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PediatricSepsisGuidelines:Summaryforresourcelimitedcountries

IndianJCritCareMed.2010JanMar14(1):4152.

PMCID:PMC2888329

doi:10.4103/09725229.63029

PediatricSepsisGuidelines:Summaryforresourcelimitedcountries
PraveenKhilnani,SunitSinghi,RakeshLodha,IndumathiSanthanam,AnilSachdev,KrishanChugh,M.Jaishree,Suchitra
Ranjit,BalaRamachandran,UmaAli,SoonuUdani,RajivUttam,andSatishDeopujari
From:IAP(IntensiveCareChapter),B42PanchsheelenclaveNewDelhi110017,India
Correspondence:PraveenKhilnani,Chairperson,IAP(IntensivecareChapter)2008,B42Panchsheelenclave,NewDelhi110017,India.Email:
Khilnanip@hotmail.com
CopyrightIndianJournalofCriticalCareMedicine
ThisisanopenaccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense,whichpermitsunrestricteduse,distribution,and
reproductioninanymedium,providedtheoriginalworkisproperlycited.

ThisarticlehasbeencitedbyotherarticlesinPMC.

Abstract

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Justification:

Pediatricsepsisisacommonlyencounteredglobalissue.Existingguidelinesforsepsisseemtobeapplicabletothe
developedcountries,andonlyfewarticlesarepublishedregardingapplicationoftheseguidelinesinthedeveloping
countries,especiallyinresourcelimitedcountriessuchasIndiaandAfrica.
Process:

AnexpertrepresentativepaneldrawnfromalloverIndia,underaegisofIntensiveCareChapterofIndian
AcademyofPediatrics(IAP)mettodiscussanddrawguidelinesforclinicalpracticeandfeasibilityofdeliveryof
careintheearlyhoursinpediatricpatientwithsepsis,keepinginviewuniquepatientpopulationandlimited
availabilityofequipmentandresources.Discussionincludedissuessuchassepsisdefinitions,rapid
cardiopulmonaryassessment,feasibilityofearlyaggressivefluidtherapy,inotropicsupport,corticosteriodtherapy,
earlyendotrachealintubationanduseofpositiveendexpiratorypressure/mechanicalventilation,initialempirical
antibiotictherapy,glycemiccontrol,androleofimmunoglobulin,blood,andbloodproducts.
Objective:

Toachieveareasonableevidencebasedconsensusonthebasisofpublishedliteratureandexpertopinionto
formulatingclinicalpracticeguidelinesapplicabletoresourcelimitedcountriessuchasIndia.
Recommendations:

Pediatricsepsisguidelinesarepresentedintextandflowchartformatkeepingresourcelimitationsinmindfor
countriessuchasIndiaandAfrica.Levelsofevidenceareindicatedwhereverapplicable.Itisanticipatedthatonce
theguidelinesareusedandoutcomesdataevaluated,furthermodificationswillbenecessary.Itisplannedto
periodicallyreviewandrevisetheseguidelinesevery35yearsasnewbodyofevidenceaccumulates.
Keywords:Pediatric,sepsis,septicshock
Introduction
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Sepsisisacommonlyencounteredproblemandamajorcauseofmortalityin80%ofchildrenworldwide.[1,2]Till
date,publishedpediatricsepsisguidelinesaremostlyapplicabletodevelopedcountries.[3,4]Thereareno
publishedguidelinesforresourcelimitedcountries.Aperceivedneedforsimpleguidelinesparticularlyapplicable
toresourcelimitedcountriesinspiredtheIndianAcademyofPediatrics(IAP)IntensiveCareChaptertoformulate
suchguidelines.AnexpertrepresentativepanelappointedbyIAPIntensiveCareChapter,metinDelhionMay31,
2008toputtogetherevidencebasedpediatricsepsisguidelinessuitableforresourcelimitedsettings.
AimsandObjectives

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1.Toidentifylevelsofresourcelimitationsandfeasibilityofinterventions.
2.Toformulateguidelineswithreferencetoconsensussepsisdefinitions,rapidcardiopulmonaryassessment,
andmanagementofseveresepsisandshock.
AvailableResourceandLimitations

