eMedicine Specialties > Nephrology > Acid-Base, Fluid, and Electrolyte Disorders

Hyponatremia

Eric E Simon, MD, Associate Professor, Department of Medicine, Tulane University School of Medicine; Co-Director of Nephrology Training, Medical Director, Dialysis Clinic, Inc
Seyed Mehrdad Hamrahian, MD, Staff Nephrologist, Ochsner Medical Center

Updated: May 29, 2009

Introduction

Background

Hyponatremia is an important and common electrolyte abnormality that can be seen in isolation or, as most often is the case, as a complication of other medical illnesses.

Sodium is the dominant extracellular cation and cannot freely cross the cell membrane. Its homeostasis is vital to the normal physiologic function of cells. The normal serum sodium level is 135-145 mEq/L. Hyponatremia is defined as a serum level of less than 135 mEq/L and is considered severe when the serum level is below 125 mEq/L.

This article reviews the epidemiology, pathophysiology, differential diagnosis, evaluation, and treatment of this disorder.

Pathophysiology

Hypoosmolality (serum osmolality <260 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 compartment and the extracellular compartment. This imbalance can be due to solute depletion, solute dilution, or a combination of both.

In the normal condition, renal handling of water is sufficient to excrete as much as 15-20 L of free water per day. Further, in the normal condition, the body's response to a decreased osmolality is decreased thirst. Thus, hyponatremia can occur only when some condition impairs normal free water excretion.^{[1 ]}Generally, hyponatremia is of clinical significance only 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.

The recommendations for treatment of hyponatremia rely on the current understanding of CNS adaptation to an alteration in serum osmolality. 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, Frank Starling forces). Swelling of the brain cells elicits the following 2 osmoregulatory responses:

• It inhibits both arginine vasopressin secretion from neurons in the hypothalamus and hypothalamic thirst center. This leads to excess water elimination as dilute urine.
• There is an immediate cellular adaptation with loss of electrolytes, and over the next few days, there is a more gradual loss of organic intracellular osmolytes.^{[2 ]}

Therefore, correction of hyponatremia must take into account the chronicity of the condition. Acute hyponatremia (duration <48h) can be safely corrected more quickly than chronic hyponatremia. Correction of serum sodium that is too rapid can precipitate severe neurologic complications. Most individuals who present for diagnosis, versus individuals who develop it while in an inpatient setting, have had hyponatremia for some time, so the condition is chronic, and correction should proceed accordingly.

Frequency

United States

The incidence of hyponatremia depends largely on the patient population and the criteria used to establish the diagnosis. A hospital incidence of 15-20% is common (defined as a serum sodium level of <135 mEq/L), while only 3-5% of patients who are hospitalized have a serum sodium level of less than 130 mEq/L. Hyponatremia's prevalence is lower in the ambulatory setting.

Mortality/Morbidity

Severe hyponatremia (<125 mEq/L) has a high mortality rate; for instance, when the serum sodium level is less than 105 mEq/L, the mortality is over 50%, especially in alcoholics.^{[3 ]}In patients with acute ST-elevation myocardial infarction, 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.^{[4 ]}Similarly, cirrhotic patients with persistent ascites and a low serum sodium level awaiting transplant have a high mortality risk despite low severity (MELD) scores. The independent predictors ascites and hyponatremia are findings indicative of hemodynamic decompensation.^{[5,6 ]}

Race

Hyponatremia affects all races.

Sex

No sexual predilection exists for hyponatremia. However, symptoms are more likely to occur in young women than in men.

Age

Hyponatremia is more common in elderly persons, because they have an increased incidence of comorbid conditions (eg, cardiac, hepatic, or renal failure) that can be complicated by it.

Clinical

History

• Patients may present to medical attention owing to symptoms directly referable to low serum sodium concentrations. However, many patients present due to manifestations of other medical comorbidities, with hyponatremia being recognized only secondarily. For many people, therefore, the recognition is entirely incidental.
  • Patients may develop clinical symptoms due to the cause of hyponatremia or the hyponatremia itself.
  • Many medical illnesses, such as congestive heart failure, liver failure, renal failure, or pneumonia, may be associated with hyponatremia. These patients frequently present because of primary disease symptomatology (eg, dyspnea, jaundice, uremia, cough).
  • Symptoms range from nausea and malaise, with mild reduction in the serum sodium, to lethargy, a decreased level of consciousness, headache, and (if severe) seizures and coma. 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. This neurologic symptom complex can lead to tentorial herniation with subsequent brain stem compression and respiratory arrest, resulting in death in the most severe cases.
• The severity of neurologic symptoms correlates well with the rapidity and severity of the drop in serum sodium. A gradual drop in serum sodium, even to very low levels, may be tolerated well if it occurs over several days or weeks, because of neuronal adaptation. The presence of an underlying neurologic disease, like a seizure disorder, or nonneurologic metabolic abnormalities, like hypoxia, hypercapnia, or acidosis, also affects the severity of neurologic symptoms.
• In interviewing the patient, obtaining a detailed medication history, including information on over-the-counter (OTC) drugs the patient has been using, is important, because many medications may precipitate hyponatremia (eg, antipsychotic medications). A dietary history with reference to salt, protein, and water intake is useful as well. For patients who are hospitalized, reviewing the records of parenteral fluids administered is crucial.

