital LOS.18 Delirious patients are less likely and able to mobilize and participate in physical therapy. As such, they are more often bed‐bound and at increased risk for aspiration and other preventable issues, including deep vein thrombosis, bed sores, and debility, all of which may increase their LOS and cost of care.

MORTALITY

Hyponatremia is associated with a significantly increased mortality risk not only during hospitalization, but also at 1 and 5 years following discharge.31 In a prospective cohort study of approximately 100,000 patients, even those with mild hyponatremia ([Na⁺] 130134 mEq/L) had a significantly higher mortality at 5 years. The adjusted odds ratio for mortality in patients with serum sodium less than 135 mEq/L was 1.47 during hospitalization (95% CI, 1.331.62), 1.38 at 1 year post‐discharge (1.321.46), and 1.25 at 5 years (1.211.30). The significance of hyponatremia varied according to the underlying clinical condition, with the greatest risk observed in patients with metastatic cancer, heart disease, and those who had undergone orthopedic surgery.31 While the association between hyponatremia and mortality is profound, most experts do not believe that hyponatremia directly causes mortality per se. Instead, hyponatremia is felt to be a marker for increased illness severity.

It is difficult to isolate the direct costs of hyponatremia in the acute care setting because the condition is rarely treated in isolation. However, in a study of a managed‐care claims database of nearly 1,300 patients (excluding Medicare patients), hyponatremia was a predictor of higher medical costs at 6 months and at 1 year.32

DIAGNOSIS

The most common presentation of hyponatremia involves nonspecific symptoms or a total lack of symptoms.19 Many patients have comorbid diseases, and symptoms of these illnesses often predominate at hospital admission. Patients with mild to moderate hyponatremia may present with nausea, weakness, malaise, headache, and/or impaired mobility. With more severe hyponatremia, more dangerous neurologic symptoms appear, including generalized seizures, lethargy, and coma.19 Once hyponatremia is identified, the next step is to determine its acuity and classify it.

Although several classification systems exist to describe hyponatremia, the most common scheme begins with assessment of plasma osmolality and volume status.19 The majority of hyponatremic patients present with hypotonic or hypo‐osmolar serum (eg, plasma osmolality <275 mOsm/kg). The primary causes of hyponatremia in patients with normal or high serum osmolality are hyperglycemia, pseudohyponatremia, and advanced renal failure. Marked hyperglycemia increases plasma osmolality, and as a result, water moves out of cells into plasma and lowers serum sodium concentration in the process. Pseudohyponatremia arises from hyperlipidemia or hyperproteinemia, in which high concentrations of lipids/proteins reduce the free water component of plasma, therefore reducing the sodium concentration per liter of plasma. These patients do not have true hyponatremia since the physiologically important sodium concentration per liter of plasma water is normal. Finally, patients with advanced renal failure develop hyponatremia due to the inability to excrete water.

The first step in the diagnosis of hyponatremia is to assess the plasma osmolality and rule out the aforementioned conditions that cause normal or elevated serum osmolality. Patients with hypotonic serum must then be evaluated clinically to determine their volume status. Appropriate classification here has important implications for management.

In addition to clinical history and physical examination, additional laboratory assessments should be carried out. Thyroid dysfunction and adrenal insufficiency should be ruled out on the basis of thyroid stimulating hormone (TSH) and plasma cortisol levels. In addition, urine sodium and urine osmolality should be checked, as they can often help confirm the assessment of the patient's volume status and assist in the classification of the hyponatremia.

Hypovolemic hyponatremia commonly results from either renal or gastrointestinal losses of solute (sodium and potassium).19, 33 Such patients will typically have urine sodium values below 25 mEq/L. Hypervolemic hyponatremia occurs when both solute and water are increased, with water increases that are out of proportion to solute. It is seen in patients with HF, cirrhosis, and nephrotic syndrome.19, 33 These patients often also demonstrate low urine sodium levels. Although plasma and extracellular volumes are increased in these states, patients with HF and cirrhosis experience effective arterial blood volume depletion due to reduced cardiac output and arterial vasodilatation, respectively.

In euvolemic patients, hyponatremia is most often due to the syndrome of inappropriate antidiuretic hormone secretion. Such patients typically have urine sodium levels above 40 mEq/L. Free water excretion is impaired in SIADH, as evidenced by urine osmolality levels greater than 100 mOsm/kg (and often much higher). SIADH is the most common cause of hyponatremia in hospitalized patients.22 The heterogeneity of conditions that can lead to SIADH is striking, including pulmonary and CNS diseases, cancer, and various forms of endocrinopathy.22, 23 Consequently, SIADH is often a diagnosis of exclusion.

Other important causes of hyponatremia in euvolemic patients include primary polydipsia and low dietary solute intake. Primary polydipsia most commonly affects those with psychiatric illness.34 Increased thirst is a common side effect of antipsychotic medications. If water intake is excessive, the ability of the kidney to excrete water is overwhelmed and hyponatremia develops. These patients manifest with low urine osmolality (less than 100 mOsm/kg). In contrast, beer drinkers and other malnourished patients often have reduced ability to excrete free water based on low solute intake.35 In order to maximize the kidney's ability to excrete free water, a basic level of solute intake is required. Severe alcoholics (in particular beer drinkers) often do not meet this minimum solute level since beer is very low in solute. The result is markedly impaired free water excretion. Such patients develop hyponatremia with low urine omolality (less than 100 mOsm/kg).

MANAGEMENT

Although effective management of hyponatremia can be challenging, it is important to recognize that even modest improvements in serum [Na⁺] are associated with survival benefits.22, 36 The most important treatment factors relate to the severity of hyponatremia, its acuity, and the patient's volume status.33, 36 The first steps in effective management are to optimize treatment of any underlying disease(s) and to discontinue any medications that may be contributing to hyponatremia.

