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The Management of Hyponatremic Emergencies
En1ergendes fl
MD*
CASE STUDIES Case l an elective
Case 2
7, No. 1,
j&J1E2-ry
1991
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DISCUSSION OF HYPONATREMIA The two study cases illustrate the problems in selecting the correct treatment for symptomatic hyponatremia. For the first patient, rapid correction to a serum sodium level above 120 mEq/L can stop seizures and reduce life-threatening cerebral edema. 6 But for the second, the same treatment can cause severe neurologic injury. 6 · 10 · 25 · 29 · 3 s- 44 In treating hyponatremia, the thoughtful clinician must make individualized choices, balancing the benefits of therapy against its risks in each case. To do so requires an understanding of the pathogenesis of hyponatremia and careful consideration of the clinical and experimental evidence concerning the dangers of the electrolyte abnormality itself and its treatment. The Meaning of the Serum Sodium Concentration Ironically, the serum sodium concentration provides no information about the state of sodium balance; rather, it is a measure of the adequacy of body water content. 33 • 44 Because water moves freely across cell membranes in response to osmotic forces, the osmolalities of cellular and extracellular fluids are equal. Furthermore, because sodium salts usually account for most of the impermeant solutes present in the extracellular fluid, the serum sodium concentration is, in effect, a measure of the concentration or "tonicity" of all body fluids. This relationship can be expressed by the equation 15 : Serum [Na+]
Total body sodium + Total body potassium Total body water
Because the total solute content of the body is relatively stable, changes in water balance have the greatest impact on the serum sodium concentration. Hence, disorders of the serum sodium concentration are primarily disorders of water metabolism. Cell solute content in particular is relatively fixed because most intracellular anions are macromolecules that cannot cross the cell membrane. Thus, when the concentration of solutes outside of cells decreases, water moves into the cell, raising intracellular volume-i.e., hypotonicity is associated with cell swelling. When we speak of "hyponatremia" in this article, we equate it with hypotonicity (and cellular overhydration). It is important to note, however, that there are conditions in which the serum sodium concentration does not accurately reflect plasma tonicity (Table l). VVhen these disorders are suspected, measurement of the plasma osmolality may be indicated to decide whether or not a low serum sodium concentration means that body fluids are too dilute. Pathogenesis of Hyponatremia Hyponatremia occurs when the intake of electrolyte-free water exceeds free water losses. 33 · 44 Most of the fluids ingested and excreted
']fable . ,Causes
decreases serum J\J a
l . .5
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Table 2. Causes of Hypotonic Hyponatremia Diluting ability intact 1. Psychotic polydipsia 2. Beer potomania-water excretion limited because urinary solute excretion reduced Diluting ability impaired Vasopressin secretion normal 1. Oliguric renal failure 2. Thiazide diuretics (some cases) Vasopressin secretion abnormal Abnormal hemodynamics 1. Volume depletion 2. Edematous conditions-congestive heart failure, cirrhosis, nephrotic syndrome 3. Thiazide diuretics (some cases) 4. Addison's disease 5. Cerebral salt wasting Normal hemodynamics 1. SIADH -Ectopic antidiuretic hormone production by tumors -Central nervous system disorders -Pulmonary diseases -Postoperative -Nausea -Drug induced 2. Endocrine disorders-hypothyroidism, cortisol deficiency SIADH = Syndrome of inappropriate antidiuretic hormone.
brainstem that have been stimulated by parasympathetic inputs from baroreceptors in the great vessels and from volume receptors in the left atrium. Vasopressin secretion may also be stimulated by angiotensin II. Thus, conditions that normally stimulate sodium retention (hypovolemia, edema-forming states) are also associated with elevated vasopressin levels, water retention, and hyponatremia. Hyponatremia caused by a hemodynamic stimulus to vasopressin release can usually be identified by a low urinary sodium concentration (or chloride in alkalotic subjects), providing the patient's intake of sodium is not also very low. Exceptions include patients with Addison's disease, those receiving diuretics, and those with a rare condition known as "cerebral salt wasting." 31 In addition, vasopressin secretion may be independent of osmotic or hemodynamic stimuli (see Table 2). In these conditions (often referred to as the syndrome of inappropriate antidiuretic hormone secretion or SIADH), the normal controls of sodium balance are unaffected: A high sodium intake increases urinary sodium excretion and a low sodium intake reduces it so that extracellular volume is maintained within normal limits. 5• 14 In SIADH, however, free water cannot be excreted normally; persistent vasopressin secretion results in water retention, hyponatremia, and cell swelling. Diuretic agents are an important cause of severe hyponatremia. 1• 16 • 39 • 44 Thiazides and metolazone block the reabsorption of sodium chloride in the distal convoluted tubule, thereby preventing the formation of a maximally dilute urine. Unlike "loop" diuretics like furo-
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semide, bumetanide, and ethacrynic acid, these agents (i.e., thiazides, metolazone) leave the ability to excrete a maximally concentrated urine intact, permitting simultaneous retention of water and depletion of sodium, potassium, and chloride. Consequences of Hyponatremia The major consequences of hyponatremia are neurologic. Water moves relatively freely across the blood- brain barrier in response to osmotic forces. Thus, when the serum sodium concentration falls, creating an osmotic gradient between the brain and plasma, the brain ought to swell. Because of the confines of the skull, however, an increase in brain volume of more than about 10% is incompatible with life. 6, 38, 40-42 Fortunately, brain swelling in hyponatremia is much less than would be predicted on the basis of ideal osmotic behavior. If this were not true, only mild hyponatremia could be tolerated; a reduction in serum sodium concentration from 140 to 127 mEq/L (a 10% change) would result in fatal cerebral edema. The fact that humans can survive (sometimes with few neurologic symptoms) with serum sodium concentrations below 100 mEq/L-low enough to increase brain volume by 40%-indicates that the brain is remarkably well defended against osmotic swelling. Two lines of defense diminish the severity of brain swelling in hyponatremia: (1) loss of interstitial fluid (and sodium) by bulk flow into the cerebrospinal fluid, and (2) loss of cellular solute (potassium and organic osmolytes), which allows the brain cell to maintain osmotic equilibrium with the plasma while avoiding a large increase in volume. 6, 38, 40, 44, 45 The first defense is provided by anatomic communications between the brain's interstitial space and the cerebrospinal fluid (CSF). When the serum sodium concentration falls, drawing water into the brain by osmosis, the increasing hydrostatic pressure of the cerebral interstitial space forces interstitial fluid out of the brain into the CSF via extracellular channels. The surplus CSF then enters the systemic circulation. In this way, the CSF serves as a "sink" for the drainage of excess interstitial fluid from the brain. Within minutes of the onset of hyponatremia, bulk flow of sodium-rich interstitial fluid out of the brain limits the increase in brain water to about half of what would be predicted by ideal osmotic behavior. Cellular adaptations to hyponatremia occur more slowly . Potassium losses from the brain can first be detected 3 to 4 hours after the onset of hyponatremia and they become maximal within about 24 hours. Somewhat later, organic osmolytes are extruded from the brain, permitting a further reduction in cell swelling. The brain cell cytoplasm normally contains relatively high concentrations of taurine, phosphocreatine, myoinositol, and several amino acids-most notably glutamine and glutamate.26 · 46 • 47 The concentration of -these organic osmol-y-tes- (once known-as-.:·' idiogenic-osmoles.!2-) can vary widely without disrupting cellular functions . Accumulation of extra organic osmolytes when the serum sodium concentration rises
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and depletion of these compounds when it falls allows the brain cell to adjust to severe hypo- and hypernatremia. 26 ' 46 • 47 Because these adjustments take time, however, the brain cannot tolerate large rapid changes in the serum sodium concentration. 45 • 46 The time-dependent adaptations of the brain to osmotic disturbances have two major clinical consequences: (1) Acute hyponatremia may be fatal at serum sodium concentrations that are well tolerated chronically2• 3 • 6 ; and (2) once an adaptation has taken place, rapid correction of the electrolyte disturbance can cause brain dehydration because of slow re accumulation of lost potassium and organic osmolytes by the brain cell. 6 • 38 - 46 Dangers of a Rapid Onset of Hyponatremia When hyponatremia develops faster than the brain can adapt to the disturbance, cerebral edema accompained by a syndrome known as "water intoxication" results. Acute water intoxication presents with headache, nervousness, vomiting, and, in its later stages, disorientation, twitching, stupor, convulsions, and coma. 6 Rarely, respiratory arrest and death caused by transtentorial herniation may occur. 2• 3 • 17 Deaths and neurologic sequelae from acute hyponatremia can be seen when the serum sodium concentration falls below 120 mEq/L by more than 0.5 mEq/L/hour; sequelae become increasingly common when it decreases by more than 1 mEq/L/hour. 10 Severe complications from acute hyponatremia occur primarily at a time when the serum sodium concentration is still falling-either because of the continued infusion of intravenous fluids 2• 17 or soon after the oral ingestion of gallons of water by psychotic patients. 8 Fatalities from acute water intoxication command respect for the electrolyte disturbance. Most patients with acute symptomatic hyponatremia do not die however; the incidence of death and permanent neurologic disability after seizures and coma is probably less than 5%. The often-quoted mortality rate of 50% is a gross overestimate based primarily on individual case reports of fatalities and series devoted solely to patients with adverse outcomes. 12 • 39 - 44 Dangers of Rapid Correction of Hyponatremia The adaptations that defend against brain swelling in hyponatremia predispose to complications when the chronic electrolyte disturbance is repaired too rapidly. 6• 7• 10• 22 - 25• 29• 30• 38 - 46• 48 Cerebral edema is minimal in chronic hyponatremia, even at extremely low serum sodium concentrations45• 46 ; neurologic symptoms appear to be caused primarily by depletion of brain solute rather than by brain swelling. 12• 14 There is little evidence that chronic hyponatremia itself causes brain damage. 2. 6, 12, 39 As the serum sodium concentration returns to normal, solutes lost in the adaptation to hyponatremia must be recovered by the brain. Unless this process keeps pace with the rising serum sodium concentration, brain dehydration and injury may result. For reasons that remain unclear, the clinical manifestations of this injury are delayed,
