3/5/2017 Advancesinsepsisdiagnosisandtreatment

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PauloR.A.CarvalhoIElianadeA.TrottaII
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I Associateprofessor,DepartmentofPediatrics,SchoolofMedicine,
Howtocitethisarticle
UniversidadeFederaldoRioGrandedoSul(UFRGS)
II DepartmentofPediatrics,SchoolofMedicine,UniversidadeFederaldoRio SciELOAnalytics
GrandedoSul,PortoAlegre,RS,Brazil
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ABSTRACT
More
OBJECTIVE:Topresentacriticalandupdatedreviewaboutsepsis,
focusingespeciallyondiagnosisandtreatment. More
SOURCEOFDATA:LiteraturereviewofMedline,includingreviewarticles,
clinicaltrialsandoriginalresearch. Permalink
SUMMARYOFTHEFINDINGS:TheInternationalSepsisDefinitions
Conferenceamplifiedthelistofpossibleclinicalandlaboratorysignsof
sepsis,whichmayallowformoreefficacioussuspicionandmanagement.Intermsoflaboratoryevaluation,in
additiontotheresearchforinfectiousagents,manyinflammatoryresponsemarkers,suchasinflammatory
cytokinesandprocalcitonin,havebeenidentified.However,theylacksensitivityandspecificityforsafe
diagnosis.Intermsoftreatment,earlyinterventiontopreventhemodynamicdisturbancesisstillessentialfora
positiveoutcome,togetherwiththeappropriateuseofantimicrobials.Thevalueoftreatmentstoremovetoxins
andtoincreasetheinnateimmuneresponsehasnotyetbeenestablished.Theuseofisolatedinflammatory
responseblockers,atanystageofsepsis,doesnotdecreasemortality.Theuseofcorticosteroidmakesa
comebackwithencouragingresults,eveninpatientswithoutsepsisrelatedadrenalinsufficiency.Alargestudy
onactivatedproteinC(drotrecogin)reportsa6%decreaseinmortalityinaselectedsample,suggestingthe
possibilityofabetterprognosisforsepsispatients.
CONCLUSIONS:Incomparisontotheadvancesofthepastfewyears,littlehasbeenachievedintermsof
decreasingsepsisrelatedmortalityduetothecomplexityofthepathogenhostrelationships.Theindividual
regulationofhostreactionsdidnothavetheexpectedeffects.Thebenefitsofsomeknownstrategieswere
confirmed.Othertypesoftreatment,suchascorticosteroidsandactivatedproteinCtherapies,areemergingas
promisingalternatives.Researchindicatesthatthecombinationofimmunemodulatortherapiesisprobablythe
bestchoicetoimproveoutcomesinsepsis.

Keywords:sepsis,systemicinflammatoryresponsesyndrome,criticalcare.

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"Ourarsenalsforfightingoffbacteriaaresopowerful,
andinvolvesomanydifferentdefensemechanisms,thatweare
moreindangerfromthemthanfromtheinvaders.
Weliveinthemidstofexplosivedeviceswearemined."

LewisThomas,1972

Introduction
Sepsisisacomplexsyndromecausedbyanuncontrolledsystemicinflammatoryresponse,ofinfectiousorigin,
characterizedbymultiplemanifestationsandwhichcanresultindysfunctionorfailureofoneormoreorgans
andevendeath.

Duringthelastdecadeinnumerableadvancesweremadeinunderstandingthepathophysiologyofthis
syndrome,bymeansofmulticenterstudies,whichresultedinthesuggestionofcertaindiagnosticmarkersand
inthepotentialbenefitofinnumerabletreatmentsalternatives.13Inrecentyearsresearchersinrecentyears
havepersistentlypursuedtheachievementbothofearlydiagnosisandofachangeorarrestofitsclinical
course.However,thepoorclinicalevolutionandthecontinuedhighmortalityamongsepsispatientsdoarenot
signsofanearlyorsuccessfuloutcometothehuntforsolutionstothiscondition.

Sincethe1991Consensus,newdefinitionsandcriteriaforthediagnosisofsepsis,althoughlackingspecificity,
particularlyforpediatricpatients,4haveenabledresearcherstospeakthesamelanguageandcomparethe
resultsoftheirexperiments.In2001,theInternationalSepsisDefinitionsConference,congregatingalarger
numberofresearchersandexpertsfromallovertheworld,optednottomodifytheexistingdefinitionsandto
increasethelistofsignsandsymptomsofsepsis(Table1),thusvaluingtheclinicalexperienceofintensivecare
professionals.5

