OVERVIEW: What every practitioner needs to know

Are you sure your patient has hyponatremia? What are the typical findings for this disease?

Hyponatremia (serum sodium concentration <130 mEq/L) in children most commonly results from severe dehydration, sodium depletion, or excessive administration of hypotonic fluids (especially in infancy). In contrast, the syndrome of inappropriate antidiuretic hormone (SIADH) release is uncommon in children.

Determine the intravascular volume status by carefully reviewing the history, physical examination, changes in weight, and vital signs. The history should focus on identifying recent changes in fluid intake/output, medication use, central nervous system or renal conditions associated with regulation of water balance, or conditions affecting oncotic pressure or shifts in intravascular fluid compartments (e.g., positive pressure ventilation).

The physical examination should establish whether intravascular volume status is increased or decreased and whether extravascular fluid is present.

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The determination of hyper- or hypovolemia is central to the evaluation and can be supported by laboratory investigations.

Serum: electrolyte, blood urea nitrogen, creatinine, uric acid levels and osmolality

Urine: sodium levels, specific gravity, osmolality

Causes of Hyponatremia

Volume Contraction

Systemic dehydration (common cause of hyponatremia)

Whatever the cause, the initial manifestation of systemic dehydration is usually hypernatremia and hyperosmolality, which leads to the appropriate stimulation of vasopressin secretion and decreased free water clearance. The combination of ongoing excessive free water intake with salt loss can lead to hyponatremia. Activation of the renin-angiotensin-aldosterone system leads to sodium retention with a low (<10 mEq/L) urine sodium level (assuming the absence of renal disease or diuretic therapy).

Decreased effective plasma volume (decreased oncotic pressure) (volume contraction)

Conditions associated with decreased cardiac output—as diverse as congestive heart failure, severe burns, cirrhosis, nephrotic syndrome, bronchopulmonary dysplasia, positive pressure ventilation, and pulmonary obstruction resulting from cystic fibrosis or severe asthma—result in increased vasopressin release leading to hyponatremia. In addition, conditions associated with increased atrial volume lead to increased release of atrial natriuretic peptide, further promoting hyponatremia through natriuresis. Given activation of the renin-angiotensin-aldosterone system, however, these patients typically manifest peripheral edema due to excessive total body sodium accumulation.

Primary salt loss (renal) (nonrenal) (volume contraction)

Conditions resulting in sodium chloride loss through the kidney (polycystic disease, interstitial nephritis, renal failure, obstructive uropathy and diuretic use), gastrointestinal tract (gastroenteritis), or sweat glands (cystic fibrosis) primarily result in hypovolemia with a secondary increase in vasopressin secretion leading to hyponatremia. Additional causes of sodium loss include hypoaldosteronism and pseudohypoaldosteronism (caused by inherited defects in the epithelial sodium channel or mineralocorticoid receptor).

Cerebral salt wasting (CSW; volume contraction)

This condition is generally associated with severe brain injury resulting from causes such as trauma, tumors, stroke, or hydrocephalus and urinary salt loss. In contrast to SIADH, CSW is associated with high urine output and urine sodium content (>150 mEq/L), volume contraction, and normal/elevated serum uric acid levels. The mechanism of this condition is not known and its existence is considered controversial by some. The diagnosis hinges on clearly documenting decreased volume status and severe urinary salt wasting in the setting of acute brain injury. Distinguishing between CSW and SIADH is essential given their divergent treatment strategies: CSW requires replacement with normal saline, whereas SIADH requires fluid restriction.

Runner’s hyponatremia (volume contraction)

Long-distance marathon running increases the risk for hyponatremia in hypovolemic individuals who consume excessive free water given their appropriately elevated vasopressin levels.

Hyperglycemia-associated hyponatremia (volume contraction)

Under normal physiologic conditions, plasma glucose is not osmotically active; however, under conditions of insulin deficiency, high levels of glucose become osmotically active, leading to dehydration, stimulation of vasopressin release, and water retention. The serum sodium concentration will be decreased by 1.6 mEq/L for every 100 mg/dL of blood glucose greater than a baseline of 100 mg/dL, becoming clinically evident with glucose >500 mg/dl.

Volume Expansion

SIADH (rare cause of hyponatremia) (volume expansion)

Most cases are iatrogenic or related to the treatment of diabetes insipidus and result from the excessive administration of free water in combination with vasopressin (or its analog DDAVP).

Additional causes include encephalitis, central nervous system tumors, head trauma, pneumonia, psychiatric disease, prolonged nausea, AIDS, tuberculous meningitis, and the postictal phase after generalized seizures.

Primary polydipsia (volume expansion)

Individuals with normal renal function and the ability to dilute their urine as low as 50 mOsm/kg H2O can consume as much as 10 L/m2 in order to excrete the average daily solute load of 500 mOsm/kg/d. Ingestion of more than this amount will result in water intoxication. Infants, however, lack the ability to dilute their urine to this extent and are at increased risk of water intoxication and hyponatremic seizures after administration of free water.

