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Hyponatremia is decrease in serum sodium concentration < 136 mEq/L caused by an excess of water relative to solute. Common causes include diuretic use, diarrhea, heart failure, liver disease, renal disease, and the syndrome of inappropriate ADH secretion (SIADH). Clinical manifestations are primarily neurologic (due to an osmotic shift of water into brain cells causing edema), especially in acute hyponatremia, and include headache, confusion, and stupor; seizures and coma may occur. Diagnosis is by measuring serum sodium. Serum and urine electrolytes and osmolality and assessment of volume status help determine the cause. Treatment involves restricting water intake and promoting water loss, replacing any sodium deficit, and correcting the underlying disorder.
(See also Water and Sodium Balance.)
Hyponatremia reflects an excess of total body water (TBW) relative to total body sodium content. Because total body sodium content is reflected by ECF volume status, hyponatremia must be considered along with status of the ECF volume: hypovolemia, euvolemia, and hypervolemia (see Table: Principal Causes of Hyponatremia). Note that the ECF volume is not the same as effective plasma volume. For example, decreased effective plasma volume may occur with decreased ECF volume (as with diuretic use or hemorrhagic shock), but it may also occur with an increased ECF volume (eg, in heart failure, hypoalbuminemia, or capillary leak syndrome).
Sometimes, a low serum sodium measurement is caused by an excess of certain substances (eg, glucose, lipid) in the blood (translocational hyponatremia, pseudohyponatremia) rather than by a water-sodium imbalance.
Principal Causes of Hyponatremia
(See also Volume Depletion.)
Deficiencies in both TBW and total body sodium exist, although proportionally more sodium than water has been lost; the sodium deficit causes hypovolemia. In hypovolemic hyponatremia, both serum osmolality and blood volume decrease. Vasopressin (antidiuretic hormone—ADH) secretion increases despite a decrease in osmolality to maintain blood volume. The resulting water retention increases plasma dilution and hyponatremia.
Extrarenal fluid losses, such as those that occur with the losses of sodium-containing fluids as in protracted vomiting, severe diarrhea, or sequestration of fluids in a 3rd space (see Table: Composition of Body Fluids), can cause hyponatremia typically when losses are replaced by ingesting plain water or liquids low in sodium (see Table: Approximate Sodium Content of Common Beverages) or by hypotonic IV fluid. Significant ECF fluid losses also cause release of vasopressin, causing water retention by the kidneys, which can maintain or worsen hyponatremia. In extrarenal causes of hypovolemia, because the normal renal response to volume loss is sodium conservation, urine sodium concentration is typically < 10 mEq/L.
Renal fluid losses resulting in hypovolemic hyponatremia may occur with mineralocorticoid deficiency, thiazide diuretic therapy, osmotic diuresis, or salt-losing nephropathy. Salt-losing nephropathy encompasses a loosely defined group of intrinsic renal disorders with primarily renal tubular dysfunction. This group includes interstitial nephritis, medullary cystic disease, partial urinary tract obstruction, and, occasionally, polycystic kidney disease. Renal causes of hypovolemic hyponatremia can usually be differentiated from extrarenal causes by the history. Patients with ongoing renal fluid losses can also be distinguished from patients with extrarenal fluid losses because the urine sodium concentration is inappropriately high (> 20 mEq/L). Urine sodium concentration may not help in differentiation when metabolic alkalosis (as occurs with protracted vomiting) is present and large amounts of bicarbonate are spilled in the urine, obligating the excretion of sodium to maintain electrical neutrality. In metabolic alkalosis, urine chloride concentration frequently differentiates renal from extrarenal sources of volume depletion.
Diuretics may also cause hypovolemic hyponatremia. Thiazide diuretics, in particular, decrease the kidneys’ diluting capacity and increase sodium excretion. Once volume depletion occurs, the nonosmotic release of vasopressin causes water retention and worsens hyponatremia. Concomitant hypokalemia shifts sodium intracellularly and enhances vasopressin release, thereby worsening hyponatremia. This effect of thiazides may last for up to 2 wk after cessation of therapy; however, hyponatremia usually responds to replacement of potassium and volume deficits along with judicious monitoring of water intake until the drug effect dissipates. Elderly patients may have increased sodium diuresis and are especially susceptible to thiazide-induced hyponatremia, particularly when they have a preexisting defect in renal capacity to excrete free water. Rarely, such patients develop severe, life-threatening hyponatremia within a few weeks after the initiation of a thiazide diuretic. Loop diuretics much less commonly cause hyponatremia.
