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Hyponatremia is decrease in plasma Na concentration < 136 mEq/L caused by an excess of water relative to solute. Common causes include diuretic use, diarrhea, heart failure, and renal disease. 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 plasma Na. Plasma and urine electrolytes and osmolality help determine the cause. Treatment involves restricting water intake and promoting its loss, replacing any Na deficit, and treating the cause.

Etiology

Hyponatremia reflects an excess of total body water (TBW) relative to total body Na content. Because total body Na content is reflected by ECF volume status, hyponatremia must be considered along with status of the ECF volume: hypovolemia, euvolemia, and hypervolemia (see Table 2: Fluid and Electrolyte Metabolism: 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, but it may also occur with an increased ECF volume (eg, in heart failure, hypoalbuminemia, capillary leak syndrome).

Table 2
Principal Causes of Hyponatremia Mechanism Category Examples Hypovolemic hyponatremia Decreased TBW and Na, with a relatively greater decrease in Na GI losses* Diarrhea Vomiting   3rd-space losses* Burns Pancreatitis Peritonitis Rhabdomyolysis Small-bowel obstruction   Renal losses Diuretics Mineralocorticoid deficiency Osmotic diuresis (glucose, urea, mannitol Some Trade Names OSMITROL RESECTISOL Click for Drug Monograph ) Salt-losing nephropathies (eg, interstitial nephritis, medullary cystic disease, partial urinary tract obstruction, and polycystic kidney disease) Euvolemic hyponatremia     Increased TBW with near-normal total body Na Drugs Diuretics, barbiturates, carbamazepine Some Trade Names TEGRETOL Click for Drug Monograph , chlorpropamide Some Trade Names DIABINESE Click for Drug Monograph , clofibrate Some Trade Names ATROMID-S Click for Drug Monograph , opioids, tolbutamide Some Trade Names ORINASE Click for Drug Monograph , vincristine Some Trade Names ONCOVIN Click for Drug Monograph Possibly cyclophosphamide Some Trade Names CYTOXAN Click for Drug Monograph , NSAIDs, oxytocin Some Trade Names PITOCIN SYNTOCINON Click for Drug Monograph   Disorders Adrenal insufficiency as in Addison's disease Hypothyroidism Syndrome of inappropriate ADH secretion   Increased intake of fluids Primary polydipsia   States that increase nonosmotic release of ADH Emotional stress Pain Postoperative states Hypervolemic hyponatremia     Increased total body Na with a relatively greater increase in TBW Extrarenal disorders Cirrhosis Heart failure   Renal disorders Acute kidney dysfunction Chronic kidney disease Nephrotic syndrome TBW = total body water. *GI and 3rd-space losses cause hyponatremia if replacement fluids are hypotonic compared to losses.

Hypovolemic hyponatremia: Deficiencies in both TBW and total body Na exist, although proportionally more Na than water has been lost; the Na deficit produces hypovolemia. In hypovolemic hyponatremia, both plasma osmolality and blood volume decrease. 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 Na-containing fluids as in protracted vomiting, severe diarrhea, or sequestration of fluids in a 3rd space (see Table 3: Fluid and Electrolyte Metabolism: Composition of Body Fluids), can cause hyponatremia typically when losses are replaced by ingesting plain water or liquids low in Na (see Table 4: Fluid and Electrolyte Metabolism: Approximate Na Content of Common Beverages) or by hypotonic IV fluid. Significant ECF fluid losses also cause release of ADH, 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 Na conservation, urine Na concentration is typically < 10 mEq/L.

Table 3
Composition of Body Fluids Fluid Source NA* K* CL* Gastric 20–80 5–20 100–150 Pancreatic 120–140 5–15 90–120 Small bowel 100–140 5–15 90–130 Bile 120–140 5–15 80–120 Ileostomy 45–135 3–15 20–115 Diarrheal 10–90 10–80 10–110 Sweat 10–30 3–10 10–35 Burns 140 5 110 *Unit is mEq/L.

Table 4
Approximate Na Content of Common Beverages Beverage Na (mEq/L) Apple juice 1.3 Beer 2.2 Coffee 1 Cola 5–6.5 Diet cola 4.5–6.5 Light beer 1.3 Orange juice 3.7 Sports drink 8–33 Water (including tap water) < 1

Renal fluid losses resulting in hypovolemic hyponatremia may occur with mineralocorticoid deficiency, 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 Na concentration is inappropriately high (> 20 mEq/L). Urine Na concentration may not help in differentiation when metabolic alkalosis (as occurs with protracted vomiting) is present and large amounts of HCO₃ are spilled in the urine, obligating the excretion of Na to maintain electrical neutrality. In metabolic alkalosis, urine Cl concentration frequently differentiates renal from extrarenal sources of volume depletion (see Acid-Base Regulation and Disorders: Metabolic Alkalosis).

