Manifestations of hyponatremia and hypernatremiaAuthorBurton D Rose, MDSection EditorRichard H Sterns, MDDeputy EditorTheodore W Post, MDLast literature review version 18.3: September 2010 | This topic last updated: May 12, 2010 (More)

INTRODUCTION — The symptoms that may be seen with hyponatremia or

hypernatremia are primarily neurologic and related to the severity and, in particular,

the rapidity of onset of the change in the plasma sodium concentration [1,2]. It

should be emphasized that patients with hyponatremia and hypernatremia may also

have complaints related to concurrent volume depletion and possible underlying

neurologic diseases that predispose to the electrolyte abnormality. These include: (1)

impaired mental status of any cause, leading to lack of expression of thirst, which is

normally the major protective mechanism against the development of

hypernatremia; and (2) a wide variety of neurologic disorders that can lead

sequentially to the inappropriate secretion of antidiuretic hormone, water retention,

and hyponatremia. (See "Causes of hyponatremia" and "Causes of hypernatremia".)

HYPONATREMIA — The symptoms directly attributable to hyponatremia primarily

ine spacing

occur with acute and marked reductions in the plasma sodium concentration and

reflect neurologic dysfunction induced by cerebral edema [1,3,4] and possibly

adaptive responses of brain cells to osmotic swelling. In this setting, the associated

fall in plasma osmolality creates an osmolal gradient that favors water movement

into the cells, leading to brain edema.

The development of cerebral edema is specifically dependent upon the transfer of

water from plasma and cerebrospinal fluid into the brain. Insight into this process is

provided by mice without the genes for aquaporin-4, a water channel expressed at

the interface between the brain and blood and between the brain and cerebrospinal

fluid [5]. Compared with wild-type mice, knockout mice exhibit considerably less

brain edema, morbidity, and mortality after the induction of acute hyponatremia,

suggesting that aquaporin-4 mediates a substantial portion of osmotic water

transport into the brain.

Hyponatremia-induced cerebral edema occurs primarily with rapid (over one to three

days) reductions in the plasma sodium concentration [4], as most often occurs in

postoperative patients given large quantities of hypotonic fluid and in patients with

self-induced water intoxication due to primary polydipsia, and exercise-associated

hyponatremia. Hypoxic brain injury also may contribute to the neurologic deficit, if

respiratory arrest has occurred [6]. (See "Exercise-associated hyponatremia".)

Clinical manifestations of acute hyponatremia — The severity of symptoms

generally reflects the severity of cerebral overhydration [1]. Nausea and malaise are

the earliest findings, and may be seen when the plasma sodium concentration falls

below 125 to 130 meq/L. This may be followed by headache, lethargy, and

obtundation and eventually seizures, coma, and respiratory arrest if the plasma

sodium concentration falls below 115 to 120 meq/L [1,6-9]. Noncardiogenic

pulmonary edema has also been described [10].

Acute hyponatremic encephalopathy may be reversible, although permanent

neurologic damage or death can occur, particularly in premenopausal women (see

below) [6,9]. Overly rapid correction also may be deleterious, especially in patients

with chronic hyponatremia (see below).

Osmolytes and cerebral adaptation to hyponatremia — The degree of cerebral

edema and therefore the severity of neurologic symptoms are much less with chronic

hyponatremia [1,11,12]. This protective response, which begins on the first day and

is complete within several days, occurs in two major steps.

• The initial cerebral edema elevates the interstitial hydraulic pressure, creating a

gradient for extracellular fluid movement out of the brain into the

cerebrospinal fluid [13].

• The brain cells lose solutes, leading to the osmotic movement of water out of the

cells and less brain swelling [4,11,13-16]. Most of this volume regulatory

response initially consists of the loss of potassium and sodium salts; this is

then followed over the next few days by the loss of organic solutes. Electrolyte

movement occurs quickly because it is mediated by the activation of

quiescent cation channels in the cell membrane; organic solute loss occurs

later because it requires the synthesis of new transporters [3,4].

These processes are reversed with correction of the hyponatremia [3,4,16]. However,

the reuptake of brain solutes during correction occurs more slowly than loss of brain

solutes during the onset of hyponatremia.

The organic solutes (which are called osmolytes) account for approximately one-third

of the solute loss in chronic hyponatremia (figure 1) [15]. Reducing the cell's content

of these solutes has the advantage of restoring cell volume without interfering with

protein function. In comparison, there would be a potentially deleterious effect on

protein function if the volume adaptation were mediated entirely by changes in the

cell cation (potassium plus sodium) concentration. (See "Chapter 4C: Maintenance of

cell volume".)

Studies in hyponatremic animals have shown that the major osmolytes lost from the

brain cells are the amino acids glutamine, glutamate, and taurine, and, to a lesser

degree, the carbohydrate myoinositol [4,14,15]. A study using proton NMR

spectroscopy found a slightly different pattern in humans with chronic hyponatremia;

myoinositol and choline compounds were the primary organic solutes lost, with a

smaller change occurring in glutamine and glutamate [16]. (Myoinositol also appears

to be the primary osmolyte taken up by the brain as part of the protective response

in patients with hypernatremia; see below).

Clinical manifestations of chronic hyponatremia — The cerebral adaptation

permits patients with chronic hyponatremia to appear to be asymptomatic despite a

plasma sodium concentration that is persistently as low as 115 to 120 meq/L. When

symptoms do occur in patients with plasma sodium concentrations at this level, they

are relatively nonspecific, including fatigue, nausea, dizziness, gait disturbances,

forgetfulness, confusion, lethargy, and muscle cramps [8,17,18].

Seizures and coma are uncommon and often reflect an acute exacerbation of the

hyponatremia. Symptomatic chronic hyponatremia is rarely, if ever, associated with

cerebral edema severe enough to cause herniation of the brain. In a series of 223

patients hospitalized for symptomatic chronic hyponatremia due to thiazide diuretics,

there was a 1 percent incidence of seizures and no cases of herniation [18]. (See

"Diuretic-induced hyponatremia".)

The older literature includes reports of brain damage in outpatients with thiazide-

induced hyponatremia [7]. However, at the time of the study, the consequences of

overly rapid correction were unknown. The reported patients were all treated with

hypertonic saline, increasing the plasma sodium concentration by more than 25

meq/L in 48 hours, a rate of correction now associated with osmotic demyelination.

Manifestations in apparently asymptomatic patients — Patients with moderate

chronic hyponatremia often appear asymptomatic but may have subtle neurologic

manifestations that can easily be missed. The following observations illustrate the

range of findings:

• In the SALT-1 and SALT-2 trials of the oral vasopressin receptor antagonist

tolvaptan compared to placebo in patients with chronic hyponatremia, none of

the patients had clinically apparent neurologic symptoms at baseline and

almost all had a plasma sodium concentration of 120 meq/L or higher [19].

Gradually raising the plasma sodium with tolvaptan was associated with

significant improvement on the Mental Component of the Medical Outcomes

Study Short-Form General Health Survey at 30 days. This benefit was

significant only in patients with a plasma sodium concentration between 120

and 129 meq/L and was not seen in the placebo group. (See "Overview of the

treatment of hyponatremia", section on 'Vasopressin receptor antagonists'.)

• A case control study suggested that elderly patients (mean age 72) with chronic

mild to moderate hyponatremia (plasma sodium concentration 120 to 130

meq/L, mean 126 meq/L) were more likely to have falls, which may have

resulted from a higher rate of gait disturbance and attention deficits [20].

Serial studies in the same patients suggested improvement in symptoms

when the plasma sodium concentration was normal, compared to when

hyponatremic.

Falls in elderly hyponatremic patients may be associated with an increased risk of

fractures compared to falls in elderly normonatremic patients [21]. An increased

incidence of osteoporosis has been described in hyponatremic patients, which may

contribute to fractures [22].

Hyponatremia, even if mild, is associated with increased mortality [23,24]. This was

best shown in a prospective cohort study of 98,311 patients hospitalized between

2000 and 2003 [23]. Compared to normonatremic patients, hyponatremic patients

(plasma sodium 130 to 134 meq/L in 83 percent) had an increased risk of death

during the initial hospitalization (adjusted odds ratio 1.47, 95% CI 1.3-1.6) and at one

and five years (hazard ratios of 1.38 and 1.25, respectively). However, this study

could not determine whether the hyponatremia was causally associated with

mortality. Since most patients had only mild hyponatremia, it seems likely that

hyponatremia was a marker for more severe underlying disease. Such a relationship

has been clearly established in hyponatremic patients with heart failure or cirrhosis

(figure 2). (See "Hyponatremia in patients with heart failure" and "Hyponatremia in

patients with cirrhosis".)

Susceptibility of premenopausal women — For reasons that are not well

understood, premenopausal women seem to make a less efficient osmotic adaptation

[6]. As a result, they appear to be at greater risk for severe hyponatremic symptoms

and at much greater risk (up to 25-fold when compared to men) for residual

neurologic injury following symptomatic hyponatremia (figure 3) [6,25]. In an

epidemiologic study of postoperative patients, women were as likely as men to

develop hyponatremia (defined as a plasma sodium concentration ≤128 meq/L) [6].

However, women comprised 97 percent of cases of death or irreversible brain

damage after an episode of symptomatic hyponatremia; these complications

developed in up to 60 percent of these women, even if the plasma sodium

concentration were raised at an appropriate rate. Premenopausal women had a

relative risk of death or permanent brain damage from hyponatremic encephalopathy

of 26 to 28 compared to men and postmenopausal women.

Premenopausal women may progress rapidly from minimal symptoms (headache and

nausea) to respiratory arrest [6,25]. Cerebral edema and herniation have been found

at autopsy, suggesting a possible hormonally-mediated decrease in the degree of

osmotic adaptation [6,26]. The observation that prepubertal boys and girls are at

equal risk of symptomatic hyponatremia is also compatible with the importance of

sex hormones in conferring susceptibility to adult women [27].

Osmotic demyelination — The adaptation that returns the brain volume toward

normal in chronic hyponatremia protects against the development of cerebral edema

but also creates a potential problem for therapy. In this setting, an overly rapid

increase in the plasma sodium concentration can lead to an osmotic demyelination

syndrome (also called central pontine myelinolysis, although demyelination is often

more diffuse and does not necessarily involve the pons). These changes can lead to

potentially severe neurologic symptoms that are delayed for two to six days after

correction and may be irreversible, Thus, initially symptomatic patients may improve

and then show late deterioration (figure 3). These issues are discussed in detail

elsewhere. (See "Osmotic demyelination syndrome and overly rapid correction of

hyponatremia", section on 'Pathogenesis'.)

