Journal of the American Society of
Nephrology
Volume 8 • Number 10 • October 1997
Copyright © 1997 American Society of Nephrology
DISEASE OF THE MONTH
The Hyponatremic
Patient: Practical Focus on Therapy
Sandra M. Lauriat
Tomas Berl
Department of Medicine, University of Colorado School of Medicine, Denver,
Colorado.
Correspondence to
Dr. Tomas Berl, Division of Renal Diseases and Hypertension, Department of
Medicine, University of Colorado Health Sciences Center, Campus Box C281, 4200
East Ninth Avenue, Denver, CO 80262.
Physicians must
consider a number of factors when formulating a therapeutic plan for patients
with hyponatremia. A prudent assessment of the clinical situation would include
the following questions. Is the patient symptomatic? Is the duration of the
hyponatremia known? Does the patient have risk factors that could lead to
neurological sequelae? Only after this assessment is complete can a rational
and safe therapeutic plan be implemented. This article will focus on these
questions and outline specific therapeutic options as dictated by varying
clinical settings.
Is the Patient
Symptomatic?
The therapeutic
approach to the hyponatremic patient is determined more by the presence or
absence of symptoms than by the absolute level of serum sodium. At any level of
serum sodium, the development of symptoms is often related to the rate at which
the serum sodium has fallen. Although there is considerable individual
variation, symptoms are more likely to occur when the serum sodium declines
rapidly (at a rate of 0.5 mEq/L per h or greater) [1] [2]
. Conversely, the absence of symptoms in patients with severe hyponatremia
strongly suggests that the serum sodium has declined slowly over a longer time
frame.
The signs and
symptoms of hyponatremia are diverse and nonspecific. As such, only a high
index of suspicion in the appropriate clinical setting allows the signs and
symptoms to be recognized as a consequence of the electrolyte disorder. These
symptoms occur more commonly, but not exclusively, when the serum sodium has
fallen below 125 mEq/L. The most common symptoms are nausea, emesis, and
headaches, followed by seizures, respiratory arrest, and coma. The signs and
symptoms observed in 15 patients who developed hyponatremia are summarized in
Figure 1 (Figure Not Available) [3] . These clinical manifestations
occur as a result of hypotonicity, which causes water to equilibrate across
cell membranes as it moves down an osmotic gradient from the extracellular
fluid into cells. As cellular swelling ensues, the limits set by a rigid skull
present a problem not shared by other cells. It is therefore not surprising
that neurologic symptoms frequently predominate the clinical picture. In its
extreme form, if an adaptive response is not rapidly activated, or if the serum
sodium decreases at a rate greater than the adaptive response can compensate,
severe cerebral edema may lead to increased intracranial pressure, tentorial
herniation, depression of the respiration center, and even death. The presence of
this constellation of neurological symptoms reflects the fact that a patient is
at great risk from hyponatremic-induced cerebral edema and its long-term
neurologic sequelae. Thus, when these neurological symptoms are present, prompt
correction of hyponatremia should be undertaken regardless of the duration or
the underlying cause of the condition.
Although most
symptoms occur when the serum sodium declines rapidly, symptoms may also be
present when the decline is more insidious. Symptoms are usually not as
fulminant as described above, but when present, they require therapeutic
intervention because they indicate severe cerebral dysfunction. These patients
are at a much greater risk of developing osmotic demyelination syndrome from
rapid correction, and thus their treatment must be cautiously undertaken to
prevent this complication.
Is the Duration of the
Hyponatremia Known?
Hyponatremia can be
classified as acute or chronic with regard to its duration, and treatment
options can be tailored to this classification. These differences in chronicity
are important in the proper management of the condition, because each is
associated with different cerebral pathology and neurologic syndromes. Thus,
acute hyponatremic patients are at great risk of permanent neurological
sequelae from cerebral edema if the hyponatremia is not promptly corrected. In
contrast, chronic hyponatremic patients are at risk of osmotic demyelination
syndrome if the hyponatremia is corrected too rapidly. Understanding the
cerebral volume regulatory response to hypotonicity is helpful in devising
treatment strategies in both the acute and chronic settings.
