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FILE 20201125 231142 Hyponatremia A Practical Approach
FILE 20201125 231142 Hyponatremia A Practical Approach
FILE 20201125 231142 Hyponatremia A Practical Approach
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Review Article
A B S T R A C T
Hyponatremia is an important and common clinical problem. The etiology is multifactorial. Hyponatremia may be euvolemic, hypovolemic
or hypervolemic. Proper interpretation of the various laboratory tests helps to differentiate the various types of hyponatremia. Treatment
varies with the nature of onset ‑acute or chronic, severity and symptoms. Normal saline forms the mainstay of treatment for hypovolemic
hyponatremia while 3% NaCl and fluid restriction are important for euvolemic hyponatremia. Hypervolemic hyponatremia responds well
to fluid restriction and diuretics. There have been several recent advances in the last year with revision in the guidelines for treatment
and availability of vaptans. Judicious use of vaptans may help in treatment of hyponatremia.
Corresponding Author: Dr. Manisha sahay, 6‑3‑852/A Ameerpet, Hyderabad - 500 016, Andhra Pradesh, India. E‑mail: drmanishasahay@gmail.com
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• Abnor mal ADH secretion e.g. Syndrome of plasma proteins in conditions such as multiple myeloma.
inappropriate ADH release described below (SIADH). In normal subjects, the plasma water is 93 percent of the
plasma volume, fats and proteins account for the remaining
Symptoms 7 percent. Plasma water fraction falls below 80 percent in cases
Acute hyponatremia is characterized by onset of with marked hyperlipidemia (triglycerides >1500 mg/dL)
symptoms <48h. Patients with acute hyponatremia develop or hyperproteinemia (protein >10 g/dL).[4,5] Here, the
neurologic symptoms resulting from cerebral edema plasma water sodium concentration and plasma osmolality
induced by water movement into the brain. These may are unchanged, but the measured sodium concentration
include seizures, impaired mental status or coma and death. in the total plasma volume is reduced since the specimen
contains less plasma water. In renal failure, the elevation
Chronic hyponatremia‑ Hyponatremia developing in blood urea counteracts the fall in serum osmolality due
over >48 h should be considered “chronic.” Most to hyponatremia. However, the effective serum osmolality
patients have chronic hyponatremia. The serum sodium is appropriately reduced in this setting since urea is an
concentration is usually above 120meq/L. Brain adapts ineffective osmole.
itself to hyponatremia by generation of idiogenic
osmoles. This is a protective mechanism that reduces Translocational (hyperosmolal) or hypertonic or
the degree of cerebral edema; it begins on the first day redistributive hyponatremia is due to presence of
and is complete within several days. Hence in chronic osmotically active solutes in the serum e.g., mannitol
hyponatremia patients may appear asymptomatic. Mild or glucose. [6] When the plasma contains significant
hyponatremia is characterized by gastrointestinal tract amounts of unmeasured solutes, such as mannitol or
symptoms nausea, vomiting, loss of appetite. Sometimes, radiographic contrast agents, plasma osmolality cannot
subtle neurologic abnormalities may be present when be calculated accurately and must be ascertained by direct
the serum sodium is between 120 and 130 meq/L. measurement.
Hyponatremia in the elderly may manifest with frequent
falls and gait disturbances.[3] True (hypoosmolal) hyponatremia is associated with
reduction in serum osmolality and is further classified as
Classification of hyponatremia euvolemic, hypervolemic and hypovolemic[7‑9] [Figure 2].
Hyponatremia is classified as pseudo hyponatremia, true
and translocational hyponatremia [Figure 1]. Etiology of true hyponatremia
Hypovolemia hyponatremia
Normal serum osmolality is 280‑295 mosm/kg. The It is associated with low plasma volume. The causes of
serum osmolality (S Osm) can be calculated by the hypovolemic hyponatremia may be renal or non-renal
concentration in millimoles per liter of the major serum [Figure 2].
solutes according to the following equation: Sosm
(mmol/kg) = (2 × serum [Na]) + (serum [glucose]/18) Cerebral salt wasting (CSW): Resembles SIADH [Table 1]
+ (blood urea nitrogen/2.8). except that in CSW renal salt wasting and volume depletion
is the main defect with secondary rise in ADH whereas
Pseudo (normo‑osmolal) or isotonic hyponatremia is a high arginine vasopressin (AVP) level is the primary
due to presence of hypertriglyceridemia or increase in etiologic event in patients with SIADH [Table 2].
