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Home , Aquaretic, Hyponatremia, Hypotonic hyponatremia

IVOR DOUGLAS, MD, MRCP(UK)* Assistant Professor, Pulmonary and Critical Care Medicine Director, Medical Intensive Care, Denver Health Medical Center University of Colorado at Denver and Health Sciences Center Denver, CO

Hyponatremia: Why it matters, how it presents, how we can manage it

■ ABSTRACT YPONATREMIA is common among hospi- H talized patients and can lead to serious is a common disorder among hospi- complications, yet its assessment can be a chal- talized patients and has been associated with increased mor- lenge and strategies for its management have tality. Most patients are asymptomatic, but many do present traditionally been suboptimal. New therapies with symptoms, usually of a generalized neurologic nature. are emerging that promise a more targeted Based on medical history, physical examination (including approach to regulating body water and volume-status assessment), and laboratory tests, patients can balance in patients with this disorder. This be classified as having either hypervolemic, euvolemic, or article reviews the incidence and clinical sig- hypovolemic hyponatremia. Management depends on the nificance of hyponatremia, discusses patient speed of hyponatremia onset; its degree, duration, and symp- evaluation and classification, and surveys cur- toms; and whether there are risk factors for neurologic com- rent and emerging management approaches for plications. The risks of overly rapid correction must be weighed the various types of hyponatremia. against the benefits of treating hyponatremia. Traditional therapies have significant limitations. New agents that ■ DEFINITION AND EPIDEMIOLOGY antagonize arginine at the V2 receptor or both the V1A and V2 receptors show promise for treating hyper- Hyponatremia represents an excess of body volemic and euvolemic hyponatremia, as they induce desired water relative to body sodium content and is free water without inducing sodium excretion. frequently defined as a sodium concen- tration of less than 135 mEq/L.1,2 Abnor- ■ KEY POINTS malities of the mechanisms that regulate body Hyponatremia results from changes in total body water, not water and sodium metabolism are often pres- ent in hospitalized patients. Untreated acute body sodium content. These changes are regulated primarily severe hyponatremia is associated with an by thirst, the hormone arginine vasopressin, and the . increase in mortality.3 Hyponatremia is the most common electro- The rate of decline in plasma sodium , the lyte disorder,1 reported to occur in up to 6% of patient’s age, and the extracellular fluid volume affect the hospitalized patients.4 The precise incidence of clinical presentation in patients with hyponatremia. hyponatremia varies depending on the condi- tions underlying it and the criteria used to Prompt, controlled correction of serum sodium is indicated define it.1 When defined as a serum sodium con- for acute symptomatic hyponatremia. Hypertonic and centration of less than 135 mEq/L, hyponatremia a loop are often given to achieve this goal. has been reported in 15% to 22% of hospitalized patients.1 In studies defining it as a concentra- Potentially fatal demyelination can occur with overly rapid tion of 130 mEq/L or less, hyponatremia has serum sodium correction; a moderate rate of correction been described in hospitalized patients at inci- (< 12 mEq/L/day) minimizes this risk. dences of 1% to 4%.1,5 The frequency of hypo- natremia varies by clinical setting as well. In an analysis of the prevalence of hyponatremia * Dr. Douglas reported that he has served as a paid consultant to and is on the speakers’ among 120,137 patients at initial presentation bureau of Astellas Pharma US, Inc. to health care providers, 7.2% of patients in the