As noted above,
cerebral edema occurs as water moves from the extracellular fluid into cells in
an attempt to achieve osmotic equilibrium between these two body fluid
compartments. It has been repeatedly observed that the increment in cerebral
water in response to hyponatremia is considerably lower than would be predicted
to achieve osmotic equilibrium. The brain demonstrates volume regulation, which
decreases the net amount of water entry into the brain by increasing the flow
of water from the interstitium into the cerebrospinal fluid [4] .
This excess fluid eventually re-enters the systemic circulation. This mechanism
is activated very promptly and is evident by the loss of extracellular solutes
(Na and Cl) as early as 30 min after the onset of hyponatremia. However, as
hyponatremia persists, the brain further adapts by losing cellular electrolyte
and organic solutes [5] [6] , which tends to lower the
osmolality of the brain without substantial gain of water. This slower defense
mechanism is reflected by a decrease in brain potassium content 1 to 3 h after
a hyponatremic insult. Thereafter, if the hyponatremia persists, other organic
solutes, such as amino acids and inositol, are lost [5] [6]
. This allows the brain to markedly decrease cellular swelling. In fact, this
process is so efficient that by 72 h brain water is only modestly increased
(approximately 10%). On the basis of the volume regulatory response, acute
hyponatremia has been, albeit somewhat arbitrarily, defined as occurring over a
period of less than 48 h [7] . It is during this time period that
symptoms related to cerebral edema are most likely to occur.
The brain that has
adjusted to low osmolality over at least 48 h is at risk for the osmotic
demyelination syndrome when hyponatremia is corrected rapidly. When serum
sodium is increased, the brain again adapts to prevent cellular dehydration.
This is mitigated initially by entry of NaCl into cells and then by enhanced
cellular K uptake. The organic osmolytes return very slowly to normal brain
content levels (at approximately 5 d), at which time the electrolyte content
also normalizes [8] . The pathogenesis of osmotic demyelination
syndrome has not been fully defined [4] [9] , but it may
be related to a greater susceptibility to dehydration in brains previously
adapted to hyponatremia when serum osmolality is raised. Such brains have
sustained losses of electrolytes and osmolytes and have a slower recovery of K
and organic osmolytes [10] . Therefore, brains adapted to chronic
hyponatremia may be less able to buffer effectively against increases in serum
sodium that require repletion of these solutes to prevent cerebral dehydration.
Frequently, the
duration of hyponatremia is unknown. Because acute hyponatremia usually occurs
only in well-defined clinical settings (described below), when a patient
presents with hyponatremia of unknown duration, it is prudent to assume that
delays in seeking medical care most likely indicate that the process is
chronic.
Does the Patient Have
Risk Factors for the Development of Neurologic Complications?
Several groups of
patients are at risk of developing cerebral edema from acute hyponatremia, and
other groups are at risk of developing the osmotic demyelination syndrome
(Table 1) when hyponatremia is corrected.
Risk Factors for Development of Cerebral Edema
The patients at
risk for cerebral edema include postoperative menstruant women, elderly women
recently placed on thiazide diuretics, children, psychiatric patients with
polydipsia, and hypoxic patients.
In the hospital
setting, hyponatremic menstruant women are more likely to have symptoms and
complications related to hyponatremia than post-menopausal women or men. One
study revealed that although hyponatremia develops at approximately the same
rate in both genders, women are more symptomatic than men at similar serum
sodium levels [11] . In addition, women are at increased risk for
neurologic complications related to acute hyponatremia. In women, and, in
particular, menstruant women, the risk of developing neurological complications
is 25 times greater than nonmenstruant
TABLE 1 -- Patient groups at increased risk for neurologic complication of hyponatremia
|
Acute cerebral
edema |
|
postoperative
menstruant women |
|
elderly women on
thiazide diuretics |
|
children |
|
psychiatric
polydipsic patients |
|
hypoxemic
patients |
|
Osmotic
demyelination syndrome |
|
alcoholics |
|
malnourished
patients |
|
hypokalemic patients
|
|
burn patients |
|
elderly women on
thiazide diuretics |
women or men. This
increased risk was independent of the rate of development, as well as the
magnitude, of the hyponatremia [11] . The increased risk for
menstruant women may be related to estrogen-induced defects in brain volume
regulation [12] . In addition, experimental data support gender
differences in arginine vasopressin release, with its action on cerebral
vessels interfering with the process of cerebral adaptation [13] .
