9/26/2016 Treatmentofhyponatremia:Syndromeofinappropriateantidiuretichormonesecretion(SIADH)andresetosmostat

OfficialreprintfromUpToDate
www.uptodate.com2016UpToDate

Treatmentofhyponatremia:Syndromeofinappropriateantidiuretichormonesecretion(SIADH)andreset
osmostat

Author SectionEditor DeputyEditor

RichardHSterns,MD MichaelEmmett,MD JohnPForman,MD,MSc

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Aug2016.|Thistopiclastupdated:Jul22,2014.
INTRODUCTIONHyponatremiainthesyndromeofinappropriateantidiuretichormonesecretion(SIADH)resultsfrom
ADHinducedretentionofingestedorinfusedwater.Althoughwaterexcretionisimpaired,sodiumhandlingisintactsince
thereisnoabnormalityinvolumeregulatingmechanismssuchasthereninangiotensinaldosteronesystemoratrial
natriureticpeptide[1].

ThetreatmentofhyponatremiaduetoSIADH(includingtheresetosmostatvariant)willbereviewedhere.Thechoiceof
therapyofSIADHisdependentuponanumberoffactorsincludingthedegreeofhyponatremia,thepresenceorabsence
ofsymptoms,and,tosomedegree,theurineosmolality.

ThepathogenesisandetiologyoftheSIADHandageneralreviewofthetreatmentofhyponatremiaduetoavarietyof
causesarediscussedseparately.(See"Pathophysiologyandetiologyofthesyndromeofinappropriateantidiuretic
hormonesecretion(SIADH)"and"Overviewofthetreatmentofhyponatremiainadults".)

PATHOGENESISTounderstandtheapproachtotherapyofhyponatremiainSIADH,itisworthwhiletobrieflyreview
thepathogenesisofhyponatremiainthisdisorder.AmongpatientswithSIADH,thecombinationofwaterretentionand
secondarysolute(sodiumpluspotassium)lossaccountsforessentiallyallofthereductioninserumsodium[2,3].

Thesechangesoccurinthefollowingsequence[3,4]:

HyponatremiaisinitiallymediatedbyADHinducedwaterretention.

Theensuingvolumeexpansionactivatessecondarynatriureticmechanisms,resultinginsodiumandwaterlossand
therestorationofneareuvolemia.Theneteffectisthat,withchronicSIADH,sodiumlossismoreprominentthan
waterretention[3].However,sincethereisnoimpairmentinvolumeregulatoryhormones(aldosteroneandnatriuretic
peptides),patientswithSIADHareeuvolemicunlessthereisasecondproblemleadingtosaltloss(eg,vomiting,
diarrhea,ordiuretictherapy).

Hyponatremiamayalsobeassociatedwithpotassiumloss.Sincepotassiumisasosmoticallyactiveassodium,the
lossofpotassiumcontributestothereductionsinplasmaosmolalityandsodiumconcentration.(See"Overviewof
thetreatmentofhyponatremiainadults".)

Thelostpotassiumisderivedfromthecellsandprobablyrepresentspartofthecell'svolumeregulatoryresponse[3].
Cellsthatincreaseinsizeduetowaterentryinhyponatremialosepotassiumandothersolutesinanattempttorestore
cellvolume.Thisadaptationisdiscussedelsewhere.(See"Manifestationsofhyponatremiaandhypernatremiainadults",
sectionon'Osmolytesandcerebraladaptationtohyponatremia'.)

THERAPIESTORAISETHESERUMSODIUMAnumberofmodalitiescanbeusedtocorrecthyponatremiainthe
SIADH,withfluidrestriction,saltadministration,andvasopressinreceptorantagonistsbeingmostimportant[1,5,6].When
treatingsuchpatients,attentionmustbepaidtotherateofcorrection.

TherearethreecomponentstothetreatmentofhyponatremiainSIADH:

Treatmentoftheunderlyingdisease,ifpossible
Initialtherapytoraisetheserumsodium
ProlongedtherapyinpatientswithpersistentSIADH

TreattheunderlyingdiseaseAvarietyofcausesofSIADHcanbeeffectivelytreated,leadingtoresolutionofthe
hyponatremia.Theseinclude:

http://www.uptodate.com/contents/treatmentofhyponatremiasyndromeofinappropriateantidiuretichormonesecretionsiadhandresetosmostat?topicKey 1/15
9/26/2016 Treatmentofhyponatremia:Syndromeofinappropriateantidiuretichormonesecretion(SIADH)andresetosmostat

Hormonereplacementinadrenalinsufficiency(whichcanleadtooverlyrapidcorrectionofthehyponatremia)or
hypothyroidism

Treatmentofinfectionssuchasmeningitis,pneumonia,ortuberculosis

Cessationofoffendingdrugs,suchasselectiveserotoninreuptakeinhibitorsorchlorpropamide

(See"Pathophysiologyandetiologyofthesyndromeofinappropriateantidiuretichormonesecretion(SIADH)",sectionon
'Etiology'.)

FluidrestrictionFluidrestrictionisamainstayoftherapyinmostpatientswithSIADH,withasuggestedgoalintake
oflessthan800mL/day[4].Theassociatednegativewaterbalanceinitiallyraisestheserumsodiumconcentrationtoward
normaland,withmaintenancetherapyinchronicSIADH,preventsafurtherreductioninserumsodium.Itcanalsoleadto
volumedepletionduetounmaskingofthesodiumdeficitdescribedaboveunlesssodiumintakeisalsoadequate.(See
'Pathogenesis'above.)

SubarachnoidhemorrhageFluidrestrictionmaynotbeappropriateforhyponatremiaassociatedwithsubarachnoid
hemorrhage(SAH).PatientswithSAHareatriskforcerebralvasospasmandinfarction,theincidenceofwhichis
increasedbyafallinbloodpressure[7].Becauseoftheneurologicsymptomsassociatedwiththecerebralbleeding,itis
typicallydifficulttodeterminetherole,ifany,ofthehyponatremiainthepathogenesisofthesymptoms.(See"Clinical
manifestationsanddiagnosisofaneurysmalsubarachnoidhemorrhage".)

HyponatremiainpatientswithSAHisusuallyduetoSIADH,butisofteninappropriatelycharacterizedascerebralsalt
wasting(CSW),amuchlesscommonproblem[8].Thetwodisordershavesimilarmanifestations,anditisonlythe
presenceofclearevidenceofvolumedepletion(eg,hypotension,decreasedskinturgor,possiblyincreasedbloodurea
nitrogen/serumcreatinineratio)despiteaurinesodiumconcentrationthatisnotlowthatsuggeststhatCSWmightbe
presentratherthanSIADH.(See"Cerebralsaltwasting".)

FluidrestrictionisastandardcomponentoftherapyinSIADH,butmaypromotecerebralvasospasminpatientswithSAH
whoareusuallytreatedwithvolumeexpansion.(See"Treatmentofaneurysmalsubarachnoidhemorrhage",sectionon
'Preventionofvasospasmanddelayedcerebralischemia'.)

Thus,hyponatremicpatientswithSAHshouldbetreatedwithhypertonic(3percent)salinetobothpreservecerebral
perfusionandpreventcomplicationsfromhyponatremiainducedbrainswelling.Oneproposedregimenisaninitialinfusion
rateof20mL/hwithsubsequentdosingbeingdependentuponserialmeasurementsofserumsodiumatsixhourintervals
[9].FluidtherapyinnormonatremicpatientswithSAHisdiscussedelsewhere.(See"Cerebralsaltwasting",sectionon
'TherapyofSIADHassociatedwithSAH'.)

IntravenoussalineSevere,symptomatic,orresistanthyponatremiainpatientswithSIADHoftenrequiresthe
administrationofsodiumchloride.Iftheserumsodiumconcentrationistobeelevated,theelectrolyteconcentrationofthe
fluidgivenmustexceedtheelectrolyteconcentrationoftheurine,notsimplythatoftheplasma[5].

Thecalculationsthatfollowaresimilartothosethataredescribedingreaterdetailelsewhere.(See"Overviewofthe
treatmentofhyponatremiainadults",sectionon'DonotuseisotonicsalineinSIADH'.)

Thecalculationsarebasedupontwoimportantphysiologicprinciples:

Sodiumandwaterexcretionintheurineareregulatedindependently:sodiumbyaldosteroneandatrialnatriuretic
peptideandwaterbyADH.

