Timing of Vasopressor Initiation and Mortality

8/1/2015
www.medscape.com/viewarticle/829233_print
www.medscape.com
TimingofVasopressorInitiationandMortality
inSepticShock
ACohortStudy
VanceBeck,DanChateau,GregoryLBryson,AmarnathPisipati,SergioZanotti,Joseph
EParrillo,AnandKumar
CritCare.201418(R97)
AbstractandIntroduction
Abstract
Introduction:Despiterecentadvancesinthemanagementofsepticshock,mortalityremainsunacceptablyhigh.
Earlierinitiationofkeytherapiesincludingappropriateantimicrobialsandfluidresuscitationappearstoreducethe
mortalityinthiscondition.Thisstudyexaminedwhetherearlyinitiationofvasopressortherapyisassociatedwith
improvedsurvivalinfluidtherapyrefractorysepticshock.
Methods:Utilizingawellestablisheddatabase,relevantinformationincludingdurationoftimetovasopressor
administrationfollowingtheinitialdocumentationofrecurrent/persistenthypotensionassociatedwithsepticshock
wasassessedin8,670adultpatientsfrom28ICUsinCanada,theUnitedStatesofAmerica,andSaudiArabia.
Theprimaryendpointwassurvivaltohospitaldischarge.SecondaryendpointswerelengthofICUandhospitalstay
aswellasdurationofventilatorsupportandvasopressordependence.Analysisinvolvedmultivariatelinearand
logisticregressionanalysis.
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
(OR1.88,CI,1.46to2.41),neutropenia(OR1.78,CI,1.27to2.49)andchronichypertension(OR0.62CI,0.52to
0.73).Delayofinitiationofappropriateantimicrobialtherapy(OR1.07/hr,CI,1.06to1.08),age(OR1.03/yr,CI,
1.02to1.03),andAcutePhysiologyandChronicHealthEvaluation(APACHE)IIScore(OR1.11/point,CI,1.10to
1.12)werealsofoundtobesignificantindependentcorrelatesofmortality.Afteradjustment,onlyaweak
correlationbetweenvasopressordelayandhospitalmortalitywasfound(adjustedOR1.02/hr,95%CI1.01to1.03,
P<0.001).Thisweakeffectwasentirelydrivenbythegroupofpatientswiththelongestdelays(>14.1hours).
Therewasnosignificantrelationshipofvasopressorinitiationdelaytodurationofvasopressortherapy(P=0.313)
andonlyatrendtolongerdurationofventilatorsupport(P=0.055)amongsurvivors.
Conclusion:Markeddelaysininitiationofvasopressor/inotropictherapyareassociatedwithasmallincreasein
mortalityriskinpatientswithsepticshock.
Introduction
Despiteadvancementsinunderstandingandtreatment,septicshockremainsaworldwidehealthcareproblem.With
anincreasingannualincidenceinthedevelopedworld,mortalityremainsbetween25and50%ofthoseafflicted. [1
3]Thepathophysiologyofsepticshockiscomplexandinvolvesvasodilatation,relativeandabsolutehypovolemia,
myocardialdysfunction,increasedmetabolicrateandalteredregionalandmicrovascularbloodflow. [411]Septic
shockappearstocausealossofautoregulation,makingtheperfusionofmanyvitalorgansandtissuesdependent
onbloodpressure. [5,12,13]Earlyandaggressivefluidresuscitationofsepsishasbeensuggestedtohaveacritical
roleinoptimizationoforganperfusion,preservationofendorganfunctionandimprovementofsurvival. [14]
Hypotensiondespiteadequatefluidresuscitationtherapyisadefiningcriterioninthediagnosisofsepticshock. [15]
Tomaintainorganperfusion,currentguidelinesrecommendmaintainingameanarterialpressure(MAP)of65
mmHgwithfluidtherapyandvasopressorsevenwhenhypovolemiahasnotyetbeenresolved. [15]Accordingtothe
SurvivingSepsisCampaignthisrecommendationisconsidered'strong'althoughsupportingevidenceisconsidered
http://www.medscape.com/viewarticle/829233_print
1/18
8/1/2015
'weak'. [15]
Manystudieshavecompareddifferentvasopressoragentsfortheresuscitationofsepticshockbutveryfewhave
investigatedtherolethatthetimingofvasopressorinitiationinrelationtohypotensiononsetplaysinoutcome.
[16,17]
Methods
StudyDesign
Datafromaretrospectivereviewofadultpatients(18yearsold)diagnosedwithsepticshockwasusedtocreate
