The recommendations for treatment of hyponatremia rely on the current understanding of the central nervous system (CNS) adaptation to an alteration in serum osmolality. In the setting of an acute fall in the serum osmolality, neuronal cell swelling occurs due to the water shift from the extracellular space to the intracellular space (ie, Starling forces). Therefore, correction of hyponatremia should take into account the limited capacity of this adaptation mechanism to respond to acute alteration in the serum tonicity, because the degree of brain edema and consequent neurologic symptoms depend as much on the rate and duration of hypotonicity as they do on its magnitude.
Intravenous fluids and water restriction
When faced with a patient with hyponatremia, the first decision is what type of fluid, if any, should be given. The treatment of hypertonic and pseudohyponatremia is directed at the underlying disorder in the absence of symptoms.
Hypotonic hyponatremia accounts for most clinical cases of hyponatremia. The first step in the approach and evaluation of hypotonic hyponatremia is to determine whether emergency therapy is warranted. Guide treatment by the 3 following factors:
- Patient’s volume status
- Duration and magnitude of the hyponatremia
- Degree and severity of clinical symptoms
For the asymptomatic patient, the following treatments may be of use:
- Hypovolemic hyponatremia: Administer isotonic saline to patients who are hypovolemic to replace the contracted intravascular volume (thereby treating the cause of vasopressin release). Patients with hypovolemia secondary to diuretics may also need potassium repletion, which, like sodium, is osmotically active. Correction of volume repletion turns off the stimulus to ADH secretion, so a large water diuresis may ensue, leading to a more rapid correction of hyponatremia than desired. If so, hypotonic fluid such as D5/ ½ normal saline may need to be administered (see below under normovolemic hyponatremia for guidelines).
- Hypervolemic hyponatremia: Treat patients who are hypervolemic with salt and fluid restriction, plus loop diuretics, and correction of the underlying condition. The use of a V2 receptor antagonist may be considered (see below).
For normovolemic (euvolemic), asymptomatic hyponatremic patients, free water restriction (< 1 L/d) is generally the treatment of choice. There is no role for hypertonic saline in these patients. Base the volume of restriction on the patient’s renal diluting capacity. For instance, a fluid restriction to 1 L/d, enough to raise the serum sodium in some patients, may exceed the renal free water excretion capacity in others, necessitating more severe restriction. This approach is recommended as initial treatment for patients with asymptomatic SIADH. However, many patients will not adhere to fluid restriction. Further, the definition of asymptomatic is changing due to the recognition that subtle but significant deficits such as in gait may be present. Therefore, pharmacologic treatment may be considered (see below).
When treating patients with overtly symptomatic hyponatremia (eg, seizures, severe neurological deficits), hypertonic (3%) saline should be used. There is no place in the initial treatment for aquaretics (see below). Note that normal saline can exacerbate hyponatremia in patients with SIADH, who may excrete the sodium and retain the water. A liter of normal saline contains 154 mEq sodium chloride (NaCl) and 3% saline has 513 mEq NaCl. Management decisions should also factor in ongoing renal free water and solute losses. Alternately, the combination of intravenous normal saline and diuresis with a loop diuretic (eg, furosemide) also elevates the serum sodium concentration. This latter approach is often useful for patients with high urine osmolality, because the loop diuretic acts to reduce urine osmolality. Concomitant use of loop diuretics increases free water excretion and decreases the risk of fluid overload.
The following equation helps to estimate an expected change in serum Na with respect to characteristics of infusates used : Change in serum Na = [(infusate Na + infusate K) – serum Na] / [Total body water +1]
During therapy, closely monitoring serum electrolytes (ie, every 2-4 h) to avoid overcorrection is essential.
Acute hyponatremia (duration < 48 h) can be safely corrected more quickly than chronic hyponatremia. A severely symptomatic patient with acute hyponatremia is in danger from brain edema. In contrast, a symptomatic patient with chronic hyponatremia is more at risk from rapid correction of hyponatremia. Correction of serum sodium that is too rapid can precipitate severe neurologic complications, such as central pontine myelinosis, which can produce spastic quadriparesis, swallowing dysfunction, pseudobulbar palsy, and mutism. A symptomatic patient with unknown duration of hyponatremia is the most challenging, warranting a prompt but controlled and limited correction of hyponatremia, until symptoms resolve. However, excessive therapy and fear of osmotic demyelination should not deter prompt and definitive treatment.
With patients who are acutely symptomatic (duration < 48 h, such as after surgery), the treatment goal is to increase the serum sodium level by approximately 1-2 mEq/L/h for 3-4 hours, until the neurologic symptoms subside or until plasma Na is over 120 mEq/L. Others recommend an even more rapid correction.
In chronic, severe symptomatic hyponatremia, the rate of correction should not exceed 0.5-1 mEq/L/h, with a total increase not to exceed 8-12 mEq/L/d and no more than 18 mEq/L in the first 48 h. It is necessary to correct the hyponatremia to a safe range (usually to no greater than 120 mEq/L) rather than to a normal value. As noted above, spontaneous diuresis secondary to ADH suppression with intravascular volume repletion could lead to unintended overcorrection.
Pharmacologic agents can be used in some cases of more refractory SIADH, allowing more liberal fluid intake. Demeclocycline has been the drug of choice to increase the diluting capacity of the kidneys, by achieving vasopressin antagonism and a functional diabetes insipidus. This treatment requires 3-4 days for maximal effect. Demeclocycline is contraindicated in cirrhotic patients. Other agents, such as lithium, have been used with variable success. Lithium is also associated with several untoward effects, including thyroid dysfunction, interstitial kidney disease, and, in overdosage, CNS dysfunction, which make its use problematic. The treatment of psychogenic polydipsia can be difficult and may require psychiatric, pharmacologic, and fluid intervention.
A new class of drugs, AVP receptor antagonists, designed specifically to promote aquaresis (ie, electrolyte-sparing excretion of free water), has been evaluated in clinical trials for the treatment of hyponatremia.[29, 30] The first agent to be approved was conivaptan, a V1A and V2 vasopressin receptor antagonist. It is available only for intravenous use and is approved for use in the hospital setting for euvolemic and hypervolemic hyponatremia. It is contraindicated in hypovolemic patients. It induces both a water and sodium diuresis with improvement in plasma sodium levels. Most of the clinical experience has been in heart failure. It is effective in raising serum sodium levels; however, conivaptan has not been shown to improve heart failure per se. Close monitoring of the rate of correction is needed and is approved for treatment for only 4 days.
In addition, the effects in patients with renal and hepatic impairment have not been well studied and caution is advised with use in this population. There are several drug interactions that need close monitoring and the use of conivaptan with CYP3A4 inhibitors is contraindicated.
Tolvaptan, a selective V2 receptor antagonist, has now been approved for use. It is available orally and has been approved for use in the treatment of euvolemic and hypervolemic hyponatremia, including those with cirrhosis and heart failure. The treatment must be initiated in the hospital to avoid the possibility of too rapid correction (although there have not been reported cases). It shows great promise but because of the requirement for hospitalization for initiation or reintroduction and the expense of the drug, its use at this time is limited. It also interacts with CYP3A inhibitors and use with such drugs is contraindicated. In April 2013, the FDA limited use of tolvaptan to no more than 30 days and indicated that it should not be used in patients with underlying liver disease. This decision was based on reports of liver injury, including those potentially leading to liver transplant or death.
The use of these new vaptans is limited and exact benefits have yet to be determined. There are reports that even mild hyponatremia can cause deficits with gait stability and possibly increase the risk of falls and hip fractures. In this setting, vaptans may be beneficial to improve hyponatremia and gait.