Association of Vasopressin Plus Catecholamine Vasopressors vs Catecholamines Alone With

65 Pages·2017·2.46 MB·English

by  Kevin Um

Research
JAMA | OriginalInvestigation
Association of Vasopressin Plus Catecholamine Vasopressors
vs Catecholamines Alone With Atrial Fibrillation in Patients
With Distributive Shock
A Systematic Review and Meta-analysis
WilliamF.McIntyre,MD;KevinJ.Um,BA;WaleedAlhazzani,MD,MSc;AlexandraP.Lengyel;LudhmilaHajjar,MD;AnthonyC.Gordon,MD;
FrançoisLamontagne,MD,MSc;JeffS.Healey,MD,MSc;RichardP.Whitlock,MD,PhD;EmilieP.Belley-Côté,MD,MSc
Supplementalcontent
IMPORTANCEVasopressinisanalternativetocatecholaminevasopressorsforpatientswith
CMEQuizat
distributiveshock—aconditionduetoexcessivevasodilation,mostfrequentlyfromsevere jamanetwork.com/learning
infection.Bloodpressuresupportwithanoncatecholaminevasopressormayreduce andCMEQuestionspage1934
stimulationofadrenergicreceptorsanddecreasemyocardialoxygendemand.Atrial
fibrillationiscommonwithcatecholaminesandisassociatedwithadverseevents,including
mortalityandincreasedlengthofstay(LOS).
OBJECTIVES Todeterminewhethertreatmentwithvasopressin+catecholamine
vasopressorscomparedwithcatecholaminevasopressorsalonewasassociatedwith
reductionsintheriskofadverseevents.
DATASOURCES MEDLINE,EMBASE,andCENTRALweresearchedfrominceptiontoFebruary
2018.Expertswereaskedandmeta-registriessearchedtoidentifyongoingtrials.
STUDYSELECTION Pairsofreviewersidentifiedrandomizedclinicaltrialscomparing
vasopressinincombinationwithcatecholaminevasopressorstocatecholaminesalonefor
patientswithdistributiveshock.
DATAEXTRACTIONANDSYNTHESIS Tworeviewersabstracteddataindependently.
Arandom-effectsmodelwasusedtocombinedata.
MAINOUTCOMESANDMEASURES Theprimaryoutcomewasatrialfibrillation.Other
outcomesincludedmortality,requirementforrenalreplacementtherapy(RRT),myocardial
injury,ventriculararrhythmia,stroke,andLOSintheintensivecareunitandhospital.
Measuresofassociationarereportedasriskratios(RRs)forclinicaloutcomesandmean
differencesforLOS.
RESULTS Twenty-threerandomizedclinicaltrialswereidentified(3088patients;
meanage,61.1years[14.2];women,45.3%).High-qualityevidencesupportedalower
riskofatrialfibrillationassociatedwithvasopressintreatment(RR,0.77[95%CI,0.67to
0.88];riskdifference[RD],−0.06[95%CI,−0.13to0.01]).Formortality,theoverallRR AuthorAffiliations:McMaster
University,Hamilton,Ontario,Canada
estimatewas0.89(95%CI,0.82to0.97;RD,−0.04[95%CI,−0.07to0.00]);however,
(McIntyre,Um,Alhazzani,Lengyel,
whenlimitedtotrialsatlowriskofbias,theRRestimatewas0.96(95%CI,0.84to1.11). Healey,Whitlock,Belley-Côté);
TheoverallRRestimateforRRTwas0.74(95%CI,0.51to1.08;RD,−0.07[95%CI,−0.12to UniversitariodeSaoPaulo,SaoPaulo,
−0.01]).However,inananalysislimitedtotrialsatlowriskofbias,RRwas0.70(95%CI, Brazil(Hajjar);CharingCross
Hospital,Hammersmith,London,
0.53to0.92,Pforinteraction=.77).Therewerenosignificantdifferencesinthepooledrisks
UnitedKingdom(Gordon);Imperial
forotheroutcomes. CollegeLondon,Kensington,London,
UnitedKingdom(Gordon);Université
deSherbrooke,Sherbrooke,Quebec,
CONCLUSIONSANDRELEVANCE Inthissystematicreviewandmeta-analysis,theadditionof
Canada(Lamontagne).
vasopressintocatecholaminevasopressorscomparedwithcatecholaminesalonewas
CorrespondingAuthor:EmilieP.
associatedwithalowerriskofatrialfibrillation.Findingsforsecondaryoutcomesvaried.
Belley-Côté,MD,MSc,DavidBraley
Cardiac,VascularandStroke
ResearchInstitute,237BartonStE,
Room1C1-5B,Hamilton,ONL8L2X2,
JAMA.2018;319(18):1889-1900.doi:10.1001/jama.2018.4528 Canada([email protected]).
(Reprinted) 1889
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Research OriginalInvestigation EffectsofVasopressinWithvsWithoutCatecholamineVasopressorsonAdverseOutcomesinPatientsWithShock
I
ndistributiveshock,widespreadvasodilationleadsto
decreasedsystemicvascularresistancesandmeanarte- KeyPoints
rialpressure(MAP).1Ifnotreversed,end-organhypoper-
Question Inpatientswithdistributiveshock(aconditiondue
fusion results in significant morbidity; mortality rates toexcessivevasodilation,mostfrequentlyfromsevereinfection),
reached50%inobservationalstudiesconductedin2013 istheadditionofvasopressintocatecholaminevasopressors
and2014.2,3Sepsisisthemostcommoncauseofdistribu- superiortocatecholaminevasopressorsaloneforatrialfibrillation?
tiveshock.Itcanalsooccuraftercardiovascularsurgery,
Findings Inthissystematicreviewandmeta-analysisof23trials
spinalcordinjury,orariseasaconsequenceofanaphylaxis thatincluded3088patientswithdistributiveshock,theaddition
orprolongedhypoperfusion.1,4 ofvasopressintocatecholaminevasopressorscomparedwith
Managingdistributiveshockinvolvestreatingtheunder- catecholaminevasopressorsalonewassignificantlyassociated
lyingcause,volumeresuscitation,andinfusingvasopressors withalowerriskofatrialfibrillation(relativerisk,0.77).
tomaintainaperfusingbloodpressure.5,6Cliniciansfre- Meaning Additionofvasopressintocatecholaminesmayoffer
quentlyusecatecholaminergicvasopressors(eg,norepineph- aclinicaladvantageforpreventionofatrialfibrillation.
rine,epinephrine,dopamine,dobutamine).However,cat-
echolamineshaveadverseeffectsincludingmyocardial
ischemiaandarrhythmia,6-8whichmayaffectoutcomes.9
Atrialfibrillationisacommonadverseeventinpatients
Theprimaryoutcomewasatrialfibrillation.Secondary
withdistributiveshockandisindependentlyassociatedwith
outcomesweremortality,requirementforrenalreplace-
morbidity,mortality,andincreasesinlengthofstay(LOS).10-12
menttherapy(RRT),myocardialinjury,ventriculararrhyth-
Vasopressin,anendogenouspeptidehormone,canalso
mia,stroke,andLOSintheintensivecareunit(ICU)and
beusedasavasopressor.Patientswithsepticshockhave
hospital(eAppendices4-5intheSupplement).Acutekidney
relativevasopressindeficiencyandexogenousadministra-
injuryanddigitalischemiawereposthocoutcomes.
