SIADHSYNDROME OF INAPPROPRIATE

ANTIDIURETIC HORMONE SECRETION

Speaker- Dr Rahul Arya

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.

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.

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.

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.

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.

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.

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.

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.

Patient can have cerebral edema manisfesting as

headache, nausea, restlessness, irritability, muscle

cramps, generalized weakness, hyporeflexia,

confusion, coma, seizures, brainstem herniation or

death.

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.

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.

DIAGNOSIS OF SIADH

Supplemental features-

Plasma uric acid <4 mg/dl.

Blood urea nitrogen <10 mg/dl.

Correction of hyponatremia through fluid restriction.

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

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

TREATMENT

Treatment depends on-

Symptoms

Serum sodium concentration

Rapidity of onset of hyponatremia

Primary etiology

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.

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.

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.

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

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.

Chronic SIADH-

High sodium diet with loop diuretics.

Treatment of underlying cause.

Other agents which can be used are-

Demeclocycline

Lithium

Urea

Vaptans

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.

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.

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.

OTHER OPTIONS..

Extracorporeal Treatments-

Veno-venous hemofiltration.

SLEDD (Slow Low Efficacy Daily Dialysis).

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.

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.

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.

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.

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.

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.

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.

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.