S4 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • SUPPLEMENT 3 SEPTEMBER 2006 community-care setting were hyponatremic compared with as many as 28.2% of patients in Algorithm for classifying hyponatremia the acute-care hospital setting.6 Serum sodium <135 mEq/L ■ PHYSIOLOGY OF WATER AND SODIUM BALANCE 280–295 Plasma >295 Hyponatremia is associated with decreased mOsm/kg osmolality mOsm/kg serum osmolality resulting from changes in <280 mOsm/kg 7 Isotonic Hypertonic total body water, not body sodium content. hyponatremia hyponatremia These changes are regulated primarily by thirst, arginine vasopressin (AVP), and the 7 kidney. A net increase in water reabsorption, <100 Urine osmolality >100 however, fails to account entirely for the mOsm/kg mOsm/kg decrease in serum sodium concentration seen 8 in patients with hyponatremia. Excess water intake Impaired renal concentrating ability What stimulates AVP release? Extracellular fluid AVP is synthesized in the and Hypovolemic Hypervolemic transported to the pituitary, where it is hyponatremia hyponatremia stored.7 Changes in effective arterial volume stimulate AVP release, causing a decrease in Urine sodium Urine sodium urine flow, maximal concentration of urine, >20 mEq/L <10 mEq/L >20 mEq/L <10 mEq/L and water reabsorption. The primary stimuli Renal Extrarenal Renal Edematous disorders of AVP release are changes in plasma osmo- solute loss solute loss failure • lality and changes in effective arterial volume Urine sodium • >20 mEq/L • Nephrotic that are sensed by the carotid baroreceptors syndrome and left atrium. Other important stimuli causing AVP release include certain medica- Euvolemic hyponatremia tions (eg, ), pulmonary infections, 7 , and mechanical ventilation. SIADH Reset osmostat Endocrinopathies depletion • • Diuretic use Aging increases likelihood of hyponatremia • Glucocorticoid Several changes in the mechanisms that regu- deficiency late water and sodium balance occur as a nor- SIADH = syndrome of inappropriate antidiuretic hormone secretion mal part of the aging process, such as decreased glomerular filtration rate, decreased renal FIGURE 1. On the basis of volume status, urine osmolality, and urine sodium, blood flow, impaired ability to dilute urine, and patients with hypotonic hyponatremia can be categorized into one of three impaired water excretion.1 These physiologic clinically important classes of hyponatremia: hypovolemic, euvolemic, or changes result in an increased likelihood of hypervolemic. Adapted from references 2 and 10. developing hyponatremia with increasing age. Based on the initial assessment of volume ■ INITIAL PATIENT EVALUATION status, medical history, and laboratory meas- urements of urine osmolality and sodium, The initial evaluation of a patient with patients with hypotonic hyponatremia can known or suspected hyponatremia consists of have their hyponatremia classified into one a careful medical history and physical exami- of three main categories (Figure 1):2,10 nation, including a thorough neurologic • Hypervolemic evaluation and clinical assessment of volume 1 • Euvolemic status. Additionally, laboratory measure- • Hypovolemic. ments of serum , glucose, blood nitrogen, creatinine, uric acid,1 plasma What to exclude osmolality, urine osmolality,9 and urine sodium Because spurious (normo-osmolar) hypona- concentration may be useful. tremia is a common cause of decreased serum

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the brain.1 Gastrointestinal symptoms, such Clinical symptoms in severe hyponatremia as nausea and , are more common in patients with serum sodium levels between 12 Altered sensorium 51.7% 125 and 130 mEq/L. Acute hyponatremia (< 48 hours in duration) in a previously Seizures 22.5% asymptomatic young adult can cause severe central nervous system symptoms even at Nausea/vomiting 4.8% serum sodium levels between 125 and 130 2,13 Gait disturbance/ 3.6% mEq/L. Once the level falls below 125 frequent falls mEq/L, neurologic symptoms predominate.12 Dysarthric speech 2.2% , muscle , reversible ataxia, , lethargy, restlessness, disorienta- Comatose state 2.2% tion, apathy, , and agitation are symptoms seen in patients with serum sodium 12 0 10 20 30 40 50 60 levels below 125 mEq/L. Percentage of patients Clinical signs include abnormal sensorium, hypothermia, depressed reflexes, pseudobul- 2 FIGURE 2. Incidences of symptoms observed in a retrospective study of 168 bar palsy, and Cheyne-Stokes respiration. hospitalized patients with severe hyponatremia (serum sodium < 115 mEq/L) in a US medical center. Adapted from data in reference 14. Complications can be severe Complications of severe and rapidly develop- sodium levels, (> 1,500 ing hyponatremia include , , mg/dL) and hyperproteinemia (> 10 g/dL) brainstem herniation, , per- Accurate should be excluded in patients with compati- manent brain damage, and death. These com- assessment ble clinical syndromes, such as acute pancre- plications result primarily from hyponatremia- induced cerebral , which is most often of effective atitis or myeloma, and in patients receiving total parenteral nutrition. seen in patients following surgery or in those arterial volume with primary . Menstruating women is key to Clinical presentation are also at elevated risk of severe neurologic complications associated with hyponatremia.11 interpreting Although most hyponatremic patients may appear asymptomatic, severe symptomatic Clinically important hyponatremia is a hyponatremic hyponatremia is a medical emergency that calls particular challenge in patients with acute states for immediate treatment. neurologic diseases such as cerebral salt-wast- depend on several factors and vary by patient. ing syndrome, syndrome of inappropriate The rate of decline in serum sodium concen- antidiuretic hormone secretion (SIADH), tration, the patient’s age, and the volume of anoxic or traumatic brain injury, or subarach- extracellular fluid (ECF) all affect the clinical noid hemorrhage, since the presentations can presentation.2 overlap significantly.