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evolving in a characteristic fashion called the "osmotic demyelination syndrome.' ' 43 In typical cases of the syndrome, hyponatremic symptoms improve during correction of the electrolyte abnormality, but improvement is followed within one to several days by gradual neurologic deterioration. A spectrum of neurologic findings distinct from the original hyponatremic symptoms can occur. Mild cases may be manifest by transient behavioral disturbances, seizures, movement disorders, or akinetic mutism. 38 - 40 More severe cases develop clinical features of a pontine disorder (pseudobulbar palsy, quadriparesis, and unresponsiveness).6· 7· 43 In fatal cases, disruption of myelin with sparing of neurons and axons is usually found in the center of the basal pons-a pathologic finding known as central pontine myelinolysis or "CPM." 6· 25 · 29 · 43 Histologically similar lesions often are found in a symmetrical distribution in extrapontine areas of the brain in which there is a close admixture of gray and white matter. 6· 25 · 43 Magnetic resonance imaging (MRI) can usually demonstrate areas of demyelination in patients who develop this syndrome, but the scans must be properly timed. 7· 27 Lesions cannot usually be documented until 3 to 4 weeks after the clinical onset and they may eventually resolve. The osmotic demyelination syndrome has been reproduced in animal models of hyponatremia. 21 · 23 ' 24 ' 45 ' 48 These studies confirm clinical observations suggesting that the syndrome is a complication of the treatment of hyponatremia rather than the electrolyte disturbance itself. The disorder does not develop in animals with uncorrected or slowly corrected hyponatremia. 23 · 45 · 48 The susceptibility to osmotic demyelination increases with the duration of hyponatremia prior to treatment and lesions are most severe in animals undergoing large, rapid increases in sodium concentration. 22 · 45 · 48 In the rat, the "threshold" for causing the syndrome is approximately 25 mEq/L/day, 48 but in the dog, an increase of only 15 mEq/L/day is required 24 and in humans the increase may be as little as 12 mEq/L/day, particularly in patients with alcoholism, liver disease, and other debilitating illnesses that appear to predispose to this complication. 43 Patients at greatest risk for the osmotic demyelination syndrome have been hyponatremic for more than 2 days, usually with very low serum sodium concentrations (105 mEq/L or less). 7· 10 · 39 · 43 Larger increases in sodium concentration tend to be associated with more severe damage, and most patients with fatal disease have undergone correction by more than 20 mEq/L/ day. 10· 43 Correction by less than 12 mEq/L/day is associated with uncomplicated recovery in chronic hyponatremia, even when the serum sodium concentration is less than 105 mEq/L.39 Acute Versus Chronic Symptomatic Hyponatremia The distinction between acute and chronic hyponatremia is somewhat arbitrar-y-and various- definitions h-ave-app-earetl-in-th-e- literature. We will consider hyponatremia acute when it is of less than 48 hours'
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duration and chronic when it has evolved (or persisted) over the course of more than 48 hours. Acute hyponatremia tends to be symptomatic when the serum sodium concentration has fallen by more than 12 mEq/ L/day. 10 Patients with chronic hyponatremia tend to become symptomatic when the serum sodium concentration falls below 115 mEq/L or when hyponatremia exacerbates underlying neurologic conditions. s, 14, 39, 43 In practice, the precise duration of hyponatremia is seldom known because most patients develop the electrolyte disturbance outside the hospital. Except for psychotic water drinkers, however, patients who become severely hyponatremic at home can be presumed to have a chronic condition. With a normal water intake, it usually takes at least 2 days to lower the serum sodium concentration enough to become symptomatic. 39 Even when the patient becomes hyponatremic in the hospital, the duration of the disturbance may be unclear if chemistry determinations have been infrequent. Still, it is usually possible to infer the rate of onset from fluid orders and other indicators. In most cases of uncertainty, it is best to assume that the case is chronic (i.e., of more than 2 days' duration). When symptoms demand aggressive action and the chronicity of the condition is unknown, extreme care must be taken to assure that the amount of correction of hyponatremia does not exceed the limits of safety (see next section). Approach to Acute Hyponatremia There are only a few settings in which acute symptomatic hyponatremia is likely to be seen in adults: (1) in psychotic water drinkers, (2) in patients with impaired water excretion who are treated intravenously with hypotonic fluids, and (3) in patients who systemically absorb electrolyte-free irrigating solutions during prostate surgery. Most patients with acute hyponatremia tolerate large rapid increases in sodium concentration without developing the osmotic demyelination syndrome. When possible, however, a change of more than 12 mEq/L/ day should be avoided because rare instances of this complication have been reported in patients with acute hyponatremia. Psychotic Polydipsia. Extreme polydipsia is relatively common in psychiatric patients. 21 This usually only causes marked polyuria; if the renal excretory capacity is overwhelmed for a few hours, however, severe symptomatic hyponatremia may be seen. Patients often have dilute urine at presentation, so by the time hyponatremia is recognized, it has already begun to improve. 19 • 37• 38 Once water intake is interrupted (usually by a convulsion), the electrolyte disturbance "autocorrects" rapidly via a water diuresis. In such cases, active therapeutic interventions (beyond discontinuing water intake) are unnecessary; in fact, it may be difficult to prevent a rapid return of the serum sodium concentration to near normal levels. Other patients briefly excrete inappropriately concentrated urine because of transient vasopressin release caused by smoking, psychosis, or possibly by water intoxication itself, but ultimately these patients also "autocorrect" as vasopressin is cleared21 • 37 • 38 ; a few cases have a more persistent defect in water excre-
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tion caused by chronic SIADH or thiazide diuretics. When neurologic symptoms are severe and urine output is less than 300 mL/hour, an infusion of 3% saline may be needed, as described later. The vast majority of psychotic water drinkers recover uneventfully-even those who develop seizures and coma. 8 · 39 Most also tolerate large and rapid increases in serum sodium concentration. 8 · 39 The low incidence of complications from rapid correction is best explained by the short duration of hyponatremia in patients who have only subtle defects in water excretion. 39 Parenteral Water Intoxication. Patients receiving hypotonic intravenous fluids may become acutely hyponatremic if water excretion is impaired. Because of smaller body size and lower body water content, women are more susceptible than men to rapid changes in sodium concentration. A 50-kg woman has a body water content of only about 25 L (50% of body weight), for example. A positive balance of electrolytefree water at a rate of 200 mL/hr will lower the serum sodium by 1 mEq/L/hour. (In an elderly female with a water content equal to only 40% of body weight, the susceptibility to hyponatremia is even greater.) By contrast, an 80-kg man with a body water content of 48 L (60% of body weight) requires about twice as much free water to lower his serum sodium to the same degree. Many cases of parenteral water intoxication have been recorded postoperatively. Anesthesia and surgery are almost invariably associated with elevated levels of vasopressin. 9 · 11 If the patient is given enough hypotonic fluid (e.g., 5% dextrose, one half normal saline, 5% dextrose in one half normal saline) during the early postoperative period, symptoms of acute water intoxication may develop, usually within 48 hours of surgery. 2 • 17 · 36 · 49 · 50 As expected, elderly women are particularly susceptible to this complication, and although symptoms are typically severe, permanent sequelae are unusual. 36 • 49 • 50 Not all patients with acute postoperative hyponatremia are so fortunate, however. Two recent papers have recorded 18 deaths from cerebral edema in healthy young women who became hyponatremic after elective surgery (cases were gathered over several years from all over the country). 2· 17 The presentation was frighteningly similar in all cases. After a variable period of headaches, vomiting, and mild confusion, the patients suddenly (and without warning) suffered convulsions and respiratory arrest followed by signs of transtentorial herniation. This experience, although rare, emphasizes that even relatively minor symptoms of water intoxication should be taken very seriously if the patient is still receiving hypotonic fluids intravenously. Unlike patients who control their own water intake (and tend to stop drinking when they become symptomatic), the victim of parenteral water intoxication will be subjected to a progressive drop in sodium concentration even when the brain's adaptation to hypotonicity has failed to prevent serious cerebral edema. Thus, corrective measures should be started immediately and the disorder should be regarded as one with at least -mrac:ure component. In most cases, infusion of 3Yo sallne is indicated (see later discussion). The same recommendation applies to patients
