Hyponatremia in children: Etiology and clinical manifestations

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, to significant morbidity and mortality, especially in those with acute and rapid changes in plasma or serum sodium.

The etiology and clinical findings of pediatric hyponatremia are reviewed here. The detection, diagnostic evaluation, prevention, and treatment of pediatric hyponatremia are discussed separately. In addition, hyponatremia in adults is discussed separately. (See "Hyponatremia in children: Evaluation and management" and "Causes of hypotonic hyponatremia in adults" and "Overview of the treatment of hyponatremia in adults" and "Diagnostic evaluation of adults with hyponatremia".)

TERMINOLOGY AND DEFINITIONS

Serum versus plasma — Serum and plasma sodium levels are typically interchangeable, except for the uncommon cases of pseudohyponatremia. Because most laboratory testing of blood sodium (clotted blood samples) is based on the serum sodium, this topic preferentially uses serum sodium except if a study specifies the use of plasma sodium. This is also true for serum and plasma tonicity.

Severity of hyponatremia — Severity of hyponatremia is defined by the serum sodium level as follows:

●Mild hyponatremia – Serum concentration between 130 and 134 mEq/L

●Moderate hyponatremia – Serum concentration between 120 to 129 mEq/L

●Severe hyponatremia – Serum concentration <120 mEq/L

Acute versus chronic hyponatremia — The duration of hyponatremia is defined as follows:

●Acute hyponatremia develops over a period of less than 48 hours

●Chronic hyponatremia is defined as hyponatremia that has been present for more than 48 hours

EPIDEMIOLOGY

Hospital admission — The true incidence of pediatric hyponatremia is unknown as published data are based on hospitalized children. For example, 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].

Hospital-acquired — In-hospital interventions, such as recent surgery (which is associated with ADH release) and administration of hypotonic intravenous solutions, contribute to the development of hospital-acquired 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, 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].

SODIUM AS A MARKER OF TONICITY — Serum tonicity is defined as the concentration of solutes that do not easily cross the cell membrane (effective osmoles). These solutes are primarily sodium salts contained in the extracellular space. As a result, serum sodium is used as a surrogate for assessing tonicity of the extracellular fluid.

Serum 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 tonicity and water balance are similar in adults and children, resulting in a normal range of serum 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'.)

The formulas used to estimate serum tonicity are similar to those for serum 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:

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

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

Most pediatric patients have an underlying condition that results in hyponatremia with hypotonicity (table 1), caused by an imbalance in the body's handling of water. However, there are exceptions of hyponatremic conditions when tonicity is normal or increased due to the presence of another osmole (eg, hyperglycemia). (See 'Hypotonic hyponatremia' below and 'Hyponatremia without hypotonicity' below.)

In addition, the routinely measured value of sodium concentration may be low when there is pseudohyponatremia, in which the water content of plasma is reduced (eg, hyperlipidemia). (See 'Pseudohyponatremia' below.)

HYPOTONIC HYPONATREMIA

Pathogenesis and volume status — In children, hypotonic hyponatremia is typically due to a loss of sodium as well as free water or excess free water retention. These can be classified according to volume status as follows:

●Hypovolemia and persistent antidiuretic hormone (ADH) levels – In most pediatric cases, hyponatremia occurs in children with hypovolemia due to gastrointestinal loss. In this setting, ADH is appropriately released, resulting in a concentrated urine and decrease in urine volume. If hypotonic fluids are given for volume repletion, either orally or intravenously, retention of free water in excess of solutes results in a decrease in serum sodium. (See "Treatment of hypovolemia (dehydration) in children in resource-abundant settings", section on 'Intravenous rehydration therapy'.)

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 serum 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, leading to a drop in serum sodium (table 2). These include pulmonary and oncologic disorders, recent surgery, central nervous system (CNS) injury or infection, endocrine disorders, and certain medications including some anticonvulsants and chemotherapeutic drugs (table 3). (See 'Euvolemia' below and "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)", section on 'Etiology' and 'Medications' below.)

●Normovolemia – Other less common causes of hyponatremia in children who are euvolemic include primary polydipsia and reset osmostat (those with a lower-than-normal plasma osmolality threshold for ADH release). (See 'Primary polydipsia' below and 'Reset osmostat' below.)

●Hypervolemia – Hypervolemic conditions resulting in pediatric hyponatremia include:

•Conditions with decreased effective circulating volume (ECV; eg, nephrotic syndrome, cirrhosis, and heart failure) result in hypervolemia with excess water retention promoted by a decrease in kidney perfusion and urine output, leading to a drop in serum sodium. (See 'Hypervolemia' below.)