Diuretics may also produce hypovolemic hyponatremia. Thiazide diuretics, in particular, decrease the kidneys' diluting capacity and increase Na excretion. Once volume depletion occurs, the nonosmotic release of ADH causes water retention and worsens hyponatremia. Concomitant hypokalemia shifts Na intracellularly and enhances ADH 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 K and volume deficits along with judicious monitoring of water intake until the drug effect dissipates. Elderly patients may have increased Na 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 Na 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's disease, hypothyroidism, or nonosmotic ADH release (eg, from stress; postoperative states; use of drugs such as chlorpropamide Some Trade Names
DIABINESE
Click for Drug Monograph
or tolbutamide Some Trade Names
ORINASE
Click for Drug Monograph
, opioids, barbiturates, vincristine Some Trade Names
ONCOVIN
Click for Drug Monograph
, clofibrate Some Trade Names
ATROMID-S
Click for Drug Monograph
, carbamazepine Some Trade Names
TEGRETOL
Click for Drug Monograph
). Postoperative hyponatremia most commonly occurs because of a combination of nonosmotic ADH release and excessive administration of hypotonic fluids after surgery. Certain drugs (eg, cyclophosphamide Some Trade Names
CYTOXAN
Click for Drug Monograph
, NSAIDs, chlorpropamide Some Trade Names
DIABINESE
Click for Drug Monograph
) potentiate the renal effect of endogenous ADH, whereas others (eg, oxytocin Some Trade Names
PITOCIN
SYNTOCINON
Click for Drug Monograph
) have a direct ADH-like effect on the kidneys. 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 Sidebar 1: Fluid and Electrolyte Metabolism: Syndrome of Inappropriate ADH Secretion) is another cause of euvolemic hyponatremia.

Sidebar 1
Syndrome of Inappropriate ADH Secretion The syndrome of inappropriate ADH secretion (SIADH) is attributed to excessive ADH 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 drugs that stimulate ADH secretion in patients with normal cardiac, hepatic, renal, adrenal, and thyroid function. SIADH is associated with myriad disorders (see Table 5: Fluid and Electrolyte Metabolism: Disorders Associated with Syndrome of Inappropriate Antidiuretic Hormone Secretion).

Table 5
Disorders Associated with Syndrome of Inappropriate Antidiuretic Hormone Secretion Disorder Examples Cancer CNS Duodenum Lung Lymphoma Pancreas CNS disorders Acute intermittent porphyria Acute psychosis Brain abscess Encephalitis Guillain-Barré syndrome Head trauma Meningitis Stroke Subdural or subarachnoid hemorrhage Endocrine disorders Addison's disease Hypopituitarism Hypothyroidism Pulmonary disorders and treatments Aspergillosis Lung abscess Pneumonia Positive-pressure breathing TB Miscellaneous Protein-energy undernutrition Surgery

Hypervolemic hyponatremia: Hypervolemic hyponatremia is characterized by an increase in both total body Na (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 Na measurement by elevated lipids. In each of these disorders, a decrease in effective circulating volume results in the release of ADH and angiotensin II. The following factors contribute to hyponatremia:

• The antidiuretic effect of ADH on the kidneys
• Direct impairment of renal water excretion by angiotensin II
• Decreased GFR
• Stimulation of thirst by angiotensin II

Urine Na excretion is usually < 10 mEq/L, and urine osmolality is high relative to plasma osmolality.

Hyponatremia in AIDS: Hyponatremia has been reported in > 50% of hospitalized patients with AIDS. Among the many potential contributing factors are

• Administration of hypotonic fluids
• Impaired renal function
• Nonosmotic ADH release due to intravascular volume depletion
• Administration of drugs that impair renal water excretion

In addition, adrenal insufficiency has become increasingly common in AIDS patients as the result of cytomegalovirus adrenalitis, mycobacterial infection, or interference with adrenal glucocorticoid and mineralocorticoid synthesis by ketoconazole Some Trade Names
NIZORAL
Click for Drug Monograph
. SIADH may be present because of coexistent pulmonary or CNS infections.

Symptoms and Signs

Symptoms mainly involve CNS dysfunction. However, when hyponatremia is accompanied by disturbances in total body Na content, signs of ECF volume depletion or overload also occur (see Fluid and Electrolyte Metabolism: Volume Overload). 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 plasma Na 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 brain stem herniation.

Diagnosis

• Plasma and urine electrolytes and osmolality
• Clinical assessment of volume status

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 plasma electrolyte measurement.

Plasma Na may be low when severe hyperglycemia increases osmolality and water moves out of cells into the ECF. Plasma Na concentration falls about 1.6 mEq/L for every 100-mg/dL (5.55-mmol/L) rise in the plasma glucose concentration above normal. This condition is often called translocational hyponatremia because it is caused by translocation of Na across cell membranes. Pseudohyponatremia with normal plasma osmolality may occur in hyperlipidemia or extreme hyperproteinemia, because the lipid or protein occupies space in the volume of plasma taken for analysis; the concentration of Na in plasma itself is not affected. Newer methods of measuring plasma electrolytes with ion-selective electrodes circumvent this problem.

