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CME EDUCATIONAL OBJECTIVE: Readers will treat hyponatremia appropriately, taking care to avoid overcorrection
CREDIT
CHIRAG VAIDYA, MD WARREN HO, MD BENJAMIN J. FREDA, DO
Tufts University School of Medicine; Nephrologist/Hospitalist, Franklin Assistant Professor of Medicine, Tufts Uni-
Renal Division, Baystate Medical Square Hospital, Baltimore, MD versity School of Medicine, Renal Division,
Center, Springfield, MA Baystate Medical Center, Springfield, MA
Management of hyponatremia:
Providing treatment and avoiding harm
■ ■A BSTRACT
H yponatremia, defined as a serum sodium
concentration below 135 mmol/L, is one
of the most frequently encountered electro-
Hyponatremia, in its most severe form, requires urgent
infusion of hypertonic saline to correct cerebral edema. lyte disorders. In 1981, Flear et al1 reported
However, overly rapid correction of chronic hyponatremia that 15% of their hospitalized patients had
can cause osmotic demyelination syndrome. The authors plasma sodium concentrations lower than 134
mmol/L, the cutoff they were using at that
review the treatment of hyponatremia in order to provide
time.
clinicians with a sound approach in a variety of settings Hyponatremia is sometimes merely a lab-
in which severity, symptoms, and underlying disease oratory artifact or a result of improper blood
states influence therapy. Also discussed is the current collection. If real, it can be due to excessive
role of vasopressin antagonists in treatment. water intake or, most often, the inability of
the kidney to excrete water coupled with
■ ■KEY POINTS continued water intake. Patients with sig-
Some hyponatremic patients present with acute, life- nificant underlying cardiac, hepatic, or renal
dysfunction are at greatest risk of developing
threatening cerebral edema due to severe hyponatremia.
hyponatremia, secondary to the nonosmotic
In others, the hyponatremia may be chronic and less release of antidiuretic hormone (ADH).
severe, causing relatively few symptoms, but represent- Others at risk include postoperative patients
ing an important, independent marker of poor prognosis (especially menstruating women), older pa-
due to an underlying disease (eg, heart failure). tients on thiazide diuretics, patients with ma-
lignant or psychiatric illness, and endurance
Even patients with chronic, less severe hyponatremia athletes.
may have subtle symptoms of neurocognitive dysfunc- In this article, we review the treatment of
tion and a higher risk of bone fractures. acute and chronic hyponatremia, emphasizing
the importance of basing the therapy on the
severity of symptoms and taking care not to
Overly rapid correction of chronic hyponatremia or raise the serum sodium level too rapidly, which
undercorrection of acute symptomatic hyponatremia can can cause neurologic dysfunction.
lead to serious neurologic injury. Guidelines for managing hyponatremia2
are based mostly on retrospective studies and
Treatment strategies vary depending on the extracellular expert opinion, since few prospective stud-
fluid volume status and the cause of hyponatremia. ies have been done. Despite the paucity of
evidence-based recommendations, we will
attempt to incorporate findings from impor-
Vasopressin antagonists (“vaptans”), a new class of tant human and animal studies and consensus
aquaretic agents, specifically target the mechanism driv- guidelines from expert panels. We will focus
ing hyponatremia in some patients. initially on the critical diagnostic consider-
doi:10.3949/ccjm.77a.08051
ations necessary to initiate treatment.
Table 2
Risk factors for cerebral edema
Risk Factors Pathophysiologic Mechanism
symptoms of cerebral edema, including visual osmolality faster than the cells can recapture
changes, focal neurologic changes, encepha- the previously transported osmoles. In this
lopathy, respiratory depression, and seizures. situation, overly rapid correction can cause
Ultimately, brain herniation can occur. excessive loss of intracellular water, resulting
Patients need to be assessed quickly because in cell shrinkage and osmotic demyelination
those with serious neurologic signs or symp- syndrome. Osmotic demyelination usually
toms thought to be related to hyponatremia re- presents during treatment of hyponatremia
quire urgent treatment with hypertonic saline after an initial improvement in mental status,
to increase the serum sodium concentration, with worsening neurologic function and vari- Significant
regardless of the underlying volume status, the ous neurologic signs, including paresis and ul- fluid shifts and
cause of hyponatremia, or the time of onset. timately even death.6
In patients with acute-onset hyponatremia cerebral edema
Determine the duration of hyponatremia (ie, with onset within the past 48 hours), in occur only if the
One should try to ascertain when the hypo- whom the above cerebral adaptations have not
natremia started, as its duration is important had time to occur completely, rapid correction
extracellular
in determining the proper pace of correction. is unlikely to result in osmotic demyelination. fluid is
The brain begins to adapt to hyponatremia In view of the serious risk of osmotic demy- hypo-osmolar
within minutes, and the cerebral adaptation is elination, if the timing of development of hy-
maximal within 2 to 3 days (FIGURE 1).6 ponatremia cannot be determined, one should relative to the
At the onset of hyponatremia, water moves assume it is chronic (> 48 hours) and avoid intracellular
from the extracellular fluid into cells, pulled rapid overcorrection (see discussion below on
in by osmosis. The brain can decrease the net the rate of correction). fluid
amount of water entering into the neurons On the other hand, patients who have se-
(and thus regulate its volume) by increasing vere neurologic signs or symptoms initially
the flow of water from the interstitium into need their serum sodium increased urgently to
the cerebrospinal fluid via increased intersti- safer levels, regardless of the timing of onset
tial hydraulic pressure.7 (see below for suggested approach). Subsequent
Over the next several days, inorganic treatment of hyponatremia—after the serum
solutes (eg, potassium and sodium salts) and sodium level has been raised enough to reverse
various organic solutes are transported out of neurologic symptoms—will be influenced by
the cells. In patients in whom this process has the duration of the hyponatremia, with careful
had time to occur, treatment of hyponatre- avoidance of overly rapid correction, especially
mia with hypertonic fluids raises the plasma in patients with chronic hyponatremia.
