Hyponatremia JEREMY BARNETT MD AMY GUTMAN MD Hyponatremia

Hyponatremia JEREMY BARNETT MD AMY GUTMAN MD

Hyponatremia �Common electrolyte abnormality �Primary vs secondary �Normal serum sodium level: 135 -145 m. Eq/L. �Hyponatremia = serum sodium <135 m. Eq/L �Hyponatremia classified as: Mild: 130 -134 mmol/L Moderate: 125 -129 mmol/L Profound: <125 mmol/L *Barnett rule: <140 m. Eq/L

�Signs and symptoms �Symptoms range from nausea and malaise, with mild reduction in the serum sodium, to lethargy, decreased level of consciousness, headache, and (if severe) seizures and coma. Overt neurologic symptoms most often are due to very low serum sodium levels (usually <115 m. Eq/L), resulting in intracerebral osmotic fluid shifts and brain edema.

� Hyponatremia is classified according to volume status, as follows: � Hypovolemic hyponatremia: decrease in total body water with greater decrease in total body sodium � Euvolemic hyponatremia: normal body sodium with increase in total body water � Hypervolemic hyponatremia: increase in total body sodium with greater increase in total body water � Hyponatremia can be further subclassified according to effective osmolality, as follows: � Hypotonic hyponatremia � Isotonic hyponatremia � Hypertonic hyponatremia

� � � � � Diagnosis There are three essential laboratory tests in the evaluation of patients with hyponatremia that, together with the history and the physical examination, help to establish the primary underlying etiologic mechanism: urine osmolality, serum osmolality, and urinary sodium concentration. Urine osmolality helps differentiate between conditions associated with impaired free-water excretion and primary polydipsia. A urine osmolality greater than 100 m. Osm/kg indicates impaired ability of the kidneys to dilute the urine. Serum osmolality readily differentiates between true hyponatremia and pseudohyponatremia. The latter may be secondary to hyperlipidemia or hyperproteinemia, or may be hypertonic hyponatremia associated with elevated glucose, mannitol, glycine (posturologic or postgynecologic procedure), sucrose, or maltose (contained in Ig. G formulations). Urinary sodium concentration helps differentiate between hyponatremia secondary to hypovolemia and syndrome of inappropriate antidiuretic hormone secretion (SIADH). With SIADH (and salt-wasting syndrome), the urine sodium is greater than 20 -40 m. Eq/L. With hypovolemia, the urine sodium typically measures less than 25 m. Eq/L. However, if sodium intake in a patient with SIADH (or salt-wasting) happens to be low, then urine sodium may fall below 25 m. Eq/L. See Workup for more detail. Management Hypotonic hyponatremia accounts for most clinical cases of hyponatremia and can be treated with fluids. Acute hyponatremia (duration < 48 hours) can be safely corrected more quickly than chronic hyponatremia. The treatment of hypertonic and pseudohyponatremia is directed at the underlying disorder in the absence of symptoms. Intravenous fluids and water restriction Administer isotonic saline to patients who are hypovolemic to replace the contracted intravascular volume. Patients with hypovolemia secondary to diuretics may also need potassium repletion, which, like sodium, is osmotically active. Treat patients who are hypervolemic with salt and fluid restriction, plus loop diuretics, and correction of the underlying condition. The use of a V 2 receptor antagonist may be considered. For euvolemic, asymptomatic hyponatremic patients, free water restriction (< 1 L/day) is generally the treatment of choice. There is no role for hypertonic saline in these patients. When treating patients with overtly symptomatic hyponatremia (eg, seizures, severe neurologic deficits), hypertonic (3%) saline should be used. Pharmacologic treatment Conivaptan, a V 1 A and V 2 vasopressin receptor antagonist, is available only for intravenous use and is approved for use in the hospital setting for euvolemic and hypervolemic hyponatremia. It is contraindicated in hypovolemic patients. It induces both a water and sodium diuresis with improvement in plasma sodium levels.

� Pathophysiology � Hypoosmolality (serum osmolality <280 m. Osm/kg) always indicates excess total body water relative to body � � � solutes or excess water relative to solute in the extracellular fluid (ECF), as water moves freely between the intracellular and the extracellular compartments. This imbalance can be due to solute depletion, solute dilution, or a combination of both. Under normal conditions, renal handling of water is sufficient to excrete as much as 15 -20 L of free water per day. Further, the body's response to a decreased osmolality is decreased thirst. Thus, hyponatremia can occur only when some condition impairs normal free water excretion. [3] Generally, hyponatremia is of clinical significance only when it reflects a drop in the serum osmolality (ie, hypotonic hyponatremia), which is measured directly via osmometry or is calculated as 2(Na) m. Eq/L + serum glucose (mg/d. L)/18 + BUN (mg/d. L)/2. 8. Note that urea is not an effective osmole, so when the urea levels are very high, the measured osmolality should be corrected for the contribution of urea. The recommendations for treatment of hyponatremia rely on the current understanding of CNS adaptation to an altered serum osmolality. In the setting of an acute drop in the serum osmolality, neuronal cell swelling occurs due to the water shift from the extracellular space to the intracellular space (ie, Starling forces). Swelling of the brain cells elicits the following two osmoregulatory responses: It inhibits both arginine vasopressin secretion from neurons in the hypothalamus and hypothalamic thirst center. This leads to excess water elimination as dilute urine. There is an immediate cellular adaptation with loss of electrolytes, and over the next few days, there is a more gradual loss of organic intracellular osmolytes. [4] Therefore, correction of hyponatremia must take into account the chronicity of the condition. Acute hyponatremia (duration < 48 h) can be safely corrected more quickly than chronic hyponatremia. Correction of serum sodium that is too rapid can precipitate severe neurologic complications. Most individuals who present for diagnosis, versus individuals who develop it while in an inpatient setting, have had hyponatremia for some time, so the condition is chronic, and correction should proceed accordingly.

