□ REVIEW ARTICLE □

Treatment of Hyponatremia
Peter Gross

Abstract
Hyponatremia is an electrolyte disorder that is defined by a serum sodium concentration of less than 136
mmol/L. Hyponatremia occurs at a high incidence. It is commonly associated with mild to moderate mental
impairment. Hypoosmolar hyponatremia occurs in the setting of plasma volume deficiency (“hypovolemia”,
e. g. after gastrointestinal fluid loss), liver cirrhosis and cardiac failure (“hypervolemic” hyponatremia) and
syndrome of inappropriate antidiuretic hormone secretion (“euvolemic” hyponatremia). Excessive antidiuretic
hormone and continued fluid intake are the pathogenetic causes of these hyponatremias. Whereas hypovo-
lemic hyponatremia is best corrected by isotonic saline, conventional proposals for euvolemic and hypervo-
lemic hyponatremia consist of the following: fluid restriction, lithium carbonate, demeclocycline, urea and
loop diuretic. None of these nonspecific treatments is entirely satisfactory. Recently a new class of pharma-
cological agents―orally available vasopressin antagonists, collectively called vaptans―have been described.
A number of clinical trials using vaptans have been performed already. They showed vaptans to be effective,
specific and safe in the treatment of euvolemic and hypervolemic hyponatremia.

Key words: hyponatremia, vasopressin receptor antagonist

(Inter Med 47: 885-891, 2008)

(DOI: 10.2169/internalmedicine.47.0918)

fied. Clinicians saw hyponatremia primarily as an important

Introduction
Hyponatremia is defined by a serum sodium concentration
of less than 136 mmol/L (1). It is the most frequent electro-
lyte disorder of patients in the hospital (2) but it is also en-
countered in ambulatory outpatients especially in the elderly
(3). The incidence of hyponatremia has apparently increased
over the last 3 decades. Although a prospective study from
1985 reported an incidence of 2.5% from a tertiary care
medical center (4), more recent studies from 2003 (5) and
2006 (2) found this number to be between 29 and 42%. Al-
though hyponatremia in the hospital was not limited to spe-
cial fields of medical practice, the departments of internal
medicine, surgery and gynaecology and the areas of inten-
sive care, pulmonology and cardiology were those most
heavily involved (2).
Clincal Relevance of Hyponatremia
Until recently the clinical relevance of hyponatremia, es-
pecially in its mild form (130-134 mmol/L) was not clari-
diagnostic marker which indicated the presence of heart fail-
ure, liver cirrhosis or neoplastic disease. Clinicians were
also well aware that acute severe hyponatremia (a serum so-
dium concentration <118 mmol/L of a duration <36-48
hours) would lead to serious symptoms such as confusion,
unconsciousness, grand mal seizures and even death. Hence,
it was common to direct therapy at the prevention of pro-
gression from mild to severe hyponatremia. However mild
hyponatremia in itself―which is by far the commonest form
of hyponatremia encountered―was considered oligosympto-
matic, exerting little if any impairment of the patient’s well-
being. There have been several recent changes regarding the
viewpoint of these aspects.
There is new evidence that even mild hyponatremia is a
cause of important symptoms (3). Renneboog et al (3)
evaluated mental functions in 16 elderly individuals(age 63
± 15 years) with chronic hyponatremia (126 ± 5 mmol/L)
due to the syndrome of inappropriate ADH secretion
(SIADH). The researchers performed tests of balance, di-
rected walking, memory, calculation and speed of reactions.
Importantly the researchers did one set of tests while the in-

Department of Nephrology, Universitätsklinikum C. G. Carus, Dresden, Germany

Received for publication January 14, 2008; Accepted for publication January 23, 2008
Correspondence to Dr. Peter Gross, peter.gross@uniklinikum-dresden.de

