12/26/2016 Early norepinephrine decreases uid and ventilatory requirements in pediatric vasodilatory septic shock

IndianJCritCareMed.2016Oct20(10):561569. PMCID:PMC5073769
doi:10.4103/09725229.192036

Earlynorepinephrinedecreasesfluidandventilatoryrequirementsin
pediatricvasodilatorysepticshock
SuchitraRanjit,RajeswariNatraj,SathishKumarKandath,NiranjanKissoon,1BalasubramaniamRamakrishnan,2and
PaulE.Marik3

From:PediatricIntensiveCareUnit,ApolloChildren'sHospital,Chennai,TamilNadu,India
1
DepartmentofPediatricsandEmergencyMedicine,BCChildren'sHospital,SunnyHillHealthCentreforChildren,UniversityofBritish
Columbia,BCV6H3V4,Canada
2
DepartmentofMedicalEducation,ApolloHospitals,Chennai,TamilNadu,India
3
DepartmentofPulmonaryandCriticalCareMedicine,EasternVirginiaMedicalSchool,VA23507,USA
Correspondence:Dr.SuchitraRanjit,PediatricIntensiveCareandEmergencyServices,ApolloChildren'sHospital,GreamsRoad,Chennai
600006,TamilNadu,India.Email:suchitraranjit@yahoo.co.in

Copyright:2016IndianJournalofCriticalCareMedicine

ThisisanopenaccessarticledistributedunderthetermsoftheCreativeCommonsAttributionNonCommercialShareAlike3.0License,
whichallowsotherstoremix,tweak,andbuildupontheworknoncommercially,aslongastheauthoriscreditedandthenewcreationsare
licensedundertheidenticalterms.

Abstract

Aims:
Wepreviouslyreportedthatvasodilatationwascommoninpediatricsepticshock,regardlessofwhether
theywerewarmorcold,providingarationaleforearlynorepinephrine(NE)toincreasevenousreturn
(VR)andarterialtone.OurprimaryaimwastoevaluatetheeffectofsmallerfluidbolusplusearlyNE
versustheAmericanCollegeofCriticalCareMedicine(ACCM)approachtomoreliberalfluidboluses
andvasoactiveinotropicagentsonfluidbalance,shockresolution,ventilatorsupportandmortalityin
childrenwithsepticshock.Secondly,theimpactofearlyNEonhemodynamicparameters,urineoutput
andlactatelevelswasassessedusingmultimodalitymonitoring.

Methods:
Inkeepingwiththeprimaryaim,theearlyNEgroup(N27)receivedNEafter30ml/kgfluid,whilethe
ACCMgroup(N41)wereahistoricalcohortmanagedaspertheACCMGuidelines,whereafter40
60ml/kgfluid,patientsreceivedfirstlinevasoactiveinotropicagents.TheeffectofearlyNEwas
characterizedbymeasuringstrokevolumevariation(SVV),systemicvascularresistanceindex(SVRI)and
cardiacfunctionbeforeandafterNE,whichweremonitoredusingECHO+UltrasoundCardiacOutput
Monitor(USCOM)andlactates.

Results:
The6hrfluidrequirementintheearlyNEgroup(88.9+31.3to37.4+15.1ml/kg),andventilateddays
[median4days(IQR2.55.25)to1day(IQR11.7)]weresignificantlylessascomparedtotheACCM
group.However,shockresolutionandmortalityratesweresimilar.IntheearlyNEgroup,theoverall
SVRIwaslow(mean679.7dynes/sec/cm5/m2,SD204.5),andSVVdecreasedfrom23.88.2to18.59.7,
p=0.005withNEinfusionsuggestingimprovedpreloadevenwithoutfurtherfluidloading.Furthermore,
lactatelevelsdecreasedandurineoutputimproved.

