the challenge of hyponatremia

BRIEF REVIEW www.jasn.org

The Challenge of Hyponatremia

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

*Department of Medicine, Baylor College of Medicine, Methodist Hospital, Houston, Texas; †Renal Section, Veterans AffairsMedical 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

ABSTRACTTreatment of hypotonic hyponatremia often challenges clinicians on many counts.Despite similar serum sodium concentrations, clinical manifestations can range frommild to life threatening. Some patients require active management, whereas othersrecover without intervention. Therapeutic measures frequently yield safe correc-tion, yet the same measures can result in osmotic demyelination. To address thischallenge, we present a practical approach to managing hyponatremia that centerson two elements: a diagnostic evaluation directed at the pathogenesis and putativecauses of hyponatremia, the case-specific clinical and laboratory features, and theassociated clinical risk; and a management plan tailored to the diagnostic findingsthat incorporates quantitative projections of fluid therapy and fluid losses on thepatient’s serum sodium, balances potential benefits and risks, and emphasizes vig-ilant monitoring. These principles should enable the clinician to formulate a man-agement plan that addresses expeditiously three critical questions: Which of thedeterminants of the serum sodium are deranged and what is the underlying culprit?How urgent is the need for intervention?What specific therapy should be institutedand which are the associated pitfalls?

J Am Soc Nephrol 23: 1140–1148, 2012. doi: 10.1681/ASN.2012020128

Hypotonichyponatremia, themost com-mon and relevant form of the disorder,often challenges clinicians. Little infor-mationmightbeavailable at presentationabout the patient and the prevailing hy-ponatremia other than its severity. One orseveral predisposing conditions might par-ticipate in the generation of hyponatremia.Clinical manifestations can vary widelydespite similar serum sodium concentra-tions. Some patients require active man-agement, whereas others recover withoutintervention. Therapeutic measures fre-quently yield safe correction, yet the samemeasures can result in osmotic demye-lination. The challenge to the clinician iscommonly heightened by major comor-bidities such as hepatic encephalopathyor potassium depletion.

Recentdevelopments inhyponatremia,including epidemiologic insights, newly

recognized adverse effects, and the intro-duction of vaptans (vasopressin receptorantagonists), have rekindled physicianinterest in thedisorderandcould improveits management.1–9 Notwithstanding,current medical care frequently provessuboptimal resulting in adverse conse-quences of eitherhyponatremia or its treat-ment both in adults and children.10–17

Relowering the serum sodium has beenintroduced to address the not uncom-mon overcorrection of hyponatremia.18–20

Even preventive administration ofdesmopressin, a hormone that can actu-ally aggravate hyponatremia, has beenproposed to counter the risk of over-correction.21,22

We contend that confronting thechallenge of hyponatremia requires atwo-pronged approach. First, a diagnos-tic evaluation is aimed at identifying the

pathogenesis and putative cause(s) ofhyponatremia, the case-specific clinicaland laboratory features, and the associ-ated clinical risk. Second, a managementplan is tailored to the diagnostic findingsthat incorporates quantitative projec-tions of prescribed fluid therapy and on-going fluid losses on the patient’s serumsodium, balances potential benefits andrisks, and emphasizes vigilant monitor-ing. Here we present a practical ap-proach to managing hyponatremia thatcenters on these principles.

DIAGNOSTIC EVALUATION

Estimating the State of theDeterminants of the DecreasedSerum SodiumThe serum sodium concentration is ap-proximated by the sum of the exchange-able (osmotically active) portions of thebody’s sodium and potassium contentdivided by total body water (Edelmanequation; Figure 1).23,24 Maintenance ofserum sodium occurs as a by-product ofmatching the intake of sodium, potassium,and water with the corresponding losses.The Edelman equation establishes thathypotonic (or dilutional) hyponatremiarepresents an excess of water relative to

Published online ahead of print. Publication dateavailable at www.jasn.org.