Physical

• Examination should include orthostatic vital signs and an accurate assessment of volume status. This determination (ie, hypervolemic, euvolemic, hypovolemic) often guides treatment decisions.
• A full assessment for medical comorbidity also is essential, with particular attention paid to cardiopulmonary and neurologic components of the examination.

Causes

Although the differential diagnosis is quite broad, hyponatremia can be divided into the following clinically useful groupings:

• Hypertonic hyponatremia: Patients with hypertonic hyponatremia have normal total body sodium and a dilutional drop in the measured serum sodium due to the presence of osmotically active molecules in the serum, which cause a water shift from the intracellular compartment to the extracellular compartment.
  • Glucose produces a drop in the serum sodium level of 1.6 mEq/L for each 100 mg/dL of serum glucose greater than 100 mg/dL. This relationship is nonlinear, with greater reduction in plasma sodium concentrations with glucose concentrations over 400 mg/dL, making 2.4 mEq/L for each 100 mg/dL increase in glucose over 100 mg/dL a more accurate correction factor when the glucose is greater than 400 mg/dL.^{[7 ]}
  • Other examples of osmotically active molecules include mannitol (often used to treat brain edema) or maltose (used with intravenous immunoglobulin administration).
• Normotonic hyponatremia: Severe hyperlipidemia and paraproteinemia can lead to low measured serum sodium concentrations with normal serum osmolality. Normally, the plasma water comprises 92-94% of plasma volume. The plasma water fraction falls with an increase in fats and proteins. The measured sodium concentration in the total plasma volume is respectively reduced, although the plasma water sodium concentration and plasma osmolality are unchanged. This artifactually low sodium (so-called pseudohyponatremia) is secondary to measurement by flame photometry. It can be avoided by direct ion-selective electrode measurement.
• Hyponatremia posttransurethral resection of the prostate (TURP) or hysteroscopy is caused by absorption of irrigants, glycine, sorbitol, or mannitol, contained in nonconductive flushing solutions used. The degree of hyponatremia is related to the quantity and the rate of fluid absorbed. The plasma osmolality is also variable and changes over time.
  • The presence of a relatively large osmolal gap due to the excess organic solute is diagnostic in the appropriate clinical setting. Symptomatic patients are treated depending on plasma osmolality and volume status of patients with either hypertonic saline in hypoosmolar state or loop diuretic in volume-overloaded patients with normal renal function.
  • Hemodialysis, which will correct the hyponatremia and remove glycine and its toxic metabolites, can be used in patients with end-stage renal disease. Use of isotonic saline as an irrigant instead of glycine with the new bipolar resectoscope for TURP in high-risk patients (with large prostates that require lengthy resection) could avoid this complication, making this disorder a diagnosis of the past.^{[8 ]}
• Hypotonic hyponatremia: Hypotonic hyponatremia always reflects the inability of the kidneys to handle the excretion of free water to match oral intake. It can be divided pathophysiologically into the following categories, according to the effective intravascular volume: hypovolemic, hypervolemic, and euvolemic. These clinically relevant groupings aid in determination of likely underlying etiology and guiding treatment.
  • Hypovolemic hypotonic hyponatremia: This usually indicates concomitant solute depletion, with patients presenting with orthostatic symptoms. The pathophysiology underlying hypovolemic hypotonic hyponatremia is complex and involves the interplay of carotid baroreceptors, the sympathetic nervous system, the renin-angiotensin system, antidiuretic hormone (ADH) secretion (vasopressin), and renal tubular function. In the setting of decreased intravascular volume (eg, severe hemorrhage or severe volume depletion secondary to GI or renal loss, or diuretic use) owing to a decreased stretch on the baroreceptors in the great veins, aortic arch, and carotid bodies, an increased sympathetic tone to maintain systemic blood pressure generally occurs.
  • This increased sympathetic tone, along with decreased renal perfusion secondary to intravascular volume depletion, results in increased renin and angiotensin excretion. This, in turn, results in increased sodium absorption in the proximal tubules of the kidney and consequent decreased delivery of solutes to distal diluting segments, causing an impairment of renal free water excretion. There also is a concomitant increase in serum ADH production that further impairs free water excretion. Because angiotensin is also a very potent stimulant of thirst, free water intake is increased, and, at the same time, water excretion is limited. Together, these changes lead to hyponatremia.
  • Cerebral salt wasting (CSW) is seen with intracranial disorders, such as subarachnoid hemorrhage, carcinomatous or infectious meningitis, and metastatic carcinoma, but especially after neurologic procedures. Disruption of sympathetic neural input into the kidney, which normally promotes salt and water reabsorption in the proximal nephron segment through various indirect and direct mechanisms, might cause renal salt wasting, resulting in reduced plasma volume. Plasma renin and aldosterone levels fail to rise appropriately in patients with CSW despite a reduced plasma volume because of disruption of the sympathetic nervous system. In addition, the release of 1 or more natriuretic factors could also play a role in the renal salt wasting seen in CSW. Volume depletion leads to an elevation of plasma vasopressin levels and impaired free water excretion.