Conclusion:
EarlyNEandfluidrestrictionmaybeofbenefitinresolvingshockwithlessfluidandventilatorsupportas
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comparedtotheACCMapproach.
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12/26/2016 Early norepinephrine decreases uid and ventilatory requirements in pediatric vasodilatory septic shock

Keywords:Criticalillness,fluidinfusion,morbidity,mortality,norepinephrine,pediatrics,sepsis,septic
shock,vasodilatory,venousreturn

IntroductionandAims
Wepreviouslyreportedthatvasodilationisapredominantfeaturein85%ofchildreninsepticshock.[1,2]
Venodilatationleadstoperipheralpoolingofbloodandrelativehypovolemiawhich,compoundedwith
arteriolarvasodilatation,exacerbateshypotension.[3,4]Whileliberalfluidsandvasoactiveagentsmaybe
beneficial,overrelianceoneithermayrealizeshorttermgainsbutmayincreasemorbidity.[5,6,7,8]Liberal
fluidsposegreaterrisksinregionswithlimitedventilatorcapabilities.Inviewofthepredominanceof
vasodilationinourcohort,wehypothesizedthatacombinationofinitialfluidbolusof30ml/kgplus
moderatedosesofnorepinephrine(NE)0.050.1mcg/kg/min(toimprovearterialtone,restorecardiac
preloadbyitsalphamediatedvenoconstriction,andprovidemodestinotropy)[3,4]wouldreversethe
disorderedphysiologywhilelimitingpositivefluidbalanceandneedforventilatorsupport.

Ourhypothesisissupportedbyreportsinadultsinwhomvasodilatorysepticshockiscommonandearly
NEimprovedpreloadandcardiacoutput(CO)withouttheneedforlargevolumefluidboluses.
[9,10,11,12]Wefeltthattheadultapproachwillbebeneficialascomparedtoourpreviousapproachwhich
wasbasedontheAmericanCollegeofCriticalCareMedicine(ACCM)guidelines[13]whereshock
refractorytoatleast4060ml/kgoffluidwastreatedwiththevariousinotropevasoactiveagent(s)
dependingonthebloodpressure(BP)andwhethertheextremitieswerecoldorwarmonclinical
examination.[1]

Ourstudyhadtwobroadaims.First,wecomparedmortality,shockresolution,6and24hfluidbalance,
anddurationofinvasiveventilationbetweentwogroups,theprospectiveearlyNEgroupversusthe
ACCMcohort(comprisingapreviouslypublishedcohortwhoweremanagedaspertheACCM
Guidelines).[1]

ThesecondpartcomparedpreandpostNEhemodynamicparameterswithintheearlyNEgroupusing
multimodalmonitoring(MMM),specificallytoassessfluidresponsiveness(FR)asasurrogateofpreload,
cardiacfunction,andsystemicvascularresistance(SVR)wealsomonitoredforadverseeffectsincluding
trendsinurineflowsandlactatelevels.

Methods
Setting Allpatientsweretreatedina10bedPediatricIntensiveCareUnit(PICU)ofatertiaryreferral
children'shospitalinChennai,India,fromApril2014toOctober2015.

TheInstitutionalEthicsCommitteeapprovedthestudyprotocolandsincestandarddrugsandnoninvasive
cardiacmonitoringwerebeingused,theneedforconsentwaswaived.

Patientselection FortheearlyNEgroup,consecutivepatientsaged1monthto16yearswithpresumed
infectionandunresolvedshockafter30ml/kgfluidwereincludedinthestudy.Themethodologyforthe
ACCMcohortwaspreviouslypublished.[1]ShockwasdefinedaccordingtotheACCM/Pediatric
AdvancedLifeSupport(PALS)guidelinesfordefiningseveresepsis.[13]

Exclusions OuraimwastostudyeffectofearlyNEonvasodilatoryshockhence,weexcluded
vasoconstrictedshock(basedonnarrowpulsepressure,definedpreviously)[1]includingdengueshock.
WealsoexcludedconditionswhereNEmightcauseworseningofcirculatorystatus,i.e.,cardiogenic
shock,moribundpatientsincludingneedforCPR.Otherexclusionswerepremorbidconditionsincluding
malaria,malnutrition,anemia,andwhereextendedMMMcouldnotbeperformedwithin4hofshock
recognition.