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with other causes of impaired water excretion who are receiving hypotonic fluids intravenously (see Table 2). Unless it is known that hyponatremia is ofless than 2 days' duration, however, the rate of correction must be carefully controlled to avoid an increase of more than 12 mEq/ L/day (see later section). Post-prostatectomy Syndrome. Large volumes of isosmolar or slightly hypo-osmolar electrolyte-free irrigating solutions may be absorbed into the systemic circulation during transurethral resection of the prostate. 28 • 34 The severity of hyponatremia initially is exaggerated because the solutes contained in the irrigant are confined to the extracellular space, causing "isotonic" hyponatremia (the serum sodium concentration is low, but the plasma osmolality is normal-or nearly so-because of the absorbed solutes). 34 Ensuing events depend on the solute contained in the irrigating solution. If an isotonic mannitol solution is used, the plasma osmolality remains normal and cerebral edema does not occur (because mannitol does not cross the blood-brain barrier or permeate cell membranes and is not metabolized) 28 ; the patient does well neurologically despite astoundingly severe hyponatremia; and the condition should never be treated with hypertonic saline. If glycine or sorbitol solutions are used, hypo-osmolality gradually emerges as the absorbed solute is metabolized; once this occurs, the serum sodium concentration rises spontaneously as water no longer held in the extracellular space by the exogenous solute diffuses intracellularly. 34 Ironically, symptoms suggestive of cerebral edema may appear as a late complication at a time when the serum sodium concentration is rising (but plasma osmolality is falling). Treatment with hypertonic saline may be indicated, but the need for treatment must be guided by the plasma osmolality rather than the serum sodium concentration. When glycine solutions are used, neurologic symptoms may reflect acute ammonia intoxication as well as hypo-osmolality because metabolism of the absorbed glycine may raise blood ammonia to extremely high levels. 34 Approach to Chronic Hyponatremia "Chronic" hyponatremia should not be equated with "asymptomatic" hyponatremia. Patients with very low serum sodium concentrations usually have some neurologic symptoms. Perhaps because cerebral edema is not severe, the symptoms of chronic hyponatremia tend to be more subtle, vague, and nonspecific than those of acute water intoxication. 3• 5 • 6• 12• 14• 39 The symptoms include lethargy, weakness, confusion, gait disturbances, muscle cramps, vomiting, and hiccups. With severe hyponatremia, tremor, stupor, and coma and, occasionally, seizures can occur. Although patients with chronic hyponatremia often succumb to underlying diseases, it is difficult to find a single published case in which a patient died as a direct consequence of the electrolyte disturbance. 6• 10 Such patients, however, are at considerable risk of neurologic injury caused by overaggressive correction of hyponatremia. 6 ' 38 - 44 Thus, although chronic hyponatremia clearly must be treated and a progressive reduction in sodium concentration must be avoided, one of the major goals in the treatment of this disorder is to make sure that
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THE MANAGEMENT OF HYPONATREMIC EMERGENCIES
Table 3. Causes of Chronic Hyponatremia at Increased Risk of Rapid Correction FEATURES
CAUSE
Volume depletion Thiazide diuretics
Drug induced Obstructive uropathy Respiratory failure/ pneumonia/nausea Endocrine disorders
Low urine sodium before treatment Urine becomes dilute after saline Usually affects elderly women Coexistent hypokalemic alkalosis Potassium repletion speeds correction Water diuresis after diuretic withdrawn Caused by oxytocin, DDAUP, chlorpropamide, carbamazepine Urine becomes dilute when drug is withdrawn Urea diuresis obligates excretion of free water when obstruction treated Water diuresis develops as condition improves and syndrome of inappropriate antidiuretic hormone resolves Water diuresis after treatment of Addison's disease, and hypopituitarism, hypothyroidism
DD AUP= 1-deamino-( 8 -o-arginine)-vasopressin .
it is not repaired too rapidly. The likelihood of inadvertent rapid correction is variable depending on the cause of hyponatremia (Table 3). Reversible Defects in Water Excretion. In many patients, hyponatremia is maintained by intravascular volume depletion. Once the volume deficit is repaired and the hemodynamic stimulus to vasopressin release is removed, the urine becomes dilute and water diuresis may increase the serum sodium concentration extremely rapidly. A urine output of 500 mL/hour will raise serum sodium by about 2 mEq/L/hour in a 50-kg woman, for example. A similar phenomenon may occur when some other factor impairing diluting ability is removed (e.g., after thiazide diuretics, oral hypoglycemic agents, oxytocin, or vasopressin are discontinued; after cortisol deficiency, hypothyroidism, or obstructive uropathy are treated; or after acute respiratory failure or vomiting resolve). Volume-depleted patients with chronic hyponatremia can be treated with isotonic saline. Careful monitoring of the urine output is mandatory during therapy and volume replacement should be limited to the amount required to correct symptomatic hypotension. If water diuresis ensues, electrolyte-free water losses must be replaced with hypotonic fluids to avoid excessive correction.30 In rare caes, it may become necessary to interrupt water diuresis with vasopressin or ldeamino-(8-n-arginine )-vasopressin (DOAVP) to prevent overly rapid correction. 44 Patients with hyponatremia caused by thiazide diuretics are extremely susceptible to a rapid increase in sodium concentration.33 • 3 s- 44 Several factors explain this vulnerability: (1) Thiazide-induced hyponatremia typically affects elderly women who have a small body -watercontent:-( 2-) 'freatrrrem-of-cueristing-potassium depl:eti on con triDu tes to the correction of hyponatremia. 1 · 16 • 33 · 40 (3) Once the diuretic agent is withdrawn, sodium chloride resorption in the diluting segment
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resumes, restoring the ability to generate maximally dilute urine, and (4) Repair of subtle volume deficits abolishes hemodynamic stimuli for vasopressin release. Because most patients with thiazide-induced hyponatremia are not clinically volume depleted, 1 · 16 ' 39 sodium replacement usually should be limited to that of a regular diet (about 150 mEq/day). Conservative repair of sodium deficits is particularly important when potassium must also be replaced. As indicated by the equation at the beginning of this discussion, the serum sodium concentration is affected by both sodium and potassium stores, such that 1 mEq of retained potassium will raise the serum sodium concentration by the same amount as will 1 mEq of sodium. 15 In an elderly woman weighing 50 kg, a mere 100 mEq of potassium plus 150 mEq of sodium will raise the serum sodium concentration by 12.5 mEq/L-more than the maximum desired daily increase. For most patients with thiazide-induced hyponatremia, therefore, an adequate diet, replacement of the potassium deficit, and withdrawal of the diuretic agent are all that are required to achieve a steady increase in sodium concentration while avoiding overly rapid correction (Table 4). Fixed Defects in Water Excretion. Patients with SIADH tend to be relatively resistant to rapid changes in sodium concentration. 5 · 14 · 39 • 40 Water restriction is the cornerstone of therapy, but this treatment alone may result in a painfully slow resolution of hyponatremia. Isotonic saline will not be helpful in speeding the process (see Table 4). Although "hypertonic" to the patients' plasma, the infused sodium can be excreted in a more concentrated form than it is administered. The net effect is retention of electrolyte-free water, and hyponatremia may be exacerbated. 33 Furosemide and other "loop" diuretics are useful in SIADH. 13 · 18 By impairing the patient's ability to concentrate urine, these agents increase electrolyte-free water excretion. Loop diuretics can be combined with oral salt or with a slow infusion of 3% saline. This strategy allows a controlled, gradual resolution of hyponatremia and the combination of furosemide and salt can be used for chronic maintenance therapy. 13 Loop diuretics are also the mainstay of therapy in patients with hyponatremia caused by edematous conditions. 32 ' 35 The combination of furosemide and an angiotensin converting enzyme (ACE) inhibitor is Table 4. Guidelines for Use of Isotonic Saline CONDITION
RECOMMENDATIONS
Volume depietion
Change to hypotonic fluids after 1 to 2 L to avoid rapid correction Indicated only when patient unable to eat. Limit infusion to 40 mL/hour Limit to 40 mL/hour. Larger volumes may lower serum sodium concentration Contraindicated. Will not improve hyponatremia; exacerbates edema
Thiazide induced SIADH Edema SIADH
=
Syndrome of inappropriate antidiuretic hormone.
