Disorders of Sodium Homeostasis

Disorders of sodium concentration (hyponatremia and hypernatremia) are generally due to water balance (too much in the case of hyponatremia; too little in the case of hypernatremia) rather than due to too little or too much sodium in the body.

Physiology of Sodium Concentration

The concentration of sodium in the plasma is determined by the ratio of sodium and potassium in the body to the total body water.

(Adapted from: Disorders of Plasma Sodium - Causes, Consequences, and Correction. N Engl J Med 2015)

Hyponatremia

Hyponatremia is defined as a decrease in the plasma sodium concentration to a level <135 mmol/L. Most cases of hyponatremia are hypotonic (i.e., an excess of water relative to sodium and potassium). Some cases can also be isotonic or hypertonic (e.g., from hyperglycemia).

The first step in managing hyponatremia is to determine the volume status of the patient. Hypotonic hyponatremia can be further broken down by volume status: hypovolemia, normovolemia, or hypervolemia.

• In a hypovolemic state, there is an increased loss of sodium relative to loss of water; common causes include therapy with thiazide diuretics and massive gastrointestinal losses.

• In a hypervolemic state, there is increased retention of water relative to sodium retention; common causes include congestive heart failure and kidney failure.

• The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) most commonly causes hyponatremia in a normovolemic state. SIADH also results in increased urinary excretion of sodium secondary to water retention. Therefore, measuring urinary sodium is also a useful tool for differentiating sodium and volume status.

Causes

The following table provides a detailed list of causes of hypotonic hyponatremia:

(Source: Hyponatremia. N Engl J Med 2000.)

Complications

Severe complications of hyponatremia are due to cerebral edema and include seizures, coma, permanent brain damage, respiratory arrest, brainstem herniation, and death.

Treatment

Treatment and the pace of correction of hyponatremia depend on whether the patient is symptomatic and on the chronicity of the hyponatremia. The main risk of rapid correction of hyponatremia is osmotic demyelination syndrome, which can result in severe neurologic dysfunction and even death.

Treatment options:

• hypertonic saline (3% saline) for patients who are euvolemic or hypervolemic

• normal saline for those who are hypovolemic

• free water restriction

• salt tablets

Therapeutic recommendations for correction of severe hyponatremia (plasma sodium concentration <120 mmol/L) based on duration of hyponatremia are described in the following table:

(Source: Disorders of Plasma Sodium — Causes, Consequences, and Correction. N Eng J Med 2015.)

Effect of treatment on sodium levels: The following table provides formulas to estimate the effect of fluid administration on sodium levels:

(Source: Hyponatremia. N Engl J Med 2000.)

Other Medications

• Medications such as demeclocycline and tolvaptan may be considered for correction of hyponatremia and may be an option in the setting of SIADH. Demeclocycline is a tetracycline that inhibits the intracellular effects of ADH on renal tubular cells, resulting in an increase in water excretion.

• Vasopressin receptor (V1a, V1b and V2) antagonists result in the inhibition of ADH and promote selective aquaresis. Tolvaptan, satavaptan and lixicaptan are oral antagonists of the V2 receptor. The SALT-1 and SALT-2 trials randomized patients with euvolemic or hypervolemic hyponatremia to receive placebo or oral tolvaptan. Tolvaptan was associated with an increase in serum sodium concentrations at day 4 and day 30. However, the rate of correction of hyponatremia that exceeded the predefined threshold was only 1.8%. Of note, rapid correction of hyponatremia can lead to irreversible brain damage and patients with liver disease should not receive tolvaptan. Tolvaptan may cause excessive thirst, which may ultimately limit the rise of sodium, if the patient has access to water.

Hypernatremia

Hypernatremia is defined as a rise in the plasma sodium concentration to a level >145 mmol/L. In hypernatremia, there is a deficit of water relative to sodium, either caused by water loss or hypertonic sodium gain. Hypernatremia is often iatrogenic in patients with impaired thirst or access to water (e.g., due to altered mental status or intubation, or infants and the elderly).

Causes

The following table lists causes of hypernatremia:

(Source: Hypernatremia. N Engl J Med 2000.)

Complications

The main complications of hypernatremia are related to brain shrinkage and include vascular rupture with cerebral bleeding, subarachnoid hemorrhage, and permanent neurologic damage or death.

Treatment

Treatment of hypernatremia requires a two-pronged approach:

• Address the underlying cause (i.e., stopping gastrointestinal losses, controlling fever, withholding diuretics, stopping hypertonic fluids).

• Correct the hypertonicity.

Treatment of patients with rapid development of hypernatremia (over several hours):

• Rapid correction improves the prognosis without increasing the risk of cerebral edema, because accumulated electrolytes are rapidly extruded from brain cells.

• Reduce plasma sodium concentration by 1 mmol/L per hour.

Treatment of patients with hypernatremia of longer (≥2 days) or unknown duration:

• A slower pace of correction is advised.

• Reduce plasma sodium concentration at a maximal rate of 0.5 mmol/L per hour to prevent cerebral edema and convulsions.

• Aim for a drop in plasma sodium concentration level of 6-8 mmol/L per day (except in patients with rapid development as described above).

• The goal of treatment is to reduce plasma sodium concentration to 145 mmol/L.

The rate of correction for hypernatremia has previously focused on the principle of establishing the duration of hypernatremia. However, recent evidence has raised questions about this approach. Currently, the best rate of correction is uncertain.

Fluid Administration: The preferred route for administering fluids is oral or via a feeding tube. Intravenous fluids should be given if the oral route is not tolerated or feasible.

Only hypotonic fluids (i.e., pure water, 5% dextrose, 0.45% sodium chloride) are appropriate for correcting hypernatremia. However, in cases of severe hypernatremia accompanied by volume depletion, correction with isotonic saline may be useful and safe.

The following table describes therapeutic recommendations for correction of hypernatremia based on duration of hypernatremia:

(Source: Disorders of Plasma Sodium — Causes, Consequences, and Correction, N Engl J Med 2015.

The following table provides formulas to calculate the appropriate solution and rate of correction of hypernatremia:

(Source: Hypernatremia. N Engl J Med 2000.)