Syndrome of Inappropriate Antidiuretic Hormone Secretion

Syndrome of Inappropriate Antidiuretic Hormone Secretion

 The syndrome of inappropriate antidiuretic hormone (SIADH) secretion is the most common cause of euvolemic hyponatremia in pediatrics. The syndrome is defined by the hyponatremia and hypoosmolality resulting from inappropriate continued secretion and/or action of antidiuretic hormone (ADH) despite normal or increased plasma volume.

Arginine vasopressin [AVP], the naturally-occurring ADH in humans, is an octapeptide similar in structure to oxytocin. It is synthesized in the cell bodies of neurons in the supraoptic and paraventricular nuclei of the anterior hypothalamus and travels along the supraopticohypophyseal tract into the posterior pituitary, where it is stored in secretory granules in association with a carrier protein, neurophysin. Neurophysins are peptides composed of 2 proteins, each capable of binding 2 molecules of antidiuretic hormone (ADH). The neurophysin-vasopressin combination is stored in the posterior pituitary in the terminal dilatations of secretory neurons that rest against blood vessels. ADH is released from the neuron onto the capillary basement membrane in the posterior pituitary and thus directly into the circulation.

Two types of receptors participate in the release of ADH from the posterior pituitary. Osmoreceptors are a group of specialized cells that perceive changes in the extracellular fluid (ECF) osmolality. A 2% increase in the serum osmolality perfusing the supraoptic nuclei can cause release of ADH, while a 1.2% decrease in the serum osmolality causes a decrease in plasma ADH levels. Secretion of ADH is suppressed at plasma osmolalities below 280 mOsm/kg.

Baroreceptors, located in the carotid sinus, aortic arch, and left atrium, participate in the nonosmolar control of ADH release by responding to a change of plasma volume. An 8-10% reduction in plasma volume will cause a significant increase in ADH release. In most physiological states, the volume receptors and osmoreceptors act in concert to increase or decrease ADH release. However, the overriding stimulus for secretion of ADH may be the effective intravascular volume, not the state of extracellular osmolality. ADH also is released in response to several drugs and various stressful stimuli such as pain or anxiety.

The primary role of the ADH is to promote the reabsorption of water from the tubular fluid along the course of the distal tubule and collecting duct, the hydroosmotic effect. A second action of ADH is to cause arteriolar vasoconstriction and a rise in arterial blood pressure, the pressor effect. ADH has no significant effect on the rate of sodium reabsorption.

Pathophysiology: The fundamental problem in SIADH is failure to maximally suppress vasopressin secretion. ADH excess results in water retention and volume expansion, leading to weight gain and natriuresis. Serum osmolality falls below the normal range. Hyponatremia will not develop unless the patient is ingesting or receiving some source of free water. The natriuresis, which occurs in SIADH despite hyponatremia and further contributes to hyponatremia, is produced by a decrease in proximal tubular sodium reabsorption secondary to the expansion of the extracellular fluid volume.

Hypervolemia suppresses the renin-angiotensin-aldosterone system during the water retention phase but later levels of renin and aldosterone rise again, perhaps in response to hyponatremia. The main mediator of the natriuresis in SIADH is probably the atrial natriuretic peptide (ANP), which may suppress proximal tubular reabsorption of sodium in response to expanded ECF volume. Sodium balance is maintained in SIADH, and the sodium output equals the intake.

Four distinct types of osmoregulatory defects have been defined on the basis of plasma AVP determinations during the infusion of hypertonic saline. In Type A (random), seen in approximately 20% of patients, there are large and unrelated fluctuations in AVP unrelated to the rise in plasma osmolality. This pattern usually occurs in association with tumors.

In Type B (reset osmostat), seen in about 35% of patients, there is a prompt and parallel rise in AVP and in plasma osmolality, but a significant lowering of the threshold for release is present. This pattern is consistent with an osmoreceptor reset at a lower-than-normal level.

In Type C (leak), seen in approximately 35% of patients, AVP is persistently elevated at low and normal plasma osmolality, however, above the threshold for AVP release, plasma AVP increases normally. This pattern is observed with meningitis or head injuries.