HYPERNATREMIA — Hypernatremia is basically a mirror image of hyponatremia

[1,3,4,28]. The rise in the plasma sodium concentration and osmolality causes acute

water movement out of the brain; this decrease in brain volume can cause rupture of

the cerebral veins, leading to focal intracerebral and subarachnoid hemorrhages and

possible irreversible neurologic damage [1,3].

Clinical manifestations — The clinical manifestations of this disorder begin with

lethargy, weakness, and irritability, and can progress to twitching, seizures, and

coma. Severe symptoms usually require an acute elevation in the plasma sodium

concentration to above 158 meq/L. Values above 180 meq/L are associated with a

high mortality rate, particularly in adults [29].

Although rarely reported, osmotic demyelination can also occur in association with

hypernatremia, primarily with extreme plasma sodium concentrations [30].

Cerebral adaptation to hypernatremia — Beginning on the first day, brain

volume is largely restored due to water movement from the cerebrospinal fluid into

the brain (thereby increasing the interstitial volume) [4,31] and to the uptake of

solutes by the cells (thereby pulling water into the cells and restoring the cell

volume) [4,32,33]. The latter response involves an initial uptake of sodium and

potassium salts, followed by the later accumulation of osmolytes, which in animals

consists primarily of myoinositol and the amino acids glutamine and glutamate

[32,33]. Myoinositol is taken up from the extracellular fluid via an increase in the

number of sodium-myoinositol cotransporters in the cell membrane [34]; the source

(uptake from the extracellular fluid or production within the cells) of glutamine and

glutamate is currently unknown. The net effect is that these osmolytes, which do not

interfere with protein function [16], account for about 35 percent of the new cell

solute [33].

A report of an infant with an initial plasma sodium concentration of 195 meq/L

confirmed the general applicability of these observations to humans [35]. The patient

was first studied using proton NMR spectroscopy on day four when the plasma

sodium concentration had fallen to 156 meq/L. At this time, there was a 17

mosmol/kg increase in brain osmolyte concentration, due primarily to the

accumulation of myoinositol. The excess brain osmolyte concentration fell to 6

mosmol/kg on day seven and was normal by day 36.

As in hyponatremia, the cerebral adaptation in hypernatremia has two important

clinical consequences:

• Chronic hypernatremia is much less likely to induce neurologic symptoms.

Assessment of symptoms attributable to hypernatremia is often difficult

because most affected adults have underlying neurologic disease. The latter is

required to diminish the protective thirst mechanism that normally prevents

the development of hypernatremia, even in patients with diabetes insipidus.

(See "Causes of hypernatremia".)

• Correction of chronic hypernatremia must occur slowly to prevent rapid fluid

movement into the brain and cerebral edema, changes that can lead to

seizures and coma [36]. Although the brain cells can rapidly lose potassium

and sodium in response to this cell swelling, the loss of accumulated

osmolytes occurs more slowly, a phenomenon that acts to hold water within

the cells [4,33]. The loss of myoinositol, for example, requires both a

reduction in synthesis of new sodium-inositol cotransporters [34] and the

activation of a specific inositol efflux mechanism in the cell membrane [37].

The delayed clearance of osmolytes from the cell can predispose to cerebral

edema if the plasma sodium concentration is lowered too rapidly. As a result,

the rate of correction in asymptomatic patients should not exceed 12 meq/L

per day, which represents an average of 0.5 meq/L per hour. (See "Treatment

of hypernatremia".)

SENSING OF CHANGES IN PLASMA OSMOLALITY — Although the mechanisms of

protective solute loss or uptake have been defined in hyponatremia and

hypernatremia, how the alterations in plasma osmolality are sensed by the cells and

then lead to the desired changes in solute balance are not well understood. There is

preliminary evidence that hyperosmolality, perhaps via stress on the cytoskeleton as

the cell volume falls, activates a specific protein kinase [38]. This kinase, via protein

phosphorylation, may then lead to activation of transporters, such as the sodium-

inositol cotransporter, that promote solute uptake into the cells.

SUMMARY

• Symptoms observed with hyponatremia or hypernatremia are primarily neurologic

and related to the severity and rapidity of the change in the plasma sodium

concentration. Such symptoms must be distinguished from those of

concurrent volume depletion and possible underlying neurologic diseases that

may predispose to the electrolyte abnormality. (See 'Introduction' above.)

• Symptoms directly attributable to hyponatremia reflect neurologic dysfunction

induced by cerebral edema. Cerebral edema is due to a decrease in plasma

osmolality which favors water movement into cells.

• Clinical manifestations of acute hyponatremia reflect the severity of cerebral

overhydration. Nausea and malaise are the earliest findings, and may be seen

at a plasma sodium concentration below 125 to 130 meq/L. Headache,

lethargy, obtundation and eventually seizures, coma, and respiratory arrest

may occur if the plasma sodium concentration falls below 115 to 120 meq/L.

Hyponatremic encephalopathy may be reversible or permanent.

Premenopausal women may be at greater risk for severe hyponatremic

symptoms and for residual neurologic injury. (See 'Clinical manifestations of

acute hyponatremia' above and 'Susceptibility of premenopausal

women' above.) ).

• Because of cerebral adaptation, neurologic symptoms are much less severe with

chronic hyponatremia. Patients with chronic hyponatremia may appear to be

asymptomatic despite a plasma sodium concentration that is as low as 115 to

120 meq/L. Symptoms that do occur include fatigue, nausea, dizziness, gait

disturbances, forgetfulness, confusion, lethargy, and muscle cramps. Seizures

and coma are uncommon and often reflect an acute exacerbation of the

hyponatremia. (See 'Osmolytes and cerebral adaptation to

hyponatremia' above and 'Clinical manifestations of chronic

hyponatremia' above.)

• Neurologic manifestations resulting from chronic hyponatremia including gait

disturbance and attention deficits may result in increased falls among elderly

patients. Even mild hyponatremia is associated with increased mortality,

although this may just be a marker for more severe underlying disease. (See

'Manifestations in apparently asymptomatic patients' above.)

• Overly rapid increase in the plasma sodium concentration can lead to an osmotic

demyelination syndrome (also called central pontine myelinolysis) resulting in

severe and potentially irreversible neurologic symptoms. (See 'Osmotic

demyelination' above and "Osmotic demyelination syndrome and overly rapid

correction of hyponatremia", section on 'Pathogenesis'.)

• Hypernatremia causes acute water movement out of the brain resulting in a

decrease in brain volume that can cause focal intracerebral and subarachnoid

hemorrhages and irreversible neurologic damage. (See

'Hypernatremia' above.)

• Hypernatremic patients present with lethargy, weakness and irritability, and may

develop twitching, seizures, and coma. Severe symptoms usually require an

acute elevation in the plasma sodium concentration to above 158 meq/L.

Values above 180 meq/L are associated with a high mortality rate, particularly

in adults. (See 'Clinical manifestations' above.)

• Because of cerebral adaptation, chronic hypernatremia is less likely to induce

neurologic symptoms. The correction of chronic hypernatremia must occur

slowly to prevent rapid fluid movement into the brain and cerebral edema.

The rate of correction in asymptomatic patients should not exceed 12 meq/L

per day, which represents an average of 0.5 meq/L per hour. (See Cerebral

adaptation to hypernatremia and (see "Treatment of hypernatremia").

Use of UpToDate is subject to the Subscription and License Agreement.REFERENCES1.Rose, BD, Post, TW, Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th

ed, McGraw-Hill, New York, 2001, pp. 716-720, 761-764.2.Yeates, KE, Singer, M, Morton, AR. Salt and water: a simple approach to

hyponatremia. CMAJ 2004; 170:365.3.McManus, ML, Churchwell, KB, Strange, K. Regulation of cell volume in health and

disease. N Engl J Med 1995; 333:1260.4.Strange, K. Regulation of solute and water balance and cell volume in the central

nervous system. J Am Soc Nephrol 1992; 3:12.5.Manley, GT, Fujimura, M, Ma, T, et al. Aquaporin-4 deletion in mice reduces brain

edema after acute water intoxication and ischemic stroke. Nat Med 2000; 6:159.

6.Ayus, JC, Wheeler, JM, Arieff, AI. Postoperative hyponatremic encephalopathy in menstruant women. Ann Intern Med 1992; 117:891.

7.Ashraf, N, Locksley, R, Arieff, AI. Thiazide-induced hyponatremia associated with death or neurologic damage in outpatients. Am J Med 1981; 70:1163.

8.Ellis, SJ. Severe hyponatraemia: complications and treatment. QJM 1995; 88:905. 9.Moritz, ML, Ayus, JC. The pathophysiology and treatment of hyponatraemic

encephalopathy: an update. Nephrol Dial Transplant 2003; 18:2486.10. Ayus, JC, Varon, J, Arieff, AI. Hyponatremia, cerebral edema, and

noncardiogenic pulmonary edema in marathon runners. Ann Intern Med 2000; 132:711.

11. Laureno, R, Karp, BI. Myelinolysis after correction of hyponatremia. Ann Intern Med 1997; 126:57.

12. Sterns, RH, Thomas, DJ, Herndon, RM. Brain dehydration and neurologic deterioration after rapid correction of hyponatremia. Kidney Int 1989; 35:69.

13. Melton, JE, Patlak, CS, Pettigrew, KD, Cserr, HF. Volume regulatory loss of Na, Cl, and K from rat brain during acute hyponatremia. Am J Physiol 1987; 252:F661.

14. Lien, YH, Shapiro, JI, Chan, L. Study of brain electrolytes and organic osmolytes during correction of chronic hyponatremia. Implications for the pathogenesis of central pontine myelinolysis. J Clin Invest 1991; 88:303.

15. Verbalis, JG, Gullans, SR. Hyponatremia causes large sustained reductions in brain content of multiple organic osmolytes in rats. Brain Res 1991; 567:274.

16. Videen, JS, Michaelis, T, Pinto, P, Ross, BD. Human cerebral osmolytes during chronic hyponatremia. A proton magnetic resonance spectroscopy study. J Clin Invest 1995; 95:788.

17. Sterns, RH, Cappuccio, JD, Silver, SM, Cohen, EP. Neurologic sequelae after treatment of severe hyponatremia: a multicenter perspective. J Am Soc

Nephrol 1994; 4:1522.18. Chow, KM, Kwan, BC, Szeto, CC. Clinical studies of thiazide-induced

hyponatremia. J Natl Med Assoc 2004; 96:1305.19. Schrier, RW, Gross, P, Gheorghiade, M, et al. Tolvaptan, a selective oral

vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006; 355:2099.