Severalresourcelimitationswereidentifiedsuchaslimitedavailabilityofpediatricintensivecareunit(PICU)beds,
[5]incontrasttodevelopedcountries,[6]inadequatetransportfacilities,[7]lackoftrainedpersonnel,medications,
monitors,infusionpumps,ventilators,andsupportservicessuchaslaboratory,bloodbank,andradiology[Figure1
].Inaddition,differencesinpatientpopulationandspectrumofdiseasessuchasmalariaanddenguewere
addressed.[8]Mostpatientswithdengueshocksyndromewouldrespondsimplytooxygenandfluidresuscitation,
whichmaynotbeasaggressiveasinsepticshock.[9]Thefluidmanagementmaybedifferentinpatientswith
malariaonestudysuggestsbenefitfortheuseofalbumin.[10]Asignificantnumberofchildrenaremalnourished
whotendtobesicker,[11,12]andthereareconcernsabouttheadverseeffectsofaggressivefluidtherapyinthese
children.ThecurrentWHOguidelinesonthemanagementofseveremalnutritionrecommendsmallfluidboluses
andthereafteruseofbloodtransfusion.[13]Finally,rampantmisuseofbroadspectrumantimicrobialsmakesiteven
morechallengingtotreatsepsiswithdrugresistantorganisms.Guidelinesweredevelopedkeepingabove
mentionedlimitationsinmind.
Figure1
Resourcesavailableatdifferentlevelsofhealthcarefacilitiesinresource
limitedcountriesandfeasibilityofmonitoringandinterventions.*Not
availableuniversallyatallleveltwofacilities
A.Sepsisdefinitions:DefinitionsofsepsisbasedonInternationalConsensusConference2005[14]are
presentedinTables13.
Table2
Agespecificupperand/orlowerlimitsofheartratetodefine
tachycardiaandbradycardia,respiratoryratetodefinetachypnea,and
systolicbloodpressuretodefinehypotensiona
Table1
Definitionsofsepsis

Table3
Organdysfunctioncriteria

B.Rapidcardiopulmonaryassessmentandclinicalexamination:Assessmentshouldbepromptand
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comprehensive.Duringclinicalassessmentonemustnotefollowingpoints:
1.Appearance:Restlessness,agitation,anxiety,progressivelethargy,anddecreasedresponsivenessare
signsofimpairedmentalstatus.
2.Airwaypatencyandstability.
3.Breathing:Respiratoryrateisincreasedinresponsetotissuehypoxiaandtocompensateformetabolic
acidosis.Progressiveworseningofrespiratorydistress(tachypnea,nasalflaring,suprasternal,
intercostal,andsubcostalretractions)withbilateralralesorwheezesorunequalbreathsoundson
auscultationaresignsofprimaryfocusofinfectioninlungs,orearlyacuterespiratorydistress
syndrome(ARDS).
4.Circulation(Cardiovascular):Heartrate,adequacyofcentralandperipheralpulse,systolicand
diastolicbloodpressure,skincolor,capillaryrefilltime(CRT),andtemperatureofextremitiesshould
benoted.
Tachycardiaoccursearlyinresponsetofallingcardiacoutputandisthemostsignificantphysical
findingsinsepticshock.
Bloodpressure:Afallinbloodpressureisalatemanifestationoflowcardiacoutputinchildren.
Childrencanpreventreductioninbloodpressurebyvasoconstriction,andanincreaseinheartrateand
mayhavefeaturesofpoorperipheralperfusioninpresenceofnormalbloodpressure.Diastolicblood
pressurefallsearlycausingwidepulsepressureasvasculartonebeginstodecrease.Systolicblood
pressurebeginstofallcausingnarrowpulsepressureoncehemodynamiccompromiseissevere.
Hepatomegalyandjugularvenousdistensionwithgalloprhythmmaysignifypredominantcardiac
involvementaspartofsepticmyocardialdepressionormyocarditis.
Petechialrashmaybepresentinmeningococcemiaordisseminatedintravascularcoagulation.
Capillaryrefilltime(CRT):Capillaryrefilltimeofmorethan3secisalwaysabnormal.Inwarmphase
ofsepticshock,CRTmaybenormalhowever,signsofhyperdynamiccirculation(boundingpulse,
widenedpulsepressure,andhyperdynamicapexbeat)arepresent.Warmshockifuntreatedwill
progresstocoldshock.Coldshockismorecommonthanwarmshock.Inolderchildren,cold
peripheries,poorlyfeltpulses,andprolongedCRTareharbingersofshock.
5.Urineoutput:Oliguriaiscommonandmayprogresstoanuria.Assessmentofurineoutputinlast6
hoursishelpful.
Inseverecases,patientmaypresentwithcardiopulmonaryfailureorcardiopulmonaryarrestboth
situationsneedaggressivehemodynamicsupportaswellasendotrachealintubationandventilatory
supportforsurvival.
Atimesensitiveprotocolizedapproachtoresolveshockinseveresepsisshouldbeimplementedwith
anefforttoresolveshockintheinitialhoursofresuscitationasitisassociatedwithsteepdeclinein
mortalityrate[1517](Level1).
C.GuidelinesforManagementofSevereSepsisandShock
Forsimplicitysake,componentsofthisflowchartaredividedintofoursteps(IIV)toaddressrecommended
interventionsaccordingtoclinicalcondition,time,andavailableresources[Flowchart:Figure2a,b].
GradingoftheliteratureandlevelsofrecommendationsisbasedonAmericanCollegeofCriticalCare
Medicine(ACCM)criteria[Table4].
Table4
ACCMguidelinesforevidencebasedmedicineratingsystemfor
strengthofrecommendationandqualityofevidencesupportingthe
references
Figure2a
IAPintensivecarechapterPediatricsepsisguidelinesforresourcelimitedcountries