� � � Epidemiology United States The incidence of hyponatremia depends largely on the patient population and the criteria used to establish the diagnosis. Among hospitalized patients, 15 -20% have a serum sodium level of <135 m. Eq/L, while only 1 -4% have a serum sodium level of less than 130 m. Eq/L. The prevalence of hyponatremia is lower in the ambulatory setting. Mortality/Morbidity Severe hyponatremia (<125 m. Eq/L) has a high mortality rate. In patients whose serum sodium level falls below 105 m. Eq/L, and especially in alcoholics, the mortality is over 50%. [5] In patients with acute ST-elevation myocardial infarction, the presence of hyponatremia on admission or early development of hyponatremia is an independent predictor of 30 -day mortality, and the prognosis worsens with the severity of hyponatremia. [6] Bae et al reported that in hospitalized survivors of acute myocardial infarction, the presence of hyponatremia at discharge was an independent predictor of 12 -month mortality. The study involved 1290 patients. [7] Similarly, cirrhotic patients with persistent ascites and a low serum sodium level awaiting transplant have a high mortality risk despite low severity (MELD) scores (see the MELD Score calculator). The independent predictors—ascites and hyponatremia—are findings indicative of hemodynamic decompensation. [8, 9] A study by Huang et al indicated that in patients with chronic kidney disease, hyponatremia and hypernatremia are associated with an increased risk for all-cause mortality and for deaths unrelated to cardiovascular problems or malignancy. Hyponatremia was also found to be linked to an increased risk for cardiovascular- and malignancy-related mortality in these patients. The study included 45, 333 patients with stage 3 or 4 chronic kidney disease, 9. 2% of whom had dysnatremia. [10] Race-, Sex-, and Age-related Demographics Hyponatremia affects all races. No sexual predilection exists for hyponatremia. However, symptoms are more likely to occur in young women than in men. Hyponatremia is more common in elderly persons, because they have anhigher rate of comorbid conditions (eg, cardiac, hepatic, or renal failure) that can lead to hyponatremia.

� History � Patients may present to medical attention with symptoms related to low serum sodium concentrations. � � However, many patients present due to manifestations of other medical comorbidities, with hyponatremia being recognized only secondarily. For many people, therefore, the recognition is entirely incidental. Patients may develop clinical symptoms due to the cause of hyponatremia or the hyponatremia itself. Many medical illnesses, such as congestive heart failure, liver failure, renal failure, or pneumonia, may be associated with hyponatremia. These patients frequently present because of primary disease symptomatology (eg, dyspnea, jaundice, uremia, and cough). [11] Symptoms range from nausea and malaise, with mild reduction in the serum sodium, to lethargy, decreased level of consciousness, headache, and (if severe) seizures and coma. Overt neurologic symptoms most often are due to very low serum sodium levels (usually <115 m. Eq/L), resulting in intracerebral osmotic fluid shifts and brain edema. This neurologic symptom complex can lead to tentorial herniation with subsequent brain stem compression and respiratory arrest, resulting in death in the most severe cases. The severity of neurologic symptoms correlates well with the rate and degree of the drop in serum sodium. A gradual drop in serum sodium, even to very low levels, may be tolerated well if it occurs over several days or weeks, because of neuronal adaptation. The presence of an underlying neurologic disease, like a seizure disorder, or nonneurologic metabolic abnormalities, like hypoxia, hypercapnia, or acidosis, also affects the severity of neurologic symptoms. In interviewing the patient, obtaining a detailed medication history, including information on over-the-counter (OTC) drugs the patient has been using, is important because many medications may precipitate hyponatremia (eg, antipsychotic medications, diuretics). A dietary history with reference to salt, protein, and water intake is useful as well. For patients who are hospitalized, reviewing the records of parenteral fluids administered is crucial.

� Hypertonic hyponatremia � Patients with hypertonic hyponatremia have normal total body sodium and a dilutional drop in the measured serum sodium due to the presence of osmotically active molecules in the serum, which causes a water shift from the intracellular compartment to the extracellular compartment. � Glucose produces a drop in the serum sodium level of 1. 6 m. Eq/L for each 100 mg/d. L of serum glucose greater than 100 mg/d. L. This relationship is nonlinear, with greater reduction in plasma sodium concentrations with glucose concentrations over 400 mg/d. L, making 2. 4 m. Eq/L for each 100 mg/d. L increase in glucose over 100 mg/d. L a more accurate correction factor when the glucose is greater than 400 mg/d. L. [12] � Other examples of osmotically active molecules include mannitol (often used to treat brain edema) or maltose (used with intravenous immunoglobulin administration).

� Normotonic hyponatremia � Severe hyperlipidemia and paraproteinemia can lead to low measured serum sodium concentrations with normal serum osmolality. Normally, the plasma water comprises 92 -94% of plasma volume. The plasma water fraction falls with an increase in fats and proteins. The measured sodium concentration in the total plasma volume is respectively reduced, although the plasma water sodium concentration and plasma osmolality are unchanged. This artifactual low sodium (so-called pseudohyponatremia) is secondary to measurement by flame photometry. It can be avoided by direct ion-selective electrode measurement. � Hyponatremia after transurethral resection of the prostate (TURP) or hysteroscopy is caused by absorption of irrigants, glycine, sorbitol, or mannitol, contained in nonconductive flushing solutions used for those procedures. The degree of hyponatremia is related to the quantity and rate of fluid absorbed. The plasma osmolality is also variable and changes over time. � The presence of a relatively large osmolal gap due to excess organic solute is diagnostic in the appropriate clinical setting. Symptomatic patients are treated depending on plasma osmolality and volume status, with hypertonic saline for patients in hypoosmolar state or a loop diuretic in volume-overloaded patients with normal renal function. � Hemodialysis, which will correct the hyponatremia and remove glycine and its toxic metabolites, can be used in patients with end-stage renal disease. Use of isotonic saline as an irrigant instead of glycine with the new bipolar resectoscope for TURP in high-risk patients (with large prostates that require lengthy resection) could avoid this complication, making this disorder a diagnosis of the past. [13]