In the severe group are patients who present with either a documented acute drop in serum [Na⁺] or neurologic symptoms that are not attributable to another disease process. The mainstay of therapy for this group is prompt administration of hypertonic saline to rapidly address neurologic symptoms or prevent their development. Experts recommend correcting serum [Na⁺] at a rate of 2 mEq/L per hour in patients with documented severe acute hyponatremia, with the assistance of a nephrologist.22 Slower correction rates (0.51 mEq/L per hour) should be used in symptomatic patients who develop severe hyponatremia in a subacute or chronic timeframe, so as to reduce the risk of osmotic demyelination, which confers irreversible damage to neurons and serious CNS sequelae. In both cases, an initial correction of 46 mEq/L is generally sufficient to address neurologic symptoms.37 Correcting the sodium by more than 10 mEq/L in the first 24‐hour period is widely felt to place the patient at risk for iatrogenic brain injury, and should therefore be avoided. Serum sodium must be monitored very frequently (up to every 2 hours) in such patients to ensure appropriate management.22

Management of patients with hyponatremia of uncertain duration and nonspecific symptoms is more common, as well as more challenging. A recently published algorithm recommends looking for and promptly treating hypovolemia if it exists, and then beginning correction at a more gradual rate with normal saline ( furosemide).22 Appropriate management of these patients addresses the sequelae of hyponatremia while at the same time minimizing the risk of iatrogenic injury. Experts recommend therapeutic goals of 6 to 8 mEq/L in 24 hours, 12 to 14 mEq/L in 48 hours, and 14 to 16 mEq/L in 72 hours.37

In asymptomatic patients with chronic hyponatremia, the aim of treatment is gradual correction of serum [Na⁺]. A significant number of SIADH patients fall into this category. A common mistake seen in the management of such patients is inaccurate assessment of volume status and a blind trial of normal saline infusion. Administration of normal saline to such patients will not improve the serum sodium concentration, and may, in fact, drive it lower. While SIADH patients have a normal ability to excrete sodium, their ability to excrete water is impaired. Therefore, normal saline infusion will lead to free water retention.

For asymptomatic chronic hyponatremia patients, oral fluid restriction is the most simple and least toxic treatment. However, it is often difficult to calculate the actual fluid intake, since water present in food must be included. In addition, thirst often leads to patient nonadherence. Treatment with sodium chloride in the form of dietary salt or sodium chloride tablets is problematic in patients with hypertension, HF or cirrhosis.22 Demeclocycline is fairly well tolerated, but can cause nephrotoxicity and skin sensitivity. Urea, although effective, is available only as a powder that is bitter and difficult to tolerate.22

AVP‐receptor antagonists, commonly called vaptans, are the newest treatment option. Known as aquaretic drugs, they lead to free water excretion.38 Conivaptan and tolvaptan have been approved by the US Food and Drug Administration (FDA) for the treatment of hyponatremia. Conivaptan, available as an intravenous (IV) formulation only, is indicated for the acute treatment of euvolemic or hypervolemic hyponatremia in hospitalized patients for up to 4 days.21, 22, 38, 39 Due to its additional effects on the V₁ receptor, this agent can cause vasodilation and resultant hypotension. In a randomized, placebo‐controlled study of patients with euvolemic or hypervolemic hyponatremia, a 4‐day IV infusion of conivaptan significantly increased serum [Na⁺] levels compared with placebo.40 Tolvaptan, available as an oral formulation, is more suitable for long‐term use, but must be started in the inpatient setting. Patients started on this agent must be followed closely after discharge. Based on the results of 2 multicenter, prospective, randomized, placebo‐controlled trials, tolvaptan is indicated for clinically significant euvolemic or hypervolemic hyponatremia (serum [Na⁺] <125 mEq/L, or less marked hyponatremia that is symptomatic and persistent, despite fluid restriction), in patients with HF, cirrhosis, and SIADH.22, 41, 42 The vaptans are contraindicated in hypovolemic patients because they can lead to hypotension and/or acute renal failure.38, 43 Fluid restrictions must also be relaxed in patients who are placed on a vaptan.

Long‐term clinical studies of these agents are needed to address their optimal duration of treatment, clinical outcomes, and comparative effectiveness to other treatment approaches. Although this is expected to change, vaptans are not included in current clinical practice guidelines for the management of hyponatremia.

SUMMARY

Hyponatremia is associated with significant morbidity and mortality in a variety of clinical scenarios. Prompt recognition and accurate diagnosis has the potential to improve patient outcomes, as even modest improvements in serum [Na⁺] are associated with survival benefits. The appropriate management of hyponatremia involves careful assessment of acuity, severity, and volume status. The recently approved vasopressin receptor antagonists show promise as a therapeutic option for this challenging clinical condition.

The high prevalence of hyponatremia in hospitalized patients has been recognized for decades. Published reports dating back to the 1960s indicate that serum sodium concentrations ([Na⁺]) tend to be lower in hospitalized patients than in outpatients in the community.1 Current estimates for the prevalence of hyponatremia in hospitalized patients range from 15% to nearly 40%.2, 3 Several factors account for this wide range. While most studies estimate the presence of hyponatremia based on International Classification of Diseases, Ninth Revision (ICD‐9) codes, accurate reporting varies widely from institution to institution.4 Furthermore, the definition of hyponatremia depends entirely on the cut‐off value of [Na⁺] used (generally, <136 mEq/L).3 In addition to patients who have hyponatremia present on admission, a significant proportion develop the condition during their hospital stay.3 Deficits in water excretion can develop or worsen during hospitalization as a result of several factors, combined with intake of hypotonic fluid.3 In a study of hyponatremia in intensive care unit (ICU) patients, as many as 80% demonstrated impaired urinary dilution during their ICU course.5