It must be noted
that other clinical studies have failed to demonstrate a higher female
predisposition for hyponatremia or its neurological sequelae [14] [15]
. Despite the absence of accurate prevalence data, at present, menstruant women
with hyponatremia should be considered at high risk for both cerebral edema and
its complications. The best approach to this problem is clearly a preventive
one. In this regard, it must be emphasized that the administration of hypotonic
fluids has no place in the postoperative setting. It should be noted, however,
that hyponatremia may occur even when isotonic saline is given if the
concentration of Na + K in the urine exceeds that of serum sodium [16]
. Serum sodium, therefore, needs to be carefully monitored in this group of
patients, particularly when nausea or other symptoms require the continuous
administration of parenteral fluids.
Elderly women are
also at risk for acute symptomatic hyponatremia soon after being placed on
thiazide diuretics. The majority will present within 2 wk from beginning the
diuretic, although one-third of the patients will present within 5 d [17]
. The mechanism appears to be related to an altered hypothalamic response and
intrarenal water excretion defects, particularly in those with a low body mass.
Age may also be a
risk factor for symptomatic hyponatremia, as children are particularly
vulnerable to acute cerebral edema [18] . This may be due to
physical factors, such as the relatively high ratio of brain volume to skull
volume. In addition, in animal experiments, there may be a decreased capacity
for cerebral adaptation to low osmolality in young rats, and this can
contribute to cerebral edema [12] . At present, the actual risk of
neurologic complications in the pediatric population remains to be determined.
However, with current data it would be prudent to consider this group at major
risk for cerebral edema.
Psychiatric
patients who may have compulsive water drinking and increased levels of
arginine vasopressin may also be predisposed to symptomatic hyponatremia.
Fortunately, these patients rarely develop long-term sequelae.
An important role
for hypoxia in cerebral edema has been suggested. The deleterious effect of
hypoxia has been demonstrated in experimental animals, because in such animals
the presence of hypoxia greatly increases brain edema and mortality [19].
Risk Factors for the Osmotic Demyelination Syndrome
The osmotic
demyelination syndrome appears to occur when there is a rapid correction of low
osmolality in a brain already chronically adapted. Several patient groups are
at risk (Table 1) . In addition to its occurrence in patients with chronic
hyponatremia, other risk groups include alcoholics, malnourished patients, burn
patients, and patients with hypokalemia [20] . As with cerebral
edema, the elderly woman on thiazide diuretics is also susceptible to this
injury.
It is of interest
that many of the predisposing clinical settings are associated with potassium
depletion. The significance of this association is not fully understood.
Potassium may be important in the cerebral recovery process of hyponatremia,
because the cellular uptake of potassium is a critical response to increasing
extracellular tonicity. Therefore, hypokalemia may predispose a patient to
demyelination by limiting the availability of potassium in the brain, thereby
rendering it more prone to dehydration.
It must be
emphasized that an element of chronicity of hyponatremia is the most important
factor that predisposes patients to the osmotic demyelination syndrome. As
described above, it is rarely seen in patients with a serum sodium greater than
120 mEq/L or in patients with hyponatremia of less than 48 h duration.
Likewise, in animal models the development of cerebral lesions also requires
pre-existent hyponatremia of this duration.
What is the Treatment
Strategy for Hyponatremia?
The treatment
strategy for the hyponatremic patient will differ depending on the clinical
situation. We will briefly outline the approach to the symptomatic patient with
either acute or chronic hyponatremia, as well as the approach to the
asymptomatic patient.
Acute Symptomatic Hyponatremia
Acute symptomatic
hyponatremia, defined as hyponatremia known to be of less than 48 h duration,
is most commonly observed in postoperative hospitalized patients receiving
hypotonic fluids. Treatment in this setting needs to be immediate when symptoms
are present, because the risk of cerebral edema far outweighs any risk of the
osmotic demyelination syndrome. Serum sodium should be raised by 2 mEq/L per h
until symptoms resolve. Although full correction is probably safe, it is by no
means necessary. The correction can be achieved by administration of 1 to 2
ml/kg per h hypertonic saline (3% NaCl). The coadministration of a loop
diuretic enhances free water excretion and thereby accelerates the correction
process. In patients with seizures or other severe neurologic symptoms
(obtundation, coma), a more rapid infusion of 3% NaCl (4 to 6 ml/kg per h) or
even 50 ml of 29.2% NaCl have been safely used [7] . In all patients,
close monitoring of serum sodium and neurologic symptoms is imperative.
