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RESEARCHOpenAccessUpdatingtheevidencefortheroleofcorticosteroidsinseveresepsisandsepticshock:aBayesianmeta-analyticperspectiveJohnLMoran1*,PetraLGraham2,SueRockliff3,AndrewDBersten4AbstractIntroduction:Currentlow(stress)dosecorticosteroidregimensmayhavetherapeuticadvantageinseveresepsisandsepticshockdespiteconflictingresultsfromtwolandmarkrandomisedcontrolledtrials(RCT).
Wesystematicallyreviewedtheefficacyofcorticosteroidtherapyinseveresepsisandsepticshock.
Methods:RCTswereidentified(1950-September2008)bymultipledata-baseelectronicsearch(MEDLINEviaOVID,OVIDPreMedline,OVIDEmbase,CochraneCentralRegisterofControlledtrials,Cochranedatabaseofsystematicreviews,HealthTechnologyAssessmentDatabaseandDatabaseofAbstractsofReviewsofEffects)andhandsearchofreferences,reviewsandscientificsocietyproceedings.
Threeinvestigatorsindependentlyassessedtrialinclusionanddataextractionintostandardisedforms;differencesresolvedbyconsensus.
Results:Corticosteroidefficacy,comparedwithcontrol,forhospital-mortality,proportionofpatientsexperiencingshock-resolution,andinfectiveandnon-infectivecomplicationswasassessedusingBayesianrandom-effectsmodels;expressedasoddsratio(OR,(95%credible-interval)).
Bayesianoutcomeprobabilitieswerecalculatedastheprobability(P)thatOR≥1.
FourteenRCTswereidentified.
High-dose(>1000mghydrocortisone(equivalent)perday)corticosteroidtrialswereassociatedwithanull(n=5;OR0.
91(0.
31-1.
25))orhigher(n=4,OR1.
46(0.
73-2.
16),outlierexcluded)mortalityprobability(P=42.
0%and89.
3%,respectively).
Low-dosetrials(1,000mgperday)[29].
Bayesianmeta-regression[21]wasusedtodeterminetherelationbetweenlogoddsmortalityand(i)averagepatientageand(ii)control-armrisk,aslog-oddsmortal-ity[17,24].
Theslope(b)with95%CrIandtheprobabil-itythatb≥0(Pb)werepresented.
Heterogeneitywaspresentedasthestandarddeviation,τ,betweenstudies[30];τcloseto0indicateslittleheterogeneity,τ=0.
5indicatesmoderateandτ>1reflectssubstantialhetero-geneity[18].
Forheuristicpurposesweseparatelyestimated:(i)pooledestimateswiththeSchumer[31]andCooperativeStudyGroup(CSG)[32]studiesremovedinasensitivityanalysisduetopreviousidentificationoftheformerasapotentialoutlier[7]andtheremotenessofthelatter1963trialfromcurrenttherapeuticregimens;(ii)certainparametersofclinicalimportintheriskdifferencemetric[21],albeitthismetricmaysufferfrompotentialbiaswithvaryingtimetoevent[24];(iii)themortalityORandprobability(P)thattheORwas1ormoreinthepredictivedistribution(thatis,inthenext'new'study);(iv)themortalityORforhypothesizedstudiesofsize2,000and4,000patients;(v)theBayesianpredictiveP-valuethattheCORTICUStrial[8]wasinconsistentwiththeothertrialsofthelow-dosecorticosteroidgroup;thatis,theCORTICUSstudywasomittedfromanalysis(leavingn=7trials)andareplicatestudyofthesamesizeastheCORTICUSstudywasdrawn,withareplicatebaseline,andanewtreatmenteffectwasestablishedbaseduponthepredictivedistribution.
ABayesianpredictiveP-valuewassubsequentlyobtained,expressingtheprobabilitythatthefuturestudywouldbeas'extreme'asthatobserved.
Publicationandtheassociatedphenomenonofsmall-studybiaswereaddressedusingtheapproachofPetersandcolleagues[33]viacontour-enhancedfunnelplots;formalquantitativetestingforsmall-study-biaswasper-formedusingtheapproachofHarbordandcolleagues[34],whichhaseffectivepropertiesinthepresenceofappreciableheterogeneity.