� � � � Hypotonic hyponatremia always reflects the inability of the kidneys to handle the excretion of free water to match intake. It can be divided pathophysiologically into the following categories, according to the effective intravascular volume: hypovolemic, hypervolemic, and euvolemic. These clinically relevant groupings aid in determination of likely underlying etiology and guide treatment. Hypovolemic hypotonic hyponatremia This usually indicates concomitant solute depletion, with patients presenting with orthostatic symptoms. The pathophysiology underlying hypovolemic hypotonic hyponatremia is complex and involves the interplay of carotid baroreceptors, the sympathetic nervous system, the renin-angiotensin system, antidiuretic hormone (ADH; vasopressin) secretion, and renal tubular function. In the setting of decreased intravascular volume (eg, severe hemorrhage or severe volume depletion secondary to GI or renal loss, or diuretic use) owing to a decreased stretch on the baroreceptors in the great veins, aortic arch, and carotid bodies, an increased sympathetic tone to maintain systemic blood pressure generally occurs. This increased sympathetic tone, along with decreased renal perfusion secondary to intravascular volume depletion, results in increased renin and angiotensin excretion. This, in turn, results in increased sodium absorption in the proximal tubules of the kidney and consequent decreased delivery of solutes to distal diluting segments, causing an impairment of renal free water excretion. There also is a concomitant increase in serum ADH production that further impairs free water excretion. Because angiotensin is also a very potent stimulant of thirst, free water intake is increased, and, at the same time, water excretion is limited. Together, these changes lead to hyponatremia. Cerebral salt wasting (CSW) is seen with intracranial disorders, such as subarachnoid hemorrhage, carcinomatous or infectious meningitis, and metastatic carcinoma, but especially after neurologic procedures. Disruption of sympathetic neural input into the kidney, which normally promotes salt and water reabsorption in the proximal nephron segment through various indirect and direct mechanisms, might cause renal salt wasting, resulting in reduced plasma volume. Plasma renin and aldosterone levels fail to rise appropriately in patients with CSW despite a reduced plasma volume because of disruption of the sympathetic nervous system. In addition, the release of 1 or more natriuretic factors could also play a role in the renal salt wasting seen in CSW. Volume depletion leads to an elevation of plasma vasopressin levels and impaired free water excretion. Distinguishing between CSW and syndrome of inappropriate ADH secretion (SIADH) can be challenging, because there is considerable overlap in the clinical presentation. Vigorous salt replacement is required in patients with CSW, whereas fluid restriction is the treatment of choice in patients with SIADH. Infusion of isotonic saline to correct the volume depletion is usually effective in reversing the hyponatremia in cerebral salt wasting, since euvolemia will suppress the release of ADH. The disorder is usually transient, with resolution occurring within 3 -4 weeks of disease onset. [14, 15] Salt-wasting nephropathy causing hypovolemic hyponatremia may rarely develop in a range of renal disorders (eg, interstitial nephropathy, medullary cystic disease, polycystic kidney disease, partial urinary obstruction) with low salt intake. Diuretics may induce hypovolemic hyponatremia. Note that thiazide diuretics, in contrast to loop diuretics, impair the diluting mechanism without limiting the concentrating mechanism, thereby impairing the ability to excrete a free water load. Thus, thiazides are more prone to causing hyponatremia than are loop diuretics. This is particularly so in elderly persons, who already have impaired diluting ability.

�Hypervolemic hypotonic hyponatremia �This is characterized by clinically detectable edema or ascites that signifies an increase in total body water and sodium. Paradoxically, however, a decrease in the effective circulating volume, critical for tissue perfusion, stimulates the same pathophysiologic mechanism of impaired water excretion by the kidney that is observed in hypovolemic hypotonic hyponatremia. Commonly encountered examples include liver cirrhosis, congestive heart failure, nephrotic syndrome, and severe hypoproteinemia (albumin level <1. 5 -2 g/d. L).

� � � � � � Normovolemic (euvolemic) hypotonic hyponatremia This is a very common cause of hyponatremia in patients who are hospitalized. It is associated with nonosmotic and non–volume-related ADH secretion (ie, SIADH) secondary to a variety of clinical conditions, including the following: CNS disturbances (eg, hypopituitarism [16] ) Major surgery Trauma Pulmonary tumors Infection Stress Certain medications Common medications associated with SIADH are as follows: chlorpropamide (potentiating renal action of ADH), carbamazepine (possesses antidiuretic property), cyclophosphamide (marked water retention secondary to SIADH and potentially fatal hyponatremia may ensue in selected cases; use of isotonic saline rather than free water to maintain a high urine output to prevent hemorrhagic cystitis can minimize the risk), vincristine, vinblastine, amitriptyline, haloperidol, selective serotonin reuptake inhibitors (particularly in elderly patients), and monoamine oxidase (MAO) antidepressants. In these circumstances, the ability of the kidney to dilute urine in the setting of serum hypotonicity is reduced. Hyponatremia is a relatively common adverse effect of desmopressin, a vasopressin analogue that acts as a pure V 2 agonist. Its common use in the treatment of central diabetes insipidus, von Willebrand disease, and nocturia in adults and of enuresis in children requires regular monitoring of serum sodium levels. The diagnostic criteria for SIADH are as follows: Normal hepatic, renal, and cardiac function - clinical euvolemia (absence of intravascular volume depletion) Normal thyroid and adrenal function Hypotonic hyponatremia Urine osmolality greater than 100 m. Osm/kg, generally greater than 400 -500 m. Osm/kg with normal renal function Urinary sodium concentrations are also typically greater than 20 m. Eq/L on a normal salt diet as sodium excretion will reflect dietary sodium intake. Serum uric acid levels are generally reduced; this is due to reduced tubular uric acid reabsorption, which parallels the decrease in proximal tubular sodium reabsorption associated with central volume expansion. These findings are also found in a renal salt wasting process. This similarity makes the differentiation between salt wasting and SIADH difficult except that in renal wasting, one would expect to find a hypovolemic state. Reset osmostat is another important cause of normovolemic hypotonic hyponatremia. This may occur in elderly patients and during pregnancy. These patients regulate their serum osmolality around a reduced set point; however, in contrast to patients with SIADH (who also have a downward resetting of the osmotic threshold for thirst), [17] they are able to dilute their urine in response to a water load to keep the serum osmolality around the preset low point. Severe hypothyroidism (unknown mechanism, possibly secondary to low cardiac output and glomerular filtration rate) and adrenal insufficiency are also associated with nonosmotic vasopressin release and impaired sodium reabsorption, leading to hypotonic hyponatremia. Hyponatremia associated with cortisol deficiency, such as primary or secondary hypoadrenalism, commonly presents subtly and may go undiagnosed. A random cortisol level check, especially in acute illness, can be misleading if the level is normal (when it should be high). Testing for adrenal insufficiency and hypothyroidism should be part of the hyponatremic workup, as the disorders respond promptly to hormone replacement. Depending on the etiology, mineralocorticoid will also need replacement. Hospitalized patients who are infected with human immunodeficiency virus (HIV) have a high incidence of hyponatremia. In these cases, hyponatremia is usually due to at least one of the following three disorders associated with an increased ADH level: Increased release of ADH due to malignancy, to occult or symptomatic infection of the central nervous system, or to pneumonia resulting from infection with Pneumocystis jiroveci or other organisms. Effective volume depletion secondary to fluid loss from the gastrointestinal tract, due primarily to infectious diarrhea. Adrenal insufficiency often due to an adrenalitis, an abnormality that may be infectious in origin, perhaps being induced by cytomegalovirus, Mycobacterium avium-intracellulare, or HIV itself. Affected patients have a high risk of morbidity and mortality.

