Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State in Adults - Treatment

25/10/2015
Diabeticketoacidosisandhyperosmolarhyperglycemicstateinadults:Treatment
OfficialreprintfromUpToDate
www.uptodate.com2015UpToDate
Authors
SectionEditor
AbbasEKitabchi,PhD,MD,FACP, DavidMNathan,MD
MACE
IrlBHirsch,MD
MichaelEmmett,MD
DeputyEditor
JeanEMulder,MD
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Sep2015.|Thistopiclastupdated:Oct17,2014.
INTRODUCTIONDiabeticketoacidosis(DKA)andhyperosmolarhyperglycemicstate(HHS,alsoknownas
hyperosmotichyperglycemicnonketoticstate[HHNK])aretwoofthemostseriousacutecomplicationsof
diabetes.Theyarepartofthespectrumofhyperglycemiaandeachrepresentsanextremeinthespectrum.
ThetreatmentofDKAandHHSinadultswillbereviewedhere.Theepidemiology,pathogenesis,clinicalfeatures,
evaluation,anddiagnosisofthesedisordersarediscussedseparately.DKAinchildrenisalsoreviewed
separately.
(See"Diabeticketoacidosisandhyperosmolarhyperglycemicstateinadults:Epidemiologyand
pathogenesis".)
(See"Diabeticketoacidosisandhyperosmolarhyperglycemicstateinadults:Clinicalfeatures,evaluation,
anddiagnosis".)
(See"Clinicalfeaturesanddiagnosisofdiabeticketoacidosisinchildren".)
(See"Treatmentandcomplicationsofdiabeticketoacidosisinchildren".)
DEFINITIONSDiabeticketoacidosis(DKA)andhyperosmolarhyperglycemicstate(HHS)differclinically
accordingtothepresenceofketoacidosisand,usually,thedegreeofhyperglycemia[13].Thedefinitions
proposedbytheAmericanDiabetesAssociation(ADA)forDKAandHHSareshowninthetable(table1)[1].
InDKA,metabolicacidosisisoftenthemajorfinding,whiletheserumglucoseconcentrationisgenerally
below800mg/dL(44.4mmol/L)andoftenapproximately350to500mg/dL(19.4to27.8mmol/L)[13].
However,serumglucoseconcentrationsmayexceed900mg/dL(50mmol/L)inpatientswithDKAwhoare
comatose[3,4].
InHHS,thereislittleornoketoacidaccumulation,theserumglucoseconcentrationfrequentlyexceeds1000
mg/dL(56mmol/L),theplasmaosmolalitymayreach380mosmol/kg,andneurologicabnormalitiesare
frequentlypresent(includingcomain25to50percentofcases)[1,2,5,6].
SignificantoverlapbetweenDKAandHHSoccursinmorethanonethirdofpatients[7].Thetypicaltotalbody
deficitsofwaterandelectrolytesinDKAandHHSarecomparedinthetable(table2).(See"Diabeticketoacidosis
andhyperosmolarhyperglycemicstateinadults:Clinicalfeatures,evaluation,anddiagnosis",sectionon
'Diagnosticcriteria'.)
TREATMENT
OverviewandprotocolsThetreatmentofdiabeticketoacidosis(DKA)andhyperosmolarhyperglycemicstate
(HHS)issimilar,includingcorrectionofthefluidandelectrolyteabnormalitiesthataretypicallypresent
(hyperosmolality,hypovolemia,metabolicacidosis[inDKA],andpotassiumdepletion)andtheadministrationof
insulin[1,810].
ThefirststepinthetreatmentofDKAorHHSisinfusionofisotonicsalinetoexpandextracellularvolumeand
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stabilizecardiovascularstatus(table3).Thisalsoincreasesinsulinresponsivenessbyloweringtheplasma
osmolality,reducingvasoconstrictionandimprovingperfusion,andreducingstresshormonelevels[11,12].The
nextstepiscorrectionofthepotassiumdeficit.Thechoiceoffluidreplacementmaybeinfluencedbythe
potassiumdeficit.Potassiumrepletionaffectsthesalinesolutionthatisgiven,sincepotassiumisasosmotically
activeassodium.(See'Potassiumreplacement'below.)
Lowdoseintravenous(IV)insulinshouldbeadministeredtoallpatientswithmoderatetosevereDKAwhohavea
serumpotassium3.3mEq/L.Iftheserumpotassiumislessthan3.3mEq/L,insulintherapyshouldbedelayed
untilpotassiumreplacementhasbegunandtheserumpotassiumconcentrationhasincreased.Thedelayis
necessarybecauseinsulinwillworsenthehypokalemiabydrivingpotassiumintothecells,andthiscouldtrigger
cardiacarrhythmias.(See'Intravenousregularinsulin'below.)
Therapyrequiresfrequentclinicalandlaboratorymonitoringandtheidentificationandtreatmentofanyprecipitating
events,includinginfection.(See'Monitoring'below.)
Ourapproachoutlinedbelowispredominantlybaseduponclinicalexperienceandislargelyinagreementwiththe
AmericanDiabetesAssociation(ADA)consensusalgorithmsforthetreatmentofDKA(algorithm1)andHHS
(algorithm2)andtheJointBritishDiabetesSocietiesguidelineforthemanagementofDKA[1,13,14].
FluidreplacementInpatientswithDKAorHHS,werecommendvigorousIVelectrolyteandfluidreplacement
tocorrectbothhypovolemiaandhyperosmolality.
Fluidrepletionisusuallyinitiatedwithisotonicsaline(0.9percentsodiumchloride).Theoptimalrateofisotonic
salineinfusionisdependentupontheclinicalstateofthepatient.Isotonicsalineshouldbeinfusedasquicklyas
possibleinpatientswithhypovolemicshock.(See"Treatmentofseverehypovolemiaorhypovolemicshockin
adults".)
Inhypovolemicpatientswithoutshock(andwithoutheartfailure),isotonicsalineisinfusedatarateof15to20
mL/kgleanbodyweightperhour(about1000mL/hourinanaveragesizedperson),forthefirstcouplehours,with
amaximumof<50mL/kginthefirstfourhours(algorithm1andalgorithm2)[1].
Afterthesecondorthirdhour,thechoiceforfluidreplacementdependsuponthestateofhydration,serum
electrolytelevels,andtheurineoutput.ThemostappropriateIVfluidcompositionisdeterminedbythecorrected
sodiumconcentration.Thecorrectedsodiumconcentrationcanbeapproximatedbyadding2.0mEq/Ltothe
plasmasodiumconcentrationforeach100mg/100mL(5.5mmol/L)increaseabovenormalinglucose
concentration(calculator1).Ifthecorrectedserumsodiumconcentrationislessthan135mEq/L,thenisotonic
salineshouldbecontinuedatarateofabout250to500mL/hour[1].However,ifthecorrectedsodium
concentrationisnormalorelevated,thentheIVfluidisgenerallyswitchedtoonehalfisotonicsalineatarateof
250to500mL/hourinordertoprovideelectrolytefreewater.Thetimingofonehalfisotonicsalinetherapymay
alsobeinfluencedbypotassiumbalance.Potassiumrepletionaffectsthesalinesolutionthatisgiven,since
potassiumisasosmoticallyactiveassodium.Thus,concurrentpotassiumreplacementmaybeanotherindication
fortheuseofonehalfisotonicsaline.(See'Potassiumreplacement'below.)