tionofvasopressinraisesbloodpressurebyincreasingvascu-
The outcomes were accepted as defined by study
lartone.13Byreducingtherequirementforcatecholamines,it
authors.Formortality,mortalityat28to30days,atlongest
decreasesthestimulationofarrhythmogenicmyocardial
follow-up,andin-hospitalwereconsideredequivalent;ICU
β-receptorsandassociatedmyocardialoxygendemand.7,14
1 mortalitywasnotpooled.Underdigitalischemia,limbische-
This,amongothermechanisms,maytranslateintoareduc-
miaandperipheralischemiaorcyanosiswereincluded.
tioninadverseevents,includingatrialfibrillation,injuryto
Myocardialinfarction,myocardialischemia,troponinrise,
otherorgans,anddeath.7,15ThemostrecentSurvivingSepsis
andacutecoronarysyndromewerepooledundermyocardial
guidelinessuggestaddingvasopressintonorepinephrineto
injury.Ventriculartachycardiaandfibrillationwerepooledas
raiseMAPtotarget,oraddingvasopressintodecreasenor-
ventriculararrhythmia.Cerebrovascularaccidentwascom-
epinephrinedosage(weakrecommendations,moderate
binedwithstroke.
qualityofevidence).5
The objective of this systematic review and meta-
SearchMethods
analysiswastodeterminetheassociationbetweentreatment
MEDLINE,EMBASE,andCENTRALweresearchedforkey-
withvasopressininadditiontocatecholaminevasopressorson
wordsdescribingthecondition,intervention,orcomparator
atrialfibrillation,morbidity,andmortalitycomparedwithcat-
frominceptiontoFebruary25,2018(eAppendices1-3in
echolaminesalone.
theSupplement).Aninformationspecialistreviewedthe
searchstrategies.
Trialregistriesweresearchedforongoingandunpub-
Methods lishedclinicaltrialsviahttp://www.isrctn.comusingthe
multipledatabasesearchoptionmetaRegisterofControlled
ThestudyprotocolwasregisteredwithPROSPERO(2017:
Trials and the World Health Organization trial registry.
CRD42017059058).Theconductandreportingofthestudyfol-
Authorshand-searchedtheconferenceproceedingsforthe
lowthePRISMAguidelines.
scientificsessionsoftheEuropeanSocietyofIntensiveCare
Medicine,theSocietyofCriticalCareMedicine,andthe
EligibilityCriteria
AmericanThoracicSocietyinthelast2years.Thereferences
Randomizedclinicaltrialswereincluded,irrespectiveof
ofeligiblepaperswerescreenedandexpertswereconsulted
publicationstatus,dateofpublication,riskofbias,out-
toidentifyadditionaltrials.
comes published, or language. Trials were included if
they enrolled adults with distributive shock, including
DataCollectionandAnalysis
septicshock,post–cardiovascularsurgeryvasoplegia,neuro-
Two reviewers independently screened studies’ titles
genic shock, and anaphylaxis. Included studies had to
andabstractsforeligibility.Fullpapersofthepotentiallyeli-
comparetheadministrationofvasopressin(oranalogues
giblestudieswereretrieved.Thesame2reviewerstheninde-
[eg,terlipressin,selepressin])withorwithoutconcomitant
pendentlyscreenedfulltextsinduplicateandrecordedthe
catecholaminergicvasopressorswiththeadministrationof
mainreasonforexclusion.Disagreementswereresolved
catecholaminergicvasopressorsalone,irrespectiveofdose,
throughdiscussion.
duration,orco-intervention.
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EffectsofVasopressinWithvsWithoutCatecholamineVasopressorsonAdverseOutcomesinPatientsWithShock OriginalInvestigation Research
DataExtractionandManagement
Figure1.FlowofStudySelectionforTrialsComparing
Independently,2reviewersabstracteddataoninterventionand
Vasopressin+CatecholaminesvsCatecholaminesAlone
outcome.Theyalsorecordedstudyandpatientcharacteris- forPatientsWithDistributiveShock
ticsincludingage,sex,typeofshock,andconcomitantcon-
ditions(eg,cirrhosis,malignancy).Theycomparedresultsand 1474Records identified
resolveddisagreementsbydiscussionwithathirdparty. 314MEDLINE
1006EMBASE
Authorswerecontactedtoclarifyambiguitiesandtorequest 153CENTRAL
dataonoutcomesmissinginprimaryreports. 1Contacted the author
of a substudy abstract
AssessmentofRiskofBias
264Excluded (duplicates)
Induplicate,2reviewauthorsassessedriskofbias.16Ineach
trial,reviewersevaluatedthefollowingdomains:sequence
1210Title and abstracts screened
generation,allocationconcealment,blindingofpatientsand
personnel,blindingofoutcomeassessors,incompleteout- 1107Excluded (not relevant)
comedata,andselectivereporting.Theresultswerecom-
paredanddisagreementsresolvedbydiscussion.Perfor- 103Full-text articles assessed for eligibility
manceanddetectionbiaswereassessedseparately.All
open-labelstudieswereclassifiedasbeingathighriskofper- 80Excluded
formancebias.Apriori,thedecisionwasmadetoclassify 33Wrong population
2Wrong intervention
open-labeldesignsas“likelylowriskofbias”fordetection 11Wrong design
biasformortality,stroke,andLOSintheabsenceofother 30Duplicate or substudy
4No outcomes of interest
concerns,buttojudge“likelyhighriskofbias”fordetection
biasforatrialfibrillation,RRT,digitalischemia,myocardial
23Randomized clinical trials included
injury,andventriculararrhythmia.Foranalysisandpresenta- in qualitative synthesis
tionpurposes,riskofbiaswasdichotomizedashigh(orlikely 23Randomized clinical trials included in
high)orlow(orlikelylow). quantitative synthesis (meta-analysis)
Forsubgroupanalyses,thestudy-levelriskofbiaswas
assessedforeachoutcome.Ifastudywasatriskofselec-
tion,performance,detection,orreportingbiasforthatout- group(intention-to-treatprinciple).Two-sidedPvaluesless
come,itwascategorizedashighriskofbias.Additionally, than.05wereconsideredstatisticallysignificant.
studiesatriskofattritionbiaswerecategorizedashighrisk
ofbiasformortality. SubgroupandSensitivityAnalyses
Prespecifiedsubgroupanalyseswereperformedhypothesiz-
MeasuresofAssociationWithTreatment ingthatpatientswithsepsiswouldderivegreaterbenefitvs
Themainreportedstandardassociationmeasureforclinical cardiovascularsurgery.Asaseparatesensitivityanalysisfor
outcomeswasriskratios(RRs)andmeandifferencesforLOS. RRT,theoutcomedefinitionwaschangedtoacutekidneyin-
Riskdifferenceandabsoluteriskdifferencewerealsocalcu- jury,asdefinedbystudyauthors.Pvaluesforinteractionbe-
latedforclinicaloutcomes.Theabsoluteriskdifferencewas tweensubgroupsweretested.
obtainedbyapplyingtheRRswith95%CIstothebaseline
riskinthecontrolgroup.Topermitmeta-analysis,ifastudy AssessmentoftheQualityoftheEvidence
reportingonLOSprovidedamedianandameasureofdisper- TheGRADE(GradesofRecommendation,Assessment,Devel-
sion,thiswasconvertedtomeanandstandarddeviation opment,andEvaluation)approach19wasusedtogradethe
assuminganormaldistribution.17 qualityofevidence.GRADEappraisestheconfidenceinesti-
Clinical and methodological heterogeneity were matesofeffectbyconsideringwithin-studyriskofbias,di-
assessedbasedonstudycharacteristics.Statisticalhetero- rectnessoftheevidence,heterogeneityofthedata,precision
geneitywasmeasuredwiththeI2statistic.AnI2statistic ofeffectestimates,andriskofpublicationbias.Funnelplots
greaterthan50%wasconsideredasshowingsubstantial ofstandarderrorsvseffectestimateswereinspectedforpub-
heterogeneity.16 licationbiasandsmall-studyeffects.