  • Distinguishing between CSW and syndrome of inappropriate ADH secretion (SIADH) can be challenging, because there is considerable overlap in the clinical presentation. Vigorous salt replacement is required in patients with CSW, whereas fluid restriction is the treatment of choice in patients with SIADH. Infusion of isotonic saline to correct the volume depletion is usually effective in reversing the hyponatremia in cerebral salt wasting, since euvolemia will suppress the release of ADH. The disorder is usually transient, with resolution occurring within 3-4 weeks of disease onset.^{[9,10 ]}
  • Salt-wasting nephropathy causing hypovolemic hyponatremia may rarely develop in a range of renal disorders (eg, interstitial nephropathy, medullary cystic disease, polycystic kidney disease, partial urinary obstruction) with low salt intake.
  • The treatment of choice for hypovolemic hypotonic hyponatremia is saline infusion.
  • Hypervolemic hypotonic hyponatremia: This is characterized by clinically detectable edema or ascites that signifies an increase in total body water and sodium. Paradoxically, however, a decrease in the effective circulating volume, critical for tissue perfusion, stimulates the same pathophysiologic mechanism of impaired water excretion by the kidney that is observed in hypovolemic hypotonic hyponatremia.
  • Commonly encountered examples include liver cirrhosis, congestive heart failure, nephrotic syndrome, and severe hypoproteinemia (albumin level <1.5-2 g/dL).
  • The treatment of these patients is usually limited to free water restriction and diuresis to induce negative water balance.
  • Patients with renal failure and hyponatremia may have normal or high plasma osmolality because of the urea retention. However, as urea is not an effective osmole, the patient should be treated as per hypotonic hyponatremia.
  • Normovolemic (euvolemic) hypotonic hyponatremia: This is a very common cause of hyponatremia in patients who are hospitalized. It is associated with nonosmotic and nonvolume related vasopressin (ADH) secretion (ie, SIADH) secondary to a variety of clinical conditions, including CNS disturbances, major surgery, trauma, pulmonary tumors, infection, stress, and certain medications.
  • Common medications associated with SIADH are as follows: chlorpropamide (potentiating renal action of ADH), carbamazepine (possesses antidiuretic property), cyclophosphamide (marked water retention secondary to SIADH and potentially fatal hyponatremia may ensue in selected cases; use of isotonic saline rather than free water to maintain a high urine output to prevent hemorrhagic cystitis can minimize the risk), vincristine, vinblastine, amitriptyline, haloperidol, selective serotonin reuptake inhibitors (particularly in elderly patients), and monoamine oxidase (MAO) antidepressants. In these circumstances, the ability of the kidney to dilute urine in the setting of serum hypotonicity is reduced.
  • Diuretics may induce hypovolemic hyponatremia. Note that thiazide diuretics, in contrast to loop diuretics, impair the diluting mechanism without limiting the concentrating mechanism, thereby impairing the ability to excrete a free water load. Thus, thiazides are more prone to causing hyponatremia than are loop diuretics.
  • Hyponatremia is a relatively common adverse effect of desmopressin, a vasopressin analogue that acts as a pure V2 agonist. Its common use in the treatment of central diabetes insipidus, von Willebrand disease, and nocturia in adults and of enuresis in children requires regular monitoring of serum sodium levels.
  • The diagnostic criteria for SIADH are as follows:
    • Normal hepatic, renal, and cardiac function - Clinical euvolemia (absence of intravascular volume depletion)
    • Normal thyroid and adrenal function
    • Hypotonic hyponatremia
    • Urine osmolality greater than 100 mOsm/kg, generally greater than 400-500 mOsm/kg with normal renal function
  • Urinary sodium concentrations are also typically greater than 20 mEq/L on a normal salt diet. Serum uric acid levels are generally reduced; this is due to reduced tubular uric acid reabsorption, which parallels the decrease in proximal tubular sodium reabsorption associated with central volume expansion.
  • Reset osmostat is another important cause of normovolemic hypotonic hyponatremia. This may occur in elderly patients and during pregnancy. These patients regulate their serum osmolality around a reduced set point; however, in contrast to patients with SIADH (who also have a downward resetting of the osmotic threshold for thirst),^{[11 ]}they are able to dilute their urine in response to a water load to keep the serum osmolality around the preset low point.
  • Severe hypothyroidism (unknown mechanism, possibly secondary to low cardiac output and glomerular filtration rate) and adrenal insufficiency are also associated with nonosmotic vasopressin release and impaired sodium reabsorption, leading to hypotonic hyponatremia. Hyponatremia associated with cortisol deficiency, such as primary or secondary hypoadrenalism, commonly presents subtly and may go undiagnosed. A random cortisol level check, especially in acute illness, can be misleading if the level is normal (when it should be high). Testing for adrenal insufficiency and hypothyroidism should be part of the hyponatremic workup, as the disorders respond promptly to hormone replacement. Depending on the etiology, mineralocorticoid will also need replacement.
  • Severe malnutrition seen in weight-conscious women (low protein, high water intake diet) is a special condition in which a markedly decreased intake of solutes occurs, which limits the ability of the kidney to handle the free water. Because a mandatory solute loss of 50-100 mOsm/kg of urine exists, free water intake in excess of solute needs can produce hyponatremia.^{[12 ]}Another example is beer drinker's potomania, because a diet consisting primarily of beer is rich in free water but solute poor.
