Syndrome of inappropriate ADH (SIADH)

Syndrome of inappropriate secretion of antidiuretic hormone serum sodium < 130 meq/l, plasma osmolality < 275 mOsm/kg, urine osmolality higher than the plasma osmolality and above 500 mOsm/kg, absence of volume depletion and normal thyroid, adrenal and renal function.

Most frequent cause of hyponatremia, although hyponatremia associated with volume depletion of the extracellular fluid is also common.

Hyponatremia typically reflects water, excess relative to these body cations, most commonly from disorders impairing electrolyte free water excretion by the kidneys (aquaresis).

Impaired aquaresis largely depends on increased secretion of arginine vasopressin (AVP),  the antidiuretic hormone, which activates the vasopressin 2 receptor in the collecting duct of the nephron, thus promoting water retention.

Arginine vasopressin is triggered by osmotic and hemodynamic, stimuli (hypertonicity and reduced defective arterial blood volume, respectively.

Reported with pulmonary, CNS conditions and paraneoplastic disorders.

Syndrome of inappropriate ADH (SIADH) is the most common cause of hyponatremia after pituitary surgery and occurs in 9% to 30 % of patients undergoing a transsphenoidal approach.

In hyponatremia associated with hypovolemia and certain hypervolemic disorders, such as heart failure, water retention is driven by AVP release caused by reduced effective arterial blood volume.

In contrast, SIADH is a euvolemic disorder, and AVP secretion occurs in the absence of osmotic and hemodynamic stimuli, and the anti-diuresis is deemed inappropriate.

Causes of SIADH are cancer (24%), drugs (18%), pulmonary conditions (11%), and CNS disorders (9%).

Manifestations of SIAD, depend on the rapidity of its development, and the severity and duration of the hyponatremia.

Additionally, exercise, pain, stress, severe nausea, postoperative state, and rarely gain of function variants encoding vasopressin2 receptor can cause it.

Antidepressants are the most commonly implicated drugs, especially underweight, older women, and relative risk to the use of anti-depressants reported to be highest with the use of selective serotonin retake uptake inhibitors, and lowest with mirtazapine.

A causes not identified in 17 to 60% of patients.

Reversal of hyponatremia, upon discontinuation of a drug establishes a causal relationship.

Acute symptoms of SIAD result from cerebral edema and range from mild and nonspecific to severe and life-threatening seizures, and coma.

Chronic SIAD of 48 hours of greater have subtle findings, although can be associated with nausea, vomiting, headache, confusion, delirium, and rarely seizures.

Correction must be slow 0.5 meq/L/hour, since a rapid correction can cause brain damage.

The initial treatment should be halted when serum sodium reaches 125-130 meq/L.

Increased plasma concentration of ADH in elderly and accounts for the hyponatremia of aging.

Increases with age and is especially common among nursing home residents.

Level of secretion of antidiuretic hormone, arginine vasopressin, inappropriately elevated.

Increased plasma concentration of ADH in elderly and accounts for the hyponatremia of aging.

In about one third of cases the secretion of arginine vasopressin independent of plasma osmolality, and in the other cases secretion of the hormone is fully suppressed, resulting in dilute urine, but at a serum sodium level lower than normal.

Less commonly plasma levels of arginine vasopressin are low or undetectable, even in the presence of hyponatremia.

Some patients mutations of the aquaretic vasopressin receptor occur with concentration of urine in the absence of vasopressin.

Not all patients with the syndrome have elevated circulating levels of arginine vasopressin.

Inappropriate antidiuresis is essential to the diagnosis, excessive water intake driven by nonosmotic stimuli, is also required to develop hyponatremia.

The diagnosis of SIADH requires clinical confirmation of an euvolemic, hypotonic hyponatremia.

Urine studies show natriuresis with sodium greater than 30 mmol per liter and inappropriate concentration with greater than 100 mL moles per kilogram of water.

The diagnosis of SIADH requires ruling out, secondary adrenal, insufficiency and severe hypothyroidism.

Serum osmolality must be measured to rule out pseuodohyponatremia due to elevated proteins or lipids and laboratory artifacts when serum sodium levels are measured by indirect techniques.

Hyponatremia can reflect impaired aquaresis independent of AVP release, including lowmsolute intake, acute kidney injury, and chronic kidney disease.

Infrequently hyponatremia results from excessive water intake that overwhelms aquaresis.

SIAD and hyponatremia overall, increase with age; 40% of older inpatients have hyponatremia with 25 to 40% of cases attributed to SIAD.

Older patients have an increased incidence of hyponatremia due to the presence of coexisting conditions, such as cancer, pulmonary disease, disorders of the CNS and medication that predispose to SIAD.

Old age impairs aquaresis by diminishing GFR, decreases renal prostaglandins, and increases AVP response to osmotic and non-osmotic  stimuli: low salt and protein intake common in older persons also contributes to impaired aquaresis.


Emergency management is required for patients with SIAD, who have severe symptoms of somnolence, seizures, respiratory abnormalities, or coma,

Moderate symptoms include vomiting, or confusion, and a high risk for progression on the basis of clinical presentation, or any hyponatremia accompanying intracranial disease, in which case worsening of cerebral edema could be catastrophic.

Treatment has been administration of 3% sodium chloride with a slow continuous infusion to raise serum sodium by 1 to 2 mmol/L per hour for a few hours, with the correction limit of 8 to 10 mmol per liter, over 24 hrs. and 18 to 24 mmol per liter over 48 hours.

Presently treatment is the administration of 100 mL and 150 mL of sodium chloride, respectively, administered by IV bolus and repeated two or three times as needed.

The goal is to increase serum sodium by 4-6 Mollii/L within one to two hours, an increase sufficient to reverse clinical manifestations of cerebral edema.

Guidelines  set a correction limit of 10 mmol/liter within the first 24 hours and 18 mmol/L within the first 48 hours.

Correction limits exist to prevent osmotic demyelination involving the central pons or extra pontine structures that can cause hyperreflexia, pseudobulbarpalsy, parkinsonism, locked-in syndrome and death.

For patients with acute hyponatremia correction limits are unnecessary.

Fewer than 5% of patients with hyponatremia have sufficiently associated severe symptoms to require emergency treatment.

For the majority of patients, addressing the underlying cause and treatment is typically administered as an outpatient.

Patients with a sodium level of less than 120 mmol/L should be at hospitalized.

If the underline cause can be reversed, the hyponatremia resolves within several days.

Several therapies are available for SIAD:fluid restriction 1000cc/d is the first line of treatment for chronic SIAD.

Other therapies, including increasing salt, urea, and proteins.

Tolvaptan completely inhibits the vasopressin 2 receptor in the collecting duct, and is a highly effective therapeutic agent.

Tolvaptan is associated with thirst and dry mouth, and overcorrection of hyponatremia occurs in 5.9% of patients.

Tolvaptan is in effective for nephrogenic SIAD.

Empagliflozin, a sodium glucose  cotransporter 2 inhibitor promotes osmotic diuresis by means of glycosuria and has a role in patients with SIAD.









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