TheurinevolumeisnormallyregulatedbyADHinresponsetochangesinwaterintake.WhenADHreleasedoesnot
respondtochangesinwaterintake,asusuallyoccursinSIADH,theurineosmolalityisrelativelyfixedandtheurine
volumevarieswithchangesinsoluteexcretion.Increasingsoluteexcretionbygivingsaltorureawillincreasethe
urinevolumeandtendtoraisetheserumsodium.

TheeffectofisotonicsalineinpatientswithSIADHcanbeillustratedbyasimpleexample.Supposeapatientwith
SIADHhasaserumsodiumof120meq/Landaurineosmolalitythatisrelativelyfixedat616mosmol/kg.If1000mLof
isotonicsalineisgiven(containing154meqeachofsodiumandchlorideor308mosmol),theserumsodiumwillinitially
rise(byabout1meq/Lperliterofisotonicsaline)becauseisotonicsalinehasahighersodiumconcentrationthanthe
patient'sserum.However,allofthesodiumchloridewillbeexcreted(becausesodiumhandlingisintactinSIADH)butin

http://www.uptodate.com/contents/treatmentofhyponatremiasyndromeofinappropriateantidiuretichormonesecretionsiadhandresetosmostat?topicKey 2/15
9/26/2016 Treatmentofhyponatremia:Syndromeofinappropriateantidiuretichormonesecretion(SIADH)andresetosmostat

only500mLofwater(308mosmolin500mLofwaterequals616mosmol/kg).Theexcretionofallofadministeredsaline
withretentionofonehalfoftheadministeredwaterwillworsenthehyponatremia.

Thishypotheticalexamplehasbeenconfirmedinpostoperativepatients,manyofwhomhavetransientSIADH.Inone
report,forexample,theadministrationofisotonicsalineorlactatedRinger'ssolutionto22womenwhohadundergone
uncomplicatedgynecologicsurgeryresultedinafallintheserumsodiumconcentrationbyameanof4.2meq/Lin21of
thepatients[10].Duringthefirst16hoursaftertheinductionofanesthesia,themeanpeakurineosmolalitywasmorethan
600mosmol/kg,andthemeanurinarysodiumpluspotassiumconcentrationwasalmost300meq/L(twicethatinplasma).
Thelossofsodiumpluspotassiumintheurineatamuchhigherconcentrationthanintheplasmawasresponsibleforthe
fallinserumsodium.

Theresponseisdifferentifhypertonicsalineisgiven.Eachliterof3percentsalinecontains1026mosmol(513meqeach
ofsodiumandchloride).If500mLofthissolution(whichcontains257meqofsodium)isslowlygiventoa60kgwoman
withatotalbodywaterofapproximately30litersandabaselineserumsodiumof120meq/L,theinfusedsodiumwill
increasetotalbodysodiumpluspotassiumfrom3600meqto3857meq,andtheinfusedvolumewillincreasetotalbody
waterfrom30Lto30.5L,raisingtheserumsodiumby6.5meq/L.Theriseinserumsodiumafter500mLofhypertonic
salinewillbesmallerina70kgmanwhohasalargertotalbodywaterofapproximately42liters.Inthissetting,theextra
257meqofsodiumwilldistributeover42.5liters,raisingtheserumsodiumby4.6meq/L.

However,theriseinserumsodiuminresponseto3percentsalinewillpartiallydissipateovertime,becauseallofthe
sodiumchloridewillbeexcreted(aswithisotonicsaline),butinalargervolumeofapproximately830mL(513mosmolata
urineosmolalityof616mosmol/kg).Theneteffectisthatsodiumchloridebalanceisunchangedbut330mLoffluidhave
beenlost,whichwillresultinfinalelevationintheserumsodiumofonly1.3meq/Lina60kgwoman(120meq/Lat
baselinex[30/29.67])and1meq/Lina70kgman(120x[42/41.67]).

Thus,aftertheadministrationofhypertonicsalineinahyponatremicpatientwithahighurineosmolality,therewillbean
initiallargeriseintheserumsodiumconcentrationthatfallsovertimeastheadministeredsodiumisexcreted.

Thelatereductioninserumsodiumislesspronounced(ie,thereisagreaterpersistentelevationinserumsodium)ifthe
urineosmolalityisnotsohighsincemorewaterwillfollowtheexcretionofsodiumchloride.If,forexample,theurine
osmolalityis300not616mosmol/kg,thenthe513mosmolofsodiumchloridewillbeexcretedin1710mLofurine.Thus,
thenetfluidlosswillbe1210mL(1710minus500mLgiven),resultinginafinalelevationinserumsodiumof5meq/Lina
60kgwoman(120meq/Latbaselinex[30/28.8])and3.5meq/Lina70kgman(120meq/Latbaselinex[42/40.8]).

ThesecalculationsillustratethelimitedlongtermeffectofevenhypertonicsalineinhyponatremicpatientswithSIADH
whohaveahighlyconcentratedurine.Thus,inadditiontorestrictingwaterintake,effortsmustalsobemadeinsuch
patientstoreducetheurinaryconcentration(ie,lowertheurineosmolality),whichcanbeachievedwithaloopdiureticora
vasopressinreceptorantagonist.

HighsoluteintakeInnormalindividuals,theurineoutputisprimarilydeterminedbyfluidintake,arelationshipthatis
mediatedbychangesinthereleaseofantidiuretichormonethatleadtoappropriatechangesintheurineosmolality.
However,whentheurineosmolalityisfixed,asinSIADH,theurineoutputisdeterminedbytheintakeandsubsequent
urinaryexcretionofsolutes(mostlysodiumsaltsandurea),whichhasbeencalledtherenalsoluteload.Asanexample,at
afixedurineosmolalityof600mosmol/kginapatientwithSIADH,theurineoutputwillbe1L/dayifurinarysolute
excretionin600mosmol/dayand2L/dayifurinarysoluteexcretionisincreasedto1200mosmol/daybyahighsodium,
highproteindietorwiththeingestionofsaltand/orureatablets.Suchahighsolutedietcanbecombinedwithaloop
diuretic,whichinterfereswithconcentratingabilityandlowerstheurineosmolality.

OralsalttabletsTheprinciplesdescribedintheabovesectiononintravenoussalinealsoapplytooralsaltintake.
Supposethesame60kgwomanwithaserumsodiumof120meq/Landtotalbodywaterofapproximately30Ltakesin9
gofsalt(154meqeachofsodiumandchloride)intabletform.All308mosmolwillbeexcretedsincesodiumhandlingis
normal,whichwillincreasetheurineoutputby500mLiftheurineosmolalityis616mosmol/kgandbyapproximately1000
mLiftheurineosmolalityis308mosmol/kg.Usingthecalculationsintheabovesection,thisextralossofwaterwilltend
toraisetheserumsodiumby2meq/L(120meq/Latbaselinex[30/29.5])iftheurineosmolalityis616mosmol/kg,andby
4.1meq/L(120meq/Latbaselinex[30/29])iftheurineosmolalityis308mosmol/kg.(See'Intravenoussaline'above.)

SomepatientswithchronicSIADHhaveamajorunderlyingillness(suchassmallcellcarcinoma)thatmaylimit
compliancewithincreaseddietarysaltintake.
http://www.uptodate.com/contents/treatmentofhyponatremiasyndromeofinappropriateantidiuretichormonesecretionsiadhandresetosmostat?topicKey 3/15
9/26/2016 Treatmentofhyponatremia:Syndromeofinappropriateantidiuretichormonesecretion(SIADH)andresetosmostat

SaltplusaloopdiureticTheeffectofsalttablets(aswithhypertonicsaline)canbeenhancedifgivenwitha
drugthatlowerstheurineosmolalityandincreaseswaterexcretion.Thiscanbeachievedbyimpairingtherenal
responsivenesstoADHbytheadministrationofaloopdiureticoravasopressinreceptorantagonist.Aloopdiuretic(eg,
20mgoffurosemideorallytwiceaday)directlyinterfereswiththecountercurrentconcentratingmechanismbydecreasing
sodiumchloridereabsorptioninthemedullaryaspectoftheloopofHenle[1,11,12].

Aloopdiureticwillbeeffectiveiftheurineosmolalityismorethantwicetheplasmaosmolality,whichtypicallymeansa
urineosmolalityabove500mosmol/kg.Monitoringoftheserumpotassiumisimportant,particularlyintheearlystagesof
therapy.Somepatientsrequirepotassiumchloridesupplementationoruseofapotassiumsparingdiuretic,suchas
amiloride[12].

