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The Challenge of

† ‡ Horacio J. Adrogué* and Nicolaos E. Madias §

*Department of Medicine, Baylor College of Medicine, Methodist Hospital, Houston, Texas; †Renal Section, Veterans Affairs Medical Center, Houston, Texas; ‡Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts; and §Division of Nephrology, Department of Medicine, St. Elizabeth’s Medical Center, Boston, Massachusetts

ABSTRACT Treatment of hypotonic hyponatremia often challenges clinicians on many counts. pathogenesis and putative cause(s) of Despite similar serum sodium concentrations, clinical manifestations can range from hyponatremia, the case-specificclinical mild to life threatening. Some patients require active management, whereas others and laboratory features, and the associ- recover without intervention. Therapeutic measures frequently yield safe correc- ated clinical risk. Second, a management tion, yet the same measures can result in osmotic demyelination. To address this plan is tailored to the diagnostic findings challenge, we present a practical approach to managing hyponatremia that centers that incorporates quantitative projec- on two elements: a diagnostic evaluation directed at the pathogenesis and putative tions of prescribed fluid therapy and on- causes of hyponatremia, the case-specific clinical and laboratory features, and the going fluid losses on the patient’sserum associated clinical risk; and a management plan tailored to the diagnostic findings sodium, balances potential benefits and that incorporates quantitative projections of fluid therapy and fluid losses on the risks, and emphasizes vigilant monitor- patient’s serum sodium, balances potential benefits and risks, and emphasizes vig- ing. Here we present a practical ap- ilant monitoring. These principles should enable the clinician to formulate a man- proach to managing hyponatremia that agement plan that addresses expeditiously three critical questions: Which of the centers on these principles. determinants of the serum sodium are deranged and what is the underlying culprit? How urgent is the need for intervention? What specific therapy should be instituted and which are the associated pitfalls? DIAGNOSTIC EVALUATION

J Am Soc Nephrol 23: 1140–1148, 2012. doi: 10.1681/ASN.2012020128 Estimating the State of the Determinants of the Decreased Serum Sodium Hypotonic hyponatremia, the most com- recognized adverse effects, and the intro- The serum sodium concentration is ap- mon and relevant form of the disorder, duction of vaptans ( receptor proximated by the sum of the exchange- often challenges clinicians. Little infor- antagonists), have rekindled physician able (osmotically active) portions of the mation might beavailable at presentation interestinthedisorderandcouldimprove body’s sodium and content about the patient and the prevailing hy- its management.1–9 Notwithstanding, divided by total body water (Edelman ponatremia other than its severity. One or current medical care frequently proves equation; Figure 1).23,24 Maintenance of several predisposing conditions might par- suboptimal resulting in adverse conse- serumsodiumoccursasaby-productof ticipate in the generation of hyponatremia. quences of either hyponatremia or its treat- matching the intake of sodium, potassium, Clinical manifestations can vary widely ment both in adults and children.10–17 and water with the corresponding losses. despite similar serum sodium concentra- Relowering the serum sodium has been The Edelman equation establishes that tions. Some patients require active man- introduced to address the not uncom- hypotonic (or dilutional) hyponatremia agement, whereas others recover without mon overcorrection of hyponatremia.18–20 represents an excess of water relative to intervention. Therapeutic measures fre- Even preventive administration of quently yield safe correction, yet the same desmopressin, a hormone that can actu- Published online ahead of print. Publication date measures can result in osmotic demye- ally aggravate hyponatremia, has been available at www.jasn.org. lination. The challenge to the clinician is proposed to counter the risk of over- commonly heightened by major comor- correction.21,22 Correspondence: Dr. Nicolaos E. Madias, Division of Nephrology, Department of Medicine, St. Elizabeth’s bidities such as hepatic encephalopathy We contend that confronting the Medical Center, 736 Cambridge Street, Boston, or potassium depletion. challenge of hyponatremia requires a MA 02135. Email: [email protected]

