hyponatremia in heart failure.pdf

8/14/2019 Hyponatremia in heart failure.pdf

1/5

natremia in heart failure http://www.uptodate.com/online/content/topic.do?topicKey=fld

5 7/23/2008

Official reprint from UpToDate

www.uptodate.com

Print | Back

Hyponatremia in heart failure

AuthorBurton D Rose, MD

Section EditorRichard H Sterns, MD

Wilson S Colucci, MD

Deputy EditorTheodore W Post, MD

Last literature review for version 16.1:January 31, 2008 | This topic last updated:February

11, 2008

INTRODUCTION Hyponatremia in patients with heart failure (HF) results from an inability to excrete

ingested water. This problem is largely related to the associated fall in cardiac output and systemic blood

pressure, which stimulate secretion of the three "hypovolemic" hormones renin (with a subsequent

increase in angiotensin II formation), antidiuretic hormone(ADH), and norepinephrine[1-3] . It is

important to appreciate that edematous patients with HF, who have increased plasma and extracellular

fluid volumes, are effectively volume depleted, since the low cardiac output decreases the pressureperfusing the baroreceptors in the carotid sinus and the renal afferent arteriole. ( See "Chapter 8A:

Effective circulating volume and the steady state").

There is a general correlation between the degree of neurohumoral activation and the severity of cardiac

dysfunction, as assessed by left ventricular ejection fraction or functional class [2,4] . There is, however,

interpatient variability. As an example, patients with advanced but stable HF may have a normal plasma

renin activity despite having a cardiac output that is as low as that in unstable patients with often

marked hyperreninemia [5] . One possible explanation for this finding is that the circulating renin levels

do not necessarily reflect the activity of tissue renin-angiotensin systems. Studies in experimental

animals are consistent with this hypothesis as persistent activation of the intrarenal renin-angiotensin

system can be demonstrated in the absence of an elevation in the plasma renin activity [ 6] .

The neurohumoral changes that are induced 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 norepinephrinelimit distal water delivery (and thereby water

excretion) by lowering the glomerular filtration rate (due to a marked reduction in renal perfusion) and

by increasing proximal sodium and water reabsorption. Both the low cardiac output and high angiotensin

II levels are also potent stimuli to thirst, leading to enhanced water intake.

EFFECT ON PROGNOSIS The net effect is that the severity of the defect in water excretion (due to

the neurohumoral activation) and of the associated reduction in the serum sodium concentration parallels

the severity of the heart disease [1] . This relationship has prognostic importance, since patient survival

is significantly reduced (in comparison to normonatremic patients) once the serum sodium concentration

falls below 137 meq/L in patients (show figure 1), and may also be associated with an adverse prognosis

following an acute myocardial infarction [ 7,8] . A similar inverse correlation exists between patient

survival and the degree of elevation in plasma norepinephrinelevels (show figure 2). (See "Predictors of

survival in heart failure due to systolic dysfunction" , section on Neurohumoral activation).

A plasma sodium concentration below 125 meq/L represents near end-stage disease. At this time,

hyperkalemia is also a frequent finding. Distal sodium and water delivery are so low in advanced cardiac

disease that potassium excretion (which is primarily derived from distal potassium secretion) falls below

the level of intake.


2/5


5 7/23/2008

In addition to its long-term prognostic value, hyponatremia also is an adverse predictor of short-term

outcomes in patients who are hospitalized for worsening HF [ 9,10] . This was illustrated in a post hoc

analysis from the OPTIME-CHF trial of milrinonetherapy in 949 such patients [9] . 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 1.0 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 due to systolic dysfunction").

Hyponatremic patients are also at increased risk for worsening cardiac and renal function after the

administration of a NSAID [3] . In this setting of advanced heart failure and a high level of circulatingvasoconstrictors, there is increased renal secretion of vasodilator prostaglandins which act to preserve

renal perfusion and to lower systemic vascular resistance. Decreasing prostaglandin synthesis with a

NSAID in such a patient is likely to cause renal ischemia, a rise in the plasma creatinine concentration,

and a fall in cardiac output due to increased afterload [ 3] . (See "NSAIDs: Acute renal failure and

nephrotic syndrome").