CNS symptoms dominate Profile of symptoms and complications Symptoms are related largely to dysfunction A retrospective study of 168 patients with of the central nervous system and are more severe hyponatremia (serum sodium < 115 evident when the decrease in the serum sodium mEq/L) found that 89 patients (52.9%) devel- concentration is large or fast.11 However, oped one or more symptoms, the incidences of patients also present with nonneurologic which are detailed in Figure 2.14 The mean symptoms, such as , thirst, weakness, serum sodium level of symptomatic patients cramping, nausea, vomiting, bloating, was 109 mEq/L before treatment and 120 ± 8 swelling, and tightness of the hands and feet. mEq/L after 48 hours of therapy. Twenty-eight Most patients with a serum sodium con- patients (16.7%) in this cohort were consid- centration greater than 125 mEq/L or with ered to have chronic hyponatremia, with the chronic hyponatremia do not have neurologic remainder considered to have acute hypona- symptoms, owing to volume adaptation by tremia. The overall mortality was 20%, and

S6 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • SUPPLEMENT 3 SEPTEMBER 2006 there was a trend toward increasing mortality with a slow rate of correction. Comorbidities associated with hyponatremia One percent of all postoperative patients are believed to develop hyponatremia, of whom approximately 15% develop sympto- Congestive heart failure matic hyponatremic encephalopathy.15 Various comorbidities that complicate Postoperative state patient care have been associated with Renal failure hyponatremia,3 as detailed in Figure 3.5 Intracranial disease Disseminated ■ CLINICALLY IMPORTANT TYPES Gastrointestinal (GI) loss OF HYPONATREMIA Diuretic use A key to the interpretation of hyponatremic GI loss + diuretic use states is accurate assessment of the effective arterial volume. Baroreceptor sensing of arte- Nondiuretic medication rial fullness tightly regulates autonomic out- Liver disease puts for vasomotor tone and neurohormonal Hypoalbuminemia production of AVP. Hypervolemic hypona- Burns tremia is associated with an increased ECF volume, indicative of total body sodium Pneumonia excess, whereas hypovolemic hyponatremia is More than one cause N = 186 associated with a reduction in ECF volume Other and often in effective arterial volume. By con- 0 5 10 15 20 trast, euvolemic hyponatremia involves AVP Percentage of patients stimulation that is not volume-mediated. Assessment of volume status in hypona- FIGURE 3. Prevalences of various comorbidities in a prospective analysis of tremic patients is essential in helping to dif- hospitalized adults with hyponatremia at a US medical center. Adapted from ferentiate the types of hyponatremia and data in reference 5. determining the most appropriate treatment. Body weight, skin turgor, axillary and mucosal 4 moistness, positional variation in blood pres- ated with hypervolemic hyponatremia. sure, and hemodynamic responses to volume Despite an increased ECF volume, these disor- challenge are useful indicators. ders all have in common a decreased effective arterial blood volume or pressure, elevated Hypervolemic hyponatremia plasma AVP levels leading to water retention, Hypervolemic hyponatremia is associated with and concomitant hyper-reninemic hyperaldos- impaired water excretion.12 In patients with teronism1 with resulting sodium retention that congestive heart failure, cirrhosis, or nephrotic exacerbates the dilutional state. syndrome, results from salt A typical patient with hypervolemic hypo- retention, increased AVP levels, and decreased natremia may present with complaints of dys- glomerular filtration. This combination leads pnea with minimal activity, orthopnea, and to water and salt retention,1 which is the cause night-time awakening. Physical examination of the clinical finding of edema in patients may reveal a lethargic, confused, cyanotic with hypervolemic hyponatremia. patient with nausea or vomiting, tachycardia, Total body sodium and total body water are third heart sound, jugulovenous distension, increased in hypervolemic hyponatremia, with and pitting edema in the lower extremities, total body water exceeding total body sodium highly suggestive of congestive heart failure. (Table 1).2 This condition is detected by the presence of edema or on physical exam- Euvolemic hyponatremia ination.1 Edema-forming states, including con- The most common form of hyponatremia in gestive heart failure, , and nephrotic hospitalized patients is euvolemic hyponatrem- syndrome, are comorbidities commonly associ- ia.2,4,12 AVP-mediated water retention leads to

