Timing of Vasopressor Initiation & Mortality in Septic Shock

12/7/2014 www.medscape.
com/viewarticle/829233_print
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TimingofVasopressorInitiationandMortalityin
SepticShock
ACohortStudy
VanceBeck,DanChateau,GregoryLBryson,AmarnathPisipati,SergioZanotti,JosephE
Parrillo,AnandKumar
CritCare.201418(R97)
AbstractandIntroduction
Abstract
Introduction:Despiterecentadvancesinthemanagementofsepticshock,mortalityremainsunacceptablyhigh.
Earlierinitiationofkeytherapiesincludingappropriateantimicrobialsandfluidresuscitationappearstoreducethe
mortalityinthiscondition.Thisstudyexaminedwhetherearlyinitiationofvasopressortherapyisassociatedwith
improvedsurvivalinfluidtherapyrefractorysepticshock.
Methods:Utilizingawellestablisheddatabase,relevantinformationincludingdurationoftimetovasopressor
administrationfollowingtheinitialdocumentationofrecurrent/persistenthypotensionassociatedwithsepticshock
wasassessedin8,670adultpatientsfrom28ICUsinCanada,theUnitedStatesofAmerica,andSaudiArabia.The
primaryendpointwassurvivaltohospitaldischarge.SecondaryendpointswerelengthofICUandhospitalstayas
wellasdurationofventilatorsupportandvasopressordependence.Analysisinvolvedmultivariatelinearandlogistic
regressionanalysis.
Results:Intotal,8,640patientsmetthedefinitionofsepticshockwithtimeofvasopressor/inotropicinitiation
documented.Ofthese,6,514weresuitableforanalysis.Theoverallunadjustedhospitalmortalityratewas53%.
Independentmortalitycorrelatesincludedliverfailure(oddsratio(OR)3.46,95%confidenceinterval(CI),2.67to
4.48),metastaticcancer(OR1.63,CI,1.32to2.01),AIDS(OR1.91,CI,1.29to2.49),hematologicmalignancy(OR
1.88,CI,1.46to2.41),neutropenia(OR1.78,CI,1.27to2.49)andchronichypertension(OR0.62CI,0.52to0.73).
Delayofinitiationofappropriateantimicrobialtherapy(OR1.07/hr,CI,1.06to1.08),age(OR1.03/yr,CI,1.02to
1.03),andAcutePhysiologyandChronicHealthEvaluation(APACHE)IIScore(OR1.11/point,CI,1.10to1.12)were
alsofoundtobesignificantindependentcorrelatesofmortality.Afteradjustment,onlyaweakcorrelationbetween
vasopressordelayandhospitalmortalitywasfound(adjustedOR1.02/hr,95%CI1.01to1.03,P<0.001).Thisweak
effectwasentirelydrivenbythegroupofpatientswiththelongestdelays(>14.1hours).Therewasnosignificant
relationshipofvasopressorinitiationdelaytodurationofvasopressortherapy(P=0.313)andonlyatrendtolonger
durationofventilatorsupport(P=0.055)amongsurvivors.
Conclusion:Markeddelaysininitiationofvasopressor/inotropictherapyareassociatedwithasmallincreasein
mortalityriskinpatientswithsepticshock.
Introduction
Despiteadvancementsinunderstandingandtreatment,septicshockremainsaworldwidehealthcareproblem.With
anincreasingannualincidenceinthedevelopedworld,mortalityremainsbetween25and50%ofthoseafflicted. [13]
Thepathophysiologyofsepticshockiscomplexandinvolvesvasodilatation,relativeandabsolutehypovolemia,
myocardialdysfunction,increasedmetabolicrateandalteredregionalandmicrovascularbloodflow. [411]Septic
shockappearstocausealossofautoregulation,makingtheperfusionofmanyvitalorgansandtissuesdependenton
bloodpressure. [5,12,13]Earlyandaggressivefluidresuscitationofsepsishasbeensuggestedtohaveacriticalrolein
optimizationoforganperfusion,preservationofendorganfunctionandimprovementofsurvival. [14]
http://www.medscape.com/viewarticle/829233_print 1/18
12/7/2014 www.medscape.com/viewarticle/829233_print
Hypotensiondespiteadequatefluidresuscitationtherapyisadefiningcriterioninthediagnosisofsepticshock. [15]To
maintainorganperfusion,currentguidelinesrecommendmaintainingameanarterialpressure(MAP)of65mmHg
withfluidtherapyandvasopressorsevenwhenhypovolemiahasnotyetbeenresolved. [15]AccordingtotheSurviving
SepsisCampaignthisrecommendationisconsidered'strong'althoughsupportingevidenceisconsidered'weak'. [15]
Manystudieshavecompareddifferentvasopressoragentsfortheresuscitationofsepticshockbutveryfewhave
investigatedtherolethatthetimingofvasopressorinitiationinrelationtohypotensiononsetplaysinoutcome. [16,17]
Methods
StudyDesign
Datafromaretrospectivereviewofadultpatients(18yearsold)diagnosedwithsepticshockwasusedtocreatethe
CooperativeAntimicrobialTherapyofSepticShockDatabase(memberlistinginAdditionalfile1
http://ccforum.com/content/18/3/R97/additional).Consecutiveadultsepticshockpatientsfrom28medicalinstitutions
inCanada,theUnitedStatesandSaudiArabiaforperiodsbetween1996and2008wereretrospectivelyidentified
usingeitherinternalICUregistries/databasesand/orInternationalClassificationofDiseases(ICD9orICD10)coding
strategies.Patientsfromsurgical,medicalandmixedICUswereincluded.Eachpotentialcasewasscreenedto
determineeligibilitytomeetthecriteriaforsepticshockasdescribedbythe1991SocietyofCriticalCare
Medicine/AmericanCollegeofChestPhysiciansconsensusstatementonsepsisdefinition. [18]Allincludedcases
wererequiredtohavenootherobviouscauseofshock.Eachinstitutioncontributedaminimumof50cases.Awaived
consentprotocolwasapprovedbytheHealthEthicsBoardoftheUniversityofManitobaandateachindividual
participatingcenter(listinginAdditionalfile2http://ccforum.com/content/18/3/R97/additional).TheEthicsBoards
waivedtheneedforinformedconsentbecauseoftheretrospective,riskfreenatureofthestudyincombinationwith
theuseofdeidentifieddata.
DataManagement