•Kidney failure with a decrease in glomerular filtration rate results in water retention caused by a reduced ability to excrete free water, leading to a drop in serum sodium.

Another classification scheme divides hyponatremia based on the body's ability to excrete dilute urine (release of ADH) and, if that is impaired, the reason for the impairment. In pediatrics, the volume status classification is preferred as it is common clinical practice to assess the volume status of the patient. (See "Causes of hypotonic hyponatremia in adults", section on 'Classification of hypotonic hyponatremia'.)

Hypovolemia — Most pediatric cases of hyponatremia are due to retention of free water during repletion with hypotonic solutions for hypovolemic conditions (eg, gastroenteritis). In this setting, the initial appropriate ADH release for maintaining circulating volume in the hypovolemic child persists and results in a concentrated urine, lower urine volume, and water retention leading to a drop in serum sodium (figure 2).

●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 hypotonic fluids results in free water retention in patients, leading to hyponatremia. (See "Enterocutaneous and enteroatmospheric fistulas", section on 'Fluid therapy' and "Approach to chronic diarrhea in neonates and young infants (<6 months)".)

●Diuretic-induced hyponatremia – Hyponatremia can be a complication of diuretic use. Acutely, the initial volume loss stimulates ADH release. As a result, the combination of diuretic-enhanced sodium and potassium excretion, and the resultant water retention due to ADH release, results in excretion of urine with a higher solute concentration than that of plasma, leading to a drop in serum sodium. (See "Diuretic-induced hyponatremia".)

●Intense exercise – High rate of fluid consumption, particularly of hypotonic fluids, 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 an ongoing high rate of fluid consumption and submaximal suppression of ADH secretion. (See "Exercise-associated hyponatremia", section on 'Pathogenesis'.)

Conditions with excess salt loss — Other less common conditions associated with excess inappropriate excess salt loss (eg, renal salt-wasting disorders) due to impaired sodium resorption are also characterized by volume depletion:

●Cerebral salt wasting occurs in patients with 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".)

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

●Cystic fibrosis – Excessive skin loss of sodium and water results in volume depletion, leading to ADH release and free water retention but ongoing sodium skin losses promoting hyponatremia, especially under conditions of heat stress. (See "Cystic fibrosis: Nutritional issues", section on 'Sodium'.)

●Primary renal tubular disorders including Bartter and Gitelman syndromes. (See "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations".)

●Salt-losing nephropathy such as obstructive uropathy or bilateral dysplastic kidneys. (See "Chronic kidney disease in children: Complications", section on 'Sodium and water homeostasis'.)

Euvolemia — Most pediatric causes of hypotonic hyponatremia in patients with euvolemia (normovolemia) are due to inappropriate excess of ADH activity. Other causes of normovolemic hyponatremia include primary polydipsia, reset osmostat, and nephrogenic syndrome of inappropriate antidiuresis.

Syndrome of inappropriate ADH secretion — In euvolemic individuals with normal ECV, excess water intake lowers tonicity and suppresses ADH release, allowing for free water excretion. However, inappropriate persistent unsuppressed ADH release resulting in unnecessary water retention in normovolemic children can be seen in a number of disorders (table 2). Pediatric conditions associated with the syndrome of inappropriate ADH secretion (SIADH) include pulmonary (eg, pneumonia, bronchiolitis, mechanical ventilation), CNS (eg, brain injury and infections, 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'.)

Medications — Several medications are associated with hyponatremia due to inappropriate ADH release, increased 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 anticonvulsant agents (valproate, carbamazepine, and oxcarbazepine) (table 3).

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 serum sodium levels despite suppression of ADH release. Primary polydipsia has been reported in children [8] and has been described in a toddler who mimicked the water-loading behaviors of his mother in the setting of psychosocial stress at home [9]. (See "Causes of hypotonic hyponatremia in adults", section on 'Primary polydipsia due to psychosis'.)

Reset osmostat — Normally, ADH is not or minimally released with a plasma osmolality below 280 mosm/kg. However, patients with a reset osmostat have a lower than normal plasma osmolality threshold for ADH release. These patients typically are euvolemic and have a moderately reduced serum sodium concentration (usually between 125 and 135 mEq/L) that is stable on multiple measurements. Reset osmostat has been associated with children with severe brain injury or an underlying defect in the genes encoding hypothalamic osmoreceptor [10,11]. (See "Causes of hypotonic hyponatremia in adults", section on 'Genetic reset osmostat'.)