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T ABLE 1 Volume status and common etiologies of major classes of hyponatremia

HYPERVOLEMIC EUVOLEMIC HYPOVOLEMIC

Volume status Total body water Increased Increased Reduced Total body sodium Increased Unchanged Reduced Extracellular fluid Greatly increased Increased Reduced Edema Present Absent Absent

Etiologies Congestive heart failure SIADH Diuretic excess Cirrhosis –Drugs (antidepressants, Mineralocorticoid deficiency , barbiturates, nicotine, NSAIDs, morphine, Salt-losing nephritis Acute/chronic vincristine) Osmotic diuresis –Physical/emotional renal failure Ketonuria Glucocorticoid Bicarbonaturia deficiency Vomiting or (extrarenal origin) Third-spacing (ie, burns, Hyponatremia ) in hospitalized SIADH = syndrome of inappropriate antidiuretic hormone secretion; NSAIDs = nonsteroidal anti-inflammatory drugs patients is most Adapted from data in references 2 and 19. commonly of the euvolemic form an increase in total body water. However, intra-abdominal, or intracerebral infection, or patients with euvolemic hyponatremia show ectopic secretion by neoplasms. Hypo- no indication of an increase or decrease in thyroidism-related hyponatremia may result sodium stores.2 In contrast to hypervolemic from increased release of AVP or from hyponatremia, edema is absent (Table 1), increased renal tubular AVP sensitivity. hence the term euvolemic hyponatremia.2 Hypothyroidism may not be obvious in elderly Although urinary sodium levels vary patients because symptoms, such as depending on daily fluid and salt intake, or lethargy, may be incorrectly attributed to patients with euvolemia have urine sodium aging.1 Assessment of thyroid function is rec- generally greater than 20 ommended in patients with euvolemic hypo- mEq/L.2 Normal urine sodium levels generally natremia. Glucocorticoid deficiency is also range from 15 to 250 mEq/L and depend on associated with increased AVP release. This hydration status and daily sodium intake. A can result in impaired water excretion and high urinary sodium level indicates non– exacerbate mineralocorticoid deficiency– volume-mediated hyponatremia similar to mediated hypovolemic hyponatremia.17 that in patients with SIADH.16 Additional conditions to be considered in The more common etiologies of euvolemic the of euvolemic hypo- hyponatremia (Table 1) result from nonosmotic natremia include secondary adrenal insuffi- stimuli for AVP release or increased receptor ciency, with associated low cortisol and sensitivity to circulating AVP. SIADH is the adrenocorticotropic hormone levels, and most common cause of clinically important emotional or physical stress.2 euvolemic hypnatremia. SIADH commonly Euvolemic hyponatremia is commonly asso- results from medications, underlying thoracic, ciated with small-cell lung carcinoma leading