theCooperativeAntimicrobialTherapyofSepticShockDatabase(memberlistinginAdditionalfile1
http://ccforum.com/content/18/3/R97/additional).Consecutiveadultsepticshockpatientsfrom28medical
institutionsinCanada,theUnitedStatesandSaudiArabiaforperiodsbetween1996and2008wereretrospectively
identifiedusingeitherinternalICUregistries/databasesand/orInternationalClassificationofDiseases(ICD9or
ICD10)codingstrategies.Patientsfromsurgical,medicalandmixedICUswereincluded.Eachpotentialcasewas
screenedtodetermineeligibilitytomeetthecriteriaforsepticshockasdescribedbythe1991SocietyofCritical
CareMedicine/AmericanCollegeofChestPhysiciansconsensusstatementonsepsisdefinition. [18]Allincluded
caseswererequiredtohavenootherobviouscauseofshock.Eachinstitutioncontributedaminimumof50cases.
AwaivedconsentprotocolwasapprovedbytheHealthEthicsBoardoftheUniversityofManitobaandateach
individualparticipatingcenter(listinginAdditionalfile2http://ccforum.com/content/18/3/R97/additional).The
EthicsBoardswaivedtheneedforinformedconsentbecauseoftheretrospective,riskfreenatureofthestudyin
combinationwiththeuseofdeidentifieddata.
DataManagement
Dataincludingthetimetovasopressoradministrationafterdocumentationofpersistentorrecurrenthypotension
refractorytofluidadministrationwereretrospectivelycollectedfromclinicalrecordsusingauniformdataextraction
templatebyseveraltrainedresearchnursesorresearchassistantswithmedicaltraining(medicalstudents,
residents,fellows).Alldataextractorsreviewed>100charts.
Hypotensionwasdefinedasameanbloodpressure<65mmHg,asystolicbloodpressure<90mmHg,ora
decreaseinsystolicpressureof40mmHgfromthepatient'sbaselineconsistentwiththeSocietyofCriticalCare
Medicine/AmericanCollegeofChestPhysicianscriteriaforsepticshock. [18]Anepisodeofhypotensionwas
consideredtorepresenttheinitialonsetofsepticshockwhenhypotensionpersistedfromtheonsetdespitefluid(>2
lsalineorequivalent)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,thetruetimefrom
hypotensiononsettovasopressorinitiationisindeterminate.
Theunadjustedassociationbetweensurvivaltohospitaldischargeandvasopressordelaywasestimatedusing
simplelogisticregression.Asimilaranalysiswasdonewithrespecttotheoccurrenceofindividualandtotalnumber
oforganfailuresafterthedayofshock(incrementalorganfailuresfromday2today10).Awidevarietyof
epidemiologicfactors(age,sex),comorbidities(AIDS,hematologicmalignancy(lymphoma/leukemia/multiple
2/18
8/1/2015
myeloma),metastaticcancer,heartdisease,organtransplant,hypertension,respiratorydisease,renaldisease,
diabetes,autoimmuneconditions,thromboembolism,neurologicaldiseases),severityofillness(AcutePhysiology
andChronicHealthEvaluation(APACHE)score), [20]laboratoryvalues(admissionlacticacidandbicarbonate
levels,whitecellcount)andtherapeuticelements(timetoinitialappropriateantimicrobialtherapy)werefirst
assessedwithrespecttohospitalsurvivalandorganfailureusingunivariateanalysis.Thosethatweresignificantat
P<0.05wereretainedforinclusioninthemodel.Multivariablelogisticregressionwasthenusedtoestimatethe
adjustedassociationandtoidentifyindependentcorrelatesofmortalityandorganfailure.Mortalityandindividual
organfailureresultsareexpressedasoddsratios(ORs)with95%confidenceintervals(CIs).Totalincremental
organfailureaftertheadmissionday(day2today10)wasanalyzedusingPoissonregressionwithresults
expressedasrateratios.Becausehospitallengthofstay(LOS)andICULOSarecountvariables,thesesecondary
outcomeswereanalyzedusinggeneralizedlinearregressionwithanegativebinomialdistributionandlogarithmic
linkfunction,adjustedforthesamecovariatesasintheprimaryoutcomeanalysis.Dataareexpressedasmean
standarddeviationormedianwithinterquartilerangeasappropriate.
Results
Therewereatotalof8,670patientsthatfitthediagnosticcriteriaforsepticshock.Thirtypatientsdidnothavea
