Hyponatremia is decrease in serum sodium concentration 136 mEq/L ( 136 mmol/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 antidiuretic hormone 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.)
Etiology of Hyponatremia
Hyponatremia reflects an excess of total body water (TBW) relative to total body sodium content. Because total body sodium content is reflected by extracellular fluid (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 multiple factors contribute to hyponatremia.
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.
Hypovolemic hyponatremia
(See also Volume Depletion.)
Deficiencies in both total body water 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) 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 (< 10 mmol/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 [> 20 mmol/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 weeks 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. Older 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.
Euvolemic 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 a 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 vasopressinvasopressinvasopressin, 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) is another cause of euvolemic hyponatremia.
Euvolemic hyponatremia can occur quite rapidly during transurethral resection of the prostate, cystoscopic or hysteroscopic procedures when hypotonic fluid is used as an irrigant. Early recognition is critically important since brain edema can be caused by rapid development of hypotonicity. Bipolar electrocautery, which uses isotonic irrigation solutions, is preferred over monopolar electrocautery which uses hypotonic solutions.. When hypotonic fluid must be used, limited irrigation volume, low infusion pressure and limited duration of surgery is used to minimize absorption. If prearranged thresholds of hypotonic irrigant absorption are exceeded (1000 to 2000 mL, depending upon body weight) the procedure should be aborted.
Hypervolemic hyponatremia
Hypervolemic hyponatremia is characterized by an increase in both total body sodium (and thus ECF volume) and total body water 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:
The antidiuretic effect of vasopressin on the kidneys
Direct impairment of renal water excretion by angiotensin II
Decreased glomerular filtration rate (GFR)
Stimulation of thirst by angiotensin II
Urine sodium excretion is usually < 10 mEq/L (< 10 mmol/L), and urine osmolality is high relative to serum osmolality.
Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
The syndrome of inappropriate ADH (vasopressin) secretion is attributed to excessive vasopressin release. It is defined as less-than-maximally-dilute urine in the presence of plasma hypo-osmolality (hyponatremia) without volume depletion or overload, emotional stress, pain, diuretics, or other medications that stimulate vasopressinSIADH is associated with myriad disorders (see table Disorders Associated with SIADH).
Hyponatremia in AIDS
Hyponatremia has been reported in > 50% of hospitalized patients with AIDS. Among the many potential contributing factors are
Administration of medications that impair renal water excretion
Administration of hypotonic fluids
Impaired renal function
Nonosmotic vasopressin release due to intravascular volume depletion
Cerebral salt wasting (CSW)
Hyponatremia frequently occurs in patients with brain pathology, including concussion, intracranial hemorrhage, encephalitis, meningitis, and CNS tumors. It is most commonly due to SIADH or less commonly glucocorticoid deficiency. However, cerebral salt wasting has been recognized by some as a separate entity affecting a small group of these patients, especially those with subarachnoid hemorrhage. Cerebral salt wasting is thought to be due to either decreased sympathetic nervous system function or secretion of a circulating factor that decreases renal sodium reabsorption. It is characterized by low serum sodium (<135 mOsm/L [mmol/L] ) with low plasma osmolality (< 275 mOsm/L [mmol/L]) and high urine osmolality (> 100 mOsm/L [mmol/L] and frequently > 300 mOsm/L [mmol/L]). Urine sodium is usually > 40 mEq/L (> 40 mmol/L) and serum uric acid is low. The response to normal saline differentiates cerebral salt wasting from SIADH; cerebral salt wasting tends to resolve with isotonic saline, while SIADH does not,
Symptoms and Signs of Hyponatremia
Symptoms mainly involve central nervous system 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, in patients who are older and/or chronically ill with hyponatremia develop more symptoms than patients who are younger and/or otherwise healthy. Symptoms are also more severe with faster-onset hyponatremia. Symptoms generally occur when the effective plasma osmolality falls to < 240 mOsm/L (< 240 mmol/L). 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 (< 115 mmol/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.
