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Brian L. Springer, MD, FACEP, Associate Professor, Wright State University, Department of Emergency Medicine, Dayton, OH.
MacKenzie Gabler, MD, Resident Physician, Wright State University Emergency Medicine Residency Program, Dayton, OH.
Frank LoVecchio, DO, FACEP, Vice-Chair for Research, Medical Director, Samaritan Regional Poison Control Center, Emergency Medicine Department, Maricopa Medical Center, Phoenix, AZ.
Statement of Financial Disclosure
To reveal any potential bias in this publication, and in accordance with Accreditation Council for Continuing Medical Education guidelines, we disclose that Dr. Farel (CME question reviewer) owns stock in Johnson & Johnson. Dr. Stapczynski (editor) owns stock in Pfizer, Johnson & Johnson, Walgreens Boots Alliance Inc., GlaxoSmithKline, Bristol Myers Squibb, and AxoGen. Dr. Schneider (editor), Ms. Fessler (nurse planner), Dr. Springer (author), Dr. Gabler (author), Dr. LoVecchio (peer reviewer), Ms. Mark (executive editor), Ms. Leslie Coplin (executive editor), and Mr. Landenberger (editorial and continuing education director) report no financial relationships with companies related to the field of study covered by this CME activity.
Sodium and water balance are closely linked, and abnormalities in one often occur in association with abnormalities in the other. Hyponatremia and disordered water balance are among the most common electrolyte disturbances seen in the emergency department (ED). Given the human body’s remarkable adaptive capabilities, severe irregularities in sodium and water balance may be tolerated with surprisingly few symptoms, whereas rapid changes in sodium concentration, including the emergency physician’s attempts to correct hyponatremia, may result in life-threatening illness. It is imperative that emergency physicians (EPs) and providers be versed in the recognition and management of hyponatremia and how it fits into the body’s management of sodium and water balance. This article will review water balance and sodium, the epidemiology of hyponatremia, the clinical conditions associated with hyponatremia and their treatment, as well as preventive strategies to avoid sodium imbalance.
Note: 1 mEq/L = 1 mmol/L of sodium. The two are used interchangeably throughout this monograph.
Total body water accounts for approximately 60% of total body weight in adults, although this figure varies based on age and gender.1 Of this 60%, approximately 40% is intracellular fluid and 20% is extracellular fluid. Within the extracellular fluid, approximately two-thirds (or 15% of total body weight) resides in the interstitial space and one-third (or 5% of the total body weight) resides in the intravascular space. The primary electrolyte of the extracellular fluid is sodium. Proper fluid balance in the healthy adult requires an input of approximately 1 to 3 liters of water per day, replacing fluid lost through urine output, insensible loss (respiratory tract, skin, and feces), and sweat. Excessive loss due to fever, heavy sweating from exertion, or diarrhea increases water replacement needs. Water is able to diffuse between the intracellular and extracellular spaces via sodium and potassium transport channels, maintaining a relatively constant osmolality.
Maintenance of water balance requires normally functioning kidneys, urea production, intact thirst mechanism, and suppression of vasopressin (herein referred to as antidiuretic hormone or ADH) when serum sodium levels start to drop. In healthy individuals, the kidneys will excrete or resorb water to maintain a normal osmolality. ADH, secreted by the posterior pituitary gland, acts on the renal collecting system to increase reabsorption of water, increase urine concentration, and decrease urine output (i.e., anti-diuresis). This retention of free water has the effect of decreasing serum osmolality and sodium concentration. Ordinarily, a serum sodium level less than 135 mEq/L should trigger suppression of ADH, with resultant diuresis of dilute urine. Hyponatremia can develop if more water is ingested than can be secreted by the kidneys, or if the ability of the kidneys to provide effective diuresis of dilute urine is compromised by kidney disease, diuretics, or abnormal presence of ADH. In addition, lack of dietary protein can result in hyponatremia, as decreased excretion of urea limits water excretion, even in cases of profoundly low urine osmolality. An intact thirst mechanism provides stimulus to increase the amount of water consumed when serum osmolality increases, preventing dehydration and the development of hypernatremia.2
Hyponatremia is defined as a serum sodium level of less than 135 mEq/L. Hyponatremia may be further classified as mild (135-125 mEq/L) or severe (less than 125 mEq/L). Severity of the symptoms is dependent both on the serum sodium concentration as well as the rapidity of change. Acute and severe hyponatremia may result in cerebral edema, seizures, coma, and cardiopulmonary arrest, but even chronic mild hyponatremia is associated with poor outcomes. These patients may have subtle neurocognitive deficits that are difficult to detect, and resolve with correction of the hyponatremia. These deficits put individuals at risk for falls and traumatic injury. Patients with even mild hyponatremia have a 30% higher risk of death and are hospitalized 14% longer than those with a normal serum sodium. This increased mortality risk occurs in commonly observed clinical conditions across large numbers of patients, including those with myocardial infarction, heart failure, and pulmonary infections.3,4 Even mild abnormalities in sodium among patients in the ICU is an independent predictor for mortality.5
Hyponatremia is the most common electrolyte disorder encountered in clinical medicine. The prevalence of hyponatremia in the United States ranges from 3 million to 6 million individuals per year. Approximately 3-6% of adult patients in the ED have some degree of hyponatremia, and the reported incidence of hospital-associated hyponatremia ranges between 10% and 30%, depending on the patient population, with severe hyponatremia accounting for 1% of patients. As previously noted, hyponatremic patients have an increased risk of death and longer hospital stays than patients with normal serum sodium levels; overall mortality of hyponatremia ranges from 3% to 29%. The leading causes of hyponatremia in ED patients are diuretic use and syndrome of inappropriate antidiuretic hormone secretion (SIADH).1,2,6