timeofvasopressorinitiationavailableandwereexcluded.Another2,126patientswereexcludedduetoinadequate
dataacquisitionofothersignificantanalyticvariables,primarilytimetoappropriateantimicrobialtherapyfrom
documentationofhypotension.Intotal,6,514observationswereincludedinthisanalysis.
DemographicCharacteristicsandExistingComorbidity
Thebaselinecharacteristicsofthepatientsintheentirecohortarepresentedin.Theaverageagewas621
yearswithmalepredominance(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).The
heartratewaselevatedat11529beats/minute.Approximately40%ofcaseswereduetonosocomiallyacquired
infection().Culturenegativeandbacteremic/fungemicpatientseachaccountedforaboutonethirdofthecohort.
Thelungs,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
3/18
8/1/2015
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. aPresentedasmean
standarddeviation.
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
4/18
8/1/2015
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
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
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
1.8
1.4
16.3
16.1
Heartrate(/minute)
115
29
Number Percentage
Nosocomial
2,594
39.8
Bacteremia/fungemia
2,895
34.6
Culturepositive
4,584
70.4
APACHE,AcutePhysiologyandChronicHealthEvaluation.
5/18
8/1/2015
Pulmonary
2,643
40.6
1,814
27.8
Urinary
691
10.6
Skin/softtissue
469
7.2
54
8.3
224
3.4
Primarybloodstream
379
5.8
135
2.1
Boneandjoint
42
0.6
Mediastinal
63
Infectingorganism
Staphylococusaureus
778
17.0
350
7.6
Otherstreptococci
272
5.9
218
4.8
Escherichiacoli
940
20.5
773
16.9
10.1
314
6.8
Candida/fungi
474
10.3
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
1.8
1.4
16.3
16.1
Heartrate(/minute)
115
29
Number Percentage
6/18
8/1/2015
Nosocomial
2,594
39.8
Bacteremia/fungemia
2,895
34.6
Culturepositive
4,584
70.4
Pulmonary
2,643
40.6
1,814
27.8
Urinary
691
10.6
Skin/softtissue
469
7.2
54
8.3
224
3.4
Primarybloodstream
379
5.8
135
2.1
Boneandjoint
42
0.6
Mediastinal
63
Infectingorganism
Staphylococusaureus
778
17.0
350
7.6
Otherstreptococci
272
5.9
218
4.8
Escherichiacoli
940
20.5
773
16.9
10.1
314
6.8
Candida/fungi
474
10.3
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
1.8
1.4
7/18
8/1/2015
16.3
16.1
Heartrate(/minute)
115
29
Number Percentage
Nosocomial
2,594
39.8
Bacteremia/fungemia
2,895
34.6
Culturepositive
4,584
70.4
Pulmonary
2,643
40.6
1,814
27.8
Urinary
691
10.6
Skin/softtissue
469
7.2
54
8.3
224
3.4
Primarybloodstream
379
5.8
135
2.1
Boneandjoint
42
0.6
Mediastinal
63
Infectingorganism
Staphylococusaureus
778
17.0
350
7.6
Otherstreptococci
272
5.9
218
4.8
Escherichiacoli
940
20.5
773
16.9
10.1
314
6.8
Candida/fungi
474
10.3
TreatmentCharacteristics
Themediantimetovasopressorinitiationwas3hours(25to75%range:1to7.1hours).Thedistributionof
vasopressoruseispresentedin.Themostcommonlyusedvasopressorwasnorepinephrineinabouttwothirdsof
patients,withdopaminebeingthesecondmostcommonusedinapproximatelyonehalf.Useofagiven
vasopressorwasnotexclusiveofuseofothers.Dobutamine,aninotropicagent,wasusedforatleast30minutes
duringthefirst24hoursafterpressorinitiationin12.2%ofcases.However,inotropeswereneverinitiatedbefore
pressorsandanintropealonewasneverused(perinclusioncriteria).Steroidswereusedin32%ofpatients.
Table3.Treatmentandvasopressorusecharacteristics
8/18
8/1/2015
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
9/18
8/1/2015
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),therewasaweakassociationof
delayofvasopressorswithinhospitalmortality(adjustedOR=1.02,95%CI=1.01to1.03,P<0.001).To
examinetheimpactofdelaysinvasopressorinitiationfurther,decilesofdelaywereexaminedinthemodel.The