CLEVELAND C L I N I C J O U R N A L O F M E D I C I N E V O L U M E 7 7 • N U M B E R 1 0 O C T O B E R 2 0 1 0 717
HYPONATREMIA
Adaptation. Over the ensuing few days, brain cells pump out
osmoles, first potassium and sodium salts and then organic osmoles,
establishing a new osmotic equilibrium across the plasma mem-
brane and reducing the edema as water moves out of the cells.
CCF
©2010
FIGURE 1 ADAPTED FROM information in Adrogué HJ, Madias NE. Hyponatremia. N Engl J Med 2000; 342:1581–1589
with falls compared with age-matched con- treat, but in general they are prescribed both
trols. Further analysis suggested these patients sodium and fluid restriction. Loop diuretics
had marked impairments in gait and atten- can be given to promote excretion of water
tion, which improved in some as the serum and sodium. Thiazide diuretics are avoided,
sodium increased. as they impair urinary dilution and worsen
Another recent study19 reported that mild hyponatremia. Attempts should be made to
hyponatremia (mean serum sodium concen- optimize the treatment of the underlying hy-
tration 132 mmol/L) was independently asso- pervolemic disorder (congestive heart failure,
ciated with the risk of fracture, even after ad- cirrhosis, advanced renal failure). Vasopres-
justment for known osteoporotic risk factors. sin receptor antagonists can also be used in
Even when there is no need for acute selected cases of hypervolemic or euvolemic
therapy to raise the serum sodium level, the hyponatremia (see discussion below).
clinician should scrutinize the medical regi-
men and available clinical data to rule out How to prescribe fluid restriction rationally
reversible causes of water excess. These may Ideally, patients should not ingest any more
include ongoing administration of hypotonic fluid than they can excrete in urine and insen-
fluids (eg, parenteral nutrition or dextrose 5% sible losses—otherwise, the serum sodium can
to “keep the vein open”) or of medications continue to decrease.
that cause inappropriate release of ADH (eg, Water excretion can be estimated from
selective serotonin reuptake inhibitors) or solute intake and urine osmolarity. In theory,
that impair water excretion (eg, nonsteroi- a 70-kg person with a typical daily solute in-
dal anti-inflammatory drugs). The clinician take of about 10 mOsm/kg and intact urinary
should also search for an underlying diagnosis dilution to a urine osmolarity of 50 mOsm/L
that predisposes to water retention, such as can excrete up to 14 L of urine (700 mOsm/50
hypothyroidism, adrenal insufficiency, conges- mOsm/L) per day. However, a patient with
tive heart failure, or hepatic or renal failure. the syndrome of inappropriate ADH secretion
If hyponatremia is due to endocrine disease, (SIADH) and a fixed urine osmolality of 700
Stop 3% saline correction of hypothyroidism or adrenal insuf- mOsm/kg would excrete a similar solute load
promptly once ficiency should result in water excretion and in only 1 L of urine. Thus, any fluid intake in
improvement in the serum sodium. excess of this volume could worsen hyponatre-
severe signs If the cause of the hyponatremia is not im- mia.
and symptoms mediately apparent, treatment can be started To excrete free water, urinary sodium plus
on the basis of assessment of the patient’s ex- urinary potassium must be less than the serum
of cerebral tracellular fluid volume status using clinical sodium concentration. In this regard, the nec-
edema resolve examination and supplementary laboratory essary degree of fluid restriction can also be
data such as the serum uric acid concentration estimated made on the basis of the patient’s
and urinary sodium concentration.3 TABLE 3 urinary electrolytes.22
outlines general treatment options for hypo-
osmolar hyponatremia according to extracel- Increased solute intake
lular fluid volume status. to augment water excretion
Of note, physical examination alone has In patients without hypervolemia, solute in-
poor sensitivity and specificity in assessing ex- take can be increased to augment water excre-
tracellular fluid volume status in patients with tion.22 This can be achieved with salt tablets
hyponatremia.20,21 This highlights the impor- or oral urea. Although urea can be effective, it
tance of spot measurements of urine sodium is not commonly used because it is not avail-
and serum uric acid and, when appropriate, able the United States and it has poor gastro-
isotonic intravenous saline challenge to de- intestinal tolerability. In patients whose nutri-
tect occult hypovolemia. tional intake is limited and who continue to
In general, patients with euvolemia are ingest fluids (such as, for example, an elderly
treated with fluid restriction, and patients patient subsisting on tea and toast) every ef-
with hypovolemia are given isotonic saline. fort should be made to increase solute intake
Patients with hypervolemia can be difficult to with high-protein foods or supplements.