To identify those with hyponatremia, as well as to institute preventive measures, it is first necessary to identify at-risk populations. In patients with no underlying kidney disease, the most common cause of hyponatremia is excessive intake of free water before, during, and after endurance events. This most commonly occurs during sustained, high-intensity endurance activities such as marathons or triathlons.7 “Blanket” hydration advice in which one recommendation fits all has led to overdrinking by well-meaning athletes.8 They will typically consume more fluid than they lose in sweat, and may actually gain weight over the course of an event. As the event proceeds, the athlete may develop lethargy and nausea secondary to low sodium. These symptoms may inadvertently be taken as signs of dehydration, prompting even greater fluid intake.9 Some degree of hyponatremia may occur in as many as 2-7% of participants.10 Most cases lead to little or no complications and may be treated with close monitoring and fluid restriction. Mentally ill patients may rapidly consume large amounts of water and become hyponatremic. Individuals who consume large quantities of fluid but little protein may also become hyponatremic, due to limited free water excretion in the setting of low urea levels.
Secretion of ADH (with resultant limiting of free water excretion) in spite of low plasma sodium concentration can occur in the setting of hypovolemia, heart failure, or liver disease. SIADH occurs when ADH continues to be released without an osmotic or hemodynamic stimulus. ADH may be released in response to pain, stress, or hypoxia. Other causes of SIADH include malignancy, pulmonary disease, and central nervous system (CNS) trauma, infection, or ischemia.1 In hospitalized patients, the risk of SIADH is highest among the elderly, postoperative patients, those in the ICU, and those with CNS disorders.2
Diuretic medications used for the treatment of hypertension or for control of peripheral edema enhance fluid loss but also impair the kidney’s ability to excrete dilute urine. The end result is excess sodium loss through the urine with resultant hyponatremia. Thiazide diuretics carry the greatest risk for development of hyponatremia, as well as increased hyponatremia severity; this risk increases with duration of use.6 Thiazide diuretics are often prescribed as first-line therapy for hypertension in elderly patients, so the EP should consider hyponatremia as a cause of even subtle neurological complaints in older patients taking these medications.
Other than diuretics, there are dozens of drugs that affect water homeostasis and may result in hyponatremia. The most common non-diuretic medications associated with development of hyponatremia include antidepressants (tricyclics, monoamine oxidase inhibitors, and selective serotonin reuptake inhibitors [SSRIs]) and antipsychotics (phenothiazines and butyrophenones). SSRIs cause hyponatremia more frequently than other antidepressants; hyponatremia may develop in up to 30% of patients, usually within the first two weeks of treatment. Elderly patients and those taking thiazide diuretics are at greatest risk. The mechanism is believed to be medication-induced increases in central ADH secretion.11 Antiepileptics (carbamazepine and valproic acid) and opioid analgesics are associated with the development of hyponatremia via the same mechanism. Nonsteroidal anti-inflammatory drugs (NSAIDs) decrease water secretion by potentiating the effects of ADH, and are associated with development of hyponatremia in patients with preexisting SIADH (discussed below). NSAID use by marathon and ultramarathon runners is also associated with hyponatremia, although this may be confounded by other factors such as overconsumption of free water resulting in decreased serum sodium concentrations.
The use of 3, 4-methylenedioxymethylamphetamine (MDMA, ecstasy, XTC, E, X, rolls, beans, Adam, Molly) has been associated with development of hyponatremia. Direct stimulation of ADH secretion by MDMA and its metabolites results in dilutional hyponatremia; excess water intake to counter hypothermia is common in MDMA and is likely a contributing factor.11,12 Females appear to be at greater risk for development of severe hyponatremia; instances of coma, seizure, rhabdomyolysis, and death have occurred. In patients with a history of recent MDMA use, even mild head injury has resulted in development of severe hyponatremia.13,14,15,16
Hospital-acquired hyponatremia is the most common cause of hyponatremia in children.17 Children younger than 16 years, those with hypoxia, and those with any acute neurologic injury or infection are also at risk for development of hyponatremia. As in adults, ADH levels are increased in hospitalized patients secondary to pain, stress, hypoxia, and administration of certain medications. Administration of hypotonic maintenance fluids in the setting of increased ADH levels may result in free water retention and hyponatremia. Children in the postoperative setting appear to be at the greatest risk;18 multiple nonosmotic stimuli for ADH production, such as subclinical volume depletion, pain, stress, nausea and vomiting, narcotic use, and third spacing, may lead to hyponatremia, especially if hypotonic fluids are administered. Because of a higher ratio of brain to intracranial volume, prepubescent children may be at higher risk for the development of cerebral edema and encephalopathy. Volume regulation of brain cells is impaired in patients with brain injury, and the movement of additional water into the brain as a result of even mild hyponatremia can result in herniation and death. Hypoxic brain injury, as well as CNS infection, abscess, or tumor, may result in SIADH and hyponatremia.
