Hyponatremia: A Review

Analytic Review Hyponatremia: A Review Mary Ansley Buffington, MD, JD 1 and Kenneth Abreo, MD 1 Journal of Intensive Care Medicine 2016, Vol. 31(4) 223-236 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalspermissions.nav DOI: 10.1177/0885066614566794 jic.sagepub.com Abstract Hyponatremia is the most frequently occurring electrolyte abnormality and can lead to life-threatening complications. This disorder may be present on admission to the intensive care setting or develop during hospitalization as a result of treatment or multiple comorbidities. Patients with acute hyponatremia or symptomatic chronic hyponatremia will likely require treatment in the intensive care unit (ICU). Immediate treatment with hypertonic saline is needed to reduce the risk of permanent neurologic injury. Chronic hyponatremia should be corrected at a rate sufficient to reduce symptoms but not at an excessive rate that would create a risk of osmotic injury. Determination of the etiology of chronic hyponatremia requires analysis of serum osmolality, volume status, and urine osmolality and sodium level. Correct diagnosis points to the appropriate treatment and helps identify risk factors for accelerated correction of the serum sodium level. Management in the ICU facilitates frequent laboratory draws and allows close monitoring of the patient s mentation as well as quantification of urine output. Overly aggressive correction of serum sodium levels can result in neurological injury caused by osmotic demyelination. Therapeutic measures to lower the serum sodium level should be undertaken if the rate increases too rapidly. Keywords hyponatremia, osmotic demyelination syndrome, syndrome of inappropriate antidiuretic hormone, vasopressin receptor antagonist Introduction Hyponatremia is the most common electrolyte abnormality in hospitalized patients and is frequently encountered in the intensive care setting. Treatment varies significantly according to the timing of onset and etiology of the disorder. Inadequate or improper treatment may lead to brain edema or demyelination with life-threatening consequences. Hyponatremia is the excess of total body water relative to extracellular sodium. A simplified version of the Edelman equation demonstrates the relationship in Equation 1: ½NaŠ s ¼ ½NaŠ e þ½kš e TBW : The serum sodium level is determined by the relationship of total body exchangeable sodium and potassium with total body water. Hyponatremia develops due to primary sodium deficit, primary potassium deficit, primary water excess, or a combination of these conditions. 1 Notably, increases in sodium or potassium will increase the serum sodium level. Diagnosis requires recognition of sometimes subtle neurological symptoms, evaluation of volume status, and analysis of serum and urine sodium levels and osmolality. Appropriate treatment rendered in a timely manner can result in complete recovery in many cases. Incidence and Mortality Analysis of hyponatremia in the National Health and Nutrition Examination Survey (NHANES; 1999-2004) cohort showed the prevalence in the general US population to be 1.72%. 2 Hyponatremia is common in hospitalized patients, occurring in 30% to 40% of patients with a serum sodium of <135 meq/l. 3 DeVita et al found that approximately 25% to 30% of patients admitted to an intensive care unit (ICU) had hyponatremia defined as serum sodium <134 meq/l. 4 A retrospective review of a database of patients admitted to 151,486 ICUs showed that hyponatremia, defined as serum sodium <135 meq/l, was noted in 17.7%. 5 Of the total sample, 13.8% had borderline hyponatremia (serum sodium 130-135 meq/l), 2.7% had mild hyponatremia (serum sodium 125-129 meq/l), and 1.2% had severe hyponatremia (serum sodium <125 meq/l). The adjusted odds ratio for risk of mortality in these patients was 1.32 (confidence interval [CI] 1.25-1.39), 1.89 (CI 1.71-2.09), and 1.81 (CI 1.56-2.10), respectively, compared to patients admitted with a serum sodium in the normal range. Similarly, a point prevalence study involving 1265 ICUs in 76 countries showed that 12.9% 1 LSU Health Shreveport School of Medicine, Nephrology Section of Department of Internal Medicine, Shreveport, LA, USA. Received March 19, 2014, and in revised form October 23, 2014. Accepted for publication October 24, 2014. Corresponding Author: Mary Ansley Buffington, Louisiana State University Health Sciences, 1501 Kings Highway, Shreveport, LA 71130, USA. Email: mbuffi@lsuhsc.edu

224 Journal of Intensive Care Medicine 31(4) of 13,276 patients had hyponatremia. 6 When the degree of hyponatremia is stratified, the prevalence was 10.2% with mild hyponatremia (SNa 130-134), 1.9% with moderate hyponatremia (SNa 125-129), and 0.76% with severe hyponatremia (SNa <125). The adjusted odds ratio for hospital mortality compared to patients with a normal serum sodium in the cohort were 1.27 (CI 1.08-1.49), 1.76 (CI 1.27-2.43), and 2.11 (CI 1.28-3.46) in the sub-groups, respectively. Hyponatremia that develops after admission to the ICU can increase mortality. 7 Although hyponatremia is associated with an increased risk of mortality, the presence of serious comorbidities makes it difficult to calculate the risk attributable only to the electrolyte abnormality and not coexisting illnesses. This is highlighted by variable mortality findings according to severity of hyponatremia. Waikar et al conducted a prospective cohort study evaluating hyponatremia in 98,411 patients who had been hospitalized for at least 48 hours. 8 Although the odds ratio for in-hospital mortality with serum sodium <135 meq/l was 1.47 (95% CI 1.33-1.62), there was a trend toward lower mortality for patients with a serum sodium of <120 meq/l compared to that for serum sodium of 120 to 125 meq/l. This trend toward lower mortality as the serum sodium falls is illustrated more definitively in a retrospective study of hospitalized patients with severe hyponatremia, where the mortality of patients with a serum sodium of 120 to 124 meq/l was 11.2% compared to a mortality of 6.8% of patients with serum sodium <115 meq/ L. 9 Other studies have shown increasing mortality in severe hyponatremia. More research is needed to determine whether hyponatremia per se is an independent cause of mortality. 