ImplementationwasviatheRpackage'meta'[35]anduser-writtenroutines.
ResultsUsingmultipleelectronicsearches,1,843abstractsofpublishedpaperswereidentified(includingduplicates).
Areviewoftheseabstracts(JLM,PLG)identified115papersofpotentialinterestincludingreviewpapers.
Thepublishedtextof31'randomized'clinicaltrials,includ-ingsevenabstractsfromproceedingsofscientificmeet-ings,werefurtherreviewed(JLM,PLG,AB):twowereexcludedonthebasisofreportingfromprevioustrials,onereportednomortalityoutcomedataandoneusedpseudo-randomization.
Afurther13studies,includingfourabstracts-onlywereexcludedforreasonsgiveninTable1.
Thefinalcohortwasof14trials[8,31,32,36-46],includingtwoabstractsfromthereportsofscientificmeetings;11ofthestudieshadbeenconsid-eredbypreviousmeta-analyses[4-6,10]andthethreeremainingstudies[8,42,44]werepost-2004,thepublica-tiondateofthetwocomparatormeta-analyses[6,7](Figure1andTable2).
ThetrialpatientsizevariedMoranetal.
CriticalCare2010,14:R134http://ccforum.
com/content/14/4/R134Page3of15from28[44]to499[8]andthetotalnumberofpatientswas1,991,ofmeanage55yearsand66%male.
Totalcorticosteroiddosageinthehigh-dosecohortrangedfrom7,000to42,000hydrocortisone-equivalentmgoveronetothreedays,whereasinthelow-dosecohort,dosagewas856to2,175hydrocortisone-equivalentmgover2to10daystreatmentwith0to14daysoftaper-ing(Table3).
Averagehigh-andlow-dosecontrolarmmortalitieswere47%and54%,respectively.
FurthercharacteristicsofthetrialsaregiveninTables2and3.
Theprimaryoutcomeofhospitalmortalitywasavail-ableinsixstudies[8,32,36,39,43,46];theotherstudieshadrecorded28-or30-daymortalityandonestudyrecorded14-daymortality(Table2).
Sepsisandshockdefinitionsoftrialscompletedbefore1992[31,32,38,41,43,46]weregenerallyconsistentwithdefini-tionsoftheAmericanCollegeofChestPhysiciansandSocietyofCriticalCareMedicineConsensusConferenceonsepsisandorganfailure,albeitthetwotrialspublishedin1971[41]and1963[32]used'lifethreateninginfec-tions'asacriteria(Table2).
Ofinterest,trialsbefore1998werepredominantlyreportedfromtheUSA;after1997,theywerefromEuropeanandothernon-USAsites.
Trialpatientdatabyoutcomes(hospitalmortality;shock-reversal;corticotrophin-responsiveness;shockreversalbycorticotrophin-responsiveness;andsecondarycomplications,asinfectious,gastro-intestinalbleedingandnew-onsethyperglycemia)areshowninTable4.
MortalityoutcomeNeitherthelow-dosenorhigh-dosecohortshowedasig-nificantsteroidtreatmenteffectforthemortalityOR,althoughtherewasmodestevidenceofbenefitinthelow-dosecohort(P=20.
4%)(Table5andFigure2).
Theoddsofmortality(fourstudies[8,36,42,45]),forbothcor-ticotrophinrespondersandnon-responderswasnotsig-nificantlydifferentcomparedwithcontrol(Table5).
Table1StudyexclusionsStudyYearpublishedReasonforexclusionWagnerandcolleagues[78]1955Descriptionofpneumoniatherapyonlywithnoseveritystratification.
Allocationby'historynumber'Thompsonandcolleagues[79]1976Abstract;nineof60patientswithcardiogenicshock;nosubsetanalyses.
Post-randomizationexclusionof4patientsLucasandLedgerwood[80]1984Open-labelstudy;pseudo-randomizationbyhospitalnumberVASSCS[81]1987Predominantlysepsispatientswithnosubgroupofshockedpatients.