20. Renneboog, B, Musch, W, Vandemergel, X, et al. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med 2006; 119:71.e1.

21. Gankam Kengne, F, Andres, C, Sattar, L, et al. Mild hyponatremia and risk of fracture in the ambulatory elderly. QJM 2008; 101:583.

22. Verbalis, JG, Barsony, J, Sugimura, Y, et al. Hyponatremia-induced osteoporosis. J Bone Miner Res 2010; 25:554.

23. Waikar, SS, Mount, DB, Curhan, GC. Mortality after hospitalization with mild, moderate, and severe hyponatremia. Am J Med 2009; 122:857.

24. Wald, R, Jaber, BL, Price, LL, et al. Impact of hospital-associated hyponatremia on selected outcomes. Arch Intern Med 2010; 170:294.

25. Arieff, AI. Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women. N Engl J Med 1986; 314:1529.

26. Fraser, CL, Kucharczyk, J, Arieff, AI, et al. Sex differences result in increased morbidity from hyponatremia in female rats. Am J Physiol 1989; 256:R880.

27. Arieff, AI, Ayus, JC, Fraser, CL. Hyponatraemia and death or permanent brain damage in healthy children. BMJ 1992; 304:1218.

28. Adrogué, HJ, Madias, NE. Hypernatremia. N Engl J Med 2000; 342:1493. 29. Moder, KG, Hurley, DL. Fatal hypernatremia from exogenous salt intake:

report of a case and review of the literature. Mayo Clin Proc 1990; 65:1587.30. van der Helm-van Mil, AH, van Vugt, JP, Lammers, GJ, Harinck, HI.

Hypernatremia from a hunger strike as a cause of osmotic myelinolysis. Neurology 2005; 64:574.

31. Pullen, RG, DePasquale, M, Cserr, HF. Bulk flow of cerebrospinal fluid into brain in response to acute hyperosmolality. Am J Physiol 1987; 253:F538.

32. Heilig, CW, Stromski, ME, Blumenfeld, JD, et al. Characterization of the major brain osmolytes that accumulate in salt-loaded rats. Am J Physiol 1989; 257:F1108.

33. Lien, YH, Shapiro, JI, Chan, L. Effects of hypernatremia on organic brain osmoles. J Clin Invest 1990; 85:1427.

34. Paredes, A, McManus, M, Kwon, HM, Strange, K. Osmoregulation of Na(+)- inositol cotransporter activity and mRNA levels in brain glial cells. Am J Physiol 1992; 263:C1282.

35. Lee, JH, Arcinue, E, Ross, BD. Brief report: organic osmolytes in the brain of an infant with hypernatremia. N Engl J Med 1994; 331:439.

36. Hogan, GR, Dodge, PR, Gill, SR, et al. Pathogenesis of seizures occurring during restoration of plasma tonicity to normal in animals previously chronically hypernatremic. Pediatrics 1969; 43:54.

37. Strange, K, Morrison, R, Shrode, L, Putnam, R. Mechanism and regulation of swelling-activated inositol efflux in brain glial cells. Am J Physiol 1993; 265:C244.

38. Galcheva-Gargova, Z, Dérijard, B, Wu, IH, Davis, RJ. An osmosensing signal transduction pathway in mammalian cells. Science 1994; 265:806.

© 2011 UpToDate, Inc. All rights reserved. | Subscription and License Agreement |Support Tag: [ecapp0602p.utd.com-72.159.51.130-0AEC8D4CF1-4428]Licensed to: Lincoln Mem Univ

Overview of the treatment of hyponatremiaAuthorRichard H Sterns, MDSection EditorMichael Emmett, MDDeputy EditorTheodore W Post, MDLast literature review version 18.3: September 2010 | This topic last updated: June 10, 2010 (More)

INTRODUCTION — Hyponatremia represents a relative excess of water in relation to

sodium. It can be induced by a marked increase in water intake (primary polydipsia)

or, in the great majority of cases, by impaired water excretion resulting from

advanced renal failure or from persistent release of antidiuretic hormone (ADH)

induced by effective volume depletion, the syndrome of inappropriate ADH secretion

(SIADH), thiazide diuretics, adrenal insufficiency, or hypothyroidism. (See "Causes of

hyponatremia".)

Most patients with hyponatremia have chronic (ie, gradual onset) hyponatremia, a

serum sodium concentration above 120 meq/L, and appear asymptomatic, although

subtle neurologic abnormalities may be present when the serum sodium is between

120 and 130 meq/L. (See 'Necessity for therapy' below.)

Initial treatment in such patients typically consists of slow correction of the

hyponatremia via fluid restriction or, if volume depletion is present, the

administration of isotonic saline (or oral salt tablets) [1-3]. Vasopressin receptor

antagonists also may be helpful. Among patients with SIADH, isotonic saline may

worsen the hyponatremia. (See 'SIADH' below.)

More aggressive therapy is indicated in patients who have symptomatic or severe

hyponatremia (serum sodium concentration below 110 to 115 meq/L). In this setting,

initial therapy usually consists of hypertonic saline with or without

vasopressin receptor antagonists.

When considering the treatment of patients with hyponatremia, the following issues

will be reviewed here:

• The optimal method of raising the serum sodium concentration, which varies with

the cause of hyponatremia

• Estimation of the sodium deficit if sodium is to be given

• The optimal rate of correction

The rate of correction is important because overly rapid correction of severe

hyponatremia can lead to a severe and usually irreversible neurologic disorder called

osmotic demyelination. One group that is probably not at risk for this complication is

patients with hyperacute hyponatremia that develops over a few hours due to a

marked increase in water intake as may be seen in marathon runners, psychotic

patients, and users of ecstasy. Issues related to osmotic demyelination are discussed

separately. (See "Osmotic demyelination syndrome and overly rapid correction of

hyponatremia".)

METHODS OF RAISING THE SERUM SODIUM — The serum sodium concentration

can be raised in hyponatremic patients by one or more of the following approaches

[1-5]:

• Treat the underlying disease, if possible.

• Fluid restriction.

• Oral or intravenous sodium chloride in patients with true volume depletion. Sodium

chloride administration is also effective in patients the syndrome of

inappropriate antidiuretic hormone secretion (SIADH) using either oral salt

tablets or hypertonic saline. In contrast, isotonic saline is often not effective

and may worsen the hyponatremia in SIADH. (See 'SIADH' below.)

• Administration of a vasopressin receptor antagonist.

These approaches will be discussed in detail in the following sections. In addition,

initial therapy with hypertonic saline is warranted in patients with neurologic

symptoms attributable to hyponatremia, particularly if severe. (See 'Choice of

therapy' below.)

Treat the underlying disease — In addition to the specific therapies described

below that are aimed at correcting the hyponatremia, therapy should also be

directed at the underlying disease. (See "Causes of hyponatremia".)

There are several circumstances in which the underlying disease can be corrected

quickly, possibly leading to overly rapid correction of the hyponatremia (see 'Avoid

overly rapid correction' below):

• The administration of saline to patients with true volume depletion. In this setting,

restoration of euvolemia will suppress the release of ADH (which has a half-life

of only 15 to 20 minutes), thereby allowing rapid excretion of the excess

water. (See 'True volume depletion' below.)

• The administration of glucocorticoids to patients with adrenal insufficiency, which

will directly suppress the release of ADH. (See "Hyponatremia and

hyperkalemia in adrenal insufficiency".)

• Relatively rapid reversal of the syndrome of inappropriate antidiuretic hormone

secretion (SIADH). This can occur with self-limited disease (eg, nausea, pain,

surgery) and with cessation of therapy with certain drugs that cause SIADH

such as desmopressin and selective serotonin reuptake inhibitors (eg,

fluoxetine, sertraline).

There are a number of other causes of hyponatremia that can be corrected in which

the serum sodium rises more slowly. This is most often seen with thyroid hormone

replacement in patients with hypothyroidism and by gradually reversing the cause of

SIADH by, for example, the treatment of tuberculosis or meningitis or the cessation of

long-acting drugs. (See "Hyponatremia in hypothyroidism" and "Pathophysiology and

etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)",

section on 'Etiology'.)

Fluid restriction — Fluid restriction to below the level of urine output is the primary

therapy for hyponatremia in edematous states (such as heart failure and cirrhosis),

the syndrome of inappropriate antidiuretic hormone secretion (SIADH), primary

polydipsia, and advanced renal failure. Hyponatremia develops gradually in these

settings and is not usually associated with overt symptoms. Restriction to 50 to 60

percent of daily fluid requirements may be required to achieve the goal of inducing

negative water balance [4,6]. In general, fluid intake should be less than 800 mL/day.

(See "Hyponatremia in patients with heart failure" and "Hyponatremia in patients

with cirrhosis" and "Treatment of hyponatremia: Syndrome of inappropriate

antidiuretic hormone secretion (SIADH) and reset osmostat".)

Sodium chloride administration — Sodium chloride, usually as isotonic saline or

increased dietary salt, is given to patients with true volume depletion and/or adrenal

insufficiency, and to some patients with SIADH. Salt therapy is generally

contraindicated in edematous patients (eg, heart failure, cirrhosis, renal failure) since

it will lead to exacerbation of the edema.

Administration of hypertonic saline is primarily limited to patients with symptomatic

or severe hyponatremia or, occasionally, to patients with SIADH and a highly

concentrated urine. (See 'Severe symptoms' below and 'SIADH' below.)

The degree to which isotonic saline will raise the serum sodium concentration in

hyponatremic patients varies with the cause of the hyponatremia. As illustrated by

the following discussion, the response to isotonic saline differs in volume depletion

and SIADH.

True volume depletion — In states of true volume depletion, the administered

sodium and water will initially be retained. In this setting, isotonic saline corrects the

hyponatremia by two mechanisms:

• It slowly raises the serum sodium by approximately 1 meq/L for every liter of fluid

infused, since isotonic saline has a higher sodium concentration (154 meq/L)

than the hyponatremic plasma.

• By eventually causing volume repletion, it removes the stimulus to ADH release,

thereby allowing the excess water to be excreted in a dilute urine. At this

time, the serum sodium concentration may return rapidly toward normal; in

selected patients, overly rapid correction of hyponatremia can lead to a

severe neurologic disorder called osmotic demyelination [7,8]. The

management of such patients is discussed separately. (See "Osmotic

demyelination syndrome and overly rapid correction of hyponatremia",

section on 'Prevention and treatment of overly rapid correction'.)