Diagnosis of Hyponatremia
Measurement of serum and urine electrolytes and determination of osmolality
Clinical assessment of volume status
Evaluation of renal, adrenal, thyroid, hepatic, and cardiac function
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.
Exclusion of translocational hyponatremia and pseudohyponatremia
Pseudohyponatremia with normal serum osmolality may occur in severe hyperlipidemia, most commonly hypertriglyceridemia, or extreme hyperproteinemia as occurs occasionally with multiple myeloma, 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. Autoanalyzers in many clinical laboratories are affected by this artifact. Methods of measuring serum electrolytes with direct ion-selective electrodes circumvent this problem. Such direct ion-selective electrodes are available in some hospital laboratories by special request, but are also used by most point-of-care bedside analyzers. These analyzers can be used to exclude pseudohyponatremia. Formulas exist to estimate the effect these abnormalities have on sodium measurement.
Identification of the cause
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 medications 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 [< 100 mmol/kg]) and specific gravity < 1.003). Serum sodium concentration (< 130 mOsm/L [mmol/L]) and serum osmolality (< 275 mOsm/L [mmol/L]) that are low and urine osmolality that is inappropriately high (120 to 150 mmol/L [120 to 150 mOsm/kg]) with respect to the low serum osmolality suggests volume overload, volume contraction, SIADH, or cerebral salt wasting. 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 (blood urea nitrogen) and creatinine values are normal, and serum uric acid is generally low. Urine sodium concentration is usually > 30 mEq/L (30 mmol/L), and fractional excretion of sodium is > 1% (for calculation, see Evaluation of the Renal Patient).
In patients with hypovolemia and normal renal function, sodium reabsorption results in a urine sodium of < 20 mEq/L (< 20 mmol/L). Urine sodium > 20 mEq/L (> 20 mmol/L) in hypovolemic patients suggests mineralocorticoid deficiency or salt-losing nephropathy. Hyperkalemia suggests adrenal insufficiency.
In patients with hyponatremia and a urine sodium of > 40 mEq/L (> 40 mmol/L) who have recent traumatic brain injury or CNS surgery, cerebral salt wasting should be considered.
Treatment of Hyponatremia
If hypovolemic, 0.9% saline
If hypervolemic, fluid restriction, sometimes a diuretic, occasionally a vasopressin antagonist
If euvolemic, treatment of cause
In severe, rapid onset or highly symptomatic hyponatremia, partial rapid correction with hypertonic (3%) saline
Hyponatremia can be life threatening and requires prompt recognition and proper treatment. However, too-rapid correction of hyponatremia can cause neurologic complications, such as osmotic demyelination syndrome. Guidance regarding the pace of sodium correction includes that serum sodium concentration
Should not be increased by more than 8 mEq/L (8 mmol/L) over the first 24 hours
Should be corrected no faster than 0.5 mEq/L/hour (0.5 mmol/L/hour), except during the first few hours of treatment of severe hyponatremia (replacement rate of up 2 mEq/L/hour (2 mmol/L/hour)
The degree of hyponatremia, the duration and rate of onset, and the patient's symptoms are used to determine which treatment is most appropriate. Even with severe hyponatremia,
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 (< 120 mmol/L), hyponatremia may not completely correct upon restoration of intravascular volume; restriction of oral intake of free water to 500 to 1000 mL/24 hours may be needed.
In hypervolemic patients, in whom hyponatremia is due to renal sodium retention (eg, heart failure, cirrhosis, or nephrotic syndrome) and dilution, water restriction combined with treatment of the underlying disorder is required. In patients with heart failure, an angiotensin-converting enzyme 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,demeclocycline is not widely used due to the possibility of drug-induced acute kidney injuryvasopressinvasopressin 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 hypovolemia, liver disease, or renal disease.
Mild to moderate hyponatremia
Mild to moderate, asymptomatic hyponatremia (ie, serum sodium ≥ 121 and < 135 mEq/L [≥ 121 and < 135 mmol/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.