NotimingoffluidboluswithrespecttoreportedhypotensionSchattnerandcolleagues[82]1997pseudo-randomizationofpatientswith'earlysepsis'Kehandcolleagues[60]2003Cross-overplacebostudyinsepticshockConfalonieriandcolleagues[83]2005Communityacquiredpneumoniastudy;nosubsetanalysesforshockedpatientsRinaldiandcolleagues[84]2006Postrandomizationexclusionof15patients;3withsepticshockHuhandcolleagues[85]2006Abstract;twohydrocortisonearms;noconcurrentplaceboarmreportedLoisaandcolleagues[86]2007Twohydrocortisonearms;noconcurrentplacebogroupNawabandcolleagues[87]2007Abstract;severecommunityacquiredpneumonia,nosubsetanalysis;outcomestoday-7onlyCicarelliandcolleagues[88]2007Unspecifiedpost-randomizationexclusionof'allpatientswhoprogressedtorefractorysepticshock'Kurugundlaandcolleagues[89]2008Abstract;ICUoutcomesreportedonlyVASSCS,VeteransAdministrationSystemicSepsisCooperativeStudy.
Figure1Flowchartforidentificationofstudiesoncorticosteroidsinseveresepsisandsepticshock;numberoftrialsevaluatedateachstageofthesystematicreview.
Moranetal.
CriticalCare2010,14:R134http://ccforum.
com/content/14/4/R134Page4of15Table2FinalstudycohortStudyYearpublishedYearcompletedTrialoriginTrialReportedasPaper#/abstractDesignAllocationconcealmentEffectandsamplesizecalculationEarlystoppingSepsis/shockdescriptionPredominantpatienttypePrimaryoutcomeCooperativeStudyGroup[32]1963NAUSAMulticenterPaperDouble-blindYesNoNo'Lifethreateninginfections'MedicalHospitalmortalityKlasterskyandcolleagues[41]19711970BelgiumSinglecenterPaperDouble-blindYesNoNo'Lifethreateninginfections'Cancer30-daymortalitySchumer[31]19761975USASinglecenterPaperDouble-blindNANoNoSeptichistory,fallingbloodpressureandpositivebloodculturesSurgical28-daymortalitySprungandcolleagues[43]19841982USATwo-centersPaperOpen-labelYesNoNoSBP0)=21.
9%);andforeighttrials(CSGtrialexcluded[32])was-0.
072(95%CrI=-0.
202to0.
018;P(RD>0)=5.
3%),similartothe6.
6%reportedbyAnnaneandcolleagues[48].
ThemortalityORinthepredictivedistribution(fromeighttrials)was0.
703(95%CrI=0.
156to2.
198;P(OR>1)=19.
9%).
Forhypothe-sizedstudiesofsize2,000and4,000patients,themor-talityORswerepredictedtobe0.
724(95%CrI=0.
184to2.
108)and0.
726(95%CrI=0.
184to2.
096),respec-tively.
TheBayesianpredictiveP-value,reflectingtheinconsistencyoftheCORTICUSstudy[8]withtheremainingtrials(n=7;CSGtrialexcluded[32])was0.
074.
DiscussionDespitethedisappointmentoftheCORTICUS[8]trial,ourreviewsuggestsamodesttohighprobability(80%to98%)ofefficacyforlow-dosesteroidswithrespecttobothmortalityandshockreversal;themortalityeffectbeingrisk-related(Table5).
TheseprobabilitiesaretobeinterpretedinthecontextofCrIspanningthenullforallestimates(seeStatisticalanalysis,above).
WefoundnostrongevidenceforthedeterminacyofACTHresponsivenessnorcomplicationsofcorticosteroidther-apy.
Thisbeingsaid,itisofinteresttonotetheadmoni-toryimpactoftheCORTICUSstudyonrecentsummarystatementsofsepsismanagement[2,3,13,29,49].
Consistentwithpreviousmeta-analyses[6,7]wefoundnulloradverseeffectsofhigh-dosester-oids;theprobabilityoftherapeuticcomplicationsbeinglow(Table5).
Theuseofprolongedlow-dosecorticosteroidwasjustifiedinthelandmarkAnnaneandcolleaguestrialonthebasisthat"severesepsismaybeassociatedwithrelativeadrenalinsufficiencyorsystemicinflammation-inducedglucocorticoidreceptorresistance.