10 Pathophysiology Water diffuses freely across the cell membrane; thus, the osmolality of the intracellular and extracellular fluid is the same. In hyponatremia, decreased osmolality in the extracellular compartment creates an osmotic gradient relative to the intracellular environment and causes water influx into cells with a corresponding increase in size. The resulting edema occurring in the brain can be life threatening. In response, a compensatory process begins to reduce intracellular and interstitial edema. Brain volume regulation occurs via decreases in the interstitial concentration of Na þ and intracellular content of electrolytes (K þ and Cl ) and organic solutes, such as inositol, taurine, creatine, and glutamine. 11 The loss of osmolytes causes a decrease in brain water content. Electrolytes are extruded rapidly in response to increased volume. Organic osmolytes are extruded over the course of 24 to 72 hours. Brain edema occurs when the inflow of water exceeds the compensatory mechanism. 12 As hyponatremia is corrected, the adaptive process reverses, and the brain must reaccumulate the electrolytes and organic solutes. This reaccumulation is slower and less efficient. Correction of hyponatremia causes increased osmolality in the extracellular compartment with resulting movement of water from the intracellular to extracellular compartments. Restoration of intracellular stores of organic osmolytes occurs over several days; thus, rapid correction of hyponatremia can lead to effective dehydration of brain cells and resulting demyelination. An increase in osmolality that exceeds the capacity to reaccumulate these solutes can lead to pontine and extrapontine demyelination that causes neurological sequelae. Initially, the patient may improve due to correction of the electrolyte disturbance but subsequently deteriorate as the demyelination progresses. Arginine vasopressin (AVP) is the primary regulator of plasma osmolality and total body water. It is synthesized in the supraoptic nucleus and paraventricular nucleus of the hypothalamus and stored in the posterior pituitary. 13 Release of AVP is stimulated by an increase in plasma osmolality, decrease in blood pressure or blood volume, nausea, emesis, pain, stress, hypoxia, and fear. 14 In the kidney, AVP acts on the V2 vasopressin receptors (V2Rs) on the basolateral membrane of epithelial cells in the collecting duct. Activation of the V2R stimulates adenylate cyclase resulting in increased intracellular cyclic adenosine monophosphate. This causes movement of vesicles containing aquaporin 2 channels to the apical membrane and thus increases water reabsorption. Osmotic stimulation of AVP release occurs at approximately 285 mosm/kg with AVP levels being very low or nondetectable at lower osmolality in normal physiology. 15 At a plasma osmolality of 290 to 295 mosm/kg, urine is maximally concentrated; thus, further increases in plasma osmolality or the AVP level will not cause increased renal response. However, plasma osmolality of 295 mosm/kg stimulates osmoreceptors for thirst in the hypothalamus and leads to the intake of water, which lowers plasma osmolality. 16 Reabsorption of free water and the intake of water in response to thirst lead to a return of plasma osmolality to the normal range. AVP levels and free water reabsorption then decrease. The optimum excretion of free water by the kidneys requires maximum suppression of AVP and adequate solute intake; thus, the amount of solute available for excretion is one determinant of the amount of water that can be excreted. 17-19 The following formula illustrates the relationship of solute excretion and urine concentration on the volume of urine excreted: Daily Solute Excretion ðmmol=dþ Urine Volume ¼ Urinary Solute Concentration ðmmol=lþ : A normal participant has a daily solute excretion of 800 mmol/d and a maximal urinary diluting capacity of 60 mmol/l; hence, the maximum urine volume would be 13.3 L. If reduced solute intake reduces the solute available for water clearance to 300 mmol/d, despite unchanged diluting capacity, the urine volume would drop to 5 L/d. Clinical Features The symptoms of acute hypotonic hyponatremia, present for less than 48 hours, are attributable to edema of brain cells. Symptoms in mild hyponatremia are nausea, vomiting, and headache. 20 As sodium levels decrease, symptoms include altered mental status, seizures, obtundation, coma, and death. 21 The clinical manifestations of chronic hyponatremia, or hyponatremia, that exists for at least 48 hours, are disorientation,

Buffington and Abreo 225 Figure 1. Initial evaluation of hyponatremia. lethargy, dysarthria, gait disturbances, and rarely seizure. 22 Mild chronic hyponatremia can be asymptomatic due to osmotic adaptation that reduces edema in brain cells over time; however, gait and attention impairments along with an increased incidence of falls may be subtle manifestations. 23 Correction of chronic hyponatremia can lead to osmotic demyelination syndrome (ODS). This occurs most commonly with severe hyponatremia (serum sodium <120 meq/l) when serum sodium has been corrected too quickly. 24 Symptoms attributable to ODS manifest 24 to 48 hours after correction. Those symptoms are quadriplegia, pseudobulbar palsy, coma, seizures, and death. 22 Hypoxia may play a role in the development of hyponatremic encephalopathy and may also impair the brain volume regulatory adaptation. 25 Diagnostic Approach Hyponatremia is typically categorized as hypertonic, isotonic, or hypotonic (Figure 1). Initial evaluation of a patient with hyponatremia should include a plasma osmolality to distinguish among these entities because treatment of each differs considerably. Careful history and physical examination should determine the time of onset of hyponatremia and the onset of symptoms. Further analysis of urine osmolality and sodium concentration will give clues to the etiology of the hyponatremia, which can then guide treatment. Nonhypotonic Hyponatremia There are 2 types of nonhypotonic hyponatremia, pseudohyponatremia and hypertonic hyponatremia. Pseudohyponatremia is hyponatremia occurring at an isotonic osmolality. The composition of plasma is usually 93% water and 7% lipids and protein. Electrolytes are routinely measured by indirect potentiometry, wherein the sample is diluted and measurement assumes that water constitutes 93% of plasma volume. Expansion of the lipid or protein portion decreases the water portion in comparison; thus, measured serum sodium would be at an artifactually lower level than if measured directly within the water portion of plasma volume. This inaccurate sodium level is termed pseudohyponatremia. Measurement of serum osmolality would be within the normal range. However, measurement of the sodium activity directly within the water phase without dilution of the sample shows it to be within the normal range. Measuring the sodium activity via direct potentiometry using a blood gas analyzer yields an accurate result. 