Correspondence: Dr. Nicolaos E. Madias, Division ofNephrology, Department of Medicine, St. Elizabeth’sMedical Center, 736 Cambridge Street, Boston,MA 02135. Email: [email protected]

Copyright © 2012 by the American Society ofNephrology

1140 ISSN : 1046-6673/2307-1140 J Am Soc Nephrol 23: 1140–1148, 2012

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mailto:[email protected]

the sodium and potassium stores. Waterretention usually results from impair-ment of renal excretion of electrolyte-free water (aquaresis); less commonly, itis caused by excessive intake of waterwhile excretory capacity is normal ornearly normal.25

In hyponatremia caused by water re-tention, sodium and potassium storesremain essentially unchanged but bodywater is increased; these patients exhibiteuvolemic hyponatremia, including thesyndrome of inappropriate antidiuresis(SIAD) and some endocrinopathies.25–27

Renal or extrarenal fluid losses depletesodium, potassium, and water stores;subsequent water retention results in hy-ponatremia. These patients exhibit ex-tracellular fluid volume contraction.Conversely, retention of sodium andwater in edematous disorders can alsobe associated with hyponatremia, whichreflects a disproportionate increase in

body water. Loss of potassium depletesintracellular stores, leading to transferof sodium from the extracellular to theintracellular fluid and generating hypo-natremia coupled with hypokalemia.Not infrequently, all three determinantsmight contribute to decreasing serumsodium. The clinician must collect therelevant clinical information and labo-ratory data to infer the state of thesedeterminants in the individual case ofhyponatremia.

Unraveling the PredisposingCondition and the Effector ofHyponatremiaGeneration of hypotonic hyponatremiaoccurs as aby-productofunmatching theelectrolyte (sodium and potassium) andwater content of all intake and outputsuch that a net gain of electrolyte-freewater relative to the body’s sodium andpotassium stores ensues (Figure 2).

Numerous conditions can impose anaquaretic defect and thus predispose tohyponatremia.25,28 Notwithstanding, aneffector must be superimposed thatwould result in a positive electrolyte-free water balance. Typically, the effectoris intake of electrolyte-free water inamounts that exceed the composite ofrenal and extrarenal electrolyte-free wa-ter losses. The medical history shouldprovide clues about the predisposingconditions, including an underlyingacute or chronic disease, as well as fluidand electrolyte intake and losses, proteinintake, changes in body weight, medi-cations (thiazides, selective serotoninreuptake inhibitors), and previousdiagnosis of hyponatremia. Physicalexamination allows assessment of ex-tracellular fluid volume status andidentification of signs characteristic ofpredisposing conditions. Ancillary testsmay include serumelectrolytes, BUN, cre-atinine, uric acid, serum and urine osmo-lality, serum cortisol and thyroid panel,and radiologic studies (head computedtomography scan or magnetic resonanceimaging).

Measuring urine electrolytes and com-puting the urine/serum (U/S) electrolyteratio, which is the sum of the urinaryconcentrations of sodium and potassiumdividedby the serumsodium,canpoint tothe effect of the urine output on the levelof serum sodium at the time of evaluation(Figure 3). If the ratio is approximately 1,the urine output is not affecting the se-rum sodium; if.1, the urine contributesto lowering the serum sodium; and if#0.5, it indicates that one-half or more ofthe urine volume amounts to electrolyte-free water and thus the urine contributesto raising the serum sodium.26,29 Thelarger the urine output, the greater theeffect of a U/S electrolyte ratio �1 onserum sodium.

Establishing the Clinical Risk ofHyponatremiaThe level of serum sodium correlatesinversely with clinical risk, with levels,120 mEq/L being regarded as severehyponatremia. Clinical manifestationsare dependent on the severity and acute-ness of the hypotonic state.25,30,31 Acute

Figure1. Pathogenesis of hypotonic hyponatremia asderived from theEdelmanequation.Hypotonic hyponatremia represents an excess of water relative to the body’s sodium andpotassium stores. In that context, patients with hypotonic hyponatremia can feature de-creased, normal, or increased Nae

+; decreased or normal Ke+; and decreased, normal, or

increased TBW. Nae+, exchangeable sodium; Ke

+, exchangeable potassium; TBW, totalbody water.