  • Compulsive intake of large amounts of free water exceeding the dilutional capacity of the kidneys (>20 L/d), even with a normal solute intake of 600-900 mOsm/d, may also result in hyponatremia, but in contrast to SIADH, the urine is maximally dilute. In addition to a central defect in thirst regulation, which plays an important role in the pathogenesis of primary polydipsia, different abnormalities in ADH regulation have been identified in psychotic patients, all impairing free water excretion. Transient stimulation of ADH release during acute psychotic episodes, an increase in the net renal response to ADH, downward resetting of the osmostat, and antipsychotic medication may contribute. Limiting water intake will rapidly raise the plasma sodium concentration as the excess water is readily excreted in dilute urine.^{[13 ]}
  • Hospitalized patients who are infected with human immunodeficiency virus (HIV) have a high incidence of hyponatremia. In these individuals, hyponatremia is usually due to at least 1 of the following 3 disorders associated with an increased ADH level:
    • Increased release of ADH due to malignancy, to occult or symptomatic infection of the central nervous system, or to pneumonia resulting from infection with Pneumocystis carinii or other organisms.
    • Effective volume depletion secondary to fluid loss from the gastrointestinal tract, due primarily to infectious diarrhea.
    • Adrenal insufficiency often due to an adrenalitis, an abnormality that may be infectious in origin, perhaps being induced by cytomegalovirus, Mycobacterium avium-intracellulare, or HIV itself. Affected patients have a high risk of morbidity and mortality.
  • Treatment generally is that of the underlying cause and free water restriction.
  • The most common precipitant of hyponatremia in patients after surgery^{[14 ]}is the iatrogenic infusion of hypotonic fluids. Inappropriate administration of hypotonic intravenous fluids after surgery increases the risk of developing hyponatremia in these vulnerable patients, who retain water due to nonosmotic release of ADH, which is typically elevated for a few days after most surgical procedures. Hospital-acquired acute hyponatremia is disturbingly common also among hospitalized children and adults.
  • Acute hyponatremia is associated with ultra-endurance athletes and marathon runners. With women making up a higher percentage, the strongest single predictor is weight gain during the race correlating with excessive fluid intake. Longer racing time and body mass index extremes are also associated with hyponatremia, whereas the composition of fluids consumed (plain water rather than sports drinks containing electrolytes) is not. Oxidization of glycogen and triglyceride during a race is associated with the production of "bound" water, which then becomes an endogenous, electrolyte-free water infusion contributing to hyponatremia induced by water ingestion in excess of water losses.
  • Nonsteroidal anti-inflammatory drug (NSAID) use may increase the risk of development of hyponatremia by strenuous exercise by inhibiting prostaglandin formation. Prostaglandins have a natriuretic effect. Prostaglandin depletion increases NaCl reabsorption in the thick ascending limb of Henle (ultimately increasing medullary tonicity) and ADH action in the collecting duct, leading to impaired free water excretion.^{[15 ]}
  • Some collapsed runners are normonatremic or even hypernatremic,^{[16 ]}making blanket recommendations difficult. However, fluid intake to the point of weight gain should be avoided.^{[16,17 ]}Athletes should rely on thirst as their guide for fluid replacement and avoid fixed, global recommendations for water intake. Symptomatic hyponatremic patients should receive 100 mL of 3% sodium chloride over 10 minutes in the field before transportation to hospital. This maneuver should raise the plasma sodium concentration an average of 2-3 mEq/L.^{[18 ]}
  • Symptomatic and potentially fatal hyponatremia can develop with rapid onset after ingestion of the designer drug ecstasy (methylenedioxymethamphetamine, or MDMA), an amphetamine. A marked increase in water intake via direct thirst stimulation, as well as inappropriate secretion of ADH, contributes to the hyponatremia seen with even small amount of drug intake.
  • Nephrogenic syndrome of inappropriate antidiuresis (or NSIAD) is an SIADH-like clinical and laboratory picture seen in male infants who present with neurologic symptoms secondary to hyponatremia but who have undetectable plasma arginine vasopressin (AVP) levels. This hereditary disorder is secondary to mutations in the V2 vasopressin receptor, resulting in constitutive activation of the receptor with elevated cAMP production in the collecting duct principle cells. Treatment of NSIAD poses a challenge. Water restriction improves serum sodium levels and osmolality in infants, but it limits calorie intake in these formula-fed infants. The use of demeclocycline or lithium is potentially limited because of adverse effects. The current therapy of choice is fluid restriction and the use of urea to induce an osmotic diuresis.^{[19 ]}
  • Hyponatremic hypertensive syndrome, a rare condition, consists of severe hypertension associated with renal artery stenosis, hyponatremia, hypokalemia, severe thirst, and renal dysfunction characterized by natriuresis, hypercalciuria, renal glycosuria, and proteinuria. Angiotensin-mediated thirst coupled with nonosmotic release of vasopressin provoked by angiotensin II and/or hypertensive encephalopathy are likely mechanisms for this syndrome. Sodium depletion due to pressure natriuresis and potassium depletion due to hyperaldosteronism with high plasma renin activity are also likely to play a role in the pathogenesis of hyponatremia. The abnormalities resolve with correction of the renal artery stenosis.^{[20 ]}

