Hyponatremia in patients with heart failure

INTRODUCTION — Hyponatremia can develop in patients with severe myocardial dysfunction. Issues related to hyponatremia in heart failure will be reviewed here. Overviews of the evaluation and treatment of hyponatremia are presented separately:

●(See "Overview of the treatment of hyponatremia in adults".)

●(See "Diagnostic evaluation of adults with hyponatremia".)

PATHOGENESIS — Like most other causes of hyponatremia, heart failure (with either reduced or preserved ejection fraction) impairs the ability to excrete ingested water by increasing antidiuretic hormone levels. When cardiac output and systemic blood pressure are reduced, "hypovolemic" hormones, such as renin (with a subsequent increase in angiotensin II formation), antidiuretic hormone (ADH), and norepinephrine, respond [1-3]. Although edematous patients with heart failure have increased plasma and extracellular fluid volumes, the body perceives volume depletion (reduced effective arterial blood volume) since the low cardiac output decreases the pressure perfusing the baroreceptors in the carotid sinus and the renal afferent arteriole. (Related Pathway(s): Hyponatremia: Evaluation in adults.)

The degree of neurohumoral activation is generally related to the severity of cardiac dysfunction, as assessed by left ventricular ejection fraction or functional class [2]. The neurohumoral changes limit both sodium and water excretion in an attempt to return perfusion pressure to normal. ADH release directly enhances water reabsorption in the collecting tubules, whereas angiotensin II and norepinephrine limit distal water delivery (and thereby water excretion) by lowering the glomerular filtration rate (due to a marked reduction in kidney perfusion) and by increasing proximal sodium and water reabsorption [4]. In addition, both the low cardiac output and high angiotensin II levels are potent stimuli to thirst, leading to enhanced water intake.

PREDICTOR OF ADVERSE PROGNOSIS — Both antidiuretic hormone (ADH) release and the associated reduction in the serum sodium concentration parallel the severity of the heart failure [1]. This relationship has prognostic importance since patient survival is significantly reduced (in comparison with normonatremic patients) once the serum sodium concentration falls below 137 mEq/L (figure 1), and even mild hyponatremia is associated with an adverse prognosis following an acute myocardial infarction [5,6]. (See "Predictors of survival in heart failure with reduced ejection fraction", section on 'Neurohumoral activation and heart rate'.)

Patients whose serum sodium levels fall below 125 mEq/L solely as a result of heart failure usually have near end-stage disease. Patients with heart failure who have this severity of hyponatremia also frequently have hyperkalemia. Distal sodium and water delivery are so low in advanced cardiac disease that potassium excretion (primarily dependent upon distal potassium secretion) falls below the level of intake.

In addition to its long-term prognostic value, hyponatremia is an adverse predictor of short-term outcomes in patients who are hospitalized for worsening heart failure [7-9]. This was illustrated in a post-hoc analysis from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) trial of milrinone therapy in 949 such patients [7]. Patients in the lowest quintile of serum sodium (mean 134 mEq/L [range 132 to 135 mEq/L]) had significant increases in mortality both in-hospital (5.9 versus 1 to 2.3 percent in the other quartiles) and at 30 days (15.9 versus 6.4 to 7.8 percent). (See "Inotropic agents in heart failure with reduced ejection fraction".)

Hyponatremic patients are also at increased risk for worsening of cardiac and kidney function after the administration of a nonsteroidal antiinflammatory drug (NSAID) [3]. In this setting of advanced heart failure and a high level of circulating vasoconstrictors, there is increased renal secretion of vasodilator prostaglandins which act to preserve kidney perfusion and to lower systemic vascular resistance. Decreasing prostaglandin synthesis with an NSAID in such a patient is likely to cause kidney ischemia, a rise in the serum creatinine concentration, and a fall in cardiac output due to increased afterload [3]. (See "NSAIDs: Acute kidney injury".)