885
 Inter Med 47: 885-891, 2008 DOI: 10.2169/internalmedicine.47.0918
dividuals were in hyponatremia and they performed the
same set of tests at another time in normonatremia. It was
found that hyponatremia caused: 1) the patients’ balance and
gait to be unsteady―predisposing them to falls―, 2) made
reaction time significantly longer, and 3) made mental errors
significantly more common than was seen in normonatre-
mia. In additional tests in normal healthy individuals the
authors quantified the degree of mental impairment by com-
parison with the results of drinking alcohol. They found that
a blood alcohol level of 0.6 ± 0.2 g/L lead to the degree of
mental impairment that had been observed previously at a
serum sodium concentration of approximately 126 mmol/L.
In another part of the study of Renneboog and colleagues
(3), the authors analyzed more specifically the physical con-
sequences of the dysbalance in hyponatremic patients. They
studied emergency―room admissions for the incidence of
preceding falls. They found that hyponatremic patients had
fallen approximately four times more often than their
matched normonatremic counterparts in the very recent past.
Hence, it is most likely that hyponatremia predisposes to
bone fractures. Taken together, even mild chronic hyponatre-
mia is a cause of important symptoms.
Furthermore there has been continued interest in the prog-
nostic significance of a given hyponatremia. Heumann et al
studied 507 cirrhotic patients on the waiting list for liver
transplantation (6). In this cohort of obviously very sick pa-
tients hyponatremia turned out to be an independent predic-
tor of survival or premature demise―even when the score
of severity―the MELD score―was average and not ex-
treme (6). In a similar line, hyponatremia at the time of liver
transplantation was associated with a larger intensity of neu-
rologic disease, renal failure, infectious complications and
early posttransplantation demise than normonatremia (7).
These recent publications therefore reinforce previous
knowledge depicting hyponatremia as a marker of a guarded
prognosis; yet they leave the second question unanswered:
does it actively contribute to an adverse prognosis?
In chronic cardiac disease hyponatremia is frequently
seen. As has been well described several years ago hypona-
tremia in that setting predicts worsening of the heart failure
and an unfavourable prognosis (8). It has now been shown
that hyponatremia is also a common finding in acute ST-
elevation myocardial infarction (9). A recent study of 978
acute ST-elevation myocardial infarction patients showed
that hyponatremia predicted post discharge re-hospitalization
and post discharge demise (9). It is noteworthy that these
patients did not show cardiac failure at the time of the myo-
cardial infarction. Again the data confirm previous knowl-
edge of hyponatremia as a marker of an adverse prognosis;
they do not answer the question whether hyponatremia in it-
self―or by means of the stimulated vasopressin-contributes
to the worsening of the prognosis. However, recently studies
using novel vasopressin antagonists have been initiated to
test this latter hypothesis (10).
886
Pathophysiology of Hyponatremia
Precise measurements of the serum sodium concentration
became available in 1950 with the introduction of flame
photometry into laboratory medicine. Shortly thereafter it
was suggested that excessive antidiuretic hormone (ADH,
vasopressin) was responsible for most cases of hyponatremia
(11). Leaf and Mamby gave a standard oral water load to
hyponatremic patients (11). The serum sodium concentration
fell and the urinary flow rate as well as urinary osmolality
remained unchanged. A bioassay for the measurement of
ADH was done and it indicated elevated ADH already at
baseline before the water load. Such a pattern of changes
was reminiscent of that observed when a standard oral water
load was given to normal healthy volunteers having received
an injection of vasopressin shortly before (12). In laboratory
animals hypotonic infusions together with i.v. vasopressin