Recentdevelopmentsinhyponatremia, two-pronged approach. First, a diagnos- Copyright © 2012 by the American Society of including epidemiologic insights, newly tic evaluation is aimed at identifying the Nephrology

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Numerous conditions can impose an aquaretic defect and thus predispose to hyponatremia.25,28 Notwithstanding, an effector must be superimposed that would result in a positive electrolyte- free water balance. Typically, the effector is intake of electrolyte-free water in amounts that exceed the composite of renal and extrarenal electrolyte-free wa- ter losses. The medical history should provide clues about the predisposing conditions, including an underlying acute or chronic disease, as well as fluid and electrolyte intake and losses, protein intake, changes in body weight, medi- cations (, selective serotonin reuptake inhibitors), and previous diagnosis of hyponatremia. Physical examination allows assessment of ex- tracellular fluid volume status and identification of signs characteristic of predisposing conditions. Ancillary tests may include serum electrolytes, BUN, cre- atinine, uric acid, serum and urine osmo- Figure 1. Pathogenesis of hypotonic hyponatremia as derived from the Edelman equation. lality, serum cortisol and thyroid panel, Hypotonic hyponatremia represents an excess of water relative to the body’s sodium and and radiologic studies (head computed potassium stores. In that context, patients with hypotonic hyponatremia can feature de- tomography scan or magnetic resonance + + creased, normal, or increased Nae ; decreased or normal Ke ; and decreased, normal, or imaging). + + increased TBW. Nae , exchangeable sodium; Ke , exchangeable potassium; TBW, total Measuring urine electrolytes and com- body water. puting the urine/serum (U/S) electrolyte ratio, which is the sum of the urinary concentrations of sodium and potassium the sodium and potassium stores. Water body water. Loss of potassium depletes dividedbytheserum sodium,canpointto retention usually results from impair- intracellular stores, leading to transfer the effect of the urine output on the level ment of renal excretion of electrolyte- of sodium from the extracellular to the of serum sodium at the time of evaluation free water (aquaresis); less commonly, it intracellular fluid and generating hypo- (Figure 3). If the ratio is approximately 1, is caused by excessive intake of water natremia coupled with . the urine output is not affecting the se- while excretory capacity is normal or Not infrequently, all three determinants rum sodium; if .1, the urine contributes nearly normal.25 might contribute to decreasing serum to lowering the serum sodium; and if In hyponatremia caused by water re- sodium. The clinician must collect the #0.5, it indicates that one-half or more of tention, sodium and potassium stores relevant clinical information and labo- the urine volume amounts to electrolyte- remain essentially unchanged but body ratory data to infer the state of these free water and thus the urine contributes water is increased; these patients exhibit determinants in the individual case of to raising the serum sodium.26,29 The euvolemic hyponatremia, including the hyponatremia. larger the urine output, the greater the syndrome of inappropriate antidiuresis effect of a U/S electrolyte ratio 1on (SIAD) and some endocrinopathies.25–27 Unraveling the Predisposing serum sodium. Renal or extrarenal fluid losses deplete Condition and the Effector of sodium,potassium,andwaterstores; Hyponatremia Establishing the Clinical Risk of subsequent water retention results in hy- Generation of hypotonic hyponatremia Hyponatremia ponatremia. These patients exhibit ex- occurs as a by-product of unmatching the The level of serum sodium correlates tracellular fluid volume contraction. electrolyte (sodium and potassium) and inversely with clinical risk, with levels Conversely, retention of sodium and water content of all intake and output ,120 mEq/L being regarded as severe water in edematous disorders can also such that a net gain of electrolyte-free hyponatremia. Clinical manifestations be associated with hyponatremia, which water relative to the body’ssodiumand are dependent on the severity and acute- reflects a disproportionate increase in potassium stores ensues (Figure 2). ness of the hypotonic state.25,30,31 Acute