Protocolforsepticshockmanagement
Forbothgroups:Atbaseline,demographicandclinicaldata,hemodynamicstatus(extremity
perfusion,mentalstatus,heartrates,andBP),andpediatricriskofmortalityscoreswereenteredina
standarddatasheet.Thefirstdoseofbroadspectrumantibiotic(s)wereadministeredwithin1hof
shockrecognition,andsamplesweredrawnforrelevantcultures,bloodgasanalyses,andlactate
measurementsIntubationandventilationwereperformedforrespiratoryinsufficiencyorfor
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unresolvedshockdespite3040mL/kgfluidandtofacilitatethesafeuseofsedativesduring
invasivecatheterplacement.Patientswereventilatedinvolumecontrolledmodewithlung
protectivestrategies(tidalvolumes,68mL/kg)
Fortheearlynorepinephrinegroup[Figure1a]:Oneoftheauthors(SR,RN,andSKK)evaluated
thepatientswithunresolvedshockafter30ml/kgfluid,andiftherewerenoexclusions,NEwas
initiatedat0.050.1mcg/kg/minthroughaperipheralline.Ultrasoundcardiacoutputmonitor
(USCOM)monitoringwasalsoperformedinadditiontoMMM.Thetimebetweenthetwo
consecutivemeasurementsdidnotexceed2h.PeripheralNEinfusionwaschangedtocentralNEas
soonascentralaccesswassecured.IfshockwasunresolvedafterinitialfluidbolusplusNE,further
cardiovasculartherapy(fluid,inotrope,orpressor)wasdirectedbythefindingsofMMM
FortheACCMcohort[Figure1b]:Followingearlystabilizationincludingpointofcaretesting,
firsthourantibiotics,andrespiratorysupport,[1]atleast40ml/kgfluidswereinfused,and
inotropesvasopressorswereinitiated.[1,13]MMMwasperformedinorderoffercustomized
cardiovasculartherapyforthosewithunresolvedshock.

Multimodalmonitoring

Inbothgroups,patientswithunresolvedshockreceivedMMMwhichincludedclinicalassessment,
invasivearterialmonitoring,andfocusedechocardiography.FindingsfromMMMwereusedtoguide
furthertherapyinbothgroups.However,intheearlyNEgroup,tostudytheimpactofearlyNEonthe
circulation,allpatientswereadditionallymonitoredusingUSCOMbeforeandafterNEinfusion.

Authors(SR,RN,andSKK)weretrainedandcertifiedinICUsonology(basic+advanced)andalso
USCOMasperrecommendations.[14]Moreover,tominimizeobservervariability,thefirstauthor(SR),
whohadthemostexperienceinbothmodalities,evaluatedallimages.Onlythoseimagesthatwere
satisfactoryintermsofimagequalityandwereaccurateininterpretationwereincludedinthestudy.
DuringtheUSCOM,sinusrhythmwasconfirmed,spontaneousbreathingwasnotpermitted,andthetidal
volumeswereincreasedbrieflyupto8mL/kgprovidedtheplateaupressuresdidnotexceed30cmH2O.

TechniquesandnormalvaluesforUSCOMvariablesaredescribedintheUSCOMmanual.[15]

Parametersstudiedbymultimodalmonitoringandultrasoundcardiacoutputmonitor
Volumestatus:WeuseddynamicindicesofFRassurrogatesofcardiacpreload.[16,17]We
consideredthepatienttobefluidresponsiveifthestrokevolumevariation(SVV)was>15%,based
onpediatricstudies[18]
Cardiacfunction:CardiacfunctionwasassessedbyfocusedECHOdescribedpreviously[1]and
USCOMparameters(forearlyNEgroup)includingpeakvelocityandSmithMadiganinotropy
index(SMII)orinotropyindex(INO).TheSMIIorINOindexiscalculatedbytheUSCOM
softwareandrepresentsarapid,accurate,loadingindependentindextoquantifymyocardial
contractilitythatisexpressedinwatts/m2.[19]Wealsomonitoredstrokevolumeindexandcardiac
index(CI)[15,20]
Afterload:Vasodilatoryversusvasoconstrictedshockwasdeterminedbypulsepressureanddiastolic
BP[1]SVRindex(SVRI)wasderivedbytheUSCOMsoftware[15]
Physicalexamination:Physicalexaminationwasusedtoassessperfusionandlungmechanicsbefore
andafterNE
Tissueperfusion:Wemonitoredlactatetrends,andurineflowsassurrogatesoftissueperfusion.

