Approach Considerations
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 pseudo-hyponatremia 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. The following three factors guide treatment:
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Degree and severity of clinical symptoms
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Duration and magnitude of the hyponatremia
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Patient's volume status
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.
A panel of United States experts on hyponatremia issued guidelines on the diagnosis, evaluation, and treatment of hyponatremia in 2007; the guidelines were updated in 2013. [3] Additionally, in 2014, the European Society of Intensive Care Medicine, the European Society of Endocrinology, and the European Renal Association–European Dialysis and Transplant Association released guidelines on the diagnosis, classification, and treatment of true hypotonic hyponatremia. [46]
Although not completely uniform in their recommendations (see the table below), the guideline have a common aim of acute treatment of moderately and severely symptomatic patients with the goal of increasing the serum sodium concentration by about 4-6 mmol/L in the first few hours, to prevent brain herniation and neurologic damage from cerebral ischemia. [3, 46] The treatment of chronic hyponatremia focuses on avoiding overcorrection to reduce the risk of osmotic demyelination syndrome (ODS). Noting the higher risk of ODS for some patients would lower the limit on the daily correction rate. [47] Addition of desmopressin should be discussed with an expert, particularly if the patients are at high risk of developing ODS (those with a serum sodium concentration ≤105 mmol/L or those with significant hypokalemia, alcoholism, malnutrition, and advanced liver disease), have a lower baseline starting serum sodium concentration, or have undergone overly rapid correction of hyponatremia ( > 6-8 mmol/L at 24 hours or > 18 mmol/L at 48 hours).
Table. Guidelines for Management of Hyponatremia (Open Table in a new window)
United States Guidelines |
European Guidelines |
|
Symptomatic Acute Hyponatremia < 24-48 hours |
||
Urgent correction goal to aim to prevent brain herniation |
Increase serum Na+ by 4-6 mmol/L |
Increase serum Na+ by 5 mmol/L |
Treatment based on symptoms |
||
Severe symptoms |
Bolus 100 mL of 3% NaCl over 10 minutes x 3 as needed |
Bolus 150 mL of 3% NaCl over 20 minutes, 2- 3 times as needed, checking Na every 20 minutes (First-hour management, regardless of acute or chronic condition) |
Moderate symptoms with low risk of herniation |
Continuous infusion of 3% NaCl at 0.5-2 mL/kg/h |
Bolus 150 mL 3% NaCl over 20 minutes, x 1 to prevent further decrease in Na |
Limit not to exceed |
None in true acute hyponatremia |
None in true acute hyponatremia |
Chronic Hyponatremia > 48 hours |
||
Correction rate |
||
Goal in symptomatic patients using hypertonic saline |
4-8 mmol/L/d if low risk for ODS 4-6 mmol/L/d if high risk of ODS For patients with severe symptoms, the first day’s increase can be accomplished during first 6 h |
Avoid > 10 mmol/L in the first 24 h And > 8 mmol/l during every 24 h thereafter |
Limit to avoid potential harm in asymptomatic patients |
10-12 mmol/L/d, but max 18 mmol in 48 h if at low risk for ODS 8 mmol/L/d if at high risk of ODS |
10 mmol/L in the first 24 h and 8 mmol/l during every 24 h thereafter |
Managing Overcorrection of Chronic Hyponatremia |
||
Baseline serum Na+ ≥ 120 mmol/L: Intervention probably unnecessary |
Start once above mentioned limits are exceeded |
|
Baseline serum Na+ < 120 mmol/L: Replace water orally or as D5W at 3 mL/kg/h with or without desmopressin (2-4 µg every 8 h parenterally) Withhold any vasopressin receptor antagonists (vaptans) used Consider dexamethasone, 4 mg every 6 hr for 24 hr following excessive correction |
Consult an expert to discuss infusion containing electrolyte-free water (10 mL/kg) over 1 h with or without 2 µg desmopressin IV every 8 h |
|
Other Treatment Options |
||
Hypovolemic hyponatremia |
Isotonic saline |
Isotonic saline or balanced solution at 0.5-1.0 mL/kg/h |
Euvolemic hyponatremia (SIADH) |
Fluid restriction of 500 mL/d below the 24-h urine volume (first-line treatment) Urea, vaptan, or demeclocycline (second-line treatment) |
Fluid restriction (first-line) Urea or loop diuretics + oral NaCl (second-line) Do not recommend vaptans Recommend against lithium or demeclocycline |
Hypervolemic hyponatremia |
Fluid restriction, loop diuretic Vaptans |
Fluid restriction Recommend against vaptans and demeclocycine |
Medical Care
When treating patients with overtly symptomatic hyponatremia (eg, seizures, severe neurologic deficits), hypertonic (3%) saline should be used. There is no place in the initial treatment for free-water restriction or other treatment options. Note that normal saline can exacerbate hyponatremia in patients with the syndrome of inappropriate antidiuretic hormone secretion (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. During therapy, close monitoring of serum electrolytes (ie, every 2-4 h) to avoid overcorrection is essential.