Weadddextrosetothesalinesolutionwhentheserumglucosereaches200mg/dL(11.1mmol/L)inDKAor250
to300mg/dL(13.9to16.7mmol/L)inHHS.(See'Intravenousregularinsulin'below.)
Adequaterehydrationwithcorrectionofthehyperosmolarstatemayresultinamorerobustresponsetolowdose
insulintherapy[11,12].Adequacyoffluidreplacementisjudgedbyfrequenthemodynamicandlaboratory
monitoring(see'Monitoring'below).Inpatientswithabnormalrenalorcardiacfunction,morefrequentmonitoring
mustbeperformedtoavoidiatrogenicfluidoverload[9,10,12,1518].Thegoalistocorrectestimateddeficits(table
2)withinthefirst24hours.Osmolalityshouldnotbereducedtoorapidlybecauseofconcernthatthismaycause
developmentofcerebraledema.(See'Cerebraledema'belowand"Treatmentandcomplicationsofdiabetic
ketoacidosisinchildren",sectionon'Cerebraledema'.)
PotassiumreplacementPotassiumreplacementisinitiatedimmediatelyiftheserumpotassiumis<5.3
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mEq/L.
Iftheinitialserumpotassiumisbelow3.3mEq/L,IVpotassiumchloride(KCl20to40mEq/hour,which
usuallyrequires20to40mEq/Laddedtosaline)shouldbegiven.Thechoiceofreplacementfluid(isotonicor
onehalfisotonicsaline)dependsuponthestateofhydration,correctedsodiumconcentration,doseofKCl,
bloodpressure,andaclinicalassessmentofoverallvolumestatus.Potassiumrepletionismosturgentin
patientswithmassivepotassiumdeficitswhoarehypokalemicpriortotherapy[1921].Suchpatientsrequire
aggressivepotassiumreplacement(40mEq/hour,withadditionalsupplementationbaseduponhourlyserum
potassiummeasurements)tomaintaintheserumpotassiumconcentrationwithinthenormalrangeof4to5
mEq/L.
Iftheinitialserumpotassiumisbetween3.3and5.3mEq/L,IVKCl(20to30mEq)isaddedtoeachliterof
IVreplacementfluidandcontinueduntiltheserumpotassium(K)concentrationhasincreasedtothe4.0to
5.0mEq/Lrange.
Iftheserumpotassiumconcentrationisinitiallygreaterthan5.3mEq/L,thenpotassiumreplacementshould
bedelayeduntilitsconcentrationhasfallenbelowthislevel.
WhenpotassiumsaltsareaddedtoIVfluids,theyhavethesameosmoticeffectassodiumsalts,andthisshould
beconsideredwhendeterminingthepotentialeffectsofIVfluidinfusiononchangesinosmolality.Asanexample,
40mEqofKCladdedto1Loffluidgenerates80mOsmol/Lofelectrolyteosmolality.Theadditionof40mEqof
potassiumto1Lofonehalfisotonicsalinecreatesasolutionwithanosmolalityof234mOsmol/L(77mEq
sodiumchloride[NaCl]and40mEqKCl),whichisessentiallythreequartersisotonicsaline.(Theosmolalityof
isotonicsalineis285to308mOsmol/L).If40mEqofKClisaddedtoisotonicsaline,thefinalosmolalitywillbe
about388mOsmol/L.However,KCLwillnothavenearlythesameextracellularfluid(ECF)expansioneffect
becausemostwillshiftintocellsveryrapidly.(See"Maintenanceandreplacementfluidtherapyinadults",section
on'Choiceofreplacementfluid'.)
AlmostallpatientswithDKAorHHShaveasubstantialpotassiumdeficit,mainlyduetourinarylossesrelatedto
theglucoseosmoticdiuresisandtosecondaryhyperaldosteronism.Despitethetotalbodypotassiumdeficit,the
serumpotassiumconcentrationisusuallynormalor,inaboutonethirdofcases,elevatedatpresentationdue
primarilytoinsulindeficiencyandhyperosmolality,bothofwhichresultinpotassiummovementoutofthecells
[22].Thechangeinpotassiumdistributionisrapidlyreversedwiththeadministrationofinsulin,resultinginanoften
dramaticfallintheserumpotassiumconcentration,despitepotassiumreplacement[19,20].However,cautionis
necessaryifrenalfunctionremainsdepressedand/orurineoutputdoesnotincreasetoalevel>50mL/hour.
CarefulmonitoringoftheserumpotassiumisessentialforthemanagementofbothDKAandHHS.(See
'Monitoring'belowand"Diabeticketoacidosisandhyperosmolarhyperglycemicstateinadults:Epidemiologyand
pathogenesis",sectionon'Potassium'.)
InsulinWerecommendtreatmentwithlowdoseIVinsulininallpatientswithmoderatetosevereDKAorHHS
whohaveaserumpotassium3.3mEq/L.Theonlyindicationfordelayinginsulintherapyisaserumpotassium
below3.3mEq/L,sinceinsulinwillworsenthehypokalemiabydrivingpotassiumintothecells.Patientswithan
initialserumpotassiumbelow3.3mEq/Lshouldreceiveaggressivefluidandpotassiumreplacementpriorto
treatmentwithinsulin.Insulintherapyshouldbedelayeduntiltheserumpotassiumisabove3.3mEq/Ltoavoid
possiblearrhythmias,cardiacarrest,andrespiratorymuscleweakness[1,19,20].(See'Potassiumreplacement'
above.)
IVregularinsulinandrapidactinginsulinanalogsareequallyeffectiveintreatingDKA[23].Duetocost
considerations,weprefertreatmentwithregularinsulin,ratherthanrapidactinginsulinanalogs.ChoiceofIV
insulinshouldbebaseduponinstitutionalpreferences,clinicianexperience,andcostconcerns.(See'Intravenous
regularinsulin'belowand'Intravenousinsulinanalogs'below.)
Insulintherapylowerstheserumglucoseconcentration(primarilybydecreasinghepaticglucoseproductionrather
thanenhancingperipheralutilization[24]),diminishesketoneproduction(byreducingbothlipolysisandglucagon
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secretion),andmayaugmentketoneutilization.Theantilipolyticactionofinsulinrequiresamuchlowerdosethan
thatrequiredtoreducetheserumglucoseconcentration.Therefore,iftheadministereddoseofinsulinisreducing
theglucoseconcentration,itshouldbemorethanenoughtostopketonegeneration[9,24,25].(See"Diabetic
ketoacidosisandhyperosmolarhyperglycemicstateinadults:Epidemiologyandpathogenesis",sectionon
'Pathogenesis'.)
IntravenousregularinsulinInHHSormoderatetosevereDKA,treatmentisinitiatedwithanIVbolusof
regularinsulin(0.1U/kgbodyweight)followedwithin5minutesbyacontinuousinfusionofregularinsulinof0.1
U/Kg/hour(equivalentto7U/hourina70kgpatient)[9,2629].Alternatively,thebolusdosecanbeomittedanda
continuousIVinfusionofregularinsulinatarateof0.14U/kgperhour(equivalentto10U/hourina70kgpatient)
isinitiated[30].TheinsulindosingisthesameinDKAandHHS(algorithm1andalgorithm2).Thepossibleroleof
otherinsulinpreparationsisdiscussedbelow.(See'Intravenousinsulinanalogs'belowand'Alternativesto
intravenousinsulin'below.)