� � � � Other causes There are other causes that do not fit neatly in any of the above categories and may or may not be associated with elevated levels of ADH or simply overwhelm the capacity of the kidneys to properly excrete excess water. The most common precipitant of hyponatremia in patients after surgery [18] is the iatrogenic infusion of hypotonic fluids. Inappropriate administration of hypotonic intravenous fluids after surgery increases the risk of developing hyponatremia in these vulnerable patients, who retain water due to nonosmotic release of ADH, which is typically elevated for a few days after most surgical procedures. Hospitalacquired acute hyponatremia is disturbingly common also among hospitalized children and adults. Severe malnutrition seen in weight-conscious women (low protein, high water intake diet) is a special condition in which a markedly decreased intake of solutes occurs, which limits the ability of the kidney to handle the free water. Because a mandatory solute loss of 50 -100 m. Osm/kg of urine exists, free water intake in excess of solute needs can produce hyponatremia. [19] Another example is beer drinker's potomania, because a diet consisting primarily of beer is rich in free water but solute poor. Compulsive intake of large amounts of free water exceeding the diluting capacity of the kidneys (>20 L/d), even with a normal solute intake of 600 -900 m. Osm/d, may also result in hyponatremia, but in contrast to SIADH, the urine is maximally dilute. In addition to a central defect in thirst regulation, which plays an important role in the pathogenesis of primary polydipsia, different abnormalities in ADH regulation have been identified in psychotic patients, all impairing free water excretion. Transient stimulation of ADH release during acute psychotic episodes, an increase in the net renal response to ADH, downward resetting of the osmostat, and antipsychotic medication may contribute. Limiting water intake will rapidly raise the plasma sodium concentration as the excess water is readily excreted in dilute urine [20] Acute hyponatremia is associated with ultra-endurance athletes and marathon runners. [21] With women making up a higher percentage, the strongest single predictor is weight gain during the race correlating with excessive fluid intake. Longer racing time and body mass index extremes are also associated with hyponatremia, whereas the composition of fluids consumed (plain water rather than sports drinks containing electrolytes) is not. Oxidization of glycogen and triglyceride during a race is associated with the production of "bound" water, which then becomes an endogenous, electrolyte-free water infusion contributing to hyponatremia induced by water ingestion in excess of water losses. It should be noted that some collapsed runners are normonatremic or even hypernatremic, [22] making blanket recommendations difficult. However, fluid intake to the point of weight gain should be avoided. [22, 23] Athletes should rely on thirst as their guide for fluid replacement and avoid fixed, global recommendations for water intake. Symptomatic hyponatremic patients should receive 100 m. L of 3% sodium chloride over 10 minutes in the field before transportation to hospital. This maneuver should raise the plasma sodium concentration an average of 2 -3 m. Eq/L. [24] Nonsteroidal anti-inflammatory drug (NSAID) use may increase the risk of development of hyponatremia by strenuous exercise by inhibiting prostaglandin formation. Prostaglandins have a natriuretic effect. Prostaglandin depletion increases Na. Cl reabsorption in the thick ascending limb of Henle (ultimately increasing medullary tonicity) and ADH action in the collecting duct, leading to impaired free water excretion. [25] Symptomatic and potentially fatal hyponatremia can develop with rapid onset after ingestion of the designer drug ecstasy (methylenedioxymethamphetamine, or MDMA), an amphetamine. A marked increase in water intake via direct thirst stimulation, as well as inappropriate secretion of ADH, contributes to the hyponatremia seen with even small amount of drug intake. Nephrogenic syndrome of inappropriate antidiuresis (or NSIAD) is an SIADH-like clinical and laboratory picture seen in male infants who present with neurologic symptoms secondary to hyponatremia but who have undetectable plasma arginine vasopressin (AVP) levels. This hereditary disorder is secondary to mutations in the V 2 vasopressin receptor, resulting in constitutive activation of the receptor with elevated c. AMP production in the collecting duct principle cells. Treatment of NSIAD poses a challenge. Water restriction improves serum sodium levels and osmolality in infants, but it limits calorie intake in these formula-fed infants. The use of demeclocycline or lithium is potentially limited because of adverse effects. The current therapy of choice is fluid restriction and the use of oral urea to induce an osmotic diuresis. [26] Hyponatremic hypertensive syndrome, a rare condition, consists of severe hypertension associated with renal artery stenosis, hyponatremia, hypokalemia, severe thirst, and renal dysfunction characterized by natriuresis, hypercalciuria, renal glycosuria, and proteinuria. Angiotensin-mediated thirst coupled with nonosmotic release of vasopressin provoked by angiotensin II and/or hypertensive encephalopathy are likely mechanisms for this syndrome. Sodium depletion due to pressure natriuresis and potassium depletion due to hyperaldosteronism with high plasma renin activity are also likely to play a role in the pathogenesis of hyponatremia. The abnormalities resolve with correction of the renal artery stenosis. [27] Using a retrospective case note analysis, an Irish study examined the incidence of hyponatremia in a variety of neurologic conditions. [28] The investigators found that the occurrence of hyponatremia was greater in persons with subarachnoid hemorrhage (62 out of 316 patients, or 19. 6%; P <0. 001), intracranial neoplasm (56 out of 355 patients, or 15. 8%; P <0. 001), traumatic brain injury (44 out of 457 patients, or 9. 6%; P <0. 001), and pituitary disorders (5 out of 81 patients, or 6. 25%; P = 0. 004) than it was in patients with spinal disorders (4 out of 489 patients, or 0. 81%). The investigators also determined that the median hospital stay for patients with hyponatremia was 19 days, compared with a median stay of 12 days for the study's other patients.

�Diagnostic Considerations �Other problems to consider in the differential diagnosis are as follows: �Hyperlipidemia �Paraproteinemia �Pseudohyponatremia �Differential Diagnoses �Adrenal Crisis �Alcoholism �Cardiogenic Pulmonary Edema �Cirrhosis �Hypothyroidism