Symptomatic Chronic Hyponatremia
In symptomatic
hyponatremia of an unknown duration or of a duration greater than 48 h, one
must be cautious to avoid complications of therapy. Neurologic symptoms such as
a depressed sensorium or seizures reflect cerebral dysfunction and the need for
some correction, while simultaneously avoiding the osmotic demyelination
described previously. The key controversy centers on the question of whether it
is the rate or the magnitude of correction that increases the risk of
complications.
These two variables
in the correction of hyponatremia are not readily dissociated, because a rapid
correction rate usually is accompanied by a greater absolute magnitude of
correction over a given time period. Nonetheless, this distinction is
potentially of great importance in the approach to the patient with symptomatic
hyponatremia. Evidence from experimental animals strongly points to a very
important role for magnitude of correction; however, the rate of correction
also clearly plays a role, because if either of these variables is exceeded,
the incidence of neurologic lesions increases [6] . A similar
conclusion can be reached from less controlled human studies. Therefore,
because the rate and magnitude of correction are not completely independent of
each other, each of these variables should be considered when designing therapy
for the symptomatically hyponatremic patient. The following guidelines are
useful:
- Because
cerebral water is increased only by approximately 10% in severe chronic
hyponatremia, promptly increase the serum sodium by 10%, or approximately
10 mEq/L.
- After the
initial correction, do not exceed a correction rate of 1.0 to 1.5 mEq/L
per h.
- Do not
increase serum sodium by more than 15 mEq/L per d.
The rate at which
the serum sodium will increase is dependent on the rate and electrolyte content
of infused fluids, as well as the rate and electrolyte content of the urine.
This is illustrated in the following example.
A patient is
admitted with progressive changes in mental status and is found to have a serum
sodium level of 110 mEq/L, which is thought to be secondary to the syndrome of
inappropriate antidiuretic hormone (SIADH) based on his recently diagnosed
small cell lung cancer. The patient weighs 50 kg. A computed tomography scan
reveals no focal abnormalities, but mild cerebral edema. The physician wants to
increase the patient's serum sodium from 110 to 120 mEq/L in 10 h.
- Calculate the net water loss needed to
raise serum sodium (SNa ) to 120 mEq.
- Assume TBW=60% of body weight-50×0.6=30
L
Net electrolyte-free water loss to
raise SNa = present TBW - new TBW = 30 - 27.5 = 2.5 liters
- Calculate the time course in which to
raise the serum sodium by 1 mEq/h. To increase the serum sodium, 1 mEq/h from 110 to 120 mEq/L should
occur over 10 h, or 2.5 L of electrolyte-free water should be lost in 10
h, which equals 250 ml of free water loss per hour.
- Administer furosemide, monitor urine
output, and replace any sodium and potassium or excess free water that is
lost in the urine. In
this patient, furosemide was administered and a brisk diuresis resulted in
a 1-L urine output in the first hour with a urine sodium level of 75 mEq/L
and urine potassium level of 20 mEq/L. Because this patient only needed to
lose 250 ml of electrolyte-free water, 750 ml of water plus 75 mEq of
sodium and 20 mEq of potassium need to be given back to the patient. This
can be given in any combination of fluid, sodium, and potassium
supplement, such as 500 ml of normal saline and 250 ml of D5W with 20 mEq
KCl (Table 2) .
- Continue to monitor urine output and replace
any sodium, potassium, or excess electrolyte-free water that has been lost
in the urine.
TABLE
2 -- Solute and water
balance during the first hour
|
Characteristic |
Water |
Solutes
Na/K |
|
Intake |
750 |
75/20 |
|
500 ml normal
saline |
||
|
250 ml D5W + 20
mEq KCl |
||
|
Output |
1000 |
75/20 |
|
Balance |
-250 |
0 |
In this patient,
the second hour resulted in only 800 ml of urine output, with a urine sodium of
75 mEq/L and urine potassium of 30 mEq/L. This represents a loss of only 60 mEq
sodium and 25 mEq potassium. Only 250 ml of electrolyte-free water should be
lost; therefore, during this hour, 550 ml of free water needs to be replaced
with 60 mEq sodium and 25 mEq potassium. This can be accomplished by the
administration of 400 ml of normal saline + 150 ml of D5W with 20 mEq KCl
(Table 3) .