Thesedosesofregularinsulinusuallydecreasetheserumglucoseconcentrationbyabout50to70mg/dL(2.8to
3.9mmol/L)perhour[24,2729].Higherdosesdonotgenerallyproduceamoreprominenthypoglycemiceffect,
possiblybecausetheinsulinreceptorsarealreadysaturated[26].However,iftheserumglucosedoesnotfallby
atleast50to70mg/dL(2.8to3.9mmol/L)fromtheinitialvalueinthefirsthour,checktheIVaccesstobecertain
thattheinsulinisbeingdeliveredandmakesurethatnoIVlinefiltersthatmaybindinsulinhavebeeninsertedinto
theline.Afterthesepossibilitiesareeliminated,theinsulininfusionrateshouldbedoubledeveryhouruntila
steadydeclineinserumglucoseofthismagnitudeisachieved.
Thefallinserumglucoseistheresultofbothinsulinactivityandthebeneficialeffectsofvolumerepletion.Volume
repletionalonecaninitiallyreducetheserumglucoseby35to70mg/dL(1.9to3.9mmol/L)perhourduetoECF
expansionanddilution,andincreasedurinarylossesresultingfromimprovedrenalperfusionandglomerular
filtration[16,28].TherateoffallinserumglucosemaybemorepronouncedinpatientswithHHSwhoaretypically
morevolumedepleted.
Whentheserumglucosereaches200mg/dL(11.1mmol/L)inDKAor250to300mg/dL(13.9to16.7mmol/L)in
HHS,theIVsalinesolutionisswitchedtodextroseinsaline,anditmaybepossibletodecreasetheinsulin
infusionrateto0.02to0.05U/kgperhour[10,12,26].Reducingtheserumglucoseatthistimebelow200mg/dL
(11.1mmol/L)inDKAor250to300mg/dL(13.9to16.7mmol/L)inHHSmaypromotethedevelopmentofcerebral
edema.(See'Cerebraledema'belowand"Cerebraledemainchildrenwithdiabeticketoacidosis".)
IntravenousinsulinanalogsThepossibleroleofIVinsulinpreparationsotherthanregularinsulinwas
evaluatedinatrialof74patientswithDKAwhowererandomlyassignedtoIVregularorglulisineinsulin[23].The
initialdosingwasthesame(0.1unit/kgIVbolus,followedbyaninfusionat0.1unit/kgperhour).Patientswere
otherwisetreatedsimilarly,accordingtoADAguidelines.AfterresolutionofDKA,patientstreatedwithregular
insulinreceivedsubcutaneous(SQ)NPHandregularinsulintwicedaily,whereaspatientstreatedwithIVglulisine
insulinreceivedglargineoncedailyandglulisinebeforemeals.
Therewerenodifferencesbetweenthetwogroupsinthemeandurationoftreatment,amountofinsulin
administered,ortotaldurationofinsulininfusionuntilresolutionofDKA.AftertransitiontoSQinsulin,glycemic
controlwasalsosimilar.However,patientstreatedwithNPHandregularinsulinhadahigherincidenceof
hypoglycemia.Thus,IVregularandglulisineinsulinswereequallyeffectiveintreatingDKA.Duetocost
considerations,therearenoreasonstouserapidactinganalogsinIVinsulintherapy,sincethekineticsare
identicalandthedatadonotshowanadvantage.(See"Generalprinciplesofinsulintherapyindiabetesmellitus",
sectionon'Humanversusanalogs'.)
AlternativestointravenousinsulinPatientswithmildDKAcanbesafelytreatedwithSQrapidacting
insulinanalogsonthegeneralmedicalward,butonlywhenadequatestaffingisavailabletocarefullymonitorthe
patientandcheckcapillarybloodglucosewithareliablestandardizedglucosemetereveryhour.
Directcomparisonofintramuscular,SQ,andIVinsulintherapy,forhemodynamicallystableDKApatients,shows
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similarefficacyandsafety[3133].Inaddition,SQadministrationofrapidactinginsulinanalogs(insulinlispro,
aspart,andglulisine)inthemanagementofuncomplicatedDKAhasbeendemonstratedtobesafeandcost
effectiveintworandomizedtrialsinadults[32,33].Inonetrial,forexample,40patientswithDKAwereassigned
tooneoftworegimens[32]:
SQrapidactinginsulinlisproasaninitialinjectionof0.3U/kg,followedby0.1U/kgeveryhouruntilthe
serumglucosewaslessthan250mg/dL(13.9mmol/L).Theinsulindosewasthendecreasedto0.05to0.1
U/kgandadministeredeveryoneortwohoursuntilresolutionoftheketoacidosis.Thesepatientswere
treatedontheregularmedicinewardorinanintermediatecareunit.
IVregularinsulinasaninitialbolusof0.1U/kg,followedbyaninfusionof0.1U/kgperhouruntiltheserum
glucosewaslessthan250mg/dL(13.9mmol/L).Theinsulindosewasthendecreasedto0.05to0.1U/kg
perhouruntilresolutionoftheketoacidosis.Thesepatientsweretreatedintheintensivecareunit.
Thedurationoftherapyuntilcorrectionofhyperglycemiaandresolutionofketoacidosiswasthesamewithboth
regimens(sevenand10to11hours,respectively),buttherewasa39percentreductionincostwithinsulinlispro,
mainlyrelatedtothehighercostoftreatmentintheintensivecareunit.
BicarbonateandmetabolicacidosisWesuggestadministeringbicarbonateifthearterialpHislessthan
6.90.Wegive100mEqofsodiumbicarbonatein400mLsterilewaterwith20mEqofpotassiumchloride,ifthe
serumpotassiumislessthan5.3mEq/L,administeredovertwohours.
ThevenouspHandbicarbonateconcentrationshouldbemonitoredeverytwohours,andbicarbonatedosescan
berepeateduntilthepHrisesabove7.00(see'Monitoring'below).Whenthebicarbonate(HCO3)concentration
increases,theserumKmayfallandmoreaggressiveKClreplacementmayberequired.
TheindicationsforbicarbonatetherapyinDKAarecontroversial[34],andevidenceofbenefitislacking[3537].In
arandomizedtrialof21DKApatientswithanadmissionarterialpHbetween6.90and7.14(mean7.01),
bicarbonatetherapydidnotchangemorbidityormortality[35].However,thestudywassmall,limitedtopatients
withanarterialpH6.90andabove,andtherewasnodifferenceintherateofriseinthearterialpHandserum
bicarbonatebetweenthebicarbonateandplacebogroups.Noprospectiverandomizedtrialshavebeenperformed
concerningtheuseofbicarbonateinDKAwithpHvalueslessthan6.90.
Bicarbonateadministrationisalsocontroversialbecauseinadditiontolackofevidenceforbenefit,thereare
severalpotentialharmfuleffects:
Ifbicarbonateinfusionsuccessfullyincreasesthebloodbicarbonateconcentration,thiscanreducethe
hyperventilatorydrive,whichwillraisethebloodpCO2.IncreasedbloodCO2tensionismorequickly
reflectedacrossthebloodbrainbarrierthantheincreasedarterialHCO3.Thismaycauseaparadoxicalfallin
cerebralpH.Althoughneurologicdeteriorationhasbeenattributedtothismechanism,itremainsavery
controversialeffectand,ifitoccurs,israre[38].