UreaAnotherwaytoincreaseurinarysoluteexcretionandenhancewaterexcretioninpatientswithSIADHisthe
administrationofurea,usuallyatadoseof30g/day[13,14].Thisregimenisreportedtobegenerallywelltolerated,and
hasbeenusedchronicallyinambulatorypatients.However,itisseldomusedintheUnitedStatesbecauseureaisnot
readilyavailableinpharmacies.

VasopressinreceptorantagonistsTherearethreereceptorsforvasopressin(ADH):theV1a,V1b,andV2receptors.
TheV2receptorsprimarilymediatetheantidiureticresponse,whileV1aandV1breceptorsprimarilycause
vasoconstrictionandadrenocorticotropichormone(ACTH)release,respectively[15,16].

Thevasopressinreceptorantagonistsproduceaselectivewaterdiuresis(aquaresis)withoutaffectingsodiumand
potassiumexcretion[15,16].Theensuinglossofelectrolytefreewaterwilltendtoraisetheserumsodiuminpatientswith
SIADHandmayimprovementalstatusinpatientswithaserumsodiumunder130meq/L[17].Thirstincreases
significantlywiththeseagents,whichmaylimittheriseinserumsodium[17].(See"Overviewofthetreatmentof
hyponatremiainadults",sectionon'Vasopressinreceptorantagonists'.)

Someoralformulationstolvaptan,mozavaptan,satavaptan,andlixivaptanareselectivefortheV2receptor,whilean
intravenousagent,conivaptan,blocksboththeV2andV1areceptors.Tolvaptanshouldnotbeusedforlongerthan30
daysandshouldnotbegiventopatientswithliverdisease(includingcirrhosis).(See'Limitationstouseoftolvaptan'
below.)

EfficacyRandomizeddoubleblindtrialshaveshownthatoralorintravenousvasopressinantagonists(tolvaptan,
lixivaptan,andconivaptan)aremoreeffectivethanplaceboinraisingtheserumsodiumofhyponatremicpatientsbothin
andoutofthehospital[1723].Mostofthepatientsstudiedinthesetrialshadasymptomaticormildlysymptomatic
hyponatremiaandanaverageserumsodiumconcentrationthatwasclosetonormal(rangingfrom127to131meq/L).The
increaseinserumsodiumrelativetoplacebointhesestudieswassmall(mean,1to5meq/L),andtherewasnoevidence
thatlongtermoutcomeswereimproved[24].Althoughtheincidenceofcorrectionoftheserumsodiumbymorethan12
meq/Lin24hourswiththesedrugswaslow(2to4percent),itislikelythattheincidenceofoverlyrapidcorrectionusing
thedefinitionpresentedbelow(morethan8meq/Lin24hours)wasconsiderablyhigher(see'Rateofcorrection'below).In
addition,theriskofoverlyrapidcorrectionwouldlikelybeevengreaterinpatientswithmoreseverehyponatremiaat
baseline.Tolvaptanandconivaptan,butnotlixivaptan,areapprovedforuseintheUnitedStates.However,theUnited
StatesFoodandDrugAdministration(FDA)hasissuedasafetywarningabouttolvaptan.(See'Limitationstouseof
tolvaptan'below.)

ThefollowingstudiesillustratetherangeoffindingsinSIADH:

TheeffectivenessofintravenousconivaptaninSIADHwasdemonstratedinarandomizedplacebocontrolledtrialof
84hospitalizedpatientswitheuvolemicorhypervolemichyponatremia(serumsodium115to<130meq/L)[19].
Comparedwithplacebo,intravenousconivaptan(20mgloadingdosefollowedbyacontinuousinfusionofeither40
or80mg/dayforfourdays)significantlyraisedtheserumsodiumconcentrationbystudyend(6.3and9.4meq/Lin
the40and80mg/dayarms,respectively,versus0.8meq/Lforplacebo).Theeffectivefreewaterclearanceafter24
hourswasapproximatelytwoliterswithbothdosescomparedtominus300mLwithplacebo.

Theeffectsoforallixivaptanineuvolemicpatientswithhyponatremiawereevaluatedintwodoubleblindplacebo
controlledtrials(oneamongoutpatientsandoneamonginpatients)[22,23].Intheoutpatienttrial(HARMONYstudy),
206patientswhohadhyponatremia(meanserumsodium132meq/L)withorwithoutsymptomswererandomly
assignedtoreceivelixivaptan(25to100mg/day)orplacebofor24weeks,althoughthemajoritydiscontinued
therapyearly[22].Theserumsodiumaftersevendaysoftherapy(theprimaryendpoint)wassignificantlyhigherwith
http://www.uptodate.com/contents/treatmentofhyponatremiasyndromeofinappropriateantidiuretichormonesecretionsiadhandresetosmostat?topicKey 4/15
9/26/2016 Treatmentofhyponatremia:Syndromeofinappropriateantidiuretichormonesecretion(SIADH)andresetosmostat

lixivaptan(135versus133meq/L)andremainedsignificantlyhigherthroughouttheremainderofthestudy.Compared
withplacebo,lixivaptanhadnoeffectoncognitivefunctionasassessedbytwoindependentinstruments.Therateof
correctionofhyponatremiaexceeded12meq/Lin24hoursin2percentofpatientsreceivinglixivaptantheproportion
ofpatientscorrectingmorerapidlythan8meq/Lin24hourswaspresumablymuchhigher.Sixpatientsreceiving
lixivaptandiedascomparedwithonepatientinplacebogroup.

Intheinpatienttrial(LIBRAstudy),106hyponatremicpatients(meanserumsodium127meq/L)withorwithout
symptomswererandomlyassignedtolixivaptan(25to100mg/day)orplaceboandfollowedfor30days[23].The
serumsodiumatsevendays(theprimaryoutcome)wassignificantlyhigherinthelixivaptangroup(135versus131
meq/L).Noeffectoncognitivefunctionwasobserved.Overlyrapidcorrectionofhyponatremiaoccurredin4percent
ofpatientsreceivinglixivaptanand6percentofpatientsreceivingplacebo.Fourpatientsintheplacebogroupdiedas
comparedwithnoneinthelixivaptangroup.

Theefficacyoforaltolvaptaninambulatorypatientswasdemonstratedinacombinedreportoftworandomized
doubleblind,placebocontrolledmulticentertrials(SALT1andSALT2)consistingof448patientswithhyponatremia
(meanserumsodium129meq/L)causedbytheSIADH(190patients),heartfailure,orcirrhosis[17].Comparedwith
placebo,tolvaptansignificantlyincreasedtheserumsodiumconcentrationatday4(134to135meq/Lversus130
meq/L)andday30(136versus131meq/L).

AmongallpatientsintheSALTtrials(ie,notlimitedtothosewithcirrhosis)whohadaserumsodiumbelow130
meq/Latbaseline,tolvaptanwasalsoassociatedwithastatisticallysignificantimprovementinmentalstatus
scores.However,thedifferencewasusuallynotclinicallysignificantandlongtermefficacyisuncertainsincethe
durationoffollowupwasonly30days.

Inanopenlabelextension(calledSALTWATER),111patientsweretreatedwithtolvaptanforameanfollowupof
almosttwoyears[25].Themeanserumsodiumwasmaintainedatmorethan135meq/Lcomparedto131meq/Lat
baseline.TheresponsesweresimilarinSIADHandheartfailure,andmoremodestincirrhosis.Themainadverse
effectswereabnormallyfrequenturination,thirst,drymouth,fatigue,polyuria,andpolydipsia.Adverseeffectsthat
werepossiblyorprobablyrelatedtotolvaptanledtodiscontinuationoftherapyinsixpatients(5.4percent).

However,therearesignificantlimitationstotheuseoftolvaptan.(See'Limitationstouseoftolvaptan'below.)

UseofconivaptanSinceconivaptanrequiresintravenousadministration,itisonlyusefulinthetreatmentofSIADH
inpatientswhoarehospitalized.Itspotentialrolevarieswiththeseverityofthehyponatremia:

Patientswithmildtomoderatehyponatremiaandminimalornosymptomscanbeeffectivelyandsafelytreatedwith
themodalitiesdescribedabove(eg,fluidrestrictionandsalttablets).Conivaptanwillmorerapidlyraisetheserum
sodiumconcentration,butitisunclearthatisanimportantadvantageinsuchpatientsunlessitmightshortenthe
durationofhospitalization.

Amongpatientswithmoreseverehyponatremiaormildtomoderatesymptoms,conivaptancanbegivenaloneorin
combinationwithhypertonicsaline.