Dataincludingthetimetovasopressoradministrationafterdocumentationofpersistentorrecurrenthypotension
refractorytofluidadministrationwereretrospectivelycollectedfromclinicalrecordsusingauniformdataextraction
templatebyseveraltrainedresearchnursesorresearchassistantswithmedicaltraining(medicalstudents,
residents,fellows).Alldataextractorsreviewed>100charts.
Hypotensionwasdefinedasameanbloodpressure<65mmHg,asystolicbloodpressure<90mmHg,oradecrease
insystolicpressureof40mmHgfromthepatient'sbaselineconsistentwiththeSocietyofCriticalCare
Medicine/AmericanCollegeofChestPhysicianscriteriaforsepticshock. [18]Anepisodeofhypotensionwas
consideredtorepresenttheinitialonsetofsepticshockwhenhypotensionpersistedfromtheonsetdespitefluid(>2l
salineorequivalent)administration(persistenthypotension),orwhenhypotensionwasonlytransientlyimproved
(hypotensionresolutionfor<1hour)withfluidresuscitation(recurrenthypotension).Hypotensionthatresolved
followingfluidresuscitationalone(crystalloidorcolloid)withoutsubsequentclinicaldeteriorationwasnotconsidered
torepresenttheinitialonsetofsepticshockrelatedhypotension.Similarly,patientsexclusivelytreatedwithan
inotropicagentwithoutavasopressorduringthefirst24hourswereexcludedfromthedatabase.Organfailurewas
determinedaccordingtopreviouslydescribedcriteria. [3,19]
StatisticalAnalysis
StatisticalanalysiswasperformedusingSASversion9.1(Cary,NCUSA).Descriptivestatisticswereusedto
characterizethepatientpopulation,includingmeanandstandarddeviationforcontinuousvariables(ormedianand
interquartilerangeforskeweddistributions)andfrequencyandproportionforcategoricalvariables.Empiricallogit
plotswereusedtoexplorethefunctionalformoftheassociationbetweenvasopressordelayfraction(analyzed
continuouslyandalsoascategorizedatdecilecutpoints)andsurvivaltohospitaldischarge.Theshortesttimedelay
decile(6minutes)wasexcludedfromtheanalysisasthisusuallyrepresentscaseswherehypotensionexistedfor
anunknownperiodbeforearrivalintheemergencydepartment.Inthiscircumstance,thetruetimefromhypotension
onsettovasopressorinitiationisindeterminate.
Theunadjustedassociationbetweensurvivaltohospitaldischargeandvasopressordelaywasestimatedusingsimple
logisticregression.Asimilaranalysiswasdonewithrespecttotheoccurrenceofindividualandtotalnumberoforgan
failuresafterthedayofshock(incrementalorganfailuresfromday2today10).Awidevarietyofepidemiologic
factors(age,sex),comorbidities(AIDS,hematologicmalignancy(lymphoma/leukemia/multiplemyeloma),metastatic
cancer,heartdisease,organtransplant,hypertension,respiratorydisease,renaldisease,diabetes,autoimmune
conditions,thromboembolism,neurologicaldiseases),severityofillness(AcutePhysiologyandChronicHealth
Evaluation(APACHE)score), [20]laboratoryvalues(admissionlacticacidandbicarbonatelevels,whitecellcount)and
therapeuticelements(timetoinitialappropriateantimicrobialtherapy)werefirstassessedwithrespecttohospital
survivalandorganfailureusingunivariateanalysis.ThosethatweresignificantatP<0.05wereretainedforinclusion
inthemodel.Multivariablelogisticregressionwasthenusedtoestimatetheadjustedassociationandtoidentify
independentcorrelatesofmortalityandorganfailure.Mortalityandindividualorganfailureresultsareexpressedas
oddsratios(ORs)with95%confidenceintervals(CIs).Totalincrementalorganfailureaftertheadmissionday(day2
today10)wasanalyzedusingPoissonregressionwithresultsexpressedasrateratios.Becausehospitallengthof
stay(LOS)andICULOSarecountvariables,thesesecondaryoutcomeswereanalyzedusinggeneralizedlinear
regressionwithanegativebinomialdistributionandlogarithmiclinkfunction,adjustedforthesamecovariatesasin
theprimaryoutcomeanalysis.Dataareexpressedasmeanstandarddeviationormedianwithinterquartilerange
asappropriate.
Results
Therewereatotalof8,670patientsthatfitthediagnosticcriteriaforsepticshock.Thirtypatientsdidnothaveatime
ofvasopressorinitiationavailableandwereexcluded.Another2,126patientswereexcludedduetoinadequatedata
acquisitionofothersignificantanalyticvariables,primarilytimetoappropriateantimicrobialtherapyfrom
documentationofhypotension.Intotal,6,514observationswereincludedinthisanalysis.
DemographicCharacteristicsandExistingComorbidity
Thebaselinecharacteristicsofthepatientsintheentirecohortarepresentedin.Theaverageagewas621years
withmalepredominance(57.0%).Themostcommonexistingcomorbiditieswerediabetesinclusiveoforal
hypoglycemicandinsulinrequiring(26.6%),chronicrenalfailureinclusiveofdialysis(23.6%),andhypertension
(19.1%).IllnessseverityispresentedinwiththeaverageAPACHEIIscorebeing26.18.2.Baseline(day1)
laboratoryresultsalsopresentedinshowedelevatedlevelsofserumcreatinine(219181mol/l),leukocytecount
(16.316.1106cells/l),InternationalNormalizedRatio(1.51.4)andserumlactate(4.84.4mmol/l).Theheart
ratewaselevatedat11529beats/minute.Approximately40%ofcaseswereduetonosocomiallyacquired
infection().Culturenegativeandbacteremic/fungemicpatientseachaccountedforaboutonethirdofthecohort.The
lungs,abdomenandurinarytractwerethemostcommoninfectionsitesandEscherichiacoli,Staphylococcus
aureusandStreptococcuspneumoniaewerethemostfrequentlyisolatedpathogens().
Table1.Epidemiologiccharacteristicsofthestudycohort(n=6,514)
Characteristic Number Percentage
Malegender 3,711 57.0
Age(years)a 62.116.1
Comorbiddisease
AIDS 176 2.7
Lymphoma 238 3.7
Leukemia 347 5.3