RevMan(CochraneCollaboration),version5.3,wasused
tocombinedataquantitativelywhenclinicalheterogeneity
wasnonsubstantial.Arandom-effectsmodelwithMantel-
Results
Haenszelweightingwasusedbecauseseveralcomparisons
wereexpectedtoshowheterogeneity.Afterrecognizingthat Screening
asubstantialproportionoftheweightforatrialfibrillation The electronic search resulted in 1210 unique citations
wascontributedbyasinglestudy,18wecombineddatafor (Figure1).Afterreferenceandfull-textscreening,23studies
thisoutcomewithafixed-effectmodelinasensitivityanaly- meteligibilitycriteria.Detailsonexcludedandincludedstud-
sis.Fortrialsinwhichpatientscrossedovertotheother iesand3potentiallyrelevantongoingstudiesareavailable
treatment,theanalysiswasaccordingtotheirfirstassigned (eAppendices6-8intheSupplement).
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Research OriginalInvestigation EffectsofVasopressinWithvsWithoutCatecholamineVasopressorsonAdverseOutcomesinPatientsWithShock
Table1.CharacteristicsofIncludedRandomizedClinicalTrialsComparingVasopressin+CatecholaminesvsCatecholaminesAlone
inPatientsWithDistributiveShock
RiskofBias
No.of Planned forAtrial
Source Design Setting Patients Condition TreatmentGroup(s) ComparisonGroup(s) Follow-up Fibrillation
Abdullah Openlabel Singlecenter 34 Paracentesis-induced Terlipressin:1mgover NE:0.1μg/kg/min 48h High
etal,20 vasodilatoryshockand 30min,thencontinuous titratedupandweaned
2012 end-stageliverdisease infusionof2μg/kg/min within24h
titratedupandweaned
within24h
Acevedo Openlabel Singlecenter 24 Septicshockand Terlipressin:1-2mg Adrenergicdrugs Hospital High
etal,21 cirrhosis over4h asneeded LOS
2009
Albanese Openlabel Singlecenter 20 Septicshockand2or Terlipressin:1-mg NE:0.3μg/kg,then Hospital High
etal,22 moreorgan bolus,thenanother increasedby0.3μ/kg LOS
2005 dysfunctions 1-mgbolusifMAP every4minuntilMAP
<65mmHg between65-75mmHg
Barzegar Openlabel Singlecenter 30 Septicshock Vasopressin:0.03U/min NEasneededforMAP 28d High
etal,23 >65mmHg
2014
Capoletto Double-blind NA 107 Septicshockandcancer Vasopressin:not NE:notdescribed 90d Low
etal,24 described
2017
Chenet Openlabel Singlecenter 57 Acuterespiratory TerlipressinandNE: NE:>1μg/min 28d High
al,252017 distresssyndromeand 0.01-0.04U/minof
septicshock terlipressinandNEas
neededtomaintainMAP
between65-75mmHg
Choudhury Openlabel Singlecenter 84 Septicshockand Terlipressin: NE:7.5-60μg/min 28d High
etal,26 cirrhosis 1.3-5.2μg/minover
2016 24h
Clem Openlabel Singlecenter 82 Septicshock VasopressinandNE: NE:0.05-0.5μg/kg/min 28d High
etal,27 0.05-0.5μg/kg/minof tomaintainMAP
2016 NEand0.04U/minof between65-75mmHg
vasopressintomaintain
MAPbetween
65-75mmHg
Dünser Openlabel Singlecenter 48 Vasodilatoryshock Vasopressin:4U/h NE:asneededforMAP ICULOS High
etal,28 includingsepticshock, ataconstantrate >70mmHg,and
2003 sepsis,andcardiotomy additionalvasopressin
forNErequirements
>2.26μg/kg/min
Fonseca Openlabel Singlecenter 30 Septicshock VasopressinandNE: NE 28d High
Ruiz NE+vasopressinat
etal,29 titrateddosesof
2013 0.01U/min,then
increasedby0.01U/min
every10mintoachieve
MAP>65mmHgor
untilmaximumdoseof
0.04U/min
Gordon Double-blind Multicenter 421 Septicshock Vasopressin:upto0.06 NE:upto12μg/min 28d Lowa
etal,30 U/minwithtargetMAP withtargetMAP
2016 between65-75mmHg, between65-75mmHg,
oratphysician’s oratphysician’s
discretion discretion
Hajjar Double-blind Singlecenter 330 Vasoplegiaafter Vasopressin: NE:10-60μg/minwith 30d Lowa
etal,18 cardiacsurgery 0.01-0.06U/minwith MAP>65mmHg
2017 MAP>65mmHg
Han Openlabel Singlecenter 139 Septicshock Pituitrin:1.0-2.5U/h NE:2-20μg/kg/min 28d High
etal,31
2012
Hua Openlabel Singlecenter 32 Septicshockandacute Terlipressin:1.3 Dopamine: 28d High
etal,32 respiratorydistress μg/kg/h 20μg/kg/min
2013 syndrome
Lauzier Openlabel Multicenter 23 Septicshock Vasopressin: NE:0.1-2.8μg/kg/min ICULOS High
etal,33 0.04-0.20U/min
2006
Malay Double-blind Singlecenter 10 Septicshock Vasopressin:0.04U/min Placebo 24h Low
etal,34
1999
(continued)
IncludedStudies 3088 patients (mean age, 61.1 years [14.2]; women,
The23studiesthatcomparedvasopressinincombination 45.3%)(Table1).Fivetrialsweremulticenter.30,33,37,39,40
withcatecholaminesvscatecholaminesaloneincluded Twenty-twostudiesincludedpatientswithsepticshock.20-41
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EffectsofVasopressinWithvsWithoutCatecholamineVasopressorsonAdverseOutcomesinPatientsWithShock OriginalInvestigation Research
Table1.CharacteristicsofIncludedRandomizedClinicalTrialsComparingVasopressin+CatecholaminesvsCatecholaminesAlone
inPatientsWithDistributiveShock(continued)
RiskofBias
No.of Planned forAtrial
Source Design Setting Patients Condition TreatmentGroup(s) ComparisonGroup(s) Follow-up Fibrillation
Morelli Openlabel Singlecenter 45 Septicshock Group1:vasopressin: NEasneeded ICULOS High
etal,35 0.03U/min
2009b continuouslyover48h
Group2:terlipressin:
1.3μg/kg/min
continuouslyover48h
Oliveira Double-blind Singlecenter 387 Septicshock Vasopressin: NE:0.05-2.0μg/kg/min 28d High
etal,36 0.01-0.03U/min
2014
Patel Double-blind Multicenter 24 Septicshock Vasopressin: NE:2-16μg/min 4h Low
etal,37 0.01-0.08U/min
2002
Prakash Openlabel NS 184 Cirrhosisandsepsis TerlipressinandNE: NE:7.5-60μg/min 30d High
etal,38 2mg/24hfixeddose
2017 infusionofterlipressin
and3.75-30μg/minof
NEasneededto
maintainMAP
>65mmHg
Russell Double-blind Multicenter 802 Septicshock Vasopressin:0.01 NE:5μg/minto15 90d Low
etal,39 U/min,thentitratedup μg/minwithtargetMAP
2008 to0.03U/minwith between65-75mmHg,
targetMAPbetween oratphysician’s
65-75mmHg,orat discretion
physician’sdiscretion
Russell Doubleblind Multicenter 53 Septicshock Selepressin:1.25,2.5, Placebo 28d Lowa
etal,40 or3.75ng/kg/minuntil
2017 shockresolutionora
maximumof7d
Svoboda Openlabel Singlecenter 32 Septicshock Terlipressin:4mgover NEasneeded 28d High
etal,41 24hfor72h
2012
Abbreviations:ICU,intensivecareunit;LOS,lengthofstay;MAP,meanarterial norepinephrine).Itwasconsideredas2separatetrials(vasopressinvs
pressure;NE,norepinephrineornoradrenaline;NS,notspecified. norepinephrineandterlipressinvsnorepinephrine)inthecomparison
aTrialjudgedtobeathighriskofbiasformortalityduetoviolationofthe betweenvasopressinandvasopressinanalogs.Itwasconsideredasasingle
intention-to-treatprinciple. trial(vasopressinorterlipressinvsnorepinephrine)inallothercomparisons.
