Syndrome of inappropriate antidiuretic hormone secretion
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Transcript of Syndrome of inappropriate antidiuretic hormone secretion
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SIADHSYNDROME OF INAPPROPRIATE
ANTIDIURETIC HORMONE SECRETION
Speaker- Dr Rahul Arya
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ANTI DIURETIC HORMONE
ADH/AVP is nonapeptide that is synthesized in hypothalamus and transported to posterior pituitary where it is stored.
AVP secretion is regulated by effective osmotic pressure of body fluids.
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MECHANISM OF ACTION OF AVP
Stimuli for AVP secretion
Hyperosmolarity – sensed by osmoreceptors in
the hypothalamus.
Circulating volume depletion – sensed by
baroreceptors in carotid sinus, aortic arch,
pulmonary veins and left atrium.
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SIADH
It is a disorder of impaired water excretion caused
by the inability to suppress the secretion of
antidiuretic hormone (ADH).
Inappropriate, continued secretion or action of ADH
despite normal or increased plasma volume.
Results in impaired water excretion, and
subsequently hyponatremia and hypo-osmolality.
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The release of ADH is not inhibited by a reduction in plasma osmolality.
The non-physiological secretion of AVP results in enhanced water reabsorption, leading to dilutional hyponatremia.
Transient expansion of extracellular fluid volume.
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NEUROLOGICAL PATHOPHYSIOLOGY
Hyponatremia and hypo-
osmolality cause acute
cerebral oedema.
Brain ECF moves into
CSF.
Rapid adaptation occur
within hours as a result
of loss of electrolytes.
Slow adaptation occur
over several days with
loss of organic
osmolytes.
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ETIOLOGY
Increased secretion of ADH-
CNS- stroke, hemorrhage, infection, trauma, psychosis.
Drugs- cyclophosphamide, vincristine, vinblastine, amiodarone, ciprofloxacin, theophylline, antipsychotic drugs (haloperidol, thioridazine, thiothixene), SSRI, TCAs, MAOIs, bromocriptine, clofibrate.
Pulmonary conditions- pneumonia, ARDS, asthma, atelectasis.
Post operative states- major abdominal or thoracic surgeries.
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Ectopic secretion of ADH-
Lung cancers, tumors of duodenum and pancreas,
olfactory neuroblastoma, malignant histiocytosis,
mesothelioma, occult tumors.
Increased sensitivity to ADH-
NSAIDs, cyclophosphamide, tolbutamide,
carbamazepine, mizoribine, chlorpropamide.
Miscellaneous-
exogenous administration of vasopressin,
desmopressin, cachexia, malnutrition, AIDS.
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CLINICAL FEATURES
Signs and symptoms depends on both degree of hyponatremia and rate at which hyponatremia develops.
When sodium conc’n decreased slowly-asymptomatic or non specific symptoms like anorexia, nausea, vomiting, irritability, headaches and abdominal cramps.
Rapid decline- more severe symptoms.
Serum sodium conc <120 mEq/L or serum osmolality <240mOsm/kg is serious irrespective of rate of decline.
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Patient can have cerebral edema manisfesting as
headache, nausea, restlessness, irritability, muscle
cramps, generalized weakness, hyporeflexia,
confusion, coma, seizures, brainstem herniation or
death.
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EVALUATION AND DIAGNOSIS
Careful history– comorbities, current medications
and patient’s symptoms.
No significant findings in physical examination but
signs of dehydration or edema would make
diagnosis unlikely.
Key points in diagnosing SIADH are-
Serum sodium concentration.
Tonicity of plasma and urine
Urine sodium concentration
Clinical volume status.
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DIAGNOSIS OF SIADH
Essential Features-
Plasma osmolality <275 mOsm/kg.
Urinary osmolality >100 mOsm/kg.
Urinary Na >20 mEq/l with normal dietry salt intake.
Normal thyroid, adrenal, cardiac, liver and kidney function.
Clinical euvolemia i.e no clinical signs of volume depletion/ excess like tachycardia, decreased skin turgor, dry mucus membrane, edema, ascites.
No recent use of diuretic agent.
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DIAGNOSIS OF SIADH
Supplemental features-
Plasma uric acid <4 mg/dl.
Blood urea nitrogen <10 mg/dl.
Correction of hyponatremia through fluid restriction.
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CEREBRAL SALT WASTING SYNDROME
Rare syndrome seen in patients with cerebral
tumors, subarachnoid hemorrhage, patients who
have undergone trans-sphenoidal pituitary surgery.
Mimics SIADH i.e hyponatremia, increased urine
osmolality, urine Na > 20 mEq/l and urine osmolality
> serum osmolality.
It represents appropriate water resorption with salt
wasting and a secondarily hypovolemic state
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SIADH VS CEREBRAL SALT WASTING SYNDROME
Clinical Features SIADH CSW
Plasma Na Low Low
ECF volume Normal or slightly
increased
Decreased
Postural hypotension Absent Present
ADH Increased Increased
Urine osmolality Inappropriately high Appropriately high
Urine Na excretion Increased >40 mEq/l
because of volume
expansion
Increased >40 mEq/l
because of salt wasting
Plasma uric acid level Low due to volume
expansion
Low due to urinary
losses
Effect of isotonic saline May worsen
hyponatremia
Improves hyponatremia
Treatment Free water restriction,
hypertonic saline
infusion,
diuretics,vaptans
Infusion of isotonic
saline, Salt loading
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TREATMENT
Treatment depends on-
Symptoms
Serum sodium concentration
Rapidity of onset of hyponatremia
Primary etiology
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Mild asymptomatic hyponatremia(serum Na
>125mEq/L)-
Fluid restriction is the 1st line treatment.
