2003-N-ENG-J-The-Pathophysiology-and-Treatment-of-

reviewarticleThenewenglandjournalofmedicinenengljmed348;2(R.S.H.),Medicine(R.S.H.,I.E.K.),andSurgery(R.S.H.),WashingtonUniversitySchoolofMedicine,St.Louis.Addressre-printrequeststoDr.HotchkissattheDe-partmentofAnesthesiology,WashingtonUniversitySchoolofMedicine,CampusBox8054,St.Louis,MO63110,[e-mail]deathincriticallyillpatientsintheUnitedStates.Sepsisdevelopsin750,000peopleannually,andmorethan210,000ofthemdie.1,2Afternumerousunsuccessfultrialsofantiinflammatoryagentsinpatientswithsepsis,investigatorsdoubtedthatmortalitycouldbedecreased.Advancesinunravelingthepathophysiolo-gyandgeneticbasisforthehostresponsetosepsishavechangedtheprevailingunder-standingofthesyndrome,andseveraltherapieshavedemonstratedsurprisingeffica-cy.Inthisarticle,weexamineevolvingconceptsofsepsisanddiscussnewandpotentialtherapies.Theprevailingtheoryhasbeenthatsepsisrepresentsanuncontrolledinflammatoryresponse.3-5LewisThomaspopularizedthisnotionwhenhewrotethat“themicro-organismsthatseemtohaveitinforus...turnout...toberathermorelikebystanders....Itisourresponsetotheirpresencethatmakesthedisease.Ourarse-nalsforfightingoffbacteriaaresopowerful...thatwearemoreindangerfromthemthantheinvaders.”6Aconsensusconferencedefinedsepsisas“thesystemicin-flammatoryresponsesyndromethatoccursduringinfection.”3Numeroustrialswereconductedofagentsthatblocktheinflammatorycascade—corticosteroids,7antien-dotoxinantibodies,8tumornecrosisfactor(TNF)antagonists,9,10interleukin-1–recep-torantagonists,11andotheragents.12Thefailureofantiinflammatoryagentsledinves-tigatorstoquestionwhetherdeathinpatientswithsepsisresultsfromuncontrolledinflammation.4,13-15Clinicaltrialsoftreatmentsforsepsisaredifficultbecauseoftheheterogeneityofpatientsandthehighratesofculture-negativesepsis.Interpretationiscomplicated,becausetheanalysisofoutcomesgeneratesposthocstratificationsthathavenotbeenprospectivelydefined.Thetheorythatdeathfromsepsiswasattributabletoanoverstimulatedimmunesystemwasbasedonstudiesinanimalsthatdonotseemtoreflecttheclinicalpictureinhumans.16-18Thesestudiesusedlargedosesofendotoxinorbacteria;consequently,levelsofcirculatingcytokinessuchastumornecrosisfactora(TNF-a)wereexponen-tiallyhigherinanimalsthantheyareinpatientswithsepsis.17Inthesestudies,thean-imalsdiedfrom“cytokinestorm,”andcompoundsandmacromoleculesthatblockthesemediatorsimprovedsurvival.16-18Incertainformsofsepsis—forexample,meningococcemia—circulatingTNF-alevelsarehighandcorrelatewithmortality.19,20Of55childrenwithsevereinfectiouspurpura(32ofthemwithNeisseriameningitidisinfection),91percenthadelevatedlevelsofcirculatingTNF-a.19Nevertheless,studieshaveshownthatthefrequencyofanex-aggeratedsystemicinflammatoryresponseislowerthanitwasoriginallythoughttobe.21-24Debetsetal.reportedthatonly11of43patientswithsepsishaddetectablecir-culatingTNF(limitofdetection,5to10pgpermilliliter).21Inanotherstudyof87pa-sadisorderduetouncontrolledinflammation?Downloadedfrom©2003MassachusettsMedicalSociety.Allrightsreserved.nengljmed348;2(approximately10percent)benefited.13Advancesinourunderstandingofcell-signal-ingpathwaysthatmediatetheresponsetomicrobeshavedemonstratedthattheconceptofblockingendotoxininordertopreventsepticcomplicationsmaybesimplistic.Cellsoftheinnateimmunesys-temrecognizemicroorganismsandinitiaterespons-esthroughpattern-recognitionreceptorscalledtoll-likereceptors(TLRs).30-32InsightintotheroleofTLRsincombatinginfectionhasbeenprovidedbystudiesinC3H/HeJmice,30whichareresistanttoendotoxinbecauseofamutationinthetoll-likere-ceptor4gene(TLR4).Despitetheirresistancetoendotoxin,thesemicehaveincreasedmortalitywithauthenticsepsis.33,34TLR4mutationshavebeenidentifiedinhumansandmaymakepersonsmoresusceptibletoinfection.35Therefore,althoughen-dotoxinhasdeleteriouseffects,totalblockadeofen-dotoxinmayb