Theadministrationofalkalimayslowtherateofrecoveryoftheketosis[39,40].Inastudyofsevenpatients,
thethreepatientstreatedwithbicarbonatehadariseinserumketoacidanionlevelsandasixhourdelayin
resolutionofketosis[39].Animalstudiesindicatethatbicarbonateinfusioncanaccelerateketogenesis.This
isthoughttoberelatedtothefactthatacidemiahasabrakingeffectonorganicacidosis.Thisbrakeis
lessenedbyanymaneuverthatincreasessystemicpH[35].
Alkaliadministrationcanleadtoaposttreatmentmetabolicalkalosis,sincemetabolismofketoacidanions
withinsulinresultsinthegenerationofbicarbonateandspontaneouscorrectionofmostofthemetabolic
acidosis.(See"Diabeticketoacidosisandhyperosmolarhyperglycemicstateinadults:Epidemiologyand
pathogenesis",sectionon'Aniongapmetabolicacidosis'.)
Thereare,however,selectedpatientswhomaybenefitfromcautiousalkalitherapy[38].Theyinclude:
PatientswithanarterialpH6.9inwhomdecreasedcardiaccontractilityandvasodilatationcanfurther
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impairtissueperfusion[41,42].AtanarterialpHabove7.00,mostexpertsagreethatbicarbonatetherapyis
notnecessary,sincetherapywithinsulinandvolumeexpansionlargelyreversethemetabolicacidosis[43].
Patientswithpotentiallylifethreateninghyperkalemia,sincebicarbonateadministrationinacidemicpatients
maydrivepotassiumintocells,therebyloweringtheserumpotassiumconcentration[44].(See"Treatment
andpreventionofhyperkalemiainadults".)
PhosphatedepletionBasedupontheobservationsdescribedbelow,wedonotrecommendtheroutineuseof
phosphatereplacementinthetreatmentofDKAorHHS.However,phosphatereplacementshouldbestrongly
consideredifseverehypophosphatemiaoccurs(serumphosphateconcentrationbelow1.0mg/dLor0.32mmol/L),
especiallyifcardiacdysfunction,hemolyticanemia,and/orrespiratorydepressiondevelop[4549].Whenneeded,
potassiumorsodiumphosphate20to30mEqcanbeaddedto1LofIVfluid.
Althoughwholebodyphosphatedepletioniscommoninuncontrolleddiabetesmellitus,theserumphosphate
concentrationmayinitiallybenormalorelevatedduetomovementofphosphateoutofthecells[8,46].Aswith
potassiumbalance,phosphatedepletionandhypophosphatemiaarerapidlyunmaskedfollowingtheinstitutionof
insulintherapyandIVvolumeexpansion.Thisfrequentlyleadstoasymptomatichypophosphatemia,which
graduallyresolves.(See"Signsandsymptomsofhypophosphatemia".)
ProspectiverandomizedtrialsofpatientswithDKAhavefailedtoshowabeneficialeffectofphosphate
replacementonthedurationofketoacidosis,doseofinsulinrequired,therateoffallofserumglucose,morbidity,
ormortality[5052].Inaddition,phosphatereplacementmayhaveadverseeffects,suchashypocalcemiaand
hypomagnesemia[50,5355].Consequently,routinereplacementisnotindicated.Whenthepatientstabilizes,
phospaterichfoodsuchasdairyproductsandalmondsmayberecommended.
MONITORING
GeneralTheserumglucoseshouldinitiallybemeasuredeveryhouruntilstable,whileserumelectrolytes,blood
ureanitrogen(BUN),creatinine,andvenouspH(fordiabeticketoacidosis[DKA])shouldbemeasuredeverytwoto
fourhours,dependingupondiseaseseverityandtheclinicalresponse[1,10].Theeffectiveplasmaosmolality
(posm)canbeestimatedfromthesodiumandglucoseconcentrations,usingthefollowingequations,depending
upontheunitsforsodium(Na)andglucose:
EffectivePosm=[2xNa(mEq/L)]+[glucose(mg/dL)18]
EffectivePosm=[2xNa(mmol/L)]+glucose(mmol/L)
Fortheseequations,theNaistheactualmeasuredplasmasodiumconcentrationandnotthecorrectedsodium
concentration.
Itisstronglysuggestedthataflowsheetoflaboratoryvaluesandclinicalparametersbeutilized,becauseitallows
bettervisualizationandevaluationoftheclinicalpicturethroughouttreatmentofDKA(form1).
RepeatarterialbloodgasesareunnecessaryduringthetreatmentofDKAvenouspH,whichisabout0.03units
lowerthanarterialpH[56],isadequatetoassesstheresponsetotherapyandavoidsthepainandpotential
complicationsassociatedwithrepeatedarterialpunctures.Iftheresultsofbloodchemistriescanbereturnedina
timelyfashion,analternativetomonitoringvenouspHismonitoringtheserumbicarbonateconcentration(to
assesscorrectionofthemetabolicacidosis)andtheserumaniongap(toassesscorrectionoftheketoacidemia).
Whereavailable,bedsideketonemetersthatmeasurecapillarybloodbetahydroxybutyratemaybeaconvenient
methodformonitoringtheresponsetotreatment[14].Whenameterisavailable,betahydroxybutyratecanbe
measuredeverytwohoursdependingontheclinicalresponse.However,limitationsincludehighinterindividual
variationatconcentrationsabove3mmol/Landpotentialinterferencefromacetoacetate[57].Inhospitalswhere
bedsidemetersarenotavailable,monitoringvenouspHandaniongapissufficient.
ResolutionofketoacidosisinDKAThehyperglycemiccrisisisconsideredtoberesolvedwhenthefollowing
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goalsarereached:
Theketoacidosishasresolved,asevidencedbynormalizationoftheserumaniongap(lessthan12mEq/L)
andbloodbetahydroxybutyratelevels.
Patientswithhyperosmolarhyperglycemicstate(HHS)arementallyalertandtheplasmaeffectiveosmolality
hasfallenbelow315mosmol/kg.
Thepatientisabletoeat.
Thedisappearanceofketoacidanionsintheserumandcorrectionoftheketoacidosiscanbemonitoredby
measuringvenouspH,betahydroxybutyratedirectly,and/orserumelectrolytesandbicarbonateconcentrations
withcalculationoftheserumaniongap.Theserumaniongapprovidesanestimateofthequantityofunmeasured
anionsintheplasma.Itiscalculatedbysubtractingthemajormeasuredanions(chlorideandbicarbonate)fromthe
majormeasuredcation(sodium).Thesodiumconcentrationusedforthiscalculationistheconcentrationreported
bythelaboratory,notthecorrectedsodiumconcentration.
Accumulationofketoacidanionsincreasestheaniongapaboveitsbaseline,andtheincrementreflectstheir
concentrationinserum.Monitoringtheaniongapwillprovideareasonableestimateofchangesintheserum
ketoacidanionconcentrations.Theaniongapreturnstothenormalrangewhenketoacidanionshavedisappeared
fromtheserum.However,ifnitroprussidetestingforketonesisutilized,ketonemiaandketonuriamaypersistfor
morethan36hoursduetothesloweliminationofacetone,mainlyviathelungs[58,59].Sinceacetoneisnotan
acid,itdoesnotcausemetabolicacidosis,andapersistentketonetestduetoacetonedoesnotindicate
ketoacidosis.Enzymaticmeasurementofbetahydroxybutyrateobviatesthisissue.Directmeasurementofbeta
hydroxybutyrateinthebloodisthepreferredmethodformeasuringthedegreeofketonemia.Duringinsulin
therapy,betahydroxybutyrateisconvertedtoacetoacetate,resultinginanincreasinglypositivenitroprussidetest
foracetoacetateasketosisisimproving(figure1)[25].Asaresult,assessmentsofurinaryorserumketonelevels
bythenitroprussidemethodshouldnotbeusedformonitoringresolutionofDKA.