Metastaticcancer 566 8.7
Immunosuppressed 959 14.7
Neutropenia 321 4.9
Liverfailure 508 7.8
NYHAclassIVheartfailure 196 3.0
Congestiveheartfailure 704 10.8
Acutecoronarysyndrome 74 1.1
Ischemicheartdisease 789 12.1
Hypertension 1,245 19.1
COPD(onmedications) 483 7.4
Chronicrenalfailure 1,024 15.7
Dialysis 512 7.9
Diabetesmellitus(oralhypoglycemicdependentinsulin) 1,169 17.9
Diabetesmellitus(insulindependent) 568 8.7
Electivesurgery 939 14.4
Emergencysurgery 473 7.3
Alcoholabuse 891 13.7
Autoimmunedisease 306 4.7
Organicbraindisease 362 5.6
Neuromusculardisease 106 1.6
COPD,chronicobstructivepulmonarydiseaseNYHA,NewYorkHeartAssociation. aPresentedasmeanstandard
deviation.
Table2.Laboratoryvaluesandseverityofillnesscharacteristics
Parameter Mean Standarddeviation
APACHEIIscore 26.1 8.2
Bloodassayonday1
Creatinine(mol/l) 219 181
Bilirubin(mol/l) 41 84
Bicarbonate(mEq/l) 19.4 6.5
Lactate(mmol/l) 4.8 4.4
Platelets(109/l) 196 139
InternationalNormalizedRatio 1.8 1.4
Whitebloodcellcount(106/l) 16.3 16.1
Heartrate(/minute) 115 29
Number Percentage
Infectioncharacteristics
Nosocomial 2,594 39.8
Bacteremia/fungemia 2,895 34.6
Culturepositive 4,584 70.4
Primaryinfectionsite
Pulmonary 2,643 40.6
Abdominal/gastrointestinal 1,814 27.8
Urinary 691 10.6
Skin/softtissue 469 7.2
Centralnervoussystem 54 8.3
Intravascularcatheter 224 3.4
Primarybloodstream 379 5.8
Disseminatedsystemic 135 2.1
Boneandjoint 42 0.6
Mediastinal 63 1
Infectingorganism
Staphylococusaureus 778 17.0
Sreptococcuspneumoniae 350 7.6
Otherstreptococci 272 5.9
OtherGrampositivecocci 218 4.8
Escherichiacoli 940 20.5
Otherenterobacteriaciae 773 16.9
NonenterobacteriaciaeGramnegativebacilli 464 10.1
Miscellaneousbacteria 314 6.8
Candida/fungi 474 10.3
APACHE,AcutePhysiologyandChronicHealthEvaluation.
Bloodassayonday1
Number Percentage
Urinary 691 10.6
Boneandjoint 42 0.6
Mediastinal 63 1
Infectingorganism
Bloodassayonday1
Number Percentage
Urinary 691 10.6
Boneandjoint 42 0.6
Mediastinal 63 1
Infectingorganism

Bloodassayonday1
Number Percentage
Urinary 691 10.6
Boneandjoint 42 0.6
Mediastinal 63 1
Infectingorganism
TreatmentCharacteristics
Themediantimetovasopressorinitiationwas3hours(25to75%range:1to7.1hours).Thedistributionof
vasopressoruseispresentedin.Themostcommonlyusedvasopressorwasnorepinephrineinabouttwothirdsof
patients,withdopaminebeingthesecondmostcommonusedinapproximatelyonehalf.Useofagivenvasopressor
wasnotexclusiveofuseofothers.Dobutamine,aninotropicagent,wasusedforatleast30minutesduringthefirst
24hoursafterpressorinitiationin12.2%ofcases.However,inotropeswereneverinitiatedbeforepressorsandan
intropealonewasneverused(perinclusioncriteria).Steroidswereusedin32%ofpatients.
Table3.Treatmentandvasopressorusecharacteristics
Treatment Number Percentage
Steroids 1,893 21.8
ActivatedproteinC 292 3.4
Sourcecontrolrequired 2,564 39.4
Pressor/inotropeagentsusedinfirst24hours
Norepinephrine 4,376 67.2
Dopamine 3,502 53.8
Phenylephrine 1,466 22.5
Dobutamine 793 12.2
Vasopressin 708 10.7
Epinephrine 313 4.8

Outcomes
Theoverallunadjustedmortalityratewas53%.Unadjustedmortalityamongdecilesrangedfrom47.6%to63.0%
(Figure1).
Figure1.