722 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 77 • N U M B E R 1 0 O C T O B E R 2 0 1 0
VAIDYA AND COLLEAGUES
TABLE 6
Vasopressin antagonists for treating hyponatremia
Tolvaptan (Samsca) Lixivaptan (VPA-985) Satavaptan (Aquilda) Conivaptan (VAPRISOL)
with congestive heart failure, cirrhosis, and ing water excretion and a worsening of the
SIADH. Although tolvaptan has not been volume-depleted state.
shown to reduce rates of rehospitalization or Recent clinical trials have reported that
death in congestive heart failure, it improves patients often experience increased thirst
serum sodium, overall fluid balance, and con- while taking these agents. This highlights the
gestive symptoms.27 Tolvaptan has recently need to monitor serum sodium during treat-
been approved for the treatment of euvolemic ment.
and hypervolemic hyponatremia. These agents are expensive. Tolvaptan
A recent study has confirmed the long- costs about $250 per tablet; conivaptan,
term efficacy of tolvaptan in 111 patients over which is administered intravenously, may cost
a mean duration of treatment greater than 700 a little more per treatment course.
days.28 While the clinical benefits of chronic
tolvaptan therapy have yet to be clearly dem- ■■ THERAPY IN SPECIFIC DISEASE STATES
onstrated, this study shows that tolvaptan
therapy can result in a sustained improvement Patients with hyponatremia and cirrhosis
in serum sodium concentration without an The focus of treatment remains water and salt
unacceptable increase in adverse events.29 restriction and judicious use of loop diuretics
Lixivaptan (VPA-985), another oral selec- and aldosterone antagonists such as spirono-
tive V2 receptor antagonist, is being studied lactone (Aldactone).
in patients with euvolemic and hypervolemic Tolvaptan has been effective at raising
hyponatremia. the serum sodium level in patients with cir-
rhosis,26 while conivaptan should be avoided
Current role of vasopressin antagonists at present because of vasodilation from V1a
Current studies of vasopressin antagonists in receptor antagonism and its potential effects
the treatment of hyponatremia are promising, on systemic hemodynamics and risk of vari-
though definite recommendations are needed ceal bleeding.30
to ensure slow, careful correction of hypona- As the severity of cirrhosis increases, the
Euvolemic and tremia. Most studies suggest that these agents only effective treatment of hyponatremia is
hypervolemic provide slow, reliable increases in serum sodi- liver transplantation.
um. In one large study of patients with conges-
patients with tive heart failure, serum sodium rose by more Patients with SIADH
hyponatremia than 12 mmol/L in 24 hours in fewer than 2% In most cases, water restriction is the main-
of patients.26 stay of therapy. Adequate nutritional intake
should not Notably, no cases of osmotic demyelination should also be stressed so that enough solute
ingest any syndrome have been reported in these studies. is available for ongoing water excretion. Al-
more fluid However, it should be noted that therapy was though fluid restriction is usually effective,
started in the hospital with close monitoring many patients cannot adhere to the level of
than they of serum sodium levels and discontinuation of restriction required.
can excrete fluid restriction; the incidence of overly rapid In cases in which fluid restriction is not ef-
correction of sodium may be higher outside fective on its own, demeclocyline can be used
of carefully done clinical studies. Clinicians to antagonize ADH action and increase water
should adopt monitoring strategies similar to excretion. Sodium tablets and loop diuretics
those used in these rigorous studies. can also be used, taking care to avoid hypo-
At present, there is little experience with volemia from diuretic-induced sodium losses.
vasopressin antagonists in hyponatremic pa- The use of tolvaptan in patients with SIADH
tients with serious signs or symptoms of cere- has resulted in short-term increases in serum
bral edema, and most clinicians still view 3% sodium.26 A recent study has suggested that
saline as the gold standard for these patients. this effect can be sustained with longer-term
Vasopressin antagonists should not be used treatment,28 but further studies are needed to
in patients with hypovolemic hyponatremia, show a complementary clinical benefit (eg,
due to concerns about V1a blockade causing improved neurocognition) to guide the use of
hypotension and about V2 blockade produc- these costly agents in clinical practice.
724 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 77 • N U M B E R 1 0 O C T O B E R 2 0 1 0
VAIDYA AND COLLEAGUES
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2 How do you read the average issue?
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✓Cover-to-cover
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We want to hear from you.
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