CLINICAL MANIFESTATIONS — Hyponatremia in patients with heart failure usually develops slowly (paralleling the rate of progression of the heart disease) and produces no obvious symptoms until the serum sodium concentration falls below 120 mEq/L. Such patients have severe heart disease and a poor prognosis. Similar findings have been noted in patients with cirrhosis, which is also associated with hormonal activation due to a reduction in effective arterial blood volume. (See "Manifestations of hyponatremia and hypernatremia in adults" and "Hyponatremia in patients with cirrhosis".)

It is possible that some patients with chronic moderate hyponatremia (serum sodium 120 to 129 mEq/L) have subtle neurologic manifestations that may be improved by gradually raising the serum sodium. These include reduced scores on tests of mental, social, and physical functioning and, in older adult patients, unsteadiness and falls [10,11]. (See "Manifestations of hyponatremia and hypernatremia in adults", section on 'Subtle manifestations in mild to moderate chronic hyponatremia' and 'Vasopressin receptor antagonists' below.)

TREATMENT

Indications — There is no evidence that correction of hyponatremia improves the hemodynamic abnormalities associated with the severe underlying chronic heart failure or that it improves clinical outcomes. Thus, the main indications for specific therapy to correct hyponatremia are a serum sodium concentration below 120 mEq/L (severe hyponatremia), the presence of symptoms that might be due to hyponatremia, and concern that seemingly asymptomatic hyponatremia might predispose the patient to falls and fractures. As noted above, the severity of hyponatremia parallels the severity of the heart failure, and a serum sodium concentration below 125 mEq/L represents near end-stage disease (figure 1). (See 'Predictor of adverse prognosis' above.)

Fluid restriction — Restricting fluid intake is the mainstay of therapy in patients with symptomatic or worsening and severe hyponatremia but is generally not helpful in stable patients [1]. In patients with severely noncompliant hearts (ie, diastolic dysfunction), restricting water intake may have a second benefit, minimizing acute increases in intravascular volume that can promote the development of pulmonary congestion.

Despite these potential benefits, significantly limiting water intake is often not well tolerated in heart-failure patients because the reduction in tissue perfusion that enhances antidiuretic hormone (ADH) release also stimulates thirst. Thus, fluid restriction is unlikely to be successful on a chronic basis at home. (See "Overview of the treatment of hyponatremia in adults".)

ACE inhibitors and loop diuretics — Patients who have heart failure with reduced ejection fraction are typically treated with angiotensin inhibition with an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), or an angiotensin receptor-neprilysin inhibitor (ARNI). A loop diuretic is given if the patient is volume overloaded.

●(See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Primary components of therapy'.)

●(See "Use of diuretics in patients with heart failure".)

These therapies may raise the serum sodium concentration via one or more of the following mechanisms [12,13]:

●ACE inhibitors and ARBs improve cardiac function. The associated increase in cardiac output following angiotensin inhibition can diminish the release of ADH and norepinephrine [13].

●ACE inhibitors (via the local generation of prostaglandins) appear to antagonize the effect of ADH on the collecting tubules, thereby decreasing water reabsorption at this site [14].

●Loop diuretics decrease the concentration gradient in the renal medulla, thereby reducing the driving force for water reabsorption in the collecting duct [4].

The increment in cardiac output and fall in angiotensin II levels may also reduce the sensation of thirst, thereby making the patient more comfortable.

Vasopressin receptor antagonists — There are multiple receptors for vasopressin (ADH): the V1a, V1b, and V2 receptors. The V2 receptors primarily mediate the antidiuretic response, while V1a and V1b receptors principally mediate vasoconstriction and adrenocorticotropin release, respectively [15,16].

The vasopressin receptor antagonists produce a selective water diuresis without affecting sodium and potassium excretion [15,16]. The ensuing loss of free water will tend to correct the hyponatremia. Thirst increases significantly with these agents, which may limit the rise in serum sodium [10]. (See "Overview of the treatment of hyponatremia in adults", section on 'Vasopressin receptor antagonists'.)