J Am Soc Nephrol 23: 1140–1148, 2012 Managing Hyponatremia 1141 BRIEF REVIEW www.jasn.org hyponatremia results in brain swelling THERAPEUTIC PRINCIPLES encephalopathy, while providing a margin and intracranial hypertension; it can of protection from osmotic demyelin- progress to life-threatening neurologic Treating Actual or Impending Life- ation, a condition that can occasionally de- complications, including seizures, coma, Threatening Complications velop after correcting serum sodium by brain-stem herniation, and respiratory Severely symptomatic hyponatremia and only 9–10 mEq/L in 24 hours. Although arrest, which can lead to permanent hyponatremia in association with neu- the likelihood of demyelination caused by brain damage or death. Such progression rologic or neurosurgical disease of the overcorrection of acute hyponatremia is can occur suddenly and rapidly. Symp- brain represent medical emergencies; in low, no clinical advantage is derived from tomatic and potentially life-threatening these settings, even mild augmentation exceeding this cutoff.25,27,31 cerebral edema is characteristically ob- of the cerebral edema can prove cata- served in euvolemic hyponatremia, in- strophic. Immediate intervention might Utmost Vigilance for Preventing cluding that associated with psychogenic include anticonvulsants, laryngeal in- Osmotic Demyelination polydipsia, the postoperative state, intra- tubation, oxygen administration, and Osmotic demyelination is a most serious cranial pathology, endurance exercise, ventilator support. The gravity of the demyelinating disorder typically in- recent administration of thiazides, induc- condition mandates correction of the volving the central pons (central pontine tion of delivery with oxytocin, use of ec- serum sodium by 4–6 mEq/L within 4–6 myelinolysis), but often extending into stasy (3,4-methylenedioxyamphetamine), hours; this degree of correction can re- extrapontine structures (extrapontine and water drinking contests.12,27,31–33 pair cerebral edema and is sufficient to myelinolysis).15,17,35,36 The root cause of Young women and children are partic- reverse the most ominous complications this complication is overcorrection of ularly vulnerable to hyponatremic of hyponatremic encephalopathy. This hyponatremia that has undergone sub- brain damage.12,31 Noncardiogenic pul- goal can be achieved with a continuous stantial brain adaptation. Its clinical monary edema can occur in acute hypo- infusion of hypertonic saline (3% NaCl). manifestations, including hyperreflexia, natremia and the resulting hypoxemia Intravenous (20 mg) reduces pseudobulbar palsy, quadriparesis, par- can worsen the severity of brain edema. the volume expansion resulting from the kinsonism, locked-in syndrome, and Fortunately, adaptive processes partially hypertonic saline.25–28 Instead of a con- even death, arise 1–7 days after overcorrec- restore brain volume within a few hours, tinuous infusion, a 100-ml bolus of this tion of hyponatremia. Two or more weeks with essential normalization within solution, with up to two additional bo- from the initial neurologic manifestations 2 days. As a result, hyponatremia that luses given at 10-minute intervals depend- might elapse before diagnostic findings on develops or persists over days (chronic ing on clinical manifestations, has been brain magnetic resonance imaging and hyponatremia) generally exhibits only proposed.31 Although this strategy might computed tomography become evident. modest symptomatology, including be warranted under certain circumstances Conditions posing high risk for this cognitive deficits, gait disturbance, and (severely symptomatic exercise-induced dreaded complication include chronic propensity to falls and fractures.5,6,8,31 hyponatremia or impending herniation), hyponatremia of ,110 mEq/L, alcohol- When extreme, usually ,110 mEq/L, it we caution against its indiscriminant use. ism, hepatic failure, orthotopic liver can manifest confusion, delirium, and Administration