Practice Essentials
Hyponatremia—defined as a serum sodium concentration of less than 135 mEq/L—is the most commonly encountered and important electrolyte imbalance that can be seen in isolation or, as is most often the case, as a complication of other medical illnesses (eg, heart failure, liver failure, kidney failure, pneumonia, cancer). [1, 2] The normal serum sodium concentration is 135-145 mEq/L. Hyponatremia is classified in adults according to serum sodium concentration, as follows [3] :
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Mild: 130-134 mmol/L
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Moderate: 125-129 mmol/L
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Profound or severe: < 125 mmol/L
Correction of hyponatremia varies according to its source, its severity, and its duration. In patients whose hyponatremia has a known duration of > 48 hours, treatment must be calibrated to avoid osmotic demyelination syndrome (ODS), which may result from overly rapid correction.
Signs and symptoms
Symptoms range from nausea and malaise, in those with mild reduction in the serum sodium, to lethargy, decreased level of consciousness, headache, and (with severe hyponatremia) seizures and coma. Overt neurologic symptoms most often are due to very low serum sodium levels (usually < 115 mEq/L), resulting in intracerebral osmotic fluid shifts and brain edema.
Hyponatremia can be classified according to effective osmolality, as follows:
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Hypertonic hyponatremia
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Isotonic hyponatremia
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Hypotonic hyponatremia – typically considered true hyponatremia
Hypotonic hyponatremia can be further subclassified according to volume status, as follows:
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Hypervolemic hyponatremia: Increase in total body sodium with greater increase in total body water
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Euvolemic hyponatremia: Normal body sodium with increase in total body water
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Hypovolemic hyponatremia: Decrease in total body water with greater decrease in total body sodium
See Presentation for more detail.
Diagnosis
Three laboratory tests—serum osmolality, urine osmolality, and urinary sodium concentration—are essential in the evaluation of patients with hyponatremia. Together with the history and the physical examination, those tests help to establish the primary underlying etiologic mechanism in an algorithmic fashion.
Serum osmolality
Serum osmolality readily differentiates between true hyponatremia (hypotonic hyponatremia) and pseudohyponatremia. The latter may be secondary to hyperlipidemia or hyperproteinemia (isotonic hyponatremia), or may be hypertonic hyponatremia associated with elevated glucose, mannitol, glycine (posturologic or postgynecologic procedure), sucrose, or maltose (contained in IgG formulations).
Urine osmolality
Urine osmolality helps differentiate between conditions associated with the presence or absence of antidiuretic hormone (ADH), also called arginine vasopressin. A dilute urine (urinary osmolality < 100 mOsm/kg) and hypotonic hyponatremia generally results from conditions that overwhelm the kidney’s capacity to excrete free water (as in primary polydipsia) or conditions that truncate the amount of free water that can be excreted, typically due to low solute load (as in tea and toast diet). A urine osmolality greater than 100 mOsm/kg indicates impaired ability of the kidneys to dilute the urine, usually due to physiologic or non-physiologic secretion of ADH. Some uncommon conditions may have either low or high urinary osmolality, depending on the treatment initiated.
Urinary sodium concentration
Urinary sodium concentration helps to differentiate between hyponatremia secondary to hypovolemia and syndrome of inappropriate antidiuretic hormone secretion (SIADH). In SIADH and salt-wasting syndrome the urine sodium is greater than 20-40 mEq/L. In hypovolemia, the urine sodium typically measures less than 20 mEq/L. However, if sodium intake in a patient with SIADH or salt-wasting happens to be low, then urine sodium may fall below 20 mEq/L.
See Workup for more detail.
Management
Hypotonic hyponatremia accounts for most clinical cases of hyponatremia and can be treated with fluid restriction. The treatment of hypertonic hyponatremia and pseudo-hyponatremia is directed at the underlying disorder, in the absence of symptoms.
Acute hyponatremia (duration < 48 hours) can be safely corrected more quickly than chronic hyponatremia. The rate of correction for chronic hyponatremia (duration of > 48 hours or unknown) should be tailored according to the severity of the hyponatremia so as to avoid overcorrection and risk of ODS, but should be limited to 4-8 mEq/L per 24 hours.
Intravenous fluids and water restriction
Patients with overt symptoms (eg, seizures, severe neurologic deficits) and generally those with severe hyponatremia should be treated with hypertonic (3%) saline bolus to increase serum sodium concentration and mitigate their symptoms. In patients with moderate symptoms, a slow infusion of hypertonic saline can be considered. Patients who are asymptomatic or have mild symptoms, will rarely require hypertonic saline.
Administer isotonic saline to patients who are hypovolemic to replace the contracted intravascular volume. Patients with hypovolemia secondary to diuretics may also need potassium repletion. Note that potassium, like sodium, is osmotically active.
Treat patients who are hypervolemic with fluid restriction, with or without loop diuretics, and correction of the underlying condition. The use of a vasopressin V2 receptor antagonist may be considered as second-line therapy.
For euvolemic, asymptomatic hyponatremic patients, free-water restriction is generally the treatment of choice. There is no role for hypertonic saline in these patients.
Pharmacologic treatment
Two vasopressin receptor antagonists, conivaptan (Vaprisol) and tolvaptan (Samsca), are approved for treatment of euvolemic and hypervolemic hyponatremia.