Intheabsenceofendstagerenaldisease,almostallpatientsdevelopanormalaniongapacidosis("nongapor
hyperchloremicacidosis")withresolutionoftheketoacidosis.Thisoccursbecauseaggressiveintravenous(IV)
volumeexpansionreversestheirvolumecontractedstateandimprovesrenalfunction,whichacceleratesurinary
ketoacidanionlosses[60,61].Insulintherapywillhavenofurthereffectontheacidosiswhenthisstageevolves.
Thehyperchloremicacidosiswillslowlyresolveasthekidneysexcreteammoniumchloride(NH4Cl)and
regeneratebicarbonate.
ConvertingtosubcutaneousinsulinWeinitiateamultipledosesubcutaneous(SQ)insulinschedulewhen
theketoacidosishasresolvedandthepatientisabletoeat(see'ResolutionofketoacidosisinDKA'above).For
patientswithHHS,IVinsulininfusioncanbetaperedandamultipledoseSQinsulinschedulestartedwhenthe
serumglucosefallsbelow250to300mg/dL(13.9to16.7mmol/L).TheIVinsulininfusionshouldbecontinuedfor
onetotwohoursafterinitiatingtheSQinsulin,becauseabruptdiscontinuationofIVinsulinacutelyreducesinsulin
levelsandmayresultinrecurrenceofhyperglycemiaand/orketoacidosis.Ifthepatientisunabletoeat,itis
preferabletocontinuetheIVinsulininfusion.
TheAmericanDiabetesAssociation(ADA)guidelinesforDKArecommendthatIVinsulininfusionbetaperedand
amultipledoseSQinsulinschedulebestartedwhenthebloodglucoseis<200mg/dL(11.1mmol/L)andtwoof
thefollowinggoalsaremet[1]:
Serumaniongap<12mEq/L(orattheupperlimitofnormalforthelocallaboratory)
Serumbicarbonate15mEq/L
VenouspH>7.30
Patientswithknowndiabeteswhowerepreviouslytreatedwithinsulinmaybegiveninsulinatthedosetheywere
receivingbeforetheonsetofDKAorHHS.Ininsulinnaivepatients,amultidoseinsulinregimenshouldbestarted
atadoseof0.5to0.8U/kgperday,includingbolusandbasalinsulinuntilanoptimaldoseisestablished.
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However,goodclinicaljudgmentandfrequentglucoseassessmentisvitalininitiatinganewinsulinregimenin
insulinnaivepatients.(See"Generalprinciplesofinsulintherapyindiabetesmellitus"and"Managementofblood
glucoseinadultswithtype1diabetesmellitus",sectionon'DesigninganMDIinsulinregimen'and"Insulintherapy
intype2diabetesmellitus".)
COMPLICATIONSHypoglycemiaandhypokalemiaarethemostcommoncomplicationsofthetreatmentof
diabeticketoacidosis(DKA)andhyperosmolarhyperglycemicstate(HHS),andtheyhavebeenreduced
significantlysincetheadministrationoflowdoseinsulinandcarefulmonitoringofserumpotassium[62].
Hyperglycemiamayresultfrominterruptionordiscontinuationofintravenous(IV)insulinwithoutadequate
coveragewithsubcutaneous(SQ)insulin.
CerebraledemaCerebraledemainuncontrolleddiabetesmellitus(usuallyDKA,withoccasionalreportsin
HHS)isprimarilyadiseaseofchildren,andalmostallaffectedpatientsarebelowtheageof20years[63].
Symptomstypicallyemergewithin12to24hoursoftheinitiationoftreatmentforDKA,butmaybepresentpriorto
theonsetoftherapy.IssuesrelatedtocerebraledemainDKA,includingpathogenesis,arediscussedindetail
separatelyinthepediatricsectionbutwillbebrieflyreviewedhere.(See"Cerebraledemainchildrenwithdiabetic
ketoacidosis".)
Headacheistheearliestclinicalmanifestation,followedbylethargyanddecreasedarousal.Neurologic
deteriorationmayberapid,withseizures,incontinence,pupillarychanges,bradycardia,andrespiratoryarrest.
Thesesymptomsprogressifbrainstemherniationoccurs,andtherateofprogressionmaybesorapidthat
papilledemaisnotseen.
ThedevelopmentofcerebraledemainDKAhasamortalityrateof20to40percent[1].Thus,carefulmonitoring
forchangesinmentalorneurologicstatusthatwouldpermitearlyidentificationandtherapyofcerebraledemais
essential.
The2009AmericanDiabetesAssociation(ADA)guidelinesonhyperglycemiccrisesindiabetesinadults
suggestedthatthefollowingpreventivemeasuresmayreducetheriskofcerebraledemainhighriskpatients[1]:
Gradualreplacementofsodiumandwaterdeficitsinpatientswhoarehyperosmolar.Theusualregimenfor
thefirstfewhoursisisotonicsalineatarateof15to20mL/kgleanbodyweightperhour(about1000
mL/hourinanaveragesizedperson)withamaximumof<50mL/kginthefirsttwotothreehours(algorithm
1andalgorithm2).
Theadditionofdextrosetothesalinesolutiononcetheserumglucoselevelsreach200mg/dL(11.1mmol/L)
inDKAor250to300mg/dL(13.9to16.7mmol/L)inHHS.InHHS,theserumglucoseshouldbemaintained
at250to300mg/dL(13.9to16.7mmol/L)untilthehyperosmolalityandmentalstatusimproveandthe
patientisclinicallystable.
Dataevaluatingtheoutcomeandtreatmentofcerebraledemainadultsarenotavailable.Recommendationsfor
treatmentarebaseduponclinicaljudgmentintheabsenceofscientificevidence.Casereportsandsmallseriesin
childrensuggestbenefitfrompromptadministrationofmannitol(0.25to1.0g/kg)andperhapsfromhypertonic(3
percent)saline(5to10mL/kgover30min)[63].Theseapproachesraisetheplasmaosmolality,resultingin
osmoticmovementofwateroutofthebrainandareductionincerebraledema.
NoncardiogenicpulmonaryedemaHypoxemiaandrarelynoncardiogenicpulmonaryedemacancomplicate
thetreatmentofDKA[6466].Hypoxemiaisattributedtoareductionincolloidosmoticpressurethatresultsin
increasedlungwatercontentanddecreasedlungcompliance[12].PatientswithDKAwhohaveawidened
alveolararterialoxygengradientnotedoninitialbloodgasmeasurementorralesonphysicalexaminationappearto
beathigherriskforthedevelopmentofpulmonaryedema.
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasicsand
BeyondtheBasics.TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgrade
readinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.These
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articlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.Beyond
theBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewritten
atthe10thto12thgradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortable
withsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
patientinfoandthekeyword(s)ofinterest.)