.
.
"[36].
Aproposofthisstatement,itisinstructivetonotethattheprimaryaimoftheCORTICUSstudywas28-daymortalityinpatientsnotrespondingtocorticotrophin[8].
Arecentreviewofcorticosteroidinsufficiencyinthecriticallyillhassuggestedthatinstateswheresuchinsufficiency[50]islocated"withinthetissueitself.
.
.
theadrenalglandfunctioncouldbenormal.
.
.
itwouldbeimpossibletodiagnosethisstateonthebasisofserumoreventissuelevelsofglucocorticoids.
.
.
[and].
.
.
treatmentwouldrequiresupraphysiologicallevelsofTable4Trialpatientdatabyoutcome(Continued)Annaneandcolleagues[36]95/160103/15060/15140/14936/15034/14918/3618/3465/11446/11522/15027/15011/1508/149NANATandanandcolleagues[44]11/1413/145/143/14NANANANANANANANANANANANAOppertandcolleagues[42]7/1811/2313/1818/236/189/23NANANANANANANANANANASprungandcolleagues[8]111/251100/245200/251184/248118/243136/244100/118104/13698/12576/10878/23461/13215/23413/232186/234161/232#,mortalitystatisticsforChawlaandcolleagues[47]wereabstractedfromtheAnnaneandcolleaguesmeta-analysis[6].
##,dataforhyperglycaemiaforBollaertandcolleagues[37]wasabstractedfromtheAnnaneandcolleaguesmeta-analysis[6].
GIS,gastrointestinal;NA,notavailable.
Moranetal.
CriticalCare2010,14:R134http://ccforum.
com/content/14/4/R134Page9of15glucocorticoids"[51].
Theinabilityinthecurrentmeta-analysistodemonstratetreatmentefficacywithrespecttomortalityandshock-reversalbaseduponcorticotrophinresponsivenessisinagreementwithMinneciandcolleagues[7]andsuggestsboththattestsofthelattertodirecttreatmentregimensaremis-placedandthatthenotionofadrenalinsufficiencyinseveresepsisandsepticshockisproblematic[52];a".
.
.
hardlydefinablediseaseentityorsyndrome.
.
.
"[53].
Oftheseventrialsreportingshock-reversal[8,36,37,39,40,42,44],timetothelatterend-pointwastheprimarystudyend-pointinthree[37,39,42].
Allpub-lishedstudiesusedtime-to-eventanalysisbaseduponconventionalKaplan-Meierestimates,censoringthosewhodiedand/orthoseinwhomvasopressortherapycouldnotbewithdrawnattimeofassessment.
However,suchanalysesareproblematic,becausetheyignorethecompetingriskofthosewhodiedand/orthoseinwhomvasopressortherapycouldnotbewithdrawn.
Inthepre-senceofcompetingrisksKaplan-Meierestimatescannotbeinterpretedasprobabilities[54,55].
Undertheconditionsofcompetingrisks,theprobabilityofaneventismoreappropriatelyestimatedbythecumulativeincidencefunction,which,fortheparticulareventofinterest,isafunctionofthehazardsofallthecompetingeventsandnotsolelyofthehazardoftheeventtowhichitrefers.
Hypothesistestsforthecumulativeinci-dencefunctiondonotnecessarilyequatewiththefamil-iarlog-ranktest[56].
Howthenarewetounderstandthesefavourableeffectsoflow-dosecorticosteroidsGlucocorticoidactiononinflammation[57],vascularreactivity[58]andinteractionsbetweencorticosteroidsand'signallingpath-ways'[59]mayexplainthesalutaryeffectsinsepsis[60];anti-inflammatoryandcoagulationeffectswouldappeartobedifferentiallydosedependent[61].
Loworstressdosesofhydrocortisone,ascurrentlyprescribed,arenotreplacementorphysiologicaldoses;theygenerateplasmacortisollevelsgreaterthan2,500nmol/l,inexcessoftheusualupperlimits(1,000to1,500nmol/l)ofpatientsinsepticshock[42,60,62].