+\SRQDWUHPLD
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Diuretic‑induced hyponatremia: Hyponatremia is common thiazides, may be severe and is common in elderly females.
with use of thiazides, begins soon after initiation of Thiazide‑induced hyponatremia, occurs due to increased
water intake, reduction in diluting ability and water excretion
Table 1: Diagnostic Criteria of SIADH in distal tubule. Sodium plus potassium concentration in urine
Schwartz diagnostic criteria for SIADH exceeds that in the plasma, which directly lowers plasma
Decreased measured serum osmolality (<275 mOsm/kg H2O) sodium concentration.[10] Loop diuretics cause inhibition of
Clinical euvolemia sodium chloride transport in the loop of Henle which prevents
Urinary osmolality >100 mOsm/kg H2O
Urinary [Na+] >40 mmol/L with normal dietary sodium intake
the generation of the countercurrent gradient and therefore
Normal thyroid and adrenal function. restricts water retention by ADH. Hence hyponatremia
Normal renal functions is not common with loop diuretics. Furosemide‑related
Exclude use of diuretic agents within the week prior to evaluation hyponatremia tends to occur after many months of therapy,
No hypokalemia, no acid base disorders
Supporting diagnostic criteria for SIADH often when an intercurrent illness develops.
Serum uric acid<4 mg/dL
Blood urea nitrogen <10 mg/dL Mineralocorticoid deficiency is another important cause
Fractional sodium excretion >1%; fractional urea excretion >55%
Failure to improve or worsening of hyponatremia after 0.9% saline
of hypovolemic hyponatremia and may be associated with
infusion hyperkalemia.
Improvement of hyponatremia with fluid restriction
SIADH: Syndrome of inappropriate secretion of anti diuretic hormone Euvolemic hyponatremia
It is the most common and accounts for 60% of all cases
Table 2: Differential diagnosis of SIADH
of hyponatremia. The commonest cause of euvolemic
SIADH Cerebral salt wasting
hyponatremia is Syndrome of inappropriate secretion
Pathogenesis Inappropriate Increased Brain of Anti diuretic hormone (SIADH).[11] Other causes are
ADH secretion natriuretic peptide shown in Figure 2.
Hyponatremia Yes Yes
Urinary Sodium
ECF volume
High
Increased
High
Decreased
Siadh
BP and CVP Normal Normal/low normal
Urine volume Normal/low High The criteria necessary for a diagnosis of SIADH were
Blood urea Normal/low High defined by Bartter and Schwartz in 1967.[12] The essential
BUN/creatinine ratio Decreased Increased
Plasma uric acid Decreased Normal or decreased and supporting diagnostic criteria are shown in the Table 1.
Hematocrit Normal Increased The final criterion emphasizes that SIADH remains a
Treatment Fluid restriction+ Normal saline+ diagnosis of exclusion and the absence of other potential
Furosemide Fludrocortisone rarely
causes of hypo‑osmolality must always be verified.[12‑14] The
SIADH: Syndrome of inappropriate secretion of anti diuretic hormone,
BUN: Blood urea nitrogen, BP: Blood pressure, ECF: Extracellular fluid, causes of SIADH are shown in Tables 3 and 4.
CVP: Central venous pressure
Pathogenesis of hyponatremia in SIADH
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of thirst. Thus normal osmolality is not achieved. As ADH decreased skin turgor) should be considered hypovolemic.
regulation is intact in primary polydipsia they can produce When available, direct hemodynamic measurements can
more than 400 to 600 mL of dilute urine per hour, when provide corroboration of the clinical impression. Signs of
ADH is suppressed with a minimum urine osmolality of hypothyroidism or adrenal insufficiency should be noted.