Basicstopics(see"Patientinformation:Diabeticketoacidosis(TheBasics)"and"Patientinformation:
Hyperosmolarnonketoticcoma(TheBasics)")
SUMMARYANDRECOMMENDATIONS
Thetreatmentofdiabeticketoacidosis(DKA)andhyperosmolarhyperglycemicstate(HHS)aresimilar,
includingcorrectionofthefluidandelectrolyteabnormalitiesthataretypicallypresent,including
hyperosmolality,hypovolemia,metabolicacidosis(inDKA),andpotassiumdepletion,andtheadministration
ofinsulin(table3andalgorithm1andalgorithm2).Frequentmonitoringisessential,andunderlying
precipitatingeventsshouldbeidentifiedandcorrected.(See'Overviewandprotocols'above.)
Werecommendvigorousintravenous(IV)fluidreplacementtocorrectbothhypovolemiaandhyperosmolality
(Grade1A).Fluidreplacementshouldcorrectestimateddeficitswithinthefirst24hours,withcaretoavoid
anoverlyrapidreductionintheserumosmolality.(See'Fluidreplacement'above.)
Isotonicsalineshouldbeinfusedasquicklyaspossibleinpatientswithhypovolemicshock.Inhypovolemic
patientswithoutshock(andwithoutheartfailure),webeginwithisotonic(0.9percent)salineinfusedatarate
of15to20mL/kgperhour(about1000mL/hourinanaveragesizedperson)forthefirstcouplehours.Thisis
followedbyonehalfisotonic(0.45percent)salineatarateofabout250to500mL/houriftheserumsodium
isnormalorelevatedisotonicsalineiscontinuedatarateofabout250to500mL/hourifhyponatremiais
present.Weadddextrosetothesalinesolutionwhentheserumglucosereaches200mg/dL(11.1mmol/L)in
DKAor250to300mg/dL(13.9to16.7mmol/L)inHHS.(See'Fluidreplacement'above.)
Theneedforpotassiumrepletionmayinfluencethetimingofonehalfisotonicsalinetherapy,sincethe
additionofpotassiumtoisotonicsalinecreatesahypertonicsolutionthatcanworsentheunderlying
hyperosmolality.(See'Potassiumreplacement'above.)
PatientswithDKAorHHStypicallyhaveamarkeddegreeofpotassiumdepletionduetobothrenaland,in
somepatients,gastrointestinallosses.However,becauseofpotassiumredistributionfromthecellsintothe
extracellularfluid(ECF),theinitialserumpotassiumconcentrationisoftennormalorelevated,aneffectthat
willbereversedbyinsulintherapy.WerecommendthatreplacementwithIVpotassiumchloride(Grade1A)
beinitiatedwhentheserumpotassiumconcentrationis5.3mEq/L.Patientswithaninitialserumpotassium
below3.3mEq/Lshouldreceiveaggressivefluidandpotassiumreplacementpriortotreatmentwithinsulinto
preventinitialworseningofthehypokalemia.(See'Potassiumreplacement'above.)
WerecommendinitialtreatmentwithlowdoseIVinsulininallpatientswithmoderatetosevereDKAorHHS
whohaveaserumpotassium3.3mEq/L(Grade1B).Patientswithaninitialserumpotassiumbelow3.3
mEq/Lshouldreceiveaggressivefluidandpotassiumreplacementpriortotreatmentwithinsulin.(See
'Potassiumreplacement'above.)
TheinsulinregimenisthesameinDKAandHHS.Iftheserumpotassiumis3.3mEq/L,wegivea
continuousIVinfusionofregularinsulinat0.14U/kgperhouratthisdose,aninitialIVbolusisnot
necessary.AnalternativeoptionistoadministeranIVbolus(0.1U/kgbodyweight)ofregularinsulin,
followedbyacontinuousinfusionatadoseof0.1U/kgperhour.Thedoseisdoublediftheglucosedoesnot
fallby50to70mg/dL(2.8to3.9mmol/L)inthefirsthour.(See'Insulin'above.)
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AcosteffectivealternativetoIVinsulinintheinitialtreatmentofuncomplicatedDKAistheuseof
subcutaneous(SQ)rapidactinginsulinanalogs(insulinlispro,aspart,andglulisine)inselectedpatientsin
settingsinwhichadequatemonitoringcanbeassured.(See'Alternativestointravenousinsulin'above.)
Indicationsforsodiumbicarbonatetherapytohelpcorrectthemetabolicacidosisarecontroversial.We
suggesttreatmentwithIVsodiumbicarbonateinpatientswithanarterialpHlessthan6.9(Grade2B).(See
'Bicarbonateandmetabolicacidosis'above.)
Althoughwholebodyphosphatedepletionisusuallypresent,werecommendnotadministeringphosphate
routinely(Grade1A).Wesuggestphosphatereplacementforpatientswithseverehypophosphatemia(<1.0
mg/dL[0.32mmol/L]),respiratoryorcardiacfailure,orhemolyticanemia(Grade2C).(See'Phosphate
depletion'above.)
Monitoringinvolveshourlyglucosemeasurementuntilstable,andbasicchemistryprofile,andvenouspH(for
DKA)everytwotofourhours.Thecourseofketoacidemiacanbeassessedbydirectmeasurementofbeta
hydroxybutyrate,themajorcirculatingketoacid,and/ormeasurementoftheserumaniongap.Incontrast,
nitroprussidetabletsorreagentsticksshouldnotbeusedbecausetheyreactwithacetoacetateandacetone,
butnotwithbetahydroxybutyrate.Acetoneisbiochemicallyneutralanddoesnotcontributetothe
ketoacidosis.(See'Monitoring'above.)
WeinitiateamultipledoseSQinsulinschedulewhentheketoacidosishasresolvedandthepatientisableto
eat.ForpatientswithHHS,IVinsulininfusioncanbetaperedandamultipledoseSQinsulinschedule
startedwhentheserumglucosefallsbelow250to300mg/dL(13.9to16.7mmol/L).TheIVinsulininfusion
shouldbecontinuedforonetotwohoursafterinitiatingtheSQinsulin,toavoidrecurrenceofhyperglycemia.
(See'Convertingtosubcutaneousinsulin'above.)
Cerebraledemaisrareinadults,butisassociatedwithhighratesofmorbidityandmortality.Possible
preventivemeasuresinhighriskpatientsincludegradualratherthanrapidcorrectionoffluidandsodium
deficits(maximumreductioninplasmaosmolalityof3mosmol/kgperhour),andmaintenanceofaslightly
elevatedserumglucoseuntilthepatientisstable.(See'Cerebraledema'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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23. UmpierrezGE,JonesS,SmileyD,etal.Insulinanalogsversushumaninsulininthetreatmentofpatients
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26. BrownPM,TompkinsCV,JuulS,SnksenPH.Mechanismofactionofinsulinindiabeticpatients:adose
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NEnglJMed1977297:238.
32. UmpierrezGE,LatifK,StoeverJ,etal.Efficacyofsubcutaneousinsulinlisproversuscontinuous
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36. LeverE,JaspanJB.Sodiumbicarbonatetherapyinseverediabeticketoacidosis.AmJMed198375:263.
37. LatifKA,FreireAX,KitabchiAE,etal.Theuseofalkalitherapyinseverediabeticketoacidosis.Diabetes
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39. OkudaY,AdrogueHJ,FieldJB,etal.Counterproductiveeffectsofsodiumbicarbonateindiabetic
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44. FraleyDS,AdlerS.CorrectionofhyperkalemiabybicarbonatedespiteconstantbloodpH.KidneyInt1977
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45. KreisbergRA.Phosphorusdeficiencyandhypophosphatemia.HospPract197712:121.