bMorellietal,2009,35comprised3groups(vasopressinvsterlipressinvs
Two studies evaluated patients with post–cardiac sur- randomization31,36;theydidnotdescribetheirrandomiza-
gery vasoplegia.18,28 Vasopressin was the intervention tionprocessandhadsignificantbetween-groupimbalances.
in 13 trials,18,23,24,27-30,33-37,39 whereas 9 studied terli- Ninestudies(39%)reportedtheinformationnecessaryto
pressin,20-22,25,26,32,35,38,411studiedselepressin,40and1stud- makeadefinitivejudgmentforselectionbias.Authorsrelied
ied pituitrin (a mixture of vasopressin and oxytocin).31 onimbalancesbetweengroupsandoverallmethodological
One3-groupstudycomparedvasopressinvsterlipressinvs qualityofthestudytomakethisjudgment.Attritionwas
norepinephrinealone.35Fivestudieswerepublishedonly foundin7studies,18,25,30,31,36,40,41andjudgedashavingan
asabstracts.18,21,27,36,38 effectonmortality(Table2andFigure2A).Reportingbias
wasnotdetected.“Otherbias”wasjudgedtobepresent
RiskofBias whenstudieswerepublishedasabstractsonly.Prespecified
Fifteenof23trialswerenotblinded(eAppendices9-10inthe sensitivityanalyseswereperformedtoassesstherobustness
Supplement).Performancebiasduetolackofblindingwas ofestimatestoriskofbiasifstudiesweredichotomized
judgedtohaveanimportanteffectonalloutcomes;patients accordingtotheirriskofbias.
withdistributiveshockarecriticallyillandreceivingmany
concomitantinterventionsthatcouldbeinfluencedbychoice PrimaryOutcome
ofconcomitantvasopressor.Atrialfibrillation,myocardial AtrialFibrillation
injury,anddigitalischemiaarevulnerabletodetectionbias Poolingdatafrom13studies(4studieswith0eventsineither
fromdifferentialcaptureandsubjectiveinterpretation;lack group,1462patients,374events)demonstratedasignificant
ofblindingofcliniciansandoutcomeassessorsmayinflu- reductionintheriskofatrialfibrillationassociatedwiththe
encetheseoutcomes.ThedecisiontostartRRTcouldalsobe administrationofvasopressin(RR,0.77[95%CI,0.67to
subjective.Otheroutcomeswerejudgedtobeatlowriskof 0.88],I2=1%;riskdifference[RD],−0.06[95%CI,−0.13
detectionbiasintheabsenceofblinding.Twostudieswere to0.01])(Figure2A).BasedontheGRADEframework,this
assessedtobeatriskofselectionbiasduetoinadequate wasjudgedtobehigh-qualityevidence(eAppendix13inthe
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Research OriginalInvestigation EffectsofVasopressinWithvsWithoutCatecholamineVasopressorsonAdverseOutcomesinPatientsWithShock
Table2.AssociationofVasopressin+CatecholamineVasopressorsvsCatecholaminesAloneWithAtrialFibrillation
inPatientsWithDistributiveShockandSensitivityAnalyses
No.WithEvents/TotalNo.ofPatients RelativeRiska
Vasopressin+ Catecholamines RiskDifference,% RiskRatio Qualityof
Group Catecholamines Alone (95%CI)a (95%CI) PValue I2% Evidence
Allstudies18,20,24,26-28,30,33-35,39-41 159/739 215/723 −6(−13to1) 0.77(0.67to0.88) <.001 1
Lowriskofbias18,24,30,34,39,40 136/559 182/554 −7(−20to5) 0.77(0.68to0.88) <.001 0
Highriskofbias20,26-28,33,35,41 23/180 33/169 −3(−10to4) 0.73(0.40to1.34) .31 36
Sepsis20,24,26-28,30,33-35,39-41,b 60/580 84/563 −3(−7to1) 0.76(0.55to1.05) .09 8
Cardiacsurgery18,28,c 99/159 131/160 −19(−29to−10) 0.77(0.67to0.88) <.001 0 High
Vasopressin18,24,27,28,30,33-35,39,b,c 151/621 201/626 −7(−17to3) 0.77(0.68to0.88) <.001 0
Vasopressinanalogues20,26,35,40,41,c 8/118 18/112 −0.05(−11to1) 0.52(0.18to1.51) .23 28
Fixed-effect 159/739 215/723 −7(−11to−4) 0.75(0.65to0.86) <.001 1
analysis18,20,24,26-28,30,33-35,39-41,b,c
aRelativerisk<1.0andriskdifference<0.0favorsvasopressin+ cMorellietal,2009,35comprised3groups(vasopressinvsterlipressinvs
catecholamines. norepinephrine).Itwasconsideredas2separatetrials(vasopressinvs
bDünseretal,2003,28includedpatientswithbothsepsisandpost–cardiac norepinephrineandterlipressinvsnorepinephrine)inthecomparison
surgeryvasoplegia,butsubgroupdatawereobtainedforatrialfibrillationonly. betweenvasopressinandvasopressinanalogs.Itwasconsideredasasingle
Thisstudywasexcludedfromotheroutcomeswhensepsisandpost–cardiac trial(vasopressinorterlipressinvsnorepinephrine)inallothercomparisons.
surgeryvasoplegiawerecompared.