of up to 300 ml of hyper- transplantation, potassium depletion, rarely seizures, but not the other life- tonic saline can cause overcorrection of and malnutrition.15,25,27,31,37 In the threatening complications of severe acute hyponatremia in small-sized individuals, presence of these conditions, correction hyponatremia.30,31,34 Beneficial as it is in especially if aquaresis is ongoing. Vaptans ofserumsodiumshouldnotexceed6 terms of symptoms, brain adaptation should not be prescribed in hyponatremic mEq/L in any 24-hour period. Fear of markedly increases the risk of osmotic emergencies. inducing osmotic demyelination from demyelination.15,17,27 Considering the common uncertainty overcorrection of hyponatremia caused The vast majority of hyponatremic about the duration of hyponatremia and by excessive aquaresis has prompted the patients exhibit the chronic form of the that overcorrection can lead to osmotic recommendation of treating severe hy- disorder, arbitrarily defined as .48 demyelination, we recommend that total ponatremia with the combination of hy- hours in duration. However, the dura- correction does not exceed 6–8mEq/Lin pertonic saline and desmopressin.21,22,31 tion of hyponatremia is commonly any 24-hour period; this cutoff applies to We do not support this approach for unknown, hyponatremia of shorter du- both acute and chronic hyponatremic several reasons. High levels of vasopres- ration has already mounted substantial patients, regardless of clinical presenta- sin prevail in the vast majority of hypo- brain adaptation, and an acute decrease tion and method of treatment, including natremic patients and in most, this in serum sodium can be superimposed active management and spontaneous abnormality is irreversible; adminis- on chronic hyponatremia. When the correction. This is not a target of therapy, tering desmopressin to these patients time frame of hyponatremia cannot be but rather a therapeutic threshold that strikesusasinappropriateandrisky.Those established with confidence, it is safer should not be crossed. This limit en- patients with reversible SIAD (drug- to conclude that the hypotonic state is sures effective management of the most induced) would be better served by close chronic. serious consequences of hyponatremic monitoring instead of perpetuating the

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Figure 2. Generation of hypotonic hyponatremia as a by-product of unmatching the electrolyte and water content of all intake and output. Maintenance of serum sodium occurs as a by-product of matching the electrolyte and water content of all intake and output, denoted by the subscripts i and o, respectively. Both intake and output can be viewed as composed of two components: An isotonic component (IC), which contains all the Na+ and K+ content distributed in a volume of water sufficient to attain a concentration identical to that of serum sodium, as well as an electrolyte-free water component (EFWC), which comprises water free of Na+ and K+. The latter is computed by subtracting the corresponding IC from the total volume of water intake or output. When the IC is smaller than the total volume, the difference represents the EFWC; if larger, there is negative EFWC. In the normal state, the net IC (ICi – ICo) is zero and the net EFWC (EFWCi – EFWCo) is also zero + so that [Na ]s remains stable. When net IC becomes positive, volume expansion occurs, whereas if negative, volume contraction ensues. When net EFWC is positive, serum sodium decreases, whereas if negative, serum sodium increases. The deviations of net IC and net EFWC

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higher the electrolyte-free water intake, thereby decreasing the effectiveness of this maneuver (Figure 2). Moreover, low solute intake (protein, sodium, and potassium) impairs aquaresis predispos- ing to hyponatremia.38 In euvolemic and hypervolemic hyponatremia, fluid re- striction should be complemented by a loop , which promotes aquaresis by reducing the hypertonicity of the re- nal medulla. The stringency of fluid re- striction can be lessened with the use of vaptans, agents that antagonize the effect of vasopressin, thereby promoting aquaresis. These drugs can be adminis- tered intravenously (, for up to Figure 3. Effect of urine electrolyte