J Am Soc Nephrol 23: 1140–1148, 2012 Managing Hyponatremia 1141

www.jasn.org BRIEF REVIEW

hyponatremia results in brain swellingand intracranial hypertension; it canprogress to life-threatening neurologiccomplications, including seizures, coma,brain-stem herniation, and respiratoryarrest, which can lead to permanentbrain damage or death. Such progressioncan occur suddenly and rapidly. Symp-tomatic and potentially life-threateningcerebral edema is characteristically ob-served in euvolemic hyponatremia, in-cluding that associated with psychogenicpolydipsia, the postoperative state, intra-cranial pathology, endurance exercise,recent administration of thiazides, induc-tion of delivery with oxytocin, use of ec-stasy (3,4-methylenedioxyamphetamine),and water drinking contests.12,27,31–33

Young women and children are partic-ularly vulnerable to hyponatremicbrain damage.12,31 Noncardiogenic pul-monary edema can occur in acute hypo-natremia and the resulting hypoxemiacan worsen the severity of brain edema.Fortunately, adaptive processes partiallyrestore brain volume within a few hours,with essential normalization within2 days. As a result, hyponatremia thatdevelops or persists over days (chronichyponatremia) generally exhibits onlymodest symptomatology, includingcognitive deficits, gait disturbance, andpropensity to falls and fractures.5,6,8,31

When extreme, usually ,110 mEq/L, itcan manifest confusion, delirium, andrarely seizures, but not the other life-threatening complications of severe acutehyponatremia.30,31,34 Beneficial as it is interms of symptoms, brain adaptationmarkedly increases the risk of osmoticdemyelination.15,17,27

The vast majority of hyponatremicpatients exhibit the chronic form of thedisorder, arbitrarily defined as .48hours in duration. However, the dura-tion of hyponatremia is commonlyunknown, hyponatremia of shorter du-ration has already mounted substantialbrain adaptation, and an acute decreasein serum sodium can be superimposedon chronic hyponatremia. When thetime frame of hyponatremia cannot beestablished with confidence, it is saferto conclude that the hypotonic state ischronic.

THERAPEUTIC PRINCIPLES

Treating Actual or Impending Life-Threatening ComplicationsSeverely symptomatic hyponatremia andhyponatremia in association with neu-rologic or neurosurgical disease of thebrain represent medical emergencies; inthese settings, even mild augmentationof the cerebral edema can prove cata-strophic. Immediate intervention mightinclude anticonvulsants, laryngeal in-tubation, oxygen administration, andventilator support. The gravity of thecondition mandates correction of theserum sodium by 4–6 mEq/L within 4–6hours; this degree of correction can re-pair cerebral edema and is sufficient toreverse the most ominous complicationsof hyponatremic encephalopathy. Thisgoal can be achieved with a continuousinfusion of hypertonic saline (3% NaCl).Intravenous furosemide (20 mg) reducesthe volume expansion resulting from thehypertonic saline.25–28 Instead of a con-tinuous infusion, a 100-ml bolus of thissolution, with up to two additional bo-luses given at 10-minute intervals depend-ing on clinical manifestations, has beenproposed.31 Although this strategy mightbewarranted under certain circumstances(severely symptomatic exercise-inducedhyponatremia or impending herniation),we caution against its indiscriminant use.Administration of up to 300 ml of hyper-tonic saline can cause overcorrection ofhyponatremia in small-sized individuals,especially if aquaresis is ongoing. Vaptansshould not be prescribed in hyponatremicemergencies.