Supplement).ThisresultwasdrivenbythestudybyHajjar −0.07[95%CI,−0.12to−0.01];moderate-qualityevidence).
etal,18whichcarried74.8%oftheweight.Inabsoluteterms, However,whentheanalysiswaslimitedtothe2trialsatlow
theabsoluteeffectisthat68fewerpeopleper1000patients riskofbias,24,30thepointestimatewassimilar,butvaso-
(95%CI,36to98)willexperienceatrialfibrillationwhen pressinwasassociatedwithasignificantreductioninthe
vasopressinisaddedtocatecholaminergicvasopressors. riskofRRTwithoutevidenceofheterogeneity(RR,0.70
Inasensitivityanalysisexcludingthe7studiesathighrisk [95%CI,0.53to0.92],I2=0%,Pforinteraction=.77).
ofbiasforlackofblindingofoutcomeassessors,20,26-28,33,35
theestimateofeffectwasunchanged(eAppendix11inthe MyocardialInjury
Supplement).Inasecondsensitivityanalysis,patientswith Elevenstudies(1957patients,133events)reportedonmyo-
sepsisandpost–cardiacsurgerywereconsideredseparately. cardialinjury;2trialshadeventratesof0inbothgroups.
Forthesubgroupofpost–cardiacsurgerypatients,18,28the Therewasnosignificantdifferenceintheriskofmyocardial
resultantRRestimatewas0.77(95%CI,0.67to0.88),not injurywithvasopressin(RR,0.86[95%CI,0.63to1.17],
significantlydifferentthaninpatientswithsepsis(RR,0.76 I2=0%;RD,0.00[95%CI,−0.02to0.02];low-qualityevi-
[95%CI,0.55to1.05],Pforinteraction=.97)(Table2).Even dence).Afterexcludingstudiesathighriskofbiasfrom
thoughthecruderateofatrialfibrillationinthispost–cardiac open-labeldesign,20,28,33,41theestimatedidnotchange
surgerypopulation(73%)wasconsiderablyhigherthaninthe significantly.Becausesurrogateswerereportedformyocar-
sepsisstudies(13%),therelativeeffectestimatewassimilar dialinjury(eg,alteredSTsegments),indirectnesswasrated
inbothgroups. asserious.
SecondaryOutcomes VentricularArrhythmia,Stroke,andLengthofStay
Mortality When9studiesreportingonventriculararrhythmiawere
Mortalitydatawereavailablefrom17studies(2904patients, pooled(837patients,87events),theriskwasnotsignificantly
1123events)(Figure2B).Whenpooled,theadministrationof differentwithvasopressin(RR,0.93[95%CI,0.73to1.19],
vasopressininadditiontocatecholamineswasassociated I2=0%;RD,0.00[95%CI,−0.02to0.01];low-qualityevi-
withareductioninmortality(RR,0.89[95%CI,0.82to dence).Therewasnosignificantdifferencewhenpooling
0.97],P=.009,I2=0;RD,−0.04[95%CI,−0.07to0.00]). datafrom4studies(1358patients,17events)reportingon
Inabsoluteterms,45lives(95%CI,12to73)wouldbesaved stroke(RR,1.61[95%CI,0.53to4.95],I2=7%;RD,0.01[95%
per1000patientstreatedwithvasopressin.However,when CI,−0.02to0.04];moderate-qualityevidence).LOSdata
limitedtothe2trialsatlowriskofbias(Table3),24,39theRR werereportedexclusivelyasmedianswithinterquartile
estimatewas0.96(95%CI,0.84to1.11). rangeandweretransformedtoestimatemeanLOSwithstan-
darddeviation.HospitalLOSwasnotsignificantlyassociated
RequirementforRRTandAcuteKidneyInjury withvasopressin(8studies,1939patients;meandifference,
Sixtrialswithatotalof805patients(222events)reported −1.14days[95%CI,−3.60to1.32],I2=75%;low-qualityevi-
onRRT(Figure3A).Whencombined,vasopressinwasasso- dence)(Table4).Similarly,ICULOSwasnotsignificantly
ciatedwithareducedriskforRRT,butthepooledestimate associatedwithvasopressin(meandifference,−0.40days
didnotreachstatisticalsignificanceandshowedsubstantial [95%CI,−1.05to0.25],I2=24%;moderate-qualityevidence)
heterogeneity(RR,0.74[95%CI,0.51to1.08],I2=70%;RD, when11studieswerecombined(2156patients).
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EffectsofVasopressinWithvsWithoutCatecholamineVasopressorsonAdverseOutcomesinPatientsWithShock OriginalInvestigation Research
Figure2.RelativeRisksofAllTrialsComparingVasopressin+CatecholaminesvsCatecholaminesAloneforPatientsWithDistributiveShock
A Atrial fibrillation
Vasopressin + Catecholamine
Catecholaminea Alone
Favors Favors
No. With Total No. No. With Total No. Vasopressin Catecholamine
Source Events of Patients Events of Patients Risk Ratio (95% CI) + Catecholamine Alone Weight, %
Abdullah et al,25 2012 0 17 0 17 Not estimable
Capoletto et al,38 2017 34 125 40 125 0.85 (0.58-1.25) 12.0
Choudhury et al,29 2016 1 42 3 42 0.33 (0.04-3.08) 0.4
Clem et al,30 2016 6 41 3 41 2.00 (0.54-7.46) 1.0
Dünser et al,39 2003 8 24 13 24 0.62 (0.31-1.21) 3.9
Gordon et al,20 2016 0 205 3 204 0.14 (0.01-2.73) 0.2
Hajjar et al,18 2017 95 149 124 151 0.78 (0.67-0.89) 74.8
Lauzier et al,21 2006 0 13 0 13 Not estimable
Malay et al,33 1999 0 5 0 5 Not estimable
Morelli et al,35 2009 1 30 4 15 0.13 (0.02-1.02) 0.4
Russell et al,22 2008 7 44 14 48 0.55 (0.24-1.23) 2.7
Russell et al,23 2017 0 31 1 21 0.23 (0.01-5.37) 0.2
Svoboda et al,37 2012 7 13 10 17 0.92 (0.48-1.74) 4.4
Total events (95% CI) 159 739 215 723 0.77 (0.67-0.88) 100.0
Heterogeneity: τ2 = 0.00; χ2 = 9.10 (P = .43); I2 = 1%
9
Overall effect: z = 3.79 (P <.001) 0.2 1.0 5.0
Risk Ratio (95% CI)
B 28-d or 30-d mortality
Vasopressin + Catecholamine
Catecholaminea Alone
Favors Favors
No. With Total No. No. With Total No. Vasopressin Catecholamine
Source Events of Patients Events of Patients Risk Ratio (95% CI) + Catecholamine Alone Weight, %
Acevedo et al,26 2009 6 12 9 12 0.67 (0.35-1.28) 1.6
Albanese et al,27 2005 5 10 4 10 1.25 (0.47-3.33) 0.7
Barzegar et al,28 2014 5 15 7 15 0.71 (0.29-1.75) 0.9
Capoletto et al,38 2017 71 125 68 125 1.04 (0.84-1.30) 14.1
Chen et al,40 2017 9 31 8 26 0.94 (0.43-2.09) 1.1
Choudhury et al,29 2016 31 42 36 42 0.86 (0.69-1.07) 14.6
Clem et al,30 2016 19 41 18 41 1.06 (0.65-1.70) 3.0
Fonseca Ruiz et al,34 2013 4 14 5 16 0.91 (0.30-2.75) 0.6
Gordon et al,20 2016 63 204 56 204 1.13 (0.83-1.52) 7.6
Hajjar et al,18 2017 23 149 24 151 0.97 (0.57-1.64) 2.5
Han et al,31 2012 27 66 34 73 0.88 (0.60-1.28) 4.8
Hua et al,32 2013 7 16 8 16 0.88 (0.42-1.84) 1.3
Oliveira et al,36 2014 65 191 83 196 0.80 (0.62-1.04) 10.6
Prakash et al,41 2017 37 91 57 93 0.66 (0.49-0.89) 7.9
Russell et al,22 2008 144 404 154 395 0.91 (0.76-1.09) 21.4
Russell et al,23 2017 6 29 4 19 0.98 (0.32-3.03) 0.5
Svoboda et al,37 2012 10 13 16 17 0.82 (0.59-1.13) 6.8
Total events (95% CI) 532 1453 591 1451 0.89 (0.82-0.97) 100.0
Heterogeneity: τ2 = 0.00; χ 2 = 11.29 (P = .79); I2 = 0%
16
Overall effect: z = 2.62 (P = .009) 0.2 1.0 5.0
Risk Ratio (95% CI)
Therelativeriskswerecalculatedusingarandom-effectsmodelwith aVasopressin(oranalogue[ie,terlipressin,selepressin,orpituitrin])+
Mantel-Haenszelweighting.Thesizeofdatamarkersindicatestheweightofthe catecholaminevasopressors.