Nephrogenic syndrome of inappropriate antidiuresis — Nephrogenic syndrome of inappropriate antidiuresis is a rare genetic cause of SIADH that 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) [12]. (See "Causes of hypotonic hyponatremia in adults", section on 'Syndrome of inappropriate ADH secretion (euvolemic hyponatremia)'.)

Hypervolemia — Pediatric hyponatremia is less commonly associated with hypervolemia and is typically seen in children with reduced ECV or kidney failure despite hypervolemia.

Reduced effective circulating volume — Conditions with total body volume overload (usually clinically manifested by edema) and reduced ECV are often associated with hyponatremia. Free water retention is due to the reduction in ECV, which promotes activation of endogenous vasoconstrictors including ADH.

●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 (typically used) rather than via direct measurement. (See 'Pseudohyponatremia' below.)

●Cirrhosis – In patients with cirrhosis, systemic arterial vasodilation leads to kidney hypoperfusion and ADH release, resulting in water retention (hypervolemia) and a fall in serum sodium. (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 serum sodium. (See "Hyponatremia in patients with heart failure", section on 'Pathogenesis'.)

Kidney dysfunction and inability to excrete water load — The kidney's ability to excrete a free water load becomes limited as glomerular filtration rate declines. As a result, patients with chronic kidney disease (CKD) are at risk for retaining ingested water (increased total body volume) and developing hyponatremia, despite suppression of ADH. However, as CKD progresses, accumulation of blood urea nitrogen increases plasma/serum osmolality, which may lead to hyponatremia and normal or increased serum osmolality due to azotemia. (See 'Azotemia' below.)

HYPONATREMIA WITHOUT HYPOTONICITY

Increased tonicity — Although uncommon, pediatric cases of hyponatremia with increased tonicity are caused by the presence of another osmole including endogenous (eg, hyperglycemia and urea) and exogenous sources (eg, mannitol and sorbitol). (See "Causes of hyponatremia without hypotonicity (including pseudohyponatremia)", section on 'Hypertonic or isotonic hyponatremia caused by exogenous solutes'.)

Hyperglycemia — In patients with marked hyperglycemia, the increase in serum glucose raises the serum tonicity, which pulls water out of cells, expands the extracellular water space, and thereby lowers the serum sodium concentration. The measured serum sodium is reduced by 1.6 mmol/L for every 100 mg/dL (5.5 mmol/L) increase in the blood glucose concentration above 100 mg/dL. (See "Diabetic ketoacidosis in children: Clinical features and diagnosis", section on 'Serum sodium'.)

Azotemia — In patients with advanced kidney failure, hyponatremia is due to an inability to excrete water resulting from the impairment in kidney 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, resulting in a serum osmolality that may be normal or elevated. However, there is a difference between the measured osmolality and the effective osmolality in patients with kidney failure. In contrast with 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.

PSEUDOHYPONATREMIA — In pseudohyponatremia, the sodium concentration is not affected in the water phase of plasma but rather the water content of a given volume is reduced, resulting in an overall lower sodium concentration when that volume is assayed. This most commonly occurs in patients with hyperlipidemia or hyperproteinemia. In children, hyperlipidemia can occur in children who receive intravenous lipid emulsions as part of their total parental nutrition, whereas hyperproteinemia is uncommon in children. (See "Parenteral nutrition in infants and children", section on 'Fat'.)

In pseudohyponatremia, the depressed sodium level is the result of electrolyte measurement performed using indirect ion-selective electrode potentiometry, which measures the sodium concentration per volume of plasma. However, 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 in patients with hyperlipidemia or hyperproteinemia. In this setting, checking with the clinical laboratory to see what method was used to measure sodium levels is warranted. (See "Diagnostic evaluation of adults with hyponatremia".)

CLINICAL MANIFESTATIONS

Underlying pathogenesis of symptoms — Clinical manifestations depend on the duration and degree of hyponatremia, which also impact the management decision. The presence and severity of symptoms are a result in neurologic dysfunction due to water movement into brain cells caused by an osmotic gradient across the cell membrane. Symptoms correlate with the rate and extent of changes in sodium concentration (rapid alterations less well tolerated than slowly acquired disorders) that increase brain cell volume, resulting in cerebral edema.

