Hyponatremia in children - UpToDate 15/08/18 1955

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Hyponatremia in children

Authors: Michael J Somers, MD, Avram Z Traum, MD Section Editor: Tej K Mattoo, MD, DCH, FRCP Deputy Editor: Melanie S Kim, MD

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jul 2018. | This topic last updated: Nov 11, 2016.

INTRODUCTION — Hyponatremia is defined as a serum or plasma sodium less than 135 mEq/L. Hyponatremia is among the most common electrolyte abnormalities in children. Drops in sodium level can lead to neurologic findings and in severe cases significant morbidity and mortality, especially in those with acute and rapid changes in plasma or serum sodium.

The etiology, clinical findings, diagnosis, and evaluation of pediatric hyponatremia are reviewed here. Hyponatremia in adults is discussed separately. (See "Causes of hyponatremia in adults" and "Overview of the treatment of hyponatremia in adults" and "Diagnostic evaluation of adults with hyponatremia".)

EPIDEMIOLOGY — The true incidence of pediatric hyponatremia is unknown, as published data are based on hospitalized children. As examples, the reported incidence of hyponatremia was 17 percent of children at the time of hospital admission in Japan, which was higher in febrile children [1]. The incidence increased to 45 percent in an Italian study in children with pneumonia [2]. This is most likely due to the release of antidiuretic hormone (ADH) associated with a number of clinical conditions that result in hospitalization. These include hypovolemia, fever, head injury, central nervous system (CNS) infections, and respiratory disorders (eg, pneumonia and respiratory syncytial virus bronchiolitis) [1,3].

In addition, in-hospital interventions, such as recent surgery (which is associated with ADH release), and the administration of hypotonic intravenous solutions, may contribute to the development of hyponatremia [4]. The effect of administered hypotonic intravenous solution on the development of hyponatremia, especially in children with persistent ADH release, was illustrated by the following studies:

● In a study from the United States of 1048 children who had normal serum sodium levels at the time of presentation, overall 35 percent of the cohort developed hyponatremia [5]. Patients who received hypotonic fluids were more likely to develop hyponatremia than those who received isotonic fluids (39 versus 28 percent). Additional identified risk factors for hyponatremia included admitting diagnoses of a cardiac or hematologic/oncologic condition, and surgical admission.

● In an observational Canadian study of 432 hospitalized children who had two or more measurements of plasma sodium, 40 patients developed hospital-acquired hyponatremia due to the administration of excessive free water as hypotonic solution [6].

PATHOPHYSIOLOGY — Hyponatremia is caused by an imbalance in the body's handling of water, resulting

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in a relative deficit of effective plasma osmolality (tonicity) to total body water. The plasma tonicity is defined as the concentration of solutes that do not easily cross the cell membrane, which is primarily due to sodium (Na) salts in the extracellular space. As a result, serum or plasma sodium is used as a surrogate for assessing tonicity. In this topic, we will use plasma, but in general, serum and plasma sodium can be used interchangeably. (See "General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)", section on 'Plasma tonicity'.)

The formulas used to estimate plasma tonicity are similar to those for plasma osmolality, with the one exception that the contribution of urea (an ineffective osmole) is not included. The multiplier factor of "2" accounts for the osmotic contributions of the anions that accompany sodium, the primary extracellular cation.

● Plasma tonicity = 2 x [Na] + [glucose]/18 (when glucose is measured in mg/dL)

● Plasma tonicity = 2 x [Na] + [glucose] (when glucose is measured in mmol/L)

Plasma tonicity is tightly regulated by the release of antidiuretic hormone (ADH) from the posterior pituitary promoting water retention, and by thirst-prompting water ingestion (figure 1). The homeostatic mechanisms that mediate plasma tonicity and water balance are similar in adults and children, resulting in a normal range of plasma sodium between 135 and 145 mEq/L that does not vary by age. (See "General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)", section on 'Regulation of plasma tonicity'.)

In children, the underlying pathogenesis for hyponatremia is typically due to excess free water retention that can be classified according to volume status as follows:

● Hypovolemia and appropriate ADH levels – In most pediatric cases, hyponatremia occurs in children with hypovolemia most commonly due to gastrointestinal loss, who are managed by an excess administration of free water in the setting of an elevated ADH activity. In such patients, ADH is appropriately released due to volume depletion. When hypotonic fluids are ingested or administered, free water is retained in excess of solutes resulting in a decrease in plasma sodium concentration.

Less commonly, pediatric hyponatremia may be caused by loss of sodium in excess of water (eg, urinary salt wasting in obstructive uropathy, skin losses in cystic fibrosis), which results in volume depletion and a decrease in plasma sodium.

● Normovolemia and inappropriate ADH levels – In volume replete individuals, excess water intake normally suppresses ADH release allowing for free water excretion and the generation of a dilute urine. However, several pediatric conditions are associated with inappropriate ADH release that results in retention of free water with fluid intake, leading to a drop in plasma sodium. These include pulmonary and oncologic disorders, recent surgery, central nervous system (CNS) injury or infection, endocrine disorders, and certain medications. (See 'Normovolemia' below and "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)", section on 'Etiology'.)

● Hypervolemia conditions – Renal failure or edematous conditions with decreased effective circulating volume (eg, nephrotic syndrome, cirrhosis, and heart failure) result in hypervolemia with excess water retention and a drop in plasma sodium. (See 'Hypervolemia' below.)

ETIOLOGY — As noted above, the etiology of hyponatremia can be categorized by volume status (low, normal, high). Within each category, the release of antidiuretic hormone (ADH) may be appropriate or

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inappropriate.