The degree to which one liter of a given solution will initially raise the serum sodium

concentration (SNa) can be estimated from the following formula [4]:

  Increase in SNa = (Infusate [Na] - SNa) ÷ (TBW + 1)

where TBW is the estimated total body water (lean body weight times 0.5 for women,

0.6 for men).

Thus, the administration of one liter of isotonic saline (containing 154 meq/L of

sodium) in a 60 kg women with a serum sodium of 110 meq/L and an estimated TBW

of 30 L (50 percent of lean body weight) should raise the serum sodium by

approximately 1.4 meq/L to 111.4 meq/L:

  Increase in SNa = (154 - 110) ÷ 31 = 1.4 meq/L

There are two limitations to use of this formula in patients with true volume

depletion: it does not provide information on shifts in body water, and it does not

take into account the increase in water excretion that will occur when euvolemia is

restored and ADH release is suppressed. In addition, any potassium added to the

infused solution must be considered as sodium. The formula cannot be used to

predict the increase in serum sodium in patients with SIADH, since the administered

sodium will be excreted in the urine and some of the water retained, possibly

worsening the hyponatremia. (See 'Effect of potassium' below and 'SIADH' below.)

A more complete understanding of the effect on serum sodium and total body water

is provided by the following approach. Since the osmolality in the cells (where

potassium is the primary solute) is the same as that in the extracellular fluid, the

effect of the serum sodium concentration (SNa) is distributed through the total body

water (TBW). The term effective cation in the following equations refers to cations

that are osmotically active, not, for example, sodium or potassium bound in bone.

Thus, in this 60 kg woman with a serum sodium of 110 meq/L:

  Total body effective cation = TBW x SNa = 30 x 110 = 3300 meq

Assuming that the extracellular fluid (ECF) is 33 percent (10 L) and the intracellular

fluid is 67 percent (20 L) of the total body water [9]:

  Extracellular effective cation = 10 x 110 = 1100 meq

The administration and retention of 1000 mL of isotonic saline containing 154 meq of

sodium will raise the TBW to 31 L, the total body effective cation to 3454 meq, and,

since all of the sodium chloride will stay in the ECF, the extracellular effective cation

to 1254 meq. Thus:

  New SNa = total effective solute ÷ TBW

      =  3454  ÷  31  =  111.4 meq/L

  New ECF volume = total ECF solute ÷ SNa

      =  1254  ÷  111.4  =  11.3 L

The ECF volume has increased by 1.3 L, which is more than the 1.0 L given because

the rise in the serum sodium concentration pulls water out of the cells.

These calculations illustrate the relatively limited direct effect of isotonic saline to

correct hyponatremia. In the hypovolemic patient; the much more important effect is

restoration of euvolemia with subsequent suppression of ADH release.

SIADH — The response to isotonic saline is different in SIADH. Whereas both the

sodium and water are retained in hypovolemia, sodium balance is normal in SIADH

since it is regulated by aldosterone and atrial natriuretic peptide not ADH. Thus, the

administered sodium will be excreted in the urine, while some of the water may be

retained, leading to possible worsening of the hyponatremia.

A few simple calculations can illustrate this point. Suppose a patient with SIADH and

hyponatremia has a urine osmolality that is relatively fixed at 600 mosmol/kg. If 1000

mL of isotonic saline is given (containing 150 meq each of Na and Cl or 300 mosmol),

all of the NaCl will be excreted (because sodium handling is intact) but in only 500

mL of water (300 mosmol in 500 mL of water equals 600 mosmol/kg). The retention

of one-half of the administered water will lead to a further reduction in the serum

sodium concentration even though the serum sodium concentration may initially rise

because the isotonic saline is hypertonic to the patient.

Using the calculations in the preceding section on true volume depletion in a woman

with a baseline serum sodium (SNa) of 110 meq/L:

  New SNa = total effective solute ÷ total body water (TBW)

      =  3300 meq (same as baseline)  ÷  30.5 L (500 mL increase)      =  108 meq/L

Support for possible harm from isotonic saline was provided in a report of 22 women

who underwent uncomplicated gynecologic surgery and had been treated with only

isotonic saline or near-isotonic Ringer's lactate [10]. At 24 hours after induction of

anesthesia, the serum sodium fell a mean of 4.2 meq/L.

In contrast, hypertonic saline contains 1026 mosmol per liter (513 mosmol each of

sodium and chloride). If 1000 mL of this solution is given, all of the NaCl will again be

excreted but now in a larger volume of 1700 mL. Thus, after the administration of

hypertonic saline, there will be an initial large rise in the serum sodium concentration

followed by reduction toward baseline after the administered sodium has been

excreted. At this time, the rise in the serum sodium is entirely due to the net loss of

700 mL of water:

  New SNa = total effective solute ÷ TBW

      =  3300 (same as baseline)  ÷  29.3  =  112.6 meq/L

Treatment of SIADH begins with fluid restriction. If fluid must be given or the serum

sodium concentration must be raised quickly because of symptomatic hyponatremia,

the effective osmolality (two times the sodium plus potassium concentration) of the

fluid given must exceed the osmolality of the urine. Since the urine osmolality is

usually above 300 mosmol/kg in SIADH, isotonic saline has a limited role in correction

of the hyponatremia and hypertonic saline must be given. Whenever this is done,

careful monitoring of the serum sodium is essential to prevent overly rapid

correction. (See 'Rate of correction' below.)

Concurrent use of a loop diuretic may be beneficial in patients with SIADH since, by

inhibiting sodium chloride reabsorption in the thick ascending limb of the loop of

Henle, it interferes with the countercurrent mechanism and induces a state of ADH

resistance and a more dilute urine is excreted.

Chronic therapy of SIADH is discussed separately. (See "Treatment of hyponatremia:

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset

osmostat".)

Effect of potassium — Potassium is as osmotically active as sodium. As a result,

giving potassium (usually for concurrent hypokalemia) can raise the serum sodium

concentration and osmolality in hyponatremic patients [7,8,11,12]. Since most of the

excess potassium enters the cells, electroneutrality is maintained in one of three

ways, each of which will raise the serum sodium concentration:

39. Intracellular sodium moves into the extracellular fluid.

40. Extracellular chloride moves into the cells with potassium; the increase in cell

osmolality promotes free water entry into the cells.

41. Intracellular hydrogen moves into the extracellular fluid. These hydrogen ions

are buffered by extracellular bicarbonate and to a much lesser degree plasma

proteins. This buffering renders the hydrogen ions osmotically inactive; the

ensuing fall in extracellular osmolality leads to water movement into the cells.

The net effect is that concurrent administration of potassium must be taken into

account when estimating the sodium deficit. This relationship becomes clinically

important in the patient with severe diuretic or vomiting-induced hyponatremia who

is also hypokalemic.

Suppose, for example, that the serum potassium concentration is 2 meq/L and it is

decided to give 400 meq of potassium during the first day. If the patient is a 70 kg

man, the total body water will be approximately 40 liters (60 percent of body weight).

In this setting, 800 milliosmoles of osmotically active potassium chloride (400

milliosmoles of each) distributed through 40 liters will raise the serum osmolality by

20 mosmol/kg and the serum sodium concentration by roughly 10 meq/L, which is at

the limit for safe correction. Thus, giving potassium chloride alone will correct

both the hyponatremia and the hypokalemia [8]. Giving additional sodium may lead

to an overly rapid elevation in the serum sodium concentration. (See 'Rate of

correction' below.)

Thus, when calculating the impact of a particular regimen on the serum sodium

concentration, one must use two times the sodium plus potassium concentration of

the solution, not simply two times the sodium concentration. Similar considerations

apply to calculating the impact of fluid losses induced by vomiting, diarrhea, or

diuretic therapy.

Vasopressin receptor antagonists — An alternative or possible addition to fluid

restriction or sodium chloride administration in patients with hyponatremia is the use

of an ADH receptor antagonist. 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 [3,5].

The vasopressin receptor antagonists produce a selective water diuresis without

affecting sodium and potassium excretion. The ensuing loss of free water will tend to

correct the hyponatremia. However, thirst increases significantly with these agents,

which may limit the rise in serum sodium [5,13].

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 tolvaptan and conivaptan are currently available in the United States.

Both drugs are approved for the management of patients with euvolemic

hyponatremia, mostly due to the syndrome of inappropriate ADH secretion (SIADH).

Tolvaptan is also approved for use in patients with heart failure or cirrhosis. With

respect to conivaptan, there are concerns that the concurrent V1a receptor blockade

might lower the blood pressure and increase the risk of variceal bleeding, since

vasopressin is used to treat active bleeding in such patients (a V1a effect). There is

also a concern that V1a receptor blockade might worsen renal function since

terlipressin, a V1a receptor agonist, has been used to treat hepatorenal syndrome.

The studies that have evaluated the use of vasopressin receptor antagonists in the

different settings in which hyponatremia occurs are presented elsewhere:

• SIADH (see "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic

hormone secretion (SIADH) and reset osmostat", section on 'Vasopressin

receptor antagonists').

• Heart failure (see "Hyponatremia in patients with heart failure" and "Possibly

effective emerging therapies for heart failure", section on 'Vasopressin

receptor antagonists').

• Cirrhosis (see "Hyponatremia in patients with cirrhosis", section on 'Vasopressin

receptor antagonists' and "Diagnosis and treatment of hepatorenal

syndrome", section on 'Vasopressin analogs').

An example of the potential efficacy of these drugs was provided in a combined

report of oral tolvaptan in two randomized, double-blind, placebo-controlled

multicenter trials (SALT-1 and SALT-2) in 448 patients with hyponatremia (mean

serum sodium 129 meq/L) caused by SIADH, heart failure, or cirrhosis [13].

Compared with placebo, tolvaptan significantly increased the serum sodium

concentration at day 4 (134 to 135 meq/L versus 130 meq/L) and day 30 (136 versus

131 meq/L). Among patients with a serum sodium below 130 meq/L at baseline,

tolvaptan was also associated with a statistically significant improvement in mental

status scores. However, the difference was usually not clinically significant and long-

term efficacy is uncertain since 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 [14]. The mean serum sodium

was maintained at more than 135 meq/L compared to 131 meq/L at baseline. The

responses were similar in SIADH and heart failure, 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).

Vasopressin receptor antagonists should not be used in hyponatremic patients who

are volume depleted in whom volume repletion with saline is the primary therapy.

(See 'True volume depletion' above.)

Limitations — There are two major potential adverse effects associated with oral V2

receptor antagonists:

• Increased thirst, which may limit the rise in serum sodium [13].

