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").
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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
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