Hypovolemia — ADH release in hypovolemia is a physiologic response to maintain circulating volume (figure 2) (see "General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)", section on 'Role of ADH in volume regulation'). Most pediatric cases of hyponatremia are due to hypovolemic conditions (eg, gastroenteritis) that are associated with an appropriate elevation in ADH, which in the setting of excess free water repletion leads to water retention and a drop of plasma sodium that may result in hyponatremia. Other less common conditions associated with excess salt loss (eg, renal salt-wasting disorders) are also usually characterized by volume depletion.

● Gastrointestinal losses – The most common cause of hypovolemia in children is gastroenteritis. Other less common causes of pediatric gastrointestinal losses include secretory and osmotic diarrheas, enteric fistulas, and ostomies. Rehydration with free water in patients with significant gastrointestinal losses may lead to hyponatremia. (See "Overview of the causes of chronic diarrhea in children in resource-rich countries", section on 'Congenital secretory diarrheas' and "Overview of the causes of chronic diarrhea in children in resource-rich countries", section on 'Osmotic (malabsorptive) diarrheas' and "Overview of enteric fistulas", section on 'Fluid therapy'.)

● Diuretic-induced hyponatremia – Hyponatremia can be a complication of thiazide diuretic use, which acts in the renal cortex at the level of the distal tubule, thereby not interfering with medullarly ADH-induced water retention. Acutely, the initial volume loss can stimulate ADH release. As a result, the combination of diuretic-enhanced sodium and potassium excretion, and the resultant water retention due to ADH release from hypovolemia can result in excretion of urine with a higher solute concentration than that of plasma, leading to a drop in plasma sodium. (See "Diuretic-induced hyponatremia".)

● Renal salt wasting – Several conditions result in an inappropriate loss of urinary sodium due to impaired sodium chloride reabsorption.

• Cerebral salt wasting – Cerebral salt wasting occurs in patients with central nervous system (CNS) disorders. It is characterized by hyponatremia and extracellular fluid depletion due to inappropriate renal sodium wasting. In a case series of 110 children, the most common CNS conditions associated with cerebral salt wasting were intracranial surgery, meningoencephalitis, and head injury [7]. (See "Cerebral salt wasting".)

• Primary renal tubular disorders including Bartter and Gitelman syndromes. (See "Bartter and Gitelman syndromes", section on 'Overview of common and distinctive features'.)

• Disorders of adrenal insufficiency including 21-hydroxylase deficiency and hypoaldosteronism. (See "Causes and clinical manifestations of primary adrenal insufficiency in children" and "Hyponatremia and hyperkalemia in adrenal insufficiency", section on 'Hyponatremia and hyperkalemia'.)

● Skin losses – Excessive skin loss of sodium and water results in volume depletion, leading to free water retention and hyponatremia. This can occur in patients with cystic fibrosis, especially under conditions of heat stress. (See "Cystic fibrosis: Nutritional issues", section on 'Sodium'.)

● Intense exercise – High rate of fluid consumption during and after intense exercise (eg, marathons) has also been associated with the development of hyponatremia. In this setting, the major factors for developing hyponatremia are the high rate of fluid consumption and the persistent secretion of ADH due to the initial hypovolemia. (See "Exercise-associated hyponatremia", section on 'Pathogenesis'.) https://www.uptodate.com/contents/hyponatremia-in-children/print?source=bookmarks_widget Página 3 de 20 Hyponatremia in children - UpToDate 15/08/18 1955

Normovolemia — Most pediatric causes of hyponatremia in patients with normovolemia are due to inappropriate excess of ADH activity with the exception of primary polydipsia.

Syndrome of inappropriate ADH secretion — Normally in euvolemic individuals, excess water intake lowers tonicity that suppresses antidiuretic hormone (ADH) release, allowing for free water excretion. However, persistent ADH release and water retention in normovolemic children can be seen in a number of disorders associated with the syndrome of inappropriate ADH secretion (SIADH) (table 1). These include pulmonary (eg, pneumonia, bronchiolitis, mechanical ventilation), CNS (eg, brain injury and infections, and CNS tumors), and endocrine disorders (hypothyroidism and cortisol deficiency). (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)", section on 'Etiology'.)

Nephrogenic syndrome of inappropriate antidiuresis is a rare genetic cause of SIADH, which was first described in two infants with clinical findings suggestive of SIADH, but with undetectable ADH levels. They were subsequently found to have gain-of-function mutations in the gene encoding the vasopressin type 2 receptor (AVPR2) [8].

Medications — Several medications have been associated with inappropriate ADH release, increasing sensitivity of the vasopressin receptors, or mimicking the effect of ADH at its renal receptor. These include chemotherapeutic drugs (cyclophosphamide, vincristine, and platinum-based agents) and antiepileptic agents (valproate, carbamazepine, and oxcarbazepine).

Primary polydipsia — Primary polydipsia (also called psychogenic polydipsia) typically is observed in patients with preexisting psychiatric disease. In this disorder, patients drink excessively large volumes of water that result in lower plasma sodium levels despite suppression of ADH release. Primary polydipsia has been reported in children [9] and has been described in a toddler who mimicked the water loading behaviors of his mother in the setting of psychosocial stress at home [10]. (See "Causes of hyponatremia in adults", section on 'Primary polydipsia'.)

Reset osmostat — Reset osmostat occurs when a water load appropriately suppresses ADH release, but at a lower plasma osmolality than in normal individuals. These patients typically are euvolemic and have a moderately reduced plasma sodium concentration (usually between 125 and 135 mEq/L) that is stable on multiple measurements. Reset osmostat has been associated with children born with severe brain defects [11,12].

Hypervolemia — Pediatric hyponatremia is less commonly associated with hypervolemia and is typically seen in conditions associated with reduced effective circulating volume (ECV) and renal failure.

Effective arterial blood volume depletion — Conditions characterized by total body volume overload (usually clinically manifested by edema), but decreased ECV, are associated with hyponatremia. Reduced ECV leads to ADH release resulting in free water retention, and avid sodium tubular resorption due to decreased renal perfusion and stimulation of the renin-angiotensin-aldosterone axis resulting in low urinary sodium excretion, both of which contribute to a decrease in plasma sodium.