Considering the commonuncertaintyabout the duration of hyponatremia andthat overcorrection can lead to osmoticdemyelination, we recommend that totalcorrection does not exceed 6–8mEq/L inany 24-hour period; this cutoff applies toboth acute and chronic hyponatremicpatients, regardless of clinical presenta-tion and method of treatment, includingactive management and spontaneouscorrection. This is not a target of therapy,but rather a therapeutic threshold thatshould not be crossed. This limit en-sures effective management of the mostserious consequences of hyponatremic

encephalopathy, while providing a marginof protection from osmotic demyelin-ation, a condition that can occasionally de-velop after correcting serum sodium byonly 9–10 mEq/L in 24 hours. Althoughthe likelihood of demyelination caused byovercorrection of acute hyponatremia islow, no clinical advantage is derived fromexceeding this cutoff.25,27,31

Utmost Vigilance for PreventingOsmotic DemyelinationOsmotic demyelination is a most seriousdemyelinating disorder typically in-volving the central pons (central pontinemyelinolysis), but often extending intoextrapontine structures (extrapontinemyelinolysis).15,17,35,36 The root cause ofthis complication is overcorrection ofhyponatremia that has undergone sub-stantial brain adaptation. Its clinicalmanifestations, including hyperreflexia,pseudobulbar palsy, quadriparesis, par-kinsonism, locked-in syndrome, andeven death, arise 1–7 days after overcorrec-tion of hyponatremia. Two or more weeksfrom the initial neurologic manifestationsmight elapse before diagnostic findings onbrain magnetic resonance imaging andcomputed tomography become evident.

Conditions posing high risk for thisdreaded complication include chronichyponatremia of ,110 mEq/L, alcohol-ism, hepatic failure, orthotopic livertransplantation, potassium depletion,and malnutrition.15,25,27,31,37 In thepresence of these conditions, correctionof serum sodium should not exceed 6mEq/L in any 24-hour period. Fear ofinducing osmotic demyelination fromovercorrection of hyponatremia causedby excessive aquaresis has prompted therecommendation of treating severe hy-ponatremia with the combination of hy-pertonic saline and desmopressin.21,22,31

We do not support this approach forseveral reasons. High levels of vasopres-sin prevail in the vast majority of hypo-natremic patients and in most, thisabnormality is irreversible; adminis-tering desmopressin to these patientsstrikesusas inappropriate andrisky.Thosepatients with reversible SIAD (drug-induced) would be better served by closemonitoring instead of perpetuating the

1142 Journal of the American Society of Nephrology J Am Soc Nephrol 23: 1140–1148, 2012


Figure2. Generation of hypotonic hyponatremia as aby-product of unmatching the electrolyte andwater content of all intake andoutput.Maintenanceof serumsodiumoccurs as aby-productofmatching theelectrolyte andwater content of all intakeandoutput, denotedby thesubscripts i ando, respectively. Both intake andoutput canbe viewed as composedof two components: An isotonic component (IC), whichcontains all theNa+ and K+ content distributed in a volume of water sufficient to attain a concentration identical to that of serum sodium, aswell as an electrolyte-free water component (EFWC), which comprises water free of Na+ and K+. The latter is computed by subtracting thecorresponding IC from the total volume of water intake or output. When the IC is smaller than the total volume, the difference representsthe 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 zeroso 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



antidiuresis with desmopressin. Thecombined strategy of hypertonic salineand desmopressin substantially increasesthe risk of aggravation of hyponatremiafrom retention of prescribed (medicationdiluents or tube feedings) or unprescribedhypotonic fluids. Furthermore, the so-dium and water retention resultingfrom this strategy can cause pulmonaryedema and hypoxemia, especially in el-derly patients.