resultsareshowninFigure2.Atincreasingdelaysofapproximately0.50to1.15hours,1.16to2.00hours,2.01to
2.90hours,2.91to4.00hours,4.01to5.75hours,5.76to8.45hours,8.46to14.10hoursand>14.10hours
(referenceseconddecile,7to30minutesaspertheanalysisprotocol),theadjustedORofsurvivalwassignificantly
increasedonlyforthefinal,latestdecile(OR=1.34,95%CI=1.03to1.76,P=0.048).
10/18
8/1/2015
Figure2.
Oddsratio(95%confidenceinterval)ofmortalityforeachpressordelaydecile(referencedecile,0.11to0.5
hours).
SecondaryOutcomeAnalysis(OrganFailureandLengthofStay)
Secondaryoutcomeswereadjustedforthesameindependentpredictorsofmortalityastheprimaryoutcome.In
bothunadjustedandadjustedanalyses,astrongtrendoractualsignificancewasfoundbetweenthedelayto
pressorinitiationandtheoccurrenceoforganfailures.AdjustedPvalueswereasfollows:renal,P=0.0182
respiratory,P<0.0001hematologic,P=0.0788centralnervoussystem,P=0.0208coagulation,P=0.0089
metabolic,P<0.0001.Notably,ineachcase,thelastdecile(>14.1hours)accountedfortheimpactofpressor
delayontheoccurrenceoforganfailure.Inaddition,thetotalincrementalorganfailuresafterthedayof
presentation(thatis,day2today10)wasassociatedwithpressordelay.Again,thisrelationshipwasdrivenbythe
lastdecileofdelay(Figure3).
11/18
8/1/2015
Figure3.
Mean(95%confidenceinterval)incrementalorganfailures(day2today10afterpresentation)withincreasing
pressordelays.
Forthesurvivors,whilecontrollingforsignificantvariables,delayinvasopressorinitiationwasnotpredictiveof
hospitalLOS(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]Outcome
intheseconditionsiscloselyassociatedwithearlierinitiationoftherapy. [2126]Similarly,insepticshock,early
initiationoffluidresuscitationandrapidadministrationofappropriateantimicrobialsarecriticaldeterminantsof
outcomeandcentraltenetsofmanagement. [14,27,28]Basedonthesefactors,wehypothesizedthatlongerduration
ofhypotensionwithouthemodynamicsupportusingvasopressorinfusionmayresultinahighermortalityrateand
anincreasedincidenceoforganfailureinsepticshockpatients.
Ourstudydemonstratesthattheintervalbetweendiagnosisofsepticshockandtheadministrationofvasopressor
agentsisasignificantalthoughmodestindependentcorrelatetoinhospitalmortalityanddevelopmentoflateorgan
failure.Theentireincreasingmortalityeffectwithincreaseddelaysinvasopressorinitiationisrelatedtothe
increasedmortalityinthefinaldecilegroup(>14hoursposthypotensiondocumentation)relativetothereference
group.Similarly,increasingprobabilityofincrementalaggregateorganfailuresafterthedayofshock(thatis,day2
today10)isonlyseeninthehighestdelaydecilegroups(>14hoursposthypotensiondocumentation).Newonset
renal,respiratory,centralnervoussystem,coagulationandmetabolicfailureswerealsoindividuallyassociatedwith
12/18
8/1/2015
pressordelays>14hours.Perhapsbecauseofthemodeststrengthofthecorrelationbetweenpressordelayand
mortality/organfailure,thereisnoassociationinthesurvivorgroupwithICUorhospitallengthofstay,ventilator
durationortotalvasopressoradministrationtime.
Studieshaveshownthatsepticshockasdefinedinpartbypersistenthypotensionisanindicatorofamarked
increaseinmoralityriskinsepticstates. [29,30]Atleasttworetrospectivehumansepticshockstudiesshowan
increasingmortalitywithincreasingseverityanddurationofhypotension. [31,32]Varpulaandcolleaguesshowedin
111septicshockpatientsthatthetimespentbelowaMAPof65mmHginthefirst48hourswasastrongpredictor
ofmortality. [31]Inanotherretrospectivestudy,Dnserandcolleaguessimilarlymeasuredtheareaunderthecurve
forMAPandeffectonmortalityin274sepsispatients. [32]ThisstudydemonstratedthatthetimespentwithMAP
<55mmHgwasassociatedwithincreasedriskofdeath.However,asimilarcorrelationdidnotexistwiththe
durationwhenMAPwas<60mmHg,<65mmHg,<70mmHgand<75mmHg.
