Hyponatremia, defined as a serum sodium (Na) concentration of less than 135 mEq/L, can lead to hyponatremic encephalopathy, particularly in prepubescent pediatric patients.
The image below lists drugs that impair water excretion.
Early signs of hyponatremia include the following:
Advanced signs include the following:
Impaired response to verbal stimuli
Impaired response to painful stimuli
Far-advanced signs include the following:
Decorticate or decerebrate posturing
Hypertension or hypotension
Altered temperature regulation
Cardiovascular and musculoskeletal findings
Cardiovascular: Hypotension and tachycardia
Musculoskeletal: Weakness and muscular cramps
See Clinical Presentation for more detail.
Routine laboratory studies used in the diagnosis and evaluation of hyponatremia include the following:
Serum Na level
Blood urea nitrogen (BUN) and creatinine levels
Urine Na level
Urine Na concentrations
The urine Na level differs according to the type of hyponatremia present. In hypovolemic hyponatremia, Na concentrations are as follows:
Renal losses caused by diuretic excess, osmotic diuresis, salt-wasting nephropathy, adrenal insufficiency, proximal renal tubular acidosis, metabolic alkalosis, or pseudohypoaldosteronism result in a urine Na concentration of more than 20 mEq/L
Extrarenal losses caused by vomiting, diarrhea, sweat, or third spacing result in a urine Na concentration of less than 20 mEq/L secondary to increased tubular reabsorption of Na
In normovolemic hyponatremia caused by syndrome of inappropriate antidiuretic hormone (SIADH) secretion, reset osmostat, glucocorticoid deficiency, hypothyroidism, or water intoxication, the urine Na concentration is more than 20 mEq/L
Hypervolemic hyponatremia results in the following urine Na concentrations:
If hyponatremia is caused by an edema-forming state (eg, congestive heart failure, hepatic failure), the urine Na concentration is less than 20 mEq/L
If hyponatremia is caused by acute or chronic renal failure, the urine Na concentration is more than 20 mEq/L
In SIADH with normal dietary salt intake, urine sodium concentration is more than 40 mEq/L, while in cerebral salt-wasting syndrome (CSWS), the concentration frequently exceeds 80 mEq/L.
Special laboratory studies include the following:
Free T4 and thyroid-stimulating hormone (TSH) levels
Adrenocorticotropic hormone (ACTH) level
Antidiuretic hormone (ADH) level
See Workup for more detail.
The immediate goal is to correct volume depletion with normal saline. As soon as the patient is hemodynamically stable, hyponatremia should be corrected.
Physiologic considerations indicate that a relatively small increase in the serum Na concentration, on the order of 5%, should substantially reduce cerebral edema.
Treatment of normovolemic hyponatremia due to SIADH can include fluid restriction and the administration of normal saline. The use of 3% NaCl and the intravenous (IV) administration of furosemide may also be needed.
Treatment includes the following:
Administration of 3% NaCl to stop the symptoms
Treatment of the underlying cause
Hypovolemic hyponatremia: The main principle is to avoid hypotonic fluids and to slowly correct Na levels
Normovolemic hyponatremia: Restriction of fluids to two thirds (or less) of the volume needed for maintenance is the mainstay of treatment
Recalcitrant euvolemic hyponatremia: Demeclocycline can be used to induce therapeutic nephrogenic diabetes insipidus, which may help to eliminate excessive water
Hyponatremia is defined as serum sodium (Na) concentration of less than 135 mEq/L. Plasma Na plays a significant role in plasma osmolality and tonicity (serum osmolarity = 2Na + Glu/18 + BUN/2.8). Changes in plasma osmolality are responsible for the signs and symptoms of hyponatremia and also the complications that happen during treatment in the presence of high-risk factors. Whereas hypernatremia always denotes hypertonicity, hyponatremia can be associated with low, normal, or high tonicity. Hyponatremia is the most common electrolyte disorder encountered in hospitalized patients.
Clinical presentation of hyponatremia happens as a result of a rapid of fall in serum Na and also the absolute level of serum Na. Fifty percent of presenting children develop symptoms when serum Na levels fall below 125 mEq/L, a relatively high level when compared with adults. Although morbidity widely varies, serious complications can arise from hyponatremia and can also happen during treatment. Understanding the pathophysiology and treatment options for hyponatremia is important because significant morbidity and mortality are possible.
Hyponatremia can develop because of (1) excessive free water, a common cause in hospitalized patients receiving hypotonic solutions; (2) excessive renal or extrarenal losses of Na or renal retention of free water; (3) rarely, deficient intake of Na.