Severe hyponatremia
In asymptomatic patients, severe hyponatremia (serum sodium < 121 mEq/L [< 121 mmol/L]; effective osmolality < 240 mOsm/kg [< 240 mmol/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/hour (1 mmol/L/hour). However, replacement rates of up to 2 mEq/L/hour (2 mmol/L/hour) for the first 2 to 3 hours have been suggested for patients with seizures or significantly altered sensorium. Regardless, the rise should be ≤ 8 mEq/L (≤ 8 mmol/L) over the first 24 hours. More vigorous correction risks precipitating osmotic demyelination syndrome.
Rapid-onset hyponatremia
Acute hyponatremia with known rapid onset (ie, within < 24 hours) is a special case. Such rapid onset can occur with
Acute psychogenic polydipsia
Use of the drug methylenedioxymethamphetamine (MDMA; ecstasy)
Postoperative patients who received hypotonic fluid during surgery
Marathon runners who replace sweat loss with hypotonic fluids
Rapid-onset hyponatremia is problematic because the cells of the central nervous system 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 (4 to 6 mmol/L) using hypertonic saline is indicated. The patient should be monitored in an intensive care unit and serum sodium levels monitored every 2 hours. After sodium level has increased by the initial target of 4 to 6 mEq/L(4 to 6 mmol/L), the rate of correction is slowed so that serum sodium level does not rise by > 8 mEq/L (> 8 mmol/L) in the first 24 hours.
Hypertonic saline solution
Hypertonic (3%) saline (containing 513 mEq sodium/L [513 mmol/L]) use requires frequent (every 2 hours) electrolyte determinations. In some situations, hypertonic saline may be used with a loop diuretic. Equations are available to help predict the sodium response to a given amount of hypertonic saline, but these formulas are only rough guidelines and do not decrease the need to monitor electrolyte levels frequently. For instance, in hypovolemic hyponatremia the sodium level can normalize too quickly as volume is replaced and thus removes the hypovolemic stimulus for vasopressin secretion, causing the kidneys to excrete large amounts of water.
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. After the sodium has been corrected at the appropriate rate for 24 hours, desmopressin is stopped. Hypertonic saline can then be stopped, or, if required for continuing correction of hyponatremia, continued.
For patients with rapid-onset hyponatremia and neurologic symptoms, rapid correction is accomplished by giving 100 mL of hypertonic saline IV over 15 minutes. This dose can be repeated once if neurologic symptoms are still present.
For patients with seizures or coma but slower onset hyponatremia, ≤ 100 mL/hour of hypertonic saline may be administered over 4 to 6 hours in amounts sufficient to raise the serum sodium 4 to 6 mEq/L (4 to 6 mmol/L). This amount (in mEq OR mmol) may be calculated using the sodium (Na) 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 (mmol) 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 (mmol/L). To result in a correction rate of 1 mEq/L/hour, this 0.5 L volume would be infused over about 6 hours.
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 ventilationseizures.
Patients meeting the criteria for cerebral salt wasting should not be fluid restricted because fluid restriction can cause brain vessel vasospasm. Although isotonic saline should correct the cause of hyponatremia, use of hypertonic saline is recommended to prevent more severe hyponatremia if SIADH is present.
Selective vasopressin receptor antagonists
The selective vasopressinchronic kidney disease.
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 high cost.
Chronic hyponatremia
Patients with SIADH need chronic treatment for hyponatremia. Fluid restriction alone is frequently not enough to prevent recurrence of hyponatremia. Oral salt (NaCl) tablets can be used with dosage adjusted to treat mild to moderate chronic hyponatremia in these patients.
Osmotic demyelination syndrome
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 alcohol use disorder, 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 hour [> 14 mmol/L/8 hours]) 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.
Key Points
Hyponatremia may occur with normal, increased, or decreased extracellular fluid volume.
Common causes include diuretic use, diarrhea, heart failure, liver disease, 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 (≤ 8 mmol/L) over 24 hours, 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.