40 mosmol/kg. Excess water is thus excreted and hence Also a detailed examination should be done to detect any
serum sodium concentration is normal or only slightly CNS or lung lesion.
reduced and hence these patients are usually asymptomatic
or may have polydipsia and polyuria. However; they cannot Investigations
excrete massive water load (400 to 600 mL per hour) which Step 1: Measurement of serum sodium
may be seen in psychotic patients or acute water load of Ideally by ion specific electrode (ISE) using direct
3 to 4l. This may cause fatal hyponatremia even though the potentiometry (IB).[9,30]
urine is maximally dilute.[27]
Pseudohyponatremia (falsely low Na with normal plasma
The cause for defective thirst is not known. In some osmolality) is not seen if ISE with direct potentiometry
patients hypothalamic lesions that affect the thirst center, method is used. However, many laboratory analyzers
infiltrative diseases such as sarcoidosis can result in primary that measure sodium with ion‑selective electrodes utilize
polydipsia. Patients with polydipsia should be evaluated indirect potentiometry in which the plasma sample is
with a computed tomography or magnetic resonance diluted before measurement; these analyzers will report a
imaging (MRI) scan of the brain before concluding that low sodium concentration. Flame photometers may result
excessive water intake is due to a psychiatric cause. There in low values of serum sodium as they measure the sodium
is no specific therapy for primary polydipsia.[28] Limiting only in aqueous phase.
water intake rapidly raises the plasma sodium as the excess
water is readily excreted. In long term limiting the use of Step 2: Serum osmolality
drugs that cause dry mouth, restricting fluid intake and It differentiates true, pseudo or translocational hyponatremia
frequent weighing are useful. [Figure 1]. Calculated serum osmolality may not reflect
serum osmolality if other osmotically active solutes are
Hypervolemic hyponatremia present in the plasma. Hence, serum osmolality should
It is seen in congestive heart failure and cirrhosis of liver, be measured by osmometer, (IB). If osmometer is not
nephrotic syndrome and chronic kidney disease. Even available, random blood sugar, serum triglyceride and
though the plasma and extracellular volumes is increased serum protein should be helpful in differentiating the
in heart failure and cirrhosis, there is ADH stimulation three types.[1] Each mg increase in blood glucose above
as described under pathogenesis. The development of 100 mg/dl decreases the serum sodium by 1.6 meq/l. When
hyponatremia is a poor prognostic sign. blood sugar is less than 200 to 300 mg/dl, hyperglycemia
has negligible effect on serum sodium concentration.
Hyponatremia occurs commonly in both acute and chronic When serum triglycerides are above 100 mg/dl, for every
renal failure, because the kidneys cannot maximally excrete 500 mg/dl rise in serum triglycerides, fall in serum sodium
excess ingested water. In contrast, hyponatremia is not will be about 1.0 mEq/L. When serum protein is above
very common in the nephrotic syndrome unless associated 8 gm/dl, for every 1 gm/dl rise in serum protein, fall in
with a substantial decrease in GFR. However, with severe serum sodium will be about 4.0 mEq/L.
hypoalbuminemia of <2g/dL, intravascular hypovolemia
may occur and lead to the nonosmotic release of AVP with Step 3: Urine osmolality
subsequent retention of hypotonic fluids. Fluid restriction Urine osmolality can be used to distinguish between
is the cornerstone of therapy. impaired water excretion and hyponatremia with normal
water excretion [Table 5].
Diagnosis of hyponatremia
History and examination Impaired water excretion (Urine osmolality > 150 mosm/kg).
Drug and diet history, history of volume loss i.e. diarrhea,
vomitings should be noted. The normal response to hyponatremia is marked
suppression of ADH secretion, resulting in the excretion
Determination of volume status i.e. dehydration, oedema, of a maximally dilute urine with an osmolality below
ascites should be carried out.[29] Patients with clinical signs 100 mosmol/kg and a specific gravity ≤1.003. Values above
of volume depletion (e.g. orthostatic decreases in blood this level indicate an inability to normally excrete free water,
pressure and increases in pulse rate, dry mucus membranes, most commonly because of persistent secretion of ADH.
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Table 5: Urine osmolality for differential diagnosis of Step 5: Urine to serum electrolyte ratio
hyponatremia It is the sum of the urine sodium plus potassium
High urine Low urine concentrations divided by the serum sodium concentration.
osmolality>150 mosm/kg osmolality<150 mosm/kg
Hypovolemic hyponatreima Hypovolemic hyponatremia • Ratio < 0.5 (high urine electrolyte‑free water)‑ fluid
Salt depletion Acute diuretic use
restriction is adequate
Cerebral salt wasting
Adrenal insufficiency • Ratio > 1 (urine is hypertonic compared to the
Euvolemic hyponatremia Euvolemic hyponatremia serum‑ water restriction is not sufficient and other
with high urine Na therapeutic measures are necessary to correct the
SIADH SIADH (reset osmostat variety)
Beer potomania hyponatremia.[31]
Exercise induced hyponatremia
Primary polydipsia Step 6: Fractional excretion of sodium
SIADH: Syndrome of inappropriate secretion of anti diuretic hormone Fractional excretion of sodium (FENa) provides an
accurate assessment of volume status than the urine sodium
Step 4: Urine sodium alone because it corrects for the effect of variations in urine
Determination of source of sodium loss-renal or non renal volume on the urine sodium.
is the next step.