Under normal circumstances, the human body is able to maintain serum Na in the normal range (135-145 mEq/L) despite wide fluctuations in fluid intake. The body’s defense against developing hyponatremia is the kidney’s ability to generate dilute urine and excrete free water in response to changes in serum osmolarity and intravascular volume status.
Hospital-acquired hyponatremia is the most common cause of hyponatremia in children. Some studies have outlined the association of hyponatremia and the hypotonic fluid typically used in the pediatric population. Excessive antidiuretic hormone (ADH) is present in most hospitalized patients, either as an appropriate response to hemodynamic and/or osmotic stimuli or as an inappropriate secretion of ADH. ADH is also secreted in response to pain, nausea, and vomiting and during the use of certain medications such as morphine during the postoperative period. Use of hypotonic fluids in presence of circulating ADH can causes free water retention resulting in hyponatremia. In certain clinical conditions, ADH secretion occurs even when serum osmolarity is low or normal, hence the term syndrome of inappropriate ADH secretion (SIADH).
Other conditions that can lead to hyponatremia include states with increased total body water such as with cirrhosis, cardiac failure, or nephrotic syndrome. Diuretic use and decreased intake of Na can also lead to hyponatremia.
Loss of Na via the GI tract and or urinary tract in excess of free water can result in hyponatremia. GI losses can occur in different disease states with excessive fluid loss, namely gastroenteritis, fistulas, or serous fluid drainage after surgery. Na can be lost via the kidney; use of diuretics is the most common culprit, followed by other causes, such as salt-losing nephritis, mineralocorticoid deficiency, and cerebral salt-wasting syndrome (CSWS). Hyponatremia is rarely caused by deficient Na intake.
Clinical manifestations vary from an asymptomatic state to severe neurologic dysfunction. CNS symptoms predominate in hyponatremia, although cardiovascular and musculoskeletal findings may be present. Factors that contribute to CNS symptoms are (1) the rate at which serum Na levels change, (2) the absolute serum Na level, (3) the duration of the abnormal serum Na level, (4) the presence of other CNS pathology risk factors, and (5) the presence of excessive ADH levels.
Hyponatremia exerts most of its clinical effects on the brain. Brain volume is regulated by equal osmolality of extracellular and intracellular fluid. When extracellular osmolality decreases, water influx occurs in the brain resulting in cerebral edema. Cerebral edema is responsible for symptoms such as headache, nausea, vomiting, irritability, and seizures.
If hyponatremia is acute (ie, within hours), the change in osmolality causes influx of water resulting in cerebral edema. If hyponatremia occurs slowly (ie, over days), the brain has adaptive response to protect itself from edema formation. The brain’s adaptive response is mediated through different mechanisms and also modified by different factors as discussed below.
Mechanisms implied in cerebral edema formation include the following:
Na-K ATPase system
Hyponatremia and resulting reduced osmolarity leads to an influx of water into the brain, primarily through glial cells and largely via the water channel aquaporin (AQP). Water is then shunted to astrocytes, which swell, largely preserving the neurons. Na is extruded at the same time using Na-K ATPase system. Potassium ions extrusion follows Na but is slower. In addition, inorganic osmolytes and organic osmolytes (eg, glycine, taurine, creatine, and myoinositol) have been shown to efflux from cells during hypo-osmolar states in animal studies.
The brain’s adaptive response to protect itself from edema occurs over several days. Once the brain has adapted to the hypo-osmolar conditions, a correction of the hypo-osmolar extracellular space to an euvolemic or hyper-osmolar state that is too rapid leads to a rapid efflux of water from brain tissue, resulting in dehydration of brain cells. The resultant condition is called osmotic demyelination syndrome (ODS). Previously, this pathological injury was described only in the pons, hence the term central pontine myelinolysis (CPM). Although it predominantly affects the pons, this condition is now known to occur in other parts of brain as well (see Complications).
Risk factors for hyponatremic encephalopathy include age, sex, hypoxia and vasopressin levels.
Epidemiologic data have shown that the risk for developing permanent neurologic sequelae or death from hyponatremic encephalopathy is substantially higher in menstruating women than in men or postmenopausal women.  The relative risk of death or permanent neurologic damage due to hyponatremic encephalopathy is about 30 times greater for women than for men and about 25 times greater for menstruating women than for postmenopausal women.
Although estrogen hormones have been implicated as the cause of this high incidence of hyponatremic encephalopathy, cellular level mechanisms have now been elucidated. Estrogen has a core steroidal structure similar to cardiac glycosides known to inhibit the Na-K ATPase system, impairing adaptive responses. In addition, estrogen also appears to regulate water movement and neurotransmission by affecting AQP4 expression.