Whiletherehasbeenmuchstudyintothecomparisonofvasopressors/inotropesindividuallyandincombination, [33
35]therehasbeenarelativepaucityintheliteratureregardingthetimingoftheirinitiationinsepticshock.The2012
SurvivingSepsisGuidelinesrecommendthatvasopressorsupportbestartedforfluidrefractoryshockaspartofthe
6hourbundlebasedsolelyonexpertopinion. [15]Aratmodelofendotoxicshockhassuggestedpotentialbenefit
withahigherproportionatesplanchnicbloodflow,lowerlactatelevelsandlessoverallfluidsupportrequirementfor
earlycomparedwithdelayednorepinephrineadministration. [36]Aporcinemodeloffecalperitonitis/shockhas
demonstratedthatdelayedresuscitation(inclusiveofantibiotics,fluidsandpressors)wasassociatedwithincreased
physiologicinstabilityandhigherpressorrequirements. [37]Conversely,inasmall(n=95)retrospectivehuman
study,nodifferenceinorgandysfunctionorICULOSwasnotedwithearly(<1.37hours)versuslate(>1.37hours)
administrationofvasopressors. [16]Thesestudieshavetheirlimitationsinthattwowereanimalstudiesandnone
utilizedsurvivalasanendpoint.
Inourstudy,thetimingofinitiationofvasopressorsfollowingdocumentationofhypotensionisonlyweakly
associatedwithmortalityinsepticshock,asindicatedbythelowWaldX 2valuesin.TheWaldX 2valuefor
delaysinantimicrobialinitiation,theotherremediabletreatmentparameterinthemultivariateanalysis,is16.7
timeshigher.Notethatthisdoesnotsuggestthatdurationofhypotensionbeforeresuscitation(inclusiveof
appropriateantimicrobialsandfluidresuscitation)isonlyweaklycorrelatedtooutcome.Onthecontrary,appropriate
antimicrobialdelaysrelativetohypotensionandearlyfluidresuscitationarewellestablishedtohavecriticalrolesin
improvingoutcomeofsepticshock. [14,28]Onlythedelayofvasopressorsappearstohavealimitedimpacton
outcomeinthisretrospectiveanalysis.
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.
13/18
8/1/2015
Giventhemodeststrengthoftheassociation,thestatisticalsignificanceoftimetovasopressorinitiationrelates
primarilytotheextraordinarilylargenumberofcasesinthisdataset.Theonlydecilegroupthatappearstocarryan
increasedmortalityorspecificorganfailureriskrelativetothereferencegroupisthelatestgroup(>14hourspost
hypotensiondocumentation).Allincludeddecilestothatpointappeartocarrynosignificantincreasedmortalityor
specificorganfailureriskafteradjustmentformultiplemorbid/epidemiologicfactors.Thisfindingisentirely
congruentwiththefindingsofSubramanianandcolleagues,whoshowednoimpactofvasopressordelaysupto12
hoursonorganfunctioninasmallercohortof<100patients. [16]
Ahistoryofhypertensionconveyingaprotectiveeffectwasanunexpectedresultonmultivariateanalysis.Itis
possiblethatthisfindingmaybeexplainedbyuserbias,inthatthesepatientsmayhaveactivatedthehealthcare
systemmorefrequentlytogainadiagnosisofanotherwisesilentcondition.Hypertensionisnormallyasilent
condition,whichmaysuggestthatthesepatientshadmoreroutineaccesstomedicalcare.Alternatively,thestudy
entrycriteria(decreaseinsystolicpressure>40mmHg)usedformanyofthesepatientsmaybeoverlysensitive
withrespecttodiagnosingsepticshock.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
interactionsbetweenthetimingofvasopressorinitiationandearlyfluidresuscitationthatweareunabletocapture
inthisdatasetmayexist.Thisisasignificantlimitationofthisstudyandfutureanalysesshouldalsoattemptto
factorinfluidresuscitation.
Thereareotherlimitationstothisstudy.Thisisaretrospectivereviewwithitsinherentinabilitytoaccountforall
potentialconfounders.However,therehasyettobearandomizedcontrolledtrialoftimingofvasopressorinitiation
inanycriticalillness.Giventheethicalconcernsofexposingmoribundpatientstopotentialharm,aprospective,
randomizedhumanstudyoftimingofvasopressorinitiationinsepticshockwouldbechallenging.Anotherlimitation