It generally improves with correction of underlying
cause and restriction of free fluid intake to 800-
1000 ml/d.
If no response, fluid intake can be restricted to 500-
600 ml/d.
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Mild symptomatic hyponatremia-
Fluid restriction.
Loop diuretic- it interfere with the action of ADH in
collecting tubules by inhibiting free water
reabsorption.
The osmolality of infused saline must exceed the
osmolality of patient’s urine.
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Severe symptomatic hyponatremia (serum Na
<125 mEq/L)-
Fluid restriction
Hypertonic saline- infused via pump and urine
osmolality can be followed to guide therapy.
Hypertonic saline can be switched to isotonic saline
when urine osmolality is <300 mOsm/L.
Aggressive and overly rapid correction may induce
central pontine myelinosis.
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CENTRAL PONTINE MYELINOSIS
It is a demyelinating condition affecting pontine and
extrapontine neurons.
It leads to quadriplegia, pseudobulbar palsy,
seizures, coma or even death.
High risk patients are-
Patient with hypokalemia
Burn patient
Patient on thiazide diuretics
Alcoholics
Elderly
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Serum Na level should be raised at rate no faster
then 1-2 mEq/h and rate should not exceed 8-12
mEq/d.
Once serum Na rises above 125 mEq/l, risk of
seizures and death is reduced and daily correction
is slowed to 5-6 mEq/d.
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Chronic SIADH-
High sodium diet with loop diuretics.
Treatment of underlying cause.
Other agents which can be used are-
Demeclocycline
Lithium
Urea
Vaptans
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DEMECLOCYCLINE
Tetracycline antibiotic.
Interfers with action of ADH on collecting tubules.
Induces nephrogenic diabetes insipidus in 70% of cases.
Onset of action takes over a week.
Dose is 600-1200 mg daily in divided doses.
May lead to irreversible renal failure.
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LITHIUM
Causes nephrogenic diabetes insipidus in 65% of
cases.
Reduces aquaporin-2 expression.
Effect takes 3-4 days to set in.
Narrow therapeutic index 0.6-1.2 mEq/l.
It induces tubulo-interstitial nephritis that can lead
to irreversible NDI and end stage renal failure.
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UREA
Causes osmotic diuresis and enhanced water
excretion.
15-30 g of urea in glass of orange juice 2-3 times a
day after meals.
Very cost effective and correct hyponatremia slowly
by 2-3 mmol/l/d.
Because of its bitter taste many patient are not able
to tolerate it.
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OTHER OPTIONS..
Extracorporeal Treatments-
Veno-venous hemofiltration.
SLEDD (Slow Low Efficacy Daily Dialysis).
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VAPTANS
Vasopressin receptor antagonist.
3 types of vasopressin receptors:-
subtype location action
V1a Vascular smooth
muscle
Vasoconstriction
V1b Anterior pituitary ACTH release
V2 Renal cortical and
medullary collecting
duct
Insertion of the water
channel aquaporin-2
in the luminal
membrane of the
collecting duct, thus
making it more
permeable to water.
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Types of Vaptans-
1. Non selective (mixed V1a/V2)- Conivaptan.
1. V1a selective- Relcovaptan.
2. V1b selective-Nelivaptan.
3. V2 selective- Lexivaptan
- Mozavaptan
- Satavaptan
- Tolvaptan.
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Few studies have been performed to study efficacy
of vaptans in SIADH patients.
Several studies of short duration reported that
vaptans were efficacious in increasing serum
sodium concentration.
There is however paucity of long term observations
in SIADH.
But there is little doubt that these agents will be
effective in treatment of chronic hyponatremia.
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CONIVAPTAN
Conivaptan is available as an intravenous
preparation.
There is initial loading dose of 20 mg over 30 min
followed by continuous infusion at a rate of 20 mg/d
for up to 4 days.
Side effects- infusion site reactions, postural
hypotension, mild to moderate increase in BUN or
creatinine and significantly increased thirst.
It is an efficient t/t for hyponatremia of 117-128
mmol/l.
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TOLVAPTAN
Tolvaptan is available as a tablet usually taken once
a day in morning.
The recommended dosage is 15-30 mg/day.
Patient should discontinue any previous fluid
restriction and drink fluid freely though not
excessively.
Long term t/t over 1-2 year is effective and no
tachyphylaxis occurred.
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Adverse effects- constipation, nausea, dizziness,
weakness, hyperglycemia and UTI.
The patients treated with vaptans no longer need
fluid restriction, correction of hyponatremia occur
efficiently and quickly and hospitalization is shorter.
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SUMMARY
SIADH is most common cause of hponatremia in
hospitalized patients.
Symptoms of SIADH depends on degree of
hyponatremia and rate at which it develops.
SIADH is a diagnosis of exclusion, and adrenal,
cardiac, liver, kidney and thyroid dysfunction must
be ruled out.
Mild symptomatic hyponatremia is treated with fluid
restriction.
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Severe symptomatic hyponatremia is treated with
hypertonic saline in addition to fluid restriction.
To avoid neurological complications the serum
sodium level should be raised no faster than 1 to 2
mEq/h and no faster than 8-12 mEq/day.
The use of Vaptans has been considered a
breakthrough in treatment of hyponatremia;
however long term reports on the safety profile is
not available yet.
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