● Nephrotic syndrome – Children with nephrotic syndrome present with hypervolemia, but because of decreased plasma oncotic pressure, ECV is reduced. Hyperlipidemia is also part of the nephrotic syndrome and can lead to pseudohyponatremia if sodium is measured via indirect-reading ion-selective electrode potentiometry rather than via direct measurement.

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water retention (hypervolemia) and a fall in plasma sodium, which often leads to hyponatremia. (See "Hyponatremia in patients with cirrhosis", section on 'Pathogenesis'.)

● Heart failure – In patients with heart failure, low cardiac output and reduced systemic blood pressure leads to ADH release resulting in water retention (hypervolemia) and a fall in plasma sodium, which often leads to hyponatremia. (See "Hyponatremia in patients with heart failure", section on 'Pathogenesis'.)

Renal failure — The kidney's ability to excrete a free water load becomes limited as glomerular filtration rate (GFR) declines. As a result, patients with advanced renal failure are at risk for retaining ingested water and developing hyponatremia, despite suppression of ADH.

CLINICAL MANIFESTATIONS — The clinical manifestations vary depending on the duration and severity of hyponatremia.

Acute hyponatremia — Symptomatic hyponatremia manifests most commonly with neurologic dysfunction and results more from the rate of change of sodium concentration (rapid alterations less well tolerated than slowly acquired disorders) than the degree of hyponatremia. As the plasma sodium falls, an osmotic gradient develops between the intravascular space and the intracellular space, resulting in water movement from the extracellular space into the intracellular space. Volume shifts are attenuated to some extent by both acute and chronic regulatory mechanisms that exist in cells to minimize cell volume shifts (ie, cerebral adaption). The more rapid and extensive the degree of change, the less time is available for regulatory mechanisms to minimize cell volume change and the less efficacious these changes will be. Because of limited space in the skull, such rapid shifts may significantly increase brain volume and result in cerebral edema with concomitant neurologic signs and symptoms.

Plasma sodium levels >125 mEq/L are less likely to produce any specific symptoms, and children tend to only manifest the symptoms of their underlying acute illness. As the sodium falls acutely below 125 mEq/L, neurologic symptoms are observed, beginning with nausea and malaise [13]. Headache, lethargy, obtundation, and seizures may occur as the plasma sodium continues to fall below 120 mEq/L.

Chronic hyponatremia — In the setting of low plasma sodium levels that persist for more than a day or develop gradually over the course of days, cerebral cell volume adaptation measures minimize the development of cerebral edema (see "Manifestations of hyponatremia and hypernatremia in adults", section on 'Osmolytes and cerebral adaptation to hyponatremia'). These children are less likely to have overt symptoms until their plasma sodium becomes profoundly depressed or some acute event causes more rapid perturbation, although they may have subtle neurologic manifestations such as restlessness, weakness, fatigue, or irritability.

DIAGNOSIS — The diagnosis of hyponatremia is made by detection of a plasma or serum sodium level below 135 mEq/L. In many instances, the diagnosis is made incidentally when plasma or serum electrolytes are obtained during an evaluation for another condition, especially in children with levels between 130 to 135 mEq/L, whereas levels below 130 mEq/L are more often associated with clinical signs and symptoms.

Clinicians need to be aware that sodium values in capillary and non-capillary whole blood samples tend to be 2 to 3 mEq/L lower than measurements using venous samples [14,15]. For patients in whom ongoing monitoring of sodium is needed, this variation based on sampling technique and method of analysis should be kept in mind while managing patients with abnormal sodium values.

DIFFERENTIAL DIAGNOSIS — The differential diagnoses for true hyponatremia are pseudohyponatremia https://www.uptodate.com/contents/hyponatremia-in-children/print?source=bookmarks_widget Página 5 de 20 Hyponatremia in children - UpToDate 15/08/18 1955

(also referred to as factitious hyponatremia). In pseudohyponatremia, a low plasma sodium concentration is associated with normal plasma osmolality. In patients with pseudohyponatremia, a marked elevation in serum lipids or proteins in the fraction of serum that is water results in a falsely depressed sodium level when electrolyte measurement is performed using indirect ion-selective electrode potentiometry. When a direct ion-selective electrode is used, this false decrease in serum sodium does not occur. Although an increasing number of laboratories use direct ion-selective electrode techniques, in facilities using the older method, this interference needs to be kept in mind when interpreting low sodium results. Factitious hyponatremia is associated with increased serum osmolality and is commonly seen with hyperglycemia in diabetic patients. (See "Causes of hyponatremia in adults", section on 'Pseudohyponatremia' and 'Plasma osmolality' below and "Diagnostic evaluation of adults with hyponatremia".)

EVALUATION — Once a diagnosis of hyponatremia is made, the evaluation is focused on determining the underlying etiology of the child's hyponatremia, and includes clinical assessment and further laboratory evaluation.

Clinical evaluation — The underlying etiology of the child's hyponatremia is often evident from the history. Although dehydration is the most common clinical scenario leading to hyponatremia in children, because antidiuretic release may be triggered by stimuli other than volume depletion, the hyponatremic child may also be euvolemic or hypervolemic, and clinical assessment of volume status is paramount. Since the etiology of pediatric hyponatremia can be categorized by volume status (low, normal, high), and the appropriateness of antidiuretic hormone secretion, the history and physical examination should focus on determining the volume status of the child, the history of excessive free water intake, and evidence of antidiuretic hormone (ADH) effect based on urinary output and evidence of a concentrated urine.