The prevalence of hyponatremia is significant in patients hospitalized for heart failure (HF), cirrhosis, and pneumonia.6 The prevalence of hyponatremiadefined as serum sodium <135 mEq/Lranges from 18% to 25% in patients admitted for congestive heart failure.79 Rates of hyponatremia in patients admitted with cirrhosis are even higher on average, ranging between 18% and 49%.1012 Hyponatremia is also common in patients with community‐acquired pneumonia (CAP), with prevalence estimates ranging from 8% to 28%.1315

Overall, hyponatremia in each of these disease states portends worse outcome.16 In a retrospective study of 71 adults with pneumonia, admission serum [Na⁺] <135 mEq/L was a risk factor for in‐hospital mortality.13 In each of these conditions, hyponatremia is associated with the need for ICU care and mechanical ventilation, increased hospital length of stay (LOS), and higher costs of care.17, 18

PATHOPHYSIOLOGY OF HYPONATREMIA

There are 2 primary stimuli for the secretion of antidiuretic hormone (ADH), otherwise known as arginine vasopressin (AVP). Osmoreceptors in the hypothalamus measure the osmolality of the plasma.19 When osmolality increases, AVP is secreted; alternatively, when plasma osmolality drops, secretion of AVP under normal circumstances will diminish. The other stimulus results from baroreceptors throughout the body. Decreased intravascular volume (manifested by lower blood pressure) causes activation of the renin‐angiotensin‐aldosterone system, the sympathetic nervous system, as well as AVP secretion.16, 20 In turn, AVP acts on vasopressin V₂ receptors in the kidney to encourage water reapsorption, therefore impairing the patient's ability to excrete dilute urine.6

The mechanism by which hyponatremia develops varies according to disease state. Whereas neurohormonal activation predominates in those with HF and cirrhosis, inappropriate AVP secretion (and in some cases, a resetting of the osmostat) occurs in patients with CAP.10, 13, 17 In both HF and cirrhosis, the degree of neurohormonal activation correlates with the degree of hyponatremia.17

In healthy individuals, the mechanism for free water excretion is AVP suppression caused by a fall in plasma osmolality. Patients with hyponatremia, however, are unable to suppress AVP due to true volume depletion (eg, as a result of inadequate oral intake, gastrointestinal fluids loss from vomiting/diarrhea, or use of thiazide diuretics), effective volume depletion (reduced cardiac output in HF patients vs vasodilation in patients with cirrhosis), or an inappropriate increase in AVP secretion.19, 21, 22

RISK FACTORS

The risk factors for hyponatremia are numerous.2, 22 The ability to excrete water declines with increasing age and is exacerbated by chronic illness. Other risk factors include low body weight, low sodium diets, and residence in a chronic care facility.22, 23 Patients with a low baseline serum sodium concentration also appear to be at increased risk of developing hyponatremia. Although the mechanisms by which such patients develop hyponatremia are not always clear, they generally involve an impaired ability to excrete free water due to an inability to appropriately suppress AVP secretion. Medications commonly associated with the syndrome of inappropriate ADH secretion (SIADH) include selective serotonin reuptake inhibitors (SSRIs), psychotropic drugs, non‐steroidal anti‐inflammatory drugs (NSAIDs), opiates, proton pump inhibitors, as well as certain chemotherapeutics.21, 22 Other risk factors associated with SIADH include major abdominal or thoracic surgery, pain, nausea, and excessive administration of hypotonic intravenous fluids. Finally, diuretic use (in particular thiazides) places patients at risk to develop hyponatremia by increasing total urine volume and solute excretion without an appreciable increase in free water excretion.24

MORBIDITY

The morbidities associated with hyponatremia vary widely in severity. Serious sequelae may occur as a result of hyponatremia itself, as well as from complications that occur due to the challenging nature of effective management. Much of the symptomatology relates to the central nervous system (CNS). Patients presenting with extremely low serum [Na⁺] levels (eg, <115 mEq/L) often have severe neurologic symptoms, while those with lesser degrees of hyponatremia may be asymptomatic, or present with milder nonspecific symptoms, such as confusion.25, 26 It is important to note that the clinical presentation of hyponatremia very much depends on whether it is acute (occurring over 2448 hours) or chronic (>48 hours).

Water shifts between the intracellular and extracellular fluid compartments are the primary means by which the body equalizes osmolality. When serum sodium changes, the ability of the brain to compensate is limited, and may result in various forms of neurologic impairment due to cerebral edema.25, 26 Such patients may become disoriented, restless, unable to attend, or unable to process information cognitively. There may also be peripheral neurologic dysfunction, such as muscle weakness, blunted neuromuscular reflexes, and impaired gait. Such impairments can lead to delirium, falls, and fractures.25, 27

HYPONATREMIA AND COGNITIVE IMPAIRMENT

Renneboog and colleagues performed a case‐control study to assess the impact of mild chronic asymptomatic hyponatremia (mean serum [Na⁺] 126 5 mEq/L) in 122 patients compared with 244 matched controls (mean age 72 13 years).28 Hyponatremic patients had significantly longer mean response times on concentration tests. Interestingly, the changes in cognitive function in hyponatremic patients were similar to healthy volunteers purposefully intoxicated with alcohol.28 Patients with hyponatremia have also been shown to score lower on the mental component summary of the 36‐item Short‐Form (SF‐36) survey.29 With treatment aimed at improving serum sodium, these same patients demonstrated improved cognitive function,29 suggesting that treating even mild forms of hyponatremia can improve patient outcomes.30

HYPONATREMIA AND FALLS/FRACTURES

Renneboog and colleagues also demonstrated a markedly increased risk of falls in their patients with chronic hyponatremia compared to controls.28 Hyponatremia increases not only the risk of falls, but also the risk of fracture following a fall. In another recent case‐control study of 513 patients, the adjusted odds ratio for fracture after a fall in a patient with hyponatremia was 4.16 compared with an age‐matched control with normal serum sodium who sustained a similar fall.27 Of note, hyponatremia was mild and asymptomatic in all patients studied. Medications (36% diuretics, 17% SSRIs) were the most common precipitating cause of hyponatremia in this study, which is notable because such risk factors should be recognized and addressed.