In euvolemic (dilutional) hyponatremia, total body sodium and thus ECF volume are normal or near-normal; however, TBW is increased.
Primary polydipsia can cause hyponatremia only when water intake overwhelms the kidneys’ ability to excrete water. Because normal kidneys can excrete up to 25 L urine/day, hyponatremia due solely to polydipsia results only from the ingestion of large amounts of water or from defects in renal capacity to excrete free water. Patients affected include those with psychosis or more modest degrees of polydipsia plus renal insufficiency.
Euvolemic hyponatremia may also result from excessive water intake in the presence of Addison disease, hypothyroidism, or nonosmotic vasopressin release (eg, due to stress; postoperative states; use of drugs such as chlorpropamide, tolbutamide, opioids, barbiturates, vincristine, clofibrate, or carbamazepine). Postoperative hyponatremia most commonly occurs because of a combination of nonosmotic vasopressin release and excessive administration of hypotonic fluids after surgery. Certain drugs (eg, cyclophosphamide, NSAIDs, chlorpropamide) potentiate the renal effect of endogenous vasopressin, whereas others (eg, oxytocin) have a direct vasopressin-like effect on the kidneys. Intoxication with 3,4-methylenedioxymethamphetamine (MDMA [ecstasy]) causes hyponatremia by inducing excess water drinking and enhancing vasopressin secretion. A deficiency in water excretion is common in all these conditions. Diuretics can cause or contribute to euvolemic hyponatremia if another factor causes water retention or excessive water intake.
The syndrome of inappropriate ADH secretion (SIADH—see Syndrome of Inappropriate ADH Secretion) is another cause of euvolemic hyponatremia.
Disorders Associated With Syndrome of Inappropriate ADH Secretion
Hypervolemic hyponatremia is characterized by an increase in both total body sodium (and thus ECF volume) and TBW with a relatively greater increase in TBW. Various edematous disorders, including heart failure and cirrhosis, cause hypervolemic hyponatremia. Rarely, hyponatremia occurs in nephrotic syndrome, although pseudohyponatremia may be due to interference with sodium measurement by elevated lipids. In each of these disorders, a decrease in effective circulating volume results in the release of vasopressin and angiotensin II. The following factors contribute to hyponatremia:
Urine Na excretion is usually < 10 mEq/L, and urine osmolality is high relative to serum osmolality.
Hyponatremia has been reported in >50% of hospitalized patients with AIDS. Among the many potential contributing factors are
In addition, adrenal insufficiency has become increasingly common among AIDS patients as the result of cytomegalovirus adrenalitis, mycobacterial infection, or interference with adrenal glucocorticoid and mineralocorticoid synthesis by ketoconazole. SIADH may be present because of coexistent pulmonary or CNS infections.
Symptoms mainly involve CNS dysfunction. However, when hyponatremia is accompanied by disturbances in total body sodium content, signs of ECF volume depletion or volume overload also occur. In general, older chronically ill patients with hyponatremia develop more symptoms than younger otherwise healthy patients. Symptoms are also more severe with faster-onset hyponatremia. Symptoms generally occur when the effective plasma osmolality falls to < 240 mOsm/kg. Symptoms can be subtle and consist mainly of changes in mental status, including altered personality, lethargy, and confusion. As the serum sodium falls to < 115 mEq/L, stupor, neuromuscular hyperexcitability, hyperreflexia, seizures, coma, and death can result.
Severe cerebral edema may occur in premenopausal women with acute hyponatremia, perhaps because estrogen and progesterone inhibit brain Na+,K+-ATPase and decrease solute extrusion from brain cells. Sequelae include hypothalamic and posterior pituitary infarction and occasionally osmotic demyelination syndrome or brain stem herniation.
Hyponatremia is occasionally suspected in patients who have neurologic abnormalities and are at risk. However, because findings are nonspecific, hyponatremia is often recognized only after serum electrolyte measurement.
