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
Filefailedtoload:file:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20fluid%20and%20ventilatory%20requirements%20in%20pediatric%20vasodilatory%20se
comparedtotheACCMapproach.
le:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20uid%20and%20ventilatory%20requirements%20in%20p 1/12
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
Filefailedtoload:file:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20fluid%20and%20ventilatory%20requirements%20in%20pediatric%20vasodilatory%20se
le:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20uid%20and%20ventilatory%20requirements%20in%20p 2/12
12/26/2016 Early norepinephrine decreases uid and ventilatory requirements in pediatric vasodilatory septic shock
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
Filefailedtoload:file:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20fluid%20and%20ventilatory%20requirements%20in%20pediatric%20vasodilatory%20se
le:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20uid%20and%20ventilatory%20requirements%20in%20p 3/12
12/26/2016 Early norepinephrine decreases uid and ventilatory requirements in pediatric vasodilatory septic shock
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
Filefailedtoload:file:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20fluid%20and%20ventilatory%20requirements%20in%20pediatric%20vasodilatory%20se
le:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20uid%20and%20ventilatory%20requirements%20in%20p 4/12
12/26/2016 Early norepinephrine decreases uid and ventilatory requirements in pediatric vasodilatory septic shock
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
Filefailedtoload:file:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20fluid%20and%20ventilatory%20requirements%20in%20pediatric%20vasodilatory%20se
balancebetweentheaugmentedpreloadeffects,directmyocardialinotropicandarteriolarvasoconstrictor
le:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20uid%20and%20ventilatory%20requirements%20in%20p 5/12
12/26/2016 Early norepinephrine decreases uid and ventilatory requirements in pediatric vasodilatory septic shock
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.
Filefailedtoload:file:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20fluid%20and%20ventilatory%20requirements%20in%20pediatric%20vasodilatory%20se
le:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20uid%20and%20ventilatory%20requirements%20in%20p 6/12
12/26/2016 Early norepinephrine decreases uid and ventilatory requirements in pediatric vasodilatory septic shock
Financialsupportandsponsorship Nil.
Conflictsofinterest Therearenoconflictsofinterest.
References
1.RanjitS,AramG,KissoonN,AliMK,NatrajR,ShrestiS,etal.Multimodalmonitoringfor
hemodynamiccategorizationandmanagementofpediatricsepticshock:Apilotobservationalstudy.
PediatrCritCareMed.201415:e1726.[PubMed:24196006]
2.RanjitS,KissoonN.Bedsideechocardiographyisusefulinassessingchildrenwithfluidandinotrope
resistantsepticshock.IndianJCritCareMed.201317:22430.[PMCID:PMC3796901]
[PubMed:24133330]
3.FunkDJ,JacobsohnE,KumarA.TheroleofvenousreturnincriticalillnessandshockPartI:
Physiology.CritCareMed.201341:25562.[PubMed:23269130]
4.FunkDJ,JacobsohnE,KumarA.Roleofthevenousreturnincriticalillnessandshock:PartIIshock
andmechanicalventilation.CritCareMed.201341:5739.[PubMed:23263572]
5.FolandFA,FortenberryJD,WarshawBL,NaipaulA,JeffersonLS,LoftisLL.Fluidoverloadbefore
continuoushemofiltrationandsurvivalincriticallyillchildrenaretrospectiveanalysis.CritCareMed.
200432:17716.[PubMed:15286557]
6.SinitskyL,WallsD,NadelS,InwaldDP.Fluidoverloadat48hoursisassociatedwithrespiratory
morbiditybutnotmortalityinageneralPICU:Retrospectivecohortstudy.PediatrCritCareMed.
201516:2059.[PubMed:25581632]
7.ArikanAA,ZappitelliM,GoldsteinSL,NaipaulA,JeffersonLS,LoftisLL.Fluidoverloadis
associatedwithimpairedoxygenationandmorbidityincriticallyillchildren.PediatrCritCareMed.
201213:2538.[PubMed:21760565]
8.DellingerRP,LevyMM,RhodesA,AnnaneD,GerlachH,OpalSM,etal.Survivingsepsiscampaign:
Internationalguidelinesformanagementofseveresepsisandsepticshock,2012.IntensiveCareMed.