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Theuseofthetermsepsisisnotrestrictedtoasystemicinflammatorysyndromesecondarytobacterial
infection,buttothissyndromeresultingfromanymicroorganismand/oritsproducts(toxins).Thetermsepsis
isapplicableonlywhenthesystemicresponseisclinicallyrelevant,whichcanmanifestinavarietyofsituations
ofincreasingcomplexity:(a)severesepsis,understoodassepsisassociatedwithorganfailure,hypoperfusion
(whichincludes,butisnotlimitedtolacticacidosis,oliguriaoranacutelyalteredstateofconsciousness)and
hypotension(b)septicshock,understoodassepsisassociatedwithhypoperfusionalterations,butwith
persistenthypotensionevenaftersuitablevolumetricresuscitation,and(c)multipleorganfailuresyndrome
(MOFS),whichmayrepresentthefinalstageoftheseveresystemicinflammatoryreponse.57However,the
limitswhichseparatesepsisfromseveresepsisandthisfromsepticshockarenoteasilydetectedinclinicalat
ICUs,orevenfromaconceptualpointofview.8,9Thelastconferenceonsepsisproposedthedevelopmentofa
systemofstagesforsepsiswhichwouldbetterclassifythesyndromebasedonpredisposingfactorsandon
premorbidconditions,inthenatureofthesubjacentinfection,inthecharacteristicsoftheresponseofthehost
andtheextensionofresultantorgandysfunction(PIROPredispositionInfectionResponseOrganDysfunction).

Epidemiology
Sepsisisaheavyburdenonhealthservicesallovertheworld,bothfromeconomicandsocialpointsofview.
AccordingtoanepidemiologicalstudyoftheUSA,overthelast20years,theincidenceofsepsisincreasedfrom
82.7to240.4/100thousandinhabitants,asdidthedeathsrelatedtoit,althoughthegeneralmortalityrate
amongpatientswithsepsiswasreducedovertheperiod.10AstudybyWatsonetal.,basedonpediatrichospital
dischargerecordsintheUSAin1995,revealedaprevalenceof0.56childcasesofseveresepsisper1,000

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habitants/year.11Angusetal.,across847federalhospitalsintheUSA,in1995,foundthreecasesofsevere
sepsisforeachgroupof1,000inhabitantsand2.26casesforeachgroupof100hospitaldischarges,68%of
whomhadreceivedsomesortofintensiveorintermediatecare.Globalmortalitywasaround28%,butvaried
accordingtoagegroup:10%ofchildrenand38%elderly,85yearsorolder.12AccordingtoBrunBuissonetal.,
basedonFrenchadultICUs,mortalityat28daysafterdischargewas56%forseveresepsisand60%forsevere
sepsiswithanegativeculture.13InthestudycarriedoutbyAngusetal.,thecostscausedbysepsiswere
highestamonginfants,nonsurvivors,patientsinICU,surgicalpatientsandinthosewithfailureofmorethan
oneorgan.12

Theincreaseinmorbidityandmortalityincidenceratesrelatedtosepsisofrecentdecadesisdirectlyrelatedto
themedicaladvancesachievedduringthisperiod,where,moreandmore,seriouslyillpatientsandthosein
moreadvancedstagesaretreated.Atleast50ofthecasesreportedonbyWatsonetal.Hadasubjacent
disease,while23%werelowbirthweightnewborns.11Anotherrelevantaspectwhichshouldbeconsideredis
thatofsecondarysepsisamongcriticallyillpatientshospitalizedforotherreasons,whetherbecauseof
immunologicalcompromiseorbecauseofmedicalconductandprocedurescarriedoutduringtheirICUsand
hospitalstay.14

Theratesofsepsisreportedinpublishedliteraturecanvaryaccordingtolocalcharacteristics.IntheUSAand
Europe,sepsisisresponsiblefor211%ofICUadmissions.15AretrospectiveanalysisbyJacobsetal.,ofmore
than2000PediatricICUadmissions,identified42.5%ofpatientswithandinfectiousdisease,ofwhom63%had
septicshock.16Proulxetal.,evaluating1058admissionstoaPICUataCanadianteachinghospital,identified
82%SystemicInflammatoryResponseSyndrome(SIRS),ofwhich23%hadinfectiousetiology(sepsis),2%of
whichhadsepticshock.9

Diagnosis
Thediagnosisofsepsisisthefirstofthechallengeswhichconfronttheclinicianorintensivecarespecialist,
especiallybecauseitsidentification,whennotsufficientlyearlytoallowintervention,mayresultinshock,organ
failureorevenpatientdeath.Earlysepsisdiagnosiscontinuestobeoneofthemostdifficultoftasks,whether
becausethefirstclinicalmanifestationsmaypassunnoticedorbecausetheycanbeconfusedwiththoseof
other,noninfectious,processes.Furthermore,theindirectlaboratoryindications(hemagram,coagulationstudy,
glycemia,etc),usuallyemployedtoreachadiagnosisofsepsis,individuallyhavelittlesensitivityandless
specificity.Similarly,theresultsofbacteriologicalexaminationscollectedontheoccasionoffirstsuspicionare
notimmediatelyavailabletoguidespecifictherapy.