Some oral formulations, including tolvaptan, satavaptan, and lixivaptan, are selective for the V2 receptor, while an intravenous agent, conivaptan, blocks both the V2 and V1a receptors. Only tolvaptan and conivaptan are currently available in the United States; both are approved for the treatment of hyponatremia in patients with heart failure. In general, tolvaptan should not be used for longer than 30 days and not in patients with liver disease (including cirrhosis) [17]. (See 'Limitations' below.)

However, tolvaptan and, when approved for use, other oral selective V2 receptor antagonists may have a role in the management of hyponatremia in patients with chronic heart failure when other management options have failed to increase the serum sodium above 120 mEq/L and/or ameliorate symptoms of hyponatremia.

Efficacy — Among patients with heart failure, conivaptan produces a water diuresis, raises the serum sodium concentration, and, via blockade of the V1a receptors, diminishes afterload, possibly improving systemic hemodynamics in patients who have heart failure with reduced ejection fraction [18]. It may be useful in heart-failure patients with symptomatic hyponatremia and as part of a diuretic regimen in managing hyponatremic patients with fluid overload. However, hypotension may limit its use.

The oral selective V2 receptor antagonist, tolvaptan, raises the serum sodium concentration in patients with heart failure [10,19-21]. The magnitude of this effect was demonstrated in two randomized trials:

●The EVEREST Outcome trial included over 4100 patients hospitalized for worsening heart failure who were randomly assigned to tolvaptan or placebo [19]. Among the approximately 330 patients with a baseline serum sodium concentration below 134 mEq/L, tolvaptan significantly increased the serum sodium within the first seven days (5.5 versus 1.9 mEq/L with placebo). The difference tended to become smaller over time. There was no improvement in long-term outcomes in patients who received tolvaptan (most of whom were not hyponatremic).

●The Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2 (SALT-1 and SALT-2) trials included 138 hyponatremic patients with chronic heart failure as well as hyponatremic patients with cirrhosis and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, who were randomly assigned to tolvaptan or placebo [10]. Tolvaptan raised the serum sodium significantly more than placebo (approximately 7 versus 2.5 mEq/L).

Among all patients (ie, not limited to those with heart failure) who had a serum sodium below 130 mEq/L at baseline, tolvaptan was also associated with a statistically significant improvement in mental status scores. However, this difference was of uncertain clinical importance, and the duration of follow-up was only 30 days.

In an open-label extension (called SALTWATER), 111 patients were treated with tolvaptan for a mean follow-up of almost two years [22]. The mean serum sodium was maintained at more than 135 mEq/L compared with 131 mEq/L at baseline. The responses were similar in heart failure and SIADH and more modest in cirrhosis. The main adverse effects were abnormally frequent urination, thirst, dry mouth, fatigue, polyuria, and polydipsia. Adverse effects that were possibly or probably related to tolvaptan led to discontinuation of therapy in six patients (5.4 percent).

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

●Concerns about the safety of tolvaptan were raised by a multicenter trial (TEMPO 3:4) that examined its effect on the progression of kidney disease in polycystic kidney disease [23,24]. A greater than 2.5-fold increase in liver enzymes was more common among patients who received tolvaptan compared with placebo. Based upon these and other data, the US Food and Drug Administration determined that tolvaptan should not be used in any patient for longer than 30 days and should not be used at all in patients with liver disease (including cirrhosis) because it may potentially lead to liver failure or death [17].

●Overly rapid correction of the hyponatremia can lead to irreversible neurologic injury. In the SALT trials, 1.8 percent of patients exceeded the study goal of limiting daily correction to 12 mEq/L in 24 hours (and more patients probably exceeded the currently recommended correction limit of 9 mEq/L) [10]. However, the true risk may be greater because most patients enrolled in these trials had serum sodium concentrations higher than 130 mEq/L and were therefore protected from overcorrection by thirst. Thus, the actual risk of tolvaptan in patients with severe hyponatremia is unknown.

Because of the risk of overcorrection, hospitalization is required for the initiation or reinitiation of tolvaptan therapy. (See "Osmotic demyelination syndrome (ODS) and overly rapid correction of hyponatremia" and "Overview of the treatment of hyponatremia in adults".)