ErAERGF.:NCIES
in response to osmotic grn-rnatter how will
sodium con·elin'1inate ceremag-
Saline X 2-3 hours
Seizures and
corna-ex~ept
r;;:yrrntn~n<:.::
acute
SJ0'01uh~f~;~i~n:~ 3%
saline
indh:ations: response \vate:r restrict~on -to take oral salt Caution::;
mor.e.thag l ]n patients
dilute and ur ne outpGi > intraveno;_;_s
Hr~.id
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Both 3% and 5% solutions of hypertonic saline are available. We prefer the 3% solution to avoid the catastrophic errors that have occurred when 5% saline was confused wtih 5% dextrose in water. A liter of the 3 % solution contains 512 mEq of sodium, a concentraton of 0.5 mEq/mL. Assuming that about half of body weight is water, 1 mL/ kg of the solution will raise the serum sodium concentration by 1 mEq/ L. When the clinical situation demands aggressive action, correction of hyponatremia can be initiated safely with an infusion of 3 % saline at 1 to 2 mL/kg/hour, raising the sodium concentration by 1 to 2 mEq/L/ hour. 4 • 6 • 12 • 39 - 42 In almost all cases, the rapid infusion should be stopped after 2 to 3 hours. Once the emergency has passed, aggressive therapy can be replaced with a more conservative regimen. In patients who are not volume depleted, the infusion ofhypertonic saline can be combined with a loop diuretic. 18 As indicated above, a slow infusion of hypertonic saline can be used in an occasional patient with severe SIADH who is unable to take salt by mouth and whose rate of correction is unacceptably slow with water restriction alone. The treatment should be designed to provide a salt intake comparable to a regular diet (about 200 mEq/day). This can be achieved with an infusion of 3% saline at 15 mL/hour. Most hyponatremic patients do not need any hypertonic saline. Those with only mild to moderate symptoms can be managed conservatively with measures designed to keep the rate of correction well below 0.5 mEq/L/hour. 39 The mere presence of an extremely low serum sodium concentration should not prompt more aggressive action. Indeed, patients with severe hyponatremia have the highest risk of developing the osmotic demyelination syndrome after rapid correction 7• 10 · 39• 43 ; uneventful recovery can be expected when correction is less than 12 mEq/L/ day. 10 · 39 • 43 SUMMARY Given time, the brain can tolerate extraordinarily severe hyponatremia, but it does not take well to sudden changes; both rapid onset and rapid correction of hyponatremia can be injurious. Emergency treatment of hyponatremia should be reserved for the patient who has not had time to fully adapt to the disturbance. When the clinical situation demands it, treatment can be safely initiated by infusing 3% saline at 1 to 2 mL/kg/hour for 2 to 3 hours. Once the emergency has passed, more conservative measures can be substituted so that the overall rate of correction does not exceed 12 mEq/L/day. Limiting therapy in this manner avoids the osmotic demyelination syndrome, a complication of overly rapid correction of hyponatremia. REFERENCES 1. Abramow M, Cogan E: Clinical aspects and pathophysiology of diuretic-induced hyponatremia. In Grunfeld JP, Maxwell MH (eds): Advances in Nephrology. Chicago, Year Book Medical Publishers, 1984, p 1
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2. Arieff Al: Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women. N Engl J Med 314:1529, 1986 3. Arieff AI, Llach F, Massry SG: Neurological manifestations and morbidity of hyponatremia: Correlation with brain water and electrolytes. Medicine 55:121, 1976 4. Ayus JC, Krothapalli RK, Arieff Al: Treatment of symptomatic hyponatremia and its relation to brain damage. N Engl J Med 317:1190, 1987 5. Bartter FC, Schwartz WB: The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med 42:790, 1967 6. Berl T: Treating hyponatremia: Damned if we do and damned if we don't. Kidney Int 37:1006, 1990 7. Brunner JE, Redmond JM, Haggar AM, et al: Central pontine myelinolysis and pontine lesions after rapid correction of hyponatremia: A prospective magnetic resonance imaging study. Ann Neurol 27:61, 1990 8. Cheng JC, Zikos D, Skopicki HA, et al: Long-term neurologic outcome in psychogenic water drinkers with severe symptomatic hyponatremia: The effect of rapid correction. Am J Med 88:561, 1990 9. Chung HS, Kluge R, Schrier RW, et al: Postoperative hyponatremia. Arch Intern Med 146:333, 1986 10. Cluitsman FHM, Meinders AE: Management of severe hyponatremia: Rapid or slow correction? Am J Med 88:161, 1990 11. Cochrane JPS, Forsling ML, Gow NM, et al: Arginine vasopressin release following surgical operations. Br J Surg 68:209, 1981 12. Covey CM, Arieff Al: Disorders of sodium and water metabolism and their effects on the central nervous system. In Brenner BM, Stein JH (eds): Sodium and Water Homeostasis. New York, Churchill Livingstone, 1978, p 212 13. Decaux G, Waterlot Y, Genette F, et al: Treatment of the syndrome of inappropriate secretion of antidiuretic hormone with furosemide. N Engl J Med 304:329, 1981 14. DeTroyer A, Demanet JC: Clinical, biological and pathogenic features of the syndrome of inappropriate secretion of antidiuretic hormone. Q J Med 45:521, 1976 15. Edelman IS, Leibman J, O'Meara MP, et al: Interrelations between serum sodium concentration, serum osmolality and total exchangeable sodium, total exchangeable potassium and total body water. J Clin Invest 37:1236, 1958 16. Fichman MP, Vorherr H, Kleeman CR, et al: Diuretic-induced hypontremia. Ann Intern Med 75:853, 1971 1 7. Fraser CL, Arieff Al: Fatal central diabetes mellitus and insipidus resulting from untreated hyponatremia: A new syndrome. Ann Intern Med 112:113, 1990 18. Hantman D, Rossier B, Zohlman R, et al: Rapid correction of hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone. An alternative treatment to hypertonic saline. Ann Intern Med 78:870, 1973 19. Hariprasad MK, Eisenger RP, Nadler IM, et al: Hyponatremia in psychogenic polydipsia. Arch Intern Med 140:1639, 1980 20. Hilden T, Svendsen TL: Electrolyte disturbances in beer drinkers. Lancet 2:245, 1975 21. Illowsky BP, Kirch DC: Polydipsia and hyponatremia in psychiatric patients. Am J Psychiatry 145:675, 1988 22. Illowsky BP, Laureno R: Encephalopathy and myelinolysis after rapid correction of hyponatremia. Brain 110:855, 1987 23. Kleinschmidt-DeMasters BK, Norenberg MD: Rapid correction of hyponatremia causes demyelination: Relation to central pontine myelinolysis. Science 211:1068, 1981 24. Laureno R: Central pontine myelinolysis following rapid correction ofhyponatremia. Ann Neurol 13:232, 1983 25. Laureno R, Karp Bl: Pontine and extrapontine myelinolysis following rapid correction ofhyponatremia. Lancet 1:1439, 1988 26. Lien YH, Shapiro JI, Chan L: Effects of hypernatremia on organic brain osmoles. J Clin Invest 85:1427, 1990 27. Miller GM. Baker HL Jr, Okazaki H, et al: Central pontine myelinolysis and its imitators: MR findings. Radiology 168:795, 1988 28. Mitnick PD, Bell S: Rhabdomyolysis associated with severe hyponatremia after prostatic surgery. Am J Kidney 16:73, 1990
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29. Norenberg MD, Leslie KO, Robertson AS: Association between rise in serum sodium and central pontine myelinolysis. Ann Neurol 11:128, 1982 30. Oh MS, Uribarri J, Barrido D, et al: Central pontine myelinolysis following isotonic saline. Am J Med Sci 298:4, 1989 31. Oster JR, Perez GO, Larios 0, et al: Cerebral salt wasting in a man with carcinomatous meningitis. Arch Intern Med 143:2187, 1983 32. Packer M, Medina N, Yushak M: Correction of dilutional hyponatremia in severe chronic heart failure by converting-enzyme inhibition. Ann Intern Med 100:782, 1984 33. Rose BD: New approach to disturbances in the plasma sodium concentration. Am J Med 81:1033, 1986 34. Rothenberg DM, Berns AS, Ivankovich AD: Isotonic hyponatremia following transurethral prostate resection. J Clin Anesth 2:48, 1990 35. Schrier RW, Lehman D, Zacherie B, et al: Effect of furosemide on free water excretion in edematous patients with hyponatremia. Kidney Int 3:30, 1973 36. Scott JC Jr, Welch JS, Berman IB: Water intoxication and sodium depletion in surgical patients. Obstet Gynecol 26:168, 1965 37. Smith WO, Clark ML: Self-induced water intoxication in schizophrenic patients. Am J Psychiatry 137:1055, 1980 38. Sterns RH: Neurological deterioration following treatment for hyponatremia. Am J Kidney Diseases 12:434, 1989 39. Sterns RH: Severe symptomatic hyponatremia: Treatment and outcome. A study of 64 cases. Ann Intern Med 107:656, 1987 40. Sterns RH: The management of symptomatic hyponatremia. Semin Nephrol 10(6), 1990 41. Sterns RH: The treatment of hyponatremia: First, do no harm. Am J Med 88:557, 1990 42. Sterns RH: The treatment of hyponatremia: Unsafe at any speed? Kidney Fund Nephrology Letter 6:1, 1989 43. Sterns RH, Riggs JE, Schochet SS Jr: Osmotic demyelination syndrome following correction ofhyponatremia. N Engl J Med 314:1535, 1986 44. Sterns RH, Spital A: Disorders of water balance. In Kokko JP, Tannen RL (eds): Fluids and Electrolytes, ed 2. Philadelphia, WB Saunders, 1990, p 139 45. Sterns RH, Thomas DJ, Herndon RM: Brain dehydration and neurologic deterioration after rapid correction ofhyponatremia. Kidney Int 35:69, 1989 46. Thurston JH, Hauhart RE, Nelson JS: Adaptive decreases in amino acids (taurine in particular), creatine, and electrolytes prevent cerebral edema in chronically hyponatremic mice: Rapid correction (experimental model of central pontine myelinolysis) causes dehydration and shrinkage of brain. Metab Brain Dis 2:223, 1987 4 7. Thurston JH, Sherman WR, Hauhart RE, et al: myo-lnositol: A newly identified nonnitrogenous osmoregulatory molecule in mammalian brain. Pediatric Res 26:482, 1989 48. Verbalis JG, Martinez AJ: Osmotic demyelination is dependent on both rate and magnitude of correction of chronic hyponatremia in rats. Clin Res 37:586A, 1989 49. Wynn V, Rob CG: Water intoxication. Differential diagnosis of the hypotonic syndromes. Lancet 1:587, 1954 50. Zimmerman B, Wangensteen OH: Observations on water intoxication in surgical patients. Surgery 34:654, 1952