� � � � � Laboratory Studies There are three essential laboratory tests in the evaluation of patients with hyponatremia that, together with the history and the physical examination, help to establish the primary underlying etiologic mechanism. (In general, the etiology of the hyponatremia directs its management. ) These tests are as follows Urine osmolality Serum osmolality Urinary sodium concentration Urine osmolality helps to differentiate between conditions associated with impaired free water excretion and primary polydipsia, in which water excretion should be normal (provided intact kidney function). With primary polydipsia, as with malnutrition (severe decreased solids intake) and a reset osmostat, the urine osmolality is maximally dilute, generally less than 100 m. Osm/kg. A urine osmolality greater than 100 m. Osm/kg indicates impaired ability of the kidneys to dilute the urine. This usually is secondary to elevated vasopressin (antidiuretic hormone; ADH) levels, appropriate or inappropriate. Serum osmolality readily differentiates between true hyponatremia and pseudohyponatremia secondary to hyperlipidemia, hyperproteinemia, or hypertonic hyponatremia. Sources of hypertonic hyponatremia include elevations of the following: Glucose Mannitol Glycine (after urologic or gynecologic procedures) Sucrose Maltose (contained in Ig. G formulations) Urinary sodium concentration helps to differentiate between hyponatremia secondary to hypovolemia and the syndrome of inappropriate ADH secretion (SIADH). With SIADH (and salt-wasting syndrome), the urine sodium is greater than 20 -40 m. Eq/L. With hypovolemia, the urine sodium typically measures less than 25 m. Eq/L. However, if sodium intake in a patient with SIADH (or salt-wasting) happens to be low, then urine sodium may fall below 25 m. Eq/L. Ancillary tests Serum uric acid levels can be important supportive information (they are typically reduced in SIADH and also reduced in salt wasting). After correction of hyponatremia, the hypouricemia corrects in SIADH but remains with a salt-wasting process. Thyroid-stimulating hormone (TSH) and serum cortisol levels should be measured if hypothyroidism or hypoadrenalism is suspected. Serum albumin, triglycerides, and a serum protein electrophoresis also may be indicated for particular patients.

�Imaging Studies �Head computed tomography (CT) scanning and chest radiography can be used to assess for an underlying etiology in select patients with suspected SIADH or cerebral salt wasting.

� Approach Considerations � The recommendations for treatment of hyponatremia rely on the current understanding of the central nervous � � � � system (CNS) adaptation to an alteration in serum osmolality. In the setting of an acute fall in the serum osmolality, neuronal cell swelling occurs due to the water shift from the extracellular space to the intracellular space (ie, Starling forces). Therefore, correction of hyponatremia should take into account the limited capacity of this adaptation mechanism to respond to acute alteration in the serum tonicity, because the degree of brain edema and consequent neurologic symptoms depend as much on the rate and duration of hypotonicity as they do on its magnitude. A panel of United States experts on hyponatremia issued guidelines on the diagnosis, evaluation, and treatment of hyponatremia in 2007; the guidelines were updated in 2013. [29] For treatment of symptomatic patients with acute hyponatremia (ie, with a known duration of <24 -48 hours), the panel recommended urgent correction by 4 -6 mmol/L to prevent brain herniation and neurological damage from cerebral ischemia. Recommended treatment of acute hyponatremia varies by symptom severity, as follows: Severe symptoms: 100 m. L of 3% Na. Cl infused intravenously over 10 minutes × 3 as needed Mild to moderate symptoms, in patients at low risk for herniation: 3% Na. Cl infused at 0. 5– 2 m. L/kg/h To avoid osmotic demyelination syndrome (ODS) in patients with chronic hyponatremia (known duration >48 hours), the recommendations include the following [29] : Minimum correction of serum sodium by 4 -8 mmol/L per day, with a lower goal of 4 -6 mmol/L per day if the risk of ODS is high For patients at high risk of ODS: maximum correction of 8 mmol/L in any 24 -hour period For patients at normal risk of ODS: maximum correction of 10 -12 mmol/L in any 24 -hour period; 18 mmol/L in any 48 -hour period

� For patients with inappropriate antidiuretic hormone secretion (SIADH), fluid restriction (with a goal of 500 � � � m. L/d below the 24 -hour urine volume) is generally first-line therapy, but pharmacologic treatment should be strongly considered if the patient's urinary parameters indicate low renal electrolyte-free water excretion or if the serum sodium concentration does not correct after 24 -48 hours of fluid restriction. Pharmacologic options include demeclocycline (off label use), urea, and vasopressin receptor antagonists (vaptans). Vaptans should not be used in hypovolemic hyponatremia, or in conjunction with other treatments for hyponatremia. [29] The European Society of Intensive Care Medicine, the European Society of Endocrinology, and the European Renal Association–European Dialysis and Transplant Association have released guidelines on the diagnosis, classification, and treatment of true hypotonic hyponatremia. Treatment recommendations include the following [1, 2] : For serious symptomatic hyponatremia, the first line of treatment is prompt intravenous infusion of hypertonic saline, with a target increase of 6 mmol/L over 24 hours (not exceeding 12 mmol/L) and an additional 8 mmol/L during every 24 hours thereafter until the patient’s serum sodium concentration reaches 130 mmol/L First-line treatment for patients with SIADH and moderate or profound hyponatremia should be fluid restriction; second-line treatments include increasing solute intake with 0. 25– 0. 50 g/kg per day of urea or combined treatment with low-dose loop diuretics and oral sodium chloride For patients with reduced circulating volume, extracellular volume should be restored with an intravenous infusion of 0. 9% saline or a balanced crystalloid solution at 0. 5 to 1. 0 m. L/kg per hour Lithium, demeclocycline, and vaptans are not recommended for patients with moderate or profound hyponatremia Consultation with either a nephrologist or a critical care specialist is often of considerable value in managing patients with symptomatic or refractory hyponatremia.