Dataanalysis Inkeepingwithourstudyaims,twobroadsetsofanalyseswereperformed:

EarlyNEversusACCMcohort:Demographicsandoutcomescomparingfluidbalance,ventilator
support,PICUstay,andmortality
BeforeafterNEintragroupanalysis:WecomparedMMMfindingspreandpostNEtoassess
SVRI,SVV,andcardiacfunctionamongResponders(partial/completeshockreversal)andNon
responders(worseningofperfusion/shock).

Statisticalanalysis Theresultsareexpressedasmeanstandarddeviation(SD)ormedian(25thto75th
percentile)asappropriate.Bothsetsofcomparisons,EarlyNEversusACCMcohort,andBeforeafterNE
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intragroupanalysiswerecarriedoutusingpairedStudent'sttestortheWilcoxonsignedranktestas
appropriate.P<0.05wasconsideredstatisticallysignificant.

Results
FiftyfivepatientsinsepticshockwererecognizedintheERorPICU,ofwhich27patientswith
vasodilatoryshockunresolvedafter30ml/kgwereincludedinthestudy[Figure2],anddatafor41
patientsdescribedpreviously[1]constitutedtheACCMcohort.

AmericanCollegeofCriticalCareMedicinecohortversusearlynorepinephrinegroupcomparison T
herewasnodifferenceinbaselinedemographicsorseverityamongthetwogroups[Tables1and2].
Regardingearlyantibiotics,27/27patientsintheearlyNEgroupand40/41patientsintheACCMcohort
hadreceivedthefirstdoseantibiotic(s)withinthefirsthourofshockrecognition.Allpatientsreceived
earlyfluidbolusesandhadappropriatespecimensofculturesdrawn,metabolicderangementscorrected,
andrespiratorysupportinitiated.All27intheearlyNEgroupand38/41intheACCMcohortwere
intubatedandventilatedprincipallytofacilitatesafesedationforlineplacementorforrespiratory
insufficiency.

Table1showsthespectrum,microbiology,andtypeofinfectionsamongpatientsinbothgroups,and
Table2comparesdemographicsandoutcomesbetweentheearlyNEandACCMcohort.

Fluidvolumes,ventilatorsupport,andPediatricIntensiveCareUnitstay

Inadditiontothelimited1sthourfluidbolus,the6hfluidvolumes,and24hpositivefluidbalancewere
significantlylessintheearlyNEgroup,andinvasiveventilationandPICUdayswerealsosignificantly
lower[Table2].

Shockresolutionandmortality

Shockresolutionwassimilarandtherewasnodifferenceinmortalitybetweenthegroups.

Comparisonofhemodynamicsbeforeandafternorepinephrineinearlynorepinephrinegroup Table
3aandbcompareshemodynamicvariablesbeforeandafterNEamong22patientswhohadpartialor
completeimprovement(Responders),and5withworsenedhemodynamicparameters(Nonresponders).

a.SVRIchanges:Ofatotal27patients,17hadcoldshockand10hadwarmshockhowever,the
overallSVRIwaslow(mean679.7dynes/s/cm5/m2,SD204.5),thisincreased(mean873.57
dynes/s/cm5/m2,SD199)afterNEinfusion
b.Intravascularvolumechanges:TheSVVdeclinedsignificantlyalongwithimprovedperfusion
parameters[Table2],and19(70%)patientsdidnotrequireanyfurtherfluidaftertheinitial30
ml/kg.Additionalsmallvolumebolusesweregivento8patientswithunresolvedshockwhowere
stillfluidresponsivewithnofeaturesoffluidintolerance[Table3aandb]
c.CardiacfunctionresponsetoNEdependedontheintrinsiccontractility.Forinstance,among13
patientswithhyperdynamicshock,thesupranormalejectionfraction(EF)andCIvaluesdecreased
towithinnormalrange,andshockresolved.

Among14patientswithsepticmyocardialdysfunction(SMD),theresponsetoNEwasvariable.Four
patientswithmildsystolicdysfunctionresolvedwithNEalone,fivewithmoderateSMDshowedpartial
shockresolutionandrequiredadditionalinotropy(dobutamine/epinephrine)forcompleterecovery.

