Predictive Value of Several Signs of Infection as Surrogate Markers for Mortality in a Neutropenic Guinea Pig Model of Pseudomonas aeruginosa Sepsis

摘要

Infected,neutropenicanimalsareusedasexperimentalmodelstoevaluatetherelativeefficaciesofantimicrobialagentsandhost-pathogen-antibioticinteractions.Inthepast,thesemodelsuseddeathasthestudyendpoint.Becauseoftheconcernaboutuseofdeathasanendpoint,weevaluatedtheaccuracywithwhichvarioussignsofinfectionpredictedmortalityinaneutropenicguineapigmodeloftreatedanduntreatedPseudomonasaeruginosasepsis.Thepotentialsurrogatemarkersstudiedincludedruffledfur,respiratorydistress,diarrhea,hunchedposture,lethargy,abnormalneurologicmovements(twitching,paralysisofalimb),inappetencefor48h,theinabilitytoambulate,andtheinabilityofasupineanimaltostand.Inaddition,weevaluatedwhetherpercentageofweightlossorchangeindailyfoodandwaterconsumptionwerepredictiveofmortality.Animalswereinspectedforthesesignsatleastevery4hduringthedayandevery8hintheevening.Intreatedanduntreatedanimals,100%ofsubjectsthatwereunabletoambulateortorisefromthesupinepositiondied(positivepredictivevaluefordeathwas100%foreithersign).Guineapigsthatcouldnotrisefromasupinepositionexpiredbetween1and8hafterthissignwasobserved.Thosethatcouldnotambulatediedbetween4and40hafterthatsignwasobserved.Intreatedanduntreatedanimals,noneofthesurvivorsmanifestedeithersignofdisease(100%specificityforeachsign).However,59%ofuntreatedand69%oftreatedanimalsthatwereambulatorywerefounddeadatthenextobservationperiod,underscoringtherapiditywithwhichthisinfectionprogressestodeathwhenitentersitsfinalstage.Noothersignsofinfectiondistinguishedanimalsthatsurvivedordied.Thus,theinabilityofneutropenic,infectedguineapigstorisefromasupinepositionandtheinabilitytoambulateweretheonlysignsthataccuratelypredicteddeathand,therefore,aretheonlysignsthatcanbeusedassurrogatesfordeathinthisexperimentalmodelofP.aeruginosasepsis.