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.

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 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.

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).

Overview of the Syndrome of In...

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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

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,

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.

Calculators Used to Exclude Translocational Hyponatremia and Pseudohyponatremia

Clinical Calculators

Sodium Correction in Hyperglycemia

Clinical Calculators

Sodium Change in Hypertriglyceridemia

Clinical Calculators

Sodium Change in Hyperproteinemia

Clinical Calculators

Sodium Correction in Hyperglycemia

Clinical Calculators

Sodium Change in Hypertriglyceridemia

Clinical Calculators

Sodium Change in Hyperproteinemia

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.

Clinical Calculators

Osmolality Estimator (serum)

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.

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.

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.

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 (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.

Clinical Calculators

Sodium Deficit in Hyponatremia

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.

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 (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.