Although falls and fractures lead to obvious increases in morbidity and cost, delirium has also been identified as a risk factor for increased hospital LOS.18 Delirious patients are less likely and able to mobilize and participate in physical therapy. As such, they are more often bed‐bound and at increased risk for aspiration and other preventable issues, including deep vein thrombosis, bed sores, and debility, all of which may increase their LOS and cost of care.

MORTALITY

Hyponatremia is associated with a significantly increased mortality risk not only during hospitalization, but also at 1 and 5 years following discharge.31 In a prospective cohort study of approximately 100,000 patients, even those with mild hyponatremia ([Na⁺] 130134 mEq/L) had a significantly higher mortality at 5 years. The adjusted odds ratio for mortality in patients with serum sodium less than 135 mEq/L was 1.47 during hospitalization (95% CI, 1.331.62), 1.38 at 1 year post‐discharge (1.321.46), and 1.25 at 5 years (1.211.30). The significance of hyponatremia varied according to the underlying clinical condition, with the greatest risk observed in patients with metastatic cancer, heart disease, and those who had undergone orthopedic surgery.31 While the association between hyponatremia and mortality is profound, most experts do not believe that hyponatremia directly causes mortality per se. Instead, hyponatremia is felt to be a marker for increased illness severity.

It is difficult to isolate the direct costs of hyponatremia in the acute care setting because the condition is rarely treated in isolation. However, in a study of a managed‐care claims database of nearly 1,300 patients (excluding Medicare patients), hyponatremia was a predictor of higher medical costs at 6 months and at 1 year.32

DIAGNOSIS

The most common presentation of hyponatremia involves nonspecific symptoms or a total lack of symptoms.19 Many patients have comorbid diseases, and symptoms of these illnesses often predominate at hospital admission. Patients with mild to moderate hyponatremia may present with nausea, weakness, malaise, headache, and/or impaired mobility. With more severe hyponatremia, more dangerous neurologic symptoms appear, including generalized seizures, lethargy, and coma.19 Once hyponatremia is identified, the next step is to determine its acuity and classify it.

Although several classification systems exist to describe hyponatremia, the most common scheme begins with assessment of plasma osmolality and volume status.19 The majority of hyponatremic patients present with hypotonic or hypo‐osmolar serum (eg, plasma osmolality <275 mOsm/kg). The primary causes of hyponatremia in patients with normal or high serum osmolality are hyperglycemia, pseudohyponatremia, and advanced renal failure. Marked hyperglycemia increases plasma osmolality, and as a result, water moves out of cells into plasma and lowers serum sodium concentration in the process. Pseudohyponatremia arises from hyperlipidemia or hyperproteinemia, in which high concentrations of lipids/proteins reduce the free water component of plasma, therefore reducing the sodium concentration per liter of plasma. These patients do not have true hyponatremia since the physiologically important sodium concentration per liter of plasma water is normal. Finally, patients with advanced renal failure develop hyponatremia due to the inability to excrete water.

The first step in the diagnosis of hyponatremia is to assess the plasma osmolality and rule out the aforementioned conditions that cause normal or elevated serum osmolality. Patients with hypotonic serum must then be evaluated clinically to determine their volume status. Appropriate classification here has important implications for management.

In addition to clinical history and physical examination, additional laboratory assessments should be carried out. Thyroid dysfunction and adrenal insufficiency should be ruled out on the basis of thyroid stimulating hormone (TSH) and plasma cortisol levels. In addition, urine sodium and urine osmolality should be checked, as they can often help confirm the assessment of the patient's volume status and assist in the classification of the hyponatremia.

Hypovolemic hyponatremia commonly results from either renal or gastrointestinal losses of solute (sodium and potassium).19, 33 Such patients will typically have urine sodium values below 25 mEq/L. Hypervolemic hyponatremia occurs when both solute and water are increased, with water increases that are out of proportion to solute. It is seen in patients with HF, cirrhosis, and nephrotic syndrome.19, 33 These patients often also demonstrate low urine sodium levels. Although plasma and extracellular volumes are increased in these states, patients with HF and cirrhosis experience effective arterial blood volume depletion due to reduced cardiac output and arterial vasodilatation, respectively.

In euvolemic patients, hyponatremia is most often due to the syndrome of inappropriate antidiuretic hormone secretion. Such patients typically have urine sodium levels above 40 mEq/L. Free water excretion is impaired in SIADH, as evidenced by urine osmolality levels greater than 100 mOsm/kg (and often much higher). SIADH is the most common cause of hyponatremia in hospitalized patients.22 The heterogeneity of conditions that can lead to SIADH is striking, including pulmonary and CNS diseases, cancer, and various forms of endocrinopathy.22, 23 Consequently, SIADH is often a diagnosis of exclusion.

Other important causes of hyponatremia in euvolemic patients include primary polydipsia and low dietary solute intake. Primary polydipsia most commonly affects those with psychiatric illness.34 Increased thirst is a common side effect of antipsychotic medications. If water intake is excessive, the ability of the kidney to excrete water is overwhelmed and hyponatremia develops. These patients manifest with low urine osmolality (less than 100 mOsm/kg). In contrast, beer drinkers and other malnourished patients often have reduced ability to excrete free water based on low solute intake.35 In order to maximize the kidney's ability to excrete free water, a basic level of solute intake is required. Severe alcoholics (in particular beer drinkers) often do not meet this minimum solute level since beer is very low in solute. The result is markedly impaired free water excretion. Such patients develop hyponatremia with low urine omolality (less than 100 mOsm/kg).