� � � � � Medical Care Intravenous fluids and water restriction When faced with a patient with hyponatremia, the first decision is what type of fluid, if any, should be given. The treatment of hypertonic and pseudohyponatremia is directed at the underlying disorder in the absence of symptoms. Hypotonic hyponatremia accounts for most clinical cases of hyponatremia. The first step in the approach and evaluation of hypotonic hyponatremia is to determine whether emergency therapy is warranted. The following three factors guide treatment: Patient's volume status Duration and magnitude of the hyponatremia Degree and severity of clinical symptoms For the asymptomatic patient, the following treatments may be of use: Hypovolemic hyponatremia: Administer isotonic saline to patients who are hypovolemic to replace the contracted intravascular volume (thereby treating the cause of vasopressin release). Patients with hypovolemia secondary to diuretics may also need potassium repletion, which, like sodium, is osmotically active. Correction of volume repletion turns off the stimulus to ADH secretion, so a large water diuresis may ensue, leading to a more rapid correction of hyponatremia than desired. If so, hypotonic fluid such as D 5/½ normal saline may need to be administered (see below under normovolemic hyponatremia for guidelines). Hypervolemic hyponatremia: Treat patients who are hypervolemic with salt and fluid restriction, plus loop diuretics, and correction of the underlying condition. The use of a V 2 receptor antagonist may be considered (see below). For normovolemic (euvolemic), asymptomatic hyponatremic patients, free water restriction (<1 L/d) is generally the treatment of choice. There is no role for hypertonic saline in these patients. Base the volume of restriction on the patient's renal diluting capacity. For instance, fluid restriction to 1 L/d, which is enough to raise the serum sodium in some patients, may exceed the renal free water excretion capacity in others, necessitating more severe restriction. This approach is recommended as initial treatment for patients with asymptomatic SIADH. However, many patients will not adhere to fluid restriction. Further, the definition of asymptomatic is changing due to the recognition that subtle but significant deficits, such as in gait, may be present. Therefore, pharmacologic treatment may be considered (see below). When treating patients with overtly symptomatic hyponatremia (eg, seizures, severe neurological deficits), hypertonic (3%) saline should be used. There is no place in the initial treatment for aquaretics (see below). Note that normal saline can exacerbate hyponatremia in patients with SIADH, who may excrete the sodium and retain the water. A liter of normal saline contains 154 m. Eq sodium chloride (Na. Cl) and 3% saline has 513 m. Eq Na. Cl. Management decisions should also factor in ongoing renal free water and solute losses. Alternately, the combination of intravenous normal saline and diuresis with a loop diuretic (eg, furosemide) also elevates the serum sodium concentration. This latter approach is often useful for patients with high urine osmolality, because the loop diuretic acts to reduce urine osmolality. Concomitant use of loop diuretics increases free water excretion and decreases the risk of fluid overload. The following equation helps to estimate an expected change in serum sodium (Na) with respect to characteristics of infusates used [30] : Change in serum Na = [(infusate Na + infusate K) - serum Na] / [Total body water +1] During therapy, close monitoring of serum electrolytes (ie, every 2 -4 h) to avoid overcorrection is essential. Acute hyponatremia (duration < 48 h) can be safely corrected more quickly than chronic hyponatremia. A severely symptomatic patient with acute hyponatremia is in danger from brain edema. In contrast, a symptomatic patient with chronic hyponatremia is more at risk from rapid correction of hyponatremia. Overly rapid correction of serum sodium can precipitate severe neurologic complications, such as central pontine myelinosis, which can produce spastic quadriparesis, swallowing dysfunction, pseudobulbar palsy, and mutism. A symptomatic patient with unknown duration of hyponatremia is the most challenging, warranting a prompt but controlled and limited correction of hyponatremia, until symptoms resolve. However, fear of osmotic demyelination should not deter prompt and definitive treatment. With patients who are acutely symptomatic (duration <48 h, such as after surgery), the treatment goal is to increase the serum sodium level by approximately 1 -2 m. Eq/L/h for 3 -4 hours, until the neurologic symptoms subside or until plasma sodium concentration is over 120 m. Eq/L. [31] Other authors recommend an even more rapid correction. [4] In chronic, severe symptomatic hyponatremia, the rate of correction should not exceed 0. 5 -1 m. Eq/L/h, with a total increase not to exceed 8 -12 m. Eq/L/d and no more than 18 m. Eq/L in the first 48 h. The sodium concentration must be corrected to a safe range (usually to no greater than 120 m. Eq/L) rather than to a normal value. As noted above, spontaneous diuresis secondary to ADH suppression with intravascular volume repletion could lead to unintended overcorrection.

� � � � Pharmacologic treatment Pharmacologic agents can be used in some cases of more refractory SIADH, allowing more liberal fluid intake. Demeclocycline has been the drug of choice to increase the diluting capacity of the kidneys, by achieving vasopressin antagonism and a functional diabetes insipidus. This treatment requires 3 -4 days for maximal effect. Demeclocycline is contraindicated in cirrhotic patients. Other agents, such as lithium, have been used with variable success. Lithium is also associated with several untoward effects, including thyroid dysfunction, interstitial kidney disease, and, in overdosage, CNS dysfunction, which make its use problematic. The treatment of psychogenic polydipsia can be difficult and may require psychiatric, pharmacologic, and fluid intervention. Aquaretics A new class of drugs, AVP receptor antagonists, designed specifically to promote aquaresis (ie, electrolyte-sparing excretion of free water), has been evaluated in clinical trials for the treatment of hyponatremia. [32, 33] The first agent to be approved was conivaptan, a V 1 A and V 2 vasopressin receptor antagonist. It is available only for intravenous use and is approved for use in the hospital setting for euvolemic and hypervolemic hyponatremia. It is contraindicated in hypovolemic patients. It induces both a water and sodium diuresis with improvement in plasma sodium levels. Most of the clinical experience has been in heart failure. It is effective in raising serum sodium levels; however, conivaptan has not been shown to improve heart failure per se. Close monitoring of the rate of correction is needed and is approved for treatment for only 4 days. In addition, the effects in patients with renal and hepatic impairment have not been well studied and caution is advised with use in this population. There are several drug interactions that need close monitoring and the use of conivaptan with CYP 3 A 4 inhibitors is contraindicated. Tolvaptan, a selective V 2 receptor antagonist, can be taken orally and has been approved for use in the treatment of euvolemic and hypervolemic hyponatremia, including cases associated with cirrhosis and heart failure. Tolvaptan treatment must be initiated in the hospital to avoid the possibility of too rapid correction (although there have not been reported cases). It shows great promise but because of the requirement for hospitalization for initiation or reintroduction and the expense of the drug, its use at this time is limited. It also interacts with CYP 3 A inhibitors and use with such drugs is contraindicated. In April 2013, the FDA limited use of tolvaptan to no more than 30 days and indicated that it should not be used in patients with underlying liver disease. This decision was based on reports of liver injury, including those potentially leading to liver transplant or death. [34] The use of these vaptans is limited and exact benefits have yet to be determined. There are reports that even mild hyponatremia can cause gait instability and possibly increase the risk of falls and hip fractures. In this setting, vaptans may be beneficial to improve hyponatremia and gait.

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

�Medication Summary �The primary treatments used in the management of hyponatremic patients rely on the use of intravenous sodium-containing fluids (normal saline or hypertonic saline) and fluid restriction. Less commonly, loop diuretics (eg, furosemide) or demeclocycline are used. A new class of drugs, AVP receptor antagonists (eg, conivaptan), is now available. [32, 33]

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

�Class Summary �Certain antibiotics may affect renal ADH action. �Demeclocycline (Declomycin) �View full drug information �Can cause insensitivity of distal renal tubules to the action of ADH and produce a nephrogenic diabetes insipidus. Effects are seen within 5 days and are reversed within 2 -6 days following cessation of therapy.