● A history of fluid loss (eg, vomiting, diarrhea, profound bleeding, diuretic therapy) and signs of extracellular volume depletion (eg, decreased skin turgor, tachycardia, or orthostatic or persistent hypotension) are indicative of hypovolemia, which is associated with appropriate ADH secretion and retention of free water. In children, the most common cause of fluid loss associated with hyponatremia is gastroenteritis. (See 'Hypovolemia' above and "Clinical assessment and diagnosis of hypovolemia (dehydration) in children".)

● A history or physical finding of edema and ascites is suggestive of hypervolemic conditions with effective volume depletion, such as heart failure, cirrhosis, or nephrotic syndrome. (See 'Effective arterial blood volume depletion' above.)

● A history consistent with one of the pediatric causes of the syndrome of inappropriate ADH secretion (SIADH), such as brain injury or infection, and pulmonary disease (table 1). In this setting, patients typically have an inappropriately concentrated urine (yellow appearance) and a decrease in urine output due to the release of ADH despite a low plasma sodium level and tonicity. (See 'Syndrome of inappropriate ADH secretion' above.)

● A history of excess water intake (eg, older child with psychiatric disease [ie, primary polydipsia]). (See 'Primary polydipsia' above.)

● A history of a clinical condition associated with excess renal sodium loss, such as cerebral salt wasting or primary tubular disorder (eg, Bartter or Gitelman syndromes), or skin loss, such as cystic fibrosis.

● History of anuria or oliguria may be indicative of severe renal impairment with an inability to excrete free

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water. (See 'Renal failure' above.)

Laboratory evaluation — Generally, the patient history and physical examination provide important clues to the cause of hyponatremia. However, identification of subtle states of dehydration or edema may be challenging in children. As a result, the following laboratory tests that evaluate renal sodium and water handling in children with hyponatremia may be helpful in determining the underlying etiology.

● Plasma osmolality

● Urine osmolality

● Urine sodium

Plasma osmolality — Since plasma sodium is the principal determinant of plasma osmolality, hyponatremic children should have plasma osmolality lower than the normal range of 275 to 290 mosmol/kg. (See "General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)", section on 'Regulation of plasma tonicity' and 'Pathophysiology' above.)

If there is a relative elevation of the plasma osmolality to plasma sodium, then concomitant severe azotemia or hyperglycemia should be considered.

● Azotemia – In patients with advanced renal failure, the hyponatremia is due to an inability to excrete water resulting from the impairment in renal function. Although this will tend to lower the plasma osmolality, this effect is counterbalanced to a variable degree by the associated elevation in blood urea nitrogen (BUN), resulting in a plasma osmolality that may be normal or elevated. However, there is a difference between the measured plasma osmolality and the effective plasma osmolality in patients with renal failure. In contrast to sodium and glucose, urea is an ineffective osmole, since it can freely cross cell membranes and therefore does not obligate water movement out of the cells.

● Hyperglycemia – In patients with hyperglycemia, the osmotic gradient causes water flow out of the cells into the extracellular spaces, leading to a 1.6 mEq/L decrease in plasma sodium for every 5.6 mEq/L (100 mg/dL) elevation in plasma glucose above normal. As the hyperglycemia resolves, water moves back intracellularly and the plasma sodium measurement increases, without any change in total body sodium or total body water.

In patients with pseudohyponatremia, hyperlipidemia or hyperproteinemia lower the plasma sodium concentration without changing the plasma osmolality. (See 'Differential diagnosis' above.)

Urine osmolality — Urine osmolality can help distinguish between conditions associated with impaired water excretion, in which the urine osmolality is >100 mosmol/kg, and the more uncommon disorders in which water excretion is normal (eg, primary polydipsia or osmostat resets).

● Impaired water excretion – Urine osmolality >100 mosmol/kg should be considered evidence of impaired water handling in normovolemic children with hyponatremia as ADH should be normally depressed. These patients will often have quite concentrated urines with urine osmolality significantly exceeding plasma osmolality. (See 'Syndrome of inappropriate ADH secretion' above.)

● Normal water excretion – Settings in which there is normal water excretion (suppression of ADH) with urine osmolality below 100 mosmol/kg include:

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• Psychogenic polydipsia – In this disorder, patients drink excessively large volumes of water that result in lower plasma sodium levels despite suppression of ADH release. (See 'Primary polydipsia' above.)

• Reset osmostat – Patients with reset osmostat have a threshold for ADH release that is at a lower plasma osmolality. As a result, they are able to generate a dilute urine (urine osmolality below 100 mosmol/kg) when plasma osmolality is below their reset threshold for ADH in response to a water load. (See 'Reset osmostat' above.)

Urine sodium — Assessment of urine sodium helps to determine the kidney's response to the patient's volume status. In the setting of hyponatremia, hypoosmolality, and an inappropriately concentrated urine, urine sodium concentration can help distinguish hyponatremia caused by effective volume depletion, renal salting wasting, and inappropriate ADH secretion (table 2).

● In patients with effective volume depletion, the random urine sodium concentration should be <25 mEq/L because the decrease in effective renal perfusion leads to avid sodium resorption resulting in a low urine sodium. (See 'Effective arterial blood volume depletion' above.)

However, in children with metabolic alkalosis, most commonly seen with ongoing vomiting, there are obligate sodium losses in the urine accompanying the bicarbonaturia. In this setting, despite the effective circulating volume (ECV) depletion, random urine sodium concentrations can exceed 25 mEq/L. Urine chloride concentrations, which generally parallel urinary sodium in volume depletion, will be <25 mEq/L and can be used to more accurately assess volume status.

● In hypovolemic patients with hypoaldosteronism or cerebral salt wasting, or who are treated with thiazide diuretics, the urine sodium typically is >25 mEq/L, reflecting renal salt wasting. (See 'Hypovolemia' above.)

