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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 cells), 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 and Pathophysiology

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 fluid status: hypovolemia, euvolemia, and hypervolemia (see Table 3: Fluid and Electrolyte Metabolism: Principal Causes of Hyponatremia).

Table 3
Principal Causes of Hyponatremia Hyponatremia with hypovolemia (decreased TBW and Na; relatively greater decrease in Na) Extrarenal losses GI: Vomiting, diarrhea Third-space losses: Pancreatitis, peritonitis, small-bowel obstruction, rhabdomyolysis, burns Renal losses Diuretics Mineralocorticoid deficiency Osmotic diuresis (glucose, urea, mannitol Some Trade Names OSMITROL RESECTISOL Click for Drug Monograph ) Salt-losing nephropathies Hyponatremia with euvolemia (increased TBW; near-normal total body Na) Diuretics Glucocorticoid deficiency Hypothyroidism Primary polydipsia States that increase release of ADH (postoperative opioids, pain, emotional stress) Syndrome of inappropriate ADH secretion Hyponatremia with hypervolemia (increased total body Na; relatively greater increase in TBW) Extrarenal disorders Cirrhosis Heart failure Renal disorders Acute renal failure Chronic renal failure Nephrotic syndrome TBW = total body water.

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. Hyponatremia can occur when 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 4: Fluid and Electrolyte Metabolism: Composition of Fluids Lost), are replaced with ingestion of free water or treated with 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 4
Composition of Fluids Lost (mEq/L) Fluid 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

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 diseases 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 those with extrarenal fluid losses by inappropriately high urine Na concentration (> 20 mEq/L). An exception occurs with metabolic alkalosis (as occurs with protracted vomiting) where 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, affect the kidneys' diluting ability while increasing 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 restriction of water intake until the drug effect dissipates. Elderly patients are especially susceptible to thiazide-induced hyponatremia, particularly if a preexisting defect in renal water excretion exists. Rarely, such patients develop severe, life-threatening hyponatremia within a few weeks after the initiation of a thiazide diuretic resulting from an exaggerated natriuresis and underlying impaired urinary diluting capacity. Loop diuretics much less commonly cause hyponatremia.

Euvolemic hyponatremia: In euvolemic hyponatremia, total body Na and thus ECF volume are 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 diluting ability. Patients affected include those with psychosis or more modest degrees of polydipsia plus renal insufficiency. Dilutional hyponatremia may also result from excessive water intake without Na retention in the presence of Addison's disease, myxedema, or nonosmotic ADH secretion (eg, stress; postoperative states; use of drugs such as chlorpropamide Some Trade Names
DIABINESE
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or tolbutamide Some Trade Names
ORINASE
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, opioids, barbiturates, vincristine Some Trade Names
ONCOVIN
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, clofibrate Some Trade Names
ATROMID-S
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, carbamazepine Some Trade Names
TEGRETOL
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). Postoperative hyponatremia 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
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, NSAIDs, chlorpropamide Some Trade Names
DIABINESE
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) potentiate the renal effect of endogenous ADH, whereas others (eg, oxytocin Some Trade Names
PITOCIN
SYNTOCINON
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) have a direct ADH-like effect on the kidney. A deficiency in water excretion is common in all these conditions.

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, and 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 Malignancy CNS Pancreas Duodenum Lung Lymphoma Pulmonary disorders Aspergillosis Lung abscess Pneumonia Positive-pressure breathing TB 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 Miscellaneous causes Protein-energy malnutrition 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. Hyponatremia results from the antidiuretic effect of ADH on the kidney as well as the direct impairment of renal water excretion by angiotensin II. Decreased GFR and stimulation of thirst by angiotensin II also potentiate the development of hyponatremia. 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, and 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
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. 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 volume depletion or overload also occur (see Fluid and Electrolyte Metabolism: Symptoms and Signs). The degree of hyponatremia, the rapidity with which it develops, its cause, and the patient's age and overall condition determine symptom severity. 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 below 115 mEq/L, stupor, neuromuscular hyperexcitability, 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

Hyponatremia is diagnosed by measuring serum electrolytes. However, serum Na may be artifactually low when severe hyperglycemia increases osmolality. Water moves out of cells into the ECF. Serum Na concentration falls about 1.6 mEq/L for every 100-mg/dL (5.55-mmol/L) rise in the plasma glucose level above normal. This condition is called translational hyponatremia because no net change in the amount of TBW or Na has occurred. 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. Newer methods of measuring plasma electrolytes with ion-selective electrodes circumvent this problem.