� Arginine Vasopressin Antagonists � Class Summary � Treats hyponatremia through V 2 antagonism of AVP in the renal collecting ducts. � � � This effect results in aquaresis (excretion of free water). [32, 33] Conivaptan (Vaprisol) View full drug information Arginine vasopressin antagonist (V 1 A, V 2) indicated for euvolemic (dilutional) and hypervolemic hyponatremia. Increases urine output of mostly free water, with little electrolyte loss. Over 80% of conivaptan excreted in feces and the rest in urine. Tolvaptan (Samsca) View full drug information Selective vasopressin V 2 -receptor antagonist. Indicated for hypervolemic and euvolemic hyponatremia (ie, serum sodium level < 125 m. Eq/L) or less-marked hyponatremia that is symptomatic and has resisted correction with fluid restriction. Used for hyponatremia associated with congestive heart failure, liver cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion. Initiate or reinitiate in hospital environment only. Duration of use is limited to 30 days to minimize risk of liver injury.

� Complications � Clinical manifestations include clouding of consciousness, confusion, stupor, or coma. Seizures commonly � � occur with rapid reductions in serum sodium or with serum sodium concentrations of less than 115 -120 m. Eq/L. For unknown reasons, premenopausal women seem to have a less efficient osmotic adaptation. This increases their susceptibility to severe hyponatremia and rapid progression from minimal symptoms (eg, headache, nausea) to respiratory arrest. Cerebral edema and herniation have been found at autopsy. [35] Correction of hyponatremia that is too rapid may cause permanent neurologic impairment. Central pontine myelinolysis (CPM) and extrapontine myelinolysis (EPM), complications of excessive correction of chronic hyponatremia, are now diagnosed by diffusion-weighted magnetic resonance imaging (MRI). Of note is that conventional CT and MRI scan findings typically lag behind the clinical manifestations of myelinosis by 2 -4 weeks. [36] The clinical course of these patients features initial encephalopathy secondary to hyponatremia, then improvement as the plasma Na concentration increases, and finally deterioration several days later. The disorder can resolve completely or result in permanent disability or death. This typical clinical course has been called the osmotic demyelination syndrome (ODS). The clinical neurologic picture may be confusing, as it may include a variety of findings from psychiatric, behavioral, and movement disorders, such as dysphagia and flaccid or spastic quadriparesis, depending on the involvement of extrapontine or central pontine myelinolysis. Disruption of the blood-brain barrier is presumed to play an important role in the pathogenesis of osmotic demyelination. An increased susceptibility to osmotic demyelination is also observed in cirrhotic patients. In this setting, myoinositol, the most abundant organic osmolyte, is depleted because of glutamine- and hyponatremiainduced brain cell swelling. CPM is a common and often fatal complication of orthotopic liver transplantation, affecting up to 10% of patients who were hyponatremic prior to transplant. [37]

� Prognosis � The prognosis for patients with hyponatremia is predicated upon the underlying etiology. A study by Doshi et al found that hyponatremia among patients with cancer is associated with extended hospital stays and higher mortality rates; however, whether long-term correction of hyponatremia would improve these outcomes is unclear. [38] � A meta-analysis of 15 studies encompassing 13, 816 patients found that any improvement in hyponatremia was associated with a reduced risk of overall mortality (odds ratio [OR]=0. 57). With the eight studies that reported a threshold for serum sodium improvement to >130 mmol/L, the association was even stronger (OR=0. 51). The reduction in mortality risk persisted at 12 -month follow-up (OR=0. 55). Reduced mortality was more evident in older patients and in patients with lower serum sodium levels at enrollment. [39]