S8 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • SUPPLEMENT 3 SEPTEMBER 2006 to SIADH. The ectopic release of vasopressin salt-wasting nephropathy.2 Other situations in causes a decrease in serum sodium, resulting in which electrolyte losses and depletion of ECF severe confusion and lethargy without causing can occur include diabetic glucosuria, post- edema. Regrettably, iatrogenic hyponatremia obstructive diuresis, and infusion continues to be common in hospitalized therapy for intracranial hypertension without patients who have a physiologic stimulus for appropriate electrolyte replacement.2 AVP release and are also receiving significant A typical patient with hypovolemic volumes of hypo-osmolar intravenous fluids.18 hyponatremia is on a low-sodium diet and a diuretic for hypertension and pre- Hypovolemic hyponatremia sents with lethargy, confusion, and dizziness Hypovolemic hyponatremia is characterized in the setting of a low serum sodium level. by deficits of both total body sodium and Excessive thirst, postural hypotension, and total body water, with the sodium deficit decreased skin turgor may be present, greater than the water deficit.11 There are a depending on fluid intake. Nonspecific signs number of etiologies of hypovolemic hypona- and symptoms such as , anorexia, tremia (Table 1).19 abdominal pain, nausea, vomiting, diarrhea, Excessive use of diuretics, specifically thia- and fever may also be observed. In contrast to zide diuretics, is responsible for most cases of patients with euvolemic or hypervolemic hypovolemic hyponatremia and is associated hyponatremia, those with hypovolemic with a preponderance of neurologic symptoms hyponatremia have decreased body sodium disproportionate to clinical signs of hypo- and water. Patients with hypovolemic hypo- volemia.20 Thiazide diuretics inhibit sodium natremia do not present with edema. chloride reabsorption in the distal convoluted tubule and impair urinary diluting capacity, ■ MANAGEMENT OF HYPONATREMIA Neurologic resulting in modest volume depletion, AVP To be optimal, therapy for hyponatremia must symptoms secretion, and water retention, without per- be individualized. In all patients, the risk of predominate once turbing urinary concentration capacity.2 A hyponatremia-associated complications must recent study by Kim et al suggests additional be balanced against the risk of serum sodium serum sodium possible mechanisms for thiazide-associated correction.1,3 Several important factors should falls below 21 hyponatremia. These researchers showed that be considered when deciding on treatment, 125 mEq/L thiazide diuretics cause upregulation of aquapor- including the following1,4: ins in animals previously treated with , a • The rapidity of onset of hyponatremia drug known to induce nephrogenic diabetes • The degree, duration, and symptoma- insipidus and to downregulate aquaporin. tology of hyponatremia Patient age, body weight, and serum potas- • The presence or absence of risk factors sium level were the strongest predictors of for neurologic complications. thiazide-mediated hyponatremia in a step- wise logistic regression analysis that com- Acute symptomatic hyponatremia pared 223 patients with thiazide-associated Acute symptomatic hyponatremia develops in hypovolemic hyponatremia with 216 con- less than 48 hours. Clinical manifestations are trols.22 Loop diuretics and other medications, largely related to central nervous system dys- such as nonsteroidal anti-inflammatory drugs, function resulting from brain cell swelling. were not strongly associated.22 Patients are at particular risk for this condi- Chronic renal insufficiency, such as diabetic tion during the perioperative period.15 Once renal disease, is commonly associated with the serum sodium level falls below 125 mEq/L, impaired sodium reabsorption and AVP sensi- neurologic symptoms predominate.12 In acute tivity. Patients with medullary cystic disease, severe and rapidly developing hyponatremia, chronic interstitial nephritis, polycystic kid- the risk of complications of ney disease, analgesic-induced nephropathy, exceeds the risk of osmotic demyelination partial urinary tract obstruction, or chronic associated with too-rapid correction of serum glomerulonephritis may in rare cases present sodium, so treatment should begin promptly.1,4 with hypovolemic hyponatremia secondary to Prompt, controlled correction of the serum