Differential Diagnoses

Adrenal Crisis
Alcoholism
Cirrhosis
Hypothyroidism
Pulmonary Edema, Cardiogenic

Other Problems to Be Considered

Alcoholic cirrhosis
Hyperlipidemia
Paraproteinemia
Pseudohyponatremia

Workup

Laboratory Studies

• There are 3 essential laboratory tests in the evaluation of patients with hyponatremia that, together with the history and the physical examination, help to establish the primary underlying etiologic mechanism. (In general, the etiology of the hyponatremia directs its management.) These tests are as follows:
  • Urine osmolality helps to differentiate between conditions associated with impaired free water excretion and primary polydipsia, in which water excretion should be normal (provided intact kidney function).
    
    With primary polydipsia, as with malnutrition (severe decreased solids intake) and reset osmostat, the urine osmolality is maximally dilute, generally less than 100 mOsm/kg. A urine osmolality greater than 100 mOsm/kg indicates impaired ability of the kidneys to dilute urine in the presence of increased total body water. This usually is secondary to elevated vasopressin (ADH) levels, appropriate or inappropriate.
  • Serum osmolality readily differentiates between true hyponatremia and pseudohyponatremia secondary to hyperlipidemia, hyperproteinemia, or hypertonic hyponatremia associated with elevated glucose, mannitol, glycine (posturologic or postgynecologic procedure), sucrose, or maltose (contained in IgG formulations).
  • Urinary sodium concentration helps to differentiate between hyponatremia secondary to hypovolemia and SIADH. With SIADH, the urine sodium is greater than 20-40 mEq/L. With hypovolemia, the urine sodium typically measures less than 25 mEq/L. However, if sodium intake in a patient with SIADH happens to be low, then urine sodium may fall below 25 mEq/L.
• Ancillary tests
  • Serum uric acid levels: Can be important supportive information (typically reduced in SIADH and also reduced in cerebral salt wasting)
  • Thyroid-stimulating hormone (TSH) and serum cortisol levels: If hypothyroidism or hypoadrenalism is suspected
  • Serum albumin, triglycerides, and a serum protein electrophoresis: Also may be indicated for particular patients

Imaging Studies

• Head computed tomography (CT) scanning and chest radiography: To assess for an underlying etiology in select patients with suspected SIADH or cerebral salt wasting

Treatment

Medical Care

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 drop in the serum osmolality, neuronal cell swelling occurs due to the water shift from the extracellular space to the intracellular space (ie, Frank 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.

• 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
• 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. Treat patients who are hypervolemic with salt and fluid restriction, plus diuretics, and correction of the underlying condition.
  • For normovolemic (euvolemic), asymptomatic, and mildly hyponatremic patients, free water restriction (<1 L/d) is generally the treatment of choice. 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 for patients with asymptomatic SIADH.
  • Pharmacologic agents can be used in some cases of more refractory SIADH, allowing more liberal fluid intake. Demeclocycline is 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 and pharmacologic intervention.
• Treating patients with overtly symptomatic hyponatremia in whom rapid correction of the hyponatremia is warranted is more challenging because it carries a significant risk of inducing neurologic damage and the guidelines for treatment are not uniformly agreed upon.
• Acute hyponatremia (duration <48 h) can be safely corrected more quickly than chronic hyponatremia. A symptomatic patient with acute hyponatremia is more in danger from brain edema. This mandates rapid correction.
  • 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.
• 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 12 mEq/L/d. 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. Spontaneous diuresis secondary to ADH suppression with intravascular volume repletion could lead to unnoticed overcorrection.
  • The following equation helps to estimate an expected change in serum Na in respect to characteristics of infusates used^{[22 ]}: Change in serum Na = [(infusate Na + infusate K) - serum Na] / [Total body water +1]
  • This correction is usually best achieved with hypertonic (3%) saline. 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 often is 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 also decreases the risk of fluid overload.
  • During therapy, closely monitor serum electrolytes (ie, every 2-4 h) to avoid overcorrection.
  • 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.^{[23 ]}Others recommend an even more rapid correction.^{[2 ]}
  • 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.^{[24,25 ]}Currently, there is a lack of clinical experience with the use of these drugs in hospitalized patients. Nevertheless, the so-called aquaretic agents may become a promising therapeutic option for the treatment of hypervolemic or euvolemic hyponatremia, especially in the setting of heart failure.^{[26 ]}

