AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

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 hypo-osmolality that results 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 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 (which are 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 causes 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 is also released in response to several drugs and various stressful stimuli such as pain or anxiety.

The primary role of 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 a 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 reference range. Hyponatremia does 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 sodium chloride solution.

In type A (random), observed in approximately 20% of patients, large and unrelated fluctuations in AVP occur unrelated to the rise in plasma osmolality. This pattern usually occurs in association with tumors.

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

In type C (leak), observed 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), observed 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

United States

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 in patients with hyponatremia is 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 rate of 5-50%, depending on the severity and rate of development; in children, the mortality rate 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 rates in children of both sexes, 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 elderly people.

CLINICAL

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History

Overt clinical manifestations of syndrome of inappropriate antidiuretic hormone (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 elderly patients and young children with hyponatremia.

• SIADH is most common in children with CNS infections, intrathoracic disease, and in postoperative patients.
• Among premature neonates, the syndrome most often accompanies brain injury and is closely associated with intracranial hemorrhage.
• Signs and symptoms of SIADH, as a rule, are those of hyponatremia and are often vague and nonspecific.
• The clinical manifestations of SIADH are usually related to the degree of the hyponatremia and to the rate at which hyponatremia develops.
• GI tract symptoms occur early in the disease and include the following:
• • Anorexia
  • Nausea
  • Vomiting
• Most of the symptoms are neuropsychiatric in nature and include the following:
• • Headaches
  • Blurred vision
  • Lethargy
  • Apathy
  • Disorientation
  • Agitation
  • Irritability
• Muscular symptoms include the following:
• • Muscle cramps
  • Muscle weakness
• Vasopressin-resistant polyuria with hyponatremia, particularly in the setting of cerebral injury or cerebral disease or when accompanied by dehydration, should prompt consideration of salt wasting in the differential diagnoses. Cerebral salt wasting must be distinguished from SIADH because management of these 2 conditions significantly differs.

Physical

• SIADH is often first recognized upon finding hypotonic hyponatremia in a child without other major symptoms and in the absence of dehydration.
• Edema is clinically undetectable, although patients with SIADH have a modest increase in ECF volume because of water retention but have normal sodium excretion.
• Usually, these patients have volume expansion short of edema and a maximum weight gain of 8%.
• Although the patient appears clinically euvolemic without signs of edema, most adult patients with normovolemic ADH excess have retained 4-5 liters of water.
• • Two thirds of total body water resides in the intracellular space (2.7-3.3 L).
  • The remaining one third (1.3-1.7 L) is found in the ECF, of which 75% (1-1.3 L) goes into the interstitial space and only 25% (300-400 mL) goes into the intravascular space.
• The absence of a decreased blood volume is one of the criteria for the diagnosis of SIADH because hypovolemia would result in appropriate ADH secretion by stimulating the baroreceptors (volume receptors).
• Skin turgor and blood pressure are usually normal.
• Hypovolemia, hypotension, and overt signs of hypervolemia are absent.
• Deep tendon reflexes are depressed.
• Pathologic reflexes, such as positive Babinski reflexes, may be present.
• Asymmetric pupils may be present.
• Abnormal sensorium may occur.
• Pseudobulbar palsy may occur.
• Cheyne-Stoke respirations may be present.
• Seizures may occur.

Causes

SIADH is most often caused by either inappropriate hypersecretion of ADH from its normal hypothalamic source or, less often, by an ADH-like substance produced by neoplastic tissues. In general, the etiology of SIADH can be classified into 3 categories including nervous system disorders, neoplasia, and pulmonary diseases. Media file 1 lists the various disorders in which SIADH may occur.