As the diuresis
slows, additional doses of furosemide may be necessary. It is important to
periodically measure serum Na, K, and spot urine Na and K to ensure that the
correction is proceeding properly. Free water is being excreted only in UNa
+ UK < PNa (P stands for plasma). After the desired
increment is attained, therapy can be continued in the form of water
restriction.
TABLE 3 -- Solute and water balance during the second hour
|
Characteristic |
Water |
Solutes
Na/K |
|
Intake |
550 |
60/20 |
|
400 ml normal
saline |
||
|
150 ml D5W + 20
mEq KCl |
||
|
Output |
800 |
60/25 |
|
Balance (second
hour) |
-250 |
-5 |
|
Balance
(cumulative) |
-500 |
-5 |
How is Chronic
Asymptomatic Hyponatremia Managed?
The asymptomatic
patient requires none of the intensive treatment described above. Initially,
the physician should look for an underlying disorder. If one is identified and
treated, such as thyroid or adrenal insufficiency, its treatment will resolve
the hyponatremia. This is also true in cases of the SIADH. Any drugs that can
be implicated in limiting water excretion also should be discontinued.
When the underlying
cause of chronic hyponatremia is SIADH and its etiology is not known or cannot
be effectively treated, SIADH must be treated as a chronic disorder. The best
management of chronic hyponatremia is conservative, because rapid increases in
serum tonicity lead to a greater degree of cerebral water loss and possible
demyelination. The treatment options as outlined in Table 4 include fluid
restriction, use of pharmacologic agents (lithium, demeclocycline, loop
diuretics), and increased solute intake (urea). In addition, vasopressin
receptor antagonists will soon be available.
Fluid Restriction
Fluid restriction
is frequently successful in normalizing the serum sodium concentration and
preventing symptomatic hyponatremia. The following approach is useful in
calculating a fluid restriction that will maintain a specific serum sodium. A
patient's maximal urine volume ( Vmax
) is determined by the daily osmolar load (OL) and the minimal urinary
osmolality (Uosmolmin ). This latter parameter is a function of the
severity of the diluting disorder. Thus, the more severe the disorder, the
higher the minimal osmolality. Thus,
On a normal diet,
osmolar load is approximately 10 mosmol/kg (700 mosmol in a 70-kg person). In a
healthy person, urine osmolality can be as low as 50 mosmol/kg; therefore 14 L
of water can be excreted per day. A patient with SIADH who cannot lower the Uosmol
below 500 mosmol/kg but who has the same osmolar load can only excrete 1.4 L of
water per day. If such a patient drinks more than 1.4 L per day, the serum
sodium will fall. Although fluid restriction is consistently effective and
inexpensive, fluid restriction of this degree is accompanied by a very high
probability of noncompliance. Hence, a variety of other approaches have been
used.
TABLE 4 -- Treatment options for SIADH a
|
Treatment |
Mechanism
of Action |
Dose |
Advantages |
Disadvantages
|
|
Fluid restriction |
Decreases
availability |
Variable |
Effective and |
Noncompliance |
|
Pharmacologic
agents |
Inhibits response
of |
900 to 1200 mg/d |
Unrestricted
water |
Polyuria |
|
demeclocycline |
Inhibits response
of |
1200 mg/d
initially |
Effective; |
Polyuria |
|
furosemide |
Increases free
water |
Titrate to
optimal |
Effective |
Ototoxicity |
|
Increased solute
intake |
Osmotic diuresis |
30 to 60 g/d |
Effective; |
Polyuria |
|
V2 receptor
antagonist |
Antagonizes |
|
Ongoing trials |
|
a SIADH, syndrome of inappropriate
antidiuretic hormone; ADH, antidiuretic hormone; GI, gastrointestinal.