TREATMENT 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. However, some patients with chronic moderate hyponatremia

(serum sodium 120 to 129 meq/L) have subtle neurologic manifestations that can be improved by

gradually raising the serum sodium. These include reduced scores on tests of mental, social, and physicalfunctioning and, in elderly patients, unsteadiness and falls [ 11,12] . (See "Manifestations of

hyponatremia and hypernatremia", section on Clinical manifestations of chronic hyponatremia).

Correction of the hyponatremia will have no effect of the hemodynamic abnormalities associated with the

severe underlying heart disease.

Restriction of water intake Restricting water intake is the mainstay of therapy in hyponatremic

patients with heart failure [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. However, significantly limiting water intake

is often not well tolerated in heart failure patients because of the intense stimulation of thirst. ( See

"Treatment of hyponatremia")

ACE inhibitors In refractory cases, the combination of an angiotensin converting enzyme (ACE)

inhibitor and a loop diuretic also may induce an elevation in the serum sodium concentration [ 13,14] .

These agents may act in three ways: (1) the increase in cardiac output following ACE inhibition can lower

the levels of ADH, angiotensin II, and norepinephrine[14] ; (2) 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 [15] ; and (3) the loop diuretic increases water delivery to the collecting

tubules which, due to the decrease in ADH secretion and responsiveness, are now less permeable to

water. The increment in cardiac output and fall in angiotensin II levels may also be beneficial by reducing

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 cause vasoconstriction and mediate adrenocorticotropin release, respectively [ 16,17]

.

The vasopressinreceptor antagonists produce a selective water diuresis without affecting sodium and

potassium excretion [16,17] . 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 [ 11] . (See

"Treatment of hyponatremia", section on Vasopressin receptor antagonists).


3/5


5 7/23/2008

Some oral formulations tolvaptan, satavaptan, and lixivaptan are selective for the V2 receptor, while

an intravenous agent, conivaptan, blocks both the V2 and V1a receptors. Only conivaptan is currently

available in the United States. It is approved for the management of patients with euvolemic (mostly the

syndrome of inappropriate ADH secretion) and hypervolemic hyponatremia.

Among patients with heart failure, conivaptanboth raises the serum sodium concentration and, via

blockade of the V1a receptors, diminishes afterload, possibly improving systemic hemodynamics in

patients with heart failure [18] . However, the safety and efficacy of conivaptan in heart failure have not

been established. (See "Possibly effective emerging therapies for heart failure", section on Vasopressinreceptor antagonists).

The oral selective V2 receptor antagonist tolvaptan also raises the serum sodium concentration in

patients with HF [11,19,20] . The magnitude of this effect was illustrated in the EVEREST Outcome trial

of 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 (mean meq/L), tolvaptan produced a greater increase in serum sodium at seven days

or time of discharge if earlier (5.5 versus 1.9 meq/L with placebo). The difference tended to become

smaller over time.

When oral V2 receptor antagonists are approved for use, they may have a role in the management of

hyponatremia that persists after water restriction and that is associated with overt symptoms or the

subtle neurologic manifestations described above [11,12] .

Use of UpToDateis subject to the Subscription and License Agreement.

REFERENCES

Leier, CV, Dei Cas, L, Metra, M. Clinical relevance and management of the major electrolyteabnormalities in congestive heart failure: Hyponatremia; hypokalemia, and hypomagnesemia.Am Heart J 1994; 128:564.

1.

Benedict, CR, Johnstone, DE, Weiner, DH, et al for the SOLVD Investigators. Relation ofneurohumoral activation to clinical variables and degree of ventricular dysfunction: A reportfrom the registry of Studies of Left Ventricular Dysfunction. J Am Coll Cardiol 1994; 23:1410.

2.

Dzau, VJ, Packer, M, Lilly, LS, et al. Prostaglandins in severe congestive heart failure. Relationto activation of the renin--angiotensin system and hyponatremia. N Engl J Med 1984;310:347.

3.

Funayama, H, Nakamura, T, Saito, T, et al. Urinary excretion of aquaporin-2 water channelexaggerated dependent upon vasopressin in congestive heart failure. Kidney Int 2004;66:1387.

4.

Dzau, VJ, Colucci, WS, Hollenberg, NK, Williams, GH. Relation of therenin-angiotensin-aldosterone system to clinical state in congestive heart failure. Circulation

1981; 63:645.

5.

Schunkert, H, Ingelfinger, JR, Hirsch, AT, et al. Evidence for tissue specific activation of renalangiotensinogen mRNA expression in chronic stable experimental heart failure. J Clin Invest1992; 90:1523.