Prepubescent children are at increased risk to develop complications because of hyponatremia. Although many other factors may contribute to this increased risk, brain–to–cranial vault ratio plays an important role.
The brain reaches adult size by age 6 years, whereas the skull does not reach adult size until age 16 years. As a consequence, children can develop symptomatic hyponatremia with relatively higher Na concentrations than those observed in adults.
Good outcomes are reported in young babies with open fontanelles; increased vault compliance supports this hypothesis.
Hypoxia is a major risk factor for hyponatremic encephalopathy. Patients with symptomatic hyponatremia can develop hypoxia by 2 different mechanisms: noncardiogenic pulmonary edema and hypercapnic respiratory failure. Hypercapnic respiratory failure is due to central respiratory depression and is often the first sign of impending herniation. Noncardiogenic pulmonary edema, on the other hand, is a complex disorder during with increased vascular permeability and increased catecholamine release that often occurs secondary to elevated intracranial pressure.
Hypoxia worsens clinical outcomes in hyponatremic encephalopathy by impairing the brain’s adaptive response through the active transport of Na, which is an energy-dependent process that requires oxygen. It also affects astrocyte volume regulation, which is also energy dependent. Under ordinary circumstances, hypoxia results in an increase in cerebral blood flow to increase the delivery of oxygen;  the increase in cerebral blood flow can lead to an increase in cerebral blood volume, which also contributes to an increase in intracranial pressure.
Hyponatremia, except in cases of pure water intoxication, virtually always occurs in the presence of increased plasma levels of vasopressin. 
Vasopressin leads to decreased cerebral oxygen use in female rat brain but not in male rats. Vasopressin decreases cerebral blood flow by vasoconstriction, resulting in decreased oxygen delivery that, in turn, impairs brain adaptation. Vasopressin also facilitates direct movement of water into brain cells independent of hyponatremia. In addition, it also decreases synthesis of ATP and phosphocreatine, lowers intracellular pH and intracellular buffering, and decreases Ca2+, which affects energy-dependent processes involved in brain adaptation.
Hyponatremia is also often classified by body water volume status: hyponatremia in conjunction with hypervolemia, euvolemia, or hypovolemia. The distribution of water and solute in the intracellular and extracellular spaces determine the intravascular volume. Fluid shifts from the extracellular space to the intracellular space with a subsequent decrease in arterial blood volume. The reduction in intravascular volume may result in hypotension. Because of this fluid shift, hyponatremia causes hemodynamic disturbance more pronounced than that expected for the degree of dehydration.
Reported frequency varies from 1-30% among hospitalized pediatric patients.
In India, the frequency of hyponatremia is 29.8%.  It is more frequent in summer (36%) than in winter (24%).
Overall morbidity and mortality is 42%.
The incidence of hyponatremia is equal in both sexes. However, CNS complications are most likely to occur among premenopausal women.
Hyponatremic encephalopathy is most common in prepubescent children.
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Muthukumar Vellaichamy, MD, FAAP Clinical Assistant Professor, Department of Pediatrics, Wesley Medical Center, University of Kansas School of Medicine-Wichita
Disclosure: Nothing to disclose.
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Barry J Evans, MD Assistant Professor of Pediatrics, Temple University Medical School; Director of Pediatric Critical Care and Pulmonology, Associate Chair for Pediatric Education, Temple University Children’s Medical Center
Disclosure: Nothing to disclose.
Timothy E Corden, MD Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children’s Hospital of Wisconsin
Disclosure: Nothing to disclose.
G Patricia Cantwell, MD, FCCM Professor of Clinical Pediatrics, Chief, Division of Pediatric Critical Care Medicine, University of Miami Leonard M Miller School of Medicine/ Holtz Children’s Hospital, Jackson Memorial Medical Center; Medical Director, Palliative Care Team, Holtz Children’s Hospital; Medical Manager, FEMA, South Florida Urban Search and Rescue, Task Force 2
G Patricia Cantwell, MD, FCCM is a member of the following medical societies: American Academy of Hospice and Palliative Medicine, American Academy of Pediatrics, American Heart Association, American Trauma Society, National Association of EMS Physicians, Society of Critical Care Medicine, Wilderness Medical Society
Disclosure: Nothing to disclose.
The author would like to acknowledge his partner at work, mentor, and great physician Lindall Smith, MD, for reading the manuscript and offering valuable advice.
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