Decreased free water clearance (volume expansion)

Clearance of free water is dependent on normal adrenal and thyroid function. Patients with unexplained hyponatremia should be screened for deficiencies in cortisol, aldosterone, and thyroid hormone. Importantly, patients presenting with both adrenal insufficiency and diabetes insipidus may not show signs of the latter until unmasked by the addition of glucocorticoid. In addition, certain drugs can also block free water clearance from the kidney, including carbamazepine, oxcarbazepine, vinblastine, cisplatin, and high-dose cyclophosphamide.

Nephrogenic syndrome of inappropriate antidiuresis (volume expansion)

Activating mutations in the vasopressin (V2) receptor (on the X chromosome) results in hyponatremia and undetectable vasopressin levels in newborn boys.

What other disease/condition shares some of these symptoms?


Before the development of methods to directly measure electrolytes, falsely low sodium values could be obtained in the setting of hypertriglyceridemia, which results in the displacement of the aqueous phase from a given volume of serum.

Factitious Hyponatremia

The inadvertent collection of a venous blood sample from a site proximal to the infusion of hypotonic fluid can results in falsely low sodium values.

Hyperglycemia-Associated Hyponatremia (see above)

Under conditions of insulin deficiency, hyperglycemia results in a lowering of sodium levels because of an osmotic effect on water as well as the stimulation of vasopressin release resulting from systemic dehydration.

What caused this disease to develop at this time?

Causes of hyponatremia can be classified into two main categories based on their association with systemic volume contraction or volume expansion. Causes associated with volume contraction include systemic dehydration, decreased effective plasma volume, primary salt loss, cerebral salt wasting, and runner’s hyponatremia. Causes associated with volume expansion include SIADH, primary polydipsia, and nephrogenic syndrome of inappropriate antidiuresis.

(See above for more details.)

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

If hyponatremia is confirmed, additional analysis of serum and urine factors is required to establish the underlying diagnosis. Serum studies should determine osmolality, electrolyte, uric acid, blood urea nitrogen, and creatinine concentrations. Simultaneous urine studies should determine osmolality, specific gravity, and sodium concentration.

Serum: electrolyte, blood urea nitrogen, creatinine, and uric acid levels; osmolality

Urine: sodium levels, specific gravity, osmolality

In patients with volume contraction resulting from systemic dehydration, the initial response is often hypernatremia and hyperosmolality, which is followed by activation of vasopressin secretion resulting in decreased water excretion and hyponatremia. The volume-contracted state will also be reflected by increased serum concentrations of blood urea nitrogen (BUN), creatinine and uric acid. Ongoing hypovolemia also results in the activation of the renin-angiotensin-aldosterone system, leading to increased sodium retention. Analysis of urine will reveal a concentrated sample with a low sodium concentration.

In patients with volume expansion resulting from SIADH hyponatremia is associated with decreased serum concentrations of BUN, creatinine and uric acid. Analysis of urine will reveal a concentrated sample with a high sodium concentration (typically 40-80 mEq/L).

Confirming the diagnosis

Table I. Parameters Distinguishing Causes of Hyponatremia

Table I.
Condition Volume Status Urine Sodium
Systemic dehydration Contracted Low
SIADH Normal/expanded High
Decreased oncotic pressure Contracted Low
Primary salt loss (renal) Contracted High
Primary salt loss (nonrenal, e.g., GI) Contracted Low
Decreased free water clearance Normal/Expanded Normal/high
Cerebral salt wasting Contracted Very high
Nephrogenic SIADH Expanded High
Runner’s Hyponatremia Contracted Low
Hyperglycemia Contracted Low/normal
Pseudohyponatremia Normal Normal
Factitious Hyponatremia Normal Normal

GI = gastrointestinal

If you are able to confirm that the patient has this disease what treatment should be initiated?

Emergency Treatment of Hyponatremia

The acute onset (<12 hours) of hyponatremia or serum sodium values <120 mEq/L can be associated with central nervous system dysfunction resulting in lethargy, loss of consciousness, psychosis, and seizures (especially in younger children). These changes are the result of acute cerebral edema and can lead to herniation if untreated. Treatment includes total fluid restriction and, if necessary, administration of 3% saline until the mental status is improved.

5 mL 3% saline × weight in kg = increases serum {Na} 5 mEq/L, usually enough to stop seizures

Care should always be taken to avoid raising the serum sodium concentration faster than 0.5 mEq/L/h (~12 mEq/L/d) to avoid central pontine myelinolysis.

Systemic Dehydration

Treatment should be directed at restoring intravascular volume with sodium-containing fluids, such as normal saline or lactated Ringer solution. In patients with chronic hyponatremia (>12 hours in duration), care should be taken to prevent too rapid correction of the hyponatremia (see above).