26 Multiple myeloma or macroglobulinemia can cause expansion of the plasma protein composition. Case reports have identified lipoprotein-x, an abnormal lipoprotein seen in cholestatic jaundice and lecithin cholesterol acyl transferase deficiency, as a cause of pseudohyponatremia. 27 Treatment of the underlying protein-related disorder may lead to an increased serum sodium concentration. Hypertonic hyponatremia occurs when plasma contains an osmotically active substance such as mannitol or excess glucose. Urea and alcohols such as ethanol and methanol are ineffective osmoles because they freely cross the cell membrane and therefore do not induce a concentration gradient that causes movement of water. As such, a normal or elevated plasma osmolality does not rule out hypotonic hyponatremia in the setting of a high blood alcohol level or azotemia. Mannitol and glucose in hyperglycemia do not cross freely into the cell; thus, there is a concentration gradient that translocates or draws water out of the cells. This increase in the water phase of plasma causes the concentration of sodium to appear reduced. For each 100 mg/dl of glucose above normal, the serum sodium should be corrected by 2.4 meq/l. 28 Measurement of osmolality would show a hypertonic state. Administration of intravenous immune globulin (IVIG) can cause both pseudohyponatremia and hypertonic hyponatremia. Administration of IVIG can cause pseudohyponatremia by increasing the protein concentration of plasma and sucrose added as a carrier in commercial IVIG preparations causes hypertonic hyponatremia. 29 Additionally, a large amount of sterile water delivered with the infusion can cause hypotonic hyponatremia. Hypotonic Hyponatremia When hypotonic hyponatremia is present, urine osmolality should be measured to determine whether the urine is maximally dilute with a urine osmolality <100 mosm/l (Figure 2). If so, antidiuretic hormone (ADH) is not a factor in causing the hyponatremia. Causes of this type of hyponatremia are from either excess fluid intake and/or low solute intake as in psychogenic polydipsia and beer potomania. In psychogenic polydipsia, the patient drinks an amount of water that exceeds the capacity of the kidney to excrete, despite suppression of ADH with an intact ability to dilute the urine. 30 Typically, the amount of intake required to cause this kind of hyponatremia is upward of 1 L/h. Hyponatremia associated with beer potomania and malnutrition results from a combination of poor solute intake and relatively excessive fluid intake. Isotonic or hypotonic irrigation solutions used during transurethral prostatectomy and hysterectomy can also cause hypotonic hyponatremia. 31 These nonelectrolyte solutions contain sorbitol, mannitol, or glycine. Absorption of large volumes of the irrigation solution causes an initial iso- or hypo-osmolar hyponatremia, which is followed by water movement into the

226 Figure 2. Evaluation of hypotonic hyponatremia.

Buffington and Abreo 227 cells as the compound gets excreted or metabolized. If the solute is cleared faster than free water, hypo-osmolality will develop. Sorbitol is metabolized by the liver with some renal excretion, mannitol is excreted in the urine, and glycine is metabolized in the liver to urea and ammonia. Patients can develop neurologic symptoms from hypo-osmolality, ammonia toxicity, and transient visual symptoms from glycine toxicity. It should be kept in mind that a patient with hypovolemic hyponatremia who has received treatment with normal saline may also have a low urine osmolality (<100 mosm/l) when hypovolemia is corrected causing suppression of ADH and excretion of free water. To evaluate other causes of hypotonic hyponatremia, it is helpful to determine volume status of the patient to decide if he or she has hypovolemic, hypervolemic, or euvolemic hyponatremia. Also, urine sodium is helpful in further distinguishing between renal and nonrenal causes of hyponatremia. Hypovolemic Hyponatremia In hypovolemic hyponatremia, the patient may have signs of volume depletion such as decreased skin turgor, dry mucous membranes, orthostatic hypotension, and tachycardia. However, detecting hypovolemia in patients with hyponatremia can be difficult in the absence of obvious signs. 32 The patient has a deficit in serum sodium and total body water but has lost relatively more sodium. These sodium deficits can be due to renal or extrarenal losses. A urine sodium concentration >30 meq/l would be consistent with renal losses of sodium and water, which can occur with diuretic use, mineralocorticoid deficiency, salt-wasting nephropathy, and cerebral salt wasting (CSW). A urine sodium <30 meq/l indicates a nonrenal loss from vomiting, diarrhea, pancreatitis, or burn injury. 32 Hypovolemia is a nonosmotic stimulus for AVP release; however, the volume- and pressure-related stimuli for AVP secretion do not act independent of the osmotically mediated stimulus. In hypovolemia, the osmotic threshold at which AVP is released shifts to the left, such that AVP is released at a lower plasma osmolality. The magnitude of the shift depends on the degree of volume depletion or hypotension. The shift of the osmotic threshold causes concentration of the urine and conservation of free water in order to correct the volume depletion. The threshold for stimulation of thirst also shifts to the left; thus, there is the drive for water intake at a lower plasma osmolality. 16 The AVP-mediated conservation of free water combined with thirst-related intake of water causes an increase in volume. However, the decreasing plasma osmolality in that setting can lead to hyponatremia. Extrarenal volume depletion can result from vomiting, diarrhea, and third spacing of fluids due to trauma, pancreatitis, or burns. The urine sodium would be <30 meq/l. However, in patients with hypovolemia having metabolic alkalosis, the urine sodium may be misleadingly high and in this setting the low urine chloride should be used to diagnose hypovolemia. Thiazide exposure has been associated with an almost 5 times higher risk of hyponatremia than nonexposure. 