Conivaptan, a V1A and V2 vasopressin receptor antagonist, 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.
Tolvaptan, a selective oral vasopressin V2-receptor antagonist is indicated for hypervolemic and euvolemic hyponatremia. It can be used for hyponatremia associated with congestive heart failure and SIADH and must be initiated or reinitiated in hospital environment.
Additional options include the following:
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Oral urea is an osmotic agent that can increase obligatory free-water excretion.
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Sodium chloride tablets, when used with loop diuretics, can enhance water excretion.
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Loop diuretics can be used in hypervolemic hyponatremia to increase free water excretion.
See Treatment and Medication for more detail.
Pathophysiology
Hypo-osmolality (serum osmolality < 275 mOsm/kg) always indicates excess total body water relative to body solutes or excess water relative to solute in the extracellular fluid (ECF), as water moves freely between the intracellular and the extracellular compartments. This imbalance can be due to solute depletion, solute dilution, or a combination of both.
Under normal conditions, renal handling of water is sufficient to excrete as much as 15-20 L of free water per day. Further, the body's response to a decreased osmolality is decreased thirst. Thus, hyponatremia can occur only when some condition impairs normal free-water excretion. [4]
Generally, hyponatremia is of clinical significance when it reflects a drop in the serum osmolality (ie, hypotonic hyponatremia), which is measured directly via osmometry or is calculated as 2(Na) mEq/L + serum glucose (mg/dL)/18 + BUN (mg/dL)/2.8. Note that urea is not an ineffective osmole, so when the urea levels are very high (as seen in azotemia, the measured osmolality should be corrected for the contribution of urea (measured serum osmolality – BUN (mg/dL)/2.8).
The recommendations for treatment of hyponatremia rely on the current understanding of central nervous system (CNS) adaptation to an altered serum osmolality. [5] In the setting of an acute drop in the serum osmolality, neuronal cell swelling occurs due to the water shift from the extracellular space to the intracellular space (ie, Starling forces). Swelling of the brain cells elicits the following two osmoregulatory responses:
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It inhibits both arginine vasopressin secretion from neurons in the hypothalamus and hypothalamic thirst center. This leads to excess water elimination as dilute urine.
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There is an immediate cellular adaptation with loss of electrolytes, and over the next few days, a more gradual loss of organic intracellular osmolytes. [6]
Therefore, correction of hyponatremia must take into account the chronicity of the condition. Acute hyponatremia (duration < 48 h) can be corrected more quickly than chronic hyponatremia. Most individuals who present with symptomatic hyponatremia, versus individuals who develop hyponatremia in an inpatient setting, have had hyponatremia for some time, so their condition is chronic, and correction should proceed accordingly. Overly rapid correction of serum sodium levels in these individuals can precipitate a severe neurologic complication, ODS. Consequently, when the duration of hyponatremia is uncertain, the condition should be considered chronic.
Epidemiology
United States
The incidence of hyponatremia depends largely on the patient population and the criteria used to establish the diagnosis. Among hospitalized patients, 15-20% have a serum sodium level of < 135 mEq/L, while only 1-4% have a serum sodium level of less than 130 mEq/L. The prevalence of hyponatremia is lower in the ambulatory setting.
The US armed forces reported 1579 incident diagnoses of exertional hyponatremia among active service members from 2003 through 2018, for a crude overall incidence rate of 7.2 cases per 100,000 person-years. Cases occurred both in training facilities and theaters of war. Diagnosis and treatment without hospitalization was accomplished in 86.3% of cases. [7]
Mortality/morbidity
Severe hyponatremia (< 125 mEq/L) has a high mortality rate. In patients whose serum sodium level falls below 105 mEq/L, and especially in alcoholics, the mortality is over 50%. [8]
In patients with acute ST-elevation myocardial infarction (MI), the presence of hyponatremia on admission or early development of hyponatremia is an independent predictor of 30-day mortality, and the prognosis worsens with the severity of hyponatremia. [9] In hospitalized survivors of acute MI, the presence of hyponatremia at discharge is an independent predictor of 12-month mortality. [10]
Similarly, cirrhotic patients with persistent ascites and a low serum sodium level who are awaiting transplant have a high mortality risk despite low- severity Model for End-Stage Liver Disease (MELD) scores (see the MELD Score calculator). The independent predictors—ascites and hyponatremia—are findings indicative of hemodynamic decompensation. [11, 12, 13]
In patients with chronic kidney disease, hyponatremia and hypernatremia are associated with an increased risk for all-cause mortality and for deaths unrelated to cardiovascular problems or malignancy. Hyponatremia is also linked to an increased risk for cardiovascular- and malignancy-related mortality in these patients. [14]
Race-, sex-, and age-related demographics
Hyponatremia affects all races.
No sexual predilection exists for hyponatremia. However, symptoms are more likely to occur in young women than in men. Hyponatremia is more common in elderly persons partially because of higher rate of comorbid conditions (eg, heart, liver, or kidney failure) that can lead to hyponatremia.
Tables
United States Guidelines |
European Guidelines |
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Symptomatic Acute Hyponatremia < 24-48 hours |
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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 |
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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 |
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Correction rate |
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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 |
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Baseline serum Na+ ≥ 120 mmol/L: Intervention probably unnecessary |
Start once above mentioned limits are exceeded |
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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 |
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Other Treatment Options |
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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 |