Thepresumedimmune-modulation[63]oftheseprolongedlow-doseTable5OutcomeeffectestimatesOutcomeNOR(95%CrI)P(%)τ(95%CrI)b(95%CrI)Pb(%)MortalityHighdose50.
912(0.
313to1.
253)42.
01.
00(0.
42to1.
89)HighdoseexcludingSchumer[31]41.
406(0.
727to2.
614)89.
30.
25(0.
01to1.
40)Lowdose90.
796(0.
396to1.
386)20.
40.
65(0.
23to1.
44)LowdoseexcludingCSG[32]80.
706(0.
371to1.
096)5.
80.
39(0.
04to1.
15)Corticotrophinresponders*40.
882(0.
285to2.
073)36.
40.
49(0.
02to1.
78)Corticotrophinnon-responders*40.
831(0.
334to1.
971)28.
00.
43(0.
02to1.
69)Shock-reversalHighdose21.
078(0.
227to6.
311)54.
91.
39(0.
06to1.
93)Lowdose71.
999(1.
069to4.
55)98.
20.
57(0.
04to1.
62)Corticotrophinresponders*31.
830(0.
499to7.
845)86.
70.
87(0.
05to-1.
92)Corticotrophinnon-responders*31.
845(0.
637to7.
267)91.
90.
55(0.
02to1.
86)Meta-regression(logoddsmortality)AverageageHighdose40.
777(0.
285to2.
426)27.
30.
72(0.
04to1.
87)0.
60(-0.
23to1.
51)94.
52ExclSchumer[31]31.
390(0.
399to4.
872)77.
00.
66(0.
03to1.
90)0.
10(-1.
57to1.
74)58.
05Lowdose60.
658(0.
334to1.
223)7.
60.
36(0.
02to1.
51)0.
05(-0.
10to0.
18)80.
53UnderlyingriskHighdose50.
943(0.
292to3.
049)45.
41.
14(0.
46to1.
49)0.
23(-1.
71to2.
58)60.
98ExclSchumer[31]41.
372(0.
596to3.
249)82.
90.
38(0.
01to1.
74)-0.
09(-1.
31to1.
42)41.
47Lowdose90.
752(0.
389to1.
291)14.
50.
57(0.
17to1.
37)-0.
49(-1.
14to0.
27)7.
80ExclCSG[32]80.
676(0.
347to1.
076)4.
90.
40(0.
03to1.
23)-0.
28(-0.
88to0.
50)19.
08Oddsofthefollowingcomplications(corticosteroidsversuscontrol)SuperinfectionHighdose41.
127(0.
364to3.
924)62.
20.
55(0.
02to2.
85)Lowdose60.
955(0.
388to1.
749)43.
60.
46(0.
03to1.
62)GIbleedingHighdose30.
824(0.
167to3.
186)37.
30.
74(0.
03to1.
90)Lowdose51.
103(0.
379to3.
031)59.
60.
58(0.
02to1.
84)HyperglycemiaHighdose31.
012(0.
244to4.
266)50.
80.
64(0.
03to1.
88)Lowdose31.
430(0.
155to3.
985)57.
40.
87(0.
05to1.
93)*allstudieswerelowdose;CI,confidenceinterval;CSG,CooperativeStudyGroup;GI,gastro-intestinal;N,numberofstudiesreportingdataforthatendpoint;NA,notapplicable;OR,oddsratio.
ExclSch=ExcludingSchumer[31];ExclCSG=ExcludingCSG[32]Moranetal.
CriticalCare2010,14:R134http://ccforum.
com/content/14/4/R134Page10of15Figure2Corticosteroidmortalityeffect(OR),stratifiedbyhigh(upperpanel)orlow(lowerpanel)dosesteroidregimen;forestplotrepresentationoftheeffect.
Theverticalstraightlinedenotesnulleffect(oddsratio(OR)=1).
TheindividualpointsdenotetheORforeachstudyandthelinesoneithersidethe95%Bayesiancredibleintervals(CrI).
Figure3Contour-enhancedfunnelplotofmortalityoddsversusstandarderrorforalltrials(n=14).