Duringthelastdecade,innumerablemarkershavebeensuggestedforearlysepsisdiagnosis,amongwhichare
serumassayofcertaincytokinesinterleukin1(IL1),interleukin6(IL6),interleukin8(IL8)einterleukin10
(IL10),tumornecrosisfactor(TNF),oftheirrespectivesolublereceptors(TNFreceptor),acutephaseproteins
(Creactiveprotein)andprocalcitonin.17

Clinical

Thecriteriaofthe1991ConsensuswhichdefinedSIRSsecondarytoinfection(sepsis),inadditiontobeing
inappropriateforpediatricpatients,wereunspecificevenforadultpatients.Observationandcareofpatientsin
PediatricandNeonatalICUshasshownthatthesignsandsymptomsofsepsisarehighlyvariable,dependingon
patientagegroup,andarenotrestrictedtosimplychangestocertainphysiologicalvariables.Thus,theyounger
thechild,thelessspecificthesymptomsofsepsis.Noclinicalsignissensitiveorspecificenoughtoindicate
severeinfection,especiallyinseriouslyillpatients.14

ArecentInternationalConferenceontheDefinitionofSepsis,whilemaintainingthedefinitionsproposedbythe
previousconsensus,extendedthelistofpossibleclinicalandlaboratorysignsofsepsis,consideringinnumerable
indicatorsofsevereinfectioninthechild(Table1).Theresearchersandexpertsconsideredbedsidediagnosisof
sepsistohavepriorityovercriteriaforinclusioninclinicalstudies.5

Therefore,fortheclinicianorintensivecarespecialist,thediagnosisofsepsisisbasedonahighlevelof
suspicion,whichdemandsaminutelydetailedcollectionofinformationonpresentstatusandmedicalhistoryof
thepatient,agoodclinicalevaluation,certainlaboratorytests,inadditiontorigorousclinicalmonitoringofthe
patient.Facedwithasuspicionofsevereinfection,thepossibilityofother,noninfectious,systemic
inflammatoryconditionsshouldberuledout.

Laboratory

Laboratory,orcomplementary,evaluationiscapableofrevealingtwodistinctaspectsofsepsis.Thefirstis
relatedtothesearchfortheaggressiveagent,bymeansofmicrobiologicaltrackingofthepatientthesecond
relatestotheidentificationofalterationstometabolismorhomeostasis,indicativeofsystemiccompromiseor
ofspecificorganinvolvement.

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Microbiologicalevaluationincludesdirecttestsandculturesofblood(twoormore),ofurine,ofcerebrospinal
fluid,offeces,ofsecretions,ofsmallintestineaspirate,ofexudates,andofpetechiaeandsuffusions(when
meningococcemiaissuspected),preferablybeforeusingantimicrobialtreatments(AMs).Cerebrospinalfluid
mustalwaysbeobtained,especiallyfornewbornsandyounginfants,beingcarefultoobtainitsafely,i.e.
withoutrisktothepatient.

Inthecaseofhospitalizedpatients,thecollectionofmaterialforcultureshouldincludealldevicesthatbreach
thehost'sprotectivebarriers,i.e.venousorarterialcatheters(bloodfromthecatheters),vesicleprobes,
trachealtubeortracheostoma(trachealaspirate),andstitchesorscarsfromrecentsurgery.

Despitethegreateffortmadetoisolatemicroorganisms,onaverage,bloodculturesarepositivein34%of
"septic"patients,varyingfrom9to64%.18Howmanyoftheseepisodesaresepsiswithoutbacteremiaor
failuresofmicrobiologicalcultivationandidentificationmethods,orevennoninfectiousSIRS,remainsunknown.

OnsuspicionofsepsiswithapatientwhohashadalongdurationICUstay,aninvestigationforsystemic
infectionbyfungusismandatory.Currently,fungi,andespeciallyspeciesofCandida,areresponsibleforaround
5%ofsepses.18Thepresenceofadditionalriskfactorsincreasethechanceoffungalinfection,suchastheuse
ofmultipleAMtreatments,broadspectrumAMs,parenteralnutrition,prolongedpresenceofcentralcatheter
andcolonizationofthedigestivetractbyCandida.

Thelaboratoryevaluationtoidentifysystemiccompromiseincludesfromthesearchforinflammatoryresponse
indicatorsinperipheralblood(endogenousmediators,acutephaseindicators)tothetestingforindicatorsof
organicandmetabolicdisturbancesinordertotreatandsupportthem.Indicatorsofthepresenceofsystemic
inflammatoryresponse,inthemajority,lacksensitivityandspecificityforsepsisdiagnosis,butcanbeofvalue
forprognosisandmonitoringtherapeuticresponse.Increasesinserumlactate,serumcytokines,granulocyte
colonystimulatingfactorandofplasmanitricoxide(bymeansofnitrite/nitrateplasmalevels)canbeearly
indicatorsofSIRS,althoughthemajorityofthemarenotavailablequickly.Procalcitonin,whichisliberatedinto
circulationtogetherwithcytokines,andhasalongerhalflife,mayhavevalueforearlydiagnosisofneonatal
sepsis.14Inadults,procalcitoninhasbeenreferredtoasanindicatorofsepsisinpatientswithSRIS,19andasa
prognosticinstrumentwithsepticpatients.20Despiteitsgreatpotential,atthemomentprocalcitonincannotyet
bedefinedasamarkerforsepsisinpatientswithSIRS,andisperhapsmoreusefulforexcludingthe
diagnosis.21

Treatment
Thesystemicinflammatoryresponseinsepsis,duetoreasonsthathavenotyetbeenestablished,maybe
restrictedtoanselflimitingphenomenonorcanproceedthroughstagesofgreaterseverity,suchassevere
sepsis,septicshockanddysfunctionorfailureofoneormoreorgans.Despitethelargenumberof
investigationsandreportsonSIRS,sepsisandrelatedsyndromesduringrecentyears,andtheundeniable
improvementinunderstandingtheirrespectivepathogeneses,theinitialapproachtosepsiscontinuestobe
predominantlyoneofsupport.OnsuspicionofSIRS,ifnoothersignificant,noninfectiouseventisdetected,
conductshouldbedirectedatsepsisinadditiontolifesupportmeasureswhenindicated,otherstepsshouldbe
takendependingupontheseverityandpresentationoftherespectivesyndrome.