concentration on serum sodium level in hypotonic 4 hospital days) or orally (, treat- + fl hyponatremia. Estimated change in [Na ]s per liter of urine is obtained using the uid-loss ment must be initiated in the hospital) in formula (Table 1) and total body water (TBW) in liters calculated as a fraction of body weight euvolemic or hypervolemic hyponatremia (0.55 in men and 0.5 in women). As an example, the 50-kg woman with a tumor-induced of mild to moderate severity but not D + SIAD has TBW equal to 25 L; thus, the [Na ]s is obtained by subtracting the sum of urinary in hypovolemic hyponatremia.9,39–43 Be- sodium and potassium from the serum sodium (120 – 180 = –60) and dividing by TBW cause the aquaretic response to these minus 1 L (25 – 1=24),i.e.,–60 4 24 = –2.5 mEq/L. Note that if the U/S electrolyte ratio is approximately 1, the urine output is not affecting the serum sodium; if .1, the urine drugsisvariable,closevigilanceof contributes to lowering the serum sodium; and if £0.5, it indicates that one-half or more of the trend of serum sodium is required. the urine volume amounts to electrolyte-free water and thus the urine contributes to raising The introduction of vaptans generated the serum sodium. The larger the urine output, the greater the effect of the U/S electrolyte great expectations, yet concerns about ratio 1onserumsodium. safety and cost currently limit the utility of these promising drugs for long-term management of hyponatremia.44–48 In antidiuresis with desmopressin. The Repairing the Abnormal State of the SIAD, conventional treatment with fluid combined strategy of hypertonic saline Determinants of Hyponatremia restriction combined with plentiful so- and desmopressin substantially increases Most patients exhibit hyponatremia of dium intake and loop has lim- the risk of aggravation of hyponatremia indeterminate duration and variable ited success.25 Urea has been used as an from retention of prescribed (medication symptomatology that deserves treatment effective alternative, but unpalatability diluents or tube feedings) or unprescribed but does not represent a medical emer- has hindered its wide application.49 In hypotonic fluids. Furthermore, the so- gency. Fluid restriction (up to ,800 ml/d) hypervolemic hyponatremia, measures dium and water retention resulting must be prescribed in all patients, ex- to optimize the underlying disease from this strategy can cause pulmonary cluding those with ongoing aquaresis.26,30 should complement fluid and sodium edema and hypoxemia, especially in el- For any level of fluid restriction, the lower restriction, and administration of loop derly patients. the dietary sodium and potassium, the diuretics.25,27,31

depicted in the figure occur during the generation of disturbances of extracellular volume or serum sodium; should net IC and net EFWC return to zero, a new steady state is established. Generation of hypotonic hyponatremia occurs as a by-product of unmatching the electrolyte and water content of all intake and output that results in a net gain of electrolyte-free water relative to the body’ssodiumand potassium stores. As examples, at an early phase of , renal retention of sodium and water causes volume expansion but no hyponatremia; at a late phase, impaired aquaresis combined with decreased dietary sodium and potassium intake and use of diuretics generate hyponatremia and potassium depletion. Fluid losses caused by diarrhea cause volume contraction and potassium depletion but no hyponatremia (early phase); actually, absent sufficient water intake, will develop, because the diarrheal losses are hypotonic (Table 2). As diarrhea continues and electrolyte losses are not replenished (late phase), impaired aquaresis will lead to water retention and hyponatremia but usually will fall short of normalizing total body water. In potassium depletion, the deficit of cellular po- tassium triggers cells to gain sodium from the extracellular fluid (to maintain volume and tonicity), generating hyponatremia coupled with hypokalemia. Potassium depletion also promotes renal sodium retention, thereby increasing exchangeable sodium. Net EFWC is positive as a result of decreased potassium intake or increased potassium loss. Excluding severe potassium depletion, water balance and thus total body water remain normal.