MANAGEMENT

Although effective management of hyponatremia can be challenging, it is important to recognize that even modest improvements in serum [Na⁺] are associated with survival benefits.22, 36 The most important treatment factors relate to the severity of hyponatremia, its acuity, and the patient's volume status.33, 36 The first steps in effective management are to optimize treatment of any underlying disease(s) and to discontinue any medications that may be contributing to hyponatremia.

In the severe group are patients who present with either a documented acute drop in serum [Na⁺] or neurologic symptoms that are not attributable to another disease process. The mainstay of therapy for this group is prompt administration of hypertonic saline to rapidly address neurologic symptoms or prevent their development. Experts recommend correcting serum [Na⁺] at a rate of 2 mEq/L per hour in patients with documented severe acute hyponatremia, with the assistance of a nephrologist.22 Slower correction rates (0.51 mEq/L per hour) should be used in symptomatic patients who develop severe hyponatremia in a subacute or chronic timeframe, so as to reduce the risk of osmotic demyelination, which confers irreversible damage to neurons and serious CNS sequelae. In both cases, an initial correction of 46 mEq/L is generally sufficient to address neurologic symptoms.37 Correcting the sodium by more than 10 mEq/L in the first 24‐hour period is widely felt to place the patient at risk for iatrogenic brain injury, and should therefore be avoided. Serum sodium must be monitored very frequently (up to every 2 hours) in such patients to ensure appropriate management.22

Management of patients with hyponatremia of uncertain duration and nonspecific symptoms is more common, as well as more challenging. A recently published algorithm recommends looking for and promptly treating hypovolemia if it exists, and then beginning correction at a more gradual rate with normal saline ( furosemide).22 Appropriate management of these patients addresses the sequelae of hyponatremia while at the same time minimizing the risk of iatrogenic injury. Experts recommend therapeutic goals of 6 to 8 mEq/L in 24 hours, 12 to 14 mEq/L in 48 hours, and 14 to 16 mEq/L in 72 hours.37

In asymptomatic patients with chronic hyponatremia, the aim of treatment is gradual correction of serum [Na⁺]. A significant number of SIADH patients fall into this category. A common mistake seen in the management of such patients is inaccurate assessment of volume status and a blind trial of normal saline infusion. Administration of normal saline to such patients will not improve the serum sodium concentration, and may, in fact, drive it lower. While SIADH patients have a normal ability to excrete sodium, their ability to excrete water is impaired. Therefore, normal saline infusion will lead to free water retention.

For asymptomatic chronic hyponatremia patients, oral fluid restriction is the most simple and least toxic treatment. However, it is often difficult to calculate the actual fluid intake, since water present in food must be included. In addition, thirst often leads to patient nonadherence. Treatment with sodium chloride in the form of dietary salt or sodium chloride tablets is problematic in patients with hypertension, HF or cirrhosis.22 Demeclocycline is fairly well tolerated, but can cause nephrotoxicity and skin sensitivity. Urea, although effective, is available only as a powder that is bitter and difficult to tolerate.22

AVP‐receptor antagonists, commonly called vaptans, are the newest treatment option. Known as aquaretic drugs, they lead to free water excretion.38 Conivaptan and tolvaptan have been approved by the US Food and Drug Administration (FDA) for the treatment of hyponatremia. Conivaptan, available as an intravenous (IV) formulation only, is indicated for the acute treatment of euvolemic or hypervolemic hyponatremia in hospitalized patients for up to 4 days.21, 22, 38, 39 Due to its additional effects on the V₁ receptor, this agent can cause vasodilation and resultant hypotension. In a randomized, placebo‐controlled study of patients with euvolemic or hypervolemic hyponatremia, a 4‐day IV infusion of conivaptan significantly increased serum [Na⁺] levels compared with placebo.40 Tolvaptan, available as an oral formulation, is more suitable for long‐term use, but must be started in the inpatient setting. Patients started on this agent must be followed closely after discharge. Based on the results of 2 multicenter, prospective, randomized, placebo‐controlled trials, tolvaptan is indicated for clinically significant euvolemic or hypervolemic hyponatremia (serum [Na⁺] <125 mEq/L, or less marked hyponatremia that is symptomatic and persistent, despite fluid restriction), in patients with HF, cirrhosis, and SIADH.22, 41, 42 The vaptans are contraindicated in hypovolemic patients because they can lead to hypotension and/or acute renal failure.38, 43 Fluid restrictions must also be relaxed in patients who are placed on a vaptan.

Long‐term clinical studies of these agents are needed to address their optimal duration of treatment, clinical outcomes, and comparative effectiveness to other treatment approaches. Although this is expected to change, vaptans are not included in current clinical practice guidelines for the management of hyponatremia.

SUMMARY

Hyponatremia is associated with significant morbidity and mortality in a variety of clinical scenarios. Prompt recognition and accurate diagnosis has the potential to improve patient outcomes, as even modest improvements in serum [Na⁺] are associated with survival benefits. The appropriate management of hyponatremia involves careful assessment of acuity, severity, and volume status. The recently approved vasopressin receptor antagonists show promise as a therapeutic option for this challenging clinical condition.