In response to a drop in extracellular sodium levels, acute and chronic cellular regulatory mechanisms are initiated to minimize cell volume shifts (ie, cerebral adaption). Cerebral adaptation begins within a day of sustained hyponatremia and generally takes several days for full measures to be in place. Thus, the more rapid and extensive the degree of change, the less time is available for regulatory mechanisms to minimize cell volume change. Rapid shifts seen with acute hyponatremia may significantly increase brain volume, and, because of limited space in the skull, the ensuing cerebral edema is manifested by the associated neurologic signs and symptoms.

Acute hyponatremia — Children with acute hyponatremia (developed over a period of less than 48 hours) are more likely to be symptomatic and are at risk for complications as there has not been sufficient time for cerebral adaption to occur. Symptoms also are dependent on the severity of hyponatremia.

Children with serum sodium levels >125 mEq/L are less likely to have any specific symptoms related to hyponatremia and 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 serum sodium continues to fall below 120 mEq/L (severe hyponatremia). In extreme cases, brain herniation and death may occur.

Chronic hyponatremia — In the setting of low serum sodium levels developing 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 (headache, seizures, obtundation, or coma), although they may have subtle neurologic manifestations such as restlessness, weakness, fatigue, or irritability. However, symptoms may be observed in children with severe hyponatremia or if some acute event causes rapid decreases in sodium level.

SUMMARY AND RECOMMENDATIONS

●Epidemiology – 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 also a common complication of in-hospital interventions. (See 'Epidemiology' above.)

●Sodium as a marker of tonicity – Pediatric hyponatremia is usually caused by an imbalance in the body's handling of water, resulting in a relative deficit of effective plasma/serum osmolality (tonicity) to total body water. Plasma or serum sodium is typically used as a clinical surrogate for assessing tonicity. (See 'Sodium as a marker of tonicity' above.)

●Classification – Most cases of pediatric hyponatremia are due to an underlying condition that results in hyponatremia with hypotonicity. These disorders can be classified based on the patient's volume status. (See 'Hypotonic hyponatremia' above.)

•Hypovolemia – Hyponatremia most commonly occurs in children with hypovolemia due to gastrointestinal loss, who are managed by an excess intake of free water in the setting of elevated antidiuretic hormone (ADH) activity. (See 'Hypovolemia' above.)

•Euvolemia – Most pediatric causes of hypotonic hyponatremia in patients with euvolemia (normovolemia) are due to inappropriate excess of ADH activity (table 2). These include pulmonary and oncologic disorders, recent surgery, central nervous system (CNS) injury or infection, endocrine disorders, and certain medications (table 3). Other less common causes of hyponatremia in euvolemic children include primary polydipsia and reset osmostat. (See 'Euvolemia' above.)

•Hypervolemia – Hypervolemic hyponatremia is less common in children and may be seen in patients with kidney failure and disorders with a reduced effective circulating volume (ECV; eg, nephrotic syndrome, heart failure, and cirrhosis). (See 'Hypervolemia' above.)

Less commonly, hyponatremia can be associated with increased tonicity due to the presence of another osmole including endogenous sources (eg, hyperglycemia and urea) and exogenous sources (eg, mannitol and sorbitol) (table 1). Pseudohyponatremia refers to depressed serum sodium measurements due to hyperlipidemia or hyperproteinemia. (See 'Hyponatremia without hypotonicity' above and 'Pseudohyponatremia' above.)

●Pathogenesis of symptoms – The presence and severity of symptoms depend on the degree and acuity of changes in sodium level, which result in neurologic dysfunction due to water movement into brain cells caused by an osmotic gradient across the cell membrane. Cellular regulatory mechanisms (cerebral adaption), which minimize cell volume change and cerebral edema, begin within a day of sustained hyponatremia but generally take several days for full measures to be in place. (See 'Underlying pathogenesis of symptoms' above.)

•Acute – Children with acute hyponatremia (developed over less than 48 hours) are likely to be symptomatic as there is insufficient time for cerebral adaption to fully develop. Children with serum sodium levels >125 mEq/L are less likely to have any specific symptoms related to hyponatremia and 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. Headache, lethargy, obtundation, seizures, and coma may occur as the serum sodium continues to fall below 120 mEq/L (severe hyponatremia). (See 'Acute hyponatremia' above.)

•Chronic – Children with chronic hyponatremia (developed over more than 48 hours) are less likely to be symptomatic due to fully developed cerebral adaption. However, those with severe hyponatremia or an acute event, which causes a rapid decrease in serum sodium, may have overt symptoms of headache, seizure, obtundation, and coma. (See 'Chronic hyponatremia' above.)