Amongpatientswithseveresymptomatichyponatremia,conivaptancanbegivenincombinationwithhypertonic
saline.Sincetheeffectofconivaptanonfreewaterclearancebeginsasearlyasonetotwohours,itmaypermita
morerapidinitialelevationinserumsodium.(See'Intravenoussaline'above.)

Asdescribedbelow,attentionmustbepaidtoavoidoverlyrapidcorrectionofthehyponatremia.(See'Rateofcorrection'
below.)

LimitationstouseoftolvaptanAlthoughtolvaptaneffectivelyraisestheserumsodiumconcentrationinpatients
withSIADH,asdemonstratedintheSALTtrialscitedabove[17],thereareimportantlimitationstoitsuse:

Concernsaboutthesafetyoftolvaptanwereraisedbyamulticentertrial(TEMPO3:4)thatexamineditseffecton
theprogressionofkidneydiseaseinpolycystickidneydisease[26,27].Agreaterthan2.5foldincreaseinliver
enzymeswasmorecommonamongpatientswhoreceivedtolvaptancomparedwithplacebo.Baseduponthese
data,theUSFDAissuedsafetywarningsregardingtheuseoftolvaptan[28,29],recommending:thatliverfunction
testsbepromptlyperformedamongpatientswhoreportsymptomsthatsuggestliverinjury(eg,fatigue,anorexia,
http://www.uptodate.com/contents/treatmentofhyponatremiasyndromeofinappropriateantidiuretichormonesecretionsiadhandresetosmostat?topicKey 5/15
9/26/2016 Treatmentofhyponatremia:Syndromeofinappropriateantidiuretichormonesecretion(SIADH)andresetosmostat

rightupperquadrantdiscomfort,darkurine,jaundice)thattolvaptanshouldnotbeusedinanypatientforlongerthan
30daysandthattolvaptanshouldnotbeusedatallinpatientswithliverdisease(includingcirrhosis)becauseit
maypotentiallyleadtoliverfailureordeath[29].(See"Courseandtreatmentofautosomaldominantpolycystic
kidneydisease",sectionon'Vasopressinreceptorantagonists'.)

Theremaybeoverlyrapidcorrectionofthehyponatremia,whichcanleadtoirreversibleneurologicinjury.Inthe
SALTtrials,1.8percentofpatientsexceededthestudygoaloflimitingdailycorrectionto12meq/L[17].However,
morerecentrecommendationshavesuggestedamaximumrateofcorrectionofhyponatremiaoflessthan10meq/L,
not12meq/L.Thus,itisalmostcertainthatmorethan1.8percentoftreatedpatientsexceededthecurrently
recommendedrateofcorrection.Becauseofthisrisk,hospitalizationisrequiredfortheinitiationorreinitiationof
therapy.(See"Osmoticdemyelinationsyndrome(ODS)andoverlyrapidcorrectionofhyponatremia"and"Overview
ofthetreatmentofhyponatremiainadults",sectionon'Theoptimalrateofcorrection'.)

Thirstisincreased,whichmaylimittheriseinserumsodium[17].

Thecostoftolvaptanmaybeprohibitive(ashighas$300pertabletinsomeareas).

Thedrugisnotapprovedtotreatseriousneurologicsymptoms.Inaddition,patientsinthePhaseIIIpivotalstudies
wereexcludediftheirserumsodiumwaslessthan120meq/L.

Giventheimportantlimitationstotheuseoftolvaptan,itshouldonlybeconsideredintherarepatientwhoseserum
sodiumconcentrationcannotbemaintainedabove120meq/Lorwhohaspersistentneurologicsymptomsthoughttobe
duechronichyponatremiadespitetreatmentwithothermeasures.Insuchcases,chronicoutpatientmanagementwith
tolvaptancanbestartedafterfirstraisingtheserumsodiumto120meq/Lwithhypertonicsaline.

DemeclocyclineorlithiumDemeclocyclineandlithiumactonthecollectingtubulecelltodiminishitsresponsiveness
toADH,therebyincreasingwaterexcretion[1,3032].Inpatientswithbipolardisorderwhoaretreatedwithchroniclithium
therapy,nephrogenicdiabetesinsipidusdevelopsinupto20to40percent[32].(See"Renaltoxicityoflithium",sectionon
'Nephrogenicdiabetesinsipidus'.)

Demeclocycline(300to600mgtwiceaday)ismorepredictablyeffective[30]andmoreoftenusedthanlithiumforthe
treatmentofhyponatremiainSIADH.However,bothdrugscanbenephrotoxicdemeclocyclinecancausenausea,
vomiting,andphotosensitivityandcosts$10to$20pertablet,andlithiumhasavarietyofneuropsychiatricsideeffects.

Thegoalserumsodiumof130meq/Lorhigher(see'Asymptomatichyponatremia'below)canbeattainedinalmostall
patientswithSIADHwithfluidrestriction,oralsalttabletsaloneorwithaloopdiuretic,and,ifnecessaryandwhere
available,urea.Theauthorandreviewersofthistopicrarelyusedemeclocyclineinsuchpatientsanddonotuselithium.
Theimpairmentinconcentratingabilitywithdemeclocyclinetakesseveraldaystooneweektobecomeapparent.

RATEOFCORRECTIONAmonghospitalizedpatients,theseverityofneurologicsymptomsattributableto
hyponatremiadeterminestheinitialrateofcorrection(see"Manifestationsofhyponatremiaandhypernatremiainadults"):

Patientswithsevereneurologicsymptoms,whichprimarilyoccurwithacuteandmarkedreductionsinserumsodium
(usuallytobelow120meq/L),requirerapidinitialcorrection,oftenwithhypertonicsaline.However,overlyrapid
correctionshouldbeavoidedsinceitcanleadtothelateonsetofneurologiccomplicationsfromosmotic
demyelination.(See"Osmoticdemyelinationsyndrome(ODS)andoverlyrapidcorrectionofhyponatremia".)

MostpatientswithSIADHandchronicmoderatehyponatremia(serumsodium120to129meq/L)appear
asymptomatic,andslowcorrectionofthehyponatremiaisrecommended.Someofthese"asymptomatic"patients
havesubtleneurologicmanifestationsthatmaybeimprovedbyraisingtheserumsodium.Theseincludereduced
scoresontestsofmental,social,andphysicalfunctioningand,inelderlypatients,unsteadinessandfalls[17,33].
(See'Asymptomatichyponatremia'below.)

Theoptimalrateofcorrectionisdiscussedindetailelsewhere.Summarizedbriefly,themaximumrateofcorrectionof
chronichyponatremiashouldbelessthan9meq/Linany24hourperiod[15,34,35].Aninitialrateofcorrectionof4to6
meq/Linthefirsttwotofourhoursmaybebeneficialinpatientswithseveresymptoms(eg,seizures).Thisrequires
carefulmonitoringoftheserumsodiumconcentration(initiallyeverytwotothreehours)untilthepatientisstable.(See
"Overviewofthetreatmentofhyponatremiainadults",sectionon'Theoptimalrateofcorrection'.)

http://www.uptodate.com/contents/treatmentofhyponatremiasyndromeofinappropriateantidiuretichormonesecretionsiadhandresetosmostat?topicKey 6/15
9/26/2016 Treatmentofhyponatremia:Syndromeofinappropriateantidiuretichormonesecretion(SIADH)andresetosmostat

IftheSIADHresolveswhilethepatientishyponatremic,ADHsecretionwillbesuppressedbythehypoosmolality,anda
waterdiuresiswillensue.Excretionofamaximallydiluteurinewillrapidlyincreasetheserumsodiumconcentration.In
selectedpatientswithseverehyponatremiawhoarecorrectingtoorapidly,preventionoffurthershorttermelevationin
serumsodiumorevenreloweringoftheserumsodiummaybewarranted.Theseissuesarediscussedseparately.(See
"Osmoticdemyelinationsyndrome(ODS)andoverlyrapidcorrectionofhyponatremia",sectionon'Patientswhohave
exceededcorrectionlimits(rescuestrategy)'.)

CHOICEOFTHERAPYThechoiceoftherapyinpatientswithhyponatremiaduetoSIADHvarieswiththeseverityof
hyponatremiaandthepresenceorabsenceofsymptoms.Inaddition,patientswitharesetosmostatdonotrequire
correctionofthehyponatremiasincetheyareasymptomaticandhaveastableserumsodium.(See'Resetosmostat'
below.)

SymptomatichyponatremiaAmongpatientswithsymptomatichyponatremia,theapproachvarieswiththeseverityof
theneurologicsymptoms.