Address reprint requests to Richard H. Sterns, MD Nephrology Unit Rochester General Hospital 1425 Portland Avenue Rochester, NY 14621
MD*
CASE STUDIES Case l an elective
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DISCUSSION OF HYPONATREMIA The two study cases illustrate the problems in selecting the correct treatment for symptomatic hyponatremia. For the first patient, rapid correction to a serum sodium level above 120 mEq/L can stop seizures and reduce life-threatening cerebral edema. 6 But for the second, the same treatment can cause severe neurologic injury. 6 · 10 · 25 · 29 · 3 s- 44 In treating hyponatremia, the thoughtful clinician must make individualized choices, balancing the benefits of therapy against its risks in each case. To do so requires an understanding of the pathogenesis of hyponatremia and careful consideration of the clinical and experimental evidence concerning the dangers of the electrolyte abnormality itself and its treatment. The Meaning of the Serum Sodium Concentration Ironically, the serum sodium concentration provides no information about the state of sodium balance; rather, it is a measure of the adequacy of body water content. 33 • 44 Because water moves freely across cell membranes in response to osmotic forces, the osmolalities of cellular and extracellular fluids are equal. Furthermore, because sodium salts usually account for most of the impermeant solutes present in the extracellular fluid, the serum sodium concentration is, in effect, a measure of the concentration or "tonicity" of all body fluids. This relationship can be expressed by the equation 15 : Serum [Na+]
Total body sodium + Total body potassium Total body water
Because the total solute content of the body is relatively stable, changes in water balance have the greatest impact on the serum sodium concentration. Hence, disorders of the serum sodium concentration are primarily disorders of water metabolism. Cell solute content in particular is relatively fixed because most intracellular anions are macromolecules that cannot cross the cell membrane. Thus, when the concentration of solutes outside of cells decreases, water moves into the cell, raising intracellular volume-i.e., hypotonicity is associated with cell swelling. When we speak of "hyponatremia" in this article, we equate it with hypotonicity (and cellular overhydration). It is important to note, however, that there are conditions in which the serum sodium concentration does not accurately reflect plasma tonicity (Table l). VVhen these disorders are suspected, measurement of the plasma osmolality may be indicated to decide whether or not a low serum sodium concentration means that body fluids are too dilute. Pathogenesis of Hyponatremia Hyponatremia occurs when the intake of electrolyte-free water exceeds free water losses. 33 · 44 Most of the fluids ingested and excreted
']fable . ,Causes
decreases serum J\J a
l . .5
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Table 2. Causes of Hypotonic Hyponatremia Diluting ability intact 1. Psychotic polydipsia 2. Beer potomania-water excretion limited because urinary solute excretion reduced Diluting ability impaired Vasopressin secretion normal 1. Oliguric renal failure 2. Thiazide diuretics (some cases) Vasopressin secretion abnormal Abnormal hemodynamics 1. Volume depletion 2. Edematous conditions-congestive heart failure, cirrhosis, nephrotic syndrome 3. Thiazide diuretics (some cases) 4. Addison's disease 5. Cerebral salt wasting Normal hemodynamics 1. SIADH -Ectopic antidiuretic hormone production by tumors -Central nervous system disorders -Pulmonary diseases -Postoperative -Nausea -Drug induced 2. Endocrine disorders-hypothyroidism, cortisol deficiency SIADH = Syndrome of inappropriate antidiuretic hormone.
brainstem that have been stimulated by parasympathetic inputs from baroreceptors in the great vessels and from volume receptors in the left atrium. Vasopressin secretion may also be stimulated by angiotensin II. Thus, conditions that normally stimulate sodium retention (hypovolemia, edema-forming states) are also associated with elevated vasopressin levels, water retention, and hyponatremia. Hyponatremia caused by a hemodynamic stimulus to vasopressin release can usually be identified by a low urinary sodium concentration (or chloride in alkalotic subjects), providing the patient's intake of sodium is not also very low. Exceptions include patients with Addison's disease, those receiving diuretics, and those with a rare condition known as "cerebral salt wasting." 31 In addition, vasopressin secretion may be independent of osmotic or hemodynamic stimuli (see Table 2). In these conditions (often referred to as the syndrome of inappropriate antidiuretic hormone secretion or SIADH), the normal controls of sodium balance are unaffected: A high sodium intake increases urinary sodium excretion and a low sodium intake reduces it so that extracellular volume is maintained within normal limits. 5• 14 In SIADH, however, free water cannot be excreted normally; persistent vasopressin secretion results in water retention, hyponatremia, and cell swelling. Diuretic agents are an important cause of severe hyponatremia. 1• 16 • 39 • 44 Thiazides and metolazone block the reabsorption of sodium chloride in the distal convoluted tubule, thereby preventing the formation of a maximally dilute urine. Unlike "loop" diuretics like furo-
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semide, bumetanide, and ethacrynic acid, these agents (i.e., thiazides, metolazone) leave the ability to excrete a maximally concentrated urine intact, permitting simultaneous retention of water and depletion of sodium, potassium, and chloride. Consequences of Hyponatremia The major consequences of hyponatremia are neurologic. Water moves relatively freely across the blood- brain barrier in response to osmotic forces. Thus, when the serum sodium concentration falls, creating an osmotic gradient between the brain and plasma, the brain ought to swell. Because of the confines of the skull, however, an increase in brain volume of more than about 10% is incompatible with life. 6, 38, 40-42 Fortunately, brain swelling in hyponatremia is much less than would be predicted on the basis of ideal osmotic behavior. If this were not true, only mild hyponatremia could be tolerated; a reduction in serum sodium concentration from 140 to 127 mEq/L (a 10% change) would result in fatal cerebral edema. The fact that humans can survive (sometimes with few neurologic symptoms) with serum sodium concentrations below 100 mEq/L-low enough to increase brain volume by 40%-indicates that the brain is remarkably well defended against osmotic swelling. Two lines of defense diminish the severity of brain swelling in hyponatremia: (1) loss of interstitial fluid (and sodium) by bulk flow into the cerebrospinal fluid, and (2) loss of cellular solute (potassium and organic osmolytes), which allows the brain cell to maintain osmotic equilibrium with the plasma while avoiding a large increase in volume. 6, 38, 40, 44, 45 The first defense is provided by anatomic communications between the brain's interstitial space and the cerebrospinal fluid (CSF). When the serum sodium concentration falls, drawing water into the brain by osmosis, the increasing hydrostatic pressure of the cerebral interstitial space forces interstitial fluid out of the brain into the CSF via extracellular channels. The surplus CSF then enters the systemic circulation. In this way, the CSF serves as a "sink" for the drainage of excess interstitial fluid from the brain. Within minutes of the onset of hyponatremia, bulk flow of sodium-rich interstitial fluid out of the brain limits the increase in brain water to about half of what would be predicted by ideal osmotic behavior. Cellular adaptations to hyponatremia occur more slowly . Potassium losses from the brain can first be detected 3 to 4 hours after the onset of hyponatremia and they become maximal within about 24 hours. Somewhat later, organic osmolytes are extruded from the brain, permitting a further reduction in cell swelling. The brain cell cytoplasm normally contains relatively high concentrations of taurine, phosphocreatine, myoinositol, and several amino acids-most notably glutamine and glutamate.26 · 46 • 47 The concentration of -these organic osmol-y-tes- (once known-as-.:·' idiogenic-osmoles.!2-) can vary widely without disrupting cellular functions . Accumulation of extra organic osmolytes when the serum sodium concentration rises
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and depletion of these compounds when it falls allows the brain cell to adjust to severe hypo- and hypernatremia. 26 ' 46 • 47 Because these adjustments take time, however, the brain cannot tolerate large rapid changes in the serum sodium concentration. 45 • 46 The time-dependent adaptations of the brain to osmotic disturbances have two major clinical consequences: (1) Acute hyponatremia may be fatal at serum sodium concentrations that are well tolerated chronically2• 3 • 6 ; and (2) once an adaptation has taken place, rapid correction of the electrolyte disturbance can cause brain dehydration because of slow re accumulation of lost potassium and organic osmolytes by the brain cell. 6 • 38 - 46 Dangers of a Rapid Onset of Hyponatremia When hyponatremia develops faster than the brain can adapt to the disturbance, cerebral edema accompained by a syndrome known as "water intoxication" results. Acute water intoxication presents with headache, nervousness, vomiting, and, in its later stages, disorientation, twitching, stupor, convulsions, and coma. 6 Rarely, respiratory arrest and death caused by transtentorial herniation may occur. 2• 3 • 17 Deaths and neurologic sequelae from acute hyponatremia can be seen when the serum sodium concentration falls below 120 mEq/L by more than 0.5 mEq/L/hour; sequelae become increasingly common when it decreases by more than 1 mEq/L/hour. 10 Severe complications from acute hyponatremia occur primarily at a time when the serum sodium concentration is still falling-either because of the continued infusion of intravenous fluids 2• 17 or soon after the oral ingestion of gallons of water by psychotic patients. 8 Fatalities from acute water intoxication command respect for the electrolyte disturbance. Most patients with acute symptomatic hyponatremia do not die however; the incidence of death and permanent neurologic disability after seizures and coma is probably less than 5%. The often-quoted mortality rate of 50% is a gross overestimate based primarily on individual case reports of fatalities and series devoted solely to patients with adverse outcomes. 12 • 39 - 44 Dangers of Rapid Correction of Hyponatremia The adaptations that defend against brain swelling in hyponatremia predispose to complications when the chronic electrolyte disturbance is repaired too rapidly. 6• 7• 10• 22 - 25• 29• 30• 38 - 46• 48 Cerebral edema is minimal in chronic hyponatremia, even at extremely low serum sodium concentrations45• 46 ; neurologic symptoms appear to be caused primarily by depletion of brain solute rather than by brain swelling. 12• 14 There is little evidence that chronic hyponatremia itself causes brain damage. 2. 6, 12, 39 As the serum sodium concentration returns to normal, solutes lost in the adaptation to hyponatremia must be recovered by the brain. Unless this process keeps pace with the rising serum sodium concentration, brain dehydration and injury may result. For reasons that remain unclear, the clinical manifestations of this injury are delayed,