Repairing the Abnormal State of theDeterminants of HyponatremiaMost patients exhibit hyponatremia ofindeterminate duration and variablesymptomatology that deserves treatmentbut does not represent a medical emer-gency. Fluid restriction (up to,800ml/d)must be prescribed in all patients, ex-cluding those with ongoing aquaresis.26,30

For any level of fluid restriction, the lowerthe dietary sodium and potassium, the

higher the electrolyte-free water intake,thereby decreasing the effectiveness ofthis maneuver (Figure 2). Moreover,low solute intake (protein, sodium, andpotassium) impairs aquaresis predispos-ing to hyponatremia.38 In euvolemic andhypervolemic hyponatremia, fluid re-striction should be complemented by aloop diuretic, which promotes aquaresisby reducing the hypertonicity of the re-nal medulla. The stringency of fluid re-striction can be lessened with the use ofvaptans, agents that antagonize the effectof vasopressin, thereby promotingaquaresis. These drugs can be adminis-tered intravenously (conivaptan, for up to4 hospital days) or orally (tolvaptan, treat-ment must be initiated in the hospital) ineuvolemic or hypervolemic hyponatremiaof mild to moderate severity but notin hypovolemic hyponatremia.9,39–43 Be-cause the aquaretic response to thesedrugs is variable, close vigilance ofthe trend of serum sodium is required.The introduction of vaptans generatedgreat expectations, yet concerns aboutsafety and cost currently limit the utilityof these promising drugs for long-termmanagement of hyponatremia.44–48 InSIAD, conventional treatment with fluidrestriction combined with plentiful so-dium intake and loop diuretics has lim-ited success.25 Urea has been used as aneffective alternative, but unpalatabilityhas hindered its wide application.49 Inhypervolemic hyponatremia, measuresto optimize the underlying diseaseshould complement fluid and sodiumrestriction, and administration of loopdiuretics.25,27,31

Figure 3. Effect of urine electrolyte concentration on serum sodium level in hypotonichyponatremia. Estimated change in [Na+]s per liter of urine is obtained using the fluid-lossformula (Table 1) and total bodywater (TBW) in liters calculated as a fraction of bodyweight(0.55 in men and 0.5 in women). As an example, the 50-kg woman with a tumor-inducedSIAD has TBW equal to 25 L; thus, theD[Na+]s is obtained by subtracting the sum of urinarysodium and potassium from the serum sodium (120 – 180 = –60) and dividing by TBWminus 1 L (25 – 1 = 24), i.e.,–604 24 = –2.5 mEq/L. Note that if the U/S electrolyte ratio isapproximately 1, the urine output is not affecting the serum sodium; if .1, the urinecontributes to lowering the serum sodium; and if £0.5, it indicates that one-half or more ofthe urine volume amounts to electrolyte-freewater and thus the urine contributes to raisingthe serum sodium. The larger the urine output, the greater the effect of the U/S electrolyteratio �1 on serum sodium.

depicted in the figure occur during the generation of disturbances of extracellular volume or serum sodium; should net IC and net EFWCreturn to zero, a new steady state is established. Generation of hypotonic hyponatremia occurs as a by-product of unmatching theelectrolyte and water content of all intake and output that results in a net gain of electrolyte-free water relative to the body’s sodium andpotassium stores. As examples, at an early phase of heart failure, renal retention of sodium and water causes volume expansion but nohyponatremia; at a late phase, impaired aquaresis combined with decreased dietary sodium and potassium intake and use of diureticsgenerate hyponatremia and potassium depletion. Fluid losses caused by diarrhea cause volume contraction and potassium depletion butno hyponatremia (early phase); actually, absent sufficient water intake, hypernatremia will develop, because the diarrheal losses arehypotonic (Table 2). As diarrhea continues and electrolyte losses are not replenished (late phase), impaired aquaresis will lead to waterretention 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 withhypokalemia. Potassiumdepletion also promotes renal sodium retention, thereby increasing exchangeable sodium. Net EFWC is positiveas a result of decreased potassium intake or increased potassium loss. Excluding severe potassiumdepletion, water balance and thus totalbody water remain normal.