Unadjustedmortalityineachpressordelaydecile.
IndependentCorrelatesofMortality
Thesignificantindependentcorrelatesofmortalityfromthemultivariableanalysisarepresentedininorderof
descendinginfluenceonmortalitybasedonWald 2values.Amongthesecorrelates,theAPACHEIIscorewas
mostsignificantwithanORof1.11perpoint(95%CI=1.10to1.12).Antimicrobialdelaywasthenextmost
importantvariable,eachhourofdelaywasassociatedwitha7%increaseinmortality(OR=1.07,95%CI=1.06to
1.08)andagewasassociatedwitha2.6%increaseinmortalityperyearoflife(OR=1.03,95%CI=1.02to1.03).
Amongcategoricalvariables,liverfailurehadthestrongestassociationwithmortality(OR=3.46,95%CI=2.67to
4.48).Ahistoryofhypertensionwasfoundtoconveyaprotectiveeffect(OR=0.62,95%CI=0.52to0.73).
Table4.Multivariatecorrelatesofdeathinsepticshock
OR 95%CI Pvalue Wald 2
APACHEIIscore(perpoint) 1.11 1.10to1.12 <0.0001 544.6
Antimicrobialdelay(perhour) 1.07 1.06to1.08 <0.0001 335.6
Age(peryear) 1.03 1.02to1.03 <0.0001 127.1
Liverfailure 3.46 2.67to4.48 <0.0001 88.3
Hypertension 0.62 0.52to0.73 <0.0001 32.2
Hematologicmalignancy 1.88 1.46to2.41 <0.0001 24.1
Metastaticcancer 1.63 1.32to2.01 <0.0001 20.4
Vasopressordelay(perhour) 1.02 1.01to1.03 0.0099 20.1
Neutropenia 1.78 1.27to2.49 0.0008 11.2
AIDS 1.91 1.29to2.81 0.0011 10.7
APACHE,AcutePhysiologyandChronicHealthEvaluationCI,confidenceintervalOR,oddsratio.
Afteradjustingforindependentcorrelatesofmortality(AIDS,hypertension,liverfailure,neutropenia,malignancy,
metastaticdisease,APACHEIIscoreanddelayinappropriateantimicrobials),therewasaweakassociationofdelay
ofvasopressorswithinhospitalmortality(adjustedOR=1.02,95%CI=1.01to1.03,P<0.001).Toexaminethe
impactofdelaysinvasopressorinitiationfurther,decilesofdelaywereexaminedinthemodel.Theresultsareshown
inFigure2.Atincreasingdelaysofapproximately0.50to1.15hours,1.16to2.00hours,2.01to2.90hours,2.91to
4.00hours,4.01to5.75hours,5.76to8.45hours,8.46to14.10hoursand>14.10hours(referenceseconddecile,7
to30minutesaspertheanalysisprotocol),theadjustedORofsurvivalwassignificantlyincreasedonlyforthefinal,
latestdecile(OR=1.34,95%CI=1.03to1.76,P=0.048).
Figure2.

Oddsratio(95%confidenceinterval)ofmortalityforeachpressordelaydecile(referencedecile,0.11to0.5hours).
SecondaryOutcomeAnalysis(OrganFailureandLengthofStay)
Secondaryoutcomeswereadjustedforthesameindependentpredictorsofmortalityastheprimaryoutcome.Inboth
unadjustedandadjustedanalyses,astrongtrendoractualsignificancewasfoundbetweenthedelaytopressor
initiationandtheoccurrenceoforganfailures.AdjustedPvalueswereasfollows:renal,P=0.0182respiratory,P<
0.0001hematologic,P=0.0788centralnervoussystem,P=0.0208coagulation,P=0.0089metabolic,P<
0.0001.Notably,ineachcase,thelastdecile(>14.1hours)accountedfortheimpactofpressordelayonthe
occurrenceoforganfailure.Inaddition,thetotalincrementalorganfailuresafterthedayofpresentation(thatis,day2
today10)wasassociatedwithpressordelay.Again,thisrelationshipwasdrivenbythelastdecileofdelay(Figure
3).
Figure3.