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evolving in a characteristic fashion called the "osmotic demyelination syndrome.' ' 43 In typical cases of the syndrome, hyponatremic symptoms improve during correction of the electrolyte abnormality, but improvement is followed within one to several days by gradual neurologic deterioration. A spectrum of neurologic findings distinct from the original hyponatremic symptoms can occur. Mild cases may be manifest by transient behavioral disturbances, seizures, movement disorders, or akinetic mutism. 38 - 40 More severe cases develop clinical features of a pontine disorder (pseudobulbar palsy, quadriparesis, and unresponsiveness).6· 7· 43 In fatal cases, disruption of myelin with sparing of neurons and axons is usually found in the center of the basal pons-a pathologic finding known as central pontine myelinolysis or "CPM." 6· 25 · 29 · 43 Histologically similar lesions often are found in a symmetrical distribution in extrapontine areas of the brain in which there is a close admixture of gray and white matter. 6· 25 · 43 Magnetic resonance imaging (MRI) can usually demonstrate areas of demyelination in patients who develop this syndrome, but the scans must be properly timed. 7· 27 Lesions cannot usually be documented until 3 to 4 weeks after the clinical onset and they may eventually resolve. The osmotic demyelination syndrome has been reproduced in animal models of hyponatremia. 21 · 23 ' 24 ' 45 ' 48 These studies confirm clinical observations suggesting that the syndrome is a complication of the treatment of hyponatremia rather than the electrolyte disturbance itself. The disorder does not develop in animals with uncorrected or slowly corrected hyponatremia. 23 · 45 · 48 The susceptibility to osmotic demyelination increases with the duration of hyponatremia prior to treatment and lesions are most severe in animals undergoing large, rapid increases in sodium concentration. 22 · 45 · 48 In the rat, the "threshold" for causing the syndrome is approximately 25 mEq/L/day, 48 but in the dog, an increase of only 15 mEq/L/day is required 24 and in humans the increase may be as little as 12 mEq/L/day, particularly in patients with alcoholism, liver disease, and other debilitating illnesses that appear to predispose to this complication. 43 Patients at greatest risk for the osmotic demyelination syndrome have been hyponatremic for more than 2 days, usually with very low serum sodium concentrations (105 mEq/L or less). 7· 10 · 39 · 43 Larger increases in sodium concentration tend to be associated with more severe damage, and most patients with fatal disease have undergone correction by more than 20 mEq/L/ day. 10· 43 Correction by less than 12 mEq/L/day is associated with uncomplicated recovery in chronic hyponatremia, even when the serum sodium concentration is less than 105 mEq/L.39 Acute Versus Chronic Symptomatic Hyponatremia The distinction between acute and chronic hyponatremia is somewhat arbitrar-y-and various- definitions h-ave-app-earetl-in-th-e- literature. We will consider hyponatremia acute when it is of less than 48 hours'
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duration and chronic when it has evolved (or persisted) over the course of more than 48 hours. Acute hyponatremia tends to be symptomatic when the serum sodium concentration has fallen by more than 12 mEq/ L/day. 10 Patients with chronic hyponatremia tend to become symptomatic when the serum sodium concentration falls below 115 mEq/L or when hyponatremia exacerbates underlying neurologic conditions. s, 14, 39, 43 In practice, the precise duration of hyponatremia is seldom known because most patients develop the electrolyte disturbance outside the hospital. Except for psychotic water drinkers, however, patients who become severely hyponatremic at home can be presumed to have a chronic condition. With a normal water intake, it usually takes at least 2 days to lower the serum sodium concentration enough to become symptomatic. 39 Even when the patient becomes hyponatremic in the hospital, the duration of the disturbance may be unclear if chemistry determinations have been infrequent. Still, it is usually possible to infer the rate of onset from fluid orders and other indicators. In most cases of uncertainty, it is best to assume that the case is chronic (i.e., of more than 2 days' duration). When symptoms demand aggressive action and the chronicity of the condition is unknown, extreme care must be taken to assure that the amount of correction of hyponatremia does not exceed the limits of safety (see next section). Approach to Acute Hyponatremia There are only a few settings in which acute symptomatic hyponatremia is likely to be seen in adults: (1) in psychotic water drinkers, (2) in patients with impaired water excretion who are treated intravenously with hypotonic fluids, and (3) in patients who systemically absorb electrolyte-free irrigating solutions during prostate surgery. Most patients with acute hyponatremia tolerate large rapid increases in sodium concentration without developing the osmotic demyelination syndrome. When possible, however, a change of more than 12 mEq/L/ day should be avoided because rare instances of this complication have been reported in patients with acute hyponatremia. Psychotic Polydipsia. Extreme polydipsia is relatively common in psychiatric patients. 21 This usually only causes marked polyuria; if the renal excretory capacity is overwhelmed for a few hours, however, severe symptomatic hyponatremia may be seen. Patients often have dilute urine at presentation, so by the time hyponatremia is recognized, it has already begun to improve. 19 • 37• 38 Once water intake is interrupted (usually by a convulsion), the electrolyte disturbance "autocorrects" rapidly via a water diuresis. In such cases, active therapeutic interventions (beyond discontinuing water intake) are unnecessary; in fact, it may be difficult to prevent a rapid return of the serum sodium concentration to near normal levels. Other patients briefly excrete inappropriately concentrated urine because of transient vasopressin release caused by smoking, psychosis, or possibly by water intoxication itself, but ultimately these patients also "autocorrect" as vasopressin is cleared21 • 37 • 38 ; a few cases have a more persistent defect in water excre-
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tion caused by chronic SIADH or thiazide diuretics. When neurologic symptoms are severe and urine output is less than 300 mL/hour, an infusion of 3% saline may be needed, as described later. The vast majority of psychotic water drinkers recover uneventfully-even those who develop seizures and coma. 8 · 39 Most also tolerate large and rapid increases in serum sodium concentration. 8 · 39 The low incidence of complications from rapid correction is best explained by the short duration of hyponatremia in patients who have only subtle defects in water excretion. 39 Parenteral Water Intoxication. Patients receiving hypotonic intravenous fluids may become acutely hyponatremic if water excretion is impaired. Because of smaller body size and lower body water content, women are more susceptible than men to rapid changes in sodium concentration. A 50-kg woman has a body water content of only about 25 L (50% of body weight), for example. A positive balance of electrolytefree water at a rate of 200 mL/hr will lower the serum sodium by 1 mEq/L/hour. (In an elderly female with a water content equal to only 40% of body weight, the susceptibility to hyponatremia is even greater.) By contrast, an 80-kg man with a body water content of 48 L (60% of body weight) requires about twice as much free water to lower his serum sodium to the same degree. Many cases of parenteral water intoxication have been recorded postoperatively. Anesthesia and surgery are almost invariably associated with elevated levels of vasopressin. 9 · 11 If the patient is given enough hypotonic fluid (e.g., 5% dextrose, one half normal saline, 5% dextrose in one half normal saline) during the early postoperative period, symptoms of acute water intoxication may develop, usually within 48 hours of surgery. 2 • 17 · 36 · 49 · 50 As expected, elderly women are particularly susceptible to this complication, and although symptoms are typically severe, permanent sequelae are unusual. 36 • 49 • 50 Not all patients with acute postoperative hyponatremia are so fortunate, however. Two recent papers have recorded 18 deaths from cerebral edema in healthy young women who became hyponatremic after elective surgery (cases were gathered over several years from all over the country). 2· 17 The presentation was frighteningly similar in all cases. After a variable period of headaches, vomiting, and mild confusion, the patients suddenly (and without warning) suffered convulsions and respiratory arrest followed by signs of transtentorial herniation. This experience, although rare, emphasizes that even relatively minor symptoms of water intoxication should be taken very seriously if the patient is still receiving hypotonic fluids intravenously. Unlike patients who control their own water intake (and tend to stop drinking when they become symptomatic), the victim of parenteral water intoxication will be subjected to a progressive drop in sodium concentration even when the brain's adaptation to hypotonicity has failed to prevent serious cerebral edema. Thus, corrective measures should be started immediately and the disorder should be regarded as one with at least -mrac:ure component. In most cases, infusion of 3Yo sallne is indicated (see later discussion). The same recommendation applies to patients