Hyponatremia can occur in spite of suppression of ADH release in a number of clinical conditions. These include overdrinking (by athletes and in primary polydipsia), advanced renal failure, and low dietary solute intake (such as beer potomania or tea and toast diet). These conditions are each discussed further below.
Often the manifestations of hyponatremia are subtle, becoming more noticeable when the changes are large or rapid.19 A recent study evaluating patients with hyponatremia in the ED found that the most common presentation was neurologic symptoms (21%) such as dysarthria, motor function deficits, sensory loss, vertigo, balance disorder, and headache, followed by fatigue (19%), abdominal pain (11%), and dyspnea (8%). More severe neurologic symptoms included seizures and coma (9%), and confusion (6%).6 Other common presenting symptoms include muscle weakness, nausea, vomiting, disorientation, depressed reflexes, irritability, and tachypnea. Most patients will develop symptoms with serum sodium less than 125 mmol/L. Both patients with extremely low serum sodium and those with an acute decrease in serum sodium are at greatest risk for acute deterioration secondary to cerebral edema.20 These patients may present with or develop seizures, coma, respiratory arrest, and brain-stem herniation. It is important to mention that although some patients may appear asymptomatic, studies suggest they often have some degree of cognitive impairment, specifically with concentration. When even mild hyponatremia is treated, cognition often improves.20,22 Hyponatremia is also associated with osteoporosis and unsteady gait, greatly increasing the rate of falls and fractures, which is an important cause of morbidity and mortality in elderly patients.21,22
Determining the underlying cause of hyponatremia is important, as it will direct therapy. The initial assessment of the patient with hyponatremia should include measurement of serum osmolality and urine sodium as well as clinical determination of the patient’s volume status. The serum osmolality should be examined first to determine if the hyponatremia is isotonic, hypertonic, or hypotonic. Isotonic hyponatremia is also termed pseudohyponatremia, as it is most often due to severe hypertriglyceridemia or hyperproteinemia. The excessive serum concentrations of lipids or proteins interfere with the measurement of sodium and result in falsely low numbers. Hypertonic hyponatremia (serum Osm > 295 mOsm/kg H2O) is usually due to the presence of other serum osmolytes. The most common scenario is the patient with significant hyperglycemia in diabetic ketoacidosis. In these cases, the sodium typically normalizes with insulin administration and reduction in the serum glucose. Hypertonic hyponatremia also may be seen with administration of IV mannitol in patients with elevated intracranial pressure. Hypotonic hyponatremia (serum Osm < 275 mOsm/kg H2O) is the common subtype of hyponatremia seen in the ED. Given the broad differential for hypotonic hyponatremia, it is helpful to further characterize it based on volume status into hypovolemic, euvolemic, and hypervolemic hyponatremia. (See Table 1.)
Hypovolemic Hyponatremia. Hypovolemic hyponatremia is the most common subtype of hypotonic hyponatremia encountered in the ED.6 Because volume depletion cannot be tested directly, clinicians must use a combination of history, physical exam, and laboratory data to determine if a patient is hypovolemic. If clinical assessment of volume status is unclear and the patient is stable, one approach that is both diagnostic and therapeutic is to give a 0.5 to 1 L bolus of 0.9% NaCl to see if the hyponatremia will begin to correct itself as euvolemia is restored.21 In patients who appear volume depleted, hyponatremia is usually secondary to either renal or gastrointestinal loss of sodium and water. Obtaining a urine sodium can aid in differentiating renal losses from extrarenal losses. Urine sodium less than 10 mmol/L suggests extrarenal losses, usually from vomiting and diarrhea. Urine sodium greater than 20 mmol/L suggests renal losses. The most common cause of renal sodium loss is diuretic therapy, and thiazides are the primary culprits. As noted earlier, they remain one of the most common causes of hyponatremia in the ED. Less common causes of medication-related renal sodium loss include loop diuretics and angiotensin-converting enzyme inhibitors. One other potential cause of hypovolemic hyponatremia is mineralocorticoid deficiency from primary adrenal insufficiency. In this instance, the lack of aldosterone results in renal salt wasting and hypovolemia. This stimulates release of ADH, which results in retention of free water and hyponatremia.
