Central pontine myelinolysis, MRI FLAIR
Hyponatremia—defined as a serum sodium concentration of less than 135 mEq/L—is a common and important electrolyte imbalance that can be seen in isolation or, as most often is the case, as a complication of other medical illnesses (eg, heart failure, liver failure, renal failure, pneumonia).[1] The normal serum sodium concentration is 135-145 mEq/L. Joint European guidelines classify hyponatremia in adults according to serum sodium concentration, as follows[2] :
Corrrection 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.
Symptoms range from nausea and malaise, with mild reduction in the serum sodium, to lethargy, decreased level of consciousness, headache, and (if severe) 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 is classified according to volume status, as follows:
Hyponatremia can be further subclassified according to effective osmolality, as follows:
See Presentation for more detail.
There are three 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: urine osmolality, serum osmolality, and urinary sodium concentration.
Urine osmolality
Urine osmolality helps differentiate between conditions associated with impaired free-water excretion and primary polydipsia. A urine osmolality greater than 100 mOsm/kg indicates impaired ability of the kidneys to dilute the urine.
Serum osmolality
Serum osmolality readily differentiates between true hyponatremia and pseudohyponatremia. The latter may be secondary to hyperlipidemia or hyperproteinemia, or may be hypertonic hyponatremia associated with elevated glucose, mannitol, glycine (posturologic or postgynecologic procedure), sucrose, or maltose (contained in IgG formulations).
Urinary sodium concentration
Urinary sodium concentration helps differentiate between hyponatremia secondary to hypovolemia and syndrome of inappropriate antidiuretic hormone secretion (SIADH). With SIADH (and salt-wasting syndrome), 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 (or salt-wasting) happens to be low, then urine sodium may fall below 25 mEq/L.
See Workup for more detail.
Hypotonic hyponatremia accounts for most clinical cases of hyponatremia and can be treated with fluids. Acute hyponatremia (duration < 48 hours) can be safely corrected more quickly than chronic hyponatremia. The treatment of hypertonic and pseudohyponatremia is directed at the underlying disorder in the absence of symptoms.
Intravenous fluids and water restriction
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, which, like sodium, is osmotically active.
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.
For euvolemic, asymptomatic hyponatremic patients, free water restriction (< 1 L/day) is generally the treatment of choice. There is no role for hypertonic saline in these patients.
When treating patients with overtly symptomatic hyponatremia (eg, seizures, severe neurologic deficits), hypertonic (3%) saline should be used.
Pharmacologic treatment
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. It induces both a water and sodium diuresis with improvement in plasma sodium levels.
See Treatment and Medication for more detail.
Hypoosmolality (serum osmolality < 280 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.[3] 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. Note that urea is not an effective osmole, so when the urea levels are very high, the measured osmolality should be corrected for the contribution of urea.
The recommendations for treatment of hyponatremia rely on the current understanding of CNS adaptation to an altered 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, Starling forces). Swelling of the brain cells elicits the following two osmoregulatory responses:
Therefore, correction of hyponatremia must take into account the chronicity of the condition. Acute hyponatremia (duration < 48 h) 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.
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.[5]
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%.[6]
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.[7] Bae et al reported that in hospitalized survivors of acute myocardial infarction, the presence of hyponatremia at discharge was an independent predictor of 12-month mortality. The study involved 1290 patients.[8]
Similarly, cirrhotic patients with persistent ascites and a low serum sodium level awaiting transplant have a high mortality risk despite low severity (MELD) scores (see the MELD Score calculator). The independent predictors—ascites and hyponatremia—are findings indicative of hemodynamic decompensation.[9, 10]
A study by Huang et al indicated that 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 was also found to be linked to an increased risk for cardiovascular- and malignancy-related mortality in these patients. The study included 45,333 patients with stage 3 or 4 chronic kidney disease, 9.2% of whom had dysnatremia.[11]
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, because they have a higher rate of comorbid conditions (eg, cardiac, hepatic, or renal failure) that can lead to hyponatremia.
Patients may present to medical attention with symptoms related to low serum sodium concentrations. However, many patients present due to manifestations of other medical comorbidities, with hyponatremia being recognized only secondarily. In many cases, therefore, the recognition is entirely incidental. Clinical symptoms may result from the cause of hyponatremia or the hyponatremia itself.