Earlygoaldirectedtherapy

Thelimitsseparatingsepsisfromseveresepsis,andthisfromsepticshockormultipleorganfailurearenot
easilydetectedinclinicalpractice.8,9Duringthecourseoftheevolutionoftheinflammatoryresponse
resuscitationphenomenasuchashypovolemia,peripheralvasodilation,myocardialdepression,increased
endothelialpermeabilityandhypermetabolismoccur.Thus,ingeneral,theintensivecarespecialistisledto
correctpreload,postloadandcardiaccontractilitytoattendtotheoxygentissuesupply/demandratio,to
maintainadequatecellularperfusionandpreventorgandysfunction.22

Similarly,justasthefirsthourisofextremeimportanceintheevaluationandprimarycareofthetrauma
victim,withsepsistoo,evolutiontoamorecriticalconditioningeneraloccursoutsideoftheICU.Itisduring
thelapseofhourswhichprecedesthepatient'sadmissiontotheICUthatearlyrecognitionofpoorevolutionof
sepsisandamoreaggressivetreatmentcanproducebenefitsnecessarytochangetheoutcome.23

AccordingtoRiversetal.,24earlyhemodynamicassessmentwithabasisinaphysicalexamination,onvital
signs,oncentralvenouspressureandurinaryoutputisnotsufficienttodetectpersistentglobaltissuehypoxia.
Theyrecommendamoredefinitiveresuscitationstrategy,withtherapyorientedbygoals,whichinclude
manipulationofpreload(CVPbetween8and12mmHg),postload(MAP>65mmHgand<90mmHg)and
cardiaccontractility(oxygensaturationofmixedvenousblood[SvO2]>70%),toachieveequilibriumbetween
supplyanddemandforsystemicoxygen.Thetherapyproposed,whichshouldoccurduringthefirst6to8hours
afteridentificationofthesepticpatient,includingvigorousvolumetricresuscitationevery30minutes,untila
CVPbetween8and12mmHgisachieveduseofvasopressorsifMAP<65mmHg,attemptingalwaysto
maintainitabovethislevel,oruseofvasodilatorsifMAP>90mmHg,attemptingtomaintainitbelowthislimit

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and,ifSvO2<70%,transfusionoferythrocyteconcentratetoachievehematocritataminimumof30%.After
optimizingCVP,MAPandhematocrit,ifSvO2remains<70%,usecontinuousdobutamineinincreasingdoses
untilSvO2>70%oruntildobutaminehasreachedalimitof20g/kg/min.Theparametersforconfirmationof
theobjectiveproposedincludethenormalizationofSvO2,arteriallactateconcentration,basecardiacoutputand
pH.Thisstrategyofearlysepsistreatmentdirectedbyobjectives,whencomparedwithastandardstrategy
resultedinfewerorganicdysfunctionsandlowermortality.1,22,24

Whiletherearenotyetanycomparativestudiesavailablethatuseobjectiveorientedtherapywithpediatric
patients,someoftheobservationsmadebyRiversetal.probablydonotapplytochildren.Inchildhoodseptic
shocktherearealwaysconsiderablevolumedeficits,irrespectiveofinvasivemonitoring,theinfusionoflarge
volumesofcrystalloidsolutionsduringthefirsthoursofcareismandatoryandisassociatedwithareduced
mortalityrate.23Evenwithavolumetricdeficitof25to30%ofthevolemia,achild'sMAPremainsstablefora
longerperiodatthecostofincreasedsystemicvascularresistance.Inthismanner,MAPisnotagoodsignfor
indicatingvolumetricreplacementinachildwithshock.Additionally,theuseofdopamineispreferredfor
inotropictreatmentofchildreninplaceofdobutamine.23

Treatmentoftheaggressiveagent

Antimicrobial(AMs)arethemostspecificandaccessibleagentsforthetreatmentofpatientswithinfections,
althoughtheyonlyrepresentapartialapproachtotheproblem.Overthelastfourdecades,studiesintothe
effectsofAMuseforsevereinfectionsbygrampositiveorgramnegativebacteriahavedemonstrateda
considerablereductioninthemorbidityandmortalityofpopulationsaffectedbythem.18Antimicrobialcanbeof
moreuseforthetreatmentofearlyclinicalstagesofsepsis,beforethehostbeginssequentialmediator
productionresultinginmoreadvancedinflammatorycascadestageswithseveretissuedamageresulting.18
However,someauthorshaveraisedtheideathatAMsmayexacerbatetheinflammatoryresponsedueto
destructionofthemicroorganisms,liberatingmaterialfromtheircellwallsandcausingendogenous
inflammatorymediators.2