Mean(95%confidenceinterval)incrementalorganfailures(day2today10afterpresentation)withincreasing
pressordelays.
Forthesurvivors,whilecontrollingforsignificantvariables,delayinvasopressorinitiationwasnotpredictiveofhospital
LOS(P=0.19)orICULOS(P=0.17).Inaddition,therewasnosignificantimpactondurationof
vasopressor/inotropictherapy(P=0.313)andonlyatrendtowardsalongerdurationofventilatorsupport(P=0.055)
amongsurvivors.
Discussion
Hypotensionisacentralfeatureinthepathophysiologyofsepticshock.Thedurationofhypotensionbefore
interventionincardiogenicshockcausedbymassivemyocardialinfarction,obstructiveshockduetopulmonary
embolusandhypovolemicshockduetomajortrauma/hemorrhageisakeydeterminantofsurvival. [2125]Outcomein
theseconditionsiscloselyassociatedwithearlierinitiationoftherapy. [2126]Similarly,insepticshock,early
initiationoffluidresuscitationandrapidadministrationofappropriateantimicrobialsarecriticaldeterminantsof
outcomeandcentraltenetsofmanagement. [14,27,28]Basedonthesefactors,wehypothesizedthatlongerdurationof
hypotensionwithouthemodynamicsupportusingvasopressorinfusionmayresultinahighermortalityrateandan
increasedincidenceoforganfailureinsepticshockpatients.
Ourstudydemonstratesthattheintervalbetweendiagnosisofsepticshockandtheadministrationofvasopressor
agentsisasignificantalthoughmodestindependentcorrelatetoinhospitalmortalityanddevelopmentoflateorgan
failure.Theentireincreasingmortalityeffectwithincreaseddelaysinvasopressorinitiationisrelatedtotheincreased
mortalityinthefinaldecilegroup(>14hoursposthypotensiondocumentation)relativetothereferencegroup.
Similarly,increasingprobabilityofincrementalaggregateorganfailuresafterthedayofshock(thatis,day2today
10)isonlyseeninthehighestdelaydecilegroups(>14hoursposthypotensiondocumentation).Newonsetrenal,
respiratory,centralnervoussystem,coagulationandmetabolicfailureswerealsoindividuallyassociatedwithpressor
delays>14hours.Perhapsbecauseofthemodeststrengthofthecorrelationbetweenpressordelayand
mortality/organfailure,thereisnoassociationinthesurvivorgroupwithICUorhospitallengthofstay,ventilator
durationortotalvasopressoradministrationtime.
Studieshaveshownthatsepticshockasdefinedinpartbypersistenthypotensionisanindicatorofamarked
increaseinmoralityriskinsepticstates. [29,30]Atleasttworetrospectivehumansepticshockstudiesshowan
increasingmortalitywithincreasingseverityanddurationofhypotension. [31,32]Varpulaandcolleaguesshowedin111
septicshockpatientsthatthetimespentbelowaMAPof65mmHginthefirst48hourswasastrongpredictorof
mortality. [31]Inanotherretrospectivestudy,Dnserandcolleaguessimilarlymeasuredtheareaunderthecurvefor
MAPandeffectonmortalityin274sepsispatients. [32]ThisstudydemonstratedthatthetimespentwithMAP<55
mmHgwasassociatedwithincreasedriskofdeath.However,asimilarcorrelationdidnotexistwiththeduration
whenMAPwas<60mmHg,<65mmHg,<70mmHgand<75mmHg.
Whiletherehasbeenmuchstudyintothecomparisonofvasopressors/inotropesindividuallyandincombination, [33
35]therehasbeenarelativepaucityintheliteratureregardingthetimingoftheirinitiationinsepticshock.The2012
SurvivingSepsisGuidelinesrecommendthatvasopressorsupportbestartedforfluidrefractoryshockaspartofthe6
hourbundlebasedsolelyonexpertopinion. [15]Aratmodelofendotoxicshockhassuggestedpotentialbenefitwitha
higherproportionatesplanchnicbloodflow,lowerlactatelevelsandlessoverallfluidsupportrequirementforearly
comparedwithdelayednorepinephrineadministration. [36]Aporcinemodeloffecalperitonitis/shockhas
demonstratedthatdelayedresuscitation(inclusiveofantibiotics,fluidsandpressors)wasassociatedwithincreased
physiologicinstabilityandhigherpressorrequirements. [37]Conversely,inasmall(n=95)retrospectivehumanstudy,
nodifferenceinorgandysfunctionorICULOSwasnotedwithearly(<1.37hours)versuslate(>1.37hours)
administrationofvasopressors. [16]Thesestudieshavetheirlimitationsinthattwowereanimalstudiesandnone
utilizedsurvivalasanendpoint.
Inourstudy,thetimingofinitiationofvasopressorsfollowingdocumentationofhypotensionisonlyweaklyassociated
withmortalityinsepticshock,asindicatedbythelowWaldX 2valuesin.TheWaldX 2valuefordelaysin
antimicrobialinitiation,theotherremediabletreatmentparameterinthemultivariateanalysis,is16.7timeshigher.
Notethatthisdoesnotsuggestthatdurationofhypotensionbeforeresuscitation(inclusiveofappropriate
antimicrobialsandfluidresuscitation)isonlyweaklycorrelatedtooutcome.Onthecontrary,appropriateantimicrobial
delaysrelativetohypotensionandearlyfluidresuscitationarewellestablishedtohavecriticalrolesinimproving
outcomeofsepticshock. [14,28]Onlythedelayofvasopressorsappearstohavealimitedimpactonoutcomeinthis
retrospectiveanalysis.
Table4.Multivariatecorrelatesofdeathinsepticshock
OR 95%CI Pvalue Wald 2
APACHEIIscore(perpoint) 1.11 1.10to1.12 <0.0001 544.6
Antimicrobialdelay(perhour) 1.07 1.06to1.08 <0.0001 335.6
Age(peryear) 1.03 1.02to1.03 <0.0001 127.1
Liverfailure 3.46 2.67to4.48 <0.0001 88.3
Hypertension 0.62 0.52to0.73 <0.0001 32.2
Hematologicmalignancy 1.88 1.46to2.41 <0.0001 24.1
Metastaticcancer 1.63 1.32to2.01 <0.0001 20.4
Vasopressordelay(perhour) 1.02 1.01to1.03 0.0099 20.1
Neutropenia 1.78 1.27to2.49 0.0008 11.2
AIDS 1.91 1.29to2.81 0.0011 10.7
APACHE,AcutePhysiologyandChronicHealthEvaluationCI,confidenceintervalOR,oddsratio.
Giventhemodeststrengthoftheassociation,thestatisticalsignificanceoftimetovasopressorinitiationrelates
primarilytotheextraordinarilylargenumberofcasesinthisdataset.Theonlydecilegroupthatappearstocarryan
increasedmortalityorspecificorganfailureriskrelativetothereferencegroupisthelatestgroup(>14hourspost
hypotensiondocumentation).Allincludeddecilestothatpointappeartocarrynosignificantincreasedmortalityor
specificorganfailureriskafteradjustmentformultiplemorbid/epidemiologicfactors.Thisfindingisentirelycongruent
withthefindingsofSubramanianandcolleagues,whoshowednoimpactofvasopressordelaysupto12hourson