• Nervous system disorders
• • SIADH in children is most often observed 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. Some studies show that although hyponatremia may frequently be observed in patients with bacterial meningitis, the degree of hyponatremia is most often clinically insignificant and usually responds to minimal fluid restriction.¹
• Neoplasms: Malignancies producing excessive ADH secretion are uncommon in children.
• Pulmonary disorders: Intrathoracic disturbances are less common causes in children than in adults.
• Acquired immunodeficiency syndrome (AIDS)
• • Hyponatremia has been reported in as many as 40% of adult patients with human immunodeficiency virus (HIV) infection.
  • Patients with AIDS can have many potential causes for increased ADH secretion, including volume depletion and infection of the lungs and the CNS.
  • Although one third of the hyponatremic patients with AIDS are clinically hypovolemic, the remaining hyponatremic patients fulfill most of the criteria for SIADH.
• Drugs
• • Many drugs that impair renal water excretion (see Media file 2), 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 causes: SIADH has been 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.

DIFFERENTIALS

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Other Problems to be Considered

Cerebral salt wasting syndrome
Chronic liver disease
Drugs that impair renal water excretion (see Media file 2)
Pituitary insufficiency
Primary polydipsia
Pure right-sided congestive heart failure
Renal disease with salt-losing nephritis
Reset osmostat
Surreptitious diuretic use
Water intoxication

WORKUP

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Lab Studies

• In the absence of a single laboratory test to confirm the diagnosis, syndrome of inappropriate antidiuretic hormone (SIADH) is best defined by the classic criteria defined by Bartter and Schwartz in 1967, which remain valid today. A summary is as follows follows:²
• • Hyponatremia with corresponding hypoosmolality
  • Continued renal excretion of sodium
  • Urine less than maximally dilute
  • Absence of clinical evidence of volume depletion
  • • Normal skin turgor
    • Blood pressure within the reference range
  • Absence of other causes of hyponatremia
  • • Adrenal insufficiency - Mineralocorticoid deficiency, glucocorticoid deficiency
    • Hypothyroidism
    • Cardiac failure
    • Pituitary insufficiency
    • Renal disease with salt wastage
    • Hepatic disease
    • Drugs that impair renal water excretion
  • Correction of hyponatremia by fluid restriction
• Hyponatremia (ie, serum sodium <135 mmol/L) is a cardinal finding of SIADH with concomitant hypo-osmolality (ie, serum osmolality <280 mOsm/kg). The combination of hyponatremia, low serum osmolality, and low urine volume is the hallmark of SIADH. Hyponatremia may not be present early in the process and may develop only when fluid retention occurs. Hypotonic hyponatremia does 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 observed 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. However, no predictable correlation between the degree of hyponatremia and the severity of symptoms is recognized.
• Consider the diagnosis of SIADH only after making sure that hyponatremia is not the result of physiologic (ie, appropriate) ADH secretion, such as observed in the presence of a decreased intravascular volume or pharmacologic agents that may impair water excretion.
• Serum bicarbonate remains within the reference range despite hypotonic expansion of body fluids in SIADH. This is postulated to be due to the movement of hydrogen ions into the cells and to 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 secondary 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 loss of sodium continues despite significant hyponatremia. In these patients, as in healthy patients, urinary sodium excretion is a reflection of sodium intake and, therefore, usually is greater than 20 mmol/L. However, in the setting of sodium restriction or of volume depletion due to extrarenal losses in patients with SIADH, renal conservation proceeds normally and urinary sodium concentration may be very low.
• Patients with hyponatremia have a urine that is maximally dilute (ie, 50-80 mOsm/kg); however, in patients with SIADH, the urine osmolality is usually 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 must only be submaxillary dilute (ie, >100 mOsm/kg) to establish a diagnosis of SIADH. The most common error in recognizing SIADH is the failure to realize that urine osmolality must only be inappropriately elevated and not necessarily greater than the corresponding serum osmolality.
• BUN levels are unusually low, usually below 10 mg/dL. A low BUN levels in SIADH occurs secondary to volume expansion because urea is distributed in total body water.
• Hypouricemia is frequently observed in patients with SIADH during the period of hyponatremia. An increase in uric acid excretion occurs 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 scanning of the brain might be indicated if cerebral edema, a relatively rare complication of SIADH, is clinically suspected. These are not routine procedures.