� � � � � � � � Barclay L, Nainggolan L. New European Guidelines Address Hyponatremia Management. Medscape Medical News. Available at http: //www. medscape. com/viewarticle/821130. Accessed: March 1, 2014. [Guideline] Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Nephrol Dial Transplant. 2014 Feb 25. [Medline]. Singhi S, Jayashre M. Free water excess is not the main cause for hyponatremia in critically ill children receiving conventional maintenance fluids. Indian Pediatr. 2009 Jul. 46(7): 577 -83. [Medline]. Gross P, Reimann D, Henschkowski J, Damian M. Treatment of severe hyponatremia: conventional and novel aspects. J Am Soc Nephrol. 2001 Feb. 12 Suppl 17: S 10 -4. [Medline]. Dubois GD, Arieff AI. Treatment of hyponatremia: the case for rapid correction. Narins RG, ed. Controversies in Nephrology and Hypertension. New York: Churchill Livingstone Inc; 1984. 393 -407. Goldberg A, Hammerman H, Petcherski S, et al. Prognostic importance of hyponatremia in acute ST-elevation myocardial infarction. Am J Med. 2004 Aug 15. 117(4): 242 -8. [Medline]. Bae MH, Kim JH, Jang SY, et al. Hyponatremia at discharge as a predictor of 12 -month clinical outcomes in hospital survivors after acute myocardial infarction. Heart Vessels. 2016 Jun 2. [Medline]. Heuman DM, Abou-Assi SG, Habib A, Williams LM, Stravitz RT, Sanyal AJ. Persistent ascites and low serum sodium identify patients with cirrhosis and low MELD scores who are at high risk for early death. Hepatology. 2004 Oct. 40(4): 802 -10. [Medline]. Kim MY, Baik SK, Yea CJ, et al. Hepatic venous pressure gradient can predict the development of hepatocellular carcinoma and hyponatremia in decompensated alcoholic cirrhosis. Eur J Gastroenterol Hepatol. 2009 Nov. 21(11): 1241 -6. [Medline]. Huang H, Jolly SE, Airy M, et al. Associations of dysnatremias with mortality in chronic kidney disease. Nephrol Dial Transplant. 2016 May 24. [Medline]. Bettari L, Fiuzat M, Shaw LK, Wojdyla DM, Metra M, Felker GM, et al. Hyponatremia and long-term outcomes in chronic heart failure-an observational study from the duke databank for cardiovascular diseases. J Card Fail. 2012 Jan. 18(1): 74 -81. [Medline]. Hillier TA, Abbott RD, Barrett EJ. Hyponatremia: evaluating the correction factor for hyperglycemia. Am J Med. 1999 Apr. 106(4): 399 -403. [Medline]. Issa MM, Young MR, Bullock AR, Bouet R, Petros JA. Dilutional hyponatremia of TURP syndrome: a historical event in the 21 st century. Urology. 2004 Aug. 64(2): 298 -301. [Medline]. Palmer BF. Hyponatraemia in a neurosurgical patient: syndrome of inappropriate antidiuretic hormone secretion versus cerebral salt wasting. Nephrol Dial Transplant. 2000 Feb. 15(2): 262 -8. [Medline]. Palmer BF. Hyponatremia in patients with central nervous system disease: SIADH versus CSW. Trends Endocrinol Metab. 2003 May-Jun. 14(4): 182 -7. [Medline]. Yang CH, Lin YC, Chou PH, Chen HC, Chan CH. A Case Report of Late Onset Mania Caused by Hyponatremia in a Patient With Empty Sella Syndrome. Medicine (Baltimore). 2016 Feb. 95 (6): e 2629. [Medline]. Smith D, Moore K, Tormey W, Baylis PH, Thompson CJ. Downward resetting of the osmotic threshold for thirst in patients with SIADH. Am J Physiol Endocrinol Metab. 2004 Nov. 287(5): E 1019 -23. [Medline]. Skippen P, Adderley R, Bennett M, et al. Iatrogenic hyponatremia in hospitalized children: Can it be avoided? . Paediatr Child Health. 2008 Jul. 13(6): 502 -6. [Medline]. [Full Text]. Thaler SM, Teitelbaum I, Berl T. "Beer potomania" in non-beer drinkers: effect of low dietary solute intake. Am J Kidney Dis. 1998 Jun. 31(6): 1028 -31. [Medline]. Goldman MB, Luchins DJ, Robertson GL. Mechanisms of altered water metabolism in psychotic patients with polydipsia and hyponatremia. N Engl J Med. 1988 Feb 18. 318(7): 397 -403. [Medline]. Danz M, Pöttgen K, Tönjes PM, Hinkelbein J, Braunecker S. Hyponatremia among Triathletes in the Ironman European Championship. N Engl J Med. 2016 Mar 10. 374 (10): 997 -8. [Medline]. Kratz A, Siegel AJ, Verbalis JG, et al. Sodium status of collapsed marathon runners. Arch Pathol Lab Med. 2005 Feb. 129(2): 227 -30. [Medline]. Almond CS, Shin AY, Fortescue EB, et al. Hyponatremia among runners in the Boston Marathon. N Engl J Med. 2005 Apr 14. 352(15): 1550 -6. [Medline]. Hew-Butler T, Almond C, Ayus JC, et al. Consensus statement of the 1 st International Exercise-Associated Hyponatremia Consensus Development Conference, Cape Town, South Africa 2005. Clin J Sport Med. 2005 Jul. 15(4): 208 -13. [Medline]. Baker J, Cotter JD, Gerrard DF, Bell ML, Walker RJ. Effects of indomethacin and celecoxib on renal function in athletes. Med Sci Sports Exerc. 2005 May. 37(5): 712 -7. [Medline]. Feldman BJ, Rosenthal SM, Vargas GA, et al. Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med. 2005 May 5. 352(18): 1884 -90. [Medline]. Trivelli A, Ghiggeri GM, Canepa A, Oddone M, Bava G, Perfumo F. Hyponatremic-hypertensive syndrome with extensive and reversible renal defects. Pediatr Nephrol. 2005 Jan. 20(1): 102 -4. [Medline]. Sherlock M, O'Sullivan E, Agha A, et al. Incidence and pathophysiology of severe hyponatraemia in neurosurgical patients. Postgrad Med J. 2009 Apr. 85(1002): 171 -5. [Medline]. [Guideline] Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier RW, Sterns RH, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013 Oct. 126 (10 Suppl 1): S 1 -42. [Medline]. Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med. 2000 May 25. 342(21): 1581 -9. [Medline].

Classic Formulas: �Na. Deficit = Sex * Normal. Wgt * (Desired. Na - Hypernatremia Serum. Na) desired Na+ Insensible water losses = 500 - 1500 cc/day. Fever increases insensible water losses by 10% per degree C Total H 2 O deficit (L) = total body water x ( 1 - ) serum Na+ Hyponatremia Na+ requirement (mmol) = total body water x (desired Na+ - serum Na+ ) Na+ requirement (mmol) x 1000 Rate of infusion (cc/hr) = infusate Na+ (mmol/L) x time (hours) Adrogue Formula: (infusate Na+ + infusate K+) - serum Na+ Change in serum Na+ = total body water + 1 Infusate Na+ (mmol/L) 5% Na. Cl 855 3% Na. Cl 513 0. 9% Na. Cl (NS) 154 Lactate Ringer's 130 0. 45% Na. Cl (½ NS) 77 0. 2% Na. Cl (¼ NS) 5% Dextrose in water (D 5 W) 34 0 Total Body Water (in liters) : Children 0. 6 x weight Women 0. 5 x weight Men 0. 6 x weight Elderly Women 0. 45 x weight Elderly Men 0. 5 x weight. Insensible water losses = 500 - 1500 cc/day. Fever increases insensible water losses by 10% per degree Celsius above 38°, or 100 -150 cc/day increase per degree Celsius above 37°.

Infusate Na+ Infusate (mmol/L) 5% Na. Cl 855 3% Na. Cl 513 0. 9% Na. Cl (NS) 154 Lactate Ringer's 130 0. 45% Na. Cl (½ NS) 77 0. 2% Na. Cl (¼ NS) 34 5% Dextrose in water (D 5 W) 0 Total Body Water (in liters) : Children 0. 6 x weight Women 0. 5 x weight Men 0. 6 x weight Elderly Women 0. 45 x weight Elderly Men 0. 5 x weight

Classic Formulas: Hypernatremia desired Na + Total H 2 O deficit (L) = total body water x ( 1 - ) serum Na+ Hyponatremia Na+ requirement (mmol) = total body water x (desired Na + - serum Na+ ) Na+ requirement (mmol) x 1000 Rate of infusion (cc/hr) = infusate Na+ (mmol/L) x time (hours) Adrogue Formula: (infusate Na+ + infusate K+) - serum Na+ Change in serum Na + = total body water + 1

� For serious symptomatic hyponatremia, the first line of treatment is prompt intravenous infusion of hypertonic saline, with a target increase of 6 mmol/L over 24 hours (not exceeding 12 mmol/L) and an additional 8 mmol/L during every 24 hours thereafter until the patient’s serum sodium concentration reaches 130 mmol/L � First-line treatment for patients with SIADH and moderate or profound hyponatremia should be fluid restriction; second-line treatments include increasing solute intake with 0. 25– 0. 50 g/kg per day of urea or combined treatment with low-dose loop diuretics and oral sodium chloride � For patients with reduced circulating volume, extracellular volume should be restored with an intravenous infusion of 0. 9% saline or a balanced crystalloid solution at 0. 5 to 1. 0 m. L/kg per hour � Lithium, demeclocycline, and vaptans are not recommended for patients with moderate or profound hyponatremia