Pharmacologic Agents
Lithium was the
first pharmacologic agent used in the treatment of hyponatremia after diabetes
insipidus was noted to be a common adverse effect. This effect occurs in 30 to
70% of patients taking therapeutic doses. Lithium acts to increase serum sodium
by inhibiting the kidney's response to antidiuretic hormone, thereby increasing
the excretion of water. An inhibition of vasopressin-stimulated cAMP formation,
as well as a decrement in the synthesis of vasopressin-regulated water channels
(AQP2), underlies the defect [21]. A dose of 900 to 1200 mg/d is
usually effective. However, the agent has a narrow therapeutic range and both
renal and neurologic toxicity have limited its usefulness as a chronic
therapeutic agent.
Demeclocycline was
first noted to cause polyuria by Singer and Rotenberg in a group of patients
treated for skin disorders [22] . These investigators found that the
polyuria was due to the drug's ability to inhibit both the formation and the
action of cAMP in the collecting duct of the renal tubule. This resulted in a
kidney that was unresponsive to antidiuretic hormone (nephrogenic diabetes
insipidus). This adverse effect was observed in patients receiving large doses
of demeclocycline (600 to 1200 mg/d), but was virtually nonexistent in patients
receiving smaller doses (less than 600 mg/d). Since then, the drug has been
valuable in the treatment of SIADH. In a comparative study with lithium, it was
found to also be more predictable in normalizing the serum sodium [23]
. The onset of action is usually 3 to 6 d after beginning treatment with the
drug, at which time the urine osmolality decreases. Polyuria then becomes
evident after 7 to 10 d. When diuresis begins, the patient must be allowed free
access to water to prevent hypernatremia from water depletion. After an initial
response is seen, the dose of demeclocycline should be decreased gradually to
the lowest level (usually between 300 and 900 mg/d), which keeps the serum
sodium normal with unrestricted fluid intake. To ensure adequate absorption,
the drug should be given 1 to 2 h after meals, and antacids (calcium, aluminum,
or magnesium) should be avoided.
There are also some
adverse effects and serious toxicities that must be considered when using
demeclocycline. Some patients are inconvenienced by the polyuria and become
noncompliant. Skin photosensitivity may occur. In the pediatric population,
demeclocycline can cause tooth or bone abnormalities. In addition, azotemia can
occur with or without nephrotoxicity. Nephrotoxicity occurs most often in
patients with liver disease and is postulated to occur because of decreased
hepatic metabolism of the drug and subsequent elevated drug levels.
Loop diuretics such
as furosemide have also been used in the treatment of SIADH. In 1983, Decaux
studied the efficacy of the loop diuretics ethacrynic acid and furosemide in
the treatment of chronic SIADH. In 11 of 12 patients with chronic SIADH, the
serum sodium increased from an average of 120.4 to 136 mmol/L [24] .
This occurred despite the patients' free access to water, as long as urinary
losses of sodium and potassium were replaced. This requires the administration
of 2 to 3 g of NaCl per day. In the remaining patients, resistance to the
diuretic was thought to be secondary to the combination of a decreased GFR (55
ml/min), a limited increase in furosemide-induced diuresis, and a large fluid
intake (21 beers/d). A single diuretic dose (40 mg of furosemide) was enough to
induce a large diuresis in most patients. Diuretic doses should be doubled if
the diuresis induced in the first 8 h is less than 60% of the total daily urine
output.
Increased Solute Intake
An alternative
option for the chronic management of hyponatremia is to increase solute intake
with urea. Urea is an important component of the osmotic gradient in the renal
interstitium and allows for proper concentration and dilution of urine. By
increasing the solute load with oral urea, an osmotic diuresis occurs, and this
increase in urine flow permits a more liberal water intake without worsening
the hyponatremia. This occurs without altering urinary concentration. The effect
of the increased solute load can be demonstrated by the quantification of
electrolyte-free water excretion both before and after urea is administered in
the example shown below.
Assume that a
patient has a serum sodium level of 134 mEq/L, a fixed urine concentration of
800 mosmol/d, with a daily obligatory solute load of 500 mosmol/d, a dietary
sodium intake of 100 mmol/d, and a potassium intake of 40 mmol/d. Calculating
the volume required to excrete the daily solute load at baseline reveals:
The concentration
of sodium and potassium in this volume can be determined as follows:
These values may
then be used to compute the electrolyte-free water clearance:
The negative value
for excretion of electrolyte-free water clearance suggests net free water
absorption, a setting that could lead to worsening hyponatremia.