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Figure2b
IAPintensivecarechapterPediatricsepsisguidelinesforresource
limitedcountries

STEP1:05min:

i.Recognizedepressedmentalstatusanddecreasedperfusionbyrapidcardiopulmonaryassessment.
ii.Beginhighflowoxygen(Level3).
iii.Establishintravenous/intraosseousaccess(Level2).
iv.Venturimasksornonrebreathingmaskmaybeusedforhighflowoxygentherapy(Level3).
Alloftheabovearereadilyachievableinfirst5minutes.
Ifairwayisunstableorthepatientislethargicorunresponsiveandadequateoxygenationandventilationisnot
achieved,bagvalvemaskventilationshouldbestartedandearlyendotrachealintubationandmechanical
ventilationshouldbeplanned(level3).Otherindicationsforintubationarehypotensiononarrivalorduring
therapy,convulsiveseizuresrefractorytotwodosesofbenzodiazepine,persistentlylowGlasgowComaScale
(GCS)oflessthaneightandsignsofincreasedintracranialpressure.Implementationofthisstepmaytake
additionaltimeencroachingupontheinterventionsexpectedinnext60minaspertheguidelines.
STEPII:540min:

i.Initialfluidresuscitation:Rapidinfusionof20mL/kgisotonicsalineeach,upto60mL/kg,titratedtoward
achievementoftherapeuticgoalsofshockresolution[Table5]orunlessralesorhepatomegalydevelop
(Level1).
Table5
Therapeuticendpointsofresuscitationofsepticshock
ii.Fluidtherapybyperipheralorintraosseousaccessshouldbeinitiatedwhileadequatecontrolofairway,and
breathingisbeingaccomplished.
iii.AsecondperipheralIVlineorcentrallineshouldbeestablishediffeasible(forpossibleinotrope:Dopamine)
(Level2).
iv.Antibioticsshouldbestarted(thirdgenerationcephalosporinandanaminoglycoside)(Level2).
v.Hypoglycemiaandhypocalcemiashouldbestarted(Level2).
Volumereplacementwith20mL/kgofisotonicsolutionssuchasnormalsalineorRingerslactatecanbesafely
givenandrepeatedifnecessary.Typically,4060mL/kgmayberequiredtocorrecthypovolemia[18]insomethe
needmaybeashighas120mL/kginfirsthour.Ithasbeensuggestedthatmalnourishedchildmaygetfluid
overloadedwithaggressivevolumereplacementcautionandaslowerrateofinfusionareadvised(Level3).This
issueneedstobesystematicallystudied.
Clinicalscenarioswherelargervolumesareneededtoachievetherapeuticendpointsarewarmsepticshockand
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shockduetogastrointestinalsepsis.Presenceofpulmonaryedemaandshockisanindicationthatmorefluidsmay
beneededtoresolveshock.[19]Repeatedassessmenthelpstodecidewhetherfurtherfluidsmaybegiven,or
stoppedandinotropeinitiatedandintubationandmechanicalventilationmaybeinitiated.Italsohelpstodecide
whetherfurtherfluidsmaybetitratedafterintubationandinotropeinfusion.[17,19]
i.Choiceoffluidforvolumereplacement
WerecommendthatisotoniccrystalloidsuchasRingersLactateorNormalsalinebeusedfortheinitialfluid
resuscitationinsepticshock(Level1).[9,18,20,21]
ii.Methodoffluidadministration
Wesuggestthatfluidsaregiveninbolusesof20mL/kg(Level1)inhypotensivepatientsasrapidlyaspossibleby