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The hyponatremia resulting from so- routes. Recall that potassium depletion treatment of hyponatremia, immediate dium depletion is commonly managed predisposes to osmotic demyelination relowering of the serum sodium should with an infusion of isotonic saline (0.9% and it frequently coexists with addi- be accompanied by administration of ste- NaCl) at rates of 1–3ml/kgperhourand tional risk factors for this complication. roids. Experimental studies and limited fluid restriction. Close observation is Retention of only 3 mEq/kg of potassium human observations are in support of required to avoid an overly rapid correc- is sufficient to raise serum sodium by as this approach.19,20 Animal data suggest tion of serum sodium upon nearing res- much as the daily threshold of 6 mEq/L that minocycline and myoinositol can titution of the extracellular fluid volume. (for total body water of 50% body weight). prevent or ameliorate the course of os- Patients with milder cases can be man- motic demyelination.50–52 aged as outpatients by increasing sodium Trend of Serum Sodium ingestion. When the extracellular fluid Concentration Estimating the Effect of Infusates volume estimate is equivocal, a 1- to 2-L Repair of hypovolemia, discontinuation of and Fluid Losses on Serum Sodium challenge of isotonic saline can aid diag- thiazides or other medications inducing Implementation of case-specificthera- nosis and treatment. SIAD, and cortisol or thyroxine replace- peutic measures requires information Potassium depletion poses a vexing ment can each rapidly reverse the defect derived from the quantitative projections challenge to managing hyponatremia. in water excretion, and thus cause brisk of prescribed fluid therapy and ongoing Failure to consider the effect of potassium aquaresis and rapid correction of hypo- fluid losses on the patient’s serum sodium, replacement on the level of serum sodium natremia (autocorrection). These patients while maintaining a sharp focus on an- has caused many cases of osmotic de- might require measures to limit the pace ticipated benefits and potential pitfalls. myelination.11,31 Prudent management of correction or terminate correction alto- Easily applicable formulas based on the requires that the clinician first focus on gether. Infusion of 5% dextrose in water at Edelmanequationallowestimationof potassium replacement. Considering that rates guided by the urine output, admin- the effect of infusates (infusate formula) 1 mEq of retained potassium affects se- istration of desmopressin (1–5 mgat6-to and fluid losses (fluid-loss formula) on rum sodium as much as 1 mEq of retained 8-hour intervals), or both can achieve this the serum sodium, and have gained pop- sodium (Figure 1), even partial correction goal.18,27,31 Should overcorrection occur, ularity among clinicians (Table 1).25,53,54 of potassium depletion can cause an exces- these measures must be applied promptly These formulas represent auxiliary instru- sive rise in serum sodium without sodium to relower serum sodium below the spec- ments to facilitate implementation of a administration. Depending on clinical ified cutoff for the corresponding time quantitative approach to fluid therapy circumstances, potassium can be admin- point.18–20 If signs suggestive of osmotic (Table 2).55–57 Concomitant fluid and istered orally, intravenously, or by both demyelination appear in the course of electrolyte losses, if substantial, can result

+ Table 1. Formulas for estimating the effect of infusates and fluid losses on [Na ]s Infusate Formula Fluid-Loss Formula þ þ þ þ þ þ þ ½Na þ K 2 ½Na þ ½Na 2 ½Na þ K D½Na ¼ inf s D½Na ¼ s fl s TBW þ 1 s TBW 2 1 + Projects the effect of gaining 1 L of any Projects the effect of losing 1 L of any fluid (fl) on the patient’s[Na ]s + infusate (inf) on the patient’s[Na ]s 23 + Derivation Formulas are based on the Edelman equation. Note that in the infusate formula, the patient’s[Na ]s is subtracted from the electrolyte composition of the infusate and 1 L is added to TBW. By contrast, in the fluid-loss formula, the electrolyte composition of the fluid is subtracted from the patient’s + [Na ]s and 1 L is subtracted from TBW. Clinical Utility Formulas aid clinicians in making quantitative projections of the effect of prescribed fluid therapy and ongoing fluid losses on patient’s serum sodium. Adjustments in fluid therapy over time are facilitated by applying the two formulas as often as needed utilizing the intercurrent data of the patient. Utilization of fluid-loss formula in the management of hyponatremia is only required when ongoing fluid losses (renal and extrarenal) are substantial (.1 L/d); in that case, the effect of the fluid loss + on the patient’s [Na ]s should be included in the computation of prescribed fluid therapy. If the fluid-loss formula predicts correction of hyponatremia at an inappropriately rapid rate, a hypotonic infusate (e.g., 0.45% NaCl, 5% dextrose in water) must be used at a rate determined by the infusate formula. Limitations Reliability of projections depends on utilizing a reasonable approximation of TBW. A substantial + overestimate of TBW would decrease the projected effect of infusates and fluid losses on [Na ]s risking overcorrection of hyponatremia. The estimated TBW (in liters) is calculated as a fraction of body weight. This fraction is 0.6 in children, 0.55 in men, and 0.5 in women.25,55,56 TBW, total body water.