EmpiricalAMtreatmentshavebeenrecommended,inparticularforpatientswithseversepsisandsepticshock.
Antimicrobialdevelopedduringthelastdecade,fromthecarbapenemgroup(imipenemandmeropenem),and
thirdandfourthgenerationcephalosporinshavebeenproposedasmonotherapytoreplaceaminoglycosides
associatedwithalactamicforseveresepsisandsepticshock.Recommendationsindicatetheuseofwide
spectrumpenicillinAMs(associationswithticarcillinorpiperacillin),ofmonobactam(aztreonam)orof
quinolones,incombinedempiricaltherapies.18

Theremovalordrainageoftheinfectiousfocus(e.g.peritonitis,empyema,septicosteoarthritis,necrotized
tissues),andequallytheremovalofinfectedforeignbodies(includinginvasivedevices),areimportantand
relevanttostoppinginfectiousstimuli,sincesuchmeasureswouldtendtoreduceorendtheproductionof
endogenoussepsismediators,witharesultantreductionintheselfsustainingpotentialofthesystemic
inflammatoryresponse.

Treatmentaimedatimprovinginnateimmunity

Oneattempttoimprovetheefficiencyofantibioticsistoincreaseinnateimmunity,byincreasingthenumberof
leukocytes.InastudybyRottetal.,earlyuseoffilgrastimwithadultpatients,despiteachievingtheeffect
expectedfromthedrug(increasingleukocytesto75x109cells/l),didnotchangepatient28daymortality.25

Therapyaimedatthesystemicinflammatoryresponse

Themajorityofresearchersagreethatimprovedseveresepsissurvivalratescanonlybeachievedwith
additionaltherapiesaswellasconventionalantimicrobialtreatments.Themorethecomplexityand
interdependenceofthepathophysiologicalmechanismsofsepsisareunderstood,themoretherapeutic
strategiesbasedonsubstanceswhichmodulateorinterrupttheeffectsofendogenousandexogenoussepsis
mediatorsaresought.

Thetherapeuticstrategywhichappearstohavethegreatestchanceofchangingthedishearteningresultsof
sepsistreatmentistointerveneatanypointinsequenceofpathophysiologicaleventswhichcharacterizethe
systemicinflammatoryresponseinsepsis,inordertomodify(modulate)thehost'sreaction.Unfortunately,the
clinicaluseoftreatmentswhichblockindividualmediatorshasfailedtoreducethegeneralmortalityassociated
withsepsis(Table2).

Morethan30randomized,blindtrialsinvolving12,000patientsshowedthattheuseofantibodyblockers
(plateletactivationfactorantagonist,antibradykinin,antiprostaglandin,monoclonalantiTNFantibody,IL1
receptorantagonist,solubleTNFreceptor,nitricoxidesynthesisinhibitor)didnotchangetheclinicalcourseor
mortalityofpatientswithsepsis,andsometimesevencompromisedthem.26

Agentswhichbondwithorneutralizecomponentsinthebacterialcellwall(antiendotoxinantibodies,
lipopolysaccharidebindingproteinantagonist,CD14receptorinhibitor,permeabilityincreasingprotein
antagonist)orthosewhichmodulatetheimmediateresponseofthehosttothesetoxicproducts(pentoxifylline,

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amrinone)didnotprovetobevalidforsepsistreatment.Themajorityofstudiesrealizedtodatedidnotreveal
definitivelynegativeresults,butanswerscontinuetobesoughtbymeansofbetterdesignedcollaborative
studies.Adoubleblind,randomizedandcontrolledmulticenterstudyof847patientsat53hospitalsintheUSA,
usingtwodosesofmonoclonalE5antibodyagainstendotoxin,demonstratedthattherewasnoreductionin
mortalityamongpatientswithsepsisfromgramnegativegermswithnoshock,butthattherewasgreater
recoveryfromorganfailureamongthesepatients.27Amorerecentstudy,whichusedthehumanmonoclonal
antibodytoacommonenterobacteriaantigen,alsofailedtoreducemortality.28

Pentoxifylline,incommonwithamrinone,inhibitsphosphodiesterase,increasingconcentrationsofintracellular
cyclicAMP,resultinginareductionincytokineaccumulation,especiallyTNF.AEuropeandoubleblindand
randomizedstudyof100newborns,demonstratedreducedmortalityamongprematuresepsispatientswithin
thegroupthatreceivedpentoxifylline,5mg/kg/hfor6hours,on6consecutivedays.29

Although,intheory,corticosteroidshavealwaysbeenconsideredtohavesomesortofcytokinesynthesis
blockingaction,theiruseandefficacyforsepsisorsepticshockhavenotbeensupportedbyclinicalevidence
andthereareevenstudiesthatsuggesttheirusemaybeprejudicialtothesepatients.30Morerecently,interest
hasoncemoreincreasedinusingcorticosteroidsforsepsis.Theobservationthatseveresepsismaybe
associatedwithrelativeadrenalinsufficiencyorresistancetoglucocorticoidreceptorsinducedbysystemic
inflammationhasawokeninterestinstudieswhichevaluatetheusefulnessoflowdosecorticoidsinsepsis
situations.Arandomized,doubleblind,placebocontrolledstudycarriedoutbyAnnaneetal.,indicatedthat
extremelyillpatientswithsepsisandpersistentshock,requiringvasopressorsandmechanicalventilation,
benefitedfromtheuseofphysiologicaldosesofcorticosteroidsfor7days,withreductionsindurationofcom
vasopressoruseandmortalityratewhencomparedwiththecontrols.31Similarly,arecentrandomized,double
blind,placebocontrolledstudybyKehetal.,indicatedthatcontinuous,lowdose,hydrocortisoneusewasof
benefittopatientsinsepticshock,restoringhemodynamicstabilitywhencomparedwithcontrols.32