●Increased thirst may limit the rise in serum sodium [10].

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

Loop diuretic combined with hypertonic saline — Infusion of hypertonic saline in combination with a loop diuretic has been used to treat hyponatremia caused by SIADH [25]. By blocking generation of the concentration gradient in the renal medulla, loop diuretics make the urine less concentrated and increase electrolyte-free water losses; replacement of urine sodium losses with hypertonic saline prevents volume depletion. If urinary sodium and potassium losses are replaced, the net effect is aquaresis. The same combination can be used to treat hyponatremia in patients with heart failure.

Although counterintuitive and still a controversial therapy, the infusion of 150 mL of 3 percent sodium chloride over 30 minutes along with high doses of loop diuretics has been reported to be effective and well tolerated in patients with heart failure; several studies suggest that this approach produces more efficient decongestion, improvement of hyponatremia, and better preservation of kidney function than diuretics alone [26-28]. (See "Use of diuretics in patients with heart failure", section on 'Management options'.)

The mechanism underlying these benefits may result from attenuation of Na-K-2Cl cotransporter activity and angiotensinogen expression as a result of hypertonic saline, thereby preventing excessive sodium reabsorption in the thick ascending limb of the loop of Henle, thereby mitigating volume overload [29].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyponatremia" and "Society guideline links: Fluid and electrolyte disorders in adults" and "Society guideline links: Heart failure in adults".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Hyponatremia (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Like most other causes of hyponatremia, heart failure impairs the ability to excrete ingested water by increasing antidiuretic hormone (ADH) levels. In addition, neurohumoral activation in heart failure limits distal water delivery (and thereby water excretion) by lowering the glomerular filtration rate (due to a marked reduction in kidney perfusion) and by increasing proximal sodium and water reabsorption. Heart failure also stimulates thirst, leading to enhanced water intake. (See 'Pathogenesis' above.)

●Both ADH release and the associated reduction in the serum sodium concentration parallel the severity of the heart failure. This relationship has prognostic importance since patient survival is significantly reduced (in comparison with normonatremic patients) once the serum sodium concentration falls below 137 mEq/L (figure 1). Patients whose serum sodium levels fall below 125 mEq/L solely as a result of heart failure usually have near end-stage disease. (See 'Predictor of adverse prognosis' above.)

●Hyponatremia in patients with heart failure usually develops slowly (paralleling the rate of progression of the heart disease) and produces no obvious symptoms until the serum sodium concentration falls below 120 mEq/L. Such patients have severe heart disease and a poor prognosis. It is possible that some patients with chronic moderate hyponatremia (serum sodium 120 to 129 mEq/L) have subtle neurologic manifestations that may be improved by gradually raising the serum sodium. These include reduced scores on tests of mental, social, and physical functioning and, in older adult patients, unsteadiness and falls. (See 'Clinical manifestations' above.)

●There is no evidence that correction of hyponatremia improves the hemodynamic abnormalities associated with the severe underlying chronic heart failure or that it improves clinical outcomes. Thus, the main indications for specific therapy to correct hyponatremia are a serum sodium concentration below 120 mEq/L (severe hyponatremia) and/or the presence of symptoms that might be due to hyponatremia. (See 'Indications' above.)

●Restricting fluid intake is the mainstay of therapy in hyponatremic patients with heart failure. (See 'Fluid restriction' above.)

●Angiotensin inhibition with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) and a loop diuretic may raise the serum sodium concentration. (See 'ACE inhibitors and loop diuretics' above.)

●Tolvaptan and, when approved for use, other oral selective V2 receptor antagonists may have a role in the management of hyponatremia in patients with chronic heart failure when other management options have failed to increase the serum sodium above 120 mEq/L and/or ameliorate symptoms of hyponatremia. However, because of potential hepatotoxicity, tolvaptan should not be used for longer than 30 days in any patient and should not be given to patients with liver disease (including cirrhosis). (See 'Vasopressin receptor antagonists' above.)