● In patients with SIADH who are euvolemic, the urine sodium concentration is usually >25 mEq/L, and reflects ongoing sodium intake similar to in other euvolemic children. These patients are euvolemic because the subsequent avid water reabsorption due to ADH generally results in euvolemia or effective volume expansion. (See 'Syndrome of inappropriate ADH secretion' above.)

MANAGEMENT

Prevention — As noted above, a significant number of children who are hospitalized develop hyponatremia as a result of excessive free water administration. In particular, children who are postoperative, or have central nervous system (CNS) illness (eg, meningitis, encephalitis, or brain trauma) or respiratory disorders (eg, pneumonia or bronchiolitis) are likely to have antidiuretic hormone (ADH) release, which is independent of effective volume contraction. This pediatric population is at risk for developing acute hyponatremia if unrestricted hypotonic fluids, either intravenously or by mouth, are provided. As a result, fluid and electrolyte therapy need to be tailored to prevent the administration of excessive free water. (See 'Syndrome of inappropriate ADH secretion' above and "Maintenance fluid therapy in children", section on 'Hospitalized children'.)

Treatment

Overview — Appropriate treatment of pediatric hyponatremia requires an understanding of the following:

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● Etiology of hyponatremia – Treatment choices may vary depending on the underlying condition.

● Child's effective circulating volume and hemodynamic stability.

● Identification and severity of symptoms, particularly neurologic findings.

● Rate of the change in sodium concentration.

● Duration of hyponatremia – Since cerebral adaptation begins within a day of sustained hyponatremia, it is safest to approach any hyponatremia of more than 24 to 48 hours' duration as chronic in nature. In patients with chronic hyponatremia, osmotic demyelination may develop when hyponatremia is corrected too quickly.

● The need to readjust therapy based on data from ongoing monitoring of the patient's fluid status based on frequent clinical examinations and follow-up laboratory evaluation, including subsequent assessment of sodium levels.

Treatment choices — Plasma sodium can be raised by one or more of the following methods:

● Fluid restriction in patients with ADH release.

● Administration of oral or intravenous sodium chloride.

● Treatment of the underlying disease, if possible. For example, treatment of pediatric diseases (eg, pneumonia and meningitis) associated with the syndrome of inappropriate ADH (SIADH) will lead to correcting the inappropriate ADH release and excessive free water retention.

Rate of correction — The rate of correction is dependent on the following factors:

● Chronicity of hyponatremia – As discussed above, patients with chronic hyponatremia (duration greater than 24 hours) are more likely than those with acute hyponatremia to have cerebral adaption, which protects them from cerebral edema, but makes them more susceptible to osmotic demyelination with overly rapid correction. (See 'Clinical manifestations' above.)

● Presence and severity of symptoms – Severe neurologic symptoms (eg, seizures and altered mental status) are most likely to occur with acute hyponatremia, which is accompanied by a rapidly decreasing sodium concentration. In these patients, there has been no time for cerebral adaption, and a more rapid approach using hypertonic saline is used for correction.

● Severe hyponatremia – Overly rapid correction of severe hyponatremia (plasma sodium concentration less than 120 mEq/L and usually less than 115 mEq/L) can lead to a severe and sometimes irreversible osmotic demyelination syndrome resulting in diffuse demyelination in the brain and the development of profound irreversible neurologic symptoms (dysarthria, confusion, obtundation, and coma). These symptoms often present several days after the sodium has been acutely corrected. Most reported cases have occurred when the plasma sodium corrections exceeded 10 mEq/L in a 24-hour period. (See "Osmotic demyelination syndrome (ODS) and overly rapid correction of hyponatremia", section on 'Risk factors for ODS'.)

Based on the above, we recommend a targeted corrected rate of 6 to 8 mEq/L increase in plasma sodium for each 24-hour period be used, and rates greater than 9 mEq/L be avoided. In most patients, even in those

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with severe symptoms, this targeted rate appears to be sufficient for symptom resolution [16,17]. In otherwise healthy patients with perturbations in plasma sodium that have developed in less than 24 hours, rapid correction has not been associated with adverse CNS effect, but there is no specific benefit in most for a more rapid correction than the targeted rate [18-20].

Maintenance needs — Because most children with hyponatremia are cared for in the hospital, hospital decisions regarding ongoing fluid and electrolyte therapy must consider ongoing maintenance needs and losses, in addition to the correction of hyponatremia, and, when appropriate, water deficit. Adjustment of fluid therapy is especially critical in patients with ADH release, as these patients will continue to retain free water, which may be exacerbated by hypotonic fluids. Clinicians must also be aware of changes of ongoing fluid and electrolyte requirements, as ADH release may be suppressed with treatment of the underlying etiology. (See "Maintenance fluid therapy in children", section on 'Hospitalized children'.)

These points are illustrated in a systematic review that reported the use of hypotonic solution as maintenance fluid for hospitalized children was associated with an increased risk of hyponatremia (plasma sodium <136 mEq/L) and severe hyponatremia (plasma sodium <130 mEq/L), which was thought to be due primarily to impaired ability to excrete free water due to ADH secretion [21].

Clinical settings — The approach to treatment depends on the child's effective volume and hemodynamic stability, the presence and severity of any symptoms related to the hyponatremia, and the chronicity of hyponatremia, as demonstrated by the following clinical settings.

Severe CNS symptoms — Symptomatic hyponatremia is one of the rare clinical settings in children in which hypertonic (3 percent) saline is used (sodium concentration of 513 mEq/L compared with 154 mEq/L in 0.9 percent or isotonic saline). In the child with seizures or altered mental status, correction of hyponatremia should not be delayed. In these patients, 3 to 5 mL/kg of 3 percent saline is the suggested initial therapy [22].

After the initial hypertonic saline infusion, plasma sodium should be measured and, if seizures are ongoing, the infusion should be repeated. Once the acute CNS symptoms have abated, the ongoing sodium correction should be tailored so that the total daily correction, including the hypertonic saline bolus, is less than 12 mEq/L [23].