In Type D (normal), seen in approximately 10% of patients, plasma AVP is appropriately suppressed under hypotonic conditions and does not rise until plasma osmolality reaches the normal threshold level; it does not result in maximal urinary dilution. This pattern is consistent with an increased renal sensitivity to vasopressin and is observed in patients with bronchogenic carcinoma and diabetes mellitus.



 The presence of hyponatremia, its severity, and delay in initiating adequate treatment appear to be the main indicators for both morbidity and mortality.


Age: The syndrome has been described in newborns, children, adults, and the elderly.


Overt clinical manifestations of SIADH are largely related to the cellular swelling and cerebral edema associated with hyponatremia. Most patients with SIADH are asymptomatic if the serum osmolality remains above 240 mOsm/kg of water. The clinical manifestations of SIADH are those of water intoxication. Symptoms are more likely to develop in the elderly and young children with hyponatremia.



SIADH most often is caused by either inappropriate hypersecretion of ADH from its normal hypothalamic source or, less often, by an ADH-like substance produced by neoplastic tissues. Etiology of SIADH can be classified into 3 categories including neoplasia, nervous system disorders, and pulmonary diseases.lists the various diseases in which SIADH may occur.

Other Problems to be Considered:

Chronic liver disease
Drugs that impair renal water excretion
Pituitary insufficiency
Primary polydipsia
Pure right-sided congestive heart failure
Renal disease with salt-losing nephritis
Reset osmostat
Surreptitious diuretic use
Water intoxication

Lab Studies:

Imaging Studies:

Other Tests:

Medical Care:

 Treatment of hyponatremia in SIADH depends on the presence or absence of symptoms, the severity of hyponatremia, and its duration. Asymptomatic patients usually are treated acutely with water restriction. Patients with CNS symptoms usually require more rapid correction of the hyponatremia than can be achieved by water restriction alone. If the hyponatremia is chronic, treatment not only is unnecessary, it may be harmful.

Surgical Care: Surgical correction of a malignant tumor secreting vasopressin, if present, is fundamental to correction of excessive ADH secretion.


A pediatric endocrinologist or nephrologist may provide useful insight into the diagnosis and management of children with apparent SIADH.
Neurologic consultation may be necessary in children with prolonged or severe symptomatic SIADH.
Pediatric intensive care and a pediatric intensivist may be necessary for the management of severely affected children.

Diet: Fluid restriction is the cornerstone of treatment for SIADH.

Drugs have no established role in the management of acute SIADH in children.

Drug Category: Loop diuretics -- The use of a combination of a loop diuretic (eg, furosemide) and the replacement of urine output with a solution that contains a higher sodium concentration (ie, 3% saline) can be dramatically successful in some patients. Concomitant use of furosemide increases free water excretion relative to sodium excretion by the kidneys, thus correcting fluid expansion induced by hypertonic saline. Excess water that needs to be removed to correct the hyponatremia can be calculated using total body water (TBW = Body weight [in kg] x 0.6), assuming that the total body solute or water has not changed.
Drug Name
Furosemide (Lasix) -- Excess water in a 20-kg child with a serum sodium of 115 mmol/L can be calculated as follows:
Excess water = TBW - [(actual serum Na/desired serum Na) X TBW]

Excess water = (20 kg) X (0.6) – [(115/130) X (20 kg X (0.6)]

Excess water = 12 L - 10.6 L = 1.4 L

Therefore, to remove 1.4 L of water, 233 mL would need to be removed over 6 h to bring the serum sodium from 115 mmol/L to 130 mmol/L.