In patients with normal renal function and hyponatremia
This is done by measuring the urinary sodium losses. cut off for FENa is <0.1%.
In patients with hypoosmolal hyponatremia and
inappropriate urine concentration, the urine sodium and • <0.1%‑ hypovolemic hyponatremia
urine chloride concentrations can be used to distinguish • >0.1%‑ hypervolemic and normovolemic hyponatremia.
between hypovolemic and euvolemic hyponatremia
In hypovolemic hyponatremic patients who have Step 7: Serum uric acid and urea concentrations
metabolic alkalosis caused by vomiting, the urine sodium Low serum uric acid and urea
concentration may be greater than 20 meq/L, but the
urine chloride concentration will be low (less than 20 • SIADH: The water retention in SIADH is associated
meq/L). with hypouricemia and low BUN. Serum uric acid
<4 mg/dL is due to increased uric acid excretion
Clinical assessment of volume status is less accurate than in the urine resulting from reduced proximal
urine sodium. sodium and uric acid absorption. Stimulation of the
vasopressor V1a receptor also contributes to the uric
If initial urine sodium concentration is equivocal, it could acid wasting. Water retention also causes low BUN.
be difficult to differentiate true hypovolemia or euvolemic Thus, in hyponatremia due to SIADH, the blood urea
hyponatremia. In this situation serial monitoring of the nitrogen (BUN) is usually less than 5 mg/dL. However
urine osmolality and urine sodium concentration in as urea excretion decreases with aging the absence
response to the administration of 1litre 0.9% NaCl can of a low BUN cannot be used to exclude SIADH in
help clarify the diagnosis. older patients[32,33]
• Hypopituitarism
• If the patient is hypovolemic, 0.9% NaCl should • Hypervolemia (V1a receptor stimulation) increases
suppress the hypovolemic stimulus to ADH release, urinary urea clearance
promoting the excretion of a dilute urine (urine • Thiazide diuretic‑induced hyponatremia similar
osmolality usually less than 100 mosmol/kg) and rapid reductions in uric acid and urea levels can occur in
correction of the hyponatremia patients with thiazide diuretic‑induced hyponatremia
• If the patient has SIADH, ADH release occurs where thiazides are used for water overload.
independently of the volume status and the urine
osmolality will remain elevated following 0.9% NaCl Normal serum uric acid and urea
therapy. • In hypovolemia the levels of urea and uric acid may be
normal or high.
In both disorders, the urine sodium concentration will
increase with saline therapy, although the increase in Step 8: Acid‑base and potassium balance
hypovolemic patients will not be seen until the hypovolemia Evaluation of acid‑base and potassium balance may be
is corrected. helpful in some patients.[34]
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• Metabolic alkalosis and hypokalemia ‑ diuretic use or acute hyponatremia. 3% NaCl is recommended with or
vomiting without vasopressin receptor antagonists.[9,30,35,36] and Initial
• Metabolic acidosis and hypokalemia ‑ diarrhea or administration of 3% NaCl therapy is needed to raise the
laxative abuse serum sodium by 4‑6 mmol above baseline.
• Metabolic acidosis and hyperkalemia ‑ primary adrenal
insufficiency in patients without renal failure Patients with mild symptoms (eg, dizziness, forgetfulness,
• Normal acid base and potassium ‑ in the SIADH gait disturbance) should be treated with less aggressive
• Mild metabolic alkalosis and normal K‑ is seen in therapy.
hypopituitarism because of higher plasma aldosterone levels.
• Fluid restriction if the urine to serum electrolyte ratio
Step 9: Saline infusion is less than 0.5
In case of doubt, one can initiate 0.9% NaCl infusion • Among patients with urine to serum electrolyte ratio
with monitoring of serum sodium and follow‑up at 6 to greater than 1, in whom fluid restriction will not be
8 h. Hypovolemic hyponatremia improves with 0.9% NaCl sufficient to achieve the desired goal, additional therapy
while hyponatremia in SIADH may not be corrected and includes salt tablets and if necessary, a loop diuretic
usually worsens with 0.9% NaCl administration. • An alternative approach is the initiation of a vasopressin
antagonist without fluid restriction.