were also shown to bring about hyponatremia (13) whereas
either component alone was not effective. As a mirror image
of the foregoing:when hypophysectomized dogs (14) or va-
sopressin deficient Brattleboro rats (15) were subjected to
manoeuvers―such as right heart failure or liver cirrhosis―
that ordinarily elicit water retention and hyponatremia, this
was no longer observable.
The introduction of the radioimmunoassay for ADH in
1973 permitted a more rigorous testing of the previous con-
cepts. Measurements of ADH have now been made in ex-
perimental hyponatremic cirrhosis (15), cardiac failure (16),
glucocorticoid deficiency (17) and several other hyponatre-
mic conditions. It was confirmed in all that the hyponatre-
mic state was associated with stimulated vasopressin, i.e.
measurable vasopressin―since osmotically it should be fully
suppressed and unmeasurable in hypoosmolality. Similar
findings have also been reported from patients with hypona-
tremia in the conditions of cardiac failure (18), liver cirrho-
sis (19), hypothyroidism (20), and SIADH and other set-
tings. Uniformly all these studies found ADH to be measur-
able, i.e. stimulated and not suppressed.
A surprising feature of the experimental and clinical re-
ports is the fact that ADH was secreted despite the presence
of hyponatremia, synonymous with hypoosmolality. It was
therefore proposed that other stimuli of ADH called “non-
osmotic” would be in operation in hyponatremia. It was
later found in many or most settings of hyponatremia that
the non-osmotic stimuli could be traced back to baroreceptor
function in large arterial vessels of the central circulation
(21). For instance in hyponatremic cardiac failure baroceptor
afferents from the central arteries and the aortic arch sense
the low cardiac output and transmit a vasopressin stimulat-
ing signal to the hypothalamus;baroceptor denervation pre-
vents such vasopressin stimulation (16). A similar chain of
events is in operation in hyponatremic liver cirrhosis or ex-
tracellular volume depletion. In SIADH paraneoplastic se-
cretion of ADH or direct involvement of the hypothalamus
by cerebral changes usually explains the nonosmotic ADH.
 Inter Med 47: 885-891, 2008 DOI: 10.2169/internalmedicine.47.0918
Clinical Settings of Hyponatremia
For the diagnosis and treatment of a given hyponatremia
the clinical evaluation has to include a careful medical his-
tory, a physical examination with attention to the patient’s
extracellular fluid volume status and laboratory measure-
ments. The latter should include the plasma-osmolality, -
potassium, -uric acid, -urea and-glucose. The urinary osmo-
lality and the urinary sodium concentration are also re-
quired.
Hyponatremia in the presence of hyperosmolality is usu-
ally due to hyperglycemia or occasionally to mannitol caus-
ing a shift of water from the intracellular to the extracellular
compartment―because the cell membrane is impermeable to
the glucose in uncontrolled diabetes or the mannitol. This
hyponatremia is a disorder of water distribution and not one
of water balance. Hence treatment should be directed to-
wards hyperglycemia and its correction with insulin in the
case of hyperglycemic hyponatremia, but not towards ADH
or water. Hypoosmolar hyponatremia may occur in the pres-
ence of advanced renal failure (stages IV or V of renal fail-
ure). It is then primarily due to the kidney’s inability to fil-
ter and excrete enough water. This hyponatremia also is not
a disturbance of ADH.
The remaining entities of hypoosmolar hyponatremia―
and the ones to be discussed herein―will be those that are
associated with cardiac failure and liver cirrhosis (also called
“hypervolemic” hyponatremia because of edema formation),
SIADH (also called “euvolemic” hyponatremia) and “hy-
povolemia” (as occurs after gastrointestinal fluid losses or
profuse sweating). SIADH is associated with a unique pat-
tern of laboratory abnormalities:low or even subnormal
serum-urea, -creatinine and importantly-uric acid, whereas
the sodium excretion rate will be high (>40 mmol/L). In the
hypervolemic and hypovolemic hyponatremias the laboratory