Other Tests

• Acute water loading test: The use of this procedure to test renal diluting capacity in patients with SIADH is unnecessary, and the test may be unsafe.
• Thyroid function tests: Results are normal.
• Adrenal function tests
• • Results are normal.
• • Aldosterone excretion or secretion rates are characteristically within the reference range.
  • Plasma cortisol or urinary 17-hydroxycorticoid levels are within the reference range.
• ADH levels
• • The use of radioimmunoassay for ADH may provide supportive evidence for the diagnosis of SIADH. However, the values are not usually available quickly enough to assist in clinical decision-making.
  • The plasma ADH is typically elevated, but its determination is not crucial for the diagnosis of SIADH.

TREATMENT

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Medical Care

Treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone (SIADH) depends on the presence or absence of symptoms, the severity of hyponatremia, and its duration. Asymptomatic patients are usually treated in the immediate period 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 is not only unnecessary, it may be harmful.

• Fluid restriction
• • Impaired water excretion by the kidneys is required for the development of all the physiological and biochemical abnormalities in SIADH, such as hyponatremia, volume expansion, and sodium depletion. Consequently, water restriction reverses all of these abnormalities and remains the mainstay of therapy in patients with SIADH. Fluid restriction to less than 75% of maintenance (ie, 1000 mL/m²/d) usually allows for the slow excretion of retained excess fluid and results in a decrease in ECF volume with a concomitant fall in urinary sodium excretion.
  • If no improvement is observed when the patient is reevaluated in 4-6 hours, further restrict fluids to 50% of maintenance (ie, 700-800 mL/m²/d) or lower if necessary. Only a few children require severe fluid restriction to 10% of maintenance (ie, 150-200 mL/m²/d). Maintain and do not restrict sodium chloride intake for urinary losses during fluid restriction. Use 5% dextrose in 0.45 isotonic sodium chloride solution or 5% dextrose in lactated Ringer solution, if intravenous fluids are indicated.
  • In most children with SIADH who are hyponatremic but who do not have severe symptom (eg, coma or convulsions), fluid restriction is sufficient to correct the hyponatremia within 24 hours. Improvement of the clinical state with water restriction is considered a retrospective diagnostic criterion. Limit fluid intake to the amount that keeps the serum sodium concentration within the reference range for the duration of the underlying condition. Fluid intake can be increased as serum electrolytes and osmolality normalize.
• Hypertonic sodium chloride solution
• • Administration of hypertonic sodium chloride solution (3%) to children with SIADH frequently is not helpful in the treatment of hyponatremia unless severe neurologic disease is present. It is only transiently effective in correcting the hyponatremia because sodium chloride solution expands the ECF volume further, resulting in greater decrease in sodium reabsorption by the proximal tubule and excretion of the administered sodium. A risk of heart failure is observed in a patient who already is volume expanded.
  • Its use could be lifesaving in the child whose hyponatremia (ie, serum sodium <120 mmol/L) has induced seizures or coma. In such cases, partially correcting the hyponatremia with 3% sodium chloride solution (0.5 mmol/mL) to raise the serum sodium by 10 mmol/L is appropriate. The mmol of sodium to be infused is determined as follows:

    mmol of sodium to be infused = body weight in kg X 0.6 X 10 mmol/L

  • Administer half of the sodium over 30-60 minutes and the rest over 2-4 hours. Follow by strict fluid restriction to normalize serum sodium. Because of the association of rapid sodium correction with central pontine myelinolysis, do not correct the serum sodium to greater than 130 mmol/L at a rate of 1-2 mmol/h and more than 20 mmol/d. Hypertonic sodium chloride solution provides only temporary and symptomatic relief until fluid restriction, or treatment of the underlying condition, can take effect.
• Corticosteroids: Steroids are of no direct benefit in SIADH. They are only indicated when they provide specific replacement therapy, such as in adrenal or pituitary insufficiency. Add them to the above therapy when adrenal insufficiency cannot be ruled out.
• Vasopressin analogs: Vasopressin analogs with intrinsic antidiuretic antagonism are very promising but still experimental.
• Thiazide diuretics: Thiazides decrease free water excretion at the cortical diluting segment and can severely aggravate hyponatremia in patients with SIADH.