Other investigations
Thyroid profile, ACTH and ACTH stimulation tests, CT/ Rate of correction: In chronic hyponatremia the
MRI brain and imaging of chest are done as needed. brain undergoes adaptation and hence the risk of
cerebral herniation is very low unlike the risk in acute
General Guidelines for Treatment hyponatremia. Instead very rapid correction can lead to
osmotic demyelination syndrome (ODS). Hence, chronic
Principles of treatment of hyponatremia hyponatremia generally needs gradual correction. High
Treatment depends on risk of ODS is seen esp. if serum sodium is 120meq/L or
• Volume status less or if comorbidities such as alcoholism, liver disease,
• Duration of hyponatremia (whether acute/<48 h or malnutrition, or severe hypokalemia are present. Apart
chronic >48 h) ) from rapid rate of correction, ODS may also occur in
• Presence or absence of symptoms patients whose hyponatremia “autocorrects” unexpectedly
• Etiology of hyponatremia.[9,30,35,36] e.g., hyponatremia caused by cortisol deficiency,
desmopressin acetate (DDAVP).etc
Euvolemic hyponatremia
General treatment • In patients with low risk of ODS a maximum 10‑12 meq/L
• Acute hyponatemia is generally symptomatic. The increase in serum sodium concentration in 24 h is
risk of brain herniation is high and rapid correction is sufficient to reverse most severe manifestations of acute
needed. Acute hyponatremia is common in marathon hyponatremia. Recent guidelines propose a rise of 4 to 8
runners, patients with primary polydipsia and users of mmol/day (maximum of 10 to 12 mmol/day)[1]
ecstasy. These patients have not had time for the brain • In patients with high risk of ODS the serum sodium
adaptations to occur. Treatment is recommended with concentration be raised by a goal of 4 to 6 meq/L
3% NaCl (1 litre = 513meq Na+). Recent guidelines per 24 h and by less than 9 meq/L in any 24 h period.
have suggested giving a bolus of 100ml 3% NaCl IV Recent guidelines suggest an increase of 4 to 6mmol
over 10 min, repeated upto 3 doses till acute symptoms is sufficient with maximum of 8 mmol/l.[1]
subside. The goal is to provide an urgent correction by
4 to 6 mmol/L to prevent brain herniation. For mild Osmotic demyelination‑It is a rare, but severe and
to moderate symptoms with a low risk of herniation, sometimes irreversible disorder. It presents with locked
3% NaCl is infused at 0.5‑2 mL/kg/h[1] in syndrome i.e. quadriparesis with preserved vertical
• Chronic hyponatremia‑ It is generally asymptomatic eye movements. This disorder was formerly called
or has mild symptoms. However; it may present with central pontine myelinolysis (CPM), but the name was
seizures if hyponatremia is very severe. changed because demyelination is more diffuse and does
not necessarily involve the pons and.[37‑40] andIn chronic
If chronic hyponatremia is symptomatic (seizures or hyponatremia brain adaptation reduces the severity of brain
confusion) or is severe (serum sodium concentration swelling but this adaptation also increase the risk of harm
below 125 meq/L aggressive therapy is indicated as for from rapid correction of the hyponatremia leading to ODS.
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Recently, it has been shown that ODS can be reversed by as per above formulae. Approximately 1 ml/kg of 3% NS
relowering sodium and giving desmopressin.[1,41] increases the serum sodium by 1meq/l. Careful monitoring
of the serum sodium is essential to prevent very rapid
Equation to estimate efficacy of initial therapy correction.
• The degree to which one liter of a given solution
initially raises the serum sodium concentration (SNa) Fluid restriction: The effectiveness of fluid restriction
in a hyponatremic patient, without any water or sodium can be predicted by the urine to serum electrolyte ratio
losses in the urine, is estimated from the Adrogué‑Madias as described above. All fluids, not only water, must be
formula, ie Increase in SNa = (Infusate [Na] – SNa) included in the restriction; several days of restriction are
÷ (TBW + 1) where TBW is the estimated total usually necessary before a significant increase in plasma
body water (lean body weight times 0.5 for women, osmolality occurs; and only fluid, not sodium, should be
0.6 for men). Adrogué‑Madias formula cannot be restricted. Thirst, can be ameliorated by substituting hard
used as the sole guide to therapy; monitoring of the candy or ice chips for drinking fluids.
serum sodium concentration is essential in all cases.