The following equation helps to estimate an expected change in serum sodium (Na) with respect to characteristics of infusate used: [48]
Change in serum Na = [(infusate Na + infusate K) - serum Na] / [Total body water +1]
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. Overly rapid correction of serum sodium can precipitate severe neurologic complications, such as ODS, 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, fear of ODS should not deter prompt and definitive treatment of symptomatic patient.
In patients with symptomatic acute hyponatremia (duration < 48 h, such as after surgery), the treatment goal is to increase the serum sodium level by approximately 4-6 mEq/L/h to prevent brain herniation or until the neurologic symptoms subside. [49] In contrast, in chronic symptomatic hyponatremia, the rate of correction should not exceed 4-6 or 4-8 mEq/L/d, depending on the ODS risk. Guidelines recommend no more than 18 mEq/L in the first 48 h. The sodium concentration must be corrected to a safe range (usually to no greater than 120 mEq/L) rather than to a normal value. As noted before, spontaneous diuresis secondary to ADH suppression with intravascular volume repletion could lead to unintended overcorrection.
Overly rapid correction of chronic hyponatremia (> 48 hours) could result in ODS. Although extremely rare in patients with plasma sodium > 120 mEq/L, the incidence may be as high as 50% in patients with plasma sodium < 105 mEq/L. It is the magnitude of daily plasma sodium rise rather than the hourly correction rate that is critical for the development of demyelination. In a large cohort of patients, overcorrection of > 8 mEq/L over a 24-hour period) was associated with the development of ODS. [47]
For patients with the SIADH, the United States guidelines recommend fluid restriction (with a goal of 500 mL/d below the 24-hour urine volume) as the general first-line therapy, but pharmacologic treatment should be strongly considered if the patient's urinary parameters indicate low renal electrolyte-free water excretion or if the serum sodium concentration does not correct after 24-48 hours of fluid restriction. Pharmacologic options include demeclocycline (off label use), urea, and vasopressin receptor antagonists (vaptans). Vaptans should not be used in hypovolemic hyponatremia, or in conjunction with other treatments for hyponatremia. [3] If vaptans are used, maintain ad libitum fluid intake during the first 24-48 hours of treatment.
Similarly, the European guidelines recommend that the first-line treatment for patients with SIADH and moderate or profound hyponatremia should be fluid restriction; second-line treatments should include increasing solute intake with 0.25–0.50 g/kg per day of urea or combined treatment of low-dose loop diuretics and oral sodium chloride. [46] In contrast to US guidelines, the European guidelines do not recommend demeclocycline or vaptans for treatment of patients with SIADH.
Consultation with either a nephrologist or a critical care specialist is often of considerable value in managing patients with symptomatic, refractory hyponatremia or overcorrection of chronic hyponatremia.
For the asymptomatic patient, the treatment options below may be of use.
Hypovolemic hyponatremia: For patients with reduced circulating volume, extracellular volume should be restored with an intravenous infusion of 0.9% saline or a balanced crystalloid solution at 0.5 to 1.0 mL/kg per hour to suppress the cause of physiologic vasopressin release. Patients with hypovolemia secondary to diuretics may also need potassium repletion; potassium, 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, electrolyte-free water orally or as an infusion (dextrose 5% in water [D5W]) with or without demopressin may need to be administered (see the table in Approach Considerations for guideline recommendations). [50]
Hypervolemic hyponatremia: Treat patients who are hypervolemic with fluid restriction plus loop diuretics, and correction of the underlying condition. Alternatively, the combination of intravenous normal saline and diuresis with a loop diuretic (eg, furosemide) will also elevate 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 use of a vaptan may be considered (see table for guidelines).
For normovolemic (euvolemic) asymptomatic hyponatremic patients, free water restriction 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, fluid restriction to 1 L/d, which is 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.