A report of 56 children who received 3 to 5 mL/kg of 3 percent saline demonstrated that such doses administered over a median time interval of only 17 minutes raised plasma sodium effectively and without adverse effect [22]. Nearly 90 percent received hypertonic saline via peripheral intravenous catheter, simplifying management by avoiding central venous access. Although the optimal rate of hypertonic saline administration for efficacy and safety is not well defined, this rapid approach using a set dose and peripheral access facilitates administration.

The primary problem with symptomatic hyponatremia is evolving cerebral edema, and the risk of morbidity from delayed therapy is greater than the risk of complication from too rapid correction and osmotic demyelination. As a result, aggressive initial correction is indicated for the first three to four hours (or until the symptoms resolve) at a rate not to exceed a rise in serum sodium of 2 mEq/L per hour [24-26]. Often, an initial goal is to raise the serum sodium by 5 mEq/L over the first several hours as seizures seem to resolve with this therapeutic approach [27].

Of note, seizures due to hyponatremia may be refractory to anticonvulsant therapy.

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total daily correction including the hypertonic saline bolus is less than 12 mEq/L.

Mild CNS or no symptoms — In the child with mild neurologic (eg, nausea and malaise) or no symptoms related to hyponatremia, there is no need for hypertonic saline provision. These children require ongoing monitoring for newly emerging CNS symptoms, but their treatment is guided more by treatment of the underlying condition that caused the sodium to drop than attention to their volume status or need for sodium supplementation. The targeted rate of correction in this setting is 6 to 8 mEq/L over 24 hours.

Normal or increased ECV — In the hyponatremic child with normal or increased effective circulating volume (ECV) due to SIADH, water restriction to 60 percent of usual daily maintenance fluid provision will allow for the slow correction of volume imbalance and normalization of plasma sodium as excess free water is excreted. Concomitant provision of maintenance electrolytes and replacement of ongoing fluid and electrolyte losses are necessary to prevent further derangements. Hypotonic fluids should be avoided since any ongoing ADH secretion will result in avid distal tubule free water reabsorption that will counter the correction of hyponatremia via fluid restriction. (See "Maintenance fluid therapy in children", section on 'Hospitalized children'.)

There is very limited experience to assess vasopressin receptor antagonist efficacy and safety in children with hyponatremia caused by the SIADH syndrome of inappropriate ADH secretion (SIADH); as a result, it is recommended that they not be used routinely to treat pediatric hyponatremia. (See "Overview of the treatment of hyponatremia in adults", section on 'Vasopressin receptor antagonists'.)

Decreased ECV — The approach to treating hyponatremia in the child with decreased effective circulating volume (ECV) depends on the underlying etiology and corresponding pathophysiology.

● In patients who are hypervolemic with a decreased ECV due to heart failure, nephrotic syndrome, or cirrhosis, the treatment choice consists of treating the underlying conditions, and fluid restriction. In these patients, the retained free water by the kidney moves from the vascular into interstitial spaces resulting in edema and ascites. Fluid restriction allows slow restoration in the balance between the preexisting total body sodium and water overload, and prevents further exacerbation of clinical symptoms. (See 'Effective arterial blood volume depletion' above.)

● In patients with true effective volume depletion due to hypovolemia, as seen with gastroenteritis, there is often both a loss of total body salt and water. Provision of isotonic fluid will restore the circulating volume and improve renal perfusion. Since the administered fluid will remain in the ECV, it will inhibit activation of the renin-angiotensin-aldosterone axis and ADH release, and limit the free water reabsorption that has mediated the hyponatremia. The child can then receive sufficient sodium and water to replace losses, and restore fluid and sodium balance. (See "Treatment of hypovolemia (dehydration) in children", section on 'Hyponatremia'.)

In this setting, sodium deficit is a combination of the sodium loss in the isotonic fluid deficit (each kilogram of body weight represents one liter deficit of water and 140 mEq loss of sodium) and the loss of sodium in the remaining current hyponatremic state, which is calculated as follows:

Hyponatremic sodium deficit = Current total body water (TBW) x (desired plasma sodium - actual sodium)

Clinical example — The following case synthesizes the information presented above in an attempt to show how the principles are applied clinically. A 10 kg child (desired TBW = 0.6 times body weight) is estimated to https://www.uptodate.com/contents/hyponatremia-in-children/print?source=bookmarks_widget Página 11 de 20 Hyponatremia in children - UpToDate 15/08/18 1955

have a 10 percent hypovolemic loss (approximately one liter of fluid) and a serum/plasma sodium concentration of 120 mEq/L. She has been ill for several days, but has no neurologic findings. In this child, rapid correction is not needed because she displays no symptoms from her hyponatremia and the assumption is that she has chronic hyponatremia (greater than 24 hours).

Therapy is directed towards replacing her water and sodium losses, which can be determined by using the following calculations:

Desired TBW = 6 L

Total fluid deficit: 10 percent of 10 kg = 1 L

Current TBW = 5 L

Sodium (Na) deficit from isotonic fluid deficit = 1 L x 140 mEq/L = 140 mEq

Hyponatremic sodium deficit = Current TBW x (desired serum Na – current serum Na) = 5 L x (135 mEq/L – 120 mEq/L) = 75 mEq

Total sodium deficit = 215 mEq

Because she has been hyponatremic for more than a day, plasma sodium should not be increased more rapidly than 8 mEq/L/day until a normal plasma sodium of 135 mEq/L is achieved, which should take place over two days.