The hyponatremia resulting from so-dium depletion is commonly managedwith an infusion of isotonic saline (0.9%NaCl) at rates of 1–3 ml/kg per hour andfluid restriction. Close observation isrequired to avoid an overly rapid correc-tion of serum sodium upon nearing res-titution of the extracellular fluid volume.Patients with milder cases can be man-aged as outpatients by increasing sodiumingestion. When the extracellular fluidvolume estimate is equivocal, a 1- to 2-Lchallenge of isotonic saline can aid diag-nosis and treatment.

Potassium depletion poses a vexingchallenge to managing hyponatremia.Failure to consider the effect of potassiumreplacement on the level of serumsodiumhas caused many cases of osmotic de-myelination.11,31 Prudent managementrequires that the clinician first focus onpotassium replacement. Considering that1 mEq of retained potassium affects se-rum sodiumasmuch as 1mEq of retainedsodium (Figure 1), even partial correctionof potassiumdepletion can cause an exces-sive rise in serum sodiumwithout sodiumadministration. Depending on clinicalcircumstances, potassium can be admin-istered orally, intravenously, or by both

routes. Recall that potassium depletionpredisposes to osmotic demyelinationand it frequently coexists with addi-tional risk factors for this complication.Retention of only 3 mEq/kg of potassiumis sufficient to raise serum sodium by asmuch as the daily threshold of 6 mEq/L(for total body water of 50% body weight).

Trend of Serum SodiumConcentrationRepair of hypovolemia, discontinuation ofthiazides or other medications inducingSIAD, and cortisol or thyroxine replace-ment can each rapidly reverse the defectin water excretion, and thus cause briskaquaresis and rapid correction of hypo-natremia (autocorrection). These patientsmight require measures to limit the paceof correction or terminate correction alto-gether. Infusion of 5% dextrose in water atrates guided by the urine output, admin-istration of desmopressin (1–5 mg at 6- to8-hour intervals), or both can achieve thisgoal.18,27,31 Should overcorrection occur,these measures must be applied promptlyto relower serum sodium below the spec-ified cutoff for the corresponding timepoint.18–20 If signs suggestive of osmoticdemyelination appear in the course of

treatment of hyponatremia, immediaterelowering of the serum sodium shouldbe accompanied by administration of ste-roids. Experimental studies and limitedhuman observations are in support ofthis approach.19,20 Animal data suggestthat minocycline and myoinositol canprevent or ameliorate the course of os-motic demyelination.50–52

Estimating the Effect of Infusatesand Fluid Losses on Serum SodiumImplementation of case-specific thera-peutic measures requires informationderived from thequantitativeprojectionsof prescribed fluid therapy and ongoingfluid losses on the patient’s serum sodium,while maintaining a sharp focus on an-ticipated benefits and potential pitfalls.Easily applicable formulas based on theEdelman equation allow estimation ofthe effect of infusates (infusate formula)and fluid losses (fluid-loss formula) onthe serum sodium, and have gained pop-ularity among clinicians (Table 1).25,53,54

These formulas represent auxiliary instru-ments to facilitate implementation of aquantitative approach to fluid therapy(Table 2).55–57 Concomitant fluid andelectrolyte losses, if substantial, can result

Table 1. Formulas for estimating the effect of infusates and fluid losses on [Na+]sInfusate Formula Fluid-Loss Formula

D½Naþ�s ¼½Naþ þ Kþ�inf 2 ½Naþ�s

TBWþ 1D½Naþ�s ¼

½Naþ�s 2 ½Naþ þ Kþ�flTBW21

Projects the effect of gaining 1 L of anyinfusate (inf) on the patient’s [Na+]s

Projects the effect of losing 1 L of any fluid (fl) on the patient’s [Na+]s

Derivation Formulas are based on the Edelman equation.23 Note that in the infusate formula, the patient’s [Na+]sis 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 therapyand ongoing fluid losses on patient’s serum sodium. Adjustments in fluid therapy over time arefacilitated by applying the two formulas as often as needed utilizing the intercurrent dataof the patient.

