PPH review revision rcpcsbrc + refs
Transcript of PPH review revision rcpcsbrc + refs
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Cit a tion for final p u blish e d ve r sion:
Collins, Pe t e r W., Bell, S a r a h , De Lloyd, Lucy a n d Collis, R ac h el 2 0 1 9.
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1
Title
Managementofpostpartumhaemorrhage:fromresearchintopractice,anarrativereviewofthe
literatureandtheCardiffexperience
PWCollinsa,SFBell
b,LdeLloyd
bandRECollis
b
a. InstituteofInfectionandImmunity,SchoolofMedicine,CardiffUniveristy,Cardiff,UK
b. DepartmentofAnaesthetics,IntensiveCareandPainMedicine,CardiffandValeUniversity
HealthBoard,Cardiff,UK
Correspondingauthor
RachelCollis:DepartmentofAnaesthetics,IntensiveCareandPainMedicine,CardiffandVale
UniversityHealthBoard,Cardiff,UK
Email:[email protected]
Keywords
Postpartumhaemorrhage;viscoelastometry;fibrinogen;coagulopathy;qualityimprovement
Highlights
• Fibrinogenfallsbeforeothercoagulationfactorsduringpostpartumhaemorrhage(PPH)
• LaboratoryClaussfibrinogenandpointofcareFibtemA5®predictprogressionofPPH
• HaemostaticimpairmentisuncommonduringPPHandcanbeassessedbyFibtem
• Afibrinogenof2g/LorFibtemA512mmandaboveisadequateforhaemostasisduringPPH
• Anationalqualityimprovementprogrammehasbeeninitiatedintegratingtheseresults
Summary
Postpartumhaemorrhage(PPH)iscausedbyobstetriccomplicationsbutmaybeexacerbatedby
haemostaticimpairment.Inatenyearprogrammeofresearchwehaveestablishedthathaemostatic
impairmentisuncommoninmoderatePPHandthatfibrinogenfallsearlierthanothercoagulation
factors.LaboratoryClaussfibrinogenandthepointofcaresurrogatemeasureoffibrinogen(Fibtem®
A5measuredontheRotem®machine)arepredictivebiomarkersforprogressionfromearlytosevere
PPH,theneedforbloodtransfusionandinvasiveprocedurestocontrolhaemorrhage.Fibrinogen
replacementisnotrequiredinPPHunlesstheplasmalevelfallsbelow2g/LortheFibtemA5is
2
below12mm.Deficienciesofcoagulationfactorsotherthanfibrinogenareuncommonevenduring
severePPH,andRotemmonitoringcaninformwithholdingFFPsafelyinmostwomen.Inthe
absenceofplacentalabruption,clinicallysignificantthrombocytopeniaisuncommonunlessthe
plateletcountislowbeforethebleedstarted,orverylargebleeds(>5000mL)occur.Measuring
bloodlossisfeasibleinroutinepracticeduringPPHandismoreaccuratethanestimation.These
researchfindingshavebeencollatedtodesignanongoingqualityimprovementprogrammeforall
maternityunitsinWalescalledOBSCymru(Wales)(TheObstetricBleedingStrategyforWales).
Aims
Theaimsofthisreviewareto:Summarisetheliteraturerelatingtothecoagulationprofileofwomen
withPPH,describehowpointofcare(POC)basedalgorithmscanprovidetimelyinformationfor
clinicianswiththepotentialtoreducebloodproductuseanddescribehowprotocolsusedduring
researchcanhaveapositiveimpactonallpatientswithfewermajorcomplicationsandmassive
bloodtransfusions.
Background
Theincidenceofpostpartumhaemorrhage(PPH)isincreasinginmanycountriesandisthemost
commoncauseofdeathforwomenofchildbearingageworldwide.1-6Blee
dingiscausedbyobstetriccomplicationsbutmaybeexacerbatedbyhaemostaticimpairment.7Itis
widelyassumedthathaemostaticimpairmentoftencomplicatesPPHandconsequently,when
coagulationtestresultsareunavailable,guidelinesendorsetheuseofformulaicinfusionoffresh
frozenplasma(FFP)orcryoprecipitateinfixedratioswithredbloodcells(RBC),8-10
basedon
evidenceextrapolatedfromnon-pregnantadultmajortrauma.Itisquestionablewhetherthese
datashouldbeappliedtothemanagementofPPHgiventheverydifferentbaselinecoagulation
statusofthegroups.
HighqualitystudiesdescribingcoagulopathiesassociatedwithPPHarelimited,howeveritis
probablythattheyresultfromcomplexinteractionsbetweendilution,localconsumption,
disseminatedconsumptionandincreasedfibrinolysis.7Thenatureofhaemostaticimpairmentvaries
accordingtothecauseofthebleedandisaffectedbycomplicationsofpregnancysuchaspre-
eclampsia,sepsisandimpairedliverfunction.Thephysiologicaladaptionsofpregnancyresultina
pro-thromboticstateattermwithincreasedlevelsofpro-coagulantsanddecreasedanti-coagulants.
3
Inparticular,attermthefibrinogenlevelis4-6g/Lattermgestation,comparedto2-4g/Linhealthy
non-pregnantwomen.11;12
Untilrecentlyitwasnotknownwhetherfibrinogenreplacementduring
severePPHshouldtarget‘normalforterm’(>4g/L),‘normalforthenon-pregnancy’(>2g/L),or
somewhereinbetween.ThisisimportantwhenconsideringtheroleofFFPintreatingcoagulopathy
inPPH.13
FFPcontainsabout2g/Loffibrinogen,whereastheaveragefibrinogenlevelinawomanwith1000-
2000mlbloodlossduetoatonyortraumaisabout4g/L.14Thismeansthatinmostcases,infusion
ofFFPduringPPHwouldreducefibrinogenbydilution.15Thisimpliesthatunmonitoredfixed-ratio
infusionsofFFPwouldexposemanywomentoFFPwithoutanyprospectofimprovinghaemostasis.
Studiesexploringtheuseoffixed-ratioinfusionsofFFP:RBCduringPPHreportfewerwomen
developinglaboratoryevidenceofcoagulopathy,however,someofthesestudiesdescribemultiple
interventionsincludingearlyinvolvementofseniorstaff.16-20
Whenguidedbyviscoelastometricpoint
ofcaretesting(VE-POCT),wehaveshownthatFFPcanbewithheldsafelyinwomenexperiencing
moderatetoseverePPH,withoutdevelopmentofclinicalsignificanthaemostaticimpairment.21A
recentreviewsuggestedthatFFPwasnottheoptimalwaytoreplacefibrinogenduringPPH.13
PPHObservationsandResearchAdvancementsinCardiff,Wales
UsingFibrinogenConcentratetoTreatPPHwithHypofibrinogenemia
WeobservedthatsomewomenexperiencingseverePPHhadlaboratoryfibrinogenlevels<1g/L
associatedwithclinicalhaemostaticimpairment.AtthistimetheRoyalCollegeofObstetricsand
Gynaecology(RCOG)guidancewastomaintainfibrinogen>1g/Lusingcryoprecipitate.22Thawing
andinfusingcryoprecipitatetakestime,delayingcorrectionofthecoagulopathy.Atourcentreand
others,weaddressedthisissuebyinfusingfibrinogenconcentratewhichrapidlyincreasedthe
fibrinogenlevelandwasassociatedwiththeclinicalimpressionofimprovementinhaemostasis.23-26
Weinfusedfibrinogenconcentratebetween2and4Gtosixwomenovera2-