Euvolemic Hyponatremia. Hyponatremic patients with no clinical evidence of volume depletion (i.e., no orthostatic hypotension, normal skin turgor, moist mucosa) and no evidence of volume overload (i.e., edema, ascites) should be considered euvolemic. In these patients, hyponatremia is almost always the result of inappropriate ADH secretion and the resulting relative excess of body water. SIADH is the most common cause of euvolemic hyponatremia and a common cause of hyponatremia in the ED.6 Laboratory features include low serum osmolality with inappropriately elevated urine osmolality (Uosm > 100), elevated urine sodium (> 20-30 mmol/L), and normal kidney function. SIADH is associated with a wide variety of disorders, the most common of which include neoplastic disease (small cell lung cancer, mesothelioma, pancreatic cancer, lymphoma), CNS disorders (mass lesions, encephalitis, meningitis, Guillain-Barre), drugs (narcotics, carbamazepine, MDMA, SSRIs, antineoplastics), and pulmonary disease (infections, asthma, chronic obstructive pulmonary disease).2 It is important to remember that SIADH is a diagnosis of exclusion, so all other causes of hyponatremia must be ruled out.
Another potential cause of euvolemic hyponatremia is glucocorticoid deficiency in patients with pituitary disorders. Here, a deficiency of cortisol results in failure to suppress ADH secretion. Euvolemic hyponatremia also may be seen in endurance athletes who have excessive fluid intake in the presence of increased ADH secretion. There are additional causes of euvolemic hyponatremia that are not related to ADH secretion. In primary polydipsia, abnormal thirst regulation results in excess water consumption; the mechanism by which this occurs is not clear. Most patients with primary polydipsia have psychiatric disease (such as acute psychosis with schizophrenia), hence the sometimes-used term “psychogenic polydipsia.” Hyponatremia can develop following water consumption that exceeds the kidneys’ ability to secrete such large volumes.2 Chronically malnourished patients who consume large volumes of fluid but little protein may develop hyponatremia. Alcoholics who consume large volumes of beer at the expense of other nutrition (beer potomania) or individuals on a high water/low protein diet (such as a “tea and toast” diet in elderly patients who can no longer prepare meals for themselves) are at risk.2,21 The decreased protein intake and subsequent lack of urea impairs free water secretion, compounding the problem of high fluid consumption and resultant hyponatremia.
Hypervolemic Hyponatremia. Hypervolemic hyponatremia occurs when the water retention exceeds sodium retention. Common causes include heart failure, cirrhosis, chronic kidney disease (CKD), and nephrotic syndrome. In heart failure, decreased cardiac output is sensed by the aortic and carotid baroreceptors. This triggers an increase in adrenergic activity, renin release, and secretion of ADH. The secretion of ADH results in water retention and hyponatremia.21 Patients with liver failure may also present with hypervolemic hyponatremia, but generally only when accompanied by third spacing due to ascites.23 Decreased intravascular volume with cardiac under-filling leads to activation of the renin-angiotensin-aldosterone system and again, release of ADH. Overall, these mechanisms cause renal vasoconstriction and water retention.
In CKD, patients with significantly impaired glomerular filtration rates have damaged nephrons that are less able to dilute urine despite appropriate suppression of ADH. The result is concentrated urine and free water retention. Water intake that exceeds urine output and insensible losses can cause hyponatremia. Patients may appear euvolemic or, if they retain salt and develop edema, hypervolemic. Significant proteinuria in nephrotic syndrome is far less common than the above entities but may result in hyponatremia. When renal protein loss causes serum albumin to drop below 2 g/dL, intravascular volume loss ensues, and decreased pressure at the baroreceptor ultimately can cause increased release of ADH and free water retention.
The treatment of hyponatremia varies and depends on multiple factors, including the underlying cause and fluid status, severity of the presenting symptoms, and the time course over which the disease process has developed. The EP must often take all these factors into account simultaneously while evaluating a hyponatremic patient in the ED.
