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 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.

Frequency:

•  Although SIADH is not unusual in adults, it is rare in the pediatric population, and other causes of hyponatremia are more common. It is the most common cause of hypotonic normovolemic hyponatremia in children. Exact incidence figures are not available.

Mortality/Morbidity:

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

• The mortality rate of hyponatremic patients is some 50-fold higher than in patients who do not develop hyponatremia. Moreover, the mortality rate in patients with serum sodium concentrations less than 120 mmol/L is 25%, or twice that of patients with mild hyponatremia.

• Acute decreases in serum sodium in adults are associated with a cited mortality of 5% to 50%, depending on the severity and rate of development, while in children it is only about 8%. Infants probably tolerate cerebral edema with fewer untoward effects because of their expandable cranium.

• Symptomatic postoperative hyponatremia can result in high morbidity and mortality in children of both genders, which is due, in large part, to inadequate brain adaptation and lack of timely treatment.

Sex:

• Controlled studies in adults have shown that women and men are equally likely to develop hyponatremia and hyponatremic encephalopathy after surgery.

• Menstruating women who develop hyponatremic encephalopathy are 25 times more likely to die or have permanent brain damage than either men or postmenopausal women.

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

History:

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 occurs most frequently in children with central nervous infections, intrathoracic disease, and in postoperative patients.

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.

• Nervous system disorders

• SIADH in children is seen most often in association with intracranial disease or injury (ie, infection, brain abscesses, encephalitis) and in postoperative patients.

• Laboratory evidence of SIADH has been reported in as many as 90% of patients with meningitis in some older studies. More recent studies show that, even though hyponatremia frequently may be observed in patients with bacterial meningitis, the degree of hyponatremia is most often clinically insignificant and usually responds to minimal fluid restriction.

• Neoplasms: Malignancies producing excessive ADH secretion are uncommon in children.

• Pulmonary disorders: Intrathoracic disturbances are less common causes in children than in adults.

• AIDS

• Hyponatremia has been reported in up to 40% of adult patients with HIV infection.

• AIDS patients can have many potential causes for increased ADH secretion, including volume depletion and infection of the lungs and the central nervous system.

• Even though one third of the hyponatremic patients with AIDS were clinically hypovolemic, the remaining hyponatremic patients fulfilled most of the criteria for SIADH.

• Drugs

• A variety of drugs that impair renal water excretion either by stimulating ADH release or by enhancing the peripheral action of ADH, have been associated with a biochemical and clinical syndrome indistinguishable from SIADH.

• The list of drugs associated with SIADH continues to grow as new drugs are described.

• Be aware that many chemotherapeutic drugs cause nausea, which is a powerful stimulus of vasopressin secretion.

• Miscellaneous: There are reports of SIADH associated with an array of other disorders including temporal arteritis, polyarteritis nodosa, sarcoidosis, Rocky Mountain spotted fever, carcinoma of the cervix, olfactory neuroblastoma, and herpes zoster infection of the chest wall.

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:

• In the absence of a single laboratory test to confirm the diagnosis, SIADH is best defined by the classical criteria defined by Bartter and Schwartz in 1967, which remain valid today

• Hyponatremia: A cardinal finding of SIADH is hyponatremia (serum sodium <135 mmol/L) with concomitant hypoosmolality (serum osmolality <280 mOsm/kg). The combination of hyponatremia, low serum osmolality, and low urine volume are the hallmark of SIADH. Hyponatremia may not be present early in the process and may develop only when fluid retention occurs. Hypotonic hyponatremia will not develop unless the patient is drinking or otherwise receiving and retaining water or other hypotonic solution. Hyponatremia may be the first clue in the diagnosis of SIADH. Symptoms are more likely to be seen when the serum sodium concentration is less than 120 mmol/L and serum osmolality is below 240 mOsm/kg of water and when this has happened rapidly. No predictable correlation exists, however, between the degree of hyponatremia and the severity of symptoms. Consider the diagnosis of SIADH only after making sure that hyponatremia is not the result of physiologic (appropriate)ADH secretion, such as seen in the
  presence of a decreased intravascular volume, or pharmacologic agents that may impair water excretion.

• Serum bicarbonate remains normal despite hypotonic expansion of body fluids in SIADH. It is postulated that this is due to the movement of hydrogen ions into the cells and by increased hydrogen ion excretion by the renal tubules, both of which avert a dilutional fall in the serum bicarbonate concentration.

• Serum potassium concentration also remains unchanged. Movement of potassium from the intracellular space to the extracellular space prevents dilutional hypokalemia. As hydrogen ions move intracellularly, they are exchanged for potassium in order to maintain electroneutrality.

• The anion gap is reduced in SIADH secretion secondary to equal dilution of all the electrolytes, particularly serum sodium and chloride, as well as to an unaffected bicarbonate (HCO3^-). Another factor that further decreases the anion gap is that the volume expansion decreases the tubular reabsorption of unmeasured anions, such as sulfate, phosphate, and urate.

• Urinary sodium: There is continuing urinary loss of sodium despite significant hyponatremia. In these patients, as in normal subjects, urinary sodium excretion is a reflection of sodium intake and, therefore, usually is greater than 20 mmol/L. In the face of sodium restriction, however, or of volume depletion due to extrarenal losses in patients with SIADH, renal conservation proceeds normally and urinary sodium concentration may be very low.

• Urine osmolality: Patients with hyponatremia have a urine that is maximally dilute (50-80 mOsm/kg); however, in patients with SIADH, the urine osmolality usually is less than maximally dilute, with values ranging from 250-1400 mOsm/kg depending on the course of the disease. Urine osmolality usually exceeds that of plasma; however, urine needs to be only submaxillary dilute (>100 mOsm/kg) to establish a diagnosis of SIADH. The most common error in recognizing SIADH is the failure to realize that urine osmolality needs to be only inappropriately elevated and not necessarily greater than the corresponding serum osmolality.

• BUN is unusually low, usually below 10 mg/dL. A low BUN in SIADH occurs secondary to volume expansion, because urea is distributed in total body water.

• Uric acid: Hypouricemia frequently is seen in patients with SIADH during the period of hyponatremia. There is an increase in uric acid excretion as a result of volume expansion and a decrease in distal tubular reabsorption. A decrease in serum uric acid concentration has been suggested as a screening procedure in patients with hyponatremia secondary to SIADH. Hypouricemia appears to occur in any volume expanded state and, therefore, lacks both sensitivity and specificity for making the diagnosis of SIADH.

• Glomerular filtration rate (GFR) is increased as a result of extracellular water expansion induced by water retention.

Imaging Studies:

• MRI or CT scan of the brain might be indicated if there is clinical suspicion of cerebral edema, a relatively rare complication of SIADH. These would not be routine procedures.

Other Tests:

• Acute water loading test: The use of this procedure to test renal diluting capacity in patients with SIADH is not only unnecessary, it may be unsafe.

• Thyroid function tests are normal.

• Adrenal function tests are normal.

• Aldosterone excretion or secretion rates are characteristically normal.

• Plasma cortisol or urinary 17-hydroxycorticoid levels are normal.

• ADH levels

• The use of radioimmunoassay for ADH may provide supportive evidence for the diagnosis of SIADH. However, the values are usually not available quickly enough to assist in clinical decision making.

• The plasma ADH typically is elevated, but its determination is not crucial for the diagnosis of SIADH.

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

Further Inpatient Care:

• Closely monitor serum and urine electrolytes.

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