study.Errorbarsindicate95%CIs.
PostHocOutcomes dencewasnotdowngradedforindirectnessbut,becauseitwas
DigitalIschemia aposthocoutcome,itwasdowngradedforriskofbias.
When 9 studies (1963 patients, 58 events) were pooled
(Figure3B),vasopressininadditiontocatecholamineswasas- AcuteKidneyInjury
sociatedwithasignificantincreaseindigitalischemia(RR,2.38 Inasensitivityanalysis,thetreatmenteffectforRRTwascon-
[95%CI,1.37to4.12],I2=0;RD,0.02[95%CI,−0.01to0.04]; sistent,butnotstatisticallysignificantwhenthedefinitionwas
moderate-qualityevidence).Inabsoluteterms,thismeans24 modifiedtoacutekidneyinjury(5trials;RR,0.73[95%CI,0.46
moreoccurrences(95%CI,6to55)ofdigitalischemiaper1000 to1.17],I2=91%).
patientstreatedwithvasopressin.Whenthe4studiesathigh
riskofbiaswereexcluded,23,26,29,41theresultantestimatewas PublicationBias
notsignificantlydifferent.Definitionsvariedforthisout- Theassessmentofpublicationbiaswaslimitedbysmallnum-
come;however,whentheanalysiswaslimitedtothe6stud- bersofstudiesformostoutcomes(eAppendix12intheSupple-
iesthatspecificallydescribed“digitalischemia,”18,23,29,30,39,40 ment).Visualinspectiondidnotleadtoconcernsaboutpub-
theresultantestimatedidnotchangesignificantly.Thus,evi- licationbias.
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Research OriginalInvestigation EffectsofVasopressinWithvsWithoutCatecholamineVasopressorsonAdverseOutcomesinPatientsWithShock
Table3.BinaryOutcomesandSensitivityAnalysesforVasopressin+CatecholaminesvsCatecholaminesAloneinPatientsWithDistributiveShock
No.WithEvents/TotalNo.ofPatients RelativeRiska
Vasopressin+ Catecholamines RiskDifference% RiskRatio QualityofEvidence
Group Catecholamines Alone (95%CI)a (95%CI) PValue I2% (ReasonforJudgment)
28-dor30-dMortality
Allstudies18,21-27,29-32,36,38-41 532/1453 591/1451 −4(−7to0) 0.89(0.82to0.97) .009 0
Lowriskofbias24,39 215/529 222/520 −2(−8to4) 0.96(0.84to1.11) .6 0
Highrisk 317/924 369/931 −4(−8to0) 0.86(0.77to0.95) .004 0
ofbias18,21-23,25-27,29-32,36,38,40,41
28-dor30-d 567/1525 623/1505 −4(−7to−1) 0.89(0.83to0.97) .006 0
orICUmortality18,21-36,38-41,b,c
Low
Fulltextonly18,22,23,25,26,29-32,39-41,d 334/993 356/984 −2(−6to2) 0.91(0.82to1.01) .09 0 (riskofbias)
Vasopressin23,24,27,29,30,36,39,41,b 404/1156 431/1160 −2(−6to2) 0.94(0.85to1.04) .21 0
Vasopressin 128/297 160/291 −10(−18to−3) 0.81(0.70to0.94) .005 0
analogues21,22,25,26,31,32,38,40,41,b
Sepsis21-27,29-32,36,38-41 509/1304 567/1300 −4(−8to−1) 0.89(0.82to0.97) .008 0
Cardiacsurgery18 23/149 24/151 −0(−9to8) 0.97(0.57to1.64) .91 NA
RequirementforRenalReplacementTherapy
Allstudies23,24,28,30,33,35,b,e 97/412 125/393 −7(−12to−1) 0.74(0.51to1.08) .12 70
Lowriskofbias24,30 62/330 89/329 −7(−13to−2) 0.70(0.53to0.92) .01 0
Highriskofbias23,28,33,35,b,c 35/82 36/64 −5(−16to7) 0.77(0.42to1.43) .41 67 Moderate
AKIasoutcome18,21,24,28,30,b 154/515 204/516 −8(−21to6) 0.73(0.46to1.17) .19 91 (imprecision)
Vasopressin23,24,28,30,33,35,b,e 93/397 125/393 −6(−11to−1) 0.76(0.53to1.10) .15 68
Vasopressinanalogues35,b,e 4/15 8/15 −27(−60to7) 0.50(0.19to1.31) .16 NA
DigitalIschemia
Allstudies18,23,24,26,29,30,39-41 41/990 17/973 2(−1to4) 2.38(1.37to4.12) .002 0
Lowriskofbias18,24,30,39,40 23/906 9/883 1(−1to3) 2.45(1.10to5.43) .03 0
Highriskofbias23,26,29,41 18/84 8/90 10(0to19) 2.31(1.08to4.94) .03 0
Moderate
Definedasdigital 25/810 8/789 2(0to3) 2.73(1.27to5.87) .01 0 (posthocoutcome)
ischemia18,23,29,30,33,39,40,f
Vasopressin18,23,24,29,30,33,39,b 24/904 10/893 1(−1to3) 2.35(1.10to5.05) .03 0
Vasopressinanalogues26,40,41,b 17/86 7/80 10(−4to25) 2.40(1.09to5.31) .03 0
MyocardialInjury
Allstudies18,20,24,28,30,33,34,37,39-41,b 62/991 71/966 0(−2to2) 0.86(0.63to1.17) .34 0
Lowriskofbias18,24,30,34,37,39,40 61/924 66/899 1(−1to3) 0.89(0.64to1.25) .52 4
Highriskofbias20,28,33,41,b 1/67 5/67 −5(−12to3) 0.37(0.07to1.95) .24 0
Low
Sepsis20,24,28,30,33,34,37,39-41,b 51/818 51/791 1(−1to2) 0.94(0.67to1.32) .71 0 (indirectness,
Cardiacsurgery18 11/149 17/151 −4(−10to3) 0.66(0.32to1.35) .25 NA imprecision)
Vasopressin18,24,28,30,33,34,37,39,b 61/930 70/912 0(−3to2) 0.87(0.61to1.23) .42 6
Vasopressinanalogues20,40,41,b 1/61 1/54 1(−6to7) 0.91(0.10to8.33) .93 0
VentricularArrhythmia
Allstudies18,20,24,26,27,33,34,37,41 39/418 48/419 0(−2to1) 0.93(0.73to1.19) .55 0
Lowriskofbias18,34,37 27/167 32/167 −2(−10to5) 0.86(0.54to1.35) .50 NA
Low
Highriskofbias20,24,26,27,33,41 12/251 16/252 0(−1to1) 0.96(0.72to1.28) .78 0 (indirectness,
Vasopressin18,24,27,33,34,37,b 28/346 32/343 0(−1to2) 0.88(0.56to1.38) .57 0 imprecision)
Vasopressinanalogues20,26,41,b 11/72 16/76 −2(−7to3) 0.95(0.71to1.27) .73 0
Stroke
Allstudies18,24,39,41 11/683 6/675 1(−2to4) 1.61(0.53to4.95) .40 7
Lowriskofbias18,24,39 11/670 6/658 1(−2to4) 1.61(0.53to4.95) .40 7
Highriskofbias41 0/13 0/17 0(−12to12) NA NA NA Moderate
(imprecision)
Vasopressin18,24,39,b 11/670 6/658 1(−2to4) 1.61(0.53to4.95) .40 7
Vasopressinanalogues41,b 0/13 0/17 0(−12to12) NA NA NA
Abbreviation:AKI,acutekidneyinjury. d“Fulltextonly”referstostudiesnotpublishedonlyasabstracts.