Agentswhichneutralizeorpreventtheactionofinflammatorycytokinesontheirrespectivereceptors,suchas
monoclonalantiTNFantibodiestendtoreducetheproductionofthenextmediatorsintheinflammatory
cascade(interleukin1[IL1]andinterleukin6[IL6]),wouldhypotheticallypreventpathophysiologicaldamage,
improvingsurvivalrates.Arandomized,doubleblindandcontrolledmulticenterstudyof1,879patientsat105
hospitalsintheUSAandCanada,usingmurinemonoclonalantibodiesforTNF(TNFMab),didnotreveal
differencesin28daymortalitybetweenpatientswhohadreceivedtheantibodyandthosewhohadreceived
placebos.33Anotherrandomized,doubleblindandcontrolledmulticenterstudyof498patientsat44hospitalsin
theUSAandEurope,receivingsolubleTNFreceptorfusionprotein(p55),alsofailedtorevealreduced
mortalityamongthosewhoreceivedtheantibodyincomparisonwiththosewhoreceivedtheplacebo.34

Interleukin1receptorantagonisttendtoattenuatehemodynamicalterations,reducingtheseverityoflactic
acidosisandimprovingsurvivalrates.TheInterleukin1ReceptorAntagonistSepsisInvestigatorGroup,by
meansofarandomized,doubleblindandcontrolledmulticenterstudyof696patientsat91hospitalsintheUSA
andEurope,didnotdemonstratereducedmortalitywiththeuseofhumanrecombinantIL1receptorantagonist
whencomparedwithaplacebo.35

Plateletactivationfactor,PAF,isaphospholipidproducedbymacrophages,neutrophils,plateletsandendothelial
cells,whichcanmediatetheeffectsofinnumerablecytokines.Thus,PAFreceptorantagonistsmaybeusefulfor
treatingsepsisduetogramnegative.Arandomized,doubleblindandcontrolledmulticenterstudyof600
patientswithseveresepsiswhichtestedPAFreceptorantagonistforfourdays,didnotdemonstrateany
reductioninmortalityrate.36

Itisnowknownthatnitricoxideproduction,(NOendogenousvasodilator),isresponsibleforsomeofthe
harmfuleffectsoftheinflammatoryresponseontargetorgans(vasodilationandhypotensionmyocardial
depressioninsepticshock).ItisproducedfromLargininewiththeaidofNOsynthase(NOs)anditsinhibition
orblockageisatherapeuticstrategytominimizetheseeffects.Althoughitsinhibitioninanimalswithsepsiscan
leadtoarterialpressurenormalization,mayresultinotherundesirableeffects(e.g.reducedcardiacindexand
increasedpulmonarypressure).ItisthoughtthatinhibitingNOsLNAME(NnitroLargininemethylester)
wouldalsoinhibitthebeneficialeffectsofNO,andthatonlyinsituationsofNOoverproductioncouldthisagent
haveanyrealbenefit.ThestrategyofemployingNOsinhibitorshasnotbeensufficientlytestedonhumans.

TheprocessofPMNactivationanddegranulationcausedbyinflammatorymediatorsresultsinlargescalefree
radicalproduction.Itisbelievedthatendogenousantioxidants(vitaminsCandE,carotene,catalaseand
superoxidedismutase)wouldnotbesufficienttoneutralizethisexposuretofreeradicalsandavoidcellular
damageinSIRS.Studiesofsepsisinanimalmodelshaveshownbeneficialeffectsfromtreatmentwith
substancestoscavengeoxygenfreeradicals(superoxidedismutaseandcatalase).2,24Othertreatmentswith
antioxidantagents(atocopherol,dimethylsulphoxide,Q10coenzyme,Nacetylcysteine,glutation,allopurinol,
amongothers)arebeingevaluatedinanimaltestsresultsaresofarinconclusive.

Itisbelievedthatproductsofthemetabolismofarachidonicacid,bybothroutes(cyclooxygenaseand
lipooxygenase),andalsoprostaglandinsandthromboxanesappeartoperformaconsiderableroleintarget
organswhentheinflammatoryresponseevolvesandthereisorgandysfunction.Anumberofdifferent
cyclooxygenaseinhibitors(indomethacin,ibuprofen)appeartohavebeneficialeffectsatspecificpointsinthe
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inflammatorycascadeandonthesurvivalofanimals.Arandomized,doubleblindandcontrolledmulticenter
studyofibuprofenwith455sepsispatientsrevealedreducedprostacyclinandthromboxanelevels,reductionsin
fever,tachycardia,lacticacidosisandoxygenconsumption,butwithoutpreventingthedevelopmentofshockor
respiratorydistresssyndromeorimprovingpatientsurvival.37AstudybyAronsetal.ofpatientswith
hypothermalsepsis,comparedwithfebrilepatients,demonstratedreducedmortalityamongpatientstreated
withibuprofen.38Themajorityoftherapeuticstrategieswithnonsteroidalantiinflammatories,boththose
attemptedtodateandthosewhicharestillunderinvestigationhavefailedtoproducedefinitivelypositive
resultsfortreatmentofseveresepsisandsepticshock.Ametaanalysisof18clinicaltrialsatphasesIIandIII
ontheuseofnonsteroidalagentswithantiinflammatorypropertiesforsepsistreatment,basedon6,429
patients,demonstratedthattherewereonlybeneficialtendencieswithoutsignificantlyalteringmortality.3