Consultations

Consultation with either a nephrologist or a critical care specialist is often of considerable value in managing patients with symptomatic or refractory hyponatremia.

Diet

• Free water restriction often is appropriate for patients with normovolemic hypotonic hyponatremia.
• Individuals who are undernourished need to maintain an appropriate solute intake. In fact, in patients with SIADH, a high protein intake increases the solute load for excretion, thereby removing more free water. Although unpalatable, oral urea has been used to achieve the same effect.
• Patients with hyperglycemia or hyperlipidemia should receive appropriate nutritional counseling.

Medication

The primary treatments used in the management of hyponatremic patients rely on the use of intravenous sodium-containing fluids (normal saline or hypertonic saline) and fluid restriction. Less commonly, loop diuretics (eg, furosemide) or demeclocycline are used. A new class of drugs, AVP receptor antagonists (eg, conivaptan), is now available.^{[24,25 ]}

Diuretics

Loop diuretics occasionally are used in patients with hyponatremia to increase renal free water excretion.

Furosemide (Lasix)

High-ceiling diuretic with a prompt onset of action that acts upon ascending limb of loop of Henle to inhibit sodium/potassium/chloride cotransport system, thereby increasing solute delivery to distal renal tubules, which acts to increase free water excretion. This can lead to increased aldosterone production, resulting in increased sodium absorption. Absorbed readily from the GI tract and also available in parenteral preparations. Diuresis begins 30-60 min with oral vs 5 min with IV administration. Potassium excretion also is increased. Elderly patients may have greater sensitivity to effects of furosemide.

Dosing

Adult

10-80 mg PO or IV 1-4 times/d; higher doses may be required for patients with renal insufficiency; 600 mg/d PO maximum; 4 mg/min IV maximum

Pediatric

1-2 mg/kg PO q6-12h

Interactions

Metformin decreases furosemide concentrations; furosemide interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration of aminoglycosides and furosemide; hearing loss of varying degrees may occur; anticoagulant activity of warfarin may be enhanced when taken concurrently with this medication; increased plasma lithium levels and toxicity are possible when taken concurrently with this medication

Contraindications

Documented hypersensitivity; hepatic coma; anuria; state of severe electrolyte depletion

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Perform frequent serum electrolyte, carbon dioxide, glucose, creatinine, uric acid, and BUN determinations during first few months of therapy and periodically thereafter; may cause hypokalemia

Antibiotics

Certain antibiotics may affect renal ADH action.

Demeclocycline (Declomycin)

Can cause insensitivity of distal renal tubules to the action of ADH and produce a nephrogenic diabetes insipidus. Effects are seen within 5 days and are reversed within 2-6 days following cessation of therapy.

Dosing

Adult

300-600 mg PO bid; consult with nephrologist

Pediatric

<8 years: Not recommended
>8 years: 3-6 mg/lb (6-12 mg/kg) PO, depending upon severity of disease, divided bid/qid; use in children in consultation with pediatric nephrologist

Interactions

Bioavailability may decrease with coadministration of antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; may increase hypoprothrombinemic effects of anticoagulants (monitor prothrombin activity); coadministration with oral contraceptives may decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; caution with preexisting hepatic (metabolism) and renal (primary excretion route) impairment resulting in increased half life; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Arginine vasopressin antagonists

Treats hyponatremia through V2 antagonism of AVP in the renal collecting ducts. This effect results in aquaresis (excretion of free water).^{[24,25 ]}

Conivaptan (Vaprisol)

Arginine vasopressin antagonist (V1A, V2) indicated for euvolemic (dilutional) and hypervolemic hyponatremia. Increases urine output of mostly free water, with little electrolyte loss. Over 80% of conivaptan excreted in feces and the rest in urine.