measurements are changed in the opposite direction from
the ones just mentioned. The urinary osmolality will be
higher than 100 mosm/kg in all conditions. This indicates
the kidney’s inability to excrete maximally dilute urine, one
which would correct any hyponatremia.
Conventional Treatment of Hyponatremia
In the entity of hypovolemic hyponatremia infusions of
isotonic saline are the treatment of choice. Such infusions
will saturate the baroreceptors, terminate the stimuli to ADH
secretion and allow the kidneys to excrete excess water, i.e.
correct any hyponatremia. In euvolemic and hypervolemic
hyponatremia saline infusions may occasionally be given as
an emergency measure―i.e. in grand mal seizures or in very
severe hyponatremia (<110 mmol/L) with major mental
changes―but in general this approach is unproductive. In-
stead other measures focusing on reducing total body water
have been recommended in the literature:
A standard procedure is the prescription of a fluid restric-
887
tion to approximately 0.8 L/day. Given that obligatory uri-
nary excretion plus insensible losses yield > 1 L/day of fluid
volume, this kind of a fluid restriction should result in a
negative fluid balance and hence an increase in the serum
sodium. However the improvement will occur at a slow
pace. Furthermore hyponatremic patients are thirsty patients
―if they were not they would stop drinking and they would
not become hyponatremic in the first place. It is therefore
notoriously difficult for hyponatremic patients to adhere to a
fluid restriction (1) and this measure may not work.
The use of pharmacologic agents has been suggested for
the induction of a nephrogenic diabetes insipidus. This can
be expected to correct a hyponatremia (22, 23). Thus, lith-
ium in lithium carbonate is an inhibitor of ADH induced
adenylate cyclase in the collecting duct principal cell.
Hence, lithium antagonizes the hydroosmotic effect of ADH
(22). However lithium is potentially nephrotoxic, its plasma
levels vary and have to be watched closely (24) and the ef-
fects on renal water excretion are not reliable.
Demeclocycline is an older tetracycline antibotic. One of
its adverse effects was polyuria and nephrogenic diabetes in-
sipidus. Doses of 600-1,200 mg/day have been given to treat
hyponatremia (23). Although demeclocycline is more effec-
tive and more predictable than lithium in the treatment of
hyponatremia (23) demeclocycline may induce azotemia in
general and it may be nephrotoxic in liver cirrhosis (25).
Furthermore demeclocycline is no longer available on the
market in most countries.
Urea given as a powder or in the form of capsules in
doses of several gram/day has been used. It induces an os-
motic diuresis and an augmented excretion of free water by
the kidneys. This has been used successfully by some to
correct the hyponatremia of SIADH (26); however urea has
not met with widespread acceptance by patients and physi-
cians.
In SIADH high doses of i.v. loop diuretics elicit a volu-
minous diuresis that has a low sodium content. If the so-
dium excreted is replenished quantitatively by giving hyper-
tonic saline, a negative water balance ensues and hyponatre-
mia can be corrected in this way (27). This treatment is ef-
fective and reliable, but it is cumbersome. Therefore it is not
used very frequently. Taken together, the conventional ap-
proaches for the treatment of hyponatremia lack specificity,
efficiency and ease of application. Therefore scientists have
been interested in other means such as vasopressin antago-
nists to improve the treatment of hyponatremia.
Vasopressin Antagonists
The pathogenetic role of ADH in most types of hypona-
tremia suggested that vasopressin antagonists would be a
suitable approach to treatment. Manning et al were the first
to describe a large number of peptidic vasopressin antago-
nists (28). It was shown that antagonists worked in principle
in animal models with hyponatremia and in human subjects
(29). However the peptidic nature of the agents, the need for
 Inter Med 47: 885-891, 2008 DOI: 10.2169/internalmedicine.47.0918