aRelativerisk<1.0andriskdifference<0.0favorsvasopressin+ eMorellietal,2009,35comprised3groups(vasopressinvsterlipressinvs
catecholamines. norepinephrine).Itwasconsideredas2separatetrials(vasopressinvs
bDünseretal,2003,28includedpatientswithbothsepsisandpost–cardiac norepinephrineandterlipressinvsnorepinephrine)inthecomparison
surgeryvasoplegia,butsubgroupdatawereobtainedforatrialfibrillationonly. betweenvasopressinandvasopressinanalogs.Itwasconsideredasasingle
Thisstudywasexcludedfromotheroutcomeswhensepsisandpost–cardiac trial(vasopressinorterlipressinvsnorepinephrine)inallothercomparisons.
surgeryvasoplegiawerecompared. fIncludesonlystudiesinwhichtheauthorsdescribedtheoutcomeasdigital
cAdded4studiesthatreportedonICUmortality. ischemia.Peripheralcyanosisandlimbischemiawereexcluded.
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EffectsofVasopressinWithvsWithoutCatecholamineVasopressorsonAdverseOutcomesinPatientsWithShock OriginalInvestigation Research
Figure3.RelativeRisksofAllTrialsComparingVasopressin+CatecholaminesvsCatecholaminesAloneforPatientsWithDistributiveShock
A Requirement of renal replacement therapy
Vasopressin + Catecholamine
Catecholaminea Alone
Favors Favors
No. With Total No. No. With Total No. Vasopressin Catecholamine
Source Events of Patients Events of Patients Risk Ratio (95% CI) + Catecholamine Alone Weight, %
Low risk of biasb
Capoletto et al,38 2017 10 125 17 125 0.59 (0.28-1.23) 14.6
Gordon et al,20 2016 52 205 72 204 0.72 (0.53-0.97) 28.5
Total events (95% CI) 62 330 89 329 0.70 (0.53-0.92) 43.1
Heterogeneity: τ2 = 0.00; χ2 = .24 (P = .62); I2 = 0%
1
Overall effect: z = 2.53 (P = .01)
High risk of biasb
Barzegar et al,28 2014 4 15 6 15 0.67 (0.23-1.89) 9.3
Dünser et al,39 2003 22 24 22 24 1.00 (0.84-1.19) 32.5
Lauzier et al,21 2006 0 13 0 10 Not estimable 15.1
Morelli et al,35 2009 9 30 8 15 0.56 (0.27-1.16) 56.9
Total events (95% CI) 35 82 36 64 0.77 (0.42-1.43)
Heterogeneity: τ2 = 0.19; χ2 = 5.99 (P = .05); I2 = 67%
2
Overall effect: z = 0.82 (P = .41)
Total (95% CI) 97 412 125 393 0.74 (0.51-1.08) 100.0
Heterogeneity: τ2 = 0.10; χ2 = 13.51 (P = .009); I2 = 70%
4
Overall effect: z = 1.56 (P = .12) 0.1 1.0 5.0
Subgroup differences: χ21 = 0.09 (P = .77); I2 = 0% Risk Ratio (95% CI)
B Digital ischemia
Vasopressin + Catecholamine
Catecholaminea Alone
Favors Favors
No. With Total No. No. With Total No. Vasopressin Catecholamine
Source Events of Patients Events of Patients Risk Ratio (95% CI) + Catecholamine Alone Weight, %
Barzegar et al,28 2014 1 15 0 15 3.00 (0.13-68.26) 3.4
Capoletto et al,38 2017 0 125 2 125 0.20 (0.01-4.12) 3.6
Choudhury et al,29 2016 12 42 4 42 3.00 (1.05-8.55) 30.4
Fonseca Ruiz et al,34 2013 1 14 1 16 1.14 (0.08-16.63) 4.7
Gordon et al,20 2016 1111 220055 33 220044 33..6655 ((11..0033--1122..8899)) 2211..00
Hajjar et al,18 2017 3 149 2 151 1.52 (0.26-8.97) 9.6
Russell et al,22 2008 8 396 2 382 3.86 (0.82-18.05) 14.0
Russell et al,23 2017 1 31 0 21 2.06 (0.09-48.34) 3.4
Svoboda et al,37 2012 4 13 3 17 1.74 (0.47-6.47) 19.4
Total events (95% CI) 41 990 17 973 2.38 (1.37-4.12) 100.0
Heterogeneity: τ2 = 0.00; χ2 = 4.36 (P = .82); I2 = 0%
8
Overall effect: z = 3.09 (P = .002) 0.1 1.0 5.0
Risk Ratio (95% CI)
Therelativeriskswerecalculatedusingarandom-effectsmodelwith bRiskofbiascategoriesforrequirementforrenalreplacementtherapyarethe
Mantel-Haenszelweighting.Thesizeofdatamarkersindicatestheweightofthe sameasthoseforatrialfibrillation,assummarizedinTable1.
study.Errorbarsindicate95%CIs.
aVasopressin(oranalogue[ie,terlipressin,selepressin,orpituitrin])+
catecholaminevasopressors.
itedutilityduetothevarietyofconditionsthatcouldbe
Discussion foundunderthisheading.Thereductioninatrialfibrillation
associatedwithvasopressinwasconsistentacross2sub-
Inthissystematicreviewandmeta-analysisofrandomized types of distributive shock and in sensitivity analyses
clinicaltrials,theadministrationofvasopressininaddition restrictedtostudiesatlowriskofbias.
tocatecholaminevasopressorsinpatientswithdistributive Vasopressinmayhavecontributedtoareductionof
shockwasassociatedwithasignificantreductionintherisk atrialfibrillationbysparingtheadrenergicstimulationpro-
ofatrialfibrillationwhencomparedwithcatecholamines videdbycatecholaminergicvasopressors.6-8,14Thiscould
alone(high-qualityevidence).Findingsforotheroutcomes havemanifestedinfewerpatientsdevelopingatrialfibrilla-
werenotconsistent.Althoughwhenallstudieswerecom- tionormayhavecausedatrialfibrillationtobeshorterin
binedtheriskofmortalitywaslowerwiththeadditionof durationandlowerinrateand,inconsequence,lesslikely
vasopressin,asensitivityanalysislimitedtolowriskofbias tobedetected.
trialsyieldedarelativeriskmuchcloserto1andwasnotsta- Theapproachtomonitoringandascertainmentofatrial
tisticallysignificant. fibrillationinpatientswhoareacutelyillaffectsthedetection
Toourknowledge,thissystematicreviewisthefirston ofthisoutcome.44Thislimitationwouldneedtobead-
thetopictoincludeatrialfibrillationasanoutcome.Prior dressedtomorepreciselyestimateeventratesinthispopula-
reviewsassessedarrhythmia,42,43butthisoutcomehaslim- tion and their association with vasopressin treatment.