Dose must be individualized to patient. Depending on response, administer in increments of 20-40 mg, no sooner than 6-8 h after the previous dose, until desired diuresis occurs. When treating infants, titrate with 1-mg/kg/dose increments until a satisfactory effect is achieved. Inhibits reabsorption of sodium and chloride, not only in proximal and distal tubules, but also loop of Henle. The high efficacy of this drug is largely because of its unique site of action. Action on distal tubule is independent of any inhibitory effect it may have on either carbonic anhydrase or aldosterone.
Adult Dose Initial: 20-40 mg IV/IM or 20-80 mg PO qd
Maintenance: 40-120 mg PO qd
Pediatric Dose Administering an initial dose of 1-2 mg/kg IV/PO, followed by subsequent doses prn, should generate a negative water balance over 6-8 h; urine volume and urine sodium concentrations are measured q1h, and excreted sodium and potassium are replaced with a solution of 3% sodium chloride to which the required amount of KCl is added
Contraindications Documented hypersensitivity; severe preexisting electrolyte imbalance, diabetes mellitus, anuria, hepatic coma
Interactions Metformin decreases furosemide concentrations; furosemide interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration of aminoglycosides and furosemide; hearing loss of varying degrees may occur; anticoagulant activity of warfarin may be enhanced when taken concurrently with this medication; increased plasma lithium levels and toxicity are possible when taken concurrently with this medication
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions This method is cumbersome, carries the risk of inducing severe fluid and electrolyte imbalances, and requires close monitoring; rarely is used in the treatment of SIADH in children; corticosteroids have been used in combination with loop diuretics to increase sodium retention, but their use remains controversial; use of furosemide alone, with replacement of measured urine electrolytes losses, also has been suggested
Drug Category: Antidiuretic hormone antagonists -- Several ADH antagonists are available, which may be useful in the treatment of chronic SIADH and in patients with acute SIADH unresponsive to nondrug therapy.
Drug Name
Lithium carbonate (Carbolith, Eskalith, Lithane) -- Inhibits the effects of ADH on the renal tubule and can correct hyponatremia, but significant complications limit its use in children. Very little pediatric literature exists regarding its use in children.
Usually not indicated for use in acute SIADH because it takes 48 h to produce any physiologic effects.
Adult Dose 900-1800 mg/d PO divided bid/tid
Pediatric Dose 15-60 mg/kg/d PO/NG divided tid/qid; to produce a diuresis, plasma levels should be 0.3-0.6 mmol/L but not higher than 1 mmol/L to avoid toxic effects
Older adolescents: 600-1800 mg/d PO divided tid/qid
Contraindications Documented hypersensitivity; severe cardiovascular disease
Interactions Lithium increases toxicity of thiazide diuretics, haloperidol, phenothiazines, neuromuscular blockers carbamazepine, fluoxetine, and ACE inhibitors
Pregnancy D - Unsafe in pregnancy
Precautions CNS disturbances (sluggishness, drowsiness, coarse tremors, muscle twitching), cardiotoxicity, GI disturbances, hyperglycemia with hyperosmolality, and thyroid dysfunction
Lithium toxicity is closely related to serum levels and can occur at therapeutic doses; serum lithium determinations are required to monitor therapy
Drug Name
Demeclocycline (Declomycin) -- Interferes with the action of AVP on the collecting duct, thus correcting hyponatremia. Appears to be effective and safer than lithium or ethanol in the treatment of SIADH.
Not useful in acute SIADH because onset of the response is variable and ranges 5-8d
Adult Dose 300-600 mg PO bid
Pediatric Dose <8 years: Not recommended
>8 years: 6-15 mg/kg/d PO divided bid
Contraindications Documented hypersensitivity; severe renal disease; lactation; avoid in children <8 y
Interactions Bioavailability may decrease with coadministration of antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; may increase hypoprothrombinemic effects of anticoagulants (monitor prothrombin activity); coadministration with oral contraceptives, may decrease effects of oral contraceptives, causing breakthrough bleeding, and increased risk of pregnancy
Pregnancy D - Unsafe in pregnancy
Precautions Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one-half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines
Drug Category: Osmotic diuretics -- Raises the osmolality of plasma and renal tubular fluid.
Drug Name
Urea (Ureaphil) -- Known to promote diuresis, decreases brain edema, restores medullary tonicity, and induces sodium retention. Isosmotic concentration of dextrose or invert sugar is coadministered with urea to prevent hemolysis produced by pure solutions of urea.