parenteral application and the unexpected property of intrin-

sic agonistic effects in addition to antagonistic effects pre-
cluded any widespread or chronic use in patients. It was
therefore a breakthrough that random screening between
1990 and 2000 yielded several non-peptide, orally available
novel vasopressin antagonists collectively called vaptans
(Fig. 1).

Mozavaptan

OPC 31260 or mozavaptan was described in 1992 (30). It

is a benzazepine derivative (Fig. 1) that bound with a high
degree of affinity to the renal hydroosmotic V-2 vasopressin
receptor but not to the vascular V-1 vasopressin receptor. It
did not cause agonistic effects of its own. When given orally
to normal human subjects at a dose of 1 mg/kg the urinary
flow rate increased eight fold, the urinary osmolality became
maximally dilute (63 mosm/kg) but the urinary sodium ex-
cretion rate changed only marginally (31). Although mo-
zavaptan was the first agent of the new class of vaptans and
hence had paradigmatic importance mozavaptan was not
very potent. Mozavaptan eventually met with limited clinical
application and subsequent agents have attracted greater in-
terest.
Fig
ure1 . Che mica
ls t
ruct
ureo fnonpe pti
de,orallyavai
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abl
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agonis
ts.Allcompoundsa revasopres
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Lixivaptan V-2r e
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V-2v a
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.(Co ni
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VPA 985 or lixivaptan is a potent, V-2 receptor selective, i
spr e
sentl
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ketasapa rent
eralpreparati
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orally available vasopressin antagonist reported in 1998 (32).
Recently, a short term study in 42 heart failure patients re-
ceiving lixivaptan was reported (33). When lixivaptan was potassium remained unchanged. There were very few side
given in doses as high as 400 mg the urinary excretion rate effects. Primarily patients noted an increase in thirst. There
more than doubled, solute-free water excretion was signifi- were no specific serious adverse events.
cantly enhanced and the serum sodium concentration in-
creased (33). A prospective randomized study in 112 pa- Conivaptan
tients with euvolemic and hypervolemic hyponatremia was
also performed. The study extended over 7 days. Patients Conivaptan or YM 087 is the first combined V-1a/V-2 va-
were placed on a fluid restriction of 1 L/day. They received sopressin receptor antagonist (35). A few clinical studies
50 or 100 mg of lixivaptan twice a day per os. have been reported using conivaptan as a parenteral prepara-
In the placebo control group the serum sodium remained tion (36). [Although originally developed as an oral antago-
unchanged (127.3 ± 3 mmol/L at baseline, 127.7 ± 4 at the nist it was later marketed as a parenteral agent only]. The
end of the study) however, there was a significant increase studies included patients with SIADH and hyponatremic car-
in the high dose lixivaptan group (receiving 200 mg of lixi- diac failure. Conivaptan was given as a continuous i.v. infu-
vaptan/day): the serum sodium went from a baseline of sion over 9 days in doses of 40-80 mg/day. Patients were
126.4 ± 4.4 mmol/L to 132.3 ± 6.9 at the end of the study supposed to be on a mild fluid restriction of 2 L/day. Coni-
(p <0.05). The increase of the serum sodium occurred vaptan increased the urinary flow rate significantly, diluted
within two to three days after the start of lixivaptan treat- the urine, caused a positive free water balance and increased
ment. Patients with a diagnosis of SIADH responded better the serum sodium concentration from 125 ± 33 mmol/L to
than those with liver cirrhosis or cardiac failure. In fact only 133 ± 3.7(p <0.05). The urinary sodium excretion rate did
55 % of hyponatremic patients with liver cirrhosis re- not charge and the serum potassium concentration remained
sponded with an increase of the serum sodium. The causes stable. Thirst, postural hypotension and headache were re-
for the apparent unresponsiveness in this many patients have ported as adverse events (36). It appears that conivaptan is
not been clarified. However, it is likely that decreased distal an efficient treatment of hyponatremia in the patients that
delivery of tubular fluid to the collecting duct is involved. require parenteral medication.
The lixivaptan treatment was associated with a slight, 8%
decline of the GFR (34). The excretion rates of sodium and