pullpushmethodusingathreewaystopcock(Level1),andinothersbygravitymethodover1520minshould
bepreferred(Level2).Infusionpumpsareidealbutnotalwaysavailable.
TheACCMguidelinesrecommendadministrationofthebolusesasfastaspossiblewhichcanonlybeadministered
bypullpushmethodusingathreewaystopcock.[22]However,arecentprospectivestudyfromIndiashowsthat
administrationoffluidsbypullpushmethodusingathreewaystopcockincreasedtheincidenceofhepatomegaly
/pulmonaryedemaandagreaterneedforintubation.[17]
Developmentofpulmonaryedemaandhepatomegalyshouldbeanticipatedduringfluidadministration.Insome
patients,evidenceofpulmonaryedemaandhepatomegalymaybepresentonarrival,asARDSandmyocardial
dysfunctionmaycoexistinseveresepsis.Clinicalsignssuggestiveofmyocardialdysfunctionorpulmonaryedema
onarrivaloritsdevelopmentduringfluidtherapyareshownin[Table6].
Table6
Signofpulmonaryedemaandmyocardialdysfunction
Otherpracticalwaystoassessfluidoverloadarejugularvenousdistension,heartsize,andpulmonarycongestion
onchestradiograph(Level3).MeasurementofCVPandbedsideechocardiographyshouldbeusedattertiarycare
centers,ifavailabletoassessadequacyofintravascularvolume,cardiacfunction,andsignsoffluidoverload(Level
2).
Patientswhodeveloppulmonaryedemaandhepatomegalyafterfluidbolusesshouldbeintubatedandgiven
positivepressureventilation.Caremustbetakentoprovideventilationwithpositiveendexpiratorypressure
(PEEP).[19,23]ThiscanbeachievedinresourcelimitedsettingusingtheusingselfinflatingbagwithPEEPvalve
orMaplesonCCircuit/Bain'scircuitifamechanicalventilatorisnotavailable.
Ifshockpersistsfollowing60mL/kgfluidandnosignsofpulmonaryedema/hepatomegalyarenoted,elective
intubationshouldbeperformed.Sinceshockcanworsenduringorfollowingintubation,initiationofanappropriate
inotropeinfusionoftenimprovesthesafetyprofileofthisprocedure,particularlyinwarmshock.
Achievementofalltherapeuticgoals[Table5]isneededtodefineshockresolutioninfluidandinotroperesponsive
shock.Discontinuingfluidtherapybasedonachievementofsomeandnotallthegoalsmayresultininadequate
resuscitation.
Earlyantibiotictherapyandinfectioncontrol

Antibioticsshouldbeadministeredwithin1houroftheidentificationofseveresepsis,ifpossible,afterappropriate
cultureshavebeenobtained(Level1).Earlyantibiotictherapyisascriticalforchildrenwithseveresepsisasitis
foradults.[24]
Choiceofinitialantibiotictherapy:Theinitialempiricantibiotictherapyshouldincludeoneormoredrugsthat
haveactivityagainstthelikelypathogensandthatpenetratethepresumedsourceofsepsis[Table7].Commonly
usedantibioticsincludeathirdgenerationcephalosporinsuchasceftriaxoneandanaminoglycosidesuchas
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amikacin(Level3).
SourceControl:Everypatientpresentingwithseveresepsisshouldbeevaluatedforthepresenceofafocusof
infectionthatisamenabletosourcecontrolmeasures,e.g.,drainageofanabscess,debridementofinfectednecrotic
tissue,removalofapotentiallyinfecteddevice,etc.
Hypoglycemia