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sodium level is indicated for patients with mulas that allow for calculation of appropri- acute symptomatic hyponatremia. The goal is ate volume and rate of infusate for patients to raise the serum sodium level by 1.5 to 2 with or without symptoms. mEq/L/hour until symptoms subside1 or until the concentration has risen to a safer level— Chronic asymptomatic hyponatremia usually greater than 118 to 120 mEq/L, with The goal in treating asymptomatic hypona- the primary focus being to minimize the risk tremia is to prevent a further decline in serum of seizures. Even in symptomatic patients, the sodium and to maintain levels as close to nor- sodium level should not be raised by more mal as possible. Treatment involves a more than 12 mEq/L in the first 24 hours and by conservative approach than for symptomatic more than 18 mEq/L in the first 48 hours, in hyponatremia. Initially, underlying causes of order to avoid osmotic demyelination (cen- hyponatremia should be investigated and tral pontine myelinolysis).23 treated; this should include evaluation for Infusion of hypertonic saline (3%) at a rate drug-induced hyponatremia. Fluid restric- of 1 to 2 mL/kg/hour and addition of a loop tion, isotonic saline, and loop diuretics may diuretic, to enhance water excretion, are com- be used to treat the hyponatremia. monly used to achieve this goal.4 Hypertonic Euvolemic hyponatremia is the most com- saline may be infused at a rate of 4 to 6 mon form of asymptomatic hyponatremia. If mL/kg/hour if severe neurologic symptoms, the underlying cause is SIADH and its etiology particularly seizures, are present.1 Once a is unknown or cannot be effectively treated, patient is asymptomatic and sodium levels are therapy should be instituted for the hypona- 2,4 greater than 118 mEq/L, correction should be tremia itself. In cases where the etiology of slowed to no more than 8 mEq/L in 24 hours SIADH is known (eg, tumor), the underlying 2 Do not raise to achieve a target level of 125 mEq/L.11 In all cause should be treated or removed in addi- tion to correcting the serum sodium level. serum sodium cases, close and frequent monitoring of serum sodium and electrolytes is mandatory until Current management options by more than sodium levels increase and symptoms subside.4 Fluid restriction can play a role in the treat- 12 mEq/L in the ment of hypervolemic and euvolemic forms first 24 hours Chronic symptomatic hyponatremia of hyponatremia. Although fluid restriction is In hyponatremia of unknown duration, or of inexpensive, it takes days for an effect to be more than 48 hours’ duration, sodium correc- seen. It also is associated with poor patient tion should be managed very cautiously adherence and may prolong hospitalization. because of significant osmotic adaptation of Pharmacologic agents may be used con- 2 the brain to prolonged hyponatremia. In comitantly with fluid restriction. Demeclo- patients presenting with severe symptoms, cycline directly inhibits AVP action at the treatment should be similar to that for acute level of the distal renal tubules and reduces symptomatic hyponatremia: hypertonic urine concentration, even in the presence of saline plus a . Careful monitor- increased AVP levels. The starting dose of ing is critical because of an increased risk of ranges from 600 to 1,200 irreversible osmotic demyelination. Cor- mg/day, and it may be used in patients with rection should be limited to no more than 10 chronic hyponatremia.1,2,4 However, demec- to 12 mEq/L on the first day of treatment and locycline is expensive, has low potency, and 4 less than 6 mEq/L/day thereafter. In patients is rarely used because of nephrotoxicity, par- presenting with mild to moderate symptoms, ticularly in patients with liver cirrhosis.2 slower correction is required, generally 0.5 Lithium is also a direct competitive antag- mEq/L/hour. Once the desired correction is onist ofs AVP action via its induction of achieved, therapy may continue in the form nephrogenic diabetes insipidus. It is rarely 2 of fluid restriction. used, however, owing to its adverse effects.24 Adequate correction of serum sodium lev- els, using appropriate infusion rates, involves Emerging options: AVP antagonists complex calculations. Adrogué and Madias11 Traditional therapeutic options for managing have described a useful approach using for- AVP-induced hyponatremia are suboptimal