Identification of the cause: Identifying the cause can be complex. The history sometimes suggests a cause (eg, significant fluid loss from vomiting or diarrhea, renal disease, compulsive fluid ingestion, intake of drugs that stimulate ADH release or enhance ADH action).

The volume status, particularly the presence of obvious volume depletion or overload, suggests certain causes (see Table 1: Fluid and Electrolyte Metabolism: Common Causes of Volume Depletion). Overtly hypovolemic patients usually have an obvious source of fluid loss (typically 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 plasma 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 sp gr < 1.003). Plasma Na concentration and plasma osmolality that are low and urine osmolality that is inappropriately high (120 to 150 mmol/L) with respect to the low plasma osmolality suggest volume overload, volume contraction, or SIADH. Volume overload and volume contraction are differentiated clinically (see Fluid and Electrolyte Metabolism: Volume depletion; see Fluid and Electrolyte Metabolism: Volume Overload). 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 Na concentration is usually > 30 mmol/L, and fractional excretion of Na is > 1% (for calculation, see Approach to the Genitourinary Patient: Other urine tests).

In patients with hypovolemia and normal renal function, Na reabsorption results in a urine Na of < 20 mmol/L. Urine Na > 20 mmol/L in hypovolemic patients suggests mineralocorticoid deficiency or salt-losing nephropathy. Hyperkalemia suggests adrenal insufficiency.

Treatment

Rapid correction of hyponatremia, even mild hyponatremia, risks neurologic complications (see Fluid and Electrolyte Metabolism: Osmotic demyelination syndrome). Except possibly in the first few hours of treatment of severe hyponatremia, Na should be corrected no faster than 0.5 mEq/L/h. Even with severe hyponatremia, increase in plasma Na concentration should not exceed 10 mEq/L over the first 24 h. Any identified cause of hyponatremia is treated concurrently.

Mild hyponatremia: Mild, asymptomatic hyponatremia (ie, plasma Na > 120 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 Na or K replacement. Similarly, when mild hyponatremia results from inappropriate hypotonic parenteral fluid administration in patients with impaired water excretion, merely altering fluid therapy may suffice.

With hypovolemia and normal adrenal function, administration of 0.9% saline usually corrects both hyponatremia and hypovolemia. When the plasma Na 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 Na 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. K 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.

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 Some Trade Names
DECLOMYCIN
Click for Drug Monograph
(300 to 600 mg q 12 h) may be helpful by inducing a concentrating defect in the kidneys; however, demeclocycline Some Trade Names
DECLOMYCIN
Click for Drug Monograph
may cause acute renal failure. Renal failure is usually reversible when the drug is stopped. IV conivaptan, an ADH 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.

Severe hyponatremia: Severe hyponatremia (plasma Na < 109 mEq/L; effective osmolality < 238 mOsm/kg) in asymptomatic patients can be treated safely with stringent restriction of water intake. Treatment is more controversial when neurologic symptoms (eg, confusion, lethargy, seizures, coma) are present. The debate primarily concerns the pace and degree of hyponatremia correction. Many experts recommend that plasma Na be raised no faster than 1 mEq/L/h, but replacement rates of up to 2 mEq/L/h for the first 2 to 3 h have been suggested for patients with seizures. Regardless, the rise should be ≤ 10 mEq/L over the first 24 h. More vigorous correction risks precipitation of osmotic demyelination syndrome.

Hypertonic (3%) saline (containing 513 mEq Na/L) may be used, but only with frequent (q 2 to 4 h) electrolyte determinations. For patients with seizures or coma, ≤ 100 mL/h may be administered over 4 to 6 h in amounts sufficient to raise the plasma Na 4 to 6 mEq/L. This amount (in mEq) may be calculated using the Na deficit formula as

(Desired change in Na) × TBW

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 Na needed to raise the Na from 106 to 112 in a 70-kg man can be calculated as follows:

(112 mEq/L − 106 mEq/L) × (0.6 L/kg × 70 kg) = 252 mEq

Because there is 513 mEq Na/L in hypertonic saline, roughly 0.5 L of hypertonic saline is needed to raise the Na from 106 to 112 mEq/L. Adjustments may be needed based on plasma Na concentrations, which are monitored closely for 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 Some Trade Names
ATIVAN
Click for Drug Monograph
1 to 2 mg IV q 5 to 10 min prn) for seizures.

Osmotic demyelination syndrome: Osmotic demyelination syndrome (previously called central pontine myelinolysis) may follow too-rapid correction of hyponatremia. Demyelination may affect the pons and other areas of the brain. Lesions are more common in patients with alcoholism, undernutrition, or other chronic debilitating illness. Flaccid paralysis, dysarthria, and dysphagia can evolve over a few days or weeks. The 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 possibly by coded eye movements). Damage often is permanent. When Na is replaced too rapidly (eg, > 14 mEq/L/8 h) and neurologic symptoms start to develop, it is critical to prevent further plasma Na increases by stopping hypertonic fluids. In such cases, inducing hyponatremia with hypotonic fluid may mitigate the development of permanent neurologic damage.

Last full review/revision May 2009 by James L. Lewis, III, MD

Content last modified May 2009