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+ a Table 2. Estimated effect of infusates and fluid losses of different electrolyte composition on [Na ]s Infusate Fluid Loss + + + + + + [Na +K ] Effect on [Na ]s [Na +K ] Effect on [Na ]s (mEq/L) per 1 L (mEq/L) (mEq/L) per 1 L (mEq/L) 3% NaCl 513 ↑ 13.0 Aquaresis (e.g., ) 20 ↑ 3.1 0.9% NaCl 154 ↑ 1.4 Natriuresis (e.g., furosemide) 55 ↑ 1.9 0.9% NaCl + 30 mEq 184 ↑ 2.4 Viral/bacterial diarrhea 90 ↑ 0.7 KCl per L Ringer’s lactate 135 ↑ 0.8 Osmotic diarrhea 40 ↑ 2.4 0.45% NaCl 77 ↓ 1.1 Gastric fluid 70 ↑ 1.4 5% dextrose 0 ↓ 3.5 + (1) SIAD with moderately severe neurologic symptoms and oliguria. Retention of 1 L of 3% NaCl is projected to increase [Na ]s by 13 mEq/L ([513 – 110]/[30 + 1]). For + a targeted increase in [Na ]s of 4 mEq/L over 6 hours, 308 ml of 3% NaCl [(1000/13) 3 4], or 51 ml/h (308/6) is required. (2) Primary polydipsia with severe neurologic + + + symptoms and large aquaresis (500 ml/h; [Na +K ] is 20 mEq/L). Loss of 1 L of urine is estimated to increase [Na ]s by 3.1 mEq/L ([110 – 20]/[30 – 1]). A targeted + + increase in [Na ]s of 4 mEq/L requires 1.3 L of urine (4/3.1) and will be achieved in 2.6 hours (1.3/0.5) At the 3-hour mark [Na ]s is 115 mEq/L. To prevent over- + correction of hyponatremia, desmopressin is prescribed. (3) Hypovolemic hyponatremia with mild neurologic symptoms and oliguria. [K ]s is 3.0 mEq/L. Retention + of 1 L of 0.9% NaCl + 30 mEq of KCl is projected to increase [Na ]s by 2.4 mEq/L ([184 – 110]/[30 + 1]). After administration of this infusate at 250 ml/h for 6 hours, + + + + [Na ]s is 114 mEq/L and [K ]s is 3.4 mEq/L. Urine output has increased and at the 6-hour mark is 150 ml/h; urine [Na +K ] is 20 mEq/L. Loss of 1 L of such urine is + estimated to increase [Na ]s by 3.2 mEq/L ([114 – 20]/[30 – 1]). To prevent overcorrection of hyponatremia, the infusate is changed to 0.45% NaCl. a + Calculations are made for initial [Na ]s of 110 mEq/L in a 60-kg woman with an estimated total body water of 30 L (6030.5) using the formulas for infusates and fluid losses, as appropriate (Table 1). Application of the formulas to the management of this patient under three clinical scenarios is presented in lower portion of this table. The electrolyte compositions of fluid losses are averages of clinically encountered values.25,57 In the absence of actual measurements, these estimates can be used in clinical practice. in a sizable deviation of the actual level of the patient’s progress, the monitoring isotonic saline infusion. At times, the pre- serum sodium from that projected sim- interval can be extended to every 6–8 disposing condition can be removed (dis- ply by applying the infusate formula. hours and subsequently to every 12–24 continuation of a drug) or controlled A large series confirmed the clinical hours.25,27,31 (hemodynamic improvement). In other utility of the infusate formula in patients Hyponatremic patients without severe cases, this may not be feasible (SIAD sec- free of aquaresis.58,59 Subsequent studies symptomatology can be managed on the ondary to cancer) and measures to counter further corroborated the predictive ac- general medical floor or as outpatients. chronically the aquaretic defect are re- curacy of the infusate formula in such In all patients, the need for a long-term quired. Severe restriction of electrolyte patients, but expectedly not in those un- follow-up depends on the pathogenesis intake predisposes to hyponatremia; dergoing substantial aquaresis.21,22,60,61 and risk factors of hyponatremia. moderating this restriction aids correc- Our experience indicates that concomi- tion of the disorder.25,38 tant application of the fluid-loss formula extends the utility of the infusate for- MEETING THE CHALLENGE How Urgent Is the Need for mula to those with substantial aquaresis Intervention? or extrarenal fluid losses (Table 2). The preceding diagnostic and therapeu- The