Heparinhasalsobeenstudiedforsepsistreatment,foritsimmunomodulatorypropertiesandbecause,invitro
itinhibitsthebondbetweenLandPselectin,basedontheobservationthatratsthataredeficientinLselectin
areimmunetolethalendotoxemia.Inarandomized,doubleblind,placebocontrolledstudy,Derhaschnigetal.
testednonfractionedheparinandlowmolecularmassheparin,afterlipopolysaccharideinfusiononhealthy
volunteersThegroupthatreceivednonfractionedheparin,thereweresignificantreductionsinlymphocytopenia
andinLselectindownregulationinducedbythetoxin,providingevidencethatheparinhasaprobable
mechanismofactionofuseinthetreatmentofsepsis.39

Anotheranticoagulantwhichhasbeeninvestigatedforsepsistreatmentisantithrombin,whichcombinestwo
effects:inadditiontobeingananticoagulantitalsohasantiinflammatoryeffects,inhibitingproteaseswhich
interactwithcellsthatliberateproinflammatorymediators.Thebondwithsyndecan4receptorsinterfereswith
intracellularsignalsinducedbymediatorssuchaslipopolysaccharide.Ithasbeendescribedasbeingofbenefit
insmallcohortsofsepticpatientswithcoagulationdisorders.40HoweverinalargephaseIIImulticenter,
doubleblind,placebocontrolledtrial(KyberSeptTrial),involving2,314adultswithseveresepsis,theuseof
antithrombinIIIstartedwithinthefirst6hoursdidnotreduce28daymortality(primaryobjective)orat56and
90days(secondaryobjective).Whenthesamplewasstratifiedforconcurrentheparinandantithrombinuse,
therewasnodifferencein28daymortality,but90daymortalitywassignificantlylessforthegroupthatdid
notreceiveheparin.41Concurrentheparinuse,inadditiontoproducingmorehemorrhages,mayhavereduced
theantiinflammatoryeffectofantithrombin.Later,Hoffmannetal.demonstratedthat,inalaboratory,theof
useantithrombinprevented,toasignificantextent,endotheliumleukocyteinteractionandcapillarydamage,in
animalsepsismodelsfromlipopolysaccharideinjectionhowever,amongtheanimalsthatreceivedantithrombin
associatedwithheparin,lesionsweresimilartothosethatoccurredinthecontrols(thathadonlyreceivedthe
toxin),thusdemonstratingtheadverseeffectsofassociatingthetwodrugs.42Amulticenter,observational
study,carriedoutinItalywith216patientswhoreceivedantithrombinforsepsis,CIVDandotherclinical
conditionsalsoconcludedthatthistherapydidnotbenefitthesepsispatientsintermsofmortality.Inthis
sampletherewasnodifferencelinkedtoconcurrentheparinuse.43

OnetreatmentthathasshownpromiseforsepsisappearstoberecombinanthumanactiveCprotein,or
drotrecogin.ActiveCproteinisanendogenousproteinwhichpromotesfibrinolysisandinhibitsthrombosisand
inflammation.Insepsis,becauseoftheeffectsofinflammatorycytokines,thereisareductionintheconversion
ofinactiveCproteinintoactiveCprotein.Theantiinflammatoryeffectofdrotrecogincancomedirectlyfromthe
inhibitionofneutrophilactivation,fromtheproductionofcytokinesinducedbylipopolysaccharides,andfrom
activatedcelladhesiontotheendothelium.Theeffectcanalsobeindirect,bymeansofinhibitingthrombin
generation,whichleadstoreducedplateletactivation,neutrophilrecruitmentandlabrocytedegranulation.Ina
randomized,multicenter,doubleblind,placebocontrolledtrialofcontinuousdrotrecogin(Xigris EliLilly
Co)for96hoursorplacebo,in1,690patientswithseveresepsis,overallmortalitywaslowerat28daysamong
thetreatedgroup,representingareductionof6.1%intheabsoluteriskofdeath.44Thedrugwasclearedfor
useonthebasisofthissingletrial.Duetoitspotentialtocauseseverehemorrhagesanditshighcost,ithas
beenrecommendedthatpatientsbeextremelycarefullyselectedbeforereceivingthistreatment.45,46