During the emergent fluid phase, she received a 20 mL/kg bolus of normal saline (200 mL of water and 30 mEq Na). Accordingly, for the next two days, her total fluid needs is 2800 mL (800 mL of remaining fluid deficit, and 2000 mL for two days of maintenance needs [daily rate of 1000 mL/day]) with total sodium needs of 245 mEq (185 mEq of the remaining sodium deficit and 60 mEq for two days of maintenance needs [daily rate of 30 mEq/day]). Any excess ongoing losses of fluid and sodium would also need to be replaced.

If there are no ongoing losses, then the provision of half isotonic saline at a rate of 60 mL/hour x 48 hours would best approximate these needs. During infusion of this fluid, plasma sodium should be assessed every four to six hours initially to make sure that the rate of correction is not proceeding too quickly. Urine output and concentration should also be carefully monitored during the correction phase, as excess free water retention may occur due to ADH release, in which case adjustments in either the rate of fluid administration or the tonicity of replacement fluid (isotonic saline) may be needed.

SUMMARY AND RECOMMENDATIONS

● Hyponatremia is defined as a serum or plasma sodium less than 135 mEq/L and is among the most common electrolyte abnormalities in children. Although the true incidence is unknown, hyponatremia is often observed in children on admission to the hospital and is a common complication of in-hospital interventions. (See 'Epidemiology' above.)

● Hyponatremia is caused by an imbalance in the body's handling of water, resulting in a relative deficit of effective plasma osmolality (tonicity) to total body water. Plasma or serum sodium is typically used as a clinical surrogate for assessing tonicity. The pathophysiology and etiology of pediatric hyponatremia can be classified based on the patient's volume status. Hyponatremia most commonly occurs in children with hypovolemia due to gastrointestinal loss, who are managed by an excess intake of free water in the

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setting of an elevated antidiuretic hormone (ADH) activity. Other causes include the syndrome of inappropriate ADH secretion (SIADH), which typically occurs in normovolemic patients and is associated with several clinical conditions (pulmonary and oncologic disorders, recent surgery, central nervous system injury or infection, endocrine disorders, and certain medications), and less common hypervolemic conditions, such as renal failure and disorders with a reduced effective circulating volume (ECV; eg, nephrotic syndrome, heart failure, and cirrhosis). (See 'Pathophysiology' above and 'Etiology' above.)

● The presence and severity of clinical manifestations correlate with the degree of plasma or serum sodium depression, its rate of decline, and chronicity. The range of findings varies from no symptoms (especially in patients with chronic hyponatremia, defined as duration greater than 24 hours) to severe neurologic symptoms (eg, seizure and coma). (See 'Clinical manifestations' above.)

● The diagnosis of hyponatremia is made by the detection of a plasma or serum sodium level below 135 mEq/L. The differential diagnosis includes pseudohyponatremia and factitious hyponatremia. (See 'Diagnosis' above and 'Differential diagnosis' above.)

● The diagnostic evaluation is focused on determining the underlying cause of hyponatremia and includes clinical assessment and further laboratory evaluation. In many cases, the etiology is evident from the history. However, when the diagnosis remains uncertain, laboratory tests (plasma and urine osmolality, and urine sodium) can help determine the underlying etiologies due to SIADH, the presence of other solutes that increase plasma osmolality, renal salt loss, or decreased ECV and impaired renal perfusion. (See 'Evaluation' above.)

● Prevention of hyponatremia includes identifying children who are hospitalized that are at risk for developing hyponatremia (eg, those with SIADH). In these patients, fluid and electrolyte therapy needs to be individually tailored to prevent the administration of excessive free water. (See 'Prevention' above.)

● Treatment of hyponatremia consists of correcting hyponatremia with one or more interventions including fluid restriction, administration of sodium chloride, and treatment of the underlying etiology. Management decisions are based on determining the magnitude and cause of the sodium deficit, the rate of sodium decline, the volume status of the patient, the presence of severe symptoms, and the chronicity of hyponatremia. (See 'Treatment' above.)

● We recommend that the rate of correction for pediatric hyponatremia does not exceed an increase of 8 mEq/L over a 24-hour period (Grade 1A). Overly rapid correction can cause osmotic demyelination syndrome resulting in diffuse demyelination in the brain and the development of profound irreversible neurologic symptoms. (See 'Rate of correction' above.)

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REFERENCES

1. Hasegawa H, Okubo S, Ikezumi Y, et al. Hyponatremia due to an excess of arginine vasopressin is common in children with febrile disease. Pediatr Nephrol 2009; 24:507. 2. Don M, Valerio G, Korppi M, Canciani M. Hyponatremia in pediatric community-acquired pneumonia. Pediatr Nephrol 2008; 23:2247. 3. Gerigk M, Gnehm HE, Rascher W. Arginine vasopressin and renin in acutely ill children: implication for https://www.uptodate.com/contents/hyponatremia-in-children/print?source=bookmarks_widget Página 13 de 20 Hyponatremia in children - UpToDate 15/08/18 1955