Fivepatientsmanifestedseverelydiminishedcardiacfunctionthatonlybecameapparentwhenafterload
increasedwithNE(Nonresponders,Table3b).TheunmaskingofthesevereunderlyingSMDinthesefive
patientsoccurredwithinanhourofNEinitiationandmanifestedasworseningperfusionandrespiratory
mechanics.ThedeteriorationincardiacfunctionwasconfirmedbybothECHOandUSCOM.Therapyin
allfiveincludedrapidadditionofmoreinotropes(epinephrineinfouranddobutamineinone)whilethe
NEdosewasreducedintwopatientsanddiscontinuedinthree.RepeatMMMdemonstratedimproved
cardiacfunctioninallfivepatients,andfourweredischargedalive.

Lactateandurineoutputafterearlynorepinephrine
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Lactatetrendsimprovedintheresponders[Table3a].Urineoutputincreasedonday1in24/27patients
andbyday3inanothertwopatients.

Threepatientshadmultiorganfailure(MOF)withacutekidneyinjury(AKI)requiringrenalreplacement
therapy(RRT)onday1,includingperitonealdialysisinoneandcontinuousRRTintwopatients.
However,therenalfunctionandurineoutputincreasedsufficientlysuchthatRRTcouldbediscontinued
within2448hintwopatients,thisincludedonepatientwhoreceivedNEplusadditionalvasopressin
(VP)forseverelydepressedSVRI.Thethirdpatientcontinuedtobeanuric,azotemic,andcouldnotbe
salvaged.

Shockresolutionandmortality

TherewasnodifferenceinshockresolutionormortalitybetweentheACCMcohortandEarlyNEgroup,
Table2.

Clinicaltrajectoryinnonsurvivors(bothgroups)

OfthethreenonsurvivorsinearlyNEgroup,twowithsevereburnsepsishadrapidshockresolutionwith
fluidandNE(plusinotropyinone)andwereextubatedandweanedoffvasoactiveinotropesbyday2and
day3,respectively.However,thepatientssufferedrepeatedepisodesofbacteremiaandMOFbothdied7
and9dayslater.Thethirdnonsurvivorhadseverecommunityacquiredpneumoniaanddiedat28hof
admissionofunresolvedcoldvasoplegicshockwithverylowSVRI(<400dynes/s/cm5/m2)thatfailedto
normalizeevenwithhighdoseNE,epinephrine,VP,andsteroids.

IntheACCMcohort,fourpatientsdied,includingtwowithunresolvedshockandtwowithhematological
malignanciesandoverwhelmingpulmonaryhemorrhage.[1]

Discussion
Inthispilotfeasibilitystudy,wecoulddemonstratethat,comparedtotheACCMcohort,thelimitedfluid
bolusandearlyNEapproachinpediatricvasodilatoryshockwasassociatedwithdecreasedpositivefluid
balanceanddaysonventilation,withnochangeinshockresolutionormortality.Moreover,usingUSCOM
beforeandafterNE,wecouldshowthattheoveralldiminishedSVRIincreased,SVVdecreased,andCI
improvedinthemajority,andthetreatmentwasassociatedwithdecreasinglactatelevelsandincreasing
urineoutputsuggestingfavorablephysiologiceffects.

WeusedthemodestfluidbolusesandearlyNEinall27casesregardlessofwhethertheywerecoldor
warm,providedtheywerevasodilated(basedonwidepulsepressures)thisincluded63%withcoldshock
onclinicalexamination.Thisapproachissupportedbyourpreviousreportedexperiencewhere85%of48
septicshockpatientswerevasodilatedwithwidepulsepressureoninvasivearterialpressuremonitoring
(including14/21withcoldshock),corroboratingotherreportsthatclinicalexaminationcanbeunreliable.
[1,21]Thepathophysiologicalrationaleofpatientswithvasodilatoryshockpresentingwithcoldshockis
providedinexcellentreviews.[3,4,22,23,24,25]

WithregardtohemodynamiccomparisonpreandpostNE,westudiedtheSVRI,FRusingSVV,and
cardiacfunction.WedemonstratedthattheSVRIafter30ml/kgfluidandbeforeNEinfusionswaslow,
reconfirmingthatvasodilatoryshockwaspredominantandjustifyingtheearlyNEbasedapproach.