Determining the cause of hyponatremia 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 patient's volume status, particularly the presence of obvious volume depletion or overload, suggests certain causes (see Table 1: Fluid and Electrolyte Metabolism: Common Causes of Extracellular Fluid Volume Depletion and Table 2: Fluid and Electrolyte Metabolism: Principal Causes of Extracellular Fluid Volume Overload). Overtly hypovolemic patients usually have an obvious source of fluid loss (typically followed by hypotonic fluid replacement). Overtly hypervolemic patients usually have a readily recognizable condition, such as heart failure or hepatic or renal disease. Euvolemic patients and those with equivocal volume status require more laboratory testing to identify a cause.

Acuity of onset helps determine permissible speed of treatment. Sudden onset of CNS dysfunction suggests acute onset of hyponatremia.

Laboratory tests should include blood and urine osmolality and electrolytes. Euvolemic patients should also have thyroid and adrenal function tested. Hypo-osmolality in an euvolemic patient should cause excretion of a large volume of dilute urine (eg, osmolality < 100 mOsm/kg and specific gravity < 1.003). Serum Na level 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 (see Fluid and Electrolyte Metabolism: Extracellular Fluid Volume Contraction; see Fluid and Electrolyte Metabolism: Extracellular Fluid Volume Expansion). If neither appears likely, SIADH is considered. Patients with SIADH are usually normovolemic or slightly hypervolemic. BUN and creatinine values are normal, and serum uric acid is generally low. Urine Na level is usually > 30 mmol/L, and fractional excretion of Na is > 1%.

In a patient with volume contraction, if renal function is normal, Na reabsorption results in a urine Na of < 20 mmol/L. Urine Na > 20 mmol/L in a hypovolemic patient 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). Generally, Na should be corrected no faster than 0.5 mEq/L/h. Increase 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. In diuretic-induced hyponatremia, elimination of the diuretic may be enough; some patients need some Na or K replacement. Similarly, if mild hyponatremia results from inappropriate parenteral fluid administration in a patient with impaired water excretion, merely stopping hypotonic fluid therapy may suffice.

With hypovolemia, if adrenal function is normal, administration of 0.9% saline usually corrects both hyponatremia and hypovolemia. If the plasma Na is < 120 mEq/L, it 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 dilutional hyponatremia is due to renal Na retention (eg, heart failure, cirrhosis, nephrotic syndrome), water restriction combined with treatment of the underlying disorder is often successful. An ACE inhibitor, in conjunction with a loop diuretic, can correct refractory hyponatremia in patients with heart failure. If hyponatremia does not respond to simple fluid restriction, 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. If hyponatremia is 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). If SIADH is present, severe water restriction (eg, 250 to 500 mL/24 h) is 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 disease. When the underlying disease is not treatable, as in metastatic lung cancer, and severe water restriction is unacceptable to the patient, demeclocycline Some Trade Names
DECLOMYCIN
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(300 to 600 mg q 12 h) may be helpful; however, demeclocycline Some Trade Names
DECLOMYCIN
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may cause acute renal failure; renal failure is usually reversible when the drug is stopped. Investigational selective vasopressin Some Trade Names
PITRESSIN
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receptor antagonists effectively produce water diuresis without significant loss of electrolytes in the urine and may provide useful future treatment for 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 (see below).

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 serum 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, so plasma Na must be monitored closely, beginning within the first 2 to 3 h after initiation of treatment. Patients with seizures, coma, or altered mental status need supportive treatment, which may involve airway intubation and benzodiazepines (eg, lorazepam Some Trade Names
ATIVAN
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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, malnutrition, 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 the patient with a locked-in syndrome (an awake and sentient state in which the patient, because of generalized motor paralysis, cannot communicate, except possibly by coded eye movements). Damage often is permanent. If 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 November 2005

Content last modified November 2005