6.

Lee, WH, Packer, M. Prognostic importance of serum sodium concentration and its modificationby converting-enzyme inhibition in patients with severe congestive heart failure. Circulation1986; 73:257.

7.

Goldberg, A, Hammerman, H, Petcherski, S, et al. Hyponatremia and long-term mortality insurvivors of acute ST-elevation myocardial infarction. Arch Intern Med 2006; 166:781.

8.

Klein, L, O'Connor, CM, Leimberger, JD, et al. Lower serum sodium is associated withincreased short-term mortality in hospitalized patients with worsening heart failure: results

9.


4/5


5 7/23/2008

from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of ChronicHeart Failure (OPTIME-CHF) study. Circulation 2005; 111:2454.

Gheorghiade, M, Abraham, WT, Albert, NM, et al. Relationship between admission serumsodium concentration and clinical outcomes in patients hospitalized for heart failure: ananalysis from the OPTIMIZE-HF registry. Eur Heart J 2007; 28:980.

10.

Schrier, RW, Gross, P, Gheorghiade, M, et al. Tolvaptan, a selective oral vasopressinV2-receptor antagonist, for hyponatremia. N Engl J Med 2006; 355:2099.

11.

Renneboog, B, Musch, W, Vandemergel, X, et al. Mild chronic hyponatremia is associated withfalls, unsteadiness, and attention deficits. Am J Med 2006; 119:71.

12.

Dzau, VJ, Hollenberg, NK. Renal response to captopril in severe heart failure: Role offurosemide in natriuresis and reversal of hyponatremia. Ann Intern Med 1984; 100:777.

13.

Riegger, GA, Kochsiek, K. Vasopressin, renin and norepinephrine levels before and aftercaptopril administration in patients with congestive heart failure due to dilatedcardiomyopathy. Am J Cardiol 1986; 58:300.

14.

Rouse, D, Dalmeida, W, Williamson, FC, Suki, WN. Captopril inhibits the hydroosmotic effect ofADH in the cortical collecting tubule. Kidney Int 1987; 32:845.

15.

Greenberg, A, Verbalis, JG. Vasopressin receptor antagonists. Kidney Int 2006; 69:2124.16.

Verbalis, JG, Goldsmith, SR, Greenberg, A, et al. Hyponatremia treatment guidelines 2007:Expert panel recommendations. Am J Med 2007; 120:S1.

17.

Udelson, JE, Smith, WB, Hendrix, GH, et al. Acute hemodynamic effects of conivaptan, a dualV1A and V2 vasopressin receptor antagonist in patients with advanced heart failure.Circulation 2001; 104:2417.

18.

Konstam, MA, Gheorghiade, M, Burnett, JC Jr, et al. Effects of oral tolvaptan in patientshospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA 2007; 297:1319.

19.

Gheorghiade, M, Niazi, I, Ouyang, J, et al. Vasopressin V2-receptor blockade with tolvaptan inpatients with chronic heart failure: results from a double-blind, randomized trial. Circulation2003; 107:2690.

20.

GRAPHICS

Hyponatremia associated with reduced survival in CHF

Survival over time in patients with severe heart failure and a normal plasmasodium concentration (solid line) or hyponatremia (dashed line). Survivalwas significantly reduced in patients with hyponatremia. Data from Lee, WH,Packer, M, Circulation 1986; 73:257.

Plasma norepinephrine and survival in CHF


5/5


5 7/23/2008

Percent probability of survival in patients with advanced congestive heartfailure according to the plasma norepinephrine concentration. Survivalwas inversely related to the degree of norepinephrine activation, apresumed reflection of worsening cardiac function. The time to 50 percentsurvival was approximately 30 months in patients with normalnorepinephrine levels (200 pg/mL), but only about 10 months in thosewith marked hypersecretion (1200 pg/mL). Data from Cohn, JN, Levine,TB, Olivaro, MT, et al, N Engl J Med 1984; 311:819.

2008 UpToDate, Inc. All rights reserved. | Subscription and License Agreement | Support Tag:[ecapp1003p.utd.com-82.76.6.152-6EBAB4CF9B-2579]

Licensed to: UpToDate Guest Pass | Your UpToDatesubscription will expire in 9 day(s). Click here torenew your subscription.

hyponatremia in heart failure.pdf

Documents