33 Factors associated with the occurrence of thiazide-induced hyponatremia are older age, lower body mass, and lower serum potassium level. 34 Thiazides block the sodium chloride cotransporter of the distal convoluted tubule, whichisanimportantmechanism of urinary dilution. They also cause volume depletion that stimulates AVP release and leads to retention of free water. 35 Potassium depletion can cause a shift of sodium into cells to restore osmotic equilibrium. 36 Also, increased water intake in the setting of elevated AVP provoked by diuretic use can be a factor in causing hyponatremia. 37 Finally, studies have shown that thiazides increase water absorption in the collecting duct by upregulation of aquaporin 2. 38 Mineralocorticoid deficiency due to primary adrenal insufficiency will cause decreased levels of aldosterone, cortisol, and adrenal androgens. 39 This results in sodium loss, hyperkalemia, metabolic acidosis, and volume depletion that can lead to hyponatremia. The urine sodium will be >30 meq/l, despite volume depletion due to an inability to reabsorb sodium. The AVP levels are elevated due to nonosmotic stimulus likely mediated by baroreceptor response to volume depletion. 40 Cerebral salt wasting syndrome is the renal loss of sodium that leads to hypovolemia and hyponatremia in the setting of intracranial injury or disease. In one retrospective review of patients in a neuroscience center, CSW syndrome occurred in 4.8% of patients with hyponatremia compared to 62% with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). 41 The clinical findings are similar to those in SIADH; however, in SIADH the patient is euvolemic rather than volume depleted. Thus, careful attention to the onset of hyponatremia, including the urine sodium excretion and volume status, is important in distinguishing the two. In CSW syndrome, the negative sodium balance must accompany the development of hyponatremia. Serum sodium should be increased by giving hypertonic saline because evaluation of volume status can be inaccurate in patients with hyponatremia and SIADH occurs much more frequently than CSW syndrome. Also, giving a trial of normal saline to a patient with SIADH and intracranial injury risks lowering serum sodium and increasing cerebral edema. 42 The exact pathophysiologic mechanism of CSW syndrome is unknown, but natriuretic factors have been associated with its development. 43,44 Euvolemic Hyponatremia Euvolemic hyponatremia occurs with an increased amount of total body water with normal or reduced total body sodium. The cause can be iatrogenic with administration of hypotonic fluids without careful monitoring of serum sodium levels. Administration of hypotonic fluid following elective surgery resulted in the acute onset of hyponatremia with resulting neurological damage in 15 otherwise healthy women. 45 The SIADH, also termed the syndrome of inappropriate antidiuresis, is the most common electrolyte disorder in hospitalized patients. 46,47 This disorder was first recognized by Schwartz in 1957. 48 Diagnostic criteria were articulated by

228 Journal of Intensive Care Medicine 31(4) Table 1. Causes of SIADH. Pulmonary disease Malignancy CNS disease Drugs Pneumonia Tuberculosis Abscess Asthma Aspergillosis Lung Gastrointestinal Genitourinary Lymphoma Hemorrhage Hematoma Infection Tumors AVP analogues Stimulate AVP release Potentiate AVP activity Table 2. Drugs that Cause SIADH. Stimulate AVP release Chlorpropamide Clofibrate Carbamazepine Vincristine Selective serotonin reuptake inhibitors 3,4-Methylenedioxy-N-methamphetamine (MDMA) Ifosfamide Antipsychotics Narcotics Potentiate action of AVP AVP analogues Chlorpropamide NSAIDs Cyclophosphamide Desmopressin Oxytocin Vasopressin Abbreviations: AVP, arginine vasopressin; SIADH, syndrome of inappropriate secretion of antidiuretic hormone. Abbreviations: AVP, arginine vasopressin; NSAIDs, nonsteroidal antiinflammatory drugs; SIADH, syndrome of inappropriate secretion of antidiuretic hormone. Bartter and Schwartz in 1967. 49 There is an excess of total body water relative to a normal amount of total body sodium. Diagnosis requires hyponatremia with hypo-osmolality of the serum and extracellular fluid. The excretion of sodium in the urine is intact with urine sodium concentrations >40 meq/l with normal salt and water intake. The urine is not maximally dilute but is inappropriately concentrated with an osmolality greater than that appropriate considering the plasma hypotonicity. In SIADH, the patient is euvolemic with normal renal, adrenal, thyroid, cardiac, and liver function. 50 A low serum BUN and uric acid occur in SIADH. A uric acid of 4 mg/dl or less was characteristic of SIADH, while a uric acid of more than 5 mg/dl occurred in non-siadh hyponatremia. 51 The fractional excretion of uric acid can be used to differentiate patients with SIADH who are on diuretics from patients with hypovolemia. 52 SIADH occurs when an excess of AVP is present with continued intake of water. A number of conditions cause an increase in AVP, including pulmonary disease, neoplasm, central nervous system injury or disease (Table 1). Drugs can cause SIADH either through the stimulation of AVP release or through enhancement of its effect on the kidney (Table 2). Hyponatremia can result in a downward resetting of the osmolality at which AVP is released or reset osmostat. Secretion of AVP occurs at a hypotonic osmolality rather than at the physiologic level of 285 mosm/kg. 53 Some patients with SIADH have an appropriately suppressed AVP level. This could be explained by a gain of function mutation in the gene for the V2 receptor that causes constitutive activation. Mutations have been identified in case reports, and this condition is referred to as the nephrogenic syndrome of inappropriate antidiuresis. 54 Glucocorticoid deficiency from hypopituitarism, hypothalamic dysfunction, Sheehan syndrome, tumors, or empty sella causes a euvolemic hyponatremia similar to that seen in SIADH. Glucocorticoids are tonic inhibitors of the secretion of AVP. 55 Without that modulating influence, AVP is inappropriately secreted. 56 However, the sodium reabsorption via the RAAS pathway is intact so that there is not the volume depletion as seen in hyponatremia from a mineralocorticoid deficiency. Additionally, glucocorticoid deficiency causes decreased cardiac output and hypotension that are nonosmotic stimulators of AVP secretion. 