isthattheuseofhypotensionasthedefiningcriteriaforsepticshockinthispatientgroupmaybeimperfect.MAP
isatbestasurrogateofinadequatemicrovascularperfusioninshock.Itdoesnotdirectlycapturemicrocirculatory
perfusionandcellularinjurythatleadtoorgandysfunctionanddeath. [7,11,13]Nonetheless,othermetabolicmarkers
suchasserumlactateandbicarbonatelevelsaswellasseverityofillnessscores(APACHEIIscores)were
incorporatedintothemodeltohelpadjustforvariationsinshockseverity.Despitetheselimitationsofblood
pressuremonitoring,givenitsuniversalaccessandeaseofuseitisthemostrelieduponclinicalparameterfor
guidingtherapyandwillremainamainstayinthetreatmentofsepticshockfortheforeseeablefuture.
Conclusion
Fromthisstudy,weconcludethatmarkedlydelayedinitiationofvasopressormedicationsinpatientswithseptic
shockismodestlyassociatedwithincreasedorganfailureriskanddecreasedsurvival.Substantialdelaysof
vasopressorinitiation(>14hoursafterhypotensiondocumentation)arerequiredtoseetheseeffects.Giventhe
almostuniversaluseofvasopressorsinsepticshockandthecriticalneedforprecisetitration,furtherstudyofthis
areaiswarranted.
Sidebar
KeyMessages
Delaysininitiationofvasopressortherapyfollowingthefirstdocumentationofhypotensioninsepticshock
aremodestlyassociatedwithincreasedspecificorganfailureandmortalityrisk.
Thisincreaseinspecificorganfailureandmortalityriskisentirelydrivenbythedecileofpatientswiththe
14/18
8/1/2015
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,Peters
C,AhsanM,ChateauD,CooperativeAntimicrobialTherapyofSepticShockDatbaseResearchGroup:
Initiationofinappropriateantimicrobialtherapyresultsinafivefoldreductionofsurvivalinhumanseptic
shock.Chest2009,136:12371248.
3. RanieriVM,ThompsonBT,BariePS,DhainautJF,DouglasIS,FinferS,GrdlundB,MarshallJC,Rhodes
A,ArtigasA,PayenD,TenhunenJ,AlKhalidiHR,ThompsonV,JanesJ,MaciasWL,VangerowB,
WilliamsMD:Drotrecoginalfa(activated)inadultswithsepticshock.NEnglJMed2012,366:20552064.
4. HotchkissRS,KarlIE:Reevaluationoftheroleofcellularhypoxiaandbioenergeticfailureinsepsis.JAMA
1992,267:15031510.
5. DeBackerD,CreteurJ,PreiserJC,DuboisMJ,VincentJL:Microvascularbloodflowisalteredinpatients
withsepsis.AmJRespirCritCareMed2002,166:98104.
6. SakrY,DuboisMJ,DeBackerD,CreteurJ,VincentJL:Persistentmicrocirculatoryalterationsare
associatedwithorganfailureanddeathinpatientswithsepticshock.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:Dysfunctionofvasomotorreactivity
inseveresepsisandsepticshock.IntensiveCareMed2001,27:12311234.
14. RiversE,NguyenB,HavstadS,ResslerJ,MuzzinA,KnoblichB,PetersonE,TomlanovichM,EarlyGoal
DirectedTherapyCollaborativeGroup:Earlygoaldirectedtherapyinthetreatmentofseveresepsisand
septicshock.NEnglJMed2001,345:13681377.
15/18
8/1/2015
15. DellingerRP,LevyMM,RhodesA,AnnaneD,GerlachH,OpalSM,SevranskyJE,SprungCL,DouglasIS,
JaeschkeR,OsbornTM,NunnallyME,TownsendSR,ReinhartK,KleinpellRM,AngusDC,Deutschman
CS,MachadoFR,RubenfeldGD,WebbSA,BealeRJ,VincentJL,MorenoR,SurvivingSepsisCampaign
GuidelinesCommitteeincludingthePediatricSubgroup:SurvivingSepsisCampaign:international
guidelinesformanagementofseveresepsisandsepticshock:2012.CritCareMed2013,41:580637.
16. SubramanianS,YilmazM,RehmanA,HubmayrRD,AfessaB,GajicO:Liberalvs.conservative
vasopressorusetomaintainmeanarterialbloodpressureduringresuscitationofsepticshock:an
observationalstudy.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.AmJ
Surg2002,184:S11S18.
20. KnausWA,DraperEA:APACHEII:aseverityofdiseaseclassificationsystem.CritCareMed1985,
13:818829.
21. BaezAA,LanePL,SorondoB,GiraldezEM:Predictiveeffectofoutofhospitaltimeinoutcomesof
severelyinjuredyoungadultandelderlypatients.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:Earlythrombolytictreatmentinacutemyocardial