Verticalaxis,standarderror;horizontalaxis,mortalityodds(logscale).
The'contours',baseduponatwo-sidedPvalue,aretheconventionallevels(not'pseudo'confidenceintervals)ofstatisticalsignificance(<0.
01,<0.
05,<0.
1)fortheprimarystudiesandareindependentofthepooledestimate(ifthepooledestimateisbiased,thecontoursarenotaffected)[33].
Figure4Contour-enhancedfunnelplotofmortalityoddsversusstandarderrorforlow-dosecorticosteroidtrials(n=9).
Verticalaxis,standarderror;horizontalaxis,mortalityodds(logscale).
The'contours',baseduponatwo-sidedPvalue,aretheconventionallevels(not'pseudo'confidenceintervals)ofstatisticalsignificance(<0.
01,<0.
05,<0.
1)fortheprimarystudiesandareindependentofthepooledestimate(ifthepooledestimateisbiased,thecontoursarenotaffected)[33]Figure5Corticosteroidshock-reversaleffect(OR),stratifiedbyhigh(upperpanel)orlow(lowerpanel)dosesteroidregimen;forestplotrepresentationoftheeffect.
Theverticalstraightlinedenotesnulleffect(oddsratio(OR)=1).
TheindividualpointsdenotetheORforeachstudyandthelinesoneithersidethe95%Bayesiancredibleintervals(CrI).
Moranetal.
CriticalCare2010,14:R134http://ccforum.
com/content/14/4/R134Page11of15regimensunderpinstherationaleofcriticalillness-relatedcorticosteroidinsufficiency[14,29].
Thisbeingsaid,theAnnaneandcolleagues[36]trialusedafixedseven-daysteroidcoursewithouttaperingandclaimedefficacyandnodifferenceinthecomplicationrateswasevidentbetweenthehigh-andlow-dosecohortsinboththecurrentandAnnaneandcolleagues'meta-analyses[6].
Asmentionedincommentary[64],differencesincontrolgroupmortalitiesoftheAnnaneandcolleagues[36]andCORTICUS[8]trialsmayexplaindifferingout-comesonthebasisofrisk-relatedtreatmenteffects.
Thelatterwerepersuasivelydemonstratedinthecurrentmeta-analysis.
Theestimateofmortalityriskatwhichlow-dosecorticosteroidsbegantoexhibitatreatmenteffect,44%,wasclinicallyplausiblegiventherangeofcontrol-armmortalitiesof30to93%.
Suchdemonstra-tion,usingappropriateBayesianmethodology[17,24],representsanovelinsightintocriticalcaretherapeuticefficacy.
CritiqueofmethodologyOuranalyticapproachwastoconsiderthetwotreat-mentcohorts,high-andlow-dosecorticosteroid,sepa-rately;wedidnotproduceanoveralltreatmenteffectonthebasisthatboththetreatmentintentionandeffective(daily)corticosteroiddoseofthetwocohortswerequitedisparate.
Analternateapproachwouldhavebeentoconsideralltrials(n=14)withtotalhydrocortisonedoseorcalendaryearaseffect-moderators.
Intheabsenceofindividualpatientdata,suchanalyses,withonly14studies,havelowpower.
Secondaryoutcomeanalysiswasbesetbyselectionbiasinreporting[65],aswitnessedbystudynumbersinTable5;parameterestimatesmaybebiasedundersuchcircumstances.
Thestudylistaddressinglow-dosecorti-costeroidmortalityefficacy(n=9)includedasinglestudy[32]in1963,theothersbeingfromtheperiod1996to2005(Figure2).
Plausibleestimatesofcurrenttherapeuticefficacywouldsuggestanalysisexcludingtheformerstudy,theresultofwhichwastoreducehetero-geneityofthemortalityeffectby40%andtorevealaprobabilityofcorticosteroidefficacyof94.
2%(Table5).
Thesingle-investigatorsingle-centreSchumerstudy,conductedoveraprolongedeight-yearperiod,hasbeenpreviouslysubjecttosubstantivecritique[7]andrecentcautionsregardingextendedrecruitmenttime[66]andinferencefromsingle-centerstudies[67]meritsitscon-siderationasanoutlier.