57 Patients will also have low serum BUN and uric acid with higher urine sodium concentrations similar to patients with SIADH. A morning cortisol level should be decreased in a patient with glucocorticoid deficiency, but if results are equivocal, a cosyntropin test can be performed to determine whether the adrenal gland is able to release glucocorticoid in response. The mechanisms by which hypothyroidism causes hyponatremia may be an inability to suppress AVP and a decreased excretion of free water due to decreased glomerular filtration rate (GFR). Some reports have shown that hyponatremia in hypothyroidism is independent of AVP secretion. 58 A decreased GFR in hypothyroidism results in decreased excretion of water simply because less fluid is delivered to the diluting segment. Hyponatremia associated with acute hypothyroidism does not occur frequently. Hammami et al prospectively evaluated 212 patients with thyroid cancer who underwent induction of hypothyroidism in preparation for radioiodine treatment of thyroid cancer. 59 Mild hyponatremia (serum sodium of 130 meq/l or more) occurred in 8.5% and moderate hyponatremia (serum sodium of 120 meq/l or more) occurred in 1.9% of hypothyroid patients. Although hyponatremia has been reported in patients with myxedema having elevated AVP levels, the stimulation for AVP secretion could have been nonosmotic and related to sequelae of hypothyroidism such as nausea, decreased cardiac output, and hypotension. Exercise-associated hyponatremia (EAH) is the occurrence of hyponatremia during or up to 24 hours after prolonged physical activity resulting in a plasma sodium concentration below the normal reference range, usually <135 meq/l. 20 Early signs

Buffington and Abreo 229 of EAH are nausea, vomiting, and headache. As the hyponatremia worsens, edema of the brain can produce neurological symptoms such as altered mental status, seizures, obtundation, coma, and death. The etiology is a dilutional hyponatremia caused by consumption of fluids in excess of fluid losses. Other factors are loss of sodium in sweat, inappropriate AVP stimulation with impaired renal diluting ability, and the inability to mobilize nonosmotically active sodium stores. 60 Risk factors for EAH include excessive fluid drinking during exercise, weight gain during exercise, low body weight, and female gender. Inexperience running marathons associated with slower pace and longer race times were also factors. For asymptomatic athletes, treatment of EAH is fluid restriction but those with symptoms of hyponatremic encephalopathy should receive intravenous hypertonic saline. 61 Hypervolemic Hyponatremia Patients with hypervolemic hyponatremia will have signs of volume overload, such as peripheral edema, pulmonary edema, or pleural effusion. This condition involves an excess of water and an excess of sodium. Hypervolemic hyponatremia occurs in congestive heart failure, cirrhosis, nephrotic syndrome, and renal failure. Hemodynamic changes occurring in these conditions cause systemic arterial underfilling, 62 which is caused by decreased cardiac output in congestive heart failure or by decreased intravascular volume due to decreased oncotic pressure in nephrotic syndrome. 51 Systemic arterial underfilling can also be caused by peripheral arterial vasodilation as seen in cirrhosis, sepsis, pregnancy, or highoutput heart failure. In response to arterial underfilling, baroreceptors in the carotid body and aortic arch sense a decreased mean arterial pressure resulting in decreased glossopharyngeal and vagal tone. 63 This leads to beta-adrenergic stimulation and nonosmotic release of AVP. Baroreceptors in the juxtaglomerular cells of the kidney stimulate the secretion of renin and production of angiotensin II and aldosterone. 62 Neurohumoral activation of the sympathetic nervous system and renin angiotensin aldosterone system cause vasoconstriction and increased vascular resistance. Aldosterone causes increased sodium reabsorption and AVP causes water reabsorption. Cardiac output increases in the setting of cirrhosis or sepsis as an additional compensatory mechanism. These responses work to restore effective arterial blood volume and perfusion; however, persistent activation of neurohumoral responses leads to edema and impaired water metabolism. Treatment of Acute Hyponatremia Acute hyponatremia develops over the course of 24 to 48 hours and most often results from psychogenic polydipsia, EAH, and ecstasy or methylenedioxy-n-methamphetamine use. 30 Also, patients treated with hypotonic IV fluids postoperatively can have acute-onset hyponatremia. 45 Rapidly developing hyponatremia causes brain edema and the risk of transtentorial herniation (TTH) is the most concerning issue. Death or profound neurologic injury has been reported when acute hyponatremia was not corrected immediately. 64 Acute hyponatremia can be corrected more rapidly than chronic hyponatremia because the process of extrusion of organic osmolytes of the brain volume regulatory response has not taken full effect. If there is any question about the time of onset of hyponatremia, then it should be treated as though it were chronic. Hypertonic saline is the mainstay of treatment for symptomatic hyponatremia because raising serum sodium reduces brain edema. A retrospective study of 63 patients receiving hypertonic saline for TTH showed that an increase in the serum sodium level of 5 meq/l was an independent predictor of reversal of TTH. 65 The increase in serum sodium concentration of 5 meq/l effectively reduced intracranial pressure by 50%. An initial 4 to 6 meq/l increase in serum sodium concentration will decrease brain edema resulting in resolution of symptoms in patients with hyponatremia. 66 There are varied recommendations for achieving this increase in serum sodium. A recent consensus guideline on treatment of EAH recommended that athletes with symptomatic hyponatremia should receive an infusion of 100 ml of 3% NaCl that can be repeated every 10 minutes for a total of 3 doses as needed until symptoms resolve. 20 This infusion can be given through peripheral intravenous access. Oral salt loading following exercise does not significantly increase serum sodium concentration. 67 Experts have agreed with this therapeutic approach in the management of acute symptomatic hyponatremia in general 66,68 ; however, caution to avoid overcorrection in smaller sized patients should be exercised. 69 When symptoms of acute hyponatremia are less severe, an infusion of 3% NaCl at a rate of 1 to 2 ml/kg/h should be started. 