• Overly rapid correction of the hyponatremia, which 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 [13]. However, more recent

recommendations have suggested a maximum rate of correction of

hyponatremia of less than 10 meq/L, not ≤12 meq/L, in the first 24 hours.

Thus, it is almost certain that more than 1.8 percent of treated patients

exceeded the currently recommended rate of correction. Because of this risk,

hospitalization is required for the initiation or reinitiation of therapy. (See

'Avoid overly rapid correction' below.)

Another limiting factor is the prohibitive cost of tolvaptan, which is as high as $300

per tablet in some areas.

ESTIMATION OF THE SODIUM DEFICIT — Patients with true volume depletion and

some with SIADH require saline administration to raise the serum sodium. Isotonic

saline is typically sufficient in true volume depletion but ineffective in SIADH where, if

saline is given, a hypertonic solution is typically required. The mechanisms

responsible for these conclusions are described above. (See 'Sodium chloride

administration' above.)

Formulas are available to estimate both the sodium deficit and the direct effect of a

given fluid (eg, hypertonic saline) on the serum concentration (the Adrogue-Madias

formula) [4]:

• Sodium deficit = TBW x (desired serum Na - actual serum Na)

Although sodium itself is restricted to the extracellular fluid, changes in the serum

sodium concentration reflect changes in osmolality and are distributed through the

total body water. TBW is estimated as lean body weight times 0.5 for women and 0.6

for men.

• Change in serum Na = (Infusate minus serum Na) / (TBW + 1)

However, these formulas have a number of limitations and often do not accurately

predict the magnitude of change in serum sodium [15]. These limitations are

discussed in detail elsewhere. (See "Estimation of the sodium deficit in patients with

hyponatremia".)

The main use of the sodium deficit formula is to estimate the initial rate of sodium

administration. Serial measurements of the serum sodium concentration are required

to assess the impact of therapy, beginning at two to three hours and then every

three to four hours while active treatment is being given.

Use of the sodium deficit formula to determine initial therapy can be illustrated by

the following example. A nonedematous, mildly symptomatic woman who weighs 60

kg (approximately 50 percent of which is water) has a serum sodium concentration of

116 meq/L. The goal is to raise the serum sodium concentration by 8 meq/L in the

first 24 hours. (See 'Rate of correction' below.)

The sodium deficit (in meq) for initial therapy can be estimated from the above

formula:

  Sodium deficit  =   TBW (0.5  x  60 L)  x  desired change in serum sodium (124 -

116)  =   240 meq

The 240 meq of sodium can be given as 480 mL of hypertonic (3 percent) saline,

which contains approximately 500 meq of sodium per liter, or 1 meq of sodium per 2

mL. This volume of hypertonic saline can be given at an initial rate of 20 mL/h, which

would be expected to raise the serum sodium concentration at close to the desired

rate of 8 meq/L during the first 24 hours which, as noted above, should be confirmed

by serial measurements of the serum sodium.

RATE OF CORRECTION

General issues — There are several general issues that must be addressed before

discussing specific therapies:

• Is the hyponatremia acute or chronic?

• Is the patient symptomatic or asymptomatic?

• What is the optimal rate of correction?

Acute versus chronic hyponatremia — Patients with acute hyponatremia are

more likely to develop neurologic symptoms resulting from cerebral edema induced

by water movement into the brain. However, the brain has a protective response that

reduces the degree of cerebral edema; this response begins on the first day and is

complete within several days. The net effect of this adaptation is that the clinical

manifestations of hyponatremia are reduced, with the potential disadvantage of

increasing the susceptibility to osmotic demyelination with overly rapid correction of

the hyponatremia [16,17]. (See 'Symptomatic versus asymptomatic

hyponatremia' below and "Manifestations of hyponatremia and hypernatremia",

section on 'Osmolytes and cerebral adaptation to hyponatremia'.)

Some have suggested that hyponatremia developing over two or more days should

be considered "chronic." In practice, however, the duration of hyponatremia is often

unknown, and patients with chronic hyponatremia may develop acute reductions in

the serum sodium concentration. Thus, while the terms "acute" and "chronic" may be

helpful conceptually, the clinical approach to the patient should be primarily

determined by the severity of symptoms and the cause of the hyponatremia.

Symptomatic versus asymptomatic hyponatremia — Symptoms are most likely

to occur with an acute (within 24 to 48 hours) and marked reduction in the serum

sodium concentration. Without time for the brain adaptation noted in the previous

section, affected patients can develop severe neurologic manifestations, including

seizures, impaired mental status or coma, and death (figure 1). These patients are

typically treated initially with hypertonic saline. (See 'Severe symptoms' below.)

Because of the brain adaptation that occurs over a few days, some patients with a

serum sodium concentration below 120 meq/L have less severe neurologic symptoms

(eg, fatigue, nausea, dizziness, gait disturbances, forgetfulness, confusion, lethargy,

and muscle cramps) [18-21]. These findings are not usually associated with

impending herniation (as with acute severe hyponatremia) and do not mandate the

urgent therapy recommended for patients with severe symptoms. (See

"Manifestations of hyponatremia and hypernatremia" and 'Mild to moderate

symptoms' below.)

In contrast to symptomatic patients, patients with chronic moderate hyponatremia

(serum sodium concentration 120 to 130 meq/L) have generally been considered to

be at low risk for neurologic symptoms because of the less marked reduction in

serum sodium concentration and the protective cerebral adaptation. However, some

"asymptomatic" patients with moderate hyponatremia have subtle neurologic

symptoms that may improve following elevation of the serum sodium concentration.

(See 'Asymptomatic hyponatremia' below.)

Avoid overly rapid correction — Overly rapid correction of severe hyponatremia

(serum sodium concentration usually less than 110 to 115 meq/L) can lead to a

severe and usually irreversible neurologic disorder called the osmotic demyelination

syndrome (also called central pontine myelinolysis, although demyelination may be

more diffuse and does not necessarily involve the pons). Premenopausal women

appear to be at greatest risk (figure 1) [22]. (See "Osmotic demyelination syndrome

and overly rapid correction of hyponatremia" and "Manifestations of hyponatremia

and hypernatremia", section on 'Susceptibility of premenopausal women'.)

One group that is probably not at risk for this complication is patients with

hyperacute hyponatremia that developed over a few hours due to a marked increase

in water intake (as can occur in marathon runners, psychotic patients, and users of

ecstasy). These patients have not had time for the brain adaptations that reduce the

severity of brain swelling but also increase the risk of harm from rapid correction of

the hyponatremia. (See 'Acute versus chronic hyponatremia' above.)

Overly rapid correction of severe and more chronic hyponatremia can result from the

too rapid or excessive administration of hypertonic saline or rapid correction of the

underlying disease, such as the administration of saline to patients with true volume

depletion and glucocorticoid therapy in adrenal insufficiency. (See 'Treat the

underlying disease' above.)

Osmotic demyelination typically occurs in patients in whom the serum sodium

concentration increases more than 10 to 12 meq/L in the first 24 hours or more than

18 meq/L in the first 48 hours. However, some patients with severe hyponatremia

develop neurologic symptoms from osmotic demyelination when the serum sodium is

increased by 10 to 12 meq/L in the first day [19,23].

Thus, the goals of therapy are to raise the serum sodium concentration by less than

10 meq/L in the first 24 hours and less than 18 meq/L in the first 48 hours

[1,3,20,24]. Studies in experimental animals suggest that the rate of correction over

the first 24 hours is more important than the maximum rate in any given hour or

several hour period [21,25].

Issues related to the osmotic demyelination syndrome, including prevention and

treatment with possible relowering of the serum sodium in patients who correct too

rapidly, are discussed in detail elsewhere. (See "Osmotic demyelination syndrome

and overly rapid correction of hyponatremia", section on 'Prevention and treatment

of overly rapid correction'.)

CHOICE OF THERAPY

General principles — As described above, there are a variety of modalities used in

the treatment of hyponatremia. The choice among them varies with the severity and

underlying cause of the hyponatremia. (See 'Methods of raising the serum

sodium' above.)

With true volume depletion, the administration of saline can correct the hypovolemia,

thereby removing the stimulus to the release of antidiuretic hormone (ADH) and

allowing the excess water to be excreted in the urine. Correction of the underlying

disorder can also be achieved with certain causes of SIADH (eg, glucocorticoids for

adrenal insufficiency or the cessation of offending drugs). (See 'Treat the underlying

disease' above.)

The following discussion will provide an overview of the approach to therapy

according to the presence or absence of symptoms that are attributable to the

hyponatremia. The treatment of hyponatremia due to specific causes is discussed in

detail separately:

• For SIADH, in which the mainstay of chronic therapy is fluid restriction with, if

necessary, the addition of oral salt tablets and, if the urine osmolality is more

than twice the plasma osmolality and the serum sodium concentration is

below goal, a loop diuretic (see "Treatment of hyponatremia: Syndrome of

inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat").

• For heart failure and cirrhosis, in which serum sodium concentrations below 130

meq/L are typically associated with close to end-stage disease (see

"Hyponatremia in patients with heart failure" and "Hyponatremia in patients

with cirrhosis").

• For transurethral resection or hysteroscopy (see "Hyponatremia following

transurethral resection or hysteroscopy")

Severe symptoms — Hypertonic saline is warranted in patients with severe and

often acute hyponatremia (serum sodium usually below 120 meq/L) who present with

seizures or other severe neurologic abnormalities or with symptomatic hyponatremia

in patients with intracerebral diseases that have been associated with brain

herniation [19,20,22,23,26,27].

Severe symptoms of hyponatremia are most likely to occur in the following settings:

• Exercise-associated hyponatremia, as in marathon runners (see "Exercise-

associated hyponatremia", section on 'Use of hypertonic saline').

• Hyponatremia associated with the use of ecstasy (see "MDMA (ecstasy)

intoxication", section on 'Hyponatremia' and "MDMA (ecstasy) intoxication",

section on 'Seizures')

• Self-induced water intoxication in primary polydipsia (see "Polydipsia and

hyponatremia in patients with mental illness").

• Postoperative hyponatremia due to SIADH in patients with known intracerebral

pathology (eg, meningitis, stroke, or brain tumor) and in premenopausal

women, who are at markedly increased risk of neurologic symptoms

compared to postmenopausal women and men. (See "Treatment of

hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion

(SIADH) and reset osmostat" and "Manifestations of hyponatremia and

hypernatremia", section on 'Susceptibility of premenopausal women'.)

The primary problem in such patients who have seizures or other severe neurologic

abnormalities is cerebral edema, and the risk of delayed therapy (eg, brain

herniation) is greater than the potential risk of overly rapid correction.