Serum sodium may be low when severe hyperglycemia (or exogenously administered mannitol or glycerol) increases osmolality and water moves out of cells into the ECF. Serum sodium concentration falls about 1.6 mEq/L for every 100-mg/dL (5.55-mmol/L) rise in the serum glucose concentration above normal. This condition is often called translocational hyponatremia because it is caused by translocation of water across cell membranes.
Pseudohyponatremia with normal serum osmolality may occur in hyperlipidemia or extreme hyperproteinemia, because the lipid or protein occupies space in the volume of serum taken for analysis; the concentration of sodium in serum itself is not affected. Newer methods of measuring serum electrolytes with ion-selective electrodes circumvent this problem.
Identifying the cause of hyponatremia can be complex. The history sometimes suggests a cause (eg, significant fluid loss due to vomiting or diarrhea, renal disease, compulsive fluid ingestion, intake of drugs that stimulate vasopressin release or enhance vasopressin action).
The volume status, particularly the presence of obvious volume depletion or volume overload, suggests certain causes (see Table: Common Causes of Volume Depletion).
Overtly hypovolemic patients usually have an obvious source of fluid loss and typically have been treated with hypotonic fluid replacement.
Overtly hypervolemic patients usually have a readily recognizable condition, such as heart failure or hepatic or renal disease.
Euvolemic patients and patients with equivocal volume status require more laboratory testing to identify a cause.
Laboratory tests should include serum and urine osmolality and electrolytes. Euvolemic patients should also have thyroid and adrenal function tested. Hypo-osmolality in euvolemic patients should cause excretion of a large volume of dilute urine (eg, osmolality < 100 mOsm/kg and specific gravity < 1.003). Serum sodium concentration and serum osmolality that are low and urine osmolality that is inappropriately high (120 to 150 mmol/L) with respect to the low serum osmolality suggest volume overload, volume contraction, or SIADH. Volume overload and volume contraction are differentiated clinically.
When neither volume overload or volume contraction appears likely, SIADH is considered. Patients with SIADH are usually euvolemic or slightly hypervolemic. BUN and creatinine values are normal, and serum uric acid is generally low. Urine sodium concentration is usually > 30 mmol/L, and fractional excretion of sodium is > 1% (for calculation, see Evaluation of the Renal Patient : Other urine tests).
In patients with hypovolemia and normal renal function, sodium reabsorption results in a urine sodium of < 20 mmol/L. Urine sodium > 20 mmol/L in hypovolemic patients suggests mineralocorticoid deficiency or salt-losing nephropathy. Hyperkalemia suggests adrenal insufficiency.
Hyponatremia can be life threatening and requires prompt recognition and proper treatment. Too-rapid correction of hyponatremia risks neurologic complications, such as osmotic demyelination syndrome. Even with severe hyponatremia, serum sodium concentration should not be increased by more than 8 mEq/L over the first 24 h. And, except during the first few hours of treatment of severe hyponatremia, sodium should be corrected no faster than 0.5 mEq/L/h. The degree of hyponatremia, the duration and rate of onset , and the patient's symptoms are used to determine which treatment is most appropriate.
In patients with hypovolemia and normal adrenal function, administration of 0.9% saline usually corrects both hyponatremia and hypovolemia. When the serum sodium is < 120 mEq/L, hyponatremia may not completely correct upon restoration of intravascular volume; restriction of free water ingestion to 500 to 1000 mL/24 h may be needed.
In hypervolemic patients, in whom hyponatremia is due to renal sodium retention (eg, heart failure, cirrhosis, nephrotic syndrome) and dilution, water restriction combined with treatment of the underlying disorder is required. In patients with heart failure, an ACE inhibitor, in conjunction with a loop diuretic, can correct refractory hyponatremia. In other patients in whom simple fluid restriction is ineffective, a loop diuretic in escalating doses can be used, sometimes in conjunction with IV 0.9% normal saline. Potassium and other electrolytes lost in the urine must be replaced. When hyponatremia is more severe and unresponsive to diuretics, intermittent or continuous hemofiltration may be needed to control ECF volume while hyponatremia is corrected with IV 0.9% normal saline. Severe or resistant hyponatremia generally occurs only when heart or liver disease is near end-stage.