47 The goal should be to increase the serum sodium up to 2 meq/l/h. Replacement of potassium will also cause an increase in sodium, and the potassium concentration should be considered when calculating your projected rate of correction. Furosemide 20 mg should be given intravenously to increase excretion of dilute urine. The serum sodium level should be checked every 2 hours and the rate of the infusion adjusted accordingly to achieve correction. The rate of correction can be reduced when symptoms improve. For psychogenic polydipsia, the symptomatic patient must be treated with hypertonic saline as mentioned earlier. Water diuresis will ensue in the absence of renal failure and the hyponatremia will correct. Risk factors for neurologic complications of correction are alcoholism, malnourishment, and nonacute hyponatremia. In those patients, the hyponatremia should be corrected at a slower rate once the risk of brain edema has been overcome. 30 Treatment of asymptomatic acute hyponatremia depends on the etiology. In asymptomatic EAH, fluid restriction is appropriate and correction will occur as the athlete excretes free water. Treatment of Chronic Hyponatremia Patients with chronic hyponatremia evidencing neurologic changes should be treated with hypertonic saline (3% NaCl)

230 Journal of Intensive Care Medicine 31(4) Table 3. Risk Factors for Osmotic Demyelination Syndrome. Chronic hyponatremia Serum [Na] <105 meq/l Hypokalemia Alcoholism Malnutrition Liver cirrhosis Abbreviation: ODS, osmotic demyelination syndrome. until symptoms resolve because those symptoms can rapidly worsen. Failure to promptly give IV NaCl for chronic hyponatremic encephalopathy in postmenopausal women resulted in a high rate of permanent neurological debilitation or death. 25 As mentioned earlier, 100 ml of 3% NaCl should be given, then repeated every 10 minutes for 2 additional doses if needed. When neurologic symptoms resolve, a long-term strategy to correct the serum sodium level must be formulated based on the etiology of the hyponatremia. Rapid increases in the serum sodium level while correcting chronic hyponatremia can lead to brain injury from ODS. In chronic hyponatremia, neurologic sequelae from correction has been well documented at rates of correction above 12 meq/l over the first 24 hours and 18 meq/l over the first 48 hours. 22,30,70,71 However, one study showed neurological sequelae in 6 patients corrected at a rate of 10 meq/l/24 h. 72 Additionally, one patient with neurological sequelae corrected at an average rate of 5 meq/l/d; however, this was an average rate of correction over 4 days because a follow-up serum sodium level was not available until the fourth day. Conversely, the serum sodium should not be corrected too slowly. Postmenopausal women with chronic hyponatremic encephalopathy had poor outcomes with serum sodium correction of <4 meq/l over the first 24 hours. 25 The recommendation for the minimum goal of correction of chronic hyponatremia is 4 to 8 mmol/l per day with a maximum limit of 10 to 12 meq/l for the first 24 hours and 18 meq/l over the first 48 hours. 68 The goal is reduced in those patients with high risk of developing ODS. Risk factors for developing ODS are chronic hyponatremia with serum sodium level of 105 meq/l or lower, hypokalemia, alcoholism, malnutrition, and advanced liver disease (Table 3). 24,73,74 One review of 74 cases of ODS where both serum sodium and serum potassium were measured noted that hypokalemia was present in 89% of cases. 75 The serum sodium should be corrected at a lower rate in patients with these risk factors, with a recent consensus recommendation that the serum sodium should be corrected at a minimum of 4 to 6mmol/L per day with a maximum limit of 8 mmol/l/d. 68 After the initial NaCl infusion to address neurological symptoms, an infusion of NaCl may be needed to attain the desired serum sodium level. Intravenous administration of potassium chloride (KCl) will increase the serum sodium level; thus, a patient with hypokalemia and hyponatremia can be treated with KCl alone or in combination with saline. We agree with a recently published expert consensus opinion that recommends starting 3% NaCl at an initial hourly infusion rate equal to body weight in kilograms multiplied by the desired hourly rate of increase in serum sodium in mmol/l/h. 68 As an example given in these guidelines, a 70-kg man needing an increase in serum sodium of 0.5 mmol/l/h would have an initial infusion of 35 ml/h of 3% NaCl. Regardless of the formula used to determine the initial rate of correction, frequent testing of serum sodium is necessary so that the rate of infusion can be adjusted. Hypovolemic hyponatremia can be treated by volume repletion with normal saline. The serum sodium should be checked every 4 to 6 hours to make sure correction of the serum sodium level is not increasing too rapidly. Diuretics should be stopped. Correction of the hyponatremia in a study of 25 patients occurred over the course of 3 to 10 days after withdrawing the medication. 36 Administration of potassium supplementation causes a shift of sodium from intracellular to extracellular space and will increase the serum sodium level. This increase should be factored into the rate of correction. As volume status is corrected with normal saline administration, the impetus for AVP secretion diminishes and the patient will begin to excrete more dilute urine. The rate of correction of hyponatremia will increase and an over correction may occur. Acute symptomatic hyponatremia due to heart failure should be treated by infusion of hypertonic saline until neurologic symptoms resolve; however, saline should be administered with caution to minimize the risk of pulmonary edema. Chronic hyponatremia due to cardiac failure is treated by fluid restriction to less than 1000 ml/d to reduce fluid overload. Loop diuretics decrease urine osmolality and increase water excretion. One small study showed that the infusion of hypertonic saline along with high-dose furosemide resulted in fewer readmissions to the hospital and improved mortality. 76 Treatment with vasopressin receptor blockers is discussed subsequently. SIADH is usually a chronic process in which hyponatremia develops over days rather than hours. Patients with neurological symptoms should receive hypertonic saline until symptoms resolve, increasing the serum sodium by 4 to 6 meq/l within a few hours. Because patients with SIADH are usually euvolemic, aldosterone is suppressed and sodium is excreted in the urine. Because AVP is inappropriately secreted, water excretion is reduced at a relatively fixed urine osmolality rather than being determined by changes in water intake or volume status. With urine osmolality being relatively fixed, changes in solute excretion will determine the water volume. For a given urinary concentration of sodium and potassium with a fixed urine osmolality, electrolyte-free water excretion depends on the excretion of solute. 17,19 The parenteral and oral fluid intake should be restricted and serum sodium should be measured frequently to monitor the rate of recovery. The degree of fluid restriction needed to cause an increase in serum sodium can be determined by calculating urine/plasma electrolyte (U/P) ratio using spot urine values for sodium and potassium. 18,47 The U/P ratio is a simplification of the formula for electrolyte-free water clearance (Equation 3):