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47. RAINEYRL,ESTESPW,NEELYCL,AMICKLD.Myoglobinuriafollowingdiabeticacidosiswith
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50. FisherJN,KitabchiAE.Arandomizedstudyofphosphatetherapyinthetreatmentofdiabeticketoacidosis.
JClinEndocrinolMetab198357:177.
51. KellerU,BergerW.Preventionofhypophosphatemiabyphosphateinfusionduringtreatmentofdiabetic
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52. WilsonHK,KeuerSP,LeaAS,etal.Phosphatetherapyindiabeticketoacidosis.ArchInternMed1982
142:517.
53. BarsottiMM.PotassiumphosphateandpotassiumchlorideinthetreatmentofDKA.DiabetesCare1980
3:569.
54. WinterRJ,HarrisCJ,PhillipsLS,GreenOC.Diabeticketoacidosis.Inductionofhypocalcemiaand
hypomagnesemiabyphosphatetherapy.AmJMed197967:897.
55. ZipfWB,BaconGE,SpencerML,etal.Hypocalcemia,hypomagnesemia,andtransienthypoparathyroidism
duringtherapywithpotassiumphosphateindiabeticketoacidosis.DiabetesCare19792:265.
56. MiddletonP,KellyAM,BrownJ,RobertsonM.Agreementbetweenarterialandcentralvenousvaluesfor
pH,bicarbonate,baseexcess,andlactate.EmergMedJ200623:622.
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58. SulwayMJ,MalinsJM.Acetoneindiabeticketoacidosis.Lancet19702:736.
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Topic1795Version23.0
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GRAPHICS
TypicallaboratorycharacteristicsofDKAandHHS*
DKA
Mild
Moderate
Severe
HHS
Plasmaglucose(mg/dL)
>250
>250
>250
>600
Plasmaglucose(mmol/L)
>13.9
>13.9
>13.9
>33.3
ArterialpH
7.25to
7.30
7.00to
7.24
<7.00
>7.30
Serumbicarbonate(mEq/L)
15to18
10to<15
<10
>18
Urineketones
Positive
Positive
Positive
Small
SerumketonesNitroprusside
reaction
Positive
Positive
Positive
Small
SerumketonesEnzymaticassay
ofbetahydroxybutyrate(normal
3to4
mmol/L
4to8
mmol/L
>8mmol/L
<0.6
mmol/L
Effectiveserumosmolality
(mOsm/kg)
Variable
Variable
Variable
>320
Aniongap
>10
>12
>12
Variable
Alterationinsensoriaormental
obtundation
Alert
Alert/drowsy
Stupor/coma
Stupor/coma
range<0.6mmol/L)
DKA:diabeticketoacidosisHHS:hyperosmolarhyperglycemicstate.
*TheremaybeconsiderablediagnosticoverlapbetweenDKAandHHS.
Nitroprussidereactionmethod.
NOTE:Manyassaysforbetahydroxybutyratecanonlyreportmarkedlyelevatedvaluesas>6.0
mmol/L.
Calculation:2[measuredNa(mEq/L)]+glucose(mg/dL)/18.
Calculation:(Na+)(Cl+HCO3)(mEq/L).Seetextfordetails.
Copyright2006AmericanDiabetesAssociation.FromDiabetesCareVol29,Issue12,2006.
InformationupdatedfromKitabchiAE,UmpierrezGE,MilesJM,FisherJN.Hyperglycemiccrisesinadult
patientswithdiabetes.DiabetesCare200932:1335.ReprintedwithpermissionfromtheAmerican
DiabetesAssociation.
Graphic72111Version7.0
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Typicaltotalbodydeficitsofwaterandelectrolytesindiabetic
ketoacidosisandhyperosmolarhyperglycemicstate*
DKA
HHS
Totalwater(L)
Water(mL/kg )
100
100to200
Na+(mEq/kg)
7to10
5to13
Cl(mEq/kg)
3to5
5to15
K+(mEq/kg)
3to5
4to6
PO4(mmol/kg)
5to7
3to7
Mg++(mEq/kg)
1to2
1to2
Ca++(mEq/kg)
1to2
1to2
*DataarefromEnnisetal(1994)andKreisberg(1978).
Perkilogramofbodyweight.
Copyright2006AmericanDiabetesAssociationFromDiabetesCareVol29,Issue12,2006.Reprinted
withpermissionfromtheAmericanDiabetesAssociation.
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Emergentdiabeticketoacidosis(DKA)managementinadults:rapid
overview
Clinicalfeatures
DKAusuallyevolvesrapidlyovera24hourperiod.
Common,earlysignsofketoacidosisincludenausea,vomiting,abdominalpain,and
hyperventilation.Theearliestsymptomsofmarkedhyperglycemiaarepolyuria,polydipsia,and
weightloss.
Ashyperglycemiaworsens,neurologicsymptomsappear,andmayprogresstoincludelethargy,
focaldeficits,obtundation,seizure,andcoma.
CommoncausesofDKAinclude:infectionnoncompliance,inappropriateadjustment,orcessation
ofinsulinnewonsetdiabetesmellitusandmyocardialischemia.
Evaluationandlaboratoryfindings
Assessvitalsigns,cardiorespiratorystatus,andmentalstatus.
Assessvolumestatus:vitalsigns,skinturgor,mucosa,urineoutput.
Obtainthefollowingstudies:serumglucose,urinalysisandurineketones,serumelectrolytes,BUN
andcreatinine,plasmaosmolality,mixedvenousbloodgas,electrocardiogramaddserumketones
ifurineketonespresent.
DKAischaracterizedbyhyperglycemia,anelevatedaniongapmetabolicacidosis,andketonemia.
Dehydrationandpotassiumdeficitsareoftensevere.
Serumglucoseisusuallygreaterthan250mg/dL(13.9mmol/L)andlessthan800mg/dL(44.4
mmol/L).Incertaininstances(eg,insulingivenpriortoemergencydepartmentarrival),the
glucosemaybeonlymildlyelevated.
Additionaltestingisobtainedbasedonclinicalcircumstancesandmayinclude:bloodorurine
cultures,lipase,chestxray.
Management
Stabilizethepatient'sairway,breathing,andcirculation.
ObtainlargeboreIV(16gauge)accessmonitorusingacardiacmonitor,capnography,andpulse
oximetry.
Monitorserumglucosehourly,andbasicelectrolytes,plasmaosmolality,andvenouspHeverytwo
tofourhoursuntilthepatientisstable.
DetermineandtreatanyunderlyingcauseofDKA(eg,pneumoniaorurinaryinfection,myocardial
ischemia).
Repletefluiddeficits:
GiveseverallitersofIVisotonic(0.9%)salineasrapidlyaspossibletopatientswithsignsof
shock.
GiveIVisotonic(0.9%)salineat15to20mL/kgperhour(ie,1to1.5Lperhourforan
averagesizedadult),intheabsenceofcardiaccompromise,forthefirstfewhoursto
hypovolemicpatientswithoutshock.
Afterintravascularvolumeisrestored,giveonehalfisotonic(0.45%)salineat4to14mL/kg
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perhourifthecorrectedserumsodium*isnormalorelevatedisotonicsalineiscontinuedif
thecorrectedserumsodium*isreduced.
Adddextrosetothesalinesolutionwhentheserumglucosereaches~200mg/dL(11.1
mmol/L).