Many medical illnesses, such as chronic heart failure, liver failure, renal failure, or pneumonia, may be associated with hyponatremia. These patients frequently present because of their primary disease (eg, with dyspnea, jaundice, uremia, cough).[12]
A retrospective Chinese study reported hyponatremia in 116 of 175 children (66.4%) with bacterial meningitis. Multivariate analyses showed that convulsions (odds ratio [OR] 12.09, P = 0.001) and blood glucose levels > 6.1 mmol/L (110 mg/dL)(OR 8.28, P = 0.01) were related to severe hyponatremia. The authors recommend checking for severe hyponatremia in pediatric patients with bacterial meningitis who have either of those findings.[13]
Exercise-associated hyponatremia (EAH), which develops during or immediately after physical activity, was first reported in athletes participating in long-duration, high-intensity exercise (eg, ultramarathons) particularly in hot weather, but has since been described in otherwise healthy participants in a variety of sporting and recreational activities, including team sports and yoga classes. EAH results from drinking hypotonic fluids (water or sports drinks) beyond thirst and in excess of sweat, urine, and insensible water losses.[14]
Symptoms of hyponatremia range from nausea and malaise, with mild reduction in the serum sodium, to lethargy, decreased level of consciousness, headache, and (if severe) 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. 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 rate and degree 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, antidepressants,[15] antiepileptic drugs,[16] diuretics). 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.
Examination should include orthostatic vital signs and an accurate assessment of volume status. This determination (ie, whether the patient is hypervolemic, euvolemic, or hypovolemic) often guides treatment decisions.
A full assessment for medical comorbidities is also essential, with particular attention paid to cardiopulmonary and neurologic components of the examination.
Although the differential diagnosis is quite broad, most hyponatremia can be divided into hypertonc, normotonic, or hypotonic in origin. Miscellaneous causes account for the remainder of cases.
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 causes 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.[17]
Other examples of osmotically active molecules include mannitol (often used to treat brain edema) or maltose (used with intravenous immunoglobulin administration).
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 artifactual low sodium (so-called pseudohyponatremia) is secondary to measurement by flame photometry. It can be avoided by direct ion-selective electrode measurement.
Hyponatremia after transurethral resection of the prostate (TURP) or hysteroscopy is caused by absorption of irrigants, glycine, sorbitol, or mannitol, contained in nonconductive flushing solutions used for those procedures. The degree of hyponatremia is related to the quantity and rate of fluid absorbed. The plasma osmolality is also variable and changes over time.
The presence of a relatively large osmolal gap due to excess organic solute is diagnostic in the appropriate clinical setting. Symptomatic patients are treated depending on plasma osmolality and volume status, with hypertonic saline for patients in hypoosmolar state or a 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.[18]
Hypotonic hyponatremia always reflects the inability of the kidneys to handle the excretion of free water to match 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 guide 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; vasopressin) secretion, 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.[19, 20]
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.
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. This is particularly so in elderly persons, who already have impaired diluting ability.
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).
Normovolemic (euvolemic) hypotonic hyponatremia
This is a very common cause of hyponatremia in patients who are hospitalized. It is associated with nonosmotic and non–volume-related ADH secretion (ie, SIADH) secondary to a variety of clinical conditions, including the following:
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 inhibitor (MAOI) antidepressants. In these circumstances, the ability of the kidney to dilute urine in the setting of serum hypotonicity is reduced.
Hyponatremia is a relatively common adverse effect of desmopressin, a vasopressin analogue that acts as a pure V2 agonist and is used in the treatment of central diabetes insipidus, von Willebrand disease, nocturia in adults, and enuresis in children. Patients receiving desmopressin require regular monitoring of serum sodium levels.
The diagnostic criteria for SIADH are as follows:
Urinary sodium concentrations are also typically greater than 20 mEq/L on a normal salt diet as sodium excretion will reflect dietary sodium intake. 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. These findings are also found in a renal salt wasting process. This similarity makes the differentiation between salt wasting and SIADH difficult except that in renal wasting, one would expect to find a hypovolemic state.
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),[22] 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.