organfunctioninasmallercohortof<100patients. [16]
Ahistoryofhypertensionconveyingaprotectiveeffectwasanunexpectedresultonmultivariateanalysis.Itis
possiblethatthisfindingmaybeexplainedbyuserbias,inthatthesepatientsmayhaveactivatedthehealthcare
systemmorefrequentlytogainadiagnosisofanotherwisesilentcondition.Hypertensionisnormallyasilent
condition,whichmaysuggestthatthesepatientshadmoreroutineaccesstomedicalcare.Alternatively,thestudy
entrycriteria(decreaseinsystolicpressure>40mmHg)usedformanyofthesepatientsmaybeoverlysensitivewith
respecttodiagnosingsepticshock.Theimpactofantimicrobialdelayonmortalityisnotsurprisingbecausean
earlierversionofthisdatabasedemonstratedthissamefinding[28]andanimalstudiesdemonstrateparallelresults.
[38,39]
Overall,theresultsofthisstudyarecongruentwiththelimitedavailablehumandata.Thestudycontributes
significantlybyaddingstatisticalpowerwithalargersamplesizewhilecorrectingforknownconfounders
(antimicrobialdelay,diseaseseverity).Therearestillsignificantstudylimitations.Thestudydidcontrolfordelaysin
antimicrobialadministration.However,wewereunabletoadjustforearlyfluidadministrationusingthisdataset.
Althoughfluidresuscitationisconsideredavitalpartoftheinitialresuscitationbyemergencyroomphysiciansand
intensivists, [15]therearestudiessuggestingincreasedmortalityassociatedwithoverresuscitationoffluids. [40,41]
Otherstudiesconverselysuggestincreasedmortalitywithunderresuscitationwithfluids. [14,42]Significant
interactionsbetweenthetimingofvasopressorinitiationandearlyfluidresuscitationthatweareunabletocapturein
thisdatasetmayexist.Thisisasignificantlimitationofthisstudyandfutureanalysesshouldalsoattempttofactor
influidresuscitation.
Thereareotherlimitationstothisstudy.Thisisaretrospectivereviewwithitsinherentinabilitytoaccountforall
potentialconfounders.However,therehasyettobearandomizedcontrolledtrialoftimingofvasopressorinitiationin
anycriticalillness.Giventheethicalconcernsofexposingmoribundpatientstopotentialharm,aprospective,
randomizedhumanstudyoftimingofvasopressorinitiationinsepticshockwouldbechallenging.Anotherlimitationis
thattheuseofhypotensionasthedefiningcriteriaforsepticshockinthispatientgroupmaybeimperfect.MAPisat
bestasurrogateofinadequatemicrovascularperfusioninshock.Itdoesnotdirectlycapturemicrocirculatory
perfusionandcellularinjurythatleadtoorgandysfunctionanddeath. [7,11,13]Nonetheless,othermetabolicmarkers
suchasserumlactateandbicarbonatelevelsaswellasseverityofillnessscores(APACHEIIscores)were
incorporatedintothemodeltohelpadjustforvariationsinshockseverity.Despitetheselimitationsofbloodpressure
monitoring,givenitsuniversalaccessandeaseofuseitisthemostrelieduponclinicalparameterforguidingtherapy
andwillremainamainstayinthetreatmentofsepticshockfortheforeseeablefuture.
Conclusion
Fromthisstudy,weconcludethatmarkedlydelayedinitiationofvasopressormedicationsinpatientswithseptic
shockismodestlyassociatedwithincreasedorganfailureriskanddecreasedsurvival.Substantialdelaysof
vasopressorinitiation(>14hoursafterhypotensiondocumentation)arerequiredtoseetheseeffects.Giventhe
almostuniversaluseofvasopressorsinsepticshockandthecriticalneedforprecisetitration,furtherstudyofthis
areaiswarranted.
Sidebar
KeyMessages
Delaysininitiationofvasopressortherapyfollowingthefirstdocumentationofhypotensioninsepticshockare
modestlyassociatedwithincreasedspecificorganfailureandmortalityrisk.
Thisincreaseinspecificorganfailureandmortalityriskisentirelydrivenbythedecileofpatientswiththe
greatestdelaysof>14hours.
Vasopressorinitiationdelaysarenotassociatedwithincreasedtimeonvasopressorsoronmechanical
ventilationamongsurvivors.
Delayofinitiationofappropriateantimicrobial,ageandAPACHEIIscorearealsoindependentcorrelatesof
mortality.
References
1. MartinGS,ManninoDM,EatonS,MossM:TheepidemiologyofsepsisintheUnitedStatesfrom1979
through2000.NEnglJMed2003,348:15461554.
2. KumarA,EllisP,ArabiY,RobertsD,LightB,ParrilloJE,DodekP,WoodG,KumarA,SimonD,PetersC,
AhsanM,ChateauD,CooperativeAntimicrobialTherapyofSepticShockDatbaseResearchGroup:Initiation
ofinappropriateantimicrobialtherapyresultsinafivefoldreductionofsurvivalinhumansepticshock.Chest
2009,136:12371248.
3. RanieriVM,ThompsonBT,BariePS,DhainautJF,DouglasIS,FinferS,GrdlundB,MarshallJC,RhodesA,
ArtigasA,PayenD,TenhunenJ,AlKhalidiHR,ThompsonV,JanesJ,MaciasWL,VangerowB,Williams
MD:Drotrecoginalfa(activated)inadultswithsepticshock.NEnglJMed2012,366:20552064.
4. HotchkissRS,KarlIE:Reevaluationoftheroleofcellularhypoxiaandbioenergeticfailureinsepsis.JAMA
1992,267:15031510.
5. DeBackerD,CreteurJ,PreiserJC,DuboisMJ,VincentJL:Microvascularbloodflowisalteredinpatientswith
sepsis.AmJRespirCritCareMed2002,166:98104.
6. SakrY,DuboisMJ,DeBackerD,CreteurJ,VincentJL:Persistentmicrocirculatoryalterationsareassociated
withorganfailureanddeathinpatientswithsepticshock.CritCareMed2004,32:18251831.
7. LedouxD,AstizME,CarpatiCM,RackowEC:Effectsofperfusionpressureontissueperfusioninseptic
shock.CritCareMed2000,28:27292732.
8. ParkerMM,ShelhamerJH,BacharachSL,GreenMV,NatansonC,FrederickTM,DamskeBA,ParrilloJE:
Profoundbutreversiblemyocardialdepressioninpatientswithsepticshock.AnnInternMed1984,100:483
490.
9. KumarA,HaeryC,ParrilloJE:Myocardialdysfunctioninsepticshock:PartI,clinicalmanifestationof
cardiovasculardysfunction.JCardiothoracVascAnesth2001,15:364376.
10. AnnaneD,BellissantE,CavaillonJM,AnnaneD,BellissantE,CavaillonJM:Septicshock.Lancet2005,
365:6378.
11. TrzeciakS,DellingerRP,ParrilloJE,GuglielmiM,BajajJ,AbateNL,ArnoldRC,ColillaS,ZanottiS,
HollenbergSM:Earlymicrocirculatoryperfusionderangementsinpatientswithseveresepsisandseptic
shock:relationshiptohemodynamics,oxygentransport,andsurvival.AnnEmergMed1998,49:8898.
12. GutteriezG,BrownSD:Responseofthemacrocirculation.InPathophysiologyofShock ,SepsisandOrgan