Potassium added to the solution should be included Diuretics: Concurrent use of a loop diuretic is beneficial
in the formula (i.e. “Infusate [Na + K]” rather than in patients with SIADH who have a high urine to serum
“Infusate [Na]”) as potassium administration for electrolyte (>1). Furosemide inhibits the sodium chloride
concurrent hypokalemia can raise the serum sodium reabsorption in the thick ascending limb of the loop of
concentration Henle and cause more of water loss than sodium loss (urine
• Another formula was proposed to estimate both the produced is like ½ normal saline). Thiazides should not
sodium deficit and the direct effect of a given fluid be used.
(3% NaCl) on the serum sodium (SNa) concentration,
for example: Other drugs used for chronic SIADH are urea,
Sodium deficit = Total body water (TBW) × (desired demeclocycline and the vaptans.
SNa – actual SNa)
However, these formulae have limitations and cannot Demeclocycline: Causes a nephrogenic form of diabetes
be used to accurately predict the magnitude of change insipidus, thereby decreasing urine concentration even
in serum sodium and frequent measurements are in the presence of high plasma AVP levels. Appropriate
necessary. doses of demeclocycline range from 600 to 1,200 mg/day
• In the current guidelines these formulae are not used. administered in divided doses. Treatment must be continued
Instead 1ml/kg of 3% NaCl is estimated to raise the for several days to achieve maximal diuretic effects; one
serum Na by 1meq/l. should wait 3 to 4 days before deciding to increase the
In addition water restriction, salt, urea, demeclocycline and dose. Demeclocycline can cause reversible azotemia and
vaptans are used according to the etiology. sometimes nephrotoxicity, especially in patients with
cirrhosis and should be discontinued if increasing azotemia
Specific treatment for euvolemic hyponatremia occurs.
SIADH: It is important to rule out hypothyroidism and
glucocorticoid deficiency before diagnosis of SIADH. Vaptans: Role of vaptans in euvolemic hyponatremia is
The treatment of SIADH follows the same principles discussed below.
as mentioned above. Hyponatremia in SIADH is usually
chronic and hence slow correction is needed. In cases of Some causes of SIADH can be corrected e.g. self‑limited
chronic hyponatremia or mild symptoms water restriction is disease (e.g. nausea, pain, surgery), cessation of drugs that
the main cornerstone of treatment. Diurectics and vaptans cause SIADH and treatment of tuberculosis or meningitis
are the other drugs used. In some severe, symptomatic or
acute cases 3% NaCl is needed. Primary polydipsia
Fluid restriction is warranted in hyponatremic patients with
3% NaCl: Fluid must be given if the serum sodium primary polydipsia in whom increased fluid intake is the
concentration must be raised quickly because of primary problem.
symptomatic hyponatremia. The cation concentration of
the administered fluid must exceed the cation concentration Adrenal insufficiency
of the urine. 0.9% NaCl has a limited role in correction of Glucocorticoid deficiency should be excluded by proper
the hyponatremia in SIADH and 3% NaCl is the fluid of tests. Although glucocorticoid deficiency can be ruled out
choice. The amount of 3% NaCl needed can be calculated in some patients with a random or early morning cortisol
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I Vaptans in euvolemic hyponatremia treated with tolvaptan for hyponatremia for extended
Treatable causes of Euvolemic Hyponatremia should be periods (e.g. >30 days) due to risk of liver damage, but this
excluded e.g. hypothyroidism, glucocorticoid deficiency etc. decision should be based upon the clinical judgment of the
treating physician. Patients who are refractory to or unable
Vaptans are not recommended as single agents for the to tolerate or obtain other therapies for hyponatremia and
treatment of hyponatremic emergencies but could be used in whom the benefit of tolvaptan treatment outweighs
as dose‑sparing adjunctive therapy with 3% NaCl. the risks, remain candidates for long‑ term therapy with
tolvaptan; but in such cases, liver function tests should be
Vaptans are useful for chronic hyponatremia. Vaptans are monitored carefully and serially (i.e. every 3 m) and the
used in addition to fluid restriction and sodium chloride drug discontinued in the event of significant changes in
administration.[42,43] liver function tests (i.e. 2 times increase in ALT beyond
upper limit).