Hospitalized patients who are infected with human immunodeficiency virus (HIV) have a high incidence of hyponatremia. In these cases, hyponatremia is usually due to at least one of the following three disorders associated with an increased ADH level:
There are other causes that do not fit neatly in any of the above categories and may or may not be associated with elevated levels of ADH or simply overwhelm the capacity of the kidneys to properly excrete excess water.
The most common precipitant of hyponatremia in patients after surgery[23] 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.
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.[24] 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 diluting 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[25]
Acute hyponatremia is associated with ultra-endurance athletes and marathon runners.[26] 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.
It should be noted that some collapsed runners are normonatremic or even hypernatremic,[27] making blanket recommendations difficult. However, fluid intake to the point of weight gain should be avoided.[27, 28] 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.[29]
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.[30]
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 oral urea to induce an osmotic diuresis.[31]
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.[32]
Using a retrospective case note analysis, an Irish study examined the incidence of hyponatremia in a variety of neurologic conditions.[33] The investigators found that the occurrence of hyponatremia was greater in persons with subarachnoid hemorrhage (62 out of 316 patients, or 19.6%; P< 0.001), intracranial neoplasm (56 out of 355 patients, or 15.8%; P< 0.001), traumatic brain injury (44 out of 457 patients, or 9.6%; P< 0.001), and pituitary disorders (5 out of 81 patients, or 6.25%; P = 0.004) than it was in patients with spinal disorders (4 out of 489 patients, or 0.81%).
The investigators also determined that the median hospital stay for patients with hyponatremia was 19 days, compared with a median stay of 12 days for the study's other patients.
There are three 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 a 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 the urine. This usually is secondary to elevated vasopressin (antidiuretic hormone; ADH) levels, appropriate or inappropriate.
Serum osmolality readily differentiates between true hyponatremia and pseudohyponatremia secondary to hyperlipidemia, hyperproteinemia, or hypertonic hyponatremia. Sources of hypertonic hyponatremia include elevations of the following:
Urinary sodium concentration helps to differentiate between hyponatremia secondary to hypovolemia and the syndrome of inappropriate ADH secretion (SIADH). With SIADH (and salt-wasting syndrome), 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 (or salt-wasting) happens to be low, then urine sodium may fall below 25 mEq/L.
Serum uric acid levels can be important supportive information (they are typically reduced in SIADH and also reduced in salt wasting). After correction of hyponatremia, the hypouricemia corrects in SIADH but remains with a salt-wasting process.
Thyroid-stimulating hormone (TSH) and serum cortisol levels should be measured if hypothyroidism or hypoadrenalism is suspected.
Serum albumin, triglycerides, and a serum protein electrophoresis also may be indicated for particular patients.
Head computed tomography (CT) scanning and chest radiography can be used to assess for an underlying etiology in select patients with suspected SIADH or cerebral salt wasting.
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.[34] For treatment of symptomatic patients with acute hyponatremia (ie, with a known duration of < 24-48 hours), the panel recommended urgent correction by 4-6 mmol/L to prevent brain herniation and neurological damage from cerebral ischemia. Recommended treatment of acute hyponatremia varies by symptom severity, as follows:
To avoid osmotic demyelination syndrome (ODS) in patients with chronic hyponatremia (known duration > 48 hours), the recommendations include the following[34] :
For patients with the syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH), fluid restriction (with a goal of 500 mL/d below the 24-hour urine volume) is generally 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.[34]
The European Society of Intensive Care Medicine, the European Society of Endocrinology, and the European Renal Association–European Dialysis and Transplant Association have released guidelines on the diagnosis, classification, and treatment of true hypotonic hyponatremia. Treatment recommendations include the following[2] :
Consultation with either a nephrologist or a critical care specialist is often of considerable value in managing patients with symptomatic or refractory hyponatremia.
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. The following three factors guide treatment:
For the asymptomatic patient, the following treatments may be of use:
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, 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. 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 sodium (Na) with respect to characteristics of infusates used[35] : Change in serum Na = [(infusate Na + infusate K) - serum Na] / [Total body water +1]
During therapy, close monitoring of 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. Overly rapid correction of serum sodium 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, 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 sodium concentration is over 120 mEq/L.[36] Other authors recommend an even more rapid correction.[4]
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. 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 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.
Aquaretics
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.[37, 38] 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, 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 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.[39]
The use of these vaptans is limited and exact benefits have yet to be determined. There are reports that even mild hyponatremia can cause gait instability and possibly increase the risk of falls and hip fractures. In this setting, vaptans may be beneficial to improve hyponatremia and gait.
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.
A joint European clinical practice guideline on the diagnosis and treatment of hyponatremia has been published. The guideline defines hyponatremia as follows[2] :
The guideline recommends excluding hyperglycemic hyponatremia by measuring the serum glucose concentration and correcting the measured serum sodium concentration for the serum glucose concentration if the latter is increased, using the following formula:
Corrected serum Na+ = measured Na+ + 2.4 × ([glucose – 100 mg/dL] /100 mg/dL)
If glucose is measured in mmol/L, 5.5 mmol/L is substituted for 100 mg/dL.
Related recommendations include the following:
To differentiate the cause of hypotonic hyponatremia, the guideline recommends interpreting the osmolality of a spot urine sample as the first step, as follows:
Related guideline suggestions are as follows:
For hyponatremia (acute or chronic) with severe symptoms, guideline statements include the following:
For patients whose symptoms improve after a 5- mmol/L increase in serum sodium concentration in the first hour, guideline statements include the following:
For patients whose symptoms show no improvement after a 5- mmol/L increase in serum sodium concentration in the first hour, guideline statements include the following:
For treatment of acute hyponatremia in patients without severe or moderately severe symptoms, guideline statements include the following:
For treatment of chronic hyponatremia in patients without severe or moderately severe symptoms, guideline statements on general management include the following:
In moderate or profound hyponatremia, consider checking the serum sodium concentration every 6 h until the serum sodium concentration has stabilized under stable treatment.
For patients with expanded extracellular fluid, guideline statements include the following:
For patients with SIADH, guideline statements include the following:
For patients with reduced circulating volume, , guideline statements include the following:
if hyponatremia is corrected too rapidly, the guidelines recommend the following:
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.[37, 38]
Clinical Context: 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.
Loop diuretics occasionally are used in patients with hyponatremia to increase renal free water excretion.
Clinical Context: 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.
Clinical Context: 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.
Clinical Context: 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. Duration of use is limited to 30 days to minimize risk of liver injury.
Treats hyponatremia through V2 antagonism of AVP in the renal collecting ducts. This effect results in aquaresis (excretion of free water).[37, 38]
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.
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.[40]
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.[41]
The clinical course of these patients features initial encephalopathy secondary to hyponatremia, then improvement as the plasma Na concentration increases, and finally deterioration several days later. The disorder can resolve completely or result in permanent disability or death. This typical clinical course has been called the osmotic demyelination syndrome (ODS). The clinical neurologic picture may be confusing, as it may include a variety of findings from psychiatric, behavioral, and movement disorders, such as dysphagia and flaccid or spastic quadriparesis, depending on the involvement of extrapontine or central pontine myelinolysis. 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.[42]
The prognosis for patients with hyponatremia is predicated upon the underlying etiology. A study by Doshi et al found that hyponatremia among patients with cancer is associated with extended hospital stays and higher mortality rates; however, whether long-term correction of hyponatremia would improve these outcomes is unclear.[43]
In patients with end-stage renal disease who are receiving hemodialysis or peritoneal dialysis, evidence suggests that the risk of death rises with incrementally lower sodium levels. Causes of hyponatremia-related mortality in the dialysis population remain uncertain, but possibilities include central nervous system toxicity, falls and fractures, infection-related complications, and impaired cardiac function.[44]
A meta-analysis of 15 studies encompassing 13,816 patients found that any improvement in hyponatremia was associated with a reduced risk of overall mortality (odds ratio [OR]=0.57). With the eight studies that reported a threshold for serum sodium improvement to > 130 mmol/L, the association was even stronger (OR=0.51). The reduction in mortality risk persisted at 12-month follow-up (OR=0.55). Reduced mortality was more evident in older patients and in patients with lower serum sodium levels at enrollment.[45]
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.
Central pontine myelinolysis, MRI FLAIR
Extrapontine myelinolysis T2
