Beruflich Dokumente
Kultur Dokumente
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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
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'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
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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
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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
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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
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
APACHE,AcutePhysiologyandChronicHealthEvaluation.
Table2.Laboratoryvaluesandseverityofillnesscharacteristics
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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
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
InternationalNormalizedRatio
1.8
1.4
Whitebloodcellcount(106/l)
16.3
16.1
Heartrate(/minute)
115
29
Number Percentage
APACHE,AcutePhysiologyandChronicHealthEvaluation.
Table2.Laboratoryvaluesandseverityofillnesscharacteristics
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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
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
InternationalNormalizedRatio
1.8
1.4
APACHE,AcutePhysiologyandChronicHealthEvaluation.
Table2.Laboratoryvaluesandseverityofillnesscharacteristics
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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
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.
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
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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
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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
Liverfailure
Hypertension
Hematologicmalignancy
Metastaticcancer
20.1
Neutropenia
11.2
AIDS
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).
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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).
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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
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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
Liverfailure
Hypertension
Hematologicmalignancy
Metastaticcancer
20.1
Neutropenia
11.2
AIDS
10.7
APACHE,AcutePhysiologyandChronicHealthEvaluationCI,confidenceintervalOR,oddsratio.
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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
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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.
http://www.medscape.com/viewarticle/829233_print
15/18
8/1/2015
www.medscape.com/viewarticle/829233_print
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
http://www.medscape.com/viewarticle/829233_print
16/18
8/1/2015
www.medscape.com/viewarticle/829233_print
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
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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.
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