Under the same
conditions of sodium and potassium intake, urine concentration, and serum
sodium level, administration of urea at 30 g/d adds approximately 500 mosmol/d
to the obligatory solute load that must be excreted. This has a profound effect
on electrolyte-free water clearance, because the daily solute excretion is
increased from 500 to 1000 mosmol.
As a result of the
increased urinary volume, urinary electrolyte concentrations decrease:
Daily potassium
excretion = 40 mmol
Note the resulting
changes in electrolyte-free water clearance:
Now
electrolyte-free water excretion is positive, allowing for higher water intake.
Urea is usually given in doses of 30 to 60 g/d, and its onset of action is
immediate. As with demeclocycline, urea permits unrestricted fluid intake. The
major side effect is gastrointestinal symptoms and its unpalatability.
Vasopressin Antagonists
Vasopressin (V2)
receptor antagonists are currently being investigated. OPC 31260 is a novel
oral V2 vasopressin receptor antagonist, which when tested in hyponatremic,
cirrhotic rats more than normalized the urinary excretion rate of water after
an oral loading test [25] . This agent may become an effective
therapeutic agent for the vasopressin-dependent water retention associated with
decompensated liver cirrhosis. OPC 31260 has also been studied in SIADH in
rats. Saito et al. first treated
vasopressin-deficient Brattleboro rats with antidiuretic hormone and showed
that OPC 31260 entirely reversed the effects of vasopressin [26] .
In human studies, OPC 31260 was given to normal volunteers. When compared with
a loop diuretic, OPC 31260 induced a significant water diuresis without
altering the urinary excretion of sodium or potassium [27] . This
class of drugs, now designated as "aquaretics," are not yet available
for clinical use.
Treatment of
Hypovolemic and Hypervolemic Hyponatremia
Much of the
preceding discussion assumed that the patient under consideration was
euvolemic, a condition that represents the majority of hyponatremic subjects.
However, we want to conclude with some comments on the treatment of hypovolemic
and hypervolemic hyponatremic patients (Table 5) .
Hypovolemic hyponatremia results from the loss of both
TABLE 5 --
Treatment of noneuvolemic hyponatremia
|
Hypovolemic
hyponatremia |
|
volume
restoration with isotonic saline |
|
identify and
correct etiology of water and sodium losses |
|
Hypervolemic
hyponatremia |
|
water restriction
|
|
sodium
restriction |
|
substitute loop
diuretics in place of thiazide diuretics |
|
treatment of
stimulus for sodium and water retention |
|
V2 receptor
antagonists (ongoing trials) |
water and solute, with a greater relative loss of solute. The nonosmotic
release of arginine vasopressin in response to reduced effective circulating
volume perpetuates the hyponatremia by producing a state of antidiuresis.
Patients with this type of hyponatremia are usually asymptomatic, probably
because the losses of sodium and water limit the development of cerebral edema.
The cornerstone of therapy is the administration of isotonic saline, with
concomitant resolution of the underlying disturbance. Resolution of the volume
disturbance removes the stimulus for arginine vasopressin and restores serum
sodium to normal levels.
Hypervolemic hyponatremia is observed when both water and solute are
increased, but in this situation water is increased to a greater extent. This
condition is very difficult to treat, as it often reflects severe, irreversible
dysfunction of either the liver, heart, or kidney. In heart failure, cirrhosis,
and nephrotic syndrome, reduced effective arterial volume results in the
nonosmotic stimulation of arginine vasopressin and an increase in thirst.
Therefore, compliance with water restriction is difficult. Diuretics are the
primary therapeutic agents for edema, but caution must be used in selecting the
appropriate regimen. Thiazide diuretics impair urinary dilution and may
exacerbate hyponatremia, whereas loop diuretics increase free water excretion
and can improve the serum sodium. Correction or improvement of the underlying
disturbances would be ideal, but this is usually not attainable. At present,
therapy relies on fluid restriction, salt restriction, and loop diuretics. The
aforementioned oral V2 antagonists are currently being tested in
hyponatremic subjects who have presented with congestive heart failure and
cirrhosis. The results of these trials are eagerly awaited, because they could
provide a valuable alternative in the management of this electrolyte disorder.
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