The high prevalence of hyponatremia in hospitalized patients has been recognized for decades. Published reports dating back to the 1960s indicate that serum sodium concentrations ([Na⁺]) tend to be lower in hospitalized patients than in outpatients in the community.1 Current estimates for the prevalence of hyponatremia in hospitalized patients range from 15% to nearly 40%.2, 3 Several factors account for this wide range. While most studies estimate the presence of hyponatremia based on International Classification of Diseases, Ninth Revision (ICD‐9) codes, accurate reporting varies widely from institution to institution.4 Furthermore, the definition of hyponatremia depends entirely on the cut‐off value of [Na⁺] used (generally, <136 mEq/L).3 In addition to patients who have hyponatremia present on admission, a significant proportion develop the condition during their hospital stay.3 Deficits in water excretion can develop or worsen during hospitalization as a result of several factors, combined with intake of hypotonic fluid.3 In a study of hyponatremia in intensive care unit (ICU) patients, as many as 80% demonstrated impaired urinary dilution during their ICU course.5

The prevalence of hyponatremia is significant in patients hospitalized for heart failure (HF), cirrhosis, and pneumonia.6 The prevalence of hyponatremiadefined as serum sodium <135 mEq/Lranges from 18% to 25% in patients admitted for congestive heart failure.79 Rates of hyponatremia in patients admitted with cirrhosis are even higher on average, ranging between 18% and 49%.1012 Hyponatremia is also common in patients with community‐acquired pneumonia (CAP), with prevalence estimates ranging from 8% to 28%.1315

Overall, hyponatremia in each of these disease states portends worse outcome.16 In a retrospective study of 71 adults with pneumonia, admission serum [Na⁺] <135 mEq/L was a risk factor for in‐hospital mortality.13 In each of these conditions, hyponatremia is associated with the need for ICU care and mechanical ventilation, increased hospital length of stay (LOS), and higher costs of care.17, 18

PATHOPHYSIOLOGY OF HYPONATREMIA

There are 2 primary stimuli for the secretion of antidiuretic hormone (ADH), otherwise known as arginine vasopressin (AVP). Osmoreceptors in the hypothalamus measure the osmolality of the plasma.19 When osmolality increases, AVP is secreted; alternatively, when plasma osmolality drops, secretion of AVP under normal circumstances will diminish. The other stimulus results from baroreceptors throughout the body. Decreased intravascular volume (manifested by lower blood pressure) causes activation of the renin‐angiotensin‐aldosterone system, the sympathetic nervous system, as well as AVP secretion.16, 20 In turn, AVP acts on vasopressin V₂ receptors in the kidney to encourage water reapsorption, therefore impairing the patient's ability to excrete dilute urine.6

The mechanism by which hyponatremia develops varies according to disease state. Whereas neurohormonal activation predominates in those with HF and cirrhosis, inappropriate AVP secretion (and in some cases, a resetting of the osmostat) occurs in patients with CAP.10, 13, 17 In both HF and cirrhosis, the degree of neurohormonal activation correlates with the degree of hyponatremia.17

In healthy individuals, the mechanism for free water excretion is AVP suppression caused by a fall in plasma osmolality. Patients with hyponatremia, however, are unable to suppress AVP due to true volume depletion (eg, as a result of inadequate oral intake, gastrointestinal fluids loss from vomiting/diarrhea, or use of thiazide diuretics), effective volume depletion (reduced cardiac output in HF patients vs vasodilation in patients with cirrhosis), or an inappropriate increase in AVP secretion.19, 21, 22

RISK FACTORS

The risk factors for hyponatremia are numerous.2, 22 The ability to excrete water declines with increasing age and is exacerbated by chronic illness. Other risk factors include low body weight, low sodium diets, and residence in a chronic care facility.22, 23 Patients with a low baseline serum sodium concentration also appear to be at increased risk of developing hyponatremia. Although the mechanisms by which such patients develop hyponatremia are not always clear, they generally involve an impaired ability to excrete free water due to an inability to appropriately suppress AVP secretion. Medications commonly associated with the syndrome of inappropriate ADH secretion (SIADH) include selective serotonin reuptake inhibitors (SSRIs), psychotropic drugs, non‐steroidal anti‐inflammatory drugs (NSAIDs), opiates, proton pump inhibitors, as well as certain chemotherapeutics.21, 22 Other risk factors associated with SIADH include major abdominal or thoracic surgery, pain, nausea, and excessive administration of hypotonic intravenous fluids. Finally, diuretic use (in particular thiazides) places patients at risk to develop hyponatremia by increasing total urine volume and solute excretion without an appreciable increase in free water excretion.24

MORBIDITY

The morbidities associated with hyponatremia vary widely in severity. Serious sequelae may occur as a result of hyponatremia itself, as well as from complications that occur due to the challenging nature of effective management. Much of the symptomatology relates to the central nervous system (CNS). Patients presenting with extremely low serum [Na⁺] levels (eg, <115 mEq/L) often have severe neurologic symptoms, while those with lesser degrees of hyponatremia may be asymptomatic, or present with milder nonspecific symptoms, such as confusion.25, 26 It is important to note that the clinical presentation of hyponatremia very much depends on whether it is acute (occurring over 2448 hours) or chronic (>48 hours).

Water shifts between the intracellular and extracellular fluid compartments are the primary means by which the body equalizes osmolality. When serum sodium changes, the ability of the brain to compensate is limited, and may result in various forms of neurologic impairment due to cerebral edema.25, 26 Such patients may become disoriented, restless, unable to attend, or unable to process information cognitively. There may also be peripheral neurologic dysfunction, such as muscle weakness, blunted neuromuscular reflexes, and impaired gait. Such impairments can lead to delirium, falls, and fractures.25, 27

HYPONATREMIA AND COGNITIVE IMPAIRMENT

Renneboog and colleagues performed a case‐control study to assess the impact of mild chronic asymptomatic hyponatremia (mean serum [Na⁺] 126 5 mEq/L) in 122 patients compared with 244 matched controls (mean age 72 13 years).28 Hyponatremic patients had significantly longer mean response times on concentration tests. Interestingly, the changes in cognitive function in hyponatremic patients were similar to healthy volunteers purposefully intoxicated with alcohol.28 Patients with hyponatremia have also been shown to score lower on the mental component summary of the 36‐item Short‐Form (SF‐36) survey.29 With treatment aimed at improving serum sodium, these same patients demonstrated improved cognitive function,29 suggesting that treating even mild forms of hyponatremia can improve patient outcomes.30