Surgical Care

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

Consultations

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

Diet

• Fluid restriction is the cornerstone of treatment for SIADH.

MEDICATION

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Drugs have no established role in the management of acute syndrome of inappropriate antidiuretic hormone (SIADH) in children. A new AVP blocker has been approved for hospitalized adults with euvolemic hyponatremia.

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% sodium chloride solution) 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 sodium chloride solution. Excess water that must be removed to correct the hyponatremia can be calculated using total body water (TBW). TBW equals body weight in kg multiplied by 0.6, assuming that the total body solute or water has not changed.

Drug Category: Antidiuretic hormone antagonists

Several of the available ADH antagonists may be useful in the treatment of chronic SIADH and in the treatment of acute SIADH unresponsive to nondrug therapy. Only conivaptan is AVP-specific. Safe and effective administration of conivaptan to a pediatric patient has recently been reported.³

Drug Category: Osmotic diuretics

These agents raise the osmolality of plasma and renal tubular fluid.

Drug Category: Inhibitors of ADH release

These agents interfere with hypothalamic release of ADH.

Drug Category: Arginine and vasopressin receptor antagonist

AVP blockade is indicated for SIADH, hypothyroidism, adrenal insufficiency, pulmonary disorders, and other selected conditions associated with euvolemic (dilutional) and hypervolemic hyponatremia in hospitalized patients.

FOLLOW-UP

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Further Inpatient Care

• Closely monitor serum and urine electrolytes.
• Reassess the patient's status frequently and readjust therapy as necessary.

Further Outpatient Care

• Fluid restriction to 1000 mL/m²/d

In/Out Patient Meds

• The use of lithium carbonate should be considered in children with chronic syndrome of inappropriate antidiuretic hormone (SIADH).
• Demeclocycline can be used in children older than 8 years with chronic SIADH.

Complications

• Fluid overload
• • Pulmonary edema
  • Hypertension
  • Anasarca
• Acute extracellular hypoosmolality
• Cerebral edema (may be observed at rates of plasma osmolality decrease faster than 10 mOsm/kg/h)
• Permanent brain damage
• Cerebral herniation (has been observed in postmortem examination in both humans and experimental animals)

Prognosis

• Prompt recovery usually follows water restriction.
• Prognosis of SIADH is usually that of the underlying disease.

Patient Education

• Stress the importance of fluid restriction in maintaining reference range serum sodium levels.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Too rapid correction of hyponatremia (>2 mmol/h or >20 mmol/d) has been associated to development within one to several days of central pontine myelinolysis (CPM) with permanent neurologic damage resulting in paraparesis, quadriparesis, dysphagia, dysarthria, seizures, and coma.
• The use of thiazide diuretics in patients with syndrome of inappropriate antidiuretic hormone secretion can result in decreased free water excretion and can severely aggravate hyponatremia.

MULTIMEDIA

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Media file 1:  Disorders associated with syndrome of inappropriate secretion of antidiuretic hormone (SIADH).
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Media file 2:  Drugs that impair water excretion.
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Media file 3:  Cerebral salt-wasting syndrome (CSWS) versus syndrome of inappropriate secretion of antidiuretic hormone (SIADH).
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Media type:  Graph

REFERENCES

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16. De Troyer A, Demanet JC. Correction of antidiuresis by demeclocycline. N Engl J Med. Oct 30 1975;293(18):915-8. [Medline].
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21. Ferry RJ Jr, Kesavulu V, Kelly A, Levitt Katz LE, Moshang T Jr. Hyponatremia and polyuria in children with central diabetes insipidus: challenges in diagnosis and management. J Pediatr. 2001;138:744-7. [Medline].
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Article Last Updated: Jul 11, 2008