Vasodilatoryshockinchildrenisnotuniquetoourpopulationandhasbeenreportedbyothers.For
instance,BrierleyandPetersreportedthatmostpatientswithhospitalacquiredinfectionshadlowSVRI
highCIshockandevenamongthecommunityacquiredinfections,64%hadlowornormalSVRI,rather
thantheexpectedhighvaluesfortheclinicalpictureofcoldshock.[20]Importantly,manypatientswere
receivingsignificantdosesofvasoactiveagents,lendingsupporttotheassumptionthatthetrueincidence
ofvasodilatoryshockmayhavebeenevenhigherbeforevasoactivetherapy.

WithrespecttovolumestatusintheearlyNEgroup,thefindingthattheelevatedSVVreducedafterNE
hadimportantimplications,suggestingthatNEcouldmimictheeffectoffluidloadingbyits
venoconstrictoreffectsmoreover,perfusionalsoimprovedin22/27responders.

TheeffectsofNEarenotalwayssalutaryandinagivenpatient,theCOchangeisdeterminedbythe
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balancebetweentheaugmentedpreloadeffects,directmyocardialinotropicandarteriolarvasoconstrictor
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effects.[4,9]

Thus,insomepatients,thegreatlydiminishedmyocardialreserveprecludesanincreaseinCOandhence
perfusioncanbesignificantlyreducedafterfluidsandNEadministration.[4,26]Indeed,inourstudy,while
4withmildSMDimprovedwithNEalone,10patients(37%)withmoderatetosevereSMDrequired
additionalinotropicagentsinadditiontoNEamongthese5hadsignificantdecompensationand
underlyingsevereSMDwasunmasked(Nonresponders)thiscouldbedetectedbyclinicalexamination
andimprovedwithadditionalinotropesandreduction/cessationofNEdose.Thattheseverelydiminished
heartfunctioncanbeeffectivelymaskedbythelowafterloadandrevealedfollowingNEinduced
vasoconstrictionhasbeenpreviouslyreported.[26]

DopamineistheinitialvasoactiveinopressoragentsuggestedintheACCMPALSGuidelines,[13]the
Indianconsensus,[27]andinourpreviousstudies.[1,2]However,recentlyit'susehasbeenquestioned,[28]
withahigherincidenceofhospitalacquiredinfectionsandmortalitywithdopamineversusepinephrine.
[29]PurevasopressorssuchasVPmayalsonotbeidealbecauseitcancausereductioninCOandeven
deathduetoabsentinotropyandincreasedafterload.[3,30]

RegardingthesafetyprofileofNEinsepticshock,despiteconcernsofrenalischemia,NEmayinfact
increaseurineoutputandimprovecreatinineclearanceinhyperdynamicsepticshock[31,32]andisthe
preferredagentforhypotensivevasodilatedpatientswithAKI.[32]Inourcohort,theimproved
hemodynamicsresultedinreducedlactatelevelsandimprovedurineoutputtherenalfunctionimproved
sufficientlyintwopatientsthatRRTcouldbediscontinued.Inaddition,theneedforlessfluidshortensthe
durationofmechanicalventilationanimportantconsiderationinareasoftheworldwherelackof
ventilatorscancontributetopooroutcomes.[27,33]

Therefore,wesuggestthatNEmaybethepreferredfirstlineinopressoragentinpediatricvasodilatory
septicshockafterearlylimitedvolumebolus,givenitsabilitytoaddressthederangedpathophysiologyby
increasingpreload,cardiaccontractility,coronaryperfusionandafterload,andwithoutdeteriorationin
urineflowsorlactates.[4,9,10,11,12,28,32]

Strengths EarlyNEandlimitedfluidbolusesarebothimportantdeparturesfromthestandardACCM
Guideline,andtojustifythatthisapproachworkedandwassafe,weusedextensiveMMMwithboth
ECHOandUSCOM.MMMwaslogisticallydifficult,challenging,andneverpreviouslyattempted
however,wedesignedthemethodologyacknowledgingthateachmonitoringmodalityhadunique
strengthsandlimitations,andmultimodalapproachmightbestprovideamorecomprehensive
hemodynamicpicture,[34]especiallyimportantwhenadifferentapproachwasattempted.