HYPONATREMIA AND FALLS/FRACTURES

Renneboog and colleagues also demonstrated a markedly increased risk of falls in their patients with chronic hyponatremia compared to controls.28 Hyponatremia increases not only the risk of falls, but also the risk of fracture following a fall. In another recent case‐control study of 513 patients, the adjusted odds ratio for fracture after a fall in a patient with hyponatremia was 4.16 compared with an age‐matched control with normal serum sodium who sustained a similar fall.27 Of note, hyponatremia was mild and asymptomatic in all patients studied. Medications (36% diuretics, 17% SSRIs) were the most common precipitating cause of hyponatremia in this study, which is notable because such risk factors should be recognized and addressed.

Although falls and fractures lead to obvious increases in morbidity and cost, delirium has also been identified as a risk factor for increased hospital LOS.18 Delirious patients are less likely and able to mobilize and participate in physical therapy. As such, they are more often bed‐bound and at increased risk for aspiration and other preventable issues, including deep vein thrombosis, bed sores, and debility, all of which may increase their LOS and cost of care.

MORTALITY

Hyponatremia is associated with a significantly increased mortality risk not only during hospitalization, but also at 1 and 5 years following discharge.31 In a prospective cohort study of approximately 100,000 patients, even those with mild hyponatremia ([Na⁺] 130134 mEq/L) had a significantly higher mortality at 5 years. The adjusted odds ratio for mortality in patients with serum sodium less than 135 mEq/L was 1.47 during hospitalization (95% CI, 1.331.62), 1.38 at 1 year post‐discharge (1.321.46), and 1.25 at 5 years (1.211.30). The significance of hyponatremia varied according to the underlying clinical condition, with the greatest risk observed in patients with metastatic cancer, heart disease, and those who had undergone orthopedic surgery.31 While the association between hyponatremia and mortality is profound, most experts do not believe that hyponatremia directly causes mortality per se. Instead, hyponatremia is felt to be a marker for increased illness severity.

It is difficult to isolate the direct costs of hyponatremia in the acute care setting because the condition is rarely treated in isolation. However, in a study of a managed‐care claims database of nearly 1,300 patients (excluding Medicare patients), hyponatremia was a predictor of higher medical costs at 6 months and at 1 year.32

DIAGNOSIS

The most common presentation of hyponatremia involves nonspecific symptoms or a total lack of symptoms.19 Many patients have comorbid diseases, and symptoms of these illnesses often predominate at hospital admission. Patients with mild to moderate hyponatremia may present with nausea, weakness, malaise, headache, and/or impaired mobility. With more severe hyponatremia, more dangerous neurologic symptoms appear, including generalized seizures, lethargy, and coma.19 Once hyponatremia is identified, the next step is to determine its acuity and classify it.

Although several classification systems exist to describe hyponatremia, the most common scheme begins with assessment of plasma osmolality and volume status.19 The majority of hyponatremic patients present with hypotonic or hypo‐osmolar serum (eg, plasma osmolality <275 mOsm/kg). The primary causes of hyponatremia in patients with normal or high serum osmolality are hyperglycemia, pseudohyponatremia, and advanced renal failure. Marked hyperglycemia increases plasma osmolality, and as a result, water moves out of cells into plasma and lowers serum sodium concentration in the process. Pseudohyponatremia arises from hyperlipidemia or hyperproteinemia, in which high concentrations of lipids/proteins reduce the free water component of plasma, therefore reducing the sodium concentration per liter of plasma. These patients do not have true hyponatremia since the physiologically important sodium concentration per liter of plasma water is normal. Finally, patients with advanced renal failure develop hyponatremia due to the inability to excrete water.

The first step in the diagnosis of hyponatremia is to assess the plasma osmolality and rule out the aforementioned conditions that cause normal or elevated serum osmolality. Patients with hypotonic serum must then be evaluated clinically to determine their volume status. Appropriate classification here has important implications for management.

In addition to clinical history and physical examination, additional laboratory assessments should be carried out. Thyroid dysfunction and adrenal insufficiency should be ruled out on the basis of thyroid stimulating hormone (TSH) and plasma cortisol levels. In addition, urine sodium and urine osmolality should be checked, as they can often help confirm the assessment of the patient's volume status and assist in the classification of the hyponatremia.

Hypovolemic hyponatremia commonly results from either renal or gastrointestinal losses of solute (sodium and potassium).19, 33 Such patients will typically have urine sodium values below 25 mEq/L. Hypervolemic hyponatremia occurs when both solute and water are increased, with water increases that are out of proportion to solute. It is seen in patients with HF, cirrhosis, and nephrotic syndrome.19, 33 These patients often also demonstrate low urine sodium levels. Although plasma and extracellular volumes are increased in these states, patients with HF and cirrhosis experience effective arterial blood volume depletion due to reduced cardiac output and arterial vasodilatation, respectively.

In euvolemic patients, hyponatremia is most often due to the syndrome of inappropriate antidiuretic hormone secretion. Such patients typically have urine sodium levels above 40 mEq/L. Free water excretion is impaired in SIADH, as evidenced by urine osmolality levels greater than 100 mOsm/kg (and often much higher). SIADH is the most common cause of hyponatremia in hospitalized patients.22 The heterogeneity of conditions that can lead to SIADH is striking, including pulmonary and CNS diseases, cancer, and various forms of endocrinopathy.22, 23 Consequently, SIADH is often a diagnosis of exclusion.