Acute Hyponatremia. Acute hyponatremia is generally estimated to have developed in less than 48 hours. Causes of acute hyponatremia include MDMA and other drugs, large gastrointestinal diuresis such as colonoscopy preparation, and endurance exercise with inadequate or excessive fluid consumption. In acute hyponatremia, patients are at increased risk for brain herniation due to cellular swelling in a closed space. Within 24-48 hours, the brain is able to compensate for the osmolality difference between the extracellular and intracellular spaces by exuding solutes; however, in acute hyponatremia, the osmolality difference leads to cellular swelling. These patients may present with severe neurologic symptoms and ultimately develop brain herniation.24 Patients with acute hyponatremia require rapid intervention. Although many of these patients will have mild symptoms such as headache, nausea, vomiting, or confusion, their clinical course can deteriorate rapidly to altered mental status, seizures, respiratory arrest, herniation, and even death. The EP should confirm that the serum sodium was drawn appropriately and in the same manner as any previous values, if available. Any factors contributing to hyponatremia should be addressed and any cause-specific therapies should be initiated. Based on present literature, most patients will have significant improvement or reversal of symptoms with an increase of 4-6 mmol/L in the serum sodium.25 Current guidelines recommend a 100-150 mL bolus of 3% hypertonic saline over 10-20 minutes, with repeat doses up to two times as needed for patients with acute symptomatic hyponatremia.2,3,20,26,27 Additional guidelines recommend somewhat less aggressive therapy for patients with mild to moderate symptoms, such as nausea, vomiting, or mild confusion, as they are less likely to develop cerebral edema. These patients should receive 3% hypertonic saline at a rate of 0.5-2 mL/kg/h. The goal of hypertonic saline is not to achieve a specific number, but rather to alleviate any significant symptoms. Once the symptoms improve, hypertonic saline can be discontinued. Recheck sodium at the one-hour mark to avoid overcorrection (see “Overcorrection” section below). (See Table 3.) At this time, the patient will require admission for continued therapy and repeat serum sodium every four hours.2,20 Further treatment will depend on the underlying cause, as discussed below.
Chronic Symptomatic Hyponatremia. The treatment of chronic hyponatremia is more complex and requires greater attention to the rate of correction. Rapid correction of chronic hyponatremia is associated with cerebral edema and increased intracranial pressure, leading to central nervous system damage such as osmotic demyelination syndrome, which may be devastating. Multiple guidelines exist for the rate of correction for chronic hyponatremia. Historically, the widely accepted rate of change was less than 25 mmol/L sodium in 48 hours. Current recommendations are highly variable, but, in general, recommend an even more conservative approach in chronic hyponatremia.3,28,29 A correction rate of 6 mmol/L/day has been found to sufficiently treat severe symptoms without creating the complications of overcorrection. This must be balanced with the inherent risks associated with hyponatremia: rates of change less than 3-4 mEq/L/24 hours are associated with increased mortality.30 Current guidelines strike a good compromise: a rate of 6-8 mmol/L per 24-hour period and any subsequent 24-hour period. Additional recent European guidelines suggest a similar rate of 10 mEq/L in the first 24 hours and 8 mmol/L for any subsequent 24-hour period. These rates are agreed upon in patients with both symptomatic and asymptomatic hyponatremia.21,31
Patients with chronic hyponatremia who develop severe symptoms require acute intervention with hypertonic saline. Severe symptoms most often include focal neurologic deficits, altered mental status, seizures, and coma, but severe vomiting and abnormal and deep somnolence also may prompt treatment with hypertonic saline. Three percent hypertonic saline is given at an infusion of 150 mL over 20 minutes. If necessary, after rechecking the serum sodium, an additional bolus may be given with a target serum sodium increase of 5 mEq/L. At this point, 0.9% normal saline (NS) should replace the hypertonic saline while the clinician investigates the cause in order to initiate cause-specific therapy. Serum sodium should be checked following any bolus of hypertonic saline, and then every 6 hours until normalization.2,31
In the patient with moderately severe symptoms, clinical guidelines recommend a single 150 mL infusion of 3% hypertonic saline given over 20 minutes with a goal of 5 mEq/L in the first 24 hours. Moderately severe symptoms include severe nausea without vomiting, headache, and confusion.31 Although mortality is less among these patients, rapid decompensation can still occur. They should be admitted to the hospital, and serum sodium should be carefully monitored.
Asymptomatic Hyponatremia. In asymptomatic or mildly and moderately symptomatic hyponatremia, treatment depends on the patient’s fluid status. Similar to other patient groups, the goals of sodium correction in asymptomatic hyponatremia are 6-8 mEq/L (with an absolute maximum of 10 mEq/L) in the first 24 hours, given the risk of overcorrection, with the serum sodium being rechecked every 6 hours.21