Adult Dose 1-1.5 g/kg/d IV divided tid; administer as a 30% solution by slow IV infusion, at a rate not to exceed 4 mL/min
Pediatric Dose 0.5-1 g/kg/d IV divided tid; administer as a 30% solution by slow IV infusion, at a rate not to exceed 4 mL/min
Contraindications Documented hypersensitivity; severely impaired renal function, active intracranial bleeding, marked dehydration, frank liver failure; infusion into veins of lower extremities in elderly may cause phlebitis and thrombosis
Interactions May decrease effects of lithium
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Do not use if intracranial bleeding present, unless before surgical intervention to control hemorrhage (reduction of brain edema by urea may result in reactivation of intracranial bleeding); may increase risk of venous thrombosis and hemoglobinuria in hypothermic patients; caution in renal impairment
Drug Name
Mannitol (Osmitrol) -- Promotes a rapid free-water diuresis and corrects hyponatremia. Typically used IV as a 15-20% solution.
Adult Dose 1-2 g/kg IV over 30-60 min
Pediatric Dose 0.5-2 g/kg/d IV over 30-60 min
Contraindications Documented hypersensitivity; anuria, severe pulmonary congestion, progressive renal damage, severe dehydration, active intracranial bleeding, and progressive heart failure
Interactions May decrease serum lithium levels
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Carefully evaluate cardiovascular status before rapid administration of mannitol since a sudden increase in extracellular fluid may lead to fulminating CHF; avoid pseudoagglutination, when blood given simultaneously, add at least 20 mEq of sodium chloride to each liter of mannitol solution; do not give electrolyte-free mannitol solutions with blood; not consistently effective in SIADH
Drug Name
Glycerin (Osmoglyn) -- Oral osmotic agent able to increase tonicity of blood until finally metabolized and eliminated by the kidneys. Lowers cerebral pressure and corrects hyponatremia. Has a lower onset of action than urea. When compared with mannitol, it offers the advantage of oral administration and less diuresis and electrolyte loss.
Adult Dose 1 g/kg PO/NG q6h
Pediatric Dose 0.5-2 g/kg PO/NG q6h
Contraindications Documented hypersensitivity; severe dehydration, well-established anuria, severe cardiac decompensation
Interactions None reported
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Headaches, nausea, vomiting, hyperglycemia, hypertension, hyperosmolality, intravascular hemolysis, and hemoglobinuria
Drug Category: Inhibitors of ADH release -- Interfere with hypothalamic release of ADH.
Drug Name
Ethanol -- Blocks ADH release and often results in the prompt and dramatic reversal of SIADH with the excretion of large volumes of hypotonic urine.
Intoxicating dose may be required; therefore, it may not be suitable for administration to children.
Adult Dose 1 mL/kg of 200 proof (ie, 100%) PO/NG
Pediatric Dose Administer as in adults
Contraindications Epilepsy; prior addiction; diabetic coma
Interactions May increase toxicity of benzodiazepines or barbiturates and result in death; additive toxicity with other CNS depressants; cimetidine may increase toxicity; disulfiram and other drugs (eg, ketoconazole, metronidazole) cause alcohol intolerance (ie, facial flushing, nausea, vomiting); may increase serum levels of drugs metabolized by alcohol dehydrogenase (ie, abacavir)
Pregnancy D - Unsafe in pregnancy
Precautions Liver or renal impairment; shock; diabetes mellitus; gout; avoid extravasation
Drug Name
Phenytoin (Dilantin) -- Blocks hypothalamic release of ADH and has been reported to be effective in the treatment of SIADH in a few cases. It helps correct hyponatremia while controlling seizures.
Adult Dose 300-600 mg/d PO divided tid
Pediatric Dose 5-10 mg/kg/d PO/IV divided bid/tid
Contraindications Documented hypersensitivity; sinoatrial block, second- and third-degree AV block, sinus bradycardia, or Adams-Stokes syndrome
Interactions Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimides, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase phenytoin toxicity
CYP450 enzyme inducer; phenytoin effects may decrease when taken concurrently with barbiturates, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate

Phenytoin may decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, oral contraceptives, valproic acid
Pregnancy D - Unsafe in pregnancy
Precautions Perform blood counts and urinalyses when therapy is begun and at monthly intervals for several months thereafter to monitor for blood dyscrasias; discontinue use if a rash appears and do not resume use if rash is exfoliative, bullous, or purpuric; rapid IV infusion may result in death from cardiac arrest, marked by QRS widening; caution in acute intermittent porphyria and diabetes (may elevate blood sugars; discontinue use if hepatic dysfunction occurs

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