Buffington and Abreo 231 Table 4. Fluid Restriction based on U/P Electrolyte Ratio. U/P Ratio Fluid Restriction >1 <500 ml/d *1 500-700 ml/d <1 <1000 ml/d Abbreviation: U/P ratio, ratio of urine electrolytes to plasma electrolytes. U Ratio ¼ ½ Na Š u þ½kš u : P ½NaŠ s The U/P ratio is the ratio of urine electrolytes to plasma electrolytes; [Na] u is urine sodium concentration; [K] u is urine potassium concentration; and [Na] s is serum sodium concentration. When the urine sodium and potassium is greater than serum sodium (U/P ratio >1), electrolyte-free water excretion is negative and fluid restriction alone is not likely to increase serum sodium. Water consumed will be conserved rather than excreted. Fluid intake in excess of insensible losses (typically about 700-800 ml/d) will be conserved rather than excreted and will cause a decrease in serum sodium. Thus, in that instance, fluid restriction should be less than 500 ml/d. This is a process referred to as desalination of fluid intake. One study demonstrated the desalination of isotonic IV fluid in 22 women who underwent surgery then developed hyponatremia after receiving normal saline or Ringer lactate solution. 77 The patients were not volume depleted; thus, the aldosteronemediated excretion of sodium was intact. However, nonosmotic stimuli for AVP such as nausea, pain, and stress caused retention of electrolyte-free water. Hypertonic fluid with electrolyte concentrations greater than that lost in the urine should be administered in order to increase serum sodium. For a U/P ratio <1, with plasma sodium concentration more than urine sodium plus potassium, some electrolyte-free water is excreted (Table 4). Fluid restriction should be <1 L/d. If needed, an infusion of hypertonic fluid can be administered to slowly correct the sodium to a level at which neurologic sequelae are not likely to occur. Drugs known to cause SIADH should be discontinued. Treatment of underlying infection or malignancy will lead to increased serum sodium over the long term. Nausea and postoperative pain can lead to transient increases in AVP, which will decrease when the nausea and pain are controlled. Longterm treatment for hyponatremia may not be necessary when the cause is attenuated or reversed. As mentioned earlier, oral solute administration will increase the excretion of solute and increase the amount of water accompanying that solute. Sodium chloride tablets at 3 g given 3 times a day will increase the solute load and lead to increased water excretion over the long term. Urea is the end product of protein catabolism and can increase urinary solute excretion and enhance solute diuresis. Doses of 30 g daily are given but are not well tolerated in patients. An Food and Drug Administration (FDA)-approved formulation of urea is not available in the United States; however, it is prescribed in Europe and has even been used to treat hyponatremia in the intensive care setting. 78,79 Urea also promotes sodium retention and can act as an osmolyte that is protective against ODS. 80 It may be necessary to initiate long-term treatment for hyponatremia in the ICU. Demeclocycline, a tetracycline antibiotic, is used to treat SIADH by decreasing osmolality of the urine. Kortenoeven et al found that demeclocycline downregulated the aquaporin 2 channel and decreased adenylate cyclase activity in mouse cortical collecting duct cells. 81 A dose of 300 to 600 mg taken orally twice daily is a long-term treatment of SIADH; however, the medication is very expensive. Renal function should be monitored because nephrotoxicity is common, particularly in cirrhotics. 82 Treatment of Hyponatremia with Vasopressin Receptor Antagonists Vaptans are vasopressin (ADH) receptor blockers. Vasopressin receptors are of 3 types, namely, V1a located predominantly on blood vessels cause vasoconstriction, V1b in the pituitary release adrenocorticotropin (ACTH), and V2 on the basolateral membrane of the chief cells of the collecting duct increase synthesis and insertion of aquaporin 2 water channels on the apical membrane results in water reabsorption. Vaptans block ADH binding to the V2 receptor and induce an electrolytefree diuresis (aquaresis). In patients with hyponatremia, the serum sodium increases as a result of aquaresis (acquired nephrogenic diabetes insipidus). Theoretically, vaptans should be excellent agents for the treatment of hyponatremia in critically ill patients. Vaptans that specifically block the V2 receptor are tolvaptan, moxavaptan, lixivaptan, and satavaptan. Conivaptan is a nonspecific receptor blocker in that it also blocks both the V2 and the V1a receptors. Tolvaptan and conivaptan are available for clinical use in the United States. Moxavaptan has been approved for the treatment of SIADH in Japan. Lixivaptan has not been released for clinical use in the United States and satavaptan has been withdrawn from further development. Conivaptan is only available as an intravenous drug, which may be of advantage in the treatment of critically ill patients. The oral preparation has not been marketed because it is a potent inhibitor of the cytochrome P450 3A4 system and prolonged use would cause many drug drug interactions. The role of vaptans in the treatment of hyponatremic critically ill patients is unclear. 83 All the randomized controlled trials with vaptans were done in asymptomatic patients with mild chronic hyponatremia (average serum sodium 130 meq/ L). Patients with symptomatic severe chronic hyponatremia were not selected for these trials because of ethical concerns that the patients in the placebo arm would be harmed. There are no randomized controlled trials comparing treatment with vaptans to administration of hypertonic saline for the treatment of chronic hyponatremia. There are also no studies evaluating the efficacy of vaptans in the treatment of acute hyponatremia. There is clearly no role for vaptans in the