Repletepotassium(K+)deficits:
Regardlessoftheinitialmeasuredserumpotassium,patientswithDKAhavealargetotalbody
potassiumdeficit.
IfinitialserumK+isbelow3.3mEq/L,holdinsulinandgivepotassiumchloride20to40
mEq/hourIVuntilK+concentrationisabove3.3mEq/Lrarely,additionalpotassium
supplementationmaybenecessarytoavoidlifethreateningmuscleweaknessandcardiac
arrhythmias.
IfinitialserumK+isbetween3.3and5.3mEq/L,givepotassiumchloride20to30mEqper
literIVfluidmaintainserumK+between4to5mEq/L.
IfinitialserumK+isabove5.3mEq/L,donotgivepotassiumcheckserumK+every2
hoursdelayadministrationofpotassiumchlorideuntilserumK+hasfallento5to5.2mEq/L.
Giveinsulin:
DonotgiveinsulinifinitialserumK+isbelow3.3mEq/LrepleteK+andfluiddeficitfirst.
GiveallpatientswithoutaserumK+below3.3mEq/Lregularinsulin.Eitheroftworegimens
canbeused:0.1units/kgIVbolus,thenstartacontinuousIVinfusion0.1units/kgperhour
ORdonotgivebolusandstartacontinuousIVinfusionatarateof0.14units/kgperhour.
Ifserumglucosedoesnotfallbyatleast50to70mg/dL(2.8to3.9mmol/L)inthefirsthour,
doubletherateofinsulininfusion.
Whentheserumglucosereaches200mg/dL(11.1mmol/L),itmaybepossibletodecrease
theinfusionrateto0.02to0.05units/kgperhour.
Continueinsulininfusionuntilketoacidosisisresolved,serumglucoseisbelow200mg/dL
(11.1mmol/L),andsubcutaneousinsulinisbegun.
GivesodiumbicarbonatetopatientswithpHbelow6.90:
IfthearterialpHisbelow6.90,give100mEqofsodiumbicarbonateplus20mEqof
potassiumchloridein400mLsterilewaterovertwohoursmayberepeatedifvenouspH
remainsbelow7.00.
BUN:bloodureanitrogenDKA:diabeticketoacidosisIV:intravenousK:potassiumNa:sodium.
*SerumNa+shouldbecorrectedforhyperglycemiaforeach100mg/dLserumglucoseexceeds100
mg/dL(5.5mmol/L),add2mEqtoplasmaNa+forcorrectionofNa+valueforhyperglycemia.A
calculatortodetermineserumNa+correctedforhyperglycemiaisavailableseparatelyinUpToDate.
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ProtocolforthemanagementofadultpatientswithDKA
DKAdiagnosticcriteria:Serumglucose>250mg/dL,arterialpH<7.3,serumbicarbonate<18mEq/L,and
laboratoryvaluesvarychecklocallabnormalrangesforallelectrolytes.
BUN:bloodureanitrogenDKA:diabeticketoacidosisHCO 3 :bicarbonateIV:intravenousK:potassiumNa:sodium
subcutaneous.
*Afterhistoryandphysicalexam,obtaincapillaryglucoseandserumorurineketones(nitroprussidemethod).Begin
arterialbloodgases,completebloodcountwithdifferential,urinalysis,serumglucose,BUN,electrolytes,chemistrypr
chestradiograph,andspecimensforbacterialcultures,asneeded.
SerumNa +shouldbecorrectedforhyperglycemia(foreach100mg/dLglucose>100mg/dL,add2.0mEqtosodiu
AnalternativeIVinsulinregimenistogiveacontinuousintravenousinfusionofregularinsulinat0.14units/kg/ho
necessary.
100mmolsodiumbicarbonate=100mEqsodiumbicarbonate.
Copyright2006AmericanDiabetesAssociationFromDiabetesCareVol29,Issue12,2006.ModificationsfromDia
permissionfromtheAmericanDiabetesAssociation.
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ProtocolforthemanagementofadultpatientswithHHS
HHSdiagnosticcriteria:serumglucose>600mg/dL,arterialpH>7.3,serumbicarbonate
>15mEq/L,andminimalketonuriaandketonemia.Normallaboratoryvaluesvarycheck
locallabnormalrangesforallelectrolytes.
BUN:bloodureanitrogenHHS:hyperosmolarhyperglycemicstateIV:intravenousK:
potassiumNa:sodiumNaCl:sodiumchlorideSC:subcutaneous.
*Afterhistoryandphysicalexam,obtaincapillaryglucoseandserumorurineketones(nitroprusside
method).Beginoneliterof0.9percentNaCloveronehouranddrawarterialbloodgases,complete
bloodcountwithdifferential,urinalysis,serumglucose,BUN,electrolytes,chemistryprofileand
creatininelevelsSTAT.Obtainelectrocardiogram,chestradiograph,andspecimensforbacterial
cultures,asneeded.
SerumNa +shouldbecorrectedforhyperglycemia(foreach100mg/dLglucose>100mg/dL,add
2.0mEqtosodiumvalueforcorrectedserumsodiumvalue).
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AnalternativeIVinsulinregimenistogiveacontinuousintravenousinfusionofregularinsulinat
0.14units/kgperhouratthisdose,aninitialintravenousbolusisnotnecessary.
Copyright2006AmericanDiabetesAssociationFromDiabetesCareVol29,Issue12,2006.
ModificationsfromDiabetesCareVol32,Issue7,2009.ReprintedwithpermissionfromtheAmerican
DiabetesAssociation.
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Patientdataflowsheet
*A:AlertD:DrowsyS:StuporousC:Comatose.
D:DeepS:ShallowN:Normal.
[2xNa(meq/L)]+[glucose(mg/dL)18].
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Ketoneresponsetotreatmentofdiabeticketoacidosis
Comparativedatain37patientswithdiabeticketoacidosiswithregardtoplasma
acetoaceticacid(AA)andhydroxybutyricacid(OH)(topleft)ratioofAAtoOH
(bottomleft)andketonebodies(nitroprussidereaction)intheurine(topright)and
plasma(bottomright)beforeandduringlowdoseintravenousinfusionofinsulinfor48
hours.
Reproducedwithpermissionfrom:KitabchiAE,FisherJN,MurphyMB,etal.Diabeticketoacidosis
andthehyperglycemichyperosmolarnonketoticstate.In:Joslin'sDiabetesMellitus,13thedition,
KahnCR,WeirGC(Eds),LeaandFebiger,Philadelphia1994.Copyright1994LippincottWilliams
&Wilkins.www.lww.com.
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Disclosures
Disclosures:AbbasEKitabchi,PhD,MD,FACP,MACENothingtodisclose.IrlBHirsch,MDGrant/Research/ClinicalTrialSupport:
Sanofi[Diabetes(Glargine,glulisine)]NovoNordisk[Diabetes(Detemir,aspart,liraglutide)].Consultant/AdvisoryBoards:Abbott[Diabetes
(Glucoseteststrips)]Roche[Diabetes(Glucoseteststrips)]Valeritas[Diabetes(Insulinpumps)].MichaelEmmett,MD
Consultant/AdvisoryBoards:ZSPharma[treatmentofhyperkalemia(potassiumbinder,zirconiumsilicate)].DavidMNathan,MD
Nothingtodisclose.JeanEMulder,MDNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthrougha
multilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriatelyreferenced
contentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy
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Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State in Adults - Treatment

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