888
 Inter Med 47: 885-891, 2008 DOI: 10.2169/internalmedicine.47.0918
Satavaptan
Satavaptan or SR 121 463 is a potent, specific orally
available vasopressin V-2 receptor antagonist first described
in 1996 (37). Clinical phase III studies have been conducted
in SIADH (38). Thirty-four hyponatremic patient received
25 or 50 mg orally once a day of satavaptan for 5 to 23
days, or placebo in a double-blind, randomized fashion (38).
Patients maintained a fluid restriction of 1.5 L/day. In this
study satavaptan increased the urinary flow rate from 1.5 to
2.5 L/day over the first 5 days of the protocol. The urinary
osmolality decreased by more than 50%, the free-water
clearance became positive and the hyponatremia corrected
from 127 ± 5 mmol/L to 140 ± 6 (38). In the treated pa-
tients there were no significant changes of the urinary excre-
tion rats of sodium or potassium. Despite the increased urine
flow patients failed to lose weight. While this lack of a
weight loss has been seen in several long term clinical stud-
ies of vaptans in the satavaptan study (38) it implies that
several patients did not comply with the fluid restriction. In-
deed thirst was reported as an adverse event. In view of the
brisk initial diuresis it is not surprising that 10% of treated
patients showed an overly rapid correction rate of their hy-
ponatremia, i.e. > 12 mmol/L/day. No osmotic demyelisation
syndrome was observed. In one arm of the protocol satavap-
tan was given for a duration of 1 year. In this part of the
study satavaptan maintained the normonatremia and was
judged to be safe. The evidence suggests that satavaptan will
become an efficient oral agent for the treatment of euvo-
lemic and hypervolemic hyponatremia.
Tolvaptan
Tolvaptan or OPC 41061 is an orally available, potent se-
lective vasopressin-V-2 antagonist (39). In addition to ex-
perimental work, several phase II-III clinical studies have
been conducted already. In the Activ trial (Acute and
Chronic Therapeutic Impact of a Vasopressin Antagonist in
Congestive Heart Failure) (40) 319 patients admitted to hos-
pital in NYHA classes III and IV for worsening of conges-
tion received tolvaptan (30-90 mg q.d.) or placebo orally in
addition to diuretic therapy for up to 60 days. Tolvaptan in-
creased urine output from 2.3 to 4 L/day in the initial days
of the study, lowered the body weight by approximately 2
kg, improved signs and symptoms of heart failure and it
normalized the serum sodium concentration in the 68 par-
ticipants who had hyponatremia. There were no changes of
vital signs, serum potassium, blood urea nitrogen or serum
creatinine, although “renal failure” occurred in 5 treated pa-
tients and resulted in discontinuation of tolvaptan. Thirst and
polyuria were the most frequently reported adverse events.
In another study of tolvaptan the efficiency of the agent in
correcting a hyponatremia was compared with that of a fluid
restriction at 1,200 cc/day (41). The study incorporated 28
patients with euvolemic or hypervolemic hyponatremia and
889
the treatment phase lasted up to 27 days. The dose of
tolvaptan was 60 mg per day. The serum sodium concentra-
tion increased from 129 ± 3 mmol/L to 134.7 ± 3.2 in the
treatment group, but it remained at 129.7 ± 3 in the placebo
group．―In a large trial of 4,133 patients with heart failure
30 mg of tolvaptan or placebo was given over 9.9 months
(42). Tolvaptan improved dyspnoea, body weight and
edema. In patients with hyponatremia the serum sodium in-
creased. The most frequently observed adverse events were
thirst and dry mouth. However considering the large number
of participating subjects and the long duration of observa-
tion it is very important that tolvaptan turned out to be a
safe agent (42)．―Another recent large trial―SALT I+II
(Study of Ascending Levels of Tolvaptan in Hyponatre-
mia)― with a total of 448 patients was primarily directed
at hyponatremia (43). Patients with euvolemic or hypervo-
lemic hyponatremia (128.8 ± 4.1 mmol/L) received tolvap-
tan 30-60 mg orally once a day or placebo in a randomized,
double blind fashion. Patients were not under a fluid restric-
tion. The study was conducted over 30 days on therapy fol-
lowed by 1 week of observation after discontinuation of
therapy. It was observed that tolvaptan―but not placebo―
corrected the hyponatremia in all diagnostic categories and
groups of severity of hyponatremia (43) (Fig. 2). After dis-
continuation of tolvaptan hyponatremia recurred. In the pa-
tients receiving tolvaptan the correction of hyponatremia
was associated with a significant improvement of the mental
health status as measured by the SF-12 questionnaire. Sur-
prisingly body weight did not change. The most frequently
encountered adverse events were: thirst, dry mouth, consti-
pation and weakness. Overly rapid correction of a hypona-
tremia was not seen and there was no therapeutic overshoot
into the hypernatremic rage. This outpatient study for the
first time demonstrated the feasibility―and the benefits―of
long term treatment of hyponatremia with an oral vaso-
pressin antagonist.
The Treatment of Hyponatremia
What are the implications of the data discussed in the
foregoing sections for the treatment of hyponatremia?
Several principles are straightforward:Hyperosmolar and
normoosmolar hyponatremia suggest the presence of hyper-
glycemia or mannitol and action should be directed at these
components. Hyponatremia in the presence of stage IV or V
renal failure is probably the result of fluid intake in excess
of 3 L/day and stopping the polydipsia will cure the hy-
ponatremia. Hyponatremia in hypovolemic states―i.e. after
gastrointestinal fluid losses―is best treated by infusions of
isotonic saline. Such infusions will suppress ADH and en-
able the kidneys to excrete the excess water rapidly.
However, hyponatremia of euvolemic and hypervolemic
states is the area in which future changes are imminent. The
vasopressin antagonist conivaptan is already on the market;
other agents are expected to follow soon. How should vaso-
pressin antagonists be used to treat hyponatremia? What will
 Inter Med 47: 885-891, 2008 DOI: 10.2169/internalmedicine.47.0918