Hypoglycemiashouldbecheckedforandcorrected(Level2).Hyperglycemiashouldbeavoided(Level2).
Hypoglycemiacanhavedevastatingneurologicalconsequencesandshouldbediagnosedearlyandtreated
immediately[25](Level1).Hypoglycemiahasbeenshowntobeassociatedwithmorbidityandmortalityin
criticallyillchildrenwithveryseverepneumonia,[26]malaria,andseverelyillmalnourishedchildren.[27]
Hyperglycemiaalsohasbeenshowntobeassociatedwithmorbidityandmortalityincriticallyillsimilartothe
hypoglycemia.[28,29]However,theeffectsofintensiveglucosecontrolonmortalityincriticallyillchildrenare
unknown,andinsulintherapymayresultinhypoglycemia.[30]Onemayconsideruseofinsulinonlyifthechild
hadsignificantglycosuriaandpolyurialeadingtodifficultyinfluidmanagement.
CalciumandHypocalcemia

Beforecardiacoutputandperfusionpressurearerestoredwithdrugs,ionizedhypocalcemiathatmightimpair
cardiacperformancesshouldbecorrected(Level2).
IonizedhypocalcemiaiscommoninneonatesandchildrenwithsepsisadmittedtoPICU.[31,32]Administrationof
calciuminsepticpatientswithionizedhypocalcemiamaytransientlyimprovebloodpressure.[33]However,thereis
noevidencetosuggestasurvivalbenefit.[34]
MonitoringandTherapeuticEndpoints

Meticulousclinicalmonitoringfortherapeuticendpointswithouthightechnologyfacilitieshasshownadramatic
reductioninmortalityinVietnamesechildrenpresentingwithmoderatedengueshocksyndrome[9]andinIndian
childrentreatedforsepticshock.[17]
EndpointssuchasO2saturation,andCVPcanbemonitoredatsecondarylevelfacilities.Useofcardiacmonitor
cangivereliablecontinuousheartrate(HR)record.Inabsenceofamonitor,HRcouldbedeterminedby
auscultationperiodicallythismaybedonebefore,during,andafterafluidbolushasbeenadministered.
BloodPressure:BPmonitoringassiststoregulaterateoffluidinfusion,theneedforvasoactiveagentsandfurther
titration.Invasodilatoryorwarmshock,withwidepulsepressurenarrowingofpulsepressureisanadditional
therapeuticgoal.
LimitationsofClinicalTherapeuticEndPoints

Alltheclinicalendpointsmaynotbeapplicableinsomepatients.
Whilenormalizationofheartrateisoneofthemostreliablesignsofshockresolution,othercausesoftachycardia
maybefever,anxiety,pain,andSIRS.Itmayalsobetheonlysignofongoingseizureactivityinasedated,muscle
relaxedchild.Antipyreticandanalgesics,antiseizuremedications,sourcecontrolandmother'scloseproximitycan
oftenhelpinachievementofnormalrangeofheartrateinappropriateclinicalscenarios.Ontheotherhandheart
rate,whichfallswithinthenormalrangeforage,inthepresenceofsevererespiratorydistressorimpending
respiratoryfailureandshock,isanominoussign(ofimminentcardiacarrest).
Poorperipheralperfusionmaybetheresultofcoolenvironmentaltemperaturesinveryyounginfants.Recognition
andresolutionofshockintheseyoungpatientswilldependonnormalizationofmentalstatus,respiratoryrates,and
heartrates.
Thereareconcernsabouttheuseofcapillaryrefillandpulsevolume,astheremaybesignificantinterobserver
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variability.[35]
Accurateurineoutputmonitoringbycatheterizationinfluidunresponsiveshockisuseful,especiallyinsettings
withoutaccesstoCVPmonitoring.
UnresolvedIssues

1.Timetoachievevarioustherapeuticendpointsmaybevariable.Therearenoevidencebasedguidelinesfor
definingexpectedtimeframeofresponseforeachofthemonitoringparameters.
2.Arterialbloodgases(ABGs)andlactateestimationsareavailableinafewcentersinothersthiscannotbe
used.Useofmixedvenousoxygensaturations(ScVO2)isstillbeyondreachofmostcenters.
3.Abilitytoplacecentrallinesparticularlysubclavianorinternaljugularveinisstilllimited.
4.Inchildrenwithshock,thenoninvasiveBPmeasurementsmaybeunreliableandinvasiveintraarterialBPis
idealitmaynotbefeasibleinmajorityofresourcelimitedcenters.
5.Echocardiographyfordeterminingthecardiacfillingisalsonotpracticalinmanycenters.
6.Precisetherapeuticendpointsforseverelymalnourishedchildrenareunknown.
STEPIII:4060min:

i.RecognizeFluidRefractoryShock:Begininotropebyintravenousorintraosseous(IO)routeDopamineup
to10g/kg/min(Level2).
ii.Obtaincentralvenousaccessandairwayifneededandfeasible(Level1).
Followingadequateintravascularvolumerepletion,continuedpresenceofhypotensionand/orpoorperfusion(fluid
refractoryshock)warrantstheconsiderationofvasoactivetherapy,whichshouldbegoaldirected.[36,37]
Theexpertgroupagreeswiththeuseofdopamineasthefirstlinevasopressorforfluidrefractoryhypotensive
shockinthesettingoflowsystemicvascularresistance.Childrenwithsepticshockmoreoftenhavemyocardial
dysfunctionandlowcardiacoutput.Hence,itispreferabletocombineinotropywithavasopressoreffect.
Dopaminewithorwithoutdobutaminecanbeusedasfirstlinedrugsforgivingthiskindofsupport(Level2).In
children,theagespecificinsensitivitytodopaminehastobekeptinmindbeforestartingdopamineparticularlyin
infants<6months.[3,38]
STEPIV:60minandBeyond

i.Recognizedopamineresistantshock.
ii.TransfertoPICU.
iii.Ifpossible,monitorCVP,echocardiography,meanarterialpressure(Level2).
iv.TitratefluidsandvasoactivedrugstoresolveshockbasedonCVP,echocardiographytoachievetherapeutic
goals.
v.Reversecoldshockresistanttodopamine(normalorlowbloodpressure)titratecentralepinephrine(0.05
0.3g/kg/min))(maximumdose1microgram/kg/min)(Level2).
(vi)Reversewarmshockwithwidepulsepressureand/orlowbloodpressurebytitratingcentralnorepinephrine
(Level2).
(v)Beginhydrocortisone(50mg/m2/24h)ifchildisatriskforabsoluteadrenalinsufficiency(Level2).
Whenachildinsepticshockdoesnotimproveandthegoalsoftreatmentarenotachievedevenafterdopamineand
ordobutamineinfusion,theshockislabeledasfluidrefractory,dopamine/dobutamineresistantshock.Dopamine
resistantshockmayreversewithepinephrineornorepinephrineinfusion[Figure2b].
Someofpediatricpatientsmayhaveadulttypemanifestationofhighcardiacoutput,vasodilatation,and
hypotension.Clinically,itwillmanifestastachycardia,flushcapillaryrefill,lowtolownormalbloodpressureand
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widepulsepressure(warmshock).Avasopressorsuchasnorepinephrineisthedrugofchoiceinsuchpatients.It
shouldbeusedonlytorestoreadequatevaluesofmeanarterialpressurethatissufficienttorestoreurineoutput.The
usualdoseis0.051.00g/kg/min.
Childrenwithsepticshockmoreoftenhavemyocardialdysfunctionwithintensecompensatoryvasoconstriction.
Thisleadstoastateoflowcardiacoutput,withhighcardiacfillingpressureandhighsystemicvascularresistance,
whichclinicallymanifestsastachycardia,signsofhypoperfusion,prolongedcapillaryrefill,coldextremitiesand
lowtolownormalbloodpressureandnarrowpulsepressure(coldshock).Aninotropesuchasepinephrineisthe
drugofchoice.Thedoserangeis0.051.00g/kg/min.
Thelowcardiacoutputstate,characterizedbypersistentnarrowpulsepressureand/orprolongedcapillaryrefill
evenafteruseofdopaminemaybeimprovedwithadditionofdobutamine(upto20g/kg/min)orlowdose
epinephrine(<0.3g/kg/min)(Level2B).
Atvariousstagesofsepsisorthetreatmentthereof,achildmaymovefromonehemodynamicstatetoanother.
Vasopressororinotropetherapyshouldbeusedaccordingtotheclinicalstate.[3]
CorticosteroidsinSepticshock