The addition of oral sodium chloride and loop diuretic to fluid restriction has been suggested as a second-line treatment option but this combination does not seem to be any more effective than fluid restriction alone. [51] Further, the definition of asymptomatic is changing due to the recognition that subtle but significant deficits, such as in gait, may be present, which could possibly increase the risk of falls and hip fractures. Therefore, pharmacologic treatment may be considered.
Pharmacologic treatment
Pharmacologic agents can be used in some cases of more refractory SIADH, allowing more liberal fluid intake. Demeclocycline can 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.
Aquaretics
The use of vaptans is limited and exact benefits have yet to be determined. 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. [52, 53, 54] 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.
Most of the clinical experience with conivaptan 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 conivaptan is approved for treatment for only 4 days. In addition, the effects in patients with kidney and liver impairment have not been well studied, so 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, can be taken orally and has been approved for use in the treatment of euvolemic and hypervolemic hyponatremia, including cases associated with cirrhosis and heart failure. Tolvaptan treatment must be initiated in the hospital to avoid the possibility of rapid correction. Because of the requirement for hospitalization for initiation or reintroduction and the expense of the drug, its use is limited. It also interacts with CYP3A inhibitors and use with such drugs is contraindicated. In 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 the need for liver transplantation or to death. [55]
Diet
Free water restriction often is appropriate for patients with normovolemic hypotonic hyponatremia.
Individuals who are undernourished need to maintain an appropriate solute intake, because a high protein diet increases the urinary solute excretion and respectively the obligatory urinary free water excretion. New oral urea formula can be used to achieve the same effect.
Patients with hyperglycemia or hyperlipidemia should receive appropriate nutritional counseling in the setting of pseudo-hyponatremia.
Tables
United States Guidelines |
European Guidelines |
|
Symptomatic Acute Hyponatremia < 24-48 hours |
||
Urgent correction goal to aim to prevent brain herniation |
Increase serum Na+ by 4-6 mmol/L |
Increase serum Na+ by 5 mmol/L |
Treatment based on symptoms |
||
Severe symptoms |
Bolus 100 mL of 3% NaCl over 10 minutes x 3 as needed |
Bolus 150 mL of 3% NaCl over 20 minutes, 2- 3 times as needed, checking Na every 20 minutes (First-hour management, regardless of acute or chronic condition) |
Moderate symptoms with low risk of herniation |
Continuous infusion of 3% NaCl at 0.5-2 mL/kg/h |
Bolus 150 mL 3% NaCl over 20 minutes, x 1 to prevent further decrease in Na |
Limit not to exceed |
None in true acute hyponatremia |
None in true acute hyponatremia |
Chronic Hyponatremia > 48 hours |
||
Correction rate |
||
Goal in symptomatic patients using hypertonic saline |
4-8 mmol/L/d if low risk for ODS 4-6 mmol/L/d if high risk of ODS For patients with severe symptoms, the first day’s increase can be accomplished during first 6 h |
Avoid > 10 mmol/L in the first 24 h And > 8 mmol/l during every 24 h thereafter |
Limit to avoid potential harm in asymptomatic patients |
10-12 mmol/L/d, but max 18 mmol in 48 h if at low risk for ODS 8 mmol/L/d if at high risk of ODS |
10 mmol/L in the first 24 h and 8 mmol/l during every 24 h thereafter |
Managing Overcorrection of Chronic Hyponatremia |
||
Baseline serum Na+ ≥ 120 mmol/L: Intervention probably unnecessary |
Start once above mentioned limits are exceeded |
|
Baseline serum Na+ < 120 mmol/L: Replace water orally or as D5W at 3 mL/kg/h with or without desmopressin (2-4 µg every 8 h parenterally) Withhold any vasopressin receptor antagonists (vaptans) used Consider dexamethasone, 4 mg every 6 hr for 24 hr following excessive correction |
Consult an expert to discuss infusion containing electrolyte-free water (10 mL/kg) over 1 h with or without 2 µg desmopressin IV every 8 h |
|
Other Treatment Options |
||
Hypovolemic hyponatremia |
Isotonic saline |
Isotonic saline or balanced solution at 0.5-1.0 mL/kg/h |
Euvolemic hyponatremia (SIADH) |
Fluid restriction of 500 mL/d below the 24-h urine volume (first-line treatment) Urea, vaptan, or demeclocycline (second-line treatment) |
Fluid restriction (first-line) Urea or loop diuretics + oral NaCl (second-line) Do not recommend vaptans Recommend against lithium or demeclocycline |
Hypervolemic hyponatremia |
Fluid restriction, loop diuretic Vaptans |
Fluid restriction Recommend against vaptans and demeclocycine |