Figure2. Co urs
eo ft
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odium co
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rati
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olvaptanonday1(ci
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.Therapywi t
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be the advantages for the patients?
It is likely that physicians will begin to utilize vaptans in
chronic mild to moderate hyponatremia because this is the
area in which experience has accumulated from previous
studies. In the treatment of chronic hyponatremia a slow
correction rate of <12 mmol/L/day will be the intended pro-
cedure. Treatment should be decelerated or stopped when a
serum―sodium of approximately 134 mmol/L―i.e. the
minimally hyponatremic range―has been reached. These
precautions should be observed to avoid the risk of osmotic
demyelination. In the future physicians may continue to rec-
ommend fluid restrictions―but this measure will no longer
be strictly required. In choosing a starting dose of any given
vaptan it shall be advisable to begin with a small dose, es-
piecially in patients with SIADH, to avoid an overly rapid
correction rate. It is foreseeable that the physician will have
to control the serum sodium concentration repeatedly, per-
haps daily in the first 3 days to titrate the dosage of the vap-
tan;thereafter weekly checking may suffice to keep the
serum-sodium in the normal range over the first 3 weeks.
Should a vaptan therapy be required over months and years
specific controls of the serum-sodium should be done during
episodes of fluid stress such as in the context of intercurrent
diarrhea, vomiting or during heat waves.
What advantages may patients expect from vaptan treat-
ment? It is likely that patients will be satisfied to be able to
discontinue fluid restrictions. It is also to be expected that
correction of hyponatremia by vaptan treatment will be fol-
lowed by improvement of patients’ neural status. Further-
more in patients with chronic forms of hyponatremia vap-
tans should prove useful in preventing occasional precipitous
decreases in the serum-sodium concentration that happen
unpredictably, especially during times of fluid stress. Finally,
vaptans are likely to make any treatment of hyponatremia
more specific and better titratable for the physician. Hence
these novel agents should turn out to be interesting thera-
peutic tools.

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