Chronic SIADH is best managed by restriction of total fluids to a maximum of 1 L/m2/d. When additional fluids are required, as with infants dependent on larger volumes to support growth and development, pharmacologic options include demeclocycline to induce nephrogenic diabetes insipidus or urea to induce an osmotic diuresis, although neither drug is particularly efficacious. Vasopressin receptor antagonists (“vaptans”) represent a promising therapeutic alternative to treat these patients, but clinical trials have been conducted only in adults.

Decreased Effective Plasma Volume (Decreased Oncotic Pressure)

Treatment of the underlying condition is the most effective therapy for this form of hyponatremia, as demonstrated by the resolution of hyponatremia with discontinuation of positive pressure ventilation. For those conditions without effective therapies, the development of vasopressin (V2) receptor antagonists (currently in clinical trials for pediatric patients) may prove effective.

Primary Salt Lost

Treatment is aimed at replacing ongoing sodium chloride losses, initially with intravenous fluids and subsequently with oral supplementation as necessary.

Decreased Free Water Clearance

Clearance of free water is dependent on normal adrenal and thyroid function. Patients with unexplained hyponatremia should be screened for deficiencies in cortisol, aldosterone, and thyroid hormone. Importantly, patients presenting with both adrenal insufficiency and diabetes insipidus may not show signs of the latter until unmasked by the addition of glucocorticoid. Treatment is aimed at identifying the underlying cause (e.g., adrenal or thyroid insufficiency) and replacement as necessary to restore homeostasis.

Cerebral Salt Wasting

This condition is generally associated with severe brain injury resulting from causes such as trauma, tumors, stroke, or hydrocephalus. In contrast to SIADH, CSW is associated with high urine output and urine sodium content (>150 mEq/L), volume contraction, and normal/elevated serum uric acid levels. Few patients with this syndrome have been documented to have hypovolemia and therefore may have SIADH. Distinguishing between CSW and SIADH is essential given their divergent treatment strategies. If present, treatment is aimed at restoring intravascular volume with isotonic fluids, as with other forms of hypovolemia and urinary salt loss.

What are the adverse effects associated with each treatment option?

Central pontine myelinolysis is a devastating complication of hyponatremia that is normalized too quickly. It results from osmotic demyelination of neurons present within the pons region of the brainstem. Clinical manifestations including acute paralysis, dysphagia, dysarthria, and other neurologic symptoms. No specific treatment options exist, so the goal is prevention, which is best accomplished through the slow correction of the serum sodium. When possible, the treatment strategy should be designed to raise the serum sodium concentration no faster than 0.5 mEq/L/h (~12 mEq/L/d).

What causes this disease and how frequent is it?

The most common cause of hyponatremia is systemic dehydration. A rare cause of hyponatremia is SIADH. This syndrome is encountered in hospitalized settings where vasopressin and DDAVP therapy are used. Another cause of hyponatremia results from decreased effective plasma volume (decreased oncotic pressure). The frequency of this condition is linked to the underlying cause. For example, the majority of patients in intensive care units on positive pressure ventilation will experience mild hyponatremia, as a result of decreased vascular return to the right atrium triggering vasopressin release.

What complications might you expect from the disease or treatment of the disease?

See above.

How can this disease be prevented?

To avoid induction of iatrogenic hyponatremia, extreme care must be used when administering fluids to dehydrated children and to those on antidiuretic therapy or in those with SIADH. Careful monitoring of serum electrolytes after the initiation of fluid replacement is essential.

What is the Evidence?

Albanese, A, Hindmarsh, P, Stanhope, R.. “Management of hyponatremia in patients with acute cerebral insults”. Arch Dis Child. vol. 85. 2001. pp. 246-51.

Almond, CS, Shin, AY, Fortescue, EB. “Hyponatremia among runners in the Boston Marathon”. N Engl J Med. vol. 352. 2005. pp. 1550-6.

Feldman, BJ, Rosenthal, SM, Vargas, GA. “Nephrogenic syndrome of inappropriate antidiuresis”. N Engl J Med. vol. 352. 2005. pp. 1884-90.

Goldsmith, SR.. “Treatment options for hyponatremia in heart failure”. Heart Fail Rev. vol. 14. 2009. pp. 65-73.

Huang, EA, Feldman, BJ, Schwartz, ID. “Oral urea for the treatment of chronic syndrome of inappropriate antidiuresis in children”. J Pediatr. vol. 148. 2006. pp. 128-31.

Majzoub, JA, Muglia, LJ, Srivatsa, A., Sperling, MA. “Disorders of the posterior pituitary”. Pediatric endocrinology. 2014.

Sterns, RH, Silver, SM.. “Cerebral salt wasting versus SIADH: what difference?”. J Am Soc Nephrol. vol. 19. 2008. pp. 194-6.

Ongoing controversies regarding etiology, diagnosis, treatment

The existence of CSW as a clinical entity distinct from SIADH is somewhat controversial. The controversy exists because few patients with CSW have been formally demonstrated with rigorous invasive monitoring to have volume depletion and might therefore have SIADH.