Based upon broad clinical experience, the administration of hypertonic saline is the

only rapid way to raise the serum sodium concentration and improve neurologic

manifestations in patients with severe symptomatic hyponatremia [28]. Hypertonic

saline may also be given to selected symptomatic patients who develop

hyponatremia and hypoosmolality during transurethral resection of the prostate or

bladder or hysteroscopy. In this setting, the serum osmolality is not reduced to the

same degree as the serum sodium due to the accumulation of glycine, sorbitol, or

mannitol irrigation fluids. (See "Hyponatremia following transurethral resection or

hysteroscopy", section on 'Role of hypertonic saline'.)

One hypertonic saline regimen that we have used was initially described in

hyponatremic athletes participating in endurance events such as marathon races. It

consists of 100 mL of 3 percent saline given as an intravenous bolus, which should

acutely raise the serum sodium concentration by 2 to 3 meq/L, thereby reducing the

degree of cerebral edema; if neurologic symptoms persist or worsen, a 100 mL bolus

of 3 percent saline can be repeated one or two more times at 10 minute intervals

[1,29,30]. The rationale for this approach is that, in patients with symptomatic

hyponatremia, rapid increases in serum sodium of approximately 4 to 6 meq/L can

reverse severe symptoms such as seizures [1,4,31-33]. (See "Exercise-associated

hyponatremia", section on 'Use of hypertonic saline'.)

The usual goals for the overall rate of correction are to raise the serum sodium less

than 10 meq/L in the first 24 hours and less than 18 meq/L in the first 48 hours.

Faster rates of correction may lead to osmotic demyelination, with premenopausal

women being at greatest risk (figure 1). (See 'Acute versus chronic

hyponatremia' above.)

The treatment of symptomatic hyponatremia due to SIADH is complicated by the fact

that, in patients with a highly concentrated urine (eg, greater than 500 to 600

mosmol/kg), the initial elevation in serum sodium induced by hypertonic saline will

fall back toward baseline as the administered sodium is excreted in the urine. Why

this occurs and recommendations for further therapy are discussed elsewhere. (See

'SIADH' above and "Treatment of hyponatremia: Syndrome of inappropriate

antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Intravenous

saline'.)

Hyponatremia developing in marathon runners, ecstasy users, or patients with

primary polydipsia is associated with marked increases in fluid intake and, with

exercise and ecstasy use, frequent failure to completely suppress ADH release. The

net effect is acute hyponatremia that can develop over a period of several hours.

Avoidance of overly rapid correction (≥10 meq/L in the first 24 hours) is often difficult

in patients with primary polydipsia. These patients tend to autocorrect since ADH is

physiologically suppressed, permitting rapid excretion of large volumes of free water.

Autocorrection can also occur in patients with exercise-associated hyponatremia or

ecstasy use. Fortunately, the acute onset of hyponatremia in these disorders is

associated with a low risk of osmotic demyelination due to overly rapid correction.

(See 'Avoid overly rapid correction' above.)

Mild to moderate symptoms — Less severe neurologic symptoms that are

attributable to hyponatremia (eg, dizziness, gait disturbances, forgetfulness,

confusion, and lethargy) can be seen in patients with a serum sodium concentration

below 120 meq/L that develops over more than 48 hours, in patients with a lesser

degree of hyponatremia that develops over less than 48 hours, and in patients with

chronic moderate hyponatremia (serum sodium 120 to 129 meq/L).

The following discussion primarily applies to hyponatremia in patients with SIADH or

volume depletion. Although mild to moderate symptoms due to hyponatremia can

also occur in patients with heart failure or cirrhosis, serum sodium concentrations

below 130 meq/L are typically associated with close to end-stage disease. (See

"Hyponatremia in patients with heart failure" and "Hyponatremia in patients with

cirrhosis".)

Moderate symptoms — For the purposes of this discussion, moderate symptoms

are defined as confusion and/or lethargy. Some of these patients, particularly those

with SIADH, may benefit from hypertonic saline, but do not require the aggressive

approach suggested in the preceding section for those with severe neurologic

symptoms. (See 'Severe symptoms' above.)

In patients with SIADH and moderate symptoms, initial hypertonic saline therapy to

raise the serum sodium at rates up to 1 meq/L per hour may be justified in the first

three to four hours. This can generally be achieved by administering hypertonic (3

percent) saline at a rate of 1 mL/kg lean body weight per hour. Such calculations are

only estimates and the serum sodium should be measured at two to three hours. The

total elevation in serum sodium in the first 24 hours should be less than 10 meq/L.

(See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone

secretion (SIADH) and reset osmostat", section on 'Mild to moderate symptoms'.)

The choice of initial therapy in patients with moderate symptoms of hyponatremia

who are volume depleted is more difficult. Isotonic saline will not rapidly raise the

serum sodium until near euvolemia is attained and ADH secretion is suppressed.

Hypertonic saline will raise the serum sodium immediately but, in some patients

(particularly the elderly), the neurologic manifestations may not be clearly

attributable to the hyponatremia. The optimal therapy in such patients must be made

on an individual basis. Isotonic saline should be used in the vast majority of patients.

Although hyponatremia is initially corrected slowly with isotonic saline in

hypovolemic patients, ADH release will be appropriately suppressed once near

euvolemia is restored. This will lead to a marked water diuresis and patients with an

initial serum sodium below 120 meq/L might be at risk for overly rapid correction and

possible osmotic demyelination. In such patients, desmopressin with or without

dextrose in water may be considered to either prevent or treat overly rapidly

correction. (See "Osmotic demyelination syndrome and overly rapid correction of

hyponatremia", section on 'Prevention and treatment of overly rapid correction'.)

Mild symptoms — Patients with SIADH or hypovolemia who have only mild

symptoms (eg, dizziness, forgetfulness, gait disturbance) should be treated with less

aggressive therapy, such as fluid restriction and oral salt tablets in SIADH or, with

hypovolemia, isotonic saline and treatment of the cause of fluid loss.

Asymptomatic hyponatremia — Patients who have asymptomatic hyponatremia

should be corrected slowly, since rapid correction is not necessary and may be

harmful. (See 'Avoid overly rapid correction' above.)

Treatment varies with the underlying disease. Among patients with SIADH, isotonic

saline may, via a mechanism described above, lower the serum sodium when the

urine osmolality is well above 300 mosmol/kg. Thus, if fluid restriction is not

sufficient, subsequent therapy includes salt tablets and, if necessary, a loop diuretic

if the urine osmolality is more than twice that of the plasma. (See 'SIADH' above and

"Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone

secretion (SIADH) and reset osmostat", section on 'Intravenous saline'.)

Among patients who are hypovolemic, either intravenous isotonic saline or oral salt

tablets may be effective in combination with treatment of the cause of hypovolemia.

The treatment of asymptomatic hyponatremia in patients with heart failure and

cirrhosis is discussed separately. (See "Hyponatremia in patients with heart

failure" and "Hyponatremia in patients with cirrhosis".)

Necessity for therapy — Patients with chronic moderate hyponatremia (serum

sodium 120 to 129 meq/L) are typically asymptomatic on routine history. Such

patients have often been treated only with fluid restriction if the underlying disease

(SIADH, heart failure, cirrhosis) cannot be corrected.

However, some of these patients have subtle neurologic symptoms that can be

improved by raising the serum sodium concentration. As an example, the SALT trials

described above evaluated the effect of the vasopressin receptor antagonist

tolvaptan compared to placebo in patients with chronic hyponatremia due to SIADH,

heart failure, or cirrhosis [13]. None of the patients had clinically apparent neurologic

symptoms from hyponatremia and almost all had a serum sodium concentration of

120 meq/L or higher.

Raising the serum sodium with tolvaptan resulted in statistically significant

improvement on the Mental Component of the Medical Outcomes Study Short-Form

General Health Survey at one month, a benefit that was significant only in patients

with a serum sodium concentration between 120 and 129 meq/L and was not seen in

the placebo group. However, the benefit was usually not clinically significant and

long-term efficacy is uncertain since the duration of follow-up was only 30 days. (See

'Vasopressin receptor antagonists' above.)

In addition to subtle impairments in mentation, an increased incidence of falls due to

impairments in gait and attention have been described in elderly patients with a

serum sodium between 120 and 129 meq/L; these manifestations may be improved

by raising the serum sodium [34]. (See "Manifestations of hyponatremia and

hypernatremia", section on 'Manifestations in apparently asymptomatic patients'.)

These observations suggest that some and perhaps many apparently asymptomatic

patients with moderate chronic hyponatremia (serum sodium 120 to 129 meq/L)

have subtle neurologic manifestations and that aiming for a goal serum sodium of

130 meq/L or higher might be beneficial. Such an approach would apply only to

patients with SIADH. (See "Treatment of hyponatremia: Syndrome of inappropriate

antidiuretic hormone secretion (SIADH) and reset osmostat", section on

'Asymptomatic hyponatremia'.)

Little benefit would be provided in patients with hyponatremia due to heart failure or

cirrhosis in whom a serum sodium concentration persistently below 130 meq/L is a

marker of end-stage disease and a poor prognosis unless transplantation or some

equivalent intervention is performed. (See "Hyponatremia in patients with heart

failure" and "Hyponatremia in patients with cirrhosis".)

SUMMARY AND RECOMMENDATIONS

• Hyponatremia represents a relative excess of water in relation to sodium. It can be

induced by an increase in water intake (primary polydipsia) or impaired water

excretion. Impaired water excretion results from advanced renal failure or

persistent release of antidiuretic hormone (ADH). ADH may be induced by

effective volume depletion, the syndrome of inappropriate ADH secretion

(SIADH), thiazide diuretics, adrenal insufficiency, or hypothyroidism. (See

'Introduction' above.)

• The serum sodium concentration can be raised in hyponatremic patients by

treating the underlying disease, restricting water intake, giving oral or

intravenous sodium chloride, or by giving a vasopressin receptor antagonist.

The choice of therapy is governed by the cause and severity of the

hyponatremia and the presence or absence of neurologic symptoms. (See

'Methods of raising the serum sodium' above.)

• Fluid restriction to below the level of urine output is the primary therapy for

hyponatremia in edematous states (such as heart failure and cirrhosis), the

syndrome of inappropriate antidiuretic hormone secretion (SIADH), and

advanced renal failure. In general, fluid intake should be less than 800

mL/day. (See 'Fluid restriction' above.)