Utilization of fluid-loss formula in the management of hyponatremia is only required when ongoingfluid losses (renal and extrarenal) are substantial (.1 L/d); in that case, the effect of the fluid losson 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 determinedby the infusate formula.

Limitations Reliability of projections depends on utilizing a reasonable approximation of TBW. A substantialoverestimate of TBW would decrease the projected effect of infusates and fluid losses on [Na+]srisking 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.



in a sizable deviation of the actual level ofserum sodium from that projected sim-ply by applying the infusate formula.

A large series confirmed the clinicalutility of the infusate formula in patientsfree of aquaresis.58,59 Subsequent studiesfurther corroborated the predictive ac-curacy of the infusate formula in suchpatients, but expectedly not in those un-dergoing substantial aquaresis.21,22,60,61

Our experience indicates that concomi-tant application of the fluid-loss formulaextends the utility of the infusate for-mula to those with substantial aquaresisor extrarenal fluid losses (Table 2).

Monitoring and PrescriptionReassessmentSuccessful management of hyponatremiawith actual or impending life-threateningcomplications requires vigilant observa-tion in an intensive-care setting, espe-cially during the initial 24–48 hours.Monitoring should be conducted every2–4 hours and include vital signs, neuro-logic status, serum electrolytes, fluid bal-ance, and urine electrolytes if applicable.During this early phase, the underlyingpathophysiology can be dynamic, therebynecessitating frequent prescription reas-sessment, particularly if the rate of cor-rection of serum sodium is overly slow orexcessive (Table 2). Commensurate with

the patient’s progress, the monitoringinterval can be extended to every 6–8hours and subsequently to every 12–24hours.25,27,31

Hyponatremic patients without severesymptomatology can be managed on thegeneral medical floor or as outpatients.In all patients, the need for a long-termfollow-up depends on the pathogenesisand risk factors of hyponatremia.

MEETING THE CHALLENGE

The preceding diagnostic and therapeu-tic principles would enable the clinicianto formulate a case-specificmanagementplan. Such formulation centers on expe-ditiously addressing the following threequestions.

Which of the Determinants of theSerum Sodium Are Deranged andWhat Is the Underlying Culprit?Proper evaluation should reveal the pre-vailing state of sodium content, potas-sium content, and total body water, andin the process, unravel the predisposingcondition and the effector of hypo-natremia. A plan for correction of each ofthe deranged determinants must be for-mulated. Uncertainty about the patient’svolume status justifies a limited trial of

isotonic saline infusion. At times, the pre-disposing condition can be removed (dis-continuation of a drug) or controlled(hemodynamic improvement). In othercases, this may not be feasible (SIAD sec-ondary to cancer) andmeasures to counterchronically the aquaretic defect are re-quired. Severe restriction of electrolyteintake predisposes to hyponatremia;moderating this restriction aids correc-tion of the disorder.25,38

How Urgent Is the Need forIntervention?The vast majority of hyponatremic pa-tients do not require urgent management.Conversely, patients with severely symp-tomatic hyponatremia and those with neu-rologic or neurosurgical conditions at riskof worsening intracranial hypertensionrepresent medical emergencies.

Whenviolationof the correction thresh-old appears likely, urgent measures to slowor halt further correction are required.62

Overcorrection should be treated as amedical emergency; prompt reloweringof the serum sodium concentration is inorder.18–20 Urgent interventionmight alsobe required for coexisting conditions thatdo not emanate from the hyponatremiaitself. As examples, severe volume deple-tion might have caused circulatory shockand AKI, whereas severe hypokalemia can

Table 2. Estimated effect of infusates and fluid losses of different electrolyte composition on [Na+]sa

Infusate Fluid Loss

[Na+ + K+](mEq/L)