SeveresymptomsSeveresymptomsfromhyponatremia(eg,seizures,inabilitytocommunicate,and/orcoma)are
mostlikelytooccurinpatientsinwhomtheserumsodiumhasfallenbelow120meq/Linlessthan48hours,leadingto
potentiallyfatalcerebraledema.Mostsuchcaseshavebeenduetotheadministrationofhypotonicintravenousfluidsto
premenopausalwomenwithpostoperativeSIADH(figure1)[36].(See"Manifestationsofhyponatremiaandhypernatremia
inadults",sectionon'Susceptibilityofpremenopausalwomen'.)

Inpatientswithseverehyponatremicsymptomsandinsymptomaticpatientswithunderlyingintracranialdiseasewho
cannottolerateevenminordegreesofbrainswellingduetohyponatremia,theserumsodiummustinitiallyberaised
quicklytopreventpossiblyirreversibleneurologicinjury.Baseduponbroadclinicalexperience,theadministrationof
hypertonicsalineistheonlyrapidwaytoraisetheserumsodiumandimproveneurologicmanifestationsinpatientswith
severesymptomatichyponatremia[37].

Oneregimenthatcanachievethisgoalwasinitiallydescribedinhyponatremicathletesparticipatinginenduranceevents,
suchasmarathonraces[11,38,39].Itconsistsof100mLof3percentsalinegivenasanintravenousbolus,whichwill
raisetheserumsodiumbyapproximately1.5meq/Linmenand2meq/Linwomen.Theriseinserumsodiumwillpull
wateroutofthebrain,decreasingthedegreeofcerebraledema.

Ifneurologicsymptomspersistorworsen,a100mLbolusof3percentsalinecanberepeatedoneortwomoretimesat
tenminuteintervals.Therationaleforthisapproachisthat,inpatientswithsymptomatichyponatremia,rapidincreasesin
serumsodiumof4to6meq/Lcanreverseseveresymptomssuchasseizures[4,11,40].(See"Overviewofthetreatment
ofhyponatremiainadults",sectionon'Regimenofhypertonicsalineintheemergencysetting'.)

Forthereasonsnotedabove,thereisnorolefortheuseofisotonicsalineinsymptomaticpatientswithhyponatremiadue
toSIADH.(See'Intravenoussaline'aboveand"Exerciseassociatedhyponatremia",sectionon'Useofhypertonic
saline'.)

Ifthesymptomsresolve,carefulmonitoringwithmeasurementoftheserumsodiumconcentrationeverytwotothree
hoursisrequiredfortworeasons:

Apotentialcomplicationofhypertonicsalinetherapyisoverlyrapidcorrectionofthehyponatremia,particularlyin
patientswithselflimitedorreversibleSIADH.Theusualgoalsareanelevationinserumsodiumoflessthan10
meq/Linthefirst24hoursandlessthan18meq/Linthefirst48hours.(See'Rateofcorrection'above.)If
symptomshaveresolvedbuttheriseinserumsodiumissubstantiallylessthanthe24hourgoal,furthertherapyin
additiontofluidrestrictionmayconsistofaslowinfusionofhypertonicsaline(eg,10to30mLperhour)withcareful
monitoringoftheserumsodium.

Inpatientswithseverehyponatremiawhoarecorrectingtoorapidly,preventionoffurthershorttermelevationinthe
serumsodiumorevenreloweringoftheserumsodiummaybewarranted.Howthiscanbeachievedisdiscussed
elsewhere.(See"Osmoticdemyelinationsyndrome(ODS)andoverlyrapidcorrectionofhyponatremia",sectionon
'Patientswhohaveexceededcorrectionlimits(rescuestrategy)'.)

Inpatientswithahighlyconcentratedurine(eg,above500mosmol/kg),theserumsodiumwillcomebackdown
towardbaselineastheadministeredsodiumisexcretedintheurineunlessfurthertherapyisgiven.(See'Intravenous

http://www.uptodate.com/contents/treatmentofhyponatremiasyndromeofinappropriateantidiuretichormonesecretionsiadhandresetosmostat?topicKey 7/15
9/26/2016 Treatmentofhyponatremia:Syndromeofinappropriateantidiuretichormonesecretion(SIADH)andresetosmostat

saline'above.)Insuchpatients,theurineosmolalitycanbereducedbyadministrationofaloopdiuretic(eg,
furosemide20mgorallytwiceaday).

MildtomoderatesymptomsLesssevereneurologicsymptoms(eg,dizziness,gaitdisturbances,forgetfulness,
confusion,andlethargy)canbeseeninpatientswithaserumsodiumconcentrationbelow120meq/Lthatdevelopsover
morethan48hours,inpatientswithalesserdegreeofhyponatremiathatdevelopsoverlessthan48hours,andin
patientswithchronicmoderatehyponatremia(serumsodium120to129meq/L).Someofthesepatientsmaybenefitfrom
hypertonicsaline,butdonotrequiretheaggressiveapproachsuggestedintheprecedingsectionforthosewithsevere
neurologicsymptoms.

Initialhypertonicsalinetherapytoraisetheserumsodiumatratesupto1meq/Lperhourmaybejustifiedinthefirstthree
tofourhoursinpatientswithdistressingsymptoms(eg,confusionandlethargy).Inthecalculationsdescribedabove,500
mLofhypertonicsalineinitiallyraisedtheserumsodiumby6.5meq/Lina60kgwomanand4.6meq/Lina70kgman.
Thus,raisingtheserumsodiumby4meq/Linfourhourswouldrequireapproximately310mL(75mLperhour)of
hypertonicsalineinthewomanand435mL(110mLperhour)intheman.Thesecalculationsareonlyestimatesandthe
serumsodiumshouldbemeasuredattwotothreehours.Thetotalelevationinserumsodiuminthefirst24hoursshould
belessthan10meq/L.(See'Intravenoussaline'above.)

Patientswithlessseveresymptomscanbetreatedwithlessaggressivetherapy,suchasfluidrestrictionandoralsalt
tablets.

Oncethesymptomshaveresolved,furthertherapyissimilartothatinpatientswithSIADHwhohaveasymptomatic
hyponatremia,withthecaveatofavoidanceofoverlyrapidcorrection.(See'Asymptomatichyponatremia'belowand'Rate
ofcorrection'above.)

MaintenancetherapyUnlesstheSIADHisreversible(eg,postoperativeorduetoadrugthatcanbediscontinued),
effectivetherapyofsymptomatichyponatremiamustbefollowedbymaintenancetherapytopreventasubsequent
reductioninserumsodiumandpossiblesymptomrecurrence.Thegoalserumsodiumisdiscussedbelow.(See
'Asymptomatichyponatremia'below.)

Oneormoreoftheabovetherapeuticmodalitiesmayberequired.Theusualsequenceofmaintenancetherapyisas
follows:

FluidrestrictionThesuggestedgoalfluidintakeinhyponatremicpatientswithSIADHislessthan800mL/day[4].
Animportantexceptionispatientswitharecentsubarachnoidhemorrhageinwhomfluidrestrictioncanbe
deleterious.(See'Fluidrestriction'aboveand'Subarachnoidhemorrhage'above.)

OralsaltInpatientswithSIADH,administeringoralsaltwillincreasetheurineoutputtheusualinitialdoseis3g
oronehalfteaspoonthreetimesdaily,resultinginatotaldoseof9gperday.Sincesodiumhandlingisnormaland
theurineosmolalityisrelativelyfixedinSIADH,increasingoralsaltintakewill,inadosedependentfashion,
increasetheurinevolume.Incalculationsdescribedabove,theintakeof9gofsalt(154meqeachofsodiumand
chloride[308mosmol])wouldbeexpectedtoincreasetheurineoutputbyapproximately500mLiftheurine
osmolalityis616mosmol/kgandbyapproximately1000mLiftheurineosmolalityis308mosmol/kg.Ina60kg
woman,thisextralossofwaterwilltendtoraisetheserumsodiumby2meq/Liftheurineosmolalityis616
mosmol/kg,andby4.1meq/Liftheurineosmolalityis308mosmol/kg.(See'Oralsalttablets'above.)