• Sodium chloride, usually as isotonic saline or oral salt tablets, is given to patients

with true volume depletion. The administered sodium and water initially

corrects the hyponatremia (by approximately 1 meq/L for every liter of

isotonic saline infused) and then, once volume repletion is attained, by

removing the stimulus to ADH release and allowing the excess water to be

excreted. Salt therapy is generally contraindicated in edematous patients.

(See 'Sodium chloride administration' above.)

• Administration of hypertonic saline is limited to patients with symptomatic or

severe hyponatremia. The rate of correction of hyponatremia is important,

since overly rapid correction of severe hyponatremia can lead to the osmotic

demyelination syndrome. To help prevent osmotic demyelination, we

recommend that among all patients with hyponatremia, the goal increase in

serum sodium concentration is by less than 10 meq/L in the first 24 hours and

less than 18 meq/L in the first 48 hours (Grade 1B). Serial measurements of

the serum sodium concentration are required to assess the impact of therapy,

beginning at two to three hours and then every three to four hours while

active treatment is being given. (See 'Avoid overly rapid correction' above.)

The choice of initial therapy in patients with hyponatremia varies with the severity

and cause of hyponatremia and the presence or absence of symptoms:

• Among patients with severe symptomatic hyponatremia who present with

seizures or other severe neurologic abnormalities or with symptomatic

hyponatremia in patients with intracerebral diseases, we recommend urgent

intervention with hypertonic saline rather than other therapies (Grade 1A).

An effective regimen is 100 mL of 3 percent saline given as an intravenous

bolus, which should raise the serum sodium concentration by approximately

1.5 meq/L in men and 2.0 meq/L in women, thereby reducing the degree of

cerebral edema. If neurologic symptoms persist or worsen, a 100 mL bolus of

3 percent saline can be repeated one or two more times at ten minute

intervals. (See 'Severe symptoms' above.)

• Less severe neurologic symptoms that are attributable to hyponatremia (eg,

dizziness, gait disturbances, forgetfulness, confusion, and lethargy) can be

seen in patients with a serum sodium concentration below 120 meq/L that

develops over more than 48 hours, in patients with a lesser degree of

hyponatremia that develops over less than 48 hours, and in patients with

chronic moderate hyponatremia (serum sodium 120 to 129 meq/L). The

approach varies with the severity of symptoms and the underlying cause of

the hyponatremia:

• Among patients with SIADH who have moderate symptoms such as confusion

and lethargy, we recommend the initial administration of hypertonic saline

therapy to raise the serum sodium (Grade 1B). The goal is to raise the serum

sodium 1 meq/L per hour for three to four hours. The serum sodium should be

measured at two to three hours and subsequent infusion rate should be

adjusted to achieve a rate of correction of less than 10 meq/L at 24 hours and

less than 18 meq/L at 48 hours. (See 'Moderate symptoms' above.)

• Among patients with moderate symptoms of hyponatremia who are volume

depleted, the vast majority of patients should be treated with isotonic saline.

Once most of the volume deficit has been repaired, ADH release will be

appropriately suppressed, leading to the potential for overly rapid correction.

(See 'Moderate symptoms' above.)

• Patients with hypovolemia or SIADH who have only mild symptoms (eg,

dizziness, forgetfulness, gait disturbance) should be treated with less

aggressive therapy, such as isotonic saline in hypovolemia and, in SIADH, fluid

restriction with, if necessary, the addition of oral salt tablets and, if the urine

osmolality is more than twice the plasma osmolality and the serum sodium

concentration is below goal, a loop diuretic. (See 'Mild symptoms' above.)

• Among asymptomatic patients with moderate hyponatremia, the treatment

varies with the underlying cause of the hyponatremia.

• For asymptomatic patients with moderate chronic hyponatremia (serum

sodium 120 to 129 meq/L) resulting from SIADH, we suggest initiating

treatment with fluid restriction (Grade 2B). (See 'Necessity for

therapy' above.) Most patients will respond to fluid restriction of 800 mL/day.

We aim for a goal serum sodium of 130 meq/L or higher. Among patients in

whom fluid restriction is not sufficient to achieve the desired goal, subsequent

therapy includes salt tablets and, if necessary, a loop diuretic if the urine

osmolality is more than twice that of the plasma.

• Among asymptomatic patients who are hypovolemic, either intravenous

isotonic saline or oral salt tablets may be effective in combination with

treatment of the cause of hypovolemia. (See 'Asymptomatic

hyponatremia' above.)

• The treatment of asymptomatic hyponatremia in patients with heart failure

and cirrhosis is discussed separately. (See "Hyponatremia in patients with

heart failure" and "Hyponatremia in patients with cirrhosis".)

• Vasopressin receptor antagonists are an alternative or possible addition to

fluid restriction or sodium chloride administration in patients with

hyponatremia. Only tolvaptan (oral) and conivaptan (intravenous) are

currently available in the United States. Both drugs are approved for the

management of patients with euvolemic hyponatremia, mostly due to SIADH.

Tolvaptan is also approved for use in patients with heart failure or cirrhosis.

There are important limitations to the use of oral tolvaptan and

conivaptan should not be used in patients with cirrhosis. (See 'Vasopressin

receptor antagonists' above.)

• Vasopressin receptor antagonists should not be used in hyponatremic patients

who are volume depleted in whom volume repletion is the primary therapy.

Use of UpToDate is subject to the Subscription and License Agreement.REFERENCES

1. Sterns, RH, Nigwekar, SU, Hix, JK. The treatment of hyponatremia. Semin Nephrol 2009; 29:282.

2. Rose, BD, Post, TW, Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York, 2001, p. 716-719.

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

4. Adrogué, HJ, Madias, NE. Hyponatremia. N Engl J Med 2000; 342:1581. 5. Greenberg, A, Verbalis, JG. Vasopressin receptor antagonists. Kidney Int 2006;

69:2124.6. Part 10.1: Life-Threatening Electrolyte Abnormalities. Circulation 2005;

112:IV121.7. Oh, MS, Uribarri, J, Barrido, D, et al. Danger of central pontine myelinolysis in

hypotonic dehydration and recommendation for treatment. Am J Med Sci 1989; 298:41.

8. Kamel, KS, Bear, RA. Treatment of hyponatremia: a quantitative analysis. Am J Kidney Dis 1993; 21:439.

9. Edelman, IS, Leibman, J. Anatomy of body water and electrolytes. Am J Med 1959; 27:256.

10. Steele, A, Gowrishankar, M, Abrahamson, S, et al. Postoperative hyponatremia despite near-isotonic saline infusion: a phenomenon of desalination. Ann Intern Med 1997; 126:20.

11. Rose, BD. New approach to disturbances in the plasma sodium concentration. Am J Med 1986; 81:1033.

12. Fichman, MP, Vorherr, H, Kleeman, CR, Telfer, N. Diuretic-induced hyponatremia. Ann Intern Med 1971; 75:853.

13. Schrier, RW, Gross, P, Gheorghiade, M, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006; 355:2099.

14. Berl, T, Quittnat-Pelletier, F, Verbalis, JG, et al. Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol 2010; 21:705.

15. Mohmand, HK, Issa, D, Ahmad, Z, et al. Hypertonic saline for hyponatremia: risk of inadvertent overcorrection. Clin J Am Soc Nephrol 2007; 2:1110.

16. Mount, DB. The brain in hyponatremia: both culprit and victim. Semin Nephrol 2009; 29:196.

17. Sterns, RH, Silver, SM. Brain volume regulation in response to hypo-osmolality and its correction. Am J Med 2006; 119:S12.

18. Chow, KM, Kwan, BC, Szeto, CC. Clinical studies of thiazide-induced hyponatremia. J Natl Med Assoc 2004; 96:1305.

19. Sterns, RH. Severe symptomatic hyponatremia: treatment and outcome. A study of 64 cases. Ann Intern Med 1987; 107:656.

20. Sterns, RH, Cappuccio, JD, Silver, SM, Cohen, EP. Neurologic sequelae after treatment of severe hyponatremia: a multicenter perspective. J Am Soc Nephrol 1994; 4:1522.

21. Soupart, A, Penninckx, R, Stenuit, A, et al. Treatment of chronic hyponatremia in rats by intravenous saline: comparison of rate versus magnitude of correction. Kidney Int 1992; 41:1662.

22. Ayus, JC, Wheeler, JM, Arieff, AI. Postoperative hyponatremic encephalopathy in menstruant women. Ann Intern Med 1992; 117:891.

23. Karp, BI, Laureno, R. Pontine and extrapontine myelinolysis: a neurologic disorder following rapid correction of hyponatremia. Medicine (Baltimore) 1993; 72:359.

24. Laureno, R, Karp, BI. Myelinolysis after correction of hyponatremia. Ann Intern Med 1997; 126:57.

25. Soupart, A, Penninckx, R, Crenier, L, et al. Prevention of brain demyelination in rats after excessive correction of chronic hyponatremia by serum sodium lowering. Kidney Int 1994; 45:193.

26. Moritz, ML, Ayus, JC. The pathophysiology and treatment of hyponatraemic encephalopathy: an update. Nephrol Dial Transplant 2003; 18:2486.

27. Berl, T. Treating hyponatremia: damned if we do and damned if we don't. Kidney Int 1990; 37:1006.

28. Arieff, AI, Ayus, JC. Endometrial ablation complicated by fatal hyponatremic encephalopathy. JAMA 1993; 270:1230.

29. Ayus, JC, Arieff, A, Moritz, ML. Hyponatremia in marathon runners. N Engl J Med 2005; 353:427.

30. Hew-Butler, T, Ayus, JC, Kipps, C, et al. Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007. Clin J Sport Med 2008; 18:111.

31. Sarnaik, AP, Meert, K, Hackbarth, R, et al. Management of hyponatremic seizures in children with hypertonic saline: a safe and effective strategy. Crit Care Med 1991; 19:758.

32. Worthley, LI, Thomas, PD. Treatment of hyponatraemic seizures with intravenous 29.2% saline. Br Med J (Clin Res Ed) 1986; 292:168.

33. Siegel, AJ, Verbalis, JG, Clement, S, et al. Hyponatremia in marathon runners due to inappropriate arginine vasopressin secretion. Am J Med 2007; 120:461.e11.

34. Renneboog, B, Musch, W, Vandemergel, X, et al. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med 2006; 119:71.e1.