infarction:reappraisalofthegoldenhour.Lancet1996,348:771775.
25. SebestaP,KlikaT,ZdrahalP,KramarJ:Rupturedabdominalaorticaneurysm:roleofinitialdelayon
survival.JMalVasc1998,23:361367.
26. SebatF,MusthafaAA,JohnsonD,KramerAA,ShoffnerD,EliasonM,HenryK,SpurlockB:Effectofa
rapidresponsesystemforpatientsinshockontimetotreatmentandmortalityduring5years.CritCareMed
2007,35:25682575.
27. GaieskiDF,PinesJM,BandRA,MikkelsonME,MassoneR,FuriaFF,ShoferFS,GoyalM:Impactoftime
toantibioticsonsurvivalinpatientswithseveresepsisorsepticshockinwhomearlygoaldirectedtherapy
wasinitiatedintheemergencydepartment.CritCareMed2010,38:10451053.
28. KumarA,RobertsD,WoodKE,LightB,ParrilloJE,SharmaS,SuppesR,FeinsteinD,ZanottiS,Taiberg
L,GurkaD,KumarA,CheangC:Durationofhypotensionbeforeinitiationofeffectiveantimicrobialtherapy
isthecriticaldeterminantofsurvivalinhumansepticshock.CritCareMed2006,34:15891596.
29. VallesJ,RelloJ,OchagaviaA,GarnachoJ,AlcalaMA:Communityacquiredbloodstreaminfectionin
criticallyilladultpatients:impactofshockandinappropriateantibiotictherapyonsurvival.Chest2003,
123:16151624.
30. RangelFraustoMS,PittetD,CostiganM,HwangT,DavisCS,WenzelRP:Thenaturalhistoryofthe
16/18
8/1/2015
systemicinflammatoryresponsesyndrome(SIRS),aprospectivestudy.JAMA1995,273:117123.
31. VarpulaM,TallgrenM,SaukkonenK,VoipioPulkkiLM,PettilV:Hemodynamicvariablesrelatedto
outcomeinsepticshock.IntensiveCareMed2005,31:10661071.
32. DnserMW,TakalaJ,UlmerH,MayrVD,LucknerG,JochbergerS,DaudelF,LepperP,HasibederWR,
JakobSM:Arterialbloodpressureduringearlysepsisandoutcome.IntensiveCareMed2009,35:1225
1233.
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,
StormsMM,CookDJ,PresneillJJ,AyersD:Vasopressinversusnorepinephrineinfusioninpatientswith
septicshock.NEnglJMed2008,58:877887.
35. DeBackerD,BistonP,DevriendtJ,MadlC,ChochradD,AldecoaC,BrasseurA,DefranceP,Gottignies
P,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:associationwithserumlactate
andinflammatorycytokinelevels.JInfectDis2006,193:251258.
39. FrimodtMollerN,ThomsenVF:Thepneumococcusandthemouseprotectiontest:inoculum,dosageand
timing.ActaPatholMicrobiolImmunolScandB1986,94:3337.
40. MaitlandK,KiguliS,OpokaRO,EngoruC,OlupotOlupotP,AkechSO,NyekoR,MtoveG,ReyburnH,
LangT,BrentB,EvansJA,TibenderanaJK,CrawleyJ,RussellEC,LevinM,BabikerAG,GibbDM:
MortalityafterfluidbolusinAfricanchildrenwithsevereinfection.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:
meanarterialpressureOR:oddsratio.
Competinginterests
AKreceivedunrestrictedfundingfortheinitialdevelopmentofthisdatabasefromLilly,Pfizer,Astellas,Merckand
17/18
8/1/2015
Bayer.AdditionalsupportwasprovidedthroughgrantsfromtheManitobaHealthResearchCouncil,theHealth
SciencesFoundationandtheDeaconFoundation.Thecurrentanalysis/paperwasnotfundedbyanysponsor.JEP
consultedwithSangart,Artisan,Philips,andImmunetrics.Allotherauthorshavenootherrelevantcompeting
interests.
Authors'contributions
AKhadfullaccesstoallthedatainthestudyandisresponsiblefortheintegrityofthedatabaseandtheaccuracy
ofthedataanalysis.Thisspecificresearchconcept,thesepticshockdatabaseandmanuscriptweredevelopedby
AK.AK,DC,AP,GLBandVBwereresponsibleforthemethodologicaldesignissuesanddataanalysis.AKand
VBdraftedthemanuscript.AK,VB,DC,AP,GLB,SZandJEPcontributedtodatainterpretationandmanuscript
revisions.Allauthorsreadandapprovedthefinalmanuscript.
CritCare.201418(R97)2014BioMedCentral,Ltd.
Copyrighttothisarticleisheldbytheauthor(s),licenseeBioMedCentralLtd.ThisisanOpenAccessarticle:
verbatimcopyingandredistributionofthisarticlearepermittedinallmediaforanypurpose,providedthisnoticeis
preservedalongwiththearticle'soriginalcitation.
18/18