Thattheinclusionofthelargebutnull-effectCORTI-CUStrial[8]inthecurrentmeta-analysisdidnotextin-guishaprobabletreatmenteffectdeservescomment.
Theimpactofthesinglelargetrialisundoubted,buttheevidenceproducedbysuchatrialmaybe"lessreli-ablethanitsstatisticalanalysissuggests"[68].
Weadoptedarandomeffectsmethodology[69]inthepre-senceofmoderatebetweenstudyheterogeneity(τ,Table5);undertheseconditionslargestudiesmayhavelittleimpactuponameta-analysis[70]andtheremaybevirtuein(clinical)heterogeneity[71].
Thedegreeofasymmetryofthecontour-enhancedfunnelplotinthelow-dosecohort(seeResults,Mortalityoutcome,above)raisesconcernsaboutarandomeffectsmethodology[69],buttherewasnoquantitativeevidenceofsmall-studyeffects(atthe0.
1level)andthenumberofstudieswassmall.
Inthepresenceofsparsedataandmoderateheterogeneity(Table5),theinterpretationoffunnelplotasymmetryisproblematic[34,72]andexplorationofthereasonsforsuchheterogeneityisthepreferredanalyticfocus[34].
Withrespecttotheefficacyofcorticosteroidsinseveresepsisandsepticshock,thedivergentpositionsrepresentedbytheAnnaneandcolleagues[36]andCORTICUS[8]trialsremainunresolved.
Tworecent(calendaryear2009)updates[48,73]ofpreviousmeta-analyses[6,7]alsomeritcomment.
Bothoftheupdatedmeta-analyses,usingfrequentistmethodology,foundefficacyoflow-doseprolongedcorticosteroidswithrespecttothemortalityeffect,Annaneandcolleagues[48]foundarelativeriskof0.
84(95%confidenceinter-val(CI)=0.
72to0.
97;P=0.
02)andMinneciandcol-leagues[73]foundanORof0.
64(95%CI=0.
45to0.
93;P=0.
02),andshockreversal,thelattereffectcon-sistentwiththeestimatesofthecurrentstudy(Table5).
Studyinclusionsinthesemeta-analysesdifferedandwerenotthesameasinourmeta-analysis,whichadoptedarigorousexclusionpolicy(Table1).
Thefre-quentistmeta-regressionmethodsusedbybothmeta-analyses[48,73]toestimatetherisk-relatedtreatmentefficacyofsteroidsareproblematic[17,24].
Althoughsuchmethodsmayidentifyputativeriskrelatedtreat-menteffectsinmeta-analysestheyfailtoallowforbothregressiontothemean(thedifferencebetweenoutcomeandbaselinebeingcorrelatedwithbaseline)andthesto-chasticnatureofthecontrolrate(regressiondilutionbias).
Thestochasticcharacteristicofthecontrolrateisalsonotaddressedastheexpectedresponsein(ordin-ary)linearregressionisconditionaluponindependent(fixed)variablesandthereisnoinherentaccountingfortherandomerrorinestimationofthiscontrolrate.
SuchproblemsareovercomebytheuseofBayesianmethods[17,24].
Bothmeta-analyseswerejudiciousintheirconclusionsabouttreatmentefficacyandthiswasreiteratedbyanaccompanyingeditorial[74].
However,neitherstudywasabletoattendtothisuncertaintyinatangiblemanner.
ThisispreciselywhatourBayesiananalysisquantifies:whatwastheprobabilityoftreatmentefficacy.
Forexample,ouranalysisdemonstratedthattheprobabilityMoranetal.
CriticalCare2010,14:R134http://ccforum.
com/content/14/4/R134Page12of15ofadversemortalityoutcomewithlow-dosecorticoster-oids(outlierexcluded)was5.
8%(Table5).
Theomissionofsuchaprobabilitystatementcannotbejustifiedbyanappealto"thenominalPvaluesfortheseoutcomeswereverycloseto0.
05.
.
.
.
"[48].
Wehavepreviouslycau-tionedtheagainstinterpretationof95%CI(andasso-ciatedfrequentistPvalues)asprobabilitystatements[75].