Ithasbeenobservedthatmanycriticalpatients,eventhosewhoarenotdiabetic,havehyperglycemiaanda
reducedresponsetoendogenousinsulin,possiblybecauseofincreasesinthelevelsofinsulinlikegrowthfactor
bindingprotein.Theuseofexogenousinsulintomaintainglycemiawithinnormalparametershasprovedtobe
ofbenefit,intermsofoutcome,withpatientssufferingfrommyocardialinfarction.Thereisahypothesisthatin
sepsis,normoglycemiarestoresneutrophilphagocyticcapacity,compromisedbyhyperglycemia.Another
potentialmechanismsistheantiapoptoticeffectofinsulinfromactivationofthephosphatidylinositol3kinase
Aktpathway.1,22Basedontheseprinciples,arandomized,controlled,prospectivestudywasconductedof1,548
adultpatientspostheartsurgery,onmechanicalventilation.Thecontrolgroupreceivedinsulininfusion,when
necessarytomaintainglycemiabetween180and220mg/dl,whilethetreatmentgroupreceivedsystematic
insulininordertomaintainnormoglycemia(glucosebetween80and110mg/dl).Thetreatmentgrouphad
reduced5daymortalityby32%(primaryobjective)andalsolowermortalityduringhospitalization,lower
multipleorganfailuremortalityandfewersepsisepisodes(secondaryobjectives).47

Anotherstrategywhichhasbeensuggestedandhasalreadywonaplaceamongsepsistreatmentstrategiesuse
thetechniquesofextracorporealsubstitution,suchascontinuousarteriovenoushemofiltrationand
plasmapheresis,especiallyincasesofseveresepsisandMOFS.Theymaybeusedatanyphaseofthe
inflammatoryprocesswiththeobjectiveofreducingconcentrationsofinflammatorycascadeinflammatory

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mediators(exogenousandendogenous),andconsequentiallytheirpotentialtocausedamagetotargetorgans.A
multicenter,randomizedandcontrolled,multicenterclinicaltrialatseventertiaryICUswith30patientswith
sepsissubjectedtocontinuousplasmapheresisfor34hours,onlyfoundattenuationoftheacutephasesepsis
responseandareducedtendencytoorganfailure,butwithnoeffectofcytokineresponseoronfinal
mortality.48Arandomizedandcontrolledclinicaltrialinvolving106adultpatientswithseveresepsisorseptic
shock,showedthatthegrouptreatedwithplasmapheresishadamortalityrate28daysafterdischargethatwas
20%lowerthanthecontrolgroupthatreceivedstandardtreatmentforshock.49

Despitesomeinitiallyencouragingresults,themajorityofresearchintosubstancesthatareinflammatory
reactionmodulatorsfailedtoeffectivelyreducemortality.Thereasonspostulatedforthisfailureinclude
disparitiesbetweenanimalmodelsandclinicalreality,theheterogeneousnatureofthepatientsandtheir
manifestationsofsepsis,andthecomplexityoftheinflammatorycascade.50

Otherpotentialtherapies

Innumerablenewagentsappeartobeeffectiveinanimalmodels,creatingnewhopeforsepsistreatment.
InterferonhasbeenconsideredcapableofrestoringmacrophageHLADRexpressionandTNFproductionin
patientswithsepsis.TheadministrationofantibodiesagainstproductsofC5aactivationreducedthefrequency
ofbacteremia,preventingapoptosisandimprovingsurvival.Theadministrationofantibodiesagainst
macrophagemigrationinhibitoryfactorprotectedratsfromperitonitis.Strategiestoblocklymphocyteor
gastrointestinalepithelialcellapoptosishaveimprovedsurvivalratesinexperimentalsepsismodels.1

Concluding,wecanstatethat,despitethediagnostictechnologicaladvancesofrecentyears,littleprogresshas
beenachievedintermsofchangingthemortalityofsepsis.Thisisduetothecomplexityofaggressorhost
relationships,whichcannotberegulatedandwhosemodulationdependsmuchmoreonhostresponsethanon
therapeuticintervention.Certainstrategiesarecertainlyofbenefit,suchasearlyrecognitionofsepsis,
aggressiveinitialinterventionagainsthemodynamicdisturbancesandrationalhandlingofantimicrobial.Any
advanceintheunderstandingofthethesethreestrategieswillundoubtedlyincreasethechancesofagood
prognosis,althoughitisnotexpectedthattheincreasewouldbeofanygreatmagnitude.Thecombinationof
immunomodulatorytherapiesappearstobethefutureforresearchinthisarea.Corticoiduse,forpatientswith
orwithoutadrenalinsufficiencyisresurfacingasapromisingstrategy.Similarly,drotrecoginappearstobe
theonlysubstancewhichhasdemonstratedanimpactonmortality,althoughinanunexceptionalmanner.
Nevertheless,werecommendcautionwiththeinitialenthusiasmaboutdrotrecogin,takingintoaccountthefact
thatsincethepublicationoftheoriginalexperimenttherehasbeennoreproductionoftheresearchina
differentscenario.Becauseofthepeculiaritiesofchildren,thescarcityofstudiesandthecomplexityofsepsis
inthisagegroup,pediatriciansshouldbealerttonewdiscoveriesinthisarea.

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Correspondenceto
PauloR.A.Carvalho
Av.Encantado,249
CEP904770420PortoAlegre,RS

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Brazil
Email:carvalho.conex@uol.com.br

Allthecontentsofthisjournal,exceptwhereotherwisenoted,islicensedunderaCreativeCommonsAttributionLicense

Av.CarlosGomes,328cj.304
90480000PortoAlegreRSBrazil
Tel.:+555133289520

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