Corticosteroidsshouldnotbeusedroutinelyinallchildrenwithsepticshock.Thegrouprecommendsstressdoses
ofhydrocortisone50mg/m2/doseevery6huntilreversalofshockforpediatricsepsispatientswithcatecholamine
resistantshockandsuspectedorprovenadrenalinsufficiency(Level2).[39,40]
Uptothispointmostoftheinterventionscanbeperformedinaperipheralsettingtobefollowedastheguidelinein
resourcelimitedsituation.FurthermanagementrequirestransferofthepatienttoaPICU,reassessmentofthe
patient'sclinicalstatus,arterialbloodpressure,CVP,echocardiographyandhemoglobinandpackedcellvolume
(PCV).Generally,alowCVPwillbeanindicationformorefluids,lowbloodpressureformorevasopressors,poor
contractilityofmyocardiumonechocardiographyfortitratingthedoseofinotropesandlowPCV,anindicationfor
packedcelltransfusion.
FurtherManagementandOtherIssues

VasoactiveDrugTherapy:FurtherTitration

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Atthisstage,childreninshockmaybeclassifiedintotwobroadcategories:warmshockandcoldshock.
Childrenincoldshockmaybefurthercategorizedintwosubgroups.(i)ChildrenwithlowBP.Inthesechildren,
thedoseofepinephrineshouldbetitratedtoachievenormalmeanarterialpressureforage.Oncethisisachieved
buttheothergoalsoftherapyarenotyetachieved,oneshouldconsideraddingavasodilatorsuchasnitroprusside
andnitroglycerine,withveryshorthalflife,ormilrinone[41]havingbothvasodilatoraswellasinotropiceffects.
Nitrosovasodilatorsareusedasfirstlinetherapyforchildrenwithepinephrineresistantlowcardiacoutputand
elevatedsystemicvascularresistance.Useofmilrinone(5075mg/kg/min)shouldbestronglyconsiderediflow
cardiacoutputandhighvascularresistancestatepersistsinspiteofepinephrineandnitrosovasodilators.Starting
milrinonemayrequireadditionalfluidbolus,andtitratingupthedoseofepinephrinetocheckthevasodilatation
andmaintainBP.
SecondcategoryisthatofchildrenwithnormalBP.Inthesechildren,furtheractionwoulddependonthepulse
pressure.Ifthepulsepressureislow,milrinonewouldbethedrugofchoice(Level1).However,ifthepulse
pressureisnormalorhigh,norepinephrineanddoubtamineshouldbetitratedup.
VasopressininShock

Vasopressintherapymaybeconsideredasalastresortifpatienthaswarmshockwithlowbloodpressure
unresponsivetonorepinephrine.[42,43]Inpediatricpatients,suggesteddoseis0.32milliunits/kg/min[equivalent
to0.0003to0.002units/kg/minor0.01to0.12units/kg/h].Theinfusionshouldbetitratedtooptimizeblood
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pressureandperfusion.
Drugs:PracticePoints

Accuratedosedeliveryisanimportantcomponentofvasoactivedrugtherapy.Thiscanonlybeachievedwith
infusionpumps.Wheninfusionpumpsarenotavailable,theinfusionsmaybegivenusingmicroinfusionsets
whosedropsizehasbeenstandardized.Mixingofmorethanonevasoactivedruginthesameinfusionsetor
infusionsyringesisnotrecommendedevenwhenlimitednumbersofintravenousaccessportsareavailable.These
drugscanbeinfusedthroughtheintraosseousroutetillthetimethatanintravenousaccessbecomesavailable.
Ameticuloussearchforthecausesofpersistentcatecholamineresistantshockshouldbemadeiftherapeuticgoals
arenotachievedinspiteofadequatevolumeloadingandhighdosesofappropriatevasoactiveagents.Onemust
ruleoutmechanicalcausesofcatecholamineresistantshocksuchastamponadebecauseofpericardialeffusion,
pneumothorax,orincreasedintrabdominalpressure.
BloodandComponentTherapy

Optimalhemoglobinforacriticallyillchildwithseveresepsisisnotknown.ACanadianmulticentertrial[44]
stronglyarguesinfavorofarestrictivetransfusionstrategyrecommendingRBCtransfusionstoonlythosecritically
illchildrenwhoseHbis7g/dL.However,thisstudyexcludedchildrenwithhemodynamicinstability,therefore,
theresultscannotbeextrapolatedtochildrenwithsepticshock.
Theadulttrialusedagoalof30%PCV(approx.10g/dLHb)duringtheresuscitationphaseofsepticshockalong
withotherinterventionsandshowedaclearbenefit.[37]Hence,arecommendationformaintainingasomewhat
higherHblevelof10g/dLduringtheresuscitationphaseisbeingmadeheretoo.
Theserecommendationsmaynotapplytoprematureinfants,childrenwithseverehypoxemia,orcyanoticheart
diseaseandtochildrenwhoareactivelybleeding.
FreshFrozenPlasma