Directed therapy for the underlying causes of hyponatremia applies to both acute and chronic hyponatremia. Once symptoms have begun to improve or resolve, therapy is tailored based on the patient’s volume status. For patients with hypovolemic hyponatremia, the goal is intravascular repletion with fluid resuscitation and removal of precipitants. Common causes of low volume hyponatremia are gastrointestinal fluid losses, diuretic use, and mineralocorticoid deficiency. With volume repletion, ADH will decrease, allowing for decreased uptake of free water and normalization of plasma sodium. Fluid resuscitation starts with isotonic fluids, generally 0.9% NS at a rate of 0.5-1.0 mL/kg per hour. However, in patients with hemodynamic instability, fluid resuscitation supersedes strict adherence to a controlled rate of correction.21,31 Fluids may be altered to reverse accompanying electrolyte or base deficits, but the clinician must recall that administration of potassium will increase the serum sodium due to cellular exchange of potassium and sodium, which may increase sodium more quickly than desired. The clinician should reevaluate the serum sodium when the patient becomes clinically euvolemic and/or every 6-8 hours. In patients with otherwise normal renal function, the serum sodium should correct slowly; however, in cases of renal impairment, the kidney may undergo free water excretion, potentially causing a correction that is too rapid. Once the goal of correction is met, the clinician may use 0.45% NS or D5W.1,21,31 When a mineralocorticoid deficiency is suspected, the patient should receive a glucocorticoid, such as 50-100 mg of hydrocortisone IV every 8 hours. Mineralocorticoid deficiency that leads to volume depletion is often severe and will require supplementation of both mineralocorticoid and glucocorticoid; however, in the acute setting, hydrocortisone is sufficient.21
Treatment of euvolemic hyponatremia is again tailored to the specific cause. In SIADH, the patient generally responds to improvement of the underlying cause, such as treatment of pneumonia.32 However, in moderate or profound hyponatremia, fluid restriction without salt restriction is considered first-line therapy. These patients may benefit from 0.25-0.5 g/day of urea or oral salt tablets with low-dose loop diuretic to increase serum solute concentration.21 All patients with concern for SIADH should be evaluated for glucocorticoid deficiency. In patients with suspected primary or secondary adrenal insufficiency, glucocorticoids should be administered after the initial blood draw. Patients may receive a stress dose or maintenance dose of steroids, as in mineralocorticoid deficiency. Replacement of glucocorticoids often causes rapid free water loss, leading to rapid change in serum sodium. Finally, patients with primary polydipsia most often require only fluid restriction. Current clinical guidelines no longer recommend lithium and demeclocycline. Lithium and demeclocycline cause polyuria and nephrogenic diabetes insipidus as a side effect and do improve hyponatremia; however, both are associated with azotemia and acute renal injury.19,21,33
Patients with hypervolemic hyponatremia require treatment of the underlying disease leading to hyponatremia and often will require fluid restriction. The most common causes include heart failure, nephrotic syndrome, and cirrhosis with concomitant ascites. Most often, patients with these syndromes receive a fluid restriction of 0.8 L/day.21 The body normally has an obligatory fluid loss of > 1.0 L/day from urinary excretion and insensible losses, so the patient will have a negative fluid balance and increased serum sodium concentration. Unfortunately, this process is slow and understandably difficult for some patients, and different strategies may be helpful. In patients with congestive heart failure (CHF), loop diuretics generally increase water loss, leading to an improved serum sodium in a more timely fashion than fluid restriction alone.34,35 Cirrhosis with ascites can be treated with water and salt restriction, paracentesis, diuretics, and albumin. However, it is important to note that the evidence for fluid restriction in cirrhosis is lacking, and these patients can be very difficult to treat. Nephrotic syndrome is treated similarly to chronic kidney disease with water and salt restriction and diuretics, but may also benefit from albumin with diuretics.2,32,36
EPs should become familiar with vaptans, which are additional agents used to treat hyponatremia. Controversy exists regarding the indications for and efficacy of these medications. Vaptans are antagonists to the vasopressin V1A, V1B, and V2 receptors, which ultimately cause free water loss by blocking the action of ADH; this leads to an increased serum sodium concentration.37 Conivaptan and tolvaptan are the most commonly used vaptans and both are FDA-approved for the inpatient treatment of euvolemic hyponatremia. Generally, these are reserved for severe hyponatremia (value < 125 mEq/L) or for those who do not respond to fluid restriction in the case of hypervolemic and euvolemic hyponatremia. Examples include individuals with recalcitrant SIADH, CHF, or cirrhosis.21,31,34,35,36,38 Although in some studies vaptans seem to normalize sodium more quickly, they are expensive and the safety of their use is not clear. Risks include overcorrection and nephrotoxicity, especially in patients with cirrhosis. Vaptans have not been well-studied in the ED setting nor for treatment of acute hyponatremia, and clinical experience in the ED is limited. The EP can consider the use of vaptans in appropriate patient populations, but should obtain close consultation with a nephrologist or endocrinologist.1,20,36,39
When treating any patient for hyponatremia, the EP must pay close attention to overcorrection, which is considered a medical emergency. Although serious complications are rare, occurring in less than 2% of cases, they can be devastating, resulting in significant neurologic disability or death.40,41 Many patients already will be admitted before serial serum sodium levels return, but in this current era of overcrowded EDs and boarding, the EP must be aware of consequences of overcorrection and understand when to intervene.
Osmotic Demyelination. Osmotic demyelination syndrome (ODS) refers to central pontine myelinolysis (CPM) and extrapontine myelinolysis (EPM) and is a commonly discussed consequence of overzealous correction of hyponatremia. ODS occurs in 1-10% of patients undergoing treatment for hyponatremia.42,43 Adams et al initially recognized ODS on an autopsy in the 1950s; in the 1970s, Tomlinson suggested it was due to a metabolic derangement, and finally the connection to rapid correction of hyponatremia was established. However, it was not until the late 1980s that Sterns et al created the term ODS after recognizing a biphasic pattern following rapid overcorrection of chronic hyponatremia wherein the patient initially improves from the acute hyponatremic symptoms and then develops progressive neurologic symptoms 2-8 days later.44,45 Animal studies also demonstrate that overcorrection of hyponatremia predictably leads to lesions visible on MRI consistent with ODS that are not present before correction. Although there are other factors associated with development of ODS, overcorrection of hyponatremia remains the most common.46,47,48
The mechanism of ODS is not clearly understood but likely is associated with osmolality differences and cellular edema. As previously mentioned, the brain adapts to chronic hyponatremia by extruding solutes; when the osmolality again changes with therapy, fluid shifts can cause cellular swelling. This edema, for unclear reasons, causes non-inflammatory loss of myelin without disrupting the neuronal cell bodies and axons.48,49,50 As the names imply, CPM predominantly affects the pons and EPM predominantly affects the cerebellum. Changes can be widespread; other parts of the brain affected in ODS include the geniculate body, external capsule, basal ganglia, thalamus, gray-white junction, and hippocampus.44,48,51
In classic biphasic ODS, the patient initially improves following treatment. This is followed by deterioration starting with corticobulbar symptoms (dysphagia and dysarthria), corticospinal tract symptoms (flaccid quadriparesis), basis pontis symptoms (spastic quadriparesis), and ultimately may progress to locked-in syndrome.48 The diagnosis of ODS is generally clinical and confirmed by either autopsy or diffusion-weighted imaging (DWI), which is the most sensitive technique for visualization of demyelination.48 Not all patients with overzealous correction develop ODS, and studies show that certain populations are at greater risk, including those with chronic alcoholism (more than half of cases), malnutrition, advanced liver disease, serum sodium < 105 mEq/L, and hypokalemia. Most cases seem to occur with rates of correction greater than 18 mEq/L/24 hr, but have been seen in rates as low as 10 mEq/L/24 hr and 21 mEq/L/48 hr. Both men and women and affected equally, and children are also susceptible.52,53
One group of patients unlikely to be at risk for ODS are those who have developed hyponatremia rapidly (within several hours) due to increased free water intake. These patients have not had time for the brain to adapt to the acute alterations in osmolality. This includes endurance athletes, people with primary polydipsia, and individuals who have used MDMA (in whom the issue of increased water intake is compounded by increased ADH secretion.) This lower risk of complicated overcorrection may in fact be a blessing, as these patients are also at the greatest risk for herniation.53
ODS can be debilitating, but complete recovery is possible. Before the use of DWI, ODS was thought to be irreversible; however, repeat images after treatment have shown complete resolution of signal abnormalities in up to 63% of patients.52 Animal studies show that active reduction of serum sodium following overcorrection reduces rates of ODS.54 Given the degree of potential harm that ODS can inflict, the EP must closely monitor the change in sodium and stop therapy and treat overcorrection when necessary.
Treatment for Overcorrection. Given the complexity of dysnatremias, it should come as no surprise that the desired rate of correction is often not met. Studies have found that as many as 49% of patients had non-optimal correction, with a total of 27% having overcorrected sodium at 24 hours.43 Both persistent hyponatremia and rapid correction of hyponatremia pose risks for patients. While it is a difficult balance, we have noted earlier that increasing the serum sodium concentration by 4-6 mEq/L is enough to reverse symptoms of hyponatremia. This falls far below the rate of overcorrection. When overcorrection does occur, the clinician can employ recently established interventional guidelines.
Current clinical practice guidelines recommend intervention for correction rates that exceed 10 mEq/L in the first 24 hours or 8 mEq/L in any 24-hour period in patients with a starting serum sodium less than 120 mEq/L.31 This is most critical in patients at risk for development of ODS (i.e., those most likely to have chronic hyponatremia.) When overcorrection occurs, stop current treatment and consult nephrology or endocrinology for recommendations on an electrolyte-free water infusion and to discuss the possible use of desmopressin, a synthetic analog of ADH. Its use has been advocated by some authors when the serum sodium rises to 6-8 mEq/L in the first 24 hours, which is actually short of the therapeutic maximum. For active reduction, the clinician can give 2-4 micrograms desmopressin every 8 hours intravenously with oral water or intravenous 5% dextrose given at 3 mL/kg/hr.21 When these interventions are undertaken, the serum sodium should be checked hourly.
The general approach for treating patients with hyponatremia is based on the duration and severity of the hyponatremia and on the presence and severity of symptoms. Use hypertonic saline in patients with acute or chronic hyponatremia with moderate to severe symptoms. Hyponatremic patients who are asymptomatic or have only mild symptoms may be treated with fluid restriction, with or without loop diuretics and oral sodium chloride. Underlying disease states, such as CHF, cirrhosis, CKD, pneumonia, etc., should be addressed. Vasopressin receptor antagonists are occasionally used, but are associated with serious limitations.
