hyponatremia

Hyponatremia is decrease in serum 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 serum Na. Serum 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 1: Electrolyte Disorders: 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, or capillary leak syndrome).

Table 1

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

)

Salt-losing nephropathies (eg, interstitial nephritis, medullary cystic disease, partial urinary tract obstruction, polycystic kidney disease)

Euvolemic hyponatremia

Increased TBW with near-normal total body Na
Drugs
Diuretics, barbiturates, carbamazepine

,
chlorpropamide

, clofibrate

,
opioids, tolbutamide

,
vincristine

Possibly cyclophosphamide

,
NSAIDs, oxytocin

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
*GI and 3rd-space losses cause hyponatremia if replacement fluids are hypotonic compared with losses.
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 causes hypovolemia. In hypovolemic hyponatremia, both serum 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 2: Electrolyte Disorders: Composition of Body Fluids), can cause hyponatremia typically when losses are replaced by ingesting plain water or liquids low in Na (see Table 3: Electrolyte Disorders: 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 2

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 3

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)
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 cause 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, 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 ADH release and excessive administration of hypotonic fluids after surgery. Certain drugs (eg, cyclophosphamide

,
NSAIDs, chlorpropamide

) potentiate the renal effect of endogenous ADH, whereas others
(eg, oxytocin

) 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: Electrolyte Disorders: 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 4: Electrolyte Disorders: Disorders Associated with Syndrome of Inappropriate ADH Secretion).

Table 4

Disorders Associated with Syndrome of Inappropriate ADH 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 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 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 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 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 serum 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

Serum 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 serum electrolyte measurement.

Serum Na may be low when severe hyperglycemia increases osmolality and 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 serum 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 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 Na in serum itself is not affected. Newer methods of measuring serum electrolytes with ion-selective electrodes circumvent this problem.
Clinical Calculator

Identification of the cause: Identifying the cause 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 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 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 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 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 in hypovolemic patients suggests mineralocorticoid deficiency or salt-losing nephropathy. Hyperkalemia suggests adrenal insufficiency.

Treatment

When hypovolemic, 0.9% saline

When hypervolemic, fluid restriction and sometimes a diuretic

When euvolemic, treatment of cause

Rarely cautious correction with hypertonic (3%) saline

Rapid correction of hyponatremia, even mild hyponatremia, risks neurologic complications (see Electrolyte Disorders: 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 serum Na concentration should not exceed 10 mEq/L over the first 24 h. Any identified cause of hyponatremia is treated concurrently.
Clinical Calculator

Mild hyponatremia: Mild, asymptomatic hyponatremia (ie, serum 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 serum 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

(300 to 600 mg q
12 h) may be helpful by inducing a concentrating defect in the kidneys. However, demeclocycline

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 (serum Na < 109 mEq/L; effective osmolality 14 mEq/L/8 h) and neurologic symptoms start to develop, it is critical to prevent further serum Na increases by stopping hypertonic fluids. In such cases, inducing hyponatremia with hypotonic fluid may mitigate the development of permanent neurologic damage.

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