fluid therapy. Acta Paediatr 1996; 85:550. 4. Choong K, Arora S, Cheng J, et al. Hypotonic versus isotonic maintenance fluids after surgery for children: a randomized controlled trial. Pediatrics 2011; 128:857. 5. Carandang F, Anglemyer A, Longhurst CA, et al. Association between maintenance fluid tonicity and hospital-acquired hyponatremia. J Pediatr 2013; 163:1646. 6. Hoorn EJ, Geary D, Robb M, et al. Acute hyponatremia related to intravenous fluid administration in hospitalized children: an observational study. Pediatrics 2004; 113:1279. 7. Bettinelli A, Longoni L, Tammaro F, et al. Renal salt-wasting syndrome in children with intracranial disorders. Pediatr Nephrol 2012; 27:733. 8. Feldman BJ, Rosenthal SM, Vargas GA, et al. Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med 2005; 352:1884. 9. Dogangün B, Hergüner S, Atar M, et al. The treatment of psychogenic polydipsia with risperidone in two children diagnosed with schizophrenia. J Child Adolesc Psychopharmacol 2006; 16:492. 10. Gurwitz A, Schulz S, Zang M, et al. Index of suspicion. Pediatr Rev 2012; 33:377. 11. Gupta P, Mick G, Fong CT, et al. Hyponatremia secondary to reset osmostat in a child with a central nervous system midline defect and a chromosomal abnormality. J Pediatr Endocrinol Metab 2000; 13:1637. 12. Arisaka O, Yabuta K. Hyponatremia caused by a reset osmostat. J Pediatr 1997; 130:162. 13. Rodríguez MJ, Alcaraz A, Solana MJ, García A. Neurological symptoms in hospitalised patients: do we assess hyponatraemia with sufficient care? Acta Paediatr 2014; 103:e7. 14. Levene I. Towards evidence based medicine for paediatricians. Question 1: Is measurement of sodium from capillary blood accurate enough for clinical decision making? Arch Dis Child 2014; 99:481. 15. Morimatsu H, Rocktäschel J, Bellomo R, et al. Comparison of point-of-care versus central laboratory measurement of electrolyte concentrations on calculations of the anion gap and the strong ion difference. Anesthesiology 2003; 98:1077. 16. Sterns RH, Nigwekar SU, Hix JK. The treatment of hyponatremia. Semin Nephrol 2009; 29:282. 17. Sterns RH, Hix JK, Silver S. Treatment of hyponatremia. Curr Opin Nephrol Hypertens 2010; 19:493. 18. Sterns RH, Silver SM. Brain volume regulation in response to hypo-osmolality and its correction. Am J Med 2006; 119:S12. 19. Keating JP, Schears GJ, Dodge PR. Oral water intoxication in infants. An American epidemic. Am J Dis Child 1991; 145:985. 20. Yeates KE, Singer M, Morton AR. Salt and water: a simple approach to hyponatremia. CMAJ 2004; 170:365. 21. Wang J, Xu E, Xiao Y. Isotonic versus hypotonic maintenance IV fluids in hospitalized children: a meta- analysis. Pediatrics 2014; 133:105. 22. Brenkert TE, Estrada CM, McMorrow SP, Abramo TJ. Intravenous hypertonic saline use in the pediatric emergency department. Pediatr Emerg Care 2013; 29:71. 23. Sterns RH, Cappuccio JD, Silver SM, Cohen EP. Neurologic sequelae after treatment of severe hyponatremia: a multicenter perspective. J Am Soc Nephrol 1994; 4:1522. 24. Berl T. Treating hyponatremia: damned if we do and damned if we don't. Kidney Int 1990; 37:1006. 25. Karp BI, Laureno R. Pontine and extrapontine myelinolysis: a neurologic disorder following rapid

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correction of hyponatremia. Medicine (Baltimore) 1993; 72:359. 26. Sterns RH. Severe symptomatic hyponatremia: treatment and outcome. A study of 64 cases. Ann Intern Med 1987; 107:656. 27. Sarnaik AP, Meert K, Hackbarth R, Fleischmann L. Management of hyponatremic seizures in children with hypertonic saline: a safe and effective strategy. Crit Care Med 1991; 19:758.

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GRAPHICS

Osmotic regulation of ADH release and thirst

Relation between plasma ADH concentration and plasma osmolality in normal humans in whom the plasma osmolality was changed by varying the state of hydration. The osmotic threshold for thirst is a few mosmol/kg higher than that for ADH.

ADH: antidiuretic hormone.

Data from Robertson GL, Aycinena P, Zerbe RL. Neurogenic disorders of osmoregulation. Am J Med 1982; 72:339.

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Hypovolemic stimulus to ADH release

Relationship of plasma antidiuretic hormone (ADH) concentrations to isosmotic changes in blood volume in the rat. Much higher ADH levels can occur with hypovolemia than with hyperosmolality, although a relatively large fall in blood volume is required before this response is initiated.

Data from Dunn FL, Brennan TJ, Nelson AE, et al. J Clin Invest 1973; 52:3212.

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Causes of antidiuretic hormone (ADH) release in children

Category Specific causes

Physiologic Hypovolemia, hyperosmolality

Pulmonary Pneumonia, bronchiolitis, asthma, pneumothorax, cystic fibrosis, positive pressure mechanical ventilation

Central nervous system (CNS) Meningitis, encephalitis, CNS tumor, brain trauma, pain, anxiety, hypoxia, nausea

Metabolic Hypothyroidism, hypoadrenalism

Medication effect Vincristine, carbamazepine, cyclophosphamide, narcotics

Adapted from: Somers MJG. Fluid and electrolyte therapy in children. In: Pediatric Nephrology, 6th ed, Avner ED, Harmon WH, Niaudet P, Yoshikawa N (Eds), Springer-Verlag, Berlin 2009.

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Causes of hyponatremia in children: Based on patient's volume status and renal sodium handling

Circulating arterial Urinary sodium concentration volume <25 mEq/L >25 mEq/L

Decreased Gastroenteritis Adrenal insufficiency

Cystic fibrosis Diuretics - Early effect

Diuretics - Late effect Salt wasting

Burns

Bleeding

Normal or increased Cardiac failure SIADH

Nephrotic syndrome Renal failure

Cirrhosis Water intoxication

SIADH: syndrome of inappropriate antidiuretic hormone.

Adapted from: Somers MJG. Fluid and electrolyte therapy in children. In: Pediatric Nephrology, 6th ed, Avner ED, Harmon WH, Niaudet P, Yoshikawa N (Eds), Springer-Verlag, Berlin 2009.

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Contributor Disclosures

Michael J Somers, MD Nothing to disclose Avram Z Traum, MD Nothing to disclose Tej K Mattoo, MD, DCH, FRCP Nothing to disclose Melanie S Kim, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

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