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Research OriginalInvestigation EffectsofVasopressinWithvsWithoutCatecholamineVasopressorsonAdverseOutcomesinPatientsWithShock
Table4.ContinuousOutcomesandSensitivityAnalysesforVasopressin+CatecholaminesvsCatecholaminesAlone
inPatientsWithDistributiveShock
MeanLengthofStayinDays(SD)a
QualityofEvidence
Vasopressin+ Catecholamines MeanDifference (Reasonfor
Group Catecholamines Alone (95%CI),db PValue I2% Judgment)
HospitalLengthofStay
Allstudies18,20,22,29,32,34,38,40 21.3(23.0) 22.6(22.9) −1.14(−3.60to1.32) .36 75
Lowriskofbias18,24,30,39 22.0(24.1) 23.3(23.8) −1.83(−4.47to0.81) .17 69
Highriskofbias29,32,34,40 15.7(8.6) 16.6(11.1) −0.45(−4.40to3.50) .82 62 Low(imprecision,
inconsistency)
Vasopressin18,24,29,30,39,c 21.8(24.0) 23.4(23.7) −2.33(−5.05to0.40) .09 67
Vasopressinanalogs29,32,40,c 16.1(7.7) 14.9(8.5) 1.03(−1.48to3.53) .42 22
IntensiveCareUnitLengthofStay
Allstudies18,20,22,28,29,31,32,35,38,39 11.1(12.2) 11.6(13.4) −0.40(−1.05to0.25) .23 24
Lowriskofbias18,24,30,39 11.2(12.7) 12.2(14.1) −0.54(−1.33to0.25) .18 34
Highriskofbias28,29,31,32,35,39,40 10.4(10.2) 9.4(8.5) −0.12(−1.37to1.13) .85 22 Moderate
(imprecision)
Vasopressin18,23,24,28,30,35,39,c 11.8(13.0) 12.4(14.0) −0.24(−1.27to0.79) .65 44
Vasopressinanalogues29,31,32,35,40,c 7.9(7.0) 7.9(7.0) −0.38(−1.33to0.58) .44 0
aMeanlengthofstaywasweightedbythenumberofpatients. norepinephrineandterlipressinvsnorepinephrine)inthecomparison
bMeandifference<0.0favorsvasopressin+catecholamines. betweenvasopressinandvasopressinanalogs.Itwasconsideredasasingle
trial(vasopressinorterlipressinvsnorepinephrine)inallothercomparisons.
cMorellietal,2009,35comprised3groups(vasopressinvsterlipressinvs
norepinephrine).Itwasconsideredas2separatetrials(vasopressinvs
Theclinicalsignificanceofatrialfibrillationinthispopula- cytokines,improvingcalciumhandling,andpotentiating
tionisnotfullyunderstood.44Whereatrialfibrillationin endogenousglucocorticoids.47-50
patientswhoarecriticallyillhasbeenassociatedwithworse ForcliniciansaimingforMAP,maintainingadequate
outcomes,includingdeath,causalityhasnotbeenproven bloodflowwhilemitigatingtheriskofexcessivevasocon-
andtheconsequencesonlong-termprognosisinsurvivors striction(thelikelymechanismofdigitalischemia)isalso
areunknown.10,11,44 important.Anunderstandingoftheclinicaleffectofthese
Thisreviewisoneoffewreviewstodirectlycompare events(ie,didtheysimplyprecipitatedrugdiscontinuation
vasopressin+catecholaminesagainstthecurrentstandard ordidtheyleadtopermanentdisability?)wouldbeneeded
ofcare—catecholaminesalone.Twosystematicreviews toevaluatetrade-offagainstadecreaseinmortality.
withnetworkmeta-analysesfoundnodifferenceinmortal- Thissystematicreviewalsoevaluatedrequirementfor
ity in any comparison, including between vasopressin RRT.ThesignificantreductioninneedforRRTwithvaso-
orterlipressinandnorepinephrine.42,43Anothersystem- pressinwaslimitedtothepooledestimateforlowriskofbias
aticreviewandmeta-analysisconcludedthattreatment studies.Renalprotectionrelatedtoreducedactivationofthe
withnoncatecholaminergicagents(includingvasopressin renin-aldosterone-angiotensinsystemisoneofthehypoth-
andmethyleneblue)improvedsurvival(RR,0.88[95%CI, esizedbenefitsofvasopressinindistributiveshock;creati-
0.79to0.98])inpatientsexperiencingor“atrisk”fordis- nineclearancehasbeenshowntoimprovewhenvasopressin
tributiveshock.45Inanothersystematicreviewandmeta- wasstartedearlyaftertheonsetofdistributiveshock.33
analysis, mortality was significantly lower in patients Thisreviewincludeddatafromtherelativelylargeand
withsepticshocktreatedwithvasopressinorterlipressin recentlypublishedVasopressinvsNorepinephrineinPatients
comparedwithnorepinephrine(RR,0.87[95%CI,0.78 withVasoplegicShockafterCardiacSurgery(VANCS)and
to0.97]).46However,thatreviewincluded4substudies EffectofEarlyVasopressinvsNorepinephrineonKidney
oftheVasopressinandSepticShockTrial(VASST)inthe FailureinPatientsWithSepticShock(VANISH)trials(751
meta-analysis of mortality and did not assess evidence patientstotal).18,30Combiningsubtypesofdistributiveshock
usingGRADE.19,39,47 andconsideringvasopressinanalogsallowedtheinclusionof
Thetheoreticalbasisforvasopressinadministration alargernumberofstudies.Biasinthereviewprocesswas
stemsfromresearchidentifyingrelativevasopressindefi- reducedbysearchingmultipledatabaseswithoutlanguage
ciencyinpatientswithdistributiveshock.13Vasopressin restriction.Significantattemptsweremadetoobtainclarifi-
administrationcouldlowermortalitybydecreasingthe cationofpublisheddataandaccesstounpublisheddata.
need for catecholaminergic drugs and reducing their
adverseeffectsincludingarrhythmia,preferentiallyperfus- Limitations
ingthebrainandrenalvascularbed—thelatterleadingto Thisstudyhasseverallimitations.First,subgroupanalyses
reductionsinacutekidneyinjury—anddecreasingactiva- wererestrictedbythestudy-levelnatureofthedata.Sec-
tionofboththerenin-aldosterone-angiotensinsystemand ond,thequalityofreportingformanystudieswasnotsuffi-
neurohormonal processes, inhibiting proinflammatory cienttopermitdefinitivejudgmentsaboutriskofbiasinall
1898 JAMA May8,2018 Volume319,Number18 (Reprinted) jama.com
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