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with other causes of impaired water excretion who are receiving hypotonic fluids intravenously (see Table 2). Unless it is known that hyponatremia is ofless than 2 days' duration, however, the rate of correction must be carefully controlled to avoid an increase of more than 12 mEq/ L/day (see later section). Post-prostatectomy Syndrome. Large volumes of isosmolar or slightly hypo-osmolar electrolyte-free irrigating solutions may be absorbed into the systemic circulation during transurethral resection of the prostate. 28 • 34 The severity of hyponatremia initially is exaggerated because the solutes contained in the irrigant are confined to the extracellular space, causing "isotonic" hyponatremia (the serum sodium concentration is low, but the plasma osmolality is normal-or nearly so-because of the absorbed solutes). 34 Ensuing events depend on the solute contained in the irrigating solution. If an isotonic mannitol solution is used, the plasma osmolality remains normal and cerebral edema does not occur (because mannitol does not cross the blood-brain barrier or permeate cell membranes and is not metabolized) 28 ; the patient does well neurologically despite astoundingly severe hyponatremia; and the condition should never be treated with hypertonic saline. If glycine or sorbitol solutions are used, hypo-osmolality gradually emerges as the absorbed solute is metabolized; once this occurs, the serum sodium concentration rises spontaneously as water no longer held in the extracellular space by the exogenous solute diffuses intracellularly. 34 Ironically, symptoms suggestive of cerebral edema may appear as a late complication at a time when the serum sodium concentration is rising (but plasma osmolality is falling). Treatment with hypertonic saline may be indicated, but the need for treatment must be guided by the plasma osmolality rather than the serum sodium concentration. When glycine solutions are used, neurologic symptoms may reflect acute ammonia intoxication as well as hypo-osmolality because metabolism of the absorbed glycine may raise blood ammonia to extremely high levels. 34 Approach to Chronic Hyponatremia "Chronic" hyponatremia should not be equated with "asymptomatic" hyponatremia. Patients with very low serum sodium concentrations usually have some neurologic symptoms. Perhaps because cerebral edema is not severe, the symptoms of chronic hyponatremia tend to be more subtle, vague, and nonspecific than those of acute water intoxication. 3• 5 • 6• 12• 14• 39 The symptoms include lethargy, weakness, confusion, gait disturbances, muscle cramps, vomiting, and hiccups. With severe hyponatremia, tremor, stupor, and coma and, occasionally, seizures can occur. Although patients with chronic hyponatremia often succumb to underlying diseases, it is difficult to find a single published case in which a patient died as a direct consequence of the electrolyte disturbance. 6• 10 Such patients, however, are at considerable risk of neurologic injury caused by overaggressive correction of hyponatremia. 6 ' 38 - 44 Thus, although chronic hyponatremia clearly must be treated and a progressive reduction in sodium concentration must be avoided, one of the major goals in the treatment of this disorder is to make sure that
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Table 3. Causes of Chronic Hyponatremia at Increased Risk of Rapid Correction FEATURES
CAUSE
Volume depletion Thiazide diuretics
Drug induced Obstructive uropathy Respiratory failure/ pneumonia/nausea Endocrine disorders
Low urine sodium before treatment Urine becomes dilute after saline Usually affects elderly women Coexistent hypokalemic alkalosis Potassium repletion speeds correction Water diuresis after diuretic withdrawn Caused by oxytocin, DDAUP, chlorpropamide, carbamazepine Urine becomes dilute when drug is withdrawn Urea diuresis obligates excretion of free water when obstruction treated Water diuresis develops as condition improves and syndrome of inappropriate antidiuretic hormone resolves Water diuresis after treatment of Addison's disease, and hypopituitarism, hypothyroidism
DD AUP= 1-deamino-( 8 -o-arginine)-vasopressin .
it is not repaired too rapidly. The likelihood of inadvertent rapid correction is variable depending on the cause of hyponatremia (Table 3). Reversible Defects in Water Excretion. In many patients, hyponatremia is maintained by intravascular volume depletion. Once the volume deficit is repaired and the hemodynamic stimulus to vasopressin release is removed, the urine becomes dilute and water diuresis may increase the serum sodium concentration extremely rapidly. A urine output of 500 mL/hour will raise serum sodium by about 2 mEq/L/hour in a 50-kg woman, for example. A similar phenomenon may occur when some other factor impairing diluting ability is removed (e.g., after thiazide diuretics, oral hypoglycemic agents, oxytocin, or vasopressin are discontinued; after cortisol deficiency, hypothyroidism, or obstructive uropathy are treated; or after acute respiratory failure or vomiting resolve). Volume-depleted patients with chronic hyponatremia can be treated with isotonic saline. Careful monitoring of the urine output is mandatory during therapy and volume replacement should be limited to the amount required to correct symptomatic hypotension. If water diuresis ensues, electrolyte-free water losses must be replaced with hypotonic fluids to avoid excessive correction.30 In rare caes, it may become necessary to interrupt water diuresis with vasopressin or ldeamino-(8-n-arginine )-vasopressin (DOAVP) to prevent overly rapid correction. 44 Patients with hyponatremia caused by thiazide diuretics are extremely susceptible to a rapid increase in sodium concentration.33 • 3 s- 44 Several factors explain this vulnerability: (1) Thiazide-induced hyponatremia typically affects elderly women who have a small body -watercontent:-( 2-) 'freatrrrem-of-cueristing-potassium depl:eti on con triDu tes to the correction of hyponatremia. 1 · 16 • 33 · 40 (3) Once the diuretic agent is withdrawn, sodium chloride resorption in the diluting segment
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resumes, restoring the ability to generate maximally dilute urine, and (4) Repair of subtle volume deficits abolishes hemodynamic stimuli for vasopressin release. Because most patients with thiazide-induced hyponatremia are not clinically volume depleted, 1 · 16 ' 39 sodium replacement usually should be limited to that of a regular diet (about 150 mEq/day). Conservative repair of sodium deficits is particularly important when potassium must also be replaced. As indicated by the equation at the beginning of this discussion, the serum sodium concentration is affected by both sodium and potassium stores, such that 1 mEq of retained potassium will raise the serum sodium concentration by the same amount as will 1 mEq of sodium. 15 In an elderly woman weighing 50 kg, a mere 100 mEq of potassium plus 150 mEq of sodium will raise the serum sodium concentration by 12.5 mEq/L-more than the maximum desired daily increase. For most patients with thiazide-induced hyponatremia, therefore, an adequate diet, replacement of the potassium deficit, and withdrawal of the diuretic agent are all that are required to achieve a steady increase in sodium concentration while avoiding overly rapid correction (Table 4). Fixed Defects in Water Excretion. Patients with SIADH tend to be relatively resistant to rapid changes in sodium concentration. 5 · 14 · 39 • 40 Water restriction is the cornerstone of therapy, but this treatment alone may result in a painfully slow resolution of hyponatremia. Isotonic saline will not be helpful in speeding the process (see Table 4). Although "hypertonic" to the patients' plasma, the infused sodium can be excreted in a more concentrated form than it is administered. The net effect is retention of electrolyte-free water, and hyponatremia may be exacerbated. 33 Furosemide and other "loop" diuretics are useful in SIADH. 13 · 18 By impairing the patient's ability to concentrate urine, these agents increase electrolyte-free water excretion. Loop diuretics can be combined with oral salt or with a slow infusion of 3% saline. This strategy allows a controlled, gradual resolution of hyponatremia and the combination of furosemide and salt can be used for chronic maintenance therapy. 13 Loop diuretics are also the mainstay of therapy in patients with hyponatremia caused by edematous conditions. 32 ' 35 The combination of furosemide and an angiotensin converting enzyme (ACE) inhibitor is Table 4. Guidelines for Use of Isotonic Saline CONDITION
RECOMMENDATIONS
Volume depietion
Change to hypotonic fluids after 1 to 2 L to avoid rapid correction Indicated only when patient unable to eat. Limit infusion to 40 mL/hour Limit to 40 mL/hour. Larger volumes may lower serum sodium concentration Contraindicated. Will not improve hyponatremia; exacerbates edema
Thiazide induced SIADH Edema SIADH
=
Syndrome of inappropriate antidiuretic hormone.