Tolvaptan: The efficacy of oral tolvaptan was demonstrated
in multicenter trials (SALT‑1 and SALT‑2)[44,45] in 448 patients Conivaptan is FDA approved for euvolemic hyponatremia
with hyponatremia caused by SIADH. Tolvaptan in hospitalized patients. It is available only as an intravenous
significantly increased serum sodium concentration. Even preparation and is given as a 20‑mg loading dose
with modest sodium improvement there was significant over 30 min, followed by a continuous infusion. Generally,
increase in mental scores. But the effect was not clinically the 20‑mg continuous infusion is used for the first 24 h.
significant and long‑term efficacy was doubtful as the If the correction of serum [Na”] is felt to be inadequate
patients were followed up for only 30 days. In SALT‑2 (e.g. <5 mmol/L), then the infusion rate can be increased
hyponatremia recurred after discontinuing of Tolvaptan. to 40 mg/d. Therapy is limited to a maximum duration
In SALTWATER trial (Safety and sodium Assessment of of 4 days because of drug‑interaction effects with other
Long‑term Tolvaptan With hyponatremia Trial to gain agents metabolized by the CYP3A4 hepatic isoenzyme.
Experience under Real‑world conditions) the mean serum Serum [Na”] concentration is measured frequently during
sodium in treated group was 135 meq/L versus 131meq/L the active phase of correction of the hyponatremia-a
at baseline in patients with SIADH,. and. At 50 weeks, the minimum of every 6 to 8 h, but more frequently in patients
serum sodium concentration normalized in approximately with risk factors. Although vaptans are not contraindicated
60% of the patients.In a multicenter trial (TEMPO 3:4)[46,47] with decreased renal function, these agents generally will
a greater than 2.5‑fold increase in liver enzymes was more not be effective if the serum creatinine is >2.5 mg/dL
common is study group versus placebo. Thus liver function
tests should be performed initially and LFT should be II Vaptans in hypervolemic hyponatremia
repeated three to four months after initiating therapy CHF
and then again at six‑month intervals. If liver injury is Vaptans can be used in CHF patients for management
suspected, tolvaptan should be discontinued. Recently of fluid overload and/or hyponatremia after water
FDA has recommended Tolvaptan use but not for greater restriction and diuretics have been tried. Hyponatremia
than 4 wks.[48] Tolvaptan treatment must be initiated in the in CHF is chronic and should be corrected till serum Na
hospital so that the rate of correction can be monitored is normal and symptoms improve.The level of serum
carefully. Patients with a serum [Na”] <125 mmol/L are Na should be normalized so that diuretic therapy for
eligible for therapy with tolvaptan as primary therapy; CHF can be optimised. In some studies , hyponatremia
if the serum [Na”] is >125 mmol/L, tolvaptan therapy was associated with increased mortality and increased
is only indicated if the patient has symptoms that could rate of re‑hospitalization in patients of acute heart
be attributable to the hyponatremia and the patient is failure.[49,50] Short‑term trials like EVEREST (Efficacy
resistant to attempts at fluid restriction. The starting of Vasopressin antagonist in hEart FailuRE outcome
dose of tolvaptan is 15mg on the first day and the dose Study with Tolvaptan)[51] and ACTIV in CHF (Acute and
can be titrated to 30mg and 60 mg at 24‑h intervals if Chronic Therapeutic Impact of Vasopressin antagonist
the serum [Na”] remains <135 mmol/L or the increase in Congestive Heart Failure)[52] showed a rapid increase
in serum [Na”] is <5 mmol/L in the previous 24 h. in serum sodium and improvement in hemodynamic
Serum [Na”] concentration should be measured during parameters with vaptans, however long‑term trials have
the active phase of correction of the hyponatremia at a failed to demonstrate a favorable effect on morbidity and
minimum of every 6 to 8 h. Fluid restriction should not be mortality. Further studies of the Vaptans are necessary to
used during the active phase of correction, thereby allowing determine whether serum sodium normalization will be
the patient’s thirst to compensate for vigorous aquaresis. translated into a better long‑term prognosis in patients
Appropriate caution should be exercised in patients with CCF.
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