© 2011 UpToDate, Inc. All rights reserved. | Subscription and License Agreement |Support Tag: [ecapp1003p.utd.com-72.159.51.130-0AEC8D4CF1-4428]Licensed to: Lincoln Mem Univ

Treatment of hypernatremiaAuthorBurton D Rose, MDSection EditorRichard H Sterns, MDDeputy EditorTheodore W Post, MDLast literature review version 18.3: September 2010 | This topic last updated: May 24, 2010 (More)

INTRODUCTION — Hypernatremia is most often due to unreplaced water losses

from the gastrointestinal or respiratory tracts or in the urine. Two questions must be

addressed when this water deficit is corrected, since lowering the serum sodium

concentration too rapidly can be more dangerous than persistent hypernatremia:

• How can the water deficit be estimated?

• At what rate can the serum sodium concentration safely be normalized?

The following discussion primarily applies to the majority of patients in whom

hypernatremia is induced by water loss. Additional factors must be considered in

patients with diabetes insipidus (in whom the serum sodium concentration is usually

in the high normal range and the primary aim of therapy is to decrease the urine

output), hypothalamic lesions impairing the thirst mechanism, or primary sodium

overload. (See "Treatment of central diabetes insipidus" and "Treatment of

nephrogenic diabetes insipidus".)

The causes and diagnosis of hypernatremia are discussed separately. (See "Causes

of hypernatremia" and "Evaluation of the patient with hypernatremia".)

ESTIMATION OF THE WATER DEFICIT — The water deficit in the hypernatremic

patient can be estimated from the following formula, which is derived below (see

'Derivation of the water deficit formula' below) [1,2].

Free water deficit = TBW [(SNa/140) - 1]

(See "Treatment of hypernatremia", section on 'Derivation of

the water deficit formula'.)

serum [Na+]  Water

deficit   =   CBW  x   (—————————    -    1)                                                   140

CBW refers to estimated current body water. The total body water is normally about

60 and 50 percent of lean body weight in younger men and women, respectively, and

is somewhat lower in the elderly (about 50 and 45 percent in men and women,

respectively) [2].

However, it is probably reasonable to use values about 10 percent lower (50 and 40

percent) in hypernatremic patients who are water-depleted. Thus, in a 60 kg woman

with a serum sodium concentration of 168 meq/L, total body water is about 40

percent of body weight and the water deficit can be approximated from:

Water deficit   =   0.4  x  60  ([168/140]  -  1)

=   4.8 liters

This formula estimates the amount of positive water balance required to return the

serum sodium concentration to 140 meq/L. When calculating the amount of free

water to give (either intravenously, as dextrose in water, or orally if the patient is

able to drink), insensible losses and some part of urine and gastrointestinal losses

must be added to the calculation. Given all of these estimates, the water deficit

formula should only be used as a guide to initial therapy. Serial measurements of the

serum sodium concentration are required to assess the true effect of water repletion.

(See 'Treatment of the patient' below.)

The water deficit formula does not include any additional isosmotic fluid deficit that is

frequently present when both sodium and water have been lost, as occurs with an

osmotic diuresis or with diarrhea. In addition, hypernatremia itself may cause mild

urinary sodium-wasting in hypovolemic subjects, largely due to reduced aldosterone

release [3]. Both hypernatremia itself and concurrent hypokalemia (due to

gastrointestinal or renal losses) may act directly on the adrenal gland, and it has

been suggested that the loss of sodium might be appropriate from an osmotic

viewpoint by tending to reduce the serum sodium concentration [3].

RATE OF CORRECTION — Overly rapid correction is potentially dangerous in

hypernatremia as it is in hyponatremia [4]. (See "Osmotic demyelination syndrome

and overly rapid correction of hyponatremia".)

The risk of overly rapid correction of hypernatremia has primarily been described in

children with a baseline serum sodium above 150 meq/L and usually above 155

meq/L. In a series of nine infants who developed seizures following therapy of

hypernatremia, the mean serum sodium was 163 meq/L (range 151 to 180 meq/L)

[5].

There are no definitive clinical trials, but data in children (particularly infants)

suggest that the maximum safe rate at which the serum sodium concentration

should be lowered in patients with hypernatremia is ≤0.5 meq/L per hour and no

more than by 12 meq/L per day [1,5,6]. In the above report, for example, the rate of

reduction in serum sodium was 1.0 meq/L per hour in the nine infants who developed

seizures compared to ≤0.6 meq/L per hour in 31 infants who did not develop

seizures. We suggest a maximum reduction of 10 meq/L per day.

The following mechanism has been proposed to explain the adverse effect of overly

rapid correction of hypernatremia. Hypernatremia initially causes fluid movement out

of the brain and cerebral contraction that is primarily responsible for the associated

symptoms. Within one to three days, however, brain volume is largely restored due

both to water movement from the cerebrospinal fluid into the brain (thereby

increasing the interstitial volume) and to the uptake of solutes by the cells (thereby

pulling water into the cells and restoring the cell volume) [1,4].

Rapidly lowering the serum sodium concentration once this adaptation has occurred

causes osmotic water movement into the brain, increasing brain size above normal.

This cerebral edema can then lead to an encephalopathy characterized by seizures,

permanent neurologic damage, or death [7]. (See "Manifestations of hyponatremia

and hypernatremia".)

TREATMENT OF THE PATIENT — The initiation of therapy in patients with

hypernatremia begins with estimation of the water deficit, using the formula

described above. This formula is based upon an estimate of the total body water,

which cannot be measured directly. Thus, the formula, which permits the following

calculations, only provides a guide to initial therapy. Given the potential risks of

overly rapid correction, the accuracy of the water deficit calculation for the individual

patient must be confirmed by serial measurements of the serum concentration at two

to three hours initially and then at four hour intervals. (See 'Estimation of the water

deficit' above.)

The 60 kg woman with a serum sodium concentration of 168 meq/L described above

had an estimated water deficit of 4.8 L. The 28 meq/L rise in the serum sodium

concentration should be corrected over a minimum of 67 h (approximately 10 meq/L

per day), which involves the administration of 4.8 L of free water (usually

intravenously, as dextrose in water) at a rate of approximately 70 mL/h.

The water deficit of 4.8 L estimates the positive water balance that must be

achieved. Thus, in addition to replacing the water losses, ongoing free water losses

must also be replaced, such as insensible losses (about 30 to 40 mL/h) and any

continued dilute urinary or gastrointestinal losses. Descriptions of sources of water

intake and loss are discussed elsewhere. (See 'Estimation of the water deficit' above

and "Maintenance and replacement fluid therapy in adults", section on 'Water

balance'.)

"Dilute" in this context refers to the sodium plus potassium concentration in the fluid

lost that is lower than that in the serum. Simply comparing osmolalities is not

sufficient. Both urine and intestinal fluids contain urea and other nonelectrolyte

solutes that contribute to the total osmolality but do not contribute to regulation of

the serum sodium concentration [8]. Thus, the excretion of 100 mL/h of urine with a

sodium plus potassium concentration half that of the serum is equivalent to losing 50

mL/h of free water, regardless of the urine osmolality.

Appropriate therapy in this patient with little ongoing urinary or gastrointestinal

losses requires the administration of about 110 mL of free water per hour (70 mL/h to

lower the serum sodium at the desired rate plus 40 mL/h to replace insensible

losses), with careful monitoring of the serum sodium concentration to confirm that

the hypernatremia is being corrected at the desired rate. This fluid is usually

administered intravenously as dextrose in water; if the patient is able to drink, oral

fluid resuscitation is an alternative.

Sodium and/or potassium can be added to the intravenous fluid as necessary to treat

concurrent volume depletion and/or hypokalemia (due, for example, to diarrhea).

However, the addition of solutes decreases the amount of free water that is being

given. If, for example, one-quarter isotonic saline is infused, then only three-quarters

of the solution is free water. As a result, 150 mL must be given per hour to provide

110 mL of free water. If potassium is also added, then even less free water is present

and a further adjustment to the rate must be made [1].

A potential complication of the administration of large volumes of dextrose-

containing intravenous fluids is the development of hyperglycemia, particularly in

patients who are stressed or have diabetes mellitus. Hyperglycemia can lead to an

osmotic diuresis, which increases electrolyte-free water losses and will therefore tend

to limit the reduction in serum sodium.

DERIVATION OF THE WATER DEFICIT FORMULA — The formula for estimating

the free water deficit in a hypernatremic patient can be derived from the following

considerations [1]. The quantity of osmoles in the body is equal to the osmolal space

[the total body water (TBW)] times the osmolality of the body fluids:

Total body osmoles   =   TBW  x  Posm

Since the Posm is primarily determined by two times the serum sodium concentration

(to account for the accompanying anions)

Total body osmoles   =   TBW  x  2  x  serum [Na+]

If hypernatremia results only from water loss, then

Current body osmoles   =   Normal body osmoles

or, if the normal serum sodium concentration is 140 meq/L,

Current body water (CBW)  x  serum [Na+]   =      Normal body water (NBW)  x  140

(The multiple 2 cancels out, since it is present on both sides of the above equation.).

If this equation is solved for NBW:

serum [Na+]  NBW   =   CBW  x   —————————                                     140

The water deficit can now be estimated from:

Water deficit   =   NBW  -  CBW

or by substituting from the equation for NBW:

serum [Na+]  Water

deficit   =   (CBW  x   —————————)   -    CBW                                                   14

0

serum

[Na+]                          =   CBW   x   (—————————    -    1)                                      

             140

Use of UpToDate is subject to the Subscription and License Agreement.REFERENCES

• Rose, BD, Post, TW, Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York, 2001, pp. 775-784.

• Adrogué, HJ, Madias, NE. Hypernatremia. N Engl J Med 2000; 342:1493. • Merrill, DC, Skelton, MM, Cowley AW, Jr. Humoral control of water and

electrolyte excretion during water restriction. Kidney Int 1986; 29:1152.• Lien, YH, Shapiro, JI, Chan, L. Effects of hypernatremia on organic brain

osmoles. J Clin Invest 1990; 85:1427.• Kahn, A, Brachet, E, Blum, D. Controlled fall in natremia and risk of seizures in

hypertonic dehydration. Intensive Care Med 1979; 5:27.• Blum, D, Brasseur, D, Kahn, A, Brachet, E. Safe oral rehydration of hypertonic

dehydration. J Pediatr Gastroenterol Nutr 1986; 5:232.• Pollock, AS, Arieff, AI. Abnormalities of cell volume regulation and their

functional consequences. Am J Physiol 1980; 239:F195.• Rose, BD. New approach to disturbances in the plasma sodium concentration.

Am J Med 1986; 81:1033.© 2011 UpToDate, Inc. All rights reserved. | Subscription and License Agreement |Support Tag: [ecapp1003p.utd.com-72.159.51.130-1A530B9388-4428]

Licensed to: Lincoln Mem Univ