Effect on [Na+]sper 1 L (mEq/L)

[Na+ + K+](mEq/L)

Effect on [Na+]sper 1 L (mEq/L)

3% NaCl 513 ↑ 13.0 Aquaresis (e.g., primary polydipsia) 20 ↑ 3.10.9% NaCl 154 ↑ 1.4 Natriuresis (e.g., furosemide) 55 ↑ 1.90.9% NaCl + 30 mEqKCl per L

184 ↑ 2.4 Viral/bacterial diarrhea 90 ↑ 0.7

Ringer’s lactate 135 ↑ 0.8 Osmotic diarrhea 40 ↑ 2.40.45% NaCl 77 ↓ 1.1 Gastric fluid 70 ↑ 1.45% dextrose 0 ↓ 3.5

(1) SIADwithmoderately severe neurologic symptoms and oliguria. Retention of 1 L of 3%NaCl is projected to increase [Na+]s by 13mEq/L ([513 – 110]/[30+ 1]). Fora targeted increase in [Na+]s of 4mEq/L over 6 hours, 308ml of 3%NaCl [(1000/13)3 4], or 51ml/h (308/6) is required. (2) Primary polydipsia with severe neurologicsymptoms 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 targetedincrease 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. Retentionof 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 isestimated 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.aCalculations aremade for initial [Na+]s of 110mEq/L in a 60-kg womanwith an estimated total bodywater of 30 L (6030.5) using the formulas for infusates and fluidlosses, as appropriate (Table 1). Application of the formulas to the management of this patient under three clinical scenarios is presented in lower portion of thistable. The electrolyte compositions of fluid losses are averages of clinically encountered values.25,57 In the absence of actual measurements, these estimates can beused in clinical practice.



lead to cardiac arrhythmias and neuro-muscular manifestations.

What Specific Therapy Should BeInstituted and Which Are theAssociated Pitfalls?Implementation of case-specific thera-peuticmeasures canbe aidedby formula-based quantitative projections andshould maintain a sharp focus on antic-ipated benefits and potential pitfalls.Fluid restriction remains the cornerstoneof managing oligosymptomatic patientswith euvolemic or hypervolemic hypo-natremia. Although variably effective,fluid restriction does not pose a risk aslong as the aquaretic defect persists. Onthe other hand, repair of the aquareticdefect can lead to overcorrection and thusrisk development of osmotic demyelin-ation. Prescription of stringent sodiumrestriction in patients with liver cirrhosisor heart failure helps control volume over-load but counters correction or even ag-gravates hyponatremia.25,38

Hypertonic saline is required for pa-tients with severe hyponatremic enceph-alopathy and concentrated urine. In viewof the high potential for overcorrection,its prescription should be based on aquantitative approach guided by a simpleformula (Table 2). The commonly coad-ministered furosemide can augmentcorrection of hyponatremia.

Isotonic salinewill correct volumede-pletion and the associated hyponatremia.However, great vigilance is required toprevent overcorrection, because briskdiuresis can ensue when extracellularfluid volume nears restitution. Isotonicsaline is unsuitable for correcting thehyponatremia of the SIAD, culminatingin worsening of the serum sodium.25,27

Hyponatremia associated with potas-sium depletion requires prompt but cau-tious repletion. Prescribing multipledoses of potassium without close mon-itoring of both serum potassium andsodium values is fraught with risk forhyperkalemia and osmotic demyelin-ation. Catastrophic overcorrection ofthe serum sodium is well documentedin such settings, especially because po-tassium depletion is a risk factor forosmotic demyelination.11

ACKNOWLEDGMENTS

The authors thank Geri Tasby for skillful as-

sistance in the preparation of thismanuscript.

DISCLOSURESH.J.A. has served on an advisory board for

Astellas Pharma and Otsuka America Pharmaceu-

tical. N.E.M. has served as a consultant for Astellas

Pharma and Otsuka America Pharmaceutical.

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