232 Journal of Intensive Care Medicine 31(4) treatment of acute hyponatremia and symptomatic hyponatremia where hypertonic saline is the unequivocal choice. There may be occasions where the vaptans could be used cautiously for euvolemic and hypervolemic hyponatremic critically ill patients, especially if there are concerns that hypertonic saline may either correct hyponatremia too quickly or may induce volume overload. Since conivaptan and tolvaptan are approved for use in the United States, only these agents will be discussed. The safety and efficacy of intravenous conivaptan was shown in a randomized placebo-controlled trial in hospitalized asymptomatic patients with euvolemic and hypervolemic hyponatremia (serum sodium 115 to <130 meq/l). 84 Intravenous conivaptan at a bolus dose of 20 mg followed by a continuous infusion of either 40 or 80 mg/d for 4 days significantly raised the serum sodium concentration 6.3 meq/l and 9.4 meq/l in the 40 mg/d and 80 mg/d study arms, respectively, compared to 0.8 meq/l in the placebo arm. In another retrospective study in a neurosurgical ICU, conivaptan was used together with hypertonic saline (1.25%-2%) in 19 patients who had a serum sodium <135 meq/l. Conivaptan was well tolerated with no episodes of hypotension, despite increased urine volume. Since the new guidelines for the correction of severe hyponatremia recommend a change in serum sodium <10 meq/l in the first 24 hours, there is clearly a danger of overcorrection with conivaptan. 85 In one study, conivaptan corrected hyponatremia too fast in 50% of patients who required stopping, interrupting, or reversing treatment. There is a theoretical danger of worsening hypotension in patients with cirrhosis from blockade of the V1a receptor on the splanchnic blood vessels and thereby worsening the prerenal state and inducing the hepatorenal syndrome. 86 The efficacy and safety of tolvaptan was shown in ambulatory (mean sodium 129 meq/l) patients with hyponatremia having SIADH, heart failure, and cirrhosis in 2 combined placebo-controlled randomized trials called study of ascending levels of tolvaptan in hyponatremia (SALT-I and SALT- II). 87,88 Tolvaptan at an oral dose of 15 mg daily with increases to 30 and 60 mg daily based on the serum sodium concentration, significantly increased the serum sodium concentration at day 4 (134 vs 130) and at day 30 (136 vs 131) when compared to placebo. Of the 448 patients enrolled in SALT-I and SALT-II trials, only 4 patients (1.8%) had correction of serum sodium level >0.5 meq/l/h in the first 24 hours of the study. 89 There were no osmotic demyelination events. However, if the more stringent guidelines were applied to this study, more patients would have overcorrection with tolvaptan. The efficacy and safety of tolvaptan was also shown in the Efficacy of Vasopressin antagonism in heart failure: outcome Study with Tolvaptan (EVEREST) trial in which tolvaptan was given to 2072 patients hospitalized for decompensated heart failure. 90 Although hyponatremia was not an inclusion criteria, there was a significant increase in the serum sodium levels in patients who had hyponatremia and received tolvaptan with no adverse effects. Two postmarketing reports of osmotic demyelination have been filed when tolvaptan was used with hypertonic saline to correct hyponatremia. 91 The FDA has issued a warning not Table 5. Risk Factors for Rapid Correction of Hyponatremia. Hypovolemia Glucocorticoid deficiency Beer potomania Polydipsia Desmopressin discontinuation to use tolvaptan in patients with liver injury and has also limited the length of use to 30 days, after the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) trial in which tolvaptan used to prevent progressive renal failure in patients with polycystic kidney disease showed a 2.5-fold increase in liver enzymes compared to placebo. 88 The dose used in this trial was significantly higher (60-120 mg/d, average 90 mg/d) when compared to the doses used in the hyponatremia trials (maximum 60 mg/d). 89 In summary, the role of vaptans in the treatment of hyponatremia remains unclear. They should not be used in patients with symptomatic hyponatremia, patients with hypovolemic hyponatremia, and in patients with liver injury. Studies have shown that they are not as effective in cirrhosis probably because glomerular filtrate is absorbed proximally or that V2 receptors remain activated by another mechanism. 92-94 They also induce a successful aquaresis in patients with congestive heart failure but do not show any benefit on survival. 90,95 Vaptans are most effective in SIADH and some experts recommend using a smaller starting dose of 7.5 mg (half tablet). 68 Vaptans should not be used together with hypertonic saline, since the danger of overcorrection is more likely to occur. To avoid overcorrection with vaptans, the experts recommend not to restrict oral fluid in the first 24 to 48 hours of treatment and to check serum sodium and urine osmolality frequently. If there is overcorrection, the vaptan should be stopped and intravenous D5W should be administered as desmopressin (DDAVP) will not work since the V2 receptor is blocked. Overly Rapid Correction of Hyponatremia Some etiologies of hyponatremia predispose to a more rapid correction of hyponatremia once the underlying cause is addressed (Table 5). These patients should have serum sodium monitored frequently to allow adjustment of the rate of correction. Secretion of AVP can be temporary; thus, when the cause of AVP secretion is reversed, an excretion of electrolyte-free water begins and causes rapid increase in serum sodium. Such reversible causes of AVP secretion are hypovolemia, nausea, and pain. Rapid correction of hyponatremia is more likely in hypovolemic hyponatremia because AVP secretion decreases when intravascular volume is repleted. 96 The ensuing excretion of electrolyte-free water causes the serum sodium level to increase more rapidly. In secondary adrenal failure due to hypopituitarism, a rapid correction of hyponatremia will result after cortisol treatment and a resulting decrease in AVP release. Increased excretion of free water will occur in beer potomania