vast majority of hyponatremic pa- tic principles would enable the clinician tients do not require urgent management. Monitoring and Prescription to formulate a case-specific management Conversely, patients with severely symp- Reassessment plan. Such formulation centers on expe- tomatic hyponatremia and those with neu- Successful management of hyponatremia ditiously addressing the following three rologic or neurosurgical conditions at risk with actual or impending life-threatening questions. of worsening intracranial hypertension complications requires vigilant observa- represent medical emergencies. tion in an intensive-care setting, espe- Which of the Determinants of the When violation of the correction thresh- cially during the initial 24–48 hours. Serum Sodium Are Deranged and old appears likely, urgent measures to slow Monitoring should be conducted every What Is the Underlying Culprit? or halt further correction are required.62 2–4 hours and include vital signs, neuro- Proper evaluation should reveal the pre- Overcorrection should be treated as a logic status, serum electrolytes, fluid bal- vailing state of sodium content, potas- medical emergency; prompt relowering ance, and urine electrolytes if applicable. sium content, and total body water, and of the serum sodium concentration is in During this early phase, the underlying in the process, unravel the predisposing order.18–20 Urgent intervention might also pathophysiology can be dynamic, thereby condition and the effector of hypo- be required for coexisting conditions that necessitating frequent prescription reas- natremia. A plan for correction of each of do not emanate from the hyponatremia sessment, particularly if the rate of cor- the deranged determinants must be for- itself. As examples, severe volume deple- rection of serum sodium is overly slow or mulated. Uncertainty about the patient’s tion might have caused circulatory shock excessive (Table 2). Commensurate with volume status justifies a limited trial of and AKI, whereas severe hypokalemia can

1146 Journal of the American Society of Nephrology J Am Soc Nephrol 23: 1140–1148, 2012 www.jasn.org BRIEF REVIEW lead to cardiac arrhythmias and neuro- ACKNOWLEDGMENTS Wong E, Robertson K: Hospital-acquired muscular manifestations. acute hyponatremia and reports of pediatric deaths. Dynamics 21: 21–26, 2010 The authors thank Geri Tasby for skillful as- 13. Singh DK, Rastogi M, Husain M: Central fi What Speci c Therapy Should Be sistance in the preparation of this manuscript. pontine myelinolysis in a pediatric head in- Instituted and Which Are the jury patient. Pediatr Neurosurg 46: 51–53, Associated Pitfalls? 2010 14. Tullu MS, Deshmukh I, Muranjan MN, Kher Implementation of case-specificthera- DISCLOSURES AS, Lahiri KR: Extrapontine myelinolysis in a peutic measures can be aided by formula- H.J.A. has served on an advisory board for child with . Pediatr based quantitative projections and Astellas Pharma and Otsuka America Pharmaceu- Neurol 43: 139–141, 2010 should maintain a sharp focus on antic- tical. N.E.M. has served as a consultant for Astellas 15. Norenberg MD: Central pontine myelinolysis: ipated benefits and potential pitfalls. Pharma and Otsuka America Pharmaceutical. Historical and mechanistic considerations. – Fluid restriction remains the cornerstone Metab Brain Dis 25: 97 106, 2010 16. Odier C, Nguyen DK, Panisset M: Central of managing oligosymptomatic patients pontine and extrapontine myelinolysis: From with euvolemic or hypervolemic hypo- REFERENCES epileptic and other manifestations to cognitive natremia. Although variably effective, prognosis. J Neurol 257: 1176–1180, 2010 fluid restriction does not pose a risk as 1. Waikar SS, Mount DB, Curhan GC: Mortality 17. Sterns RH, Hix JK, Silver S: Treatment of hy- long as the aquaretic defect persists. On after hospitalization with mild, moderate, ponatremia. 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