Timing of Vasopressor Initiation and Mortality

Загружено:

Сведения о документе

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

Timing of Vasopressor Initiation and Mortality

Загружено:

Авторское право:

Доступные форматы

8/1/2015

APACHEIIscore(perpoint) 1.11 1.10to1.12 <0.0001 544.6

1.03 1.02to1.03 <0.0001 127.1

3.46 2.67to4.48 <0.0001 88.3

0.62 0.52to0.73 <0.0001 32.2

1.88 1.46to2.41 <0.0001 24.1

1.63 1.32to2.01 <0.0001 20.4

Vasopressordelay(perhour) 1.02 1.01to1.03 0.0099

1.78 1.27to2.49 0.0008

1.91 1.29to2.81 0.0011

APACHEIIscore(perpoint) 1.11 1.10to1.12 <0.0001 544.6

1.03 1.02to1.03 <0.0001 127.1

3.46 2.67to4.48 <0.0001 88.3

0.62 0.52to0.73 <0.0001 32.2

1.88 1.46to2.41 <0.0001 24.1

1.63 1.32to2.01 <0.0001 20.4

Vasopressordelay(perhour) 1.02 1.01to1.03 0.0099

1.78 1.27to2.49 0.0008

1.91 1.29to2.81 0.0011

Вам также может понравиться