In euvolemia, treatment is directed at the cause (eg, hypothyroidism, adrenal insufficiency, diuretic use). When SIADH is present, severe water restriction (eg, 250 to 500 mL/24 h) is generally required. Additionally, a loop diuretic may be combined with IV 0.9% saline as in hypervolemic hyponatremia. Lasting correction depends on successful treatment of the underlying disorder. When the underlying disorder is not correctable, as in metastatic cancer, and patients find severe water restriction unacceptable, demeclocycline 300 to 600 mg po q 12 h may be helpful by inducing a concentrating defect in the kidneys. However, demeclocycline is not widely used due to the possibility of drug-induced acute kidney injury. IV conivaptan, a vasopressin receptor antagonist, causes effective water diuresis without significant loss of electrolytes in the urine and can be used in hospitalized patients for treatment of resistant hyponatremia. Oral tolvaptan, is another vasopressin receptor antagonist with similar action to conivaptan. Tolvaptan use is limited to less than 30 days due to the potential for liver toxicity and it should not be used in patients with liver or kidney disease.
Mild to moderate, asymptomatic hyponatremia (ie, serum sodium ≥ 121 and < 135 mEq/L) requires restraint because small adjustments are generally sufficient. In diuretic-induced hyponatremia, elimination of the diuretic may be enough; some patients need some sodium or potassium replacement. Similarly, when mild hyponatremia results from inappropriate hypotonic parenteral fluid administration in patients with impaired water excretion, merely altering fluid therapy may suffice.
In asymptomatic patients, severe hyponatremia (serum sodium < 121 mEq/L; effective osmolality <240 mOsm/kg) can be treated safely with stringent restriction of water intake.
In patients with neurologic symptoms (eg, confusion, lethargy, seizures, coma), treatment is more controversial. The debate primarily concerns the rate and degree of hyponatremia correction. Many experts recommend that, in general, serum sodium be raised no faster than 1 mEq/L/h. However, replacement rates of up to 2 mEq/L/h for the first 2 to 3 h have been suggested for patients with seizures or significantly altered sensorium. Regardless, the rise should be ≤ 8 mEq/L over the first 24 h. More vigorous correction risks precipitating osmotic demyelination syndrome.
Acute hyponatremia with known rapid onset (ie, within < 24 h) is a special case. Such rapid onset can occur with
Rapid-onset hyponatremia is problematic because the cells of the CNS have not had time to remove some of the intracellular osmolar compounds used to balance intracellular and extracellular osmolality. Thus, the intracellular environment becomes relatively hypertonic compared to the serum, causing intracellular fluid shifts that can rapidly cause cerebral edema, potentially progressing to brain stem herniation and death. In these patients, rapid correction with hypertonic saline is indicated even when neurologic symptoms are mild (eg, forgetfulness). If more severe neurologic symptoms, including seizures, are present, rapid correction of sodium by 4 to 6 mEq/L using hypertonic saline is indicated. The patient should be monitored in an intensive care unit and serum sodium levels monitored every 2 h. After sodium level has increased by the initial target of 4 to 6 mEq/L, the rate of correction is slowed so that serum sodium level does not rise by > 8 mEq/L in the first 24 h.
Hypertonic (3%) saline (containing 513 mEq sodium/L) use requires frequent (q 2 ) electrolyte determinations. In some situations, it may be used with a loop diuretic. A newer recommendation includes concurrent administration of desmopressin 1 to2 mcg q 8 h . The desmopressin prevents an unpredictable water diuresis that can follow the abrupt normalization of endogenous vasopressin that can occur as the underlying disorder causing hyponatremia is corrected.
For patients with rapid-onset hyponatremia and neurologic symptoms, rapid correction is accomplished by giving 100 mL of hypertonic saline IV over 15 min. This dose can be repeated once if neurologic symptoms are still present.
For patients with seizures or coma but slower onset hyponatremia, ≤ 100 mL/h may be administered over 4 to 6 h in amounts sufficient to raise the serum sodium 4 to 6 mEq/L. This amount (in mEq) may be calculated using the sodium deficit formula as
where TBW is 0.6× body weight in kg in men and 0.5 × body weight in kg in women.