201339:165228.[PubMed:23361625]
9.MaasJJ,GeertsBF,vandenBergPC,PinskyMR,JansenJR.Assessmentofvenousreturncurveand
meansystemicfillingpressureinpostoperativecardiacsurgerypatients.CritCareMed.200937:9128.
[PubMed:19237896]
10.MonnetX,JabotJ,MaizelJ,RichardC,TeboulJL.Norepinephrineincreasescardiacpreloadand
reducespreloaddependencyassessedbypassivelegraisinginsepticshockpatients.CritCareMed.
201139:68994.[PubMed:21263328]
11.PersichiniR,SilvaS,TeboulJL,JozwiakM,ChemlaD,RichardC,etal.Effectsofnorepinephrineon
meansystemicpressureandvenousreturninhumansepticshock.CritCareMed.201240:314653.
[PubMed:22926333]
12.HamzaouiO,GeorgerJF,MonnetX,KsouriH,MaizelJ,RichardC,etal.Earlyadministrationof
norepinephrineincreasescardiacpreloadandcardiacoutputinsepticpatientswithlifethreatening
hypotension.CritCare.201014:R142.[PMCID:PMC2945123][PubMed:20670424]
13.BrierleyJ,CarcilloJA,ChoongK,CornellT,DecaenA,DeymannA,etal.Clinicalpractice
parametersforhemodynamicsupportofpediatricandneonatalsepticshock:2007updatefromthe
AmericanCollegeofCriticalCareMedicine.CritCareMed.200937:66688.[PMCID:PMC4447433]
[PubMed:19325359]
14.DeyI,SprivulisP.Emergencyphysicianscanreliablyassessemergencydepartmentpatientcardiac
outputusingtheUSCOMcontinuouswaveDopplercardiacoutputmonitor.EmergMedAustralas.
200517:1939.[PubMed:15953218]
15.TheUSCOMandHaemodynamics.[Lastaccessedon2016Feb13].Availablefrom:
Filefailedtoload:file:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20fluid%20and%20ventilatory%20requirements%20in%20pediatric%20vasodilatory%20se
http://www.learnhemodynamics.com/The_USCOM_and_Haemodynamics.pdf.
le:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20uid%20and%20ventilatory%20requirements%20in%20p 7/12
12/26/2016 Early norepinephrine decreases uid and ventilatory requirements in pediatric vasodilatory septic shock
16.MarikPE,BaramM,VahidB.Doescentralvenouspressurepredictfluidresponsiveness.Asystematic
reviewoftheliteratureandthetaleofsevenmares?Chest.2008134:1728.[PubMed:18628220]
17.MarikPE,LemsonJ.Fluidresponsiveness:Anevolutionofourunderstanding.BrJAnaesth.
2014112:61720.[PubMed:24535603]
18.VergnaudE,VidalC,VerchreJ,MiatelloJ,MeyerP,CarliP,etal.Strokevolumevariationand
indexedstrokevolumemeasuredusingbioreactancepredictfluidresponsivenessinpostoperativechildren.
BrJAnaesth.2015114:1039.[PubMed:25315146]
19.SmithBE,MadiganVM.Noninvasivemethodforrapidbedsideestimationofinotropy:Theoryand
preliminaryclinicalvalidation.BrJAnaesth.2013111:5808.[PubMed:23645929]
20.BrierleyJ,PetersMJ.Distincthemodynamicpatternsofsepticshockatpresentationtopediatric
intensivecare.Pediatrics.2008122:7529.[PubMed:18829798]
21.TibbySM,HatherillM,MarshMJ,MurdochIA.Cliniciansabilitiestoestimatecardiacindexin
ventilatedchildrenandinfants.ArchDisChild.199777:5168.[PMCID:PMC1717412]
[PubMed:9496187]
22.HunterJD,DoddiM.Sepsisandtheheart.BrJAnaesth.2010104:311.[PubMed:19939836]
23.MerxMW,WeberC.Sepsisandtheheart.Circulation.2007116:793802.[PubMed:17698745]
24.KumarA,HaeryC,ParrilloJE.Myocardialdysfunctioninsepticshock:PartI.Clinicalmanifestation
ofcardiovasculardysfunction.JCardiothoracVascAnesth.200115:36476.[PubMed:11426372]
25.RabuelC,MebazaaA.Septicshock:Aheartstorysincethe1960s.IntensiveCareMed.200632:799
807.[PubMed:16570145]
26.VieillardBaronA.Septiccardiomyopathy.AnnIntensiveCare.20111:6.[PMCID:PMC3159902]
[PubMed:21906334]
27.KhilnaniP,SinghiS,LodhaR,SanthanamI,SachdevA,ChughK,etal.Pediatricsepsisguidelines:
Summaryforresourcelimitedcountries.IndianJCritCareMed.201014:4152.[PMCID:PMC2888329]
[PubMed:20606908]
28.DeBackerD,AldecoaC,NjimiH,VincentJL.Dopamineversusnorepinephrineinthetreatmentof
septicshock:Ametaanalysis.CritCareMed.201240:72530.[PubMed:22036860]
29.VenturaAM,ShiehHH,BoussoA,GesPF,FernandesI,deSouzaDC,etal.Doubleblind
prospectiverandomizedcontrolledtrialofdopamineversusepinephrineasfirstlinevasoactivedrugsin
pediatricsepticshock.CritCareMed.201543:2292302.[PubMed:26323041]
30.ChoongK,BohnD,FraserDD,GabouryI,HutchisonJS,JoffeAR,etal.Vasopressininpediatric
vasodilatoryshock:Amulticenterrandomizedcontrolledtrial.AmJRespirCritCareMed.2009180:632
9.[PubMed:19608718]
31.RedlWenzlEM,ArmbrusterC,EdelmannG,FischlE,KolacnyM,WechslerFrdsA,etal.The
effectsofnorepinephrineonhemodynamicsandrenalfunctioninseveresepticshockstates.IntensiveCare
Med.199319:1514.[PubMed:8315122]
32.BellomoR,WanL,MayC.Vasoactivedrugsandacutekidneyinjury.CritCareMed.200836(4
Suppl):S17986.[PubMed:18382191]
33.SanthanamI,SangareddiS,VenkataramanS,KissoonN,ThiruvengadamudayanV,KasthuriRK.A
prospectiverandomizedcontrolledstudyoftwofluidregimensintheinitialmanagementofsepticshockin
theemergencydepartment.PediatrEmergCare.200824:64755.[PubMed:19242131]
34.BealeR.Echoesofthepast?CritCareMed.200836:19501.[PubMed:18520645]
FiguresandTables
Filefailedtoload:file:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20fluid%20and%20ventilatory%20requirements%20in%20pediatric%20vasodilatory%20se
Figure1a
le:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20uid%20and%20ventilatory%20requirements%20in%20p 8/12
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
Filefailedtoload:file:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20fluid%20and%20ventilatory%20requirements%20in%20pediatric%20vasodilatory%20se
le:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20uid%20and%20ventilatory%20requirements%20in%20p 9/12
12/26/2016 Early norepinephrine decreases uid and ventilatory requirements in pediatric vasodilatory septic shock
HemodynamictreatmentpathwayforAmericanCollegeofCriticalCareMedicinecohortbasedonmultimodal
monitoringinpatientsshockrefractoryto4060ml/kgfluid
Figure2
Recruitmentandscreeningofstudypatientsinearlynorepinephrinegroup.eMMM:Extendedmultimodalmonitoring
Table1
Filefailedtoload:file:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20fluid%20and%20ventilatory%20requirements%20in%20pediatric%20vasodilatory%20se
le:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20uid%20and%20ventilatory%20requirements%20in%20 10/12
12/26/2016 Early norepinephrine decreases uid and ventilatory requirements in pediatric vasodilatory septic shock
Spectrum,microbiology,andtypeofinfectionsinearlynorepinephrinegroupandtheAmericanCollegeof
CriticalCareMedicinecohort
Table2
Filefailedtoload:file:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20fluid%20and%20ventilatory%20requirements%20in%20pediatric%20vasodilatory%20se
le:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20uid%20and%20ventilatory%20requirements%20in%20 11/12
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
Filefailedtoload:file:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20fluid%20and%20ventilatory%20requirements%20in%20pediatric%20vasodilatory%20se
le:///Users/MestyAriotedjo/Documents/septic%20shock/Early%20norepinephrine%20decreases%20uid%20and%20ventilatory%20requirements%20in%20 12/12