ReducetheurineosmolalityInpatientswithmoresevereSIADH(urineosmolalitymorethantwicetheplasma
osmolality),theefficacyofbothfluidrestrictionandincreasedsaltintakewillbereduced.(See'Intravenoussaline'
above.)Iffurthertherapyisnecessary,thenextstepistoincreaseurinarywaterexcretionbyimpairingthe
mechanismofurinaryconcentration.Thiscanbeachievedbyloopdiuretictherapy(eg,furosemide20mgorally
twiceaday).Loopdiuretictherapycanproducehypokalemiaandhypovolemiasincethediureticresponseishigher
inpatientswithSIADHwhousuallyhavenormalornearnormalrenalfunctionandarenotsodiumavid.(See'Salt
plusaloopdiuretic'above.)

Forthereasonsdescribedabove,wedonotusetolvaptan,demeclocycline,orlithiumformaintenancetherapyinpatients
withasymptomatichyponatremia.(See'Limitationstouseoftolvaptan'aboveand'Demeclocyclineorlithium'above.)

AsymptomatichyponatremiaPatientswithchronicmoderatehyponatremia(serumsodium120to129meq/L)are
typicallyasymptomaticonroutinehistory.Beforeconsideringtherapy,anyreversiblecauseofSIADHshouldbe
http://www.uptodate.com/contents/treatmentofhyponatremiasyndromeofinappropriateantidiuretichormonesecretionsiadhandresetosmostat?topicKey 8/15
9/26/2016 Treatmentofhyponatremia:Syndromeofinappropriateantidiuretichormonesecretion(SIADH)andresetosmostat

addressed.(See'Treattheunderlyingdisease'above.)

PatientswithasymptomatichyponatremiahaveoftenbeentreatedonlywithfluidrestrictionifthecauseoftheSIADH
cannotbecorrected.However,someoftheseseeminglyasymptomaticpatientshavesubtleneurologicmanifestations
thatcaninterferewiththequalityoflifeandthatmaybeimprovedbyraisingtheserumsodiumasillustratedbythe
followingobservations:

IntheSALTtrialsdescribedabove,tolvaptanimprovedscoresontestsofmental,social,andphysicalfunctioning
amongpatientswithabaselineserumsodiumbelow130meq/L[17].However,thedifferenceinmentalstatus
testingintheSALTtrialswasusuallynotclinicallysignificantandlongtermefficacyisuncertainsincetheduration
offollowupwasonly30days.(See'Vasopressinreceptorantagonists'aboveand"Manifestationsofhyponatremia
andhypernatremiainadults",sectionon'Subtlemanifestationsinmildtomoderatechronichyponatremia'.)

Inastudyofelderlypatientswhopresentedtotheemergencydepartment,thosewithasymptomaticchronic
hyponatremia(serumsodiumbetween120and129meq/L)comparedtonormonatremiccontrolshadanincreased
incidenceoffallsthatmayhaveresultedfrommarkedimpairmentsingaitandattention[33].Improvementwasseen
withrepeattestingaftertreatmentofthehyponatremia.

Theseobservationssuggestthatsome,andperhapsmany,apparentlyasymptomaticpatientswithmoderatechronic
hyponatremia(serumsodium120to129meq/L)havesubtlereversibleneurologicmanifestationsandthataimingforagoal
serumsodiumof130meq/Lorhighermightbebeneficial.Datademonstratingefficacyforroutineattainmentofthisgoal
arenotavailable.

Ifitiselectedtoaimforaserumsodiumof130meq/LorhigherinpatientswithSIADHwhodonothaveovertevidenceof
neurologicdysfunction,webeginwithfluidrestrictionand,ifnecessary,addoralsalttablets,andthen,ifnecessary,aloop
diureticinpatientswithaurineosmolalitymorethantwicethatoftheplasma.(Seeappropriatesectionsabove.)

Giventhelimitationscitedabove,wedonotrecommendtheuseoftolvaptan,demeclocycline,orlithiumtoachievethis
goalinasymptomaticpatients.(See'Limitationstouseoftolvaptan'aboveand'Demeclocyclineorlithium'above.)

RESETOSMOSTATInnormalindividuals,plasmaantidiuretichormone(ADH,argininevasopressin)levelsarevery
lowwhentheplasmaosmolalityisbelow280mosmol/kg,therebypermittingexcretionofingestedwater,andincrease
progressivelyastheplasmaosmolalityrisesabove280mosmol/kg(figure2).

HyponatremiaduetodownwardresettingofosmostatisoneformoftheSIADH[1,4143].(See"Pathophysiologyand
etiologyofthesyndromeofinappropriateantidiuretichormonesecretion(SIADH)",sectionon'PatternsofADH
secretion'.)

Downwardresettingoftheosmostatcanalsooccurinhypovolemicstates(inwhichthebaroreceptorstimulustoADH
releaseissuperimposeduponosmoreceptorfunction),quadriplegia(inwhicheffectivevolumedepletionmayresultfrom
venouspoolinginthelegs),psychosis,tuberculosis,andchronicmalnutrition[1,41].Theserumsodiumconcentrationalso
fallsbyabout5meq/Linnormalpregnancy.Notherapyisrequired.(See"Renalandurinarytractphysiologyinnormal
pregnancy".)

ThepresenceofaresetosmostatshouldbesuspectedinanypatientwithapparentSIADHwhohasmildhyponatremia
(usuallybetween125and135meq/L)thatisstableovermanydaysdespitevariationsinsodiumandwaterintake.The
diagnosiscanbeconfirmedclinicallybyobservingtheresponsetoawaterload(10to15mL/kggivenorallyor
intravenously).Normalsubjectsandthosewitharesetosmostatshouldexcretemorethan80percentofthewaterload
withinfourhours,whileexcretionwillbeimpairedintheSIADH[1].

IdentificationofaresetosmostatisimportantbecausetheabovetherapeuticrecommendationsfortheSIADHmaynot
apply[1,41,44].Thesepatientshavemildtomoderateasymptomatichyponatremiainwhichthereisdownwardresettingof
thethresholdforbothADHreleaseandthirst.Sinceosmoreceptorfunctionisnormalaroundthenewbaseline,attempting
toraisetheserumsodiumconcentrationwillincreaseADHlevelsandmakethepatientthirsty,aresponsethatissimilar
tothatseenwithfluidrestrictioninnormalsubjects.

Thus,attemptingtoraisetheserumsodiumconcentrationmaybeunnecessary(giventheapparentlackofsymptomsand
lackofriskofmoreseverehyponatremia)andlikelytobeineffective(duetoincreasedthirst).Treatmentshouldbe
primarilydirectedattheunderlyingdisease,suchastuberculosis[45].

http://www.uptodate.com/contents/treatmentofhyponatremiasyndromeofinappropriateantidiuretichormonesecretionsiadhandresetosmostat?topicKey 9/15
9/26/2016 Treatmentofhyponatremia:Syndromeofinappropriateantidiuretichormonesecretion(SIADH)andresetosmostat

INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"and"Beyond
theBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgradereadinglevel,and
theyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.Thesearticlesarebestfor
patientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.BeyondtheBasicspatienteducation
piecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe10thto12thgradereadinglevel
andarebestforpatientswhowantindepthinformationandarecomfortablewithsomemedicaljargon.

Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopicsto
yourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon"patientinfo"andthe
keyword(s)ofinterest.)

Basicstopic(see"Patienteducation:Syndromeofinappropriateantidiuretichormonesecretion(SIADH)(The
Basics)"and"Patienteducation:Hyponatremia(TheBasics)")

SUMMARYANDRECOMMENDATIONS

AmongpatientswithSIADH,hyponatremiaiscausedbythecombinationofADHinducedwaterretentionand
secondarysoluteloss.WithchronicSIADH,overallsolutelossismoreprominentthanwaterretention.(See
'Pathogenesis'above.)

ThetreatmentofhyponatremiainSIADHinvolvestreatmentoftheunderlyingdiseaseandtherapiestoraiseand
maintaintheserumsodium.CausesofSIADHthatcanbeeffectivelytreatedincludeadrenalinsufficiencyand
hypothyroidism,infectionssuchasmeningitis,pneumonia,ortuberculosis,anddruginduceddisease.(See'Treatthe
underlyingdisease'above.)

Therapiestoraisetheserumsodium

FluidrestrictionisthemainstayofthetreatmentofmostpatientswithSIADH,withasuggestedgoalintakeofless
than800mL/daypatientswithsubarachnoidhemorrhageareanexceptionsincefluidrestrictionmaypromote
cerebralvasospasm.(See'Fluidrestriction'above.)