For example, the amount of sodium needed to raise the sodium level from 106 to 112 mEq/L in a 70-kg man can be calculated as follows:
Because there is 513 mEq sodium/L in hypertonic saline, roughly 0.5 L of hypertonic saline is needed to raise the sodium level from 106 to 112 mEq/L. To result in a correction rate of 1 mEq/L/h, this 0.5 L volume would be infused over about 6 h.
Adjustments may be needed based on serum sodium concentrations, which are monitored closely during the first few hours of treatment. Patients with seizures, coma, or altered mental status need supportive treatment, which may involve endotracheal intubation, mechanical ventilation, and benzodiazepines (eg, lorazepam 1 to 2 mg IV q 5 to 10 min prn) for seizures.
The selective vasopressin (V2) receptor antagonists conivaptan (IV) and tolvaptan (oral) are relatively new treatment options for severe or resistant hyponatremia. These drugs are potentially dangerous because they may correct serum sodium concentration too rapidly; they are typically reserved for severe (< 121 mEq/L) and/or symptomatic hyponatremia that is resistant to correction with fluid restriction. The same pace of correction as for fluid restriction, ≤ 10 mEq/L over 24 h, is used. These drugs should not be used for hypovolemic hyponatremia or in patients with liver disease or advanced chronic kidney disease.
Conivaptan is indicated for treatment of hypervolemic and euvolemic hyponatremia. It requires close monitoring of patient status, fluid balance, and serum electrolytes and so its use is restricted to hospitalized patients. A loading dose is given followed by a continuous infusion over a maximum of 4 days. It is not recommended in patients with advanced chronic kidney disease (estimated GFR < 30 mL/min) and should not be used if anuria is present. Caution is advised in moderate to severe cirrhosis.
Tolvaptan is a once daily tablet indicated for hypervolemic and euvolemic hyponatremia. Close monitoring is recommended especially during initiation and dosage changes. Tolvaptan use is limited to 30 days because of the risk of liver toxicity. Tolvaptan is not recommended for patients with advanced chronic kidney disease or liver disease. Its effectiveness can be limited by increased thirst. Tolvaptan use is also limited by excessive cost.
Both of these drugs are strong inhibitors of CYP3A and as such have multiple drug interactions. Other strong CYP3A inhibitors (eg, ketoconazole, itraconazole, clarithromycin, retroviral protease inhibitors) should be avoided. Clinicians should review the other drugs the patient is taking for potentially dangerous interactions with V2 receptor antagonists before initiating a treatment trial.
Osmotic demyelination syndrome (previously called central pontine myelinolysis) may follow too-rapid correction of hyponatremia. Demyelination classically affects the pons, but other areas of the brain can also be affected. Lesions are more common among patients with alcoholism, undernutrition, or other chronic debilitating illness. Flaccid paralysis, dysarthria, and dysphagia can evolve over a few days or weeks after a hyponatremic episode. The classic pontine lesion may extend dorsally to involve sensory tracts and leave patients with a "locked-in" syndrome (an awake and sentient state in which patients, because of generalized motor paralysis, cannot communicate, except by vertical eye movements controlled above the pons). Damage often is permanent. When sodium is replaced too rapidly (eg, > 14 mEq/L/8 h) and neurologic symptoms start to develop, it is critical to prevent further serum sodium increases by stopping hypertonic fluids. In such cases, inducing hyponatremia with hypotonic fluid may mitigate the development of permanent neurologic damage.
Hyponatremia may occur with normal, increased, or decreased extracellular fluid volume.
Common causes include diuretic use, diarrhea, heart failure, liver and renal disease.
Hyponatremia is potentially life threatening. The degree, duration and symptoms of hyponatremia are used to determine how quickly to correct the serum sodium.
Treatment varies depending on fluid volume status, but in all cases serum sodium level should be corrected slowly—by ≤ 8 mEq/L over 24 h, although fairly rapid correction by 4 to 6 mEq/L using hypertonic saline over the first several hours is frequently needed to reverse severe neurologic symptoms.
Osmotic demyelination syndrome may follow too-rapid correction of hyponatremia.