Further,wecoulddocumentthatNEcouldindeedmimicfluidloadingandminimizetheneedforinfused
fluids,thusgreatlydecreasingtimeonventilationandPICUdays,andwebelievethatthisfindinghas
importantimplicationsthatmustbeexploredinlargerstudies.Wealsoshowedthatlactateandurine
outputimprovedinthemajority,thusallayingfearsthatNEmightworsenischemia.

Limitationsandgeneralizability WeusedMMMprincipallytodeterminewhetherearlyNEafterlimited
volumeresuscitationwassafeandeffectiveinpediatricsepticshockandalsotoinvestigatetheimpactof
NEonvolumestatus,SVRI,andcardiacfunction.WedonotatallsuggestthatMMMbeincorporatedin
theearlyNEalgorithmasthiswillnotbegeneralizableorevenpractical.However,whileearlyNEis
beneficialinthemajoritywithpediatricvasodilatoryshock,intheeventthatthepatientfailstoimproveor
worsens,someformofhemodynamicmonitoringdependingonlocalexpertiseisimportanttohelpguide
furthercardiovasculartherapy(fluid,inotropeorpressor).

ConclusionsandClinicalImplicationsofOurStudy
Inachildwithsepticshock,thetraditionalorderoftherapyisliberalvolumeloadingfollowedby
inotropevasoactiveinfusionsdictatedbyphysicalexamination.WesuggestthatNEmaybeconsideredas
afirstchoiceinopressorafterlimitedfluidsinvasodilatoryshock(basedonwidepulsepressures),asthis
approachmaydecreasethevolumeoffluidsneededforresuscitationandthetimeonventilatorsupport.
Carefulbedsidemonitoringisemphasizedtodetectdeteriorationandinitiateappropriateinotropetherapy
forseverelyimpairedcardiaccontractilitythatmaybeunmaskedwithNE.
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Financialsupportandsponsorship Nil.

Conflictsofinterest Therearenoconflictsofinterest.

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FiguresandTables
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Figure1a
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12/26/2016 Early norepinephrine decreases uid and ventilatory requirements in pediatric vasodilatory septic shock

Treatmentprotocolforlimitedfluidandearlynorepinephrinecohort.eMMM:Extendedmultimodalmonitoring(physical
examination,focusedECHO+USCOM)USCOM:UltrasoundcardiacoutputmonitorFI:Fluidintolerance(featuresof
fluidoverloadorpulmonaryedema)SVRI:SystemicvascularresistanceindexIVC:InferiorvenacavaSVV:Stroke
volumevariation

Figure1b

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12/26/2016 Early norepinephrine decreases uid and ventilatory requirements in pediatric vasodilatory septic shock

HemodynamictreatmentpathwayforAmericanCollegeofCriticalCareMedicinecohortbasedonmultimodal
monitoringinpatientsshockrefractoryto4060ml/kgfluid

Figure2

Recruitmentandscreeningofstudypatientsinearlynorepinephrinegroup.eMMM:Extendedmultimodalmonitoring

Table1

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12/26/2016 Early norepinephrine decreases uid and ventilatory requirements in pediatric vasodilatory septic shock

Spectrum,microbiology,andtypeofinfectionsinearlynorepinephrinegroupandtheAmericanCollegeof
CriticalCareMedicinecohort

Table2

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12/26/2016 Early norepinephrine decreases uid and ventilatory requirements in pediatric vasodilatory septic shock

DemographicsandoutcomesbetweenearlynorepinephrinegroupandAmericanCollegeofCriticalCare
Medicinecohort

Table3a

Echocardiogramandultrasoundcardiacoutputmonitorparametersbeforeandafternorepinephrinein22
responders

Table3b

Echocardiogramandultrasoundcardiacoutputmonitorparametersbeforeandafternorepinephrineinfive
nonresponderswithseveresepticmyocardialdysfunction

ArticlesfromIndianJournalofCriticalCareMedicine:Peerreviewed,OfficialPublicationofIndianSocietyof
CriticalCareMedicineareprovidedherecourtesyofMedknowPublications

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