Inadditiontofluidrestriction,thetherapyofSIADHassociatedhyponatremiaoftenrequirestheadministrationof
sodiumchloride,eitherasoralsalttabletsorintravenoussaline.Whenusingintravenoussaline,theelectrolyte
concentrationoftheadministeredfluidmustbegreaterthantheelectrolyteconcentrationoftheurine.Thisusually
requirestheuseofhypertonicsaline.Isotonicsalineisinfrequentlyeffectiveandoftenleadstofurtherloweringofthe
serumsodium.(See'Intravenoussaline'aboveand'Oralsalttablets'above.)

Amongpatientswithaurineosmolalitymorethantwicetheplasmaosmolality(whichtypicallymeansaurine
osmolalityabove500mosmol/kg),aloopdiureticmaybeusedtoreduceurinaryconcentration,therebyincreasing
waterexcretion.(See'Saltplusaloopdiuretic'above.)

Thevasopressinreceptorantagonistsproduceaselectivewaterdiuresiswithoutaffectingsodiumandpotassium
excretion.Intravenousconivaptan(whichisusedinhospitalizedpatients)andoraltolvaptanareavailableand
approvedforuseinpatientswithhyponatremiaduetoSIADH.Theutilityoftolvaptantherapyislimitedbyconcerns
abouthepatotoxicity,excessivethirst,prohibitivecost(atleastintheUnitedStates),andthepotentialforoverly
rapidcorrectionofthehyponatremiawhichhasledtothenecessityforhospitalizationfortheinitiationoftherapy.
Becauseofpotentialhepatotoxicity,tolvaptanshouldnotbeusedforlongerthan30daysandshouldnotbegivento
patientswithliverdisease(includingcirrhosis).(See'Vasopressinreceptorantagonists'above.)

Themaximumrateofcorrectionofchronichyponatremiashouldbelessthan10meq/Lat24hoursandlessthan18
meq/Lat48hours.Theserumsodiumconcentrationshouldbecheckedattwotothreehoursinitiallyandthenevery
threetofourhoursuntilthepatientisstable.Inselectedpatientswithseverehyponatremiawhoarecorrectingtoo
rapidly,preventionoffurthershorttermelevationinserumsodiumorevenreloweringoftheserumsodiummaybe
warranted.(See'Rateofcorrection'aboveand"Osmoticdemyelinationsyndrome(ODS)andoverlyrapidcorrection
ofhyponatremia",sectionon'Patientswhohaveexceededcorrectionlimits(rescuestrategy)'.)

ChoosingtheappropriatetherapyThechoiceoftherapyinpatientswithhyponatremiaduetoSIADHvarieswiththe
severityofhyponatremiaandthepresenceorabsenceofsymptoms.

http://www.uptodate.com/contents/treatmentofhyponatremiasyndromeofinappropriateantidiuretichormonesecretionsiadhandresetosmostat?topicKe 10/15
9/26/2016 Treatmentofhyponatremia:Syndromeofinappropriateantidiuretichormonesecretion(SIADH)andresetosmostat

Amongpatientswithseveresymptomatichyponatremiawhopresentwithseizuresorothersevereneurologic
abnormalitiesorwithsymptomatichyponatremiainpatientswithintracerebraldiseases,werecommendurgent
interventionwithhypertonicsalineratherthanothertherapies(Grade1C).Aneffectiveinitialregimenis100mLof3
percentsalinegivenasanintravenousbolus,whichshouldraisetheserumsodiumconcentrationbyapproximately
1.5meq/Linmenand2meq/Linwomen,therebyreducingthedegreeofcerebraledema.Ifneurologicsymptoms
persistorworsen,a100mLbolusof3percentsalinecanberepeatedoneortwomoretimesattenminuteintervals.
(See'Severesymptoms'above.)

Somepatientshavelesssevereneurologicmanifestationsandaserumsodiumconcentrationbelow120meq/Lthat
developsovermorethan48hours,alesserdegreeofhyponatremiathatdevelopsoverlessthan48hours,orchronic
moderatehyponatremia(serumsodium120to129meq/L).Initialtherapyinthesepatientsdependsinpartuponthe
severityofsymptoms.

Forpatientswithconfusionandlethargy,werecommendtheinitialadministrationofhypertonicsalinetherapyto
raisetheserumsodium(Grade1C).Thegoalistoraisetheserumsodium1meq/Lperhourforthreetofour
hours.Theserumsodiumshouldbemeasuredattwotothreehoursandthesubsequentinfusionrateshouldbe
adjustedtoachievearateofcorrectionoflessthan10meq/Lat24hoursandlessthan18meq/Lat48hours.

Forpatientswhohaveonlymildsymptoms(eg,forgetfulness,gaitdisturbance),wesuggestinitialtherapywith
fluidrestrictionandoralsalttabletsratherthanhypertonicsaline.(See'Mildtomoderatesymptoms'above.)

Maintenancetherapyinpatientswhoinitiallyhadsymptomatichyponatremiamaypreventasubsequentreductionin
serumsodiumandpossiblesymptomrecurrence.Wesuggestfluidrestrictiontolessthan800mL/day.Iftheserum
sodiumispersistentlylessthan130meq/L,weaddoralsalttabletsand,ifnecessaryinpatientswithaurine
osmolalitymorethantwicethatoftheplasma,aloopdiuretic(eg,furosemide20mgorallytwiceaday).Wewould
notusetolvaptan,demeclocycline,orlithiuminasymptomaticpatientsgiventhelimitationscitedabove.(See
'Maintenancetherapy'aboveand'Demeclocyclineorlithium'above.)

AmongasymptomaticpatientswithSIADH,weinitiatetherapywithfluidrestriction.Oralsalttabletsmaybeadded,
andthen,ifnecessaryinpatientswithaurineosmolalitymorethantwicethatoftheplasma,aloopdiuretic.(See
'Asymptomatichyponatremia'above.)

HyponatremiawitharesetosmostatpatternisavariantoftheSIADHandshouldbesuspectedinanypatientwith
mildtomoderatehyponatremia(usuallybetween125and135meq/L)thatisstableovertimedespitevariationsin
sodiumandwaterintake.ThetherapeuticrecommendationsforSIADHdonotapplytopatientswithresetosmostat.
Treatmentshouldbeprimarilydirectedattheunderlyingdisease.(See'Resetosmostat'above.)

GoalserumsodiumWesuggestagoalserumsodiumof130meq/LorhigherinpatientswithSIADHbecauseofthe
possiblepresenceofsubtleneurologicmanifestationsandfallswhentheserumsodiumisbetween120and129meq/L
(Grade2C).(See'Asymptomatichyponatremia'above.)

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

REFERENCES

1.RoseBD,PostTW.ClinicalPhysiologyofAcidBaseandElectrolyteDisorders,5thed,McGrawHill,NewYork
2001.p.729.
2.CookeCR,TurinMD,WalkerWG.Thesyndromeofinappropriateantidiuretichormonesecretion(SIADH):
pathophysiologicmechanismsinsoluteandvolumeregulation.Medicine(Baltimore)197958:240.
3.VerbalisJG.Pathogenesisofhyponatremiainanexperimentalmodelofthesyndromeofinappropriateantidiuresis.
AmJPhysiol1994267:R1617.
4.AdroguHJ,MadiasNE.Hyponatremia.NEnglJMed2000342:1581.
5.RoseBD.Newapproachtodisturbancesintheplasmasodiumconcentration.AmJMed198681:1033.
6.EllisonDH,BerlT.Clinicalpractice.Thesyndromeofinappropriateantidiuresis.NEnglJMed2007356:2064.
7.WijdicksEF,VermeulenM,MurrayGD,etal.Theeffectsoftreatinghypertensionfollowinganeurysmal
subarachnoidhemorrhage.ClinNeurolNeurosurg199092:111.

http://www.uptodate.com/contents/treatmentofhyponatremiasyndromeofinappropriateantidiuretichormonesecretionsiadhandresetosmostat?topicKey 11/15
9/26/2016 Treatmentofhyponatremia:Syndromeofinappropriateantidiuretichormonesecretion(SIADH)andresetosmostat