Failure.EditedbySchlagR,RedlH.Berlin:Springer1993:215229.
13. TerborgC,SchummerW,AlbrechtM,ReinhartK,WeillerC,RotherJ:Dysfunctionofvasomotorreactivityin
severesepsisandsepticshock.IntensiveCareMed2001,27:12311234.
14. RiversE,NguyenB,HavstadS,ResslerJ,MuzzinA,KnoblichB,PetersonE,TomlanovichM,EarlyGoal
DirectedTherapyCollaborativeGroup:Earlygoaldirectedtherapyinthetreatmentofseveresepsisandseptic
shock.NEnglJMed2001,345:13681377.
15. DellingerRP,LevyMM,RhodesA,AnnaneD,GerlachH,OpalSM,SevranskyJE,SprungCL,DouglasIS,
JaeschkeR,OsbornTM,NunnallyME,TownsendSR,ReinhartK,KleinpellRM,AngusDC,DeutschmanCS,
MachadoFR,RubenfeldGD,WebbSA,BealeRJ,VincentJL,MorenoR,SurvivingSepsisCampaign
GuidelinesCommitteeincludingthePediatricSubgroup:SurvivingSepsisCampaign:internationalguidelines
formanagementofseveresepsisandsepticshock:2012.CritCareMed2013,41:580637.
16. SubramanianS,YilmazM,RehmanA,HubmayrRD,AfessaB,GajicO:Liberalvs.conservativevasopressor
usetomaintainmeanarterialbloodpressureduringresuscitationofsepticshock:anobservationalstudy.
IntensiveCareMed2008,34:157162.
17. MorimatsuH,SinghK,UchinoS,BellomoR,HartG:Earlyandexclusiveuseofnorepinephrineinseptic
shock.Resuscitation2004,62:249254.
18. BoneR:AmericanCollegeofChestPhysicians/SocietyofCriticalCareMedicineConsensusConference:
definitionsforsepsisandorganfailureandguidelinesfortheuseofinnovativetherapiesinsepsis.CritCare
Med1992,20:864874.
19. SolletJP,GarberGE:Selectingpatientswithseveresepsisfordrotrecoginalfa(activated)therapy.AmJSurg
2002,184:S11S18.
20. KnausWA,DraperEA:APACHEII:aseverityofdiseaseclassificationsystem.CritCareMed1985,13:818
829.
21. BaezAA,LanePL,SorondoB,GiraldezEM:Predictiveeffectofoutofhospitaltimeinoutcomesofseverely
injuredyoungadultandelderlypatients.PrehospDisasterMed2006,21:427430.
22. WoodKE:Majorpulmonaryembolism:reviewofapathophysiologicapproachtothegoldenhourof
hemodynamicallysignificantpulmonaryembolism.Chest2002,121:877905.
23. BlowO,MaglioreL,ClaridgeJA,ButlerK,YoungJS:Thegoldenhourandthesilverday:detectionand
correctionofocculthypoperfusionwithin24hoursimprovesoutcomefrommajortrauma.JTrauma1999,
47:964969.
24. BoersmaE,MaasAC,DeckersJW,SimoonsML:Earlythrombolytictreatmentinacutemyocardialinfarction:
reappraisalofthegoldenhour.Lancet1996,348:771775.
25. SebestaP,KlikaT,ZdrahalP,KramarJ:Rupturedabdominalaorticaneurysm:roleofinitialdelayonsurvival.
JMalVasc1998,23:361367.
26. SebatF,MusthafaAA,JohnsonD,KramerAA,ShoffnerD,EliasonM,HenryK,SpurlockB:Effectofarapid
responsesystemforpatientsinshockontimetotreatmentandmortalityduring5years.CritCareMed2007,
35:25682575.
27. GaieskiDF,PinesJM,BandRA,MikkelsonME,MassoneR,FuriaFF,ShoferFS,GoyalM:Impactoftimeto
antibioticsonsurvivalinpatientswithseveresepsisorsepticshockinwhomearlygoaldirectedtherapywas
initiatedintheemergencydepartment.CritCareMed2010,38:10451053.
28. KumarA,RobertsD,WoodKE,LightB,ParrilloJE,SharmaS,SuppesR,FeinsteinD,ZanottiS,TaibergL,
GurkaD,KumarA,CheangC:Durationofhypotensionbeforeinitiationofeffectiveantimicrobialtherapyisthe
criticaldeterminantofsurvivalinhumansepticshock.CritCareMed2006,34:15891596.
29. VallesJ,RelloJ,OchagaviaA,GarnachoJ,AlcalaMA:Communityacquiredbloodstreaminfectionincritically
illadultpatients:impactofshockandinappropriateantibiotictherapyonsurvival.Chest2003,123:16151624.
30. RangelFraustoMS,PittetD,CostiganM,HwangT,DavisCS,WenzelRP:Thenaturalhistoryofthe
systemicinflammatoryresponsesyndrome(SIRS),aprospectivestudy.JAMA1995,273:117123.
31. VarpulaM,TallgrenM,SaukkonenK,VoipioPulkkiLM,PettilV:Hemodynamicvariablesrelatedtooutcome
insepticshock.IntensiveCareMed2005,31:10661071.
32. DnserMW,TakalaJ,UlmerH,MayrVD,LucknerG,JochbergerS,DaudelF,LepperP,HasibederWR,
JakobSM:Arterialbloodpressureduringearlysepsisandoutcome.IntensiveCareMed2009,35:12251233.
33. AnnaneD,VignonP,RenaultA,BollaertPE,CharpentierC,MartinC,TrochG,RicardJD,NitenbergG,
PapazianL,AzoulayE,BellissantE:Norepinephrineplusdobutamineversusepinephrinealonefor
managementofsepticshock:arandomisedtrial.Lancet2007,370:676684.
34. RussellJA,WalleyKR,SingerJ,GordonAC,HebertPC,CooperJ,HolmesCL,MehtaS,GrantonJT,Storms
MM,CookDJ,PresneillJJ,AyersD:Vasopressinversusnorepinephrineinfusioninpatientswithseptic
shock.NEnglJMed2008,58:877887.
35. DeBackerD,BistonP,DevriendtJ,MadlC,ChochradD,AldecoaC,BrasseurA,DefranceP,GottigniesP,
VincentJL:Comparisonofdopamineandnorepinephrineinthetreatmentofshock.NEnglJMed2010,
362:779789.
36. SennounN,MontemontC,GibotS,LacolleyP,LevyB:Comparativeeffectsofearlyversusdelayeduseof
norepinephrineinresuscitatedendotoxicshock.CritCareMed2007,35:17361740.
37. CorreaTD,VudaM,BlaserAR,TakalaJ,DjafarzadehS,DunserMW,SilvaE,LenschM,WilkensL,Jakob
SM:Effectoftreatmentdelayondiseaseseverityandneedforresuscitationinporcinefecalperitonitis.Crit
CareMed2012,40:28412849.
38. KumarA,HaeryC,PaladuguB,KumarA,SymeoneidesS,TaibergL,OsmanJ,TrenholmeG,OpalSM,
GoldfarbR,ParilloJE:Thedurationofhypotensionbeforetheinitiationofantibiotictreatmentisacritical
determinantofsurvivalinamurinemodelofEscherichiacolisepticshock:associationwithserumlactateand
inflammatorycytokinelevels.JInfectDis2006,193:251258.
39. FrimodtMollerN,ThomsenVF:Thepneumococcusandthemouseprotectiontest:inoculum,dosageand
timing.ActaPatholMicrobiolImmunolScandB1986,94:3337.
40. MaitlandK,KiguliS,OpokaRO,EngoruC,OlupotOlupotP,AkechSO,NyekoR,MtoveG,ReyburnH,Lang
T,BrentB,EvansJA,TibenderanaJK,CrawleyJ,RussellEC,LevinM,BabikerAG,GibbDM:Mortalityafter
fluidbolusinAfricanchildrenwithsevereinfection.NEnglJMed2011,364:24832495.
41. BoydJH,ForbesJ,NakadaT,WalleyKR,RussellJA:Fluidresuscitationinsepticshock:apositivefluid
balanceandelevatedcentralvenouspressureareassociatedwithincreasedmortality.CritCareMed2011,
39:259265.
42. WaechterJ,KumarA,LapinskyS,MarshallJ,DodekP,ArabiY,ParrilloJ,DellingerR,GarlandA,the
CooperativeAntimicrobialTherapyofSepticShockDatabaseResearchGroup:Interplaybetweenfluidsand
vasoactiveagentsonmortalityinsepticshock:amulticenter,observationalstudy.CritCareMed2014.in
press
Abbreviations
APACHE:AcutePhysiologyandChronicHealthEvaluationCI:confidenceintervalLOS:lengthofstayMAP:mean
arterialpressureOR:oddsratio.
Competinginterests
AKreceivedunrestrictedfundingfortheinitialdevelopmentofthisdatabasefromLilly,Pfizer,Astellas,Merckand
Bayer.AdditionalsupportwasprovidedthroughgrantsfromtheManitobaHealthResearchCouncil,theHealth
SciencesFoundationandtheDeaconFoundation.Thecurrentanalysis/paperwasnotfundedbyanysponsor.JEP
consultedwithSangart,Artisan,Philips,andImmunetrics.Allotherauthorshavenootherrelevantcompeting
interests.
Authors'contributions
AKhadfullaccesstoallthedatainthestudyandisresponsiblefortheintegrityofthedatabaseandtheaccuracyof
thedataanalysis.Thisspecificresearchconcept,thesepticshockdatabaseandmanuscriptweredevelopedbyAK.
AK,DC,AP,GLBandVBwereresponsibleforthemethodologicaldesignissuesanddataanalysis.AKandVB
draftedthemanuscript.AK,VB,DC,AP,GLB,SZandJEPcontributedtodatainterpretationandmanuscript
revisions.Allauthorsreadandapprovedthefinalmanuscript.
CritCare.201418(R97)2014BioMedCentral,Ltd.
Copyrighttothisarticleisheldbytheauthor(s),licenseeBioMedCentralLtd.ThisisanOpenAccessarticle:
verbatimcopyingandredistributionofthisarticlearepermittedinallmediaforanypurpose,providedthisnoticeis
preservedalongwiththearticle'soriginalcitation.