ErAERGF.:NCIES
in response to osmotic grn-rnatter how will
sodium con·elin'1inate ceremag-
Saline X 2-3 hours
Seizures and
corna-ex~ept
r;;:yrrntn~n<:.::
acute
SJ0'01uh~f~;~i~n:~ 3%
saline
indh:ations: response \vate:r restrict~on -to take oral salt Caution::;
mor.e.thag l ]n patients
dilute and ur ne outpGi > intraveno;_;_s
Hr~.id
140
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Both 3% and 5% solutions of hypertonic saline are available. We prefer the 3% solution to avoid the catastrophic errors that have occurred when 5% saline was confused wtih 5% dextrose in water. A liter of the 3 % solution contains 512 mEq of sodium, a concentraton of 0.5 mEq/mL. Assuming that about half of body weight is water, 1 mL/ kg of the solution will raise the serum sodium concentration by 1 mEq/ L. When the clinical situation demands aggressive action, correction of hyponatremia can be initiated safely with an infusion of 3 % saline at 1 to 2 mL/kg/hour, raising the sodium concentration by 1 to 2 mEq/L/ hour. 4 • 6 • 12 • 39 - 42 In almost all cases, the rapid infusion should be stopped after 2 to 3 hours. Once the emergency has passed, aggressive therapy can be replaced with a more conservative regimen. In patients who are not volume depleted, the infusion ofhypertonic saline can be combined with a loop diuretic. 18 As indicated above, a slow infusion of hypertonic saline can be used in an occasional patient with severe SIADH who is unable to take salt by mouth and whose rate of correction is unacceptably slow with water restriction alone. The treatment should be designed to provide a salt intake comparable to a regular diet (about 200 mEq/day). This can be achieved with an infusion of 3% saline at 15 mL/hour. Most hyponatremic patients do not need any hypertonic saline. Those with only mild to moderate symptoms can be managed conservatively with measures designed to keep the rate of correction well below 0.5 mEq/L/hour. 39 The mere presence of an extremely low serum sodium concentration should not prompt more aggressive action. Indeed, patients with severe hyponatremia have the highest risk of developing the osmotic demyelination syndrome after rapid correction 7• 10 · 39• 43 ; uneventful recovery can be expected when correction is less than 12 mEq/L/ day. 10 · 39 • 43 SUMMARY Given time, the brain can tolerate extraordinarily severe hyponatremia, but it does not take well to sudden changes; both rapid onset and rapid correction of hyponatremia can be injurious. Emergency treatment of hyponatremia should be reserved for the patient who has not had time to fully adapt to the disturbance. When the clinical situation demands it, treatment can be safely initiated by infusing 3% saline at 1 to 2 mL/kg/hour for 2 to 3 hours. Once the emergency has passed, more conservative measures can be substituted so that the overall rate of correction does not exceed 12 mEq/L/day. Limiting therapy in this manner avoids the osmotic demyelination syndrome, a complication of overly rapid correction of hyponatremia. REFERENCES 1. Abramow M, Cogan E: Clinical aspects and pathophysiology of diuretic-induced hyponatremia. In Grunfeld JP, Maxwell MH (eds): Advances in Nephrology. Chicago, Year Book Medical Publishers, 1984, p 1
THE MANAGEMENT OF HYPONATREMIC EMERGENCIES
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2. Arieff Al: Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women. N Engl J Med 314:1529, 1986 3. Arieff AI, Llach F, Massry SG: Neurological manifestations and morbidity of hyponatremia: Correlation with brain water and electrolytes. Medicine 55:121, 1976 4. Ayus JC, Krothapalli RK, Arieff Al: Treatment of symptomatic hyponatremia and its relation to brain damage. N Engl J Med 317:1190, 1987 5. Bartter FC, Schwartz WB: The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med 42:790, 1967 6. Berl T: Treating hyponatremia: Damned if we do and damned if we don't. Kidney Int 37:1006, 1990 7. Brunner JE, Redmond JM, Haggar AM, et al: Central pontine myelinolysis and pontine lesions after rapid correction of hyponatremia: A prospective magnetic resonance imaging study. Ann Neurol 27:61, 1990 8. Cheng JC, Zikos D, Skopicki HA, et al: Long-term neurologic outcome in psychogenic water drinkers with severe symptomatic hyponatremia: The effect of rapid correction. Am J Med 88:561, 1990 9. Chung HS, Kluge R, Schrier RW, et al: Postoperative hyponatremia. Arch Intern Med 146:333, 1986 10. Cluitsman FHM, Meinders AE: Management of severe hyponatremia: Rapid or slow correction? Am J Med 88:161, 1990 11. Cochrane JPS, Forsling ML, Gow NM, et al: Arginine vasopressin release following surgical operations. Br J Surg 68:209, 1981 12. Covey CM, Arieff Al: Disorders of sodium and water metabolism and their effects on the central nervous system. In Brenner BM, Stein JH (eds): Sodium and Water Homeostasis. New York, Churchill Livingstone, 1978, p 212 13. Decaux G, Waterlot Y, Genette F, et al: Treatment of the syndrome of inappropriate secretion of antidiuretic hormone with furosemide. N Engl J Med 304:329, 1981 14. DeTroyer A, Demanet JC: Clinical, biological and pathogenic features of the syndrome of inappropriate secretion of antidiuretic hormone. Q J Med 45:521, 1976 15. Edelman IS, Leibman J, O'Meara MP, et al: Interrelations between serum sodium concentration, serum osmolality and total exchangeable sodium, total exchangeable potassium and total body water. J Clin Invest 37:1236, 1958 16. Fichman MP, Vorherr H, Kleeman CR, et al: Diuretic-induced hypontremia. Ann Intern Med 75:853, 1971 1 7. Fraser CL, Arieff Al: Fatal central diabetes mellitus and insipidus resulting from untreated hyponatremia: A new syndrome. Ann Intern Med 112:113, 1990 18. Hantman D, Rossier B, Zohlman R, et al: Rapid correction of hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone. An alternative treatment to hypertonic saline. Ann Intern Med 78:870, 1973 19. Hariprasad MK, Eisenger RP, Nadler IM, et al: Hyponatremia in psychogenic polydipsia. Arch Intern Med 140:1639, 1980 20. Hilden T, Svendsen TL: Electrolyte disturbances in beer drinkers. Lancet 2:245, 1975 21. Illowsky BP, Kirch DC: Polydipsia and hyponatremia in psychiatric patients. Am J Psychiatry 145:675, 1988 22. Illowsky BP, Laureno R: Encephalopathy and myelinolysis after rapid correction of hyponatremia. Brain 110:855, 1987 23. Kleinschmidt-DeMasters BK, Norenberg MD: Rapid correction of hyponatremia causes demyelination: Relation to central pontine myelinolysis. Science 211:1068, 1981 24. Laureno R: Central pontine myelinolysis following rapid correction ofhyponatremia. Ann Neurol 13:232, 1983 25. Laureno R, Karp Bl: Pontine and extrapontine myelinolysis following rapid correction ofhyponatremia. Lancet 1:1439, 1988 26. Lien YH, Shapiro JI, Chan L: Effects of hypernatremia on organic brain osmoles. J Clin Invest 85:1427, 1990 27. Miller GM. Baker HL Jr, Okazaki H, et al: Central pontine myelinolysis and its imitators: MR findings. Radiology 168:795, 1988 28. Mitnick PD, Bell S: Rhabdomyolysis associated with severe hyponatremia after prostatic surgery. Am J Kidney 16:73, 1990
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Address reprint requests to Richard H. Sterns, MD Nephrology Unit Rochester General Hospital 1425 Portland Avenue Rochester, NY 14621