8.SternsRH,SilverSM.CerebralsaltwastingversusSIADH:whatdifference?JAmSocNephrol200819:194.
9.WooCH,RaoVA,SheridanW,FlintAC.Performancecharacteristicsofaslidingscalehypertonicsalineinfusion
protocolforthetreatmentofacuteneurologichyponatremia.NeurocritCare200911:228.
10.SteeleA,GowrishankarM,AbrahamsonS,etal.Postoperativehyponatremiadespitenearisotonicsalineinfusion:a
phenomenonofdesalination.AnnInternMed1997126:20.
11.SternsRH,NigwekarSU,HixJK.Thetreatmentofhyponatremia.SeminNephrol200929:282.
12.DecauxG,WaterlotY,GenetteF,etal.Inappropriatesecretionofantidiuretichormonetreatedwithfrusemide.Br
MedJ(ClinResEd)1982285:89.
13.DecauxG,BrimioulleS,GenetteF,MockelJ.Treatmentofthesyndromeofinappropriatesecretionofantidiuretic
hormonebyurea.AmJMed198069:99.
14.DecauxG,GenetteF.Ureaforlongtermtreatmentofsyndromeofinappropriatesecretionofantidiuretichormone.
BrMedJ(ClinResEd)1981283:1081.
15.VerbalisJG,GoldsmithSR,GreenbergA,etal.Hyponatremiatreatmentguidelines2007:expertpanel
recommendations.AmJMed2007120:S1.
16.GreenbergA,VerbalisJG.Vasopressinreceptorantagonists.KidneyInt200669:2124.
17.SchrierRW,GrossP,GheorghiadeM,etal.Tolvaptan,aselectiveoralvasopressinV2receptorantagonist,for
hyponatremia.NEnglJMed2006355:2099.
18.SoupartA,GrossP,LegrosJJ,etal.Successfullongtermtreatmentofhyponatremiainsyndromeofinappropriate
antidiuretichormonesecretionwithsatavaptan(SR121463B),anorallyactivenonpeptidevasopressinV2receptor
antagonist.ClinJAmSocNephrol20061:1154.
19.ZeltserD,RosanskyS,vanRensburgH,etal.Assessmentoftheefficacyandsafetyofintravenousconivaptanin
euvolemicandhypervolemichyponatremia.AmJNephrol200727:447.
20.SaitoT,IshikawaS,AbeK,etal.Acuteaquaresisbythenonpeptideargininevasopressin(AVP)antagonistOPC
31260improveshyponatremiainpatientswithsyndromeofinappropriatesecretionofantidiuretichormone(SIADH).
JClinEndocrinolMetab199782:1054.
21.MurphyT,DharR,DiringerM.Conivaptanbolusdosingforthecorrectionofhyponatremiaintheneurointensivecare
unit.NeurocritCare200911:14.
22.AbrahamWT,DecauxG,JosiassenRC,etal.Orallixivaptaneffectivelyincreasesserumsodiumconcentrationsin
outpatientswitheuvolemichyponatremia.KidneyInt201282:1215.
23.AbrahamWT,HensenJ,GrossPA,etal.Lixivaptansafelyandeffectivelycorrectsserumsodiumconcentrationsin
hospitalizedpatientswitheuvolemichyponatremia.KidneyInt201282:1223.
24.BorneRT,KrantzMJ.Lixivaptanforhyponatremiathenumbersgame.JAMA2012308:2345.
25.BerlT,QuittnatPelletierF,VerbalisJG,etal.Oraltolvaptanissafeandeffectiveinchronichyponatremia.JAmSoc
Nephrol201021:705.
26.HigashiharaE,TorresVE,ChapmanAB,etal.Tolvaptaninautosomaldominantpolycystickidneydisease:three
years'experience.ClinJAmSocNephrol20116:2499.
27.TorresVE,ChapmanAB,DevuystO,etal.Tolvaptaninpatientswithautosomaldominantpolycystickidney
disease.NEnglJMed2012367:2407.
28.Samsca(tolvaptan):DrugWarningPotentialRiskofLiverInjury.
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm336669.htm?
source=govdelivery(AccessedonJanuary28,2013).
29.Samsca(Tolvaptan):DrugSafetyCommunicationFDALimitsDurationandUsageDueToPossibleLiverInjury
LeadingtoOrganTransplantorDeath.
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350185.htm
(AccessedonMay20,2013).
30.ForrestJNJr,CoxM,HongC,etal.Superiorityofdemeclocyclineoverlithiuminthetreatmentofchronicsyndrome
ofinappropriatesecretionofantidiuretichormone.NEnglJMed1978298:173.
31.CoxM,GuzzoJ,MorrisonG,SingerI.Demeclocyclineandtherapyofhyponatremia.AnnInternMed197786:113.
32.GrnfeldJP,RossierBC.Lithiumnephrotoxicityrevisited.NatRevNephrol20095:270.
33.RenneboogB,MuschW,VandemergelX,etal.Mildchronichyponatremiaisassociatedwithfalls,unsteadiness,
andattentiondeficits.AmJMed2006119:71.e1.
34.SternsRH,HixJK,SilverS.Treatmentofhyponatremia.CurrOpinNephrolHypertens201019:493.
35.AdroguHJ,MadiasNE.Thechallengeofhyponatremia.JAmSocNephrol201223:1140.

http://www.uptodate.com/contents/treatmentofhyponatremiasyndromeofinappropriateantidiuretichormonesecretionsiadhandresetosmostat?topicKe 12/15
9/26/2016 Treatmentofhyponatremia:Syndromeofinappropriateantidiuretichormonesecretion(SIADH)andresetosmostat

36.AyusJC,WheelerJM,ArieffAI.Postoperativehyponatremicencephalopathyinmenstruantwomen.AnnInternMed
1992117:891.
37.ArieffAI,AyusJC.Endometrialablationcomplicatedbyfatalhyponatremicencephalopathy.JAMA1993270:1230.
38.AyusJC,ArieffA,MoritzML.Hyponatremiainmarathonrunners.NEnglJMed2005353:427.
39.HewButlerT,AyusJC,KippsC,etal.StatementoftheSecondInternationalExerciseAssociatedHyponatremia
ConsensusDevelopmentConference,NewZealand,2007.ClinJSportMed200818:111.
40.SiegelAJ,VerbalisJG,ClementS,etal.Hyponatremiainmarathonrunnersduetoinappropriatearginine
vasopressinsecretion.AmJMed2007120:461.e11.
41.RobertsonGL.Regulationofargininevasopressininthesyndromeofinappropriateantidiuresis.AmJMed2006
119:S36.
42.RobertsonGL,SheltonRL,AtharS.Theosmoregulationofvasopressin.KidneyInt197610:25.
43.DeFronzoRA,GoldbergM,AgusZS.Normaldilutingcapacityinhyponatremicpatients.Resetosmostatora
variantofthesyndromeofinappropriateantidiuretichormonesecretion.AnnInternMed197684:538.
44.KahnT.Resetosmostatandsaltandwaterretentioninthecourseofseverehyponatremia.Medicine(Baltimore)
200382:170.
45.HillAR,UribarriJ,MannJ,BerlT.Alteredwatermetabolismintuberculosis:roleofvasopressin.AmJMed1990
88:357.

Topic2357Version20.0

http://www.uptodate.com/contents/treatmentofhyponatremiasyndromeofinappropriateantidiuretichormonesecretionsiadhandresetosmostat?topicKe 13/15
9/26/2016 Treatmentofhyponatremia:Syndromeofinappropriateantidiuretichormonesecretion(SIADH)andresetosmostat

GRAPHICS

Courseofosmoticdemyelinationinhyponatremia

Clinicalcourseinsevenpreviouslyhealthywomenshowdeveloped
postoperativehyponatremiaandseizurespresumablyduetocerebral
edema.Rapidcorrectionoftheplasmasodiumconcentrationwas
associatedwithlatedeteriorationintocomaorapermanentvegetative
statethatmayhavebeenduetoosmoticdemyelination.

Datafrom:ArieffAI.NEnglJMed1986314:1529.

Graphic76471Version2.0

http://www.uptodate.com/contents/treatmentofhyponatremiasyndromeofinappropriateantidiuretichormonesecretionsiadhandresetosmostat?topicKe 14/15
9/26/2016 Treatmentofhyponatremia:Syndromeofinappropriateantidiuretichormonesecretion(SIADH)andresetosmostat

OsmoticregulationofADHreleaseandthirst

Relationbetweenplasmaantidiuretichormone(ADH)concentrationandplasma
osmolalityinnormalhumansinwhomtheplasmaosmolalitywaschangedby
varyingthestateofhydration.Theosmoticthresholdforthirstisafew
mosmol/kghigherthanthatforADH.

DatafromRobertsonGL,AycinenaP,ZerbeRL.Neurogenicdisordersofosmoregulation.
AmJMed198272:339.

Graphic65195Version4.0

http://www.uptodate.com/contents/treatmentofhyponatremiasyndromeofinappropriateantidiuretichormonesecretionsiadhandresetosmostat?topicKe 15/15