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12/7/2014 www.medscape.

Characteristic Number Percentage

Malegender 3,711 57.0

AIDS 176 2.7

Lymphoma 238 3.7

Leukemia 347 5.3

Metastaticcancer 566 8.7

Immunosuppressed 959 14.7

Neutropenia 321 4.9

Liverfailure 508 7.8

NYHAclassIVheartfailure 196 3.0

Congestiveheartfailure 704 10.8

Ischemicheartdisease 789 12.1

Hypertension 1,245 19.1

COPD(onmedications) 483 7.4

Chronicrenalfailure 1,024 15.7

Dialysis 512 7.9

Diabetesmellitus(oralhypoglycemicdependentinsulin) 1,169 17.9

Diabetesmellitus(insulindependent) 568 8.7

Electivesurgery 939 14.4

Emergencysurgery 473 7.3

Alcoholabuse 891 13.7

Autoimmunedisease 306 4.7

Organicbraindisease 362 5.6

Neuromusculardisease 106 1.6

Parameter Mean Standarddeviation

APACHEIIscore 26.1 8.2

Creatinine(mol/l) 219 181

Bicarbonate(mEq/l) 19.4 6.5

Lactate(mmol/l) 4.8 4.4

Platelets(109/l) 196 139

InternationalNormalizedRatio 1.8 1.4

Whitebloodcellcount(106/l) 16.3 16.1

Nosocomial 2,594 39.8

Bacteremia/fungemia 2,895 34.6

Culturepositive 4,584 70.4

Pulmonary 2,643 40.6

Abdominal/gastrointestinal 1,814 27.8

Urinary 691 10.6

Skin/softtissue 469 7.2

Intravascularcatheter 224 3.4

Primarybloodstream 379 5.8

Disseminatedsystemic 135 2.1

Staphylococusaureus 778 17.0

Sreptococcuspneumoniae 350 7.6

Otherstreptococci 272 5.9

OtherGrampositivecocci 218 4.8

Escherichiacoli 940 20.5

Otherenterobacteriaciae 773 16.9

NonenterobacteriaciaeGramnegativebacilli 464 10.1

Miscellaneousbacteria 314 6.8

Candida/fungi 474 10.3

Parameter Mean Standarddeviation

APACHEIIscore 26.1 8.2

Creatinine(mol/l) 219 181

Bicarbonate(mEq/l) 19.4 6.5

Lactate(mmol/l) 4.8 4.4

Platelets(109/l) 196 139

InternationalNormalizedRatio 1.8 1.4

Whitebloodcellcount(106/l) 16.3 16.1

Nosocomial 2,594 39.8

Bacteremia/fungemia 2,895 34.6

Culturepositive 4,584 70.4