Correctionofcoagulationabnormalitiesdoesnotimproveoutcomeinallthepatients[45]andunnecessarilyexposes
thechildtotherisksofbloodproducttransfusions.Hence,freshfrozenplasma(FFP)isindicatedinpatientswith
coagulationabnormalityhavinganyofthefollowing:activebleeding,beforesurgery,beforeinvasiveprocedure,
andtoreversewarfarineffect.RoutineuseofFFPtocorrectlaboratoryclottingabnormalitiesisnotindicated.
Whenrequired,theFFPinfusionshouldbegivenrelativelyrapidlytoachieveeffectivefactorlevels.
IntravenousImmunoglobulins

Althoughsomepediatricstudieshavesupportedtheuseofintravenousimmunoglobulins(IVIG)forseveresepsis,
[46,47]largeclinicaltrialsandrecentconsensusguidelines[48]donotrecommendthewidespreaduseofIVIGin
patientswithseveresepsisorsepticshock.
DeepVeinThrombosisProphylaxis

Useofdeepveinthrombosis(DVT)prophylaxisisrecommendedinpostpubertalchildrenwithseveresepsis(Level
2).
StressUlcerProphylaxis Therapymaybeindividualized.Therearenogradedrecommendations.
RenalReplacementTherapy Continuousvenovenoushemofiltrationmaybeclinicallyusefulinchildrenwith

anuria/severeoliguriaandfluidoverload.Therearenogradedrecommendationsduetolackofpediatricstudies.
Summary

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Therecommendationsincludeuseofrapidcardiopulmonaryassessmentandgreateruseofphysicalexaminationfor
achievingtherapeuticendpoints.Earlyfluidresuscitation(crystalloidorcolloids)basedonweightwith4060
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mL/kgorhighermaybeneeded.
Earlymechanicalventilationshouldbeconsideredifhemodynamicinstabilitycontinuesbeyondfluidtherapy.
Decreasedcardiacoutputandincreasedsystemicvascularresistancetendtobethemostcommonhemodynamic
profile.Dopaminewithorwithoutdobutamineisrecommendedastheinitialagentforhemodynamicsupport.Use
ofdopaminebyperipheralveinhasbeenincludedinguidelines,asresourceconstrainmayprecludeuseofcentral
lines.
Thereisenoughevidencethatearlyoxygentherapy,earlyaggressivefluidtherapytorestoreintravenousvolume,
anduseofdopamineinfluidrefractoryshockhavebroughtthemortalitydown.Theseinterventionscanbeeasily
appliedeveninresourcelimitedcircumstancesevenatprimaryand/orsecondarylevelhealthfacilities.
Earlyappropriateantibiotics,correctionofhypoglycemia,hypocalcemia,andavoidinghyperglycemiaare
recommended.Randomizedcontrolledtrialsareneededtoestablishchoiceofinotropicandvasopressortherapyfor
initialmanagement,dose,andtimingofuseofcorticosteroids,administrationofbloodandbloodproducts,
protectivemechanicalventilation,glycemiccontrol,techniquesofrenalreplacementtherapy.
Studiesshowthatcompliancewithpublishedguidelinestendstobeinadequate.Furtherresearchevaluating
individualcomponentsofguidelinesandrelativebenefitofeachoftheseinterventionsinresourcelimitedsettingis
needed,asalsothebenefitofadherencewithguidelinesandstandardizedsetorders.
Acknowledgments

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AuthorsthankNiranjanKissoon,MD(Canada)andJoeCarcillo,MD,FCCM(USA),CochairsforInternational
PediatricSepsisInitiativeUndertheauspicesofWorldFederationofPediatricIntensiveandCriticalCareSocieties
(WFPICC),forprovidingthebackgroundinformationregardingsepsisinitiativeandsuggestingIAPintensivecare
chaptertoundertakedevelopingguidelinessuitableforresourcelimitedcountriessuchasIndiaandAfrica.
Footnotes

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SourceofSupport:Nil
ConflictofInterest:Nonedeclared.

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