Dosing

Adult

20 mg IV loading dose (infuse over 30 min), followed by 20 mg via continuous IV infusion over 24 h; continue treatment for additional 1-3 d as 20-mg/d continuous IV infusion, not to exceed 4 d

Pediatric

Not established

Interactions

Sensitive CYP3A4 substrate and potent CYP3A4 inhibitor; coadministration with potent CYP3A4 inhibitors significantly increases C_max and AUC; coadministration with CYP3A4 substrates (eg, midazolam, simvastatin, amlodipine) may increase substrate's toxicity; significantly decreases digoxin clearance

Contraindications

Documented hypersensitivity; hypovolemic hyponatremia; coadministration with potent CYP3A4 inhibitors (eg ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Rapid correction of serum sodium level may result in serious sequelae (eg, osmotic demyelination); may cause infusion site reactions (most common adverse effect, over 50%), hypokalemia, headache, thirst, and vomiting; caution with hepatic impairment; limited data available in CHF and hepatic or renal impairment

Tolvaptan (Samsca)

Selective vasopressin V2-receptor antagonist. Indicated for hypervolemic and euvolemic hyponatremia (ie, serum sodium level <125 mEq/L) or less-marked hyponatremia that is symptomatic and has resisted correction with fluid restriction. Used for hyponatremia associated with congestive heart failure, liver cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion. Initiate or reinitiate in hospital environment only.

Dosing

Adult

15 mg PO qd initially; may increase at 24-h intervals to 30 mg/d; not to exceed 60 mg/d

Pediatric

Not established

Interactions

Acts as a CYP3A substrate, P-gp inhibitor, and weak CYP3A inhibitor; CYP3A inhibitors (see Contraindications) may lead to marked increase in serum concentrations; avoid coadministration with moderate CYP3A inhibitors (eg, erythromycin, fluconazole, aprepitant, diltiazem, verapamil); also avoid coadministration with CYP3A inducers (eg, rifampin, rifabutin, rifapentine, barbiturates, phenytoin, carbamazepine, St. John's wort), as these may decrease tolvaptan serum levels by up to 85% and thereby decrease effectiveness; coadministration with grapefruit juice results in a 1.8-fold increase of serum levels; dose reduction may be required when coadministered with P-gp inhibitors (eg, cyclosporine)
May increase risk for hyperkalemia when administered with drugs known to increase serum potassium levels (eg, ACE inhibitors, potassium-sparing diuretics); may increase serum levels of P-gp substrates (eg, digoxin)

Contraindications

Documented hypersensitivity; urgent correction of hypovolemia; individuals unable to sense or respond to thirst; hypovolemic hyponatremia; strong CYP3A inhibitors (eg, ketoconazole, clarithromycin, itraconazole, ritonavir, indinavir, nelfinavir, saquinavir, nefazodone, telithromycin); anuria

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Initiate only in hospital setting, since serum sodium levels and volume status require close monitoring; rapid rise in sodium levels may cause osmotic demyelination syndrome, resulting in serious neurologic sequelae, including dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, and death; use caution with cirrhosis, since may increase risk for GI bleeding; may cause hyperkalemia and other electrolyte concentration abnormalities; common adverse effects include thirst, xerostomia, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia

Follow-up

Further Inpatient Care

• Patients with hyponatremia from any cause require close attention to their electrolyte and fluid status.
• Patients with symptomatic hyponatremia who are being actively treated often require several daily measurements of serum sodium to avoid a rate of correction that is too rapid.
• After acute treatment, follow-up generally is dictated by the underlying etiology of the hyponatremia.

Complications

• Clinical manifestations include clouding of consciousness, confusion, stupor, or coma. Seizures commonly occur with rapid reductions in serum sodium or with serum sodium concentrations of less than 115-120 mEq/L.
• For unknown reasons, premenopausal women seem to have a less efficient osmotic adaptation. This increases their susceptibility to severe hyponatremia and rapid progression from minimal symptoms (eg, headache, nausea) to respiratory arrest. Cerebral edema and herniation have been found at autopsy.^{[27 ]}
• Correction of hyponatremia that is too rapid may cause permanent neurologic impairment.
  • Central pontine myelinolysis (CPM) and extrapontine myelinolysis (EPM), complications of excessive correction of chronic hyponatremia, are now diagnosed by diffusion-weighted magnetic resonance imaging (MRI). Of note is that conventional CT and MRI scan findings typically lag behind the clinical manifestations of myelinosis by 2-4 weeks.^{[28 ]}
  • The clinical course of the patient — initially encephalopathic secondary to hyponatremia, then improving as the plasma Na concentration increases, and finally deteriorating several days later — can resolve completely or result in permanent disability and fatalities. This typical clinical course has been called the osmotic demyelination syndrome (ODS). The clinical neurologic picture may be confusing, including a variety of findings from psychiatric, behavioral, and movement disorders to dysphagia, flaccid or spastic quadriparesis depending on the involvement of extrapontine or central pontine. Disruption of the blood-brain barrier is presumed to play an important role in the pathogenesis of osmotic demyelination.
  • An increased susceptibility to osmotic demyelination is also observed in cirrhotic patients. In this setting, myoinositol, the most abundant organic osmolyte, is depleted because of glutamine- and hyponatremia-induced brain cell swelling. CPM is a common and often fatal complication of orthotopic liver transplantation, affecting up to 10% of patients who were hyponatremic prior to transplant.^{[29 ]}

Prognosis

• The prognosis for hyponatremia is predicated upon the underlying etiology.