Other important causes of hyponatremia in euvolemic patients include primary polydipsia and low dietary solute intake. Primary polydipsia most commonly affects those with psychiatric illness.34 Increased thirst is a common side effect of antipsychotic medications. If water intake is excessive, the ability of the kidney to excrete water is overwhelmed and hyponatremia develops. These patients manifest with low urine osmolality (less than 100 mOsm/kg). In contrast, beer drinkers and other malnourished patients often have reduced ability to excrete free water based on low solute intake.35 In order to maximize the kidney's ability to excrete free water, a basic level of solute intake is required. Severe alcoholics (in particular beer drinkers) often do not meet this minimum solute level since beer is very low in solute. The result is markedly impaired free water excretion. Such patients develop hyponatremia with low urine omolality (less than 100 mOsm/kg).

MANAGEMENT

Although effective management of hyponatremia can be challenging, it is important to recognize that even modest improvements in serum [Na⁺] are associated with survival benefits.22, 36 The most important treatment factors relate to the severity of hyponatremia, its acuity, and the patient's volume status.33, 36 The first steps in effective management are to optimize treatment of any underlying disease(s) and to discontinue any medications that may be contributing to hyponatremia.

In the severe group are patients who present with either a documented acute drop in serum [Na⁺] or neurologic symptoms that are not attributable to another disease process. The mainstay of therapy for this group is prompt administration of hypertonic saline to rapidly address neurologic symptoms or prevent their development. Experts recommend correcting serum [Na⁺] at a rate of 2 mEq/L per hour in patients with documented severe acute hyponatremia, with the assistance of a nephrologist.22 Slower correction rates (0.51 mEq/L per hour) should be used in symptomatic patients who develop severe hyponatremia in a subacute or chronic timeframe, so as to reduce the risk of osmotic demyelination, which confers irreversible damage to neurons and serious CNS sequelae. In both cases, an initial correction of 46 mEq/L is generally sufficient to address neurologic symptoms.37 Correcting the sodium by more than 10 mEq/L in the first 24‐hour period is widely felt to place the patient at risk for iatrogenic brain injury, and should therefore be avoided. Serum sodium must be monitored very frequently (up to every 2 hours) in such patients to ensure appropriate management.22

Management of patients with hyponatremia of uncertain duration and nonspecific symptoms is more common, as well as more challenging. A recently published algorithm recommends looking for and promptly treating hypovolemia if it exists, and then beginning correction at a more gradual rate with normal saline ( furosemide).22 Appropriate management of these patients addresses the sequelae of hyponatremia while at the same time minimizing the risk of iatrogenic injury. Experts recommend therapeutic goals of 6 to 8 mEq/L in 24 hours, 12 to 14 mEq/L in 48 hours, and 14 to 16 mEq/L in 72 hours.37

In asymptomatic patients with chronic hyponatremia, the aim of treatment is gradual correction of serum [Na⁺]. A significant number of SIADH patients fall into this category. A common mistake seen in the management of such patients is inaccurate assessment of volume status and a blind trial of normal saline infusion. Administration of normal saline to such patients will not improve the serum sodium concentration, and may, in fact, drive it lower. While SIADH patients have a normal ability to excrete sodium, their ability to excrete water is impaired. Therefore, normal saline infusion will lead to free water retention.

For asymptomatic chronic hyponatremia patients, oral fluid restriction is the most simple and least toxic treatment. However, it is often difficult to calculate the actual fluid intake, since water present in food must be included. In addition, thirst often leads to patient nonadherence. Treatment with sodium chloride in the form of dietary salt or sodium chloride tablets is problematic in patients with hypertension, HF or cirrhosis.22 Demeclocycline is fairly well tolerated, but can cause nephrotoxicity and skin sensitivity. Urea, although effective, is available only as a powder that is bitter and difficult to tolerate.22

AVP‐receptor antagonists, commonly called vaptans, are the newest treatment option. Known as aquaretic drugs, they lead to free water excretion.38 Conivaptan and tolvaptan have been approved by the US Food and Drug Administration (FDA) for the treatment of hyponatremia. Conivaptan, available as an intravenous (IV) formulation only, is indicated for the acute treatment of euvolemic or hypervolemic hyponatremia in hospitalized patients for up to 4 days.21, 22, 38, 39 Due to its additional effects on the V₁ receptor, this agent can cause vasodilation and resultant hypotension. In a randomized, placebo‐controlled study of patients with euvolemic or hypervolemic hyponatremia, a 4‐day IV infusion of conivaptan significantly increased serum [Na⁺] levels compared with placebo.40 Tolvaptan, available as an oral formulation, is more suitable for long‐term use, but must be started in the inpatient setting. Patients started on this agent must be followed closely after discharge. Based on the results of 2 multicenter, prospective, randomized, placebo‐controlled trials, tolvaptan is indicated for clinically significant euvolemic or hypervolemic hyponatremia (serum [Na⁺] <125 mEq/L, or less marked hyponatremia that is symptomatic and persistent, despite fluid restriction), in patients with HF, cirrhosis, and SIADH.22, 41, 42 The vaptans are contraindicated in hypovolemic patients because they can lead to hypotension and/or acute renal failure.38, 43 Fluid restrictions must also be relaxed in patients who are placed on a vaptan.

Long‐term clinical studies of these agents are needed to address their optimal duration of treatment, clinical outcomes, and comparative effectiveness to other treatment approaches. Although this is expected to change, vaptans are not included in current clinical practice guidelines for the management of hyponatremia.

SUMMARY

Hyponatremia is associated with significant morbidity and mortality in a variety of clinical scenarios. Prompt recognition and accurate diagnosis has the potential to improve patient outcomes, as even modest improvements in serum [Na⁺] are associated with survival benefits. The appropriate management of hyponatremia involves careful assessment of acuity, severity, and volume status. The recently approved vasopressin receptor antagonists show promise as a therapeutic option for this challenging clinical condition.