S10 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 • SUPPLEMENT 3 SEPTEMBER 2006 and have significant limitations, as outlined T ABLE 2 in Table 2.24–26 As a result, newer agents that antagonize vasopressin receptors have been Traditional treatment options for hyponatremia developed. These AVP antagonists, or TREATMENT MECHANISM LIMITATIONS “,” cause increased free water clear- ance without directly affecting tubular sodium Fluid restriction Induces negative No direct inhibition handling. Some act at both the vasopressin (most common) water balance of excess hormone type 1A (V ) and vasopressin type 2 (V ) 1A 2 Increases plasma No inhibition of receptors (ie, , recently approved osmolality and serum hormone on kidneys by the US Food and Drug Administration for sodium treating euvolemic hyponatremia in hospital- Nonadherence ized patients), while others act solely at the Demeclocycline Impairs AVP action Nephrotoxicity V2 receptor (ie, the investigational agents at renal tubules (cirrhosis patients) , satavaptan, and ). Induces nephrogenic Hypersensitivity Dual V1A/V2 receptor antagonism has diabetes insipidus Drug interactions been shown to have favorable Reduces urine concen- Unsafe in effects in patients presenting with hyper- tration, even with volemic and euvolemic hyponatremia.27 increased AVP levels antagonists may also have potential therapeutic benefit in patients Urea Decreases sodium Hypersensitivity with cardiovascular diseases, such as conges- excretion Unsafe in pregnancy tive heart failure. Combined V1A/V2 recep- Azotemia tor antagonism is of particular interest Liver failure because V1A antagonism may provide further Can reduce effects of benefit by decreasing afterload in addition to lithium 27 V2-mediated aquaresis. Patients with symp- Phlebitis, thrombosis tomatic euvolemic hyponatremia are at par- ticular risk of inappropriate sodium correc- Lithium Impairs AVP at renal Inconsistent results tion or seizures. These patients are especially tubules Lithium toxicity likely to benefit from aquaretic-based correc- Anti-anabolic effects tion to avoid the unpredictable effects of vol- mainly in cirrhosis and ume restriction and saline repletion. congestive heart failure Unsafe in pregnancy Complications: Risks and strategies for avoidance Diuretics Increase water excretion Hypersensitivity Menstruating women, prepubescent children, (loop/thiazide) by inhibiting sodium Hepatic coma and chloride Anuria and patients with preexisting hypoxic cere- reabsorption in bral injury are thought to be at elevated risk loop of Henle Severe electrolyte for developing direct neurologic complica- and distal tubule depletion tions of cerebral swelling related to hypona- tremia. Osmotic demyelination is a potentially AVP = arginine vasopressin fatal complication that may develop one to Data from references 24–26. several days after aggressive treatment of hyponatremia. Hepatic failure, potassium depletion, and are risks for this 11 rection (<12 mEq/L/day), without increasing iatrogenic complication. Demyelination 11 may occur in the face of overly rapid correc- sodium to more than 125 to 130 mEq/L, will tion of hyponatremia and causes brain cell minimize the likelihood of demyelination. 1,3 shrinkage. Oligodendrocytes are thought to ■ be particularly sensitive to sudden osmotic SUMMARY AND CONCLUSIONS shrinkage, resulting in rapid cellular apopto- Hyponatremia is the most common electrolyte sis.28 A moderate and appropriate rate of cor- disorder in hospitalized patients. Severe pre-

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sentations are associated with increased mor- rection with fluid restriction and the potential tality. Hyponatremia must be managed on an for additional electrolyte losses with diuretics. individual basis, with great care taken to An ideal treatment for hypervolemic or eu- ensure safe and controlled serum sodium cor- volemic hyponatremia would provide solute rection. Important factors to consider when free water excretion with prompt, controlled managing patients with hyponatremia include correction of serum sodium. With this goal in the rapidity of hyponatremia onset; its degree, mind, new medications that antagonize AVP duration, and symptomatology; and risk factors have been developed, including a dual V1A/V2 associated with neurologic complications. receptor antagonist and several V2 receptor Traditional therapies for hyponatremia antagonists. These agents may represent a sig- have limitations that make them suboptimal. nificant advance over current therapies for These include the time to serum sodium cor- hypervolemic and euvolemic hyponatremia.