Patient Education

• Patients to be treated with a fluid restriction often require education regarding the free water content of foods and an explanation of the need to limit the intake of liquids to a predetermined level.

Miscellaneous

Medicolegal Pitfalls

• Inappropriate correction of hyponatremia that is too rapid may cause permanent neurologic sequelae. Recognizing hyponatremia early on, in order to take appropriate steps to prevent its worsening, is important. Recognizing hospitalized patients who are at risk for intolerance of free water loads also is necessary; monitor those patients carefully.

Special Concerns

• The care of elderly patients often is complicated by any existing medical comorbidity; thus, a full medical assessment is required, with special attention paid to a patient's cardiovascular status.
• In pregnancy, reset osmostat is a common cause of hyponatremia and is distinct from SIADH.

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Keywords

hyponatremia, SIADH, electrolyte, electrolytes, electrolyte imbalance, sodium deficiency, furosemide, hypertonic hyponatremia, hyponatraemia, hyponatremia treatment, hyponatremia causes, hyponatremia correction, tolvaptan, conivaptan, cerebral salt wasting, normotonic hyponatremia, hypotonic hyponatremia, normovolemic hypotonic hyponatremia, euvolemic hypotonic hyponatremia, abnormal electrolyte level, abnormal electrolyte distribution, congestive heart failure, liver failure, renal failure, hyperlipidemia, paraproteinemia, pseudohyponatremia, liver cirrhosis, nephrotic syndrome, severe hypoproteinemia, syndrome of inappropriate ADH secretion, severe hypothyroidism, adrenal insufficiency

Contributor Information and Disclosures

Author

Eric E Simon, MD, Associate Professor, Department of Medicine, Tulane University School of Medicine; Co-Director of Nephrology Training, Medical Director, Dialysis Clinic, Inc
Eric E Simon, MD is a member of the following medical societies: American Federation for Medical Research, American Heart Association, American Society for Cell Biology, American Society of Nephrology, Association for Psychological Science, Central Society for Clinical Research, International Society of Nephrology, National Kidney Foundation, Phi Beta Kappa, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

Coauthor(s)

Seyed Mehrdad Hamrahian, MD, Staff Nephrologist, Ochsner Medical Center
Seyed Mehrdad Hamrahian, MD is a member of the following medical societies: American Society of Nephrology and National Kidney Foundation
Disclosure: Nothing to disclose.

Medical Editor

James H Sondheimer, MD, Director of Hemodialysis Unit, Harper Hospital; Associate Professor, Department of Internal Medicine, Division of Nephrology, Wayne State University School of Medicine
James H Sondheimer, MD is a member of the following medical societies: American College of Physicians and American Society of Nephrology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Eleanor Lederer, MD, Consulting Staff, Louisville VA Hospital; Professor of Medicine, Director of Nephrology Training Program, Kidney Disease Program, University of Louisville School of Medicine; Director, Metabolic Stone Clinic
Eleanor Lederer, MD is a member of the following medical societies: American Association for the Advancement of Science, American Federation for Medical Research, American Society for Biochemistry and Molecular Biology, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Transplantation, International Society of Nephrology, Kentucky Medical Association, National Kidney Foundation, and Phi Beta Kappa
Disclosure: Nothing to disclose.

CME Editor

Rebecca J Schmidt, DO, FACP, FASN, Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine
Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association
Disclosure: Abbott Grant/research funds Speaking and teaching; Genzyme Honoraria Consulting; Amgen Honoraria Speaking and teaching; Ortho Biotech Honoraria Speaking and teaching

Chief Editor

Vecihi Batuman, MD, FACP, FASN, Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Medicine Service, Southeast Louisiana Veterans Health Care System
Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, and International Society of Nephrology
Disclosure: Nothing to disclose.

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Clinical guidelines:
Management of adult patients with ascites due to cirrhosis. American Association for the Study of Liver Diseases - Private Nonprofit Research Organization.  1998 Jan (revised 2004 Mar).  16 pages.  NGC:003590

Clinical trials:
A Phase 2 Efficacy and Safety Study of the Tolvaptan Tablets in Patients With Non-Hypovolemic Non-Acute Hyponatremia

Establishment of an Algorithm for a Clinical Classification of Hypoosmolar Hyponatremia (CONA)

Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Oral Lixivaptan Capsules in Subject With Euvolemic Hyponatremia

Postoperative Hyponatremia - Are There Gender Differences?

Safety and Efficacy of Conivaptan in Hyponatremic Patients With Symptomatic Acute Decompensated Heart Failure (ADHF) (CONVERT-H)

THE BALANCE Study: Treatment of Hyponatremia Based on Lixivaptan in NYHA Class III/IV Cardiac Patient Evaluation

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