Furthermore,neithermeta-analysisreportedexplorationofestimatesfromapredictivedistribution,whichmaybeconsideredasamoreappropriatefuturetreatmentsummarythanthemeaneffect[18].
SuchacapacityrecommendsBayesianmethodology,althoughmeta-analyticpredictionintervals,whichaddressthe".
.
.
dispersionoftheeffectsizes.
.
.
"arecomputablefromafrequentistperspective[76].
WithrespecttoreservationsexpressedregardingthestatusoftheCORTICUSstudy[29,74],wefoundnocompellingevidence(Bayesianpre-dictiveP-value0.
074)thatthistrialwasinconsistentwiththeremaining(n=7)trials.
Continuedcontroversyandconventionalwisdom[77]wouldappeartomandatetheconductofalarge-(mega)-trialofthistherapyinwell-definedpatientsub-sets;anabsolutetreatmenteffectof7.
2%,controlarmriskof54%and90%powerwouldsuggestatotalpatientnumberofgreaterthan2,000.
Thisbeingsaidourpre-dictiveestimateswereunabletosuggestefficacyforfuture'large'trials,albeitthetrialbasefromwhichtheseestimatesweremadewassmall.
ConclusionsAlthoughanulleffectformortalitytreatmentefficacyoflow-dosecorticosteroidtherapyinseveresepsisandsep-ticshockcouldnotbeexcluded,thereappearstobecredibleevidenceforshockreversalefficacy.
Similarly,althoughanulleffectwasnotexcluded,advantageouseffectsoflow-dosesteroidshadahighprobabilityofdependenceuponpatientageandunderlyingrisk.
Low-dosesteroidefficacywasnotdemonstratedincortico-trophinnon-responders.
Bayesianmethodsareappositetoexpressuncertaintyinefficacyestimatesfrommeta-analyses.
KeymessagesTheefficacyofcorticosteroidsinpatientswithseveresepsisandsepticshockisuncertaindespiterecentmeta-analyticreviews.
Bayesianmethodsareappositetoexpressuncer-taintyinefficacyestimatesfrommeta-analyses.
Theefficacyoflow-dosecorticosteroidshadahighprobabilityofdependenceuponpatientageandunderlyingrisk;low-dosesteroidefficacywasnotdemonstratedincorticotrophinnon-responders.
Bayesianmeta-analyticpredictiveestimateswereunabletosuggestefficacyforfuturelargetrials.
Anulleffectformortalitytreatmentefficacyoflow-dosecorticosteroidtherapyinseveresepsisandsepticshockcouldnotbeexcluded.
AdditionalmaterialAdditionalfile1:Electronicsearchstrategy.
DetailedsearchstrategyofelectronicdatabasesAbbreviationsACCP:AmericanCollegeofChestPhysicians;ACTH:adreno-corticotrophinhormone;CI:confidenceinterval;CORTICUS:CorticosteroidTherapyofSepticShock;CrI:credibleintervals;CSG:CooperativeStudyGroup;OR:oddsratio;SCCM:SocietyofCriticalCareMedicine.
Authordetails1DepartmentofIntensiveCareMedicine,TheQueenElizabethHospital,28WoodvilleRoad,Woodville,SouthAustralia5011,Australia.
2DepartmentofStatistics,FacultyofScience,MacquarieUniversity,BalaclavaRoad,NorthRyde,NSW2109,Australia.
3DepartmentofLibraryServices,TheQueenElizabethHospital,28WoodvilleRoad,Woodville,SouthAustralia5011,Australia.
4DepartmentofCriticalCareMedicine,FlindersMedicalCentreandSchoolofMedicine,FlindersUniversity,SturtRoad,BedfordPark,SouthAustralia5042,Australia.
Authors'contributionsThestudywasconceivedbyJLM,PLGandAB.
SRconstructedthesearchtermsandconductedtheelectronicsearch.
JLM,PLGandABreviewedstudiesfulfillinginclusioncriteriaandpre-definedvariables.
JLM,andPLGconductedthequalityassessmentandstatisticalanalysis.
Allauthorscontributedtothewritingofthepaper,criticalreviewandfinalapproval.
CompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.
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