Any patient undergoing treatment for hyponatremia requires close evaluation and frequent lab draws. This is important not only to monitor for symptomatic improvement or signs of herniation and deterioration, but also to track the rate of correction (and prevent over-correction.) Most patients undergoing therapy for hyponatremia will require hospitalization. Depending on the severity and acuity of the hyponatremia and nursing requirements, admission to the intensive care unit may be required. Patients who have developed hyponatremia acutely (such as an overdrinking endurance athlete) who present with mild symptoms and respond to therapy may be considered for discharge from the ED with close follow-up.
EPs should consult a nephrologist or endocrinologist as well as an intensivist when use of hypertonic saline or vaptans is contemplated, when the serum sodium is < 120 mEq/L, when the hyponatremia is acute, or if hyponatremia is accompanied by severe symptoms. Additionally, consultations should be considered when the cause of hyponatremia is unclear or if SIADH is suspected and appropriate management is uncertain.2
Athletes. Clinicians need to be aware of the risks for hyponatremia among endurance athletes, and should encourage runners to drink only when they are thirsty. Athletes should monitor their body weight during times of frequent training or competition to ensure that they are neither losing weight (putting them at risk for volume depletion and exertional heat illness) nor gaining weight (putting them at risk for hyponatremia). Exertional hyponatremia may be mistaken for exertional heat stroke, syncope, or another entity. If suspicion exists for exertional heat stroke, an accurate temperature (rectal, esophageal) must be obtained. Serum sodium should be rapidly assessed in any endurance athlete presenting with a history of altered mental status, diminished level of consciousness, excess water consumption, and a normal core temperature. Point-of-care testing of serum sodium should be made available in the medical tent of any large endurance event. Otherwise, obtain it as quickly as possible in the ED. Athletes and coaches should be educated about the fact that the key to prevention is moderate fluid consumption based on perceived need (“ad libitum”) rather than on a rigid rule.26
Elderly. Age-related impairment of water excretion and increased exposure to drugs and diseases that affect water balance place the geriatric population at increased risk of hyponatremia. Even mild hyponatremia has been linked to falls, fractures, and cognitive decline. Elderly patients with congestive heart failure, cirrhosis, or pneumonia are at greatest risk; serum sodium levels should be checked in all hospitalized patients on admission, and even mild hyponatremia should be noted and addressed.
In elderly patients started on a thiazide diuretic, SSRI, or selective norepinephrine reuptake inhibitors, arrangements should be made to check serum sodium levels within 1-2 weeks of initiation of therapy. Thiazide diuretics should be used with extreme caution in elderly patients, and avoided in individuals with diminished protein intake or during acute illness. Hospitalized and institutionalized elderly patients are at great risk for hyponatremia; care should be taken to avoid administration of diuretics, hypotonic fluids, and low-sodium tube feeding in those with impaired water-excreting capacity.2
Emergency Department. Patients may present to the ED with hyponatremia as a consequence of hyper- or hypovolemia, or may be euvolemic patients transferred from institutionalized settings. As such, the EP must be cognizant of the many etiologies behind hyponatremia and of its insidious effects, especially on elderly patients.
As a general rule, EPs should not administer hypotonic fluids to patients at risk for hyponatremia, especially those at extremes of age. Administration of normal saline or Ringer’s lactate should predominate for fluid resuscitation. As noted, elderly patients and those with CHF, cirrhosis, or pneumonia are at risk for hospital-acquired hyponatremia; this risk is even greater in those requiring ICU admission. Avoid hypotonic fluids and thiazide diuretics during the patient’s ED treatment. In patients who are started on diuretics (especially thiazide diuretics) or antidepressants in the ED, the EP should ensure that follow-up testing of serum sodium levels is facilitated. Patients should be discharged with strict return precautions, including even subtle changes in mentation, balance, or strength.1,2,6
Pediatrics. Consider all pediatric patients who receive IV fluid administration to be at risk for hyponatremia. Children younger than 16 years of age and those with hypoxia are at particular risk. Close monitoring of the serum sodium level in any child with hypoxia or neurologic injury is indicated, as even mild hyponatremia is associated with poor outcomes. Hypotonic fluids are no longer recommended for use as maintenance or resuscitation fluids in the pediatric population due to the high risk of iatrogenic hyponatremia.1
Financial Disclosure: To reveal any potential bias in this publication, and in accordance with Accreditation Council for Continuing Medical Education guidelines, we disclose that Dr. Farel (CME question reviewer) owns stock in Johnson & Johnson. Dr. Stapczynski (editor) owns stock in Pfizer, Johnson & Johnson, Walgreens Boots Alliance Inc., GlaxoSmithKline, Bristol Myers Squibb, and AxoGen. Dr. Schneider (editor), Ms. Fessler (nurse planner), Dr. Springer (author), Dr. Gabler (author), Dr. LoVecchio (peer reviewer), Ms. Mark (executive editor), Ms. Leslie Coplin (executive editor), and Mr. Landenberger (editorial and continuing education director) report no financial relationships with companies related to the field of study covered by this CME activity.