■ REFERENCES 1. Janicic N, Verbalis JG. Evaluation and management of 17. Yatagai T, Kusaka I, Nakamura T, et al. Close association hypo-osmolality in hospitalized patients. Endocrinol of severe hyponatremia with exaggerated release of argi- Metab Clin North Am 2003; 32:459–481. nine vasopressin in elderly subjects with secondary adrenal 2. Schrier R. The patient with hyponatremia or hyperna- insufficiency. Eur J Endocrinol 2003; 148:221–226. tremia. In: Schrier RW, ed. Manual of . 5th 18. Rabinstein AA, Wijdicks EF. Hyponatremia in criti- ed. Philadelphia, PA: Lippincott Williams & Wilkins; cally ill neurological patients. Neurologist 2003; 2000:21–36. 9:290–300. 3. Gross P, Reimann D, Henschkowski J, Damian M. Treat- 19. Craig S. Hyponatremia. eMedicine Web site. Updated ment of severe hyponatremia: conventional and novel January 20, 2005. Available at: http://www.emedicine.com/ aspects. J Am Soc Nephrol 2001; 12(Suppl 17):S10–S14. emerg/topic275.htm. Accessed April 13, 2005. 4. Han DS, Cho BS. Therapeutic approach to hypona- 20. Chow KM, Kwan BC, Szeto CC. Clinical studies of tremia. Nephron 2002; 92(Suppl 1):9–13. thiazide-induced hyponatremia. J Natl Med Assoc 2004; AVP antagonists 5. Anderson RJ, Chung HM, Kluge R, Schrier RW. 96:1305–1308. Hyponatremia: a prospective analysis of its epidemiology 21. Kim GH, Lee JW, Oh YK, et al. Antidiuretic effect increase free and the pathogenetic role of vasopressin. Ann Intern of in lithium-induced nephro- water clearance Med 1985; 102:164–168. genic diabetes insipidus is associated with upregula- 6. Hawkins RC. Age and gender as risk factors for hypona- tion of aquaporin-2, Na-Cl co-transporter, and epithe- without tremia and . Clin Chim Acta 2003; lial sodium channel. J Am Soc Nephrol 2004; 337:169–172. 15:2836–2843. affecting 7. Vasa FR, Molitch ME. Endocrine problems in the 22. Chow KM, Szeto CC, Wong TY, Leung CB, Li PK. chronically critically ill patient. Clin Chest Med 2001; Risk factors for thiazide-induced hyponatraemia. QJM tubular sodium 22:193–208. 2003; 96:911–917. handling 8. Brenner GM. Syndrome of inappropriate antidiuretic 23. Sterns RH, Cappuccio JD, Silver SM, Cohen EP. Neu- hormone secretion. In: Brenner GM, ed. Brenner & rologic sequelae after treatment of severe hyponatremia: a Rector’s The Kidney. 7th ed. New York, NY: Elsevier; multicenter perspective. J Am Soc Nephrol 1994; 2004:897–903. 4:1522–1530. 9. Al-Salman J, Kemp D, Randall D. Hyponatremia. West 24. Lithium carbonate. Physician’s Desk Reference. J Med 2002; 176:173–176. Montvale, NJ: Thomson PDR; 2004:1485–1486. 10. Miller M. Hyponatremia: age-related risk factors and 25. Verbalis JG. Vasopressin V2 receptor antagonists. J Mol therapy decisions. Geriatrics 1998; 53:32–42. Endocrinol 2002; 29:1–9. 11. Adrogué H, Madias N. Hyponatremia. N Engl J Med 26. Foster J. Syndrome of inappropriate antidiuretic hormone 2000; 342:1581–1589. secretion. eMedicine Web site. Updated August 23, 2001. 12. Schrier RW, ed. Atlas of Diseases of the Kidney. Available at: http://emedicine.com/emerg/topic784.htm. Philadelphia, PA: Current Medicine; 1999. Accessed April 13, 2005. 13. Fraser CL, Arieff AI. Epidemiology, pathophysiology, 27. Udelson J, Smith WB, Hendrix GH, et al. Acute hemo- and management of hyponatremic encephalopathy. Am dynamic effects of conivaptan, a dual V1A and V2 vaso- J Med 1997; 102:67–77. pressin receptor antagonist, in patients with advanced 14. Nzerue CM, Baffoe-Bonnie H, You W, Falana B, Dai S. heart failure. Circulation 2001; 104:2417–2423. Predictors of outcome in hospitalized patients with severe 28. DeLuca GC, Nagy Z, Esiri MM, Davey P. Evidence for hyponatremia. J Natl Med Assoc 2003; 95:335–343. a role for apoptosis in central pontine myelinolysis. Acta 15. Ayus JC, Arieff AI. Brain damage and postoperative Neuropathol (Berl) 2002; 103:590–598. hyponatremia: the role of gender. 1996; 46:323–328. 16. Medline Plus Medical Encyclopedia: Sodium—urine. U.S. National Library of Medicine and the Address: Ivor Douglas, MD, MRCP(UK), Denver Health National Institutes of Health. Available at: Medical Center and University of Colorado at Denver http://www.nlm.nih.gov/medlineplus/ency/arti- and Health Sciences Center, MC 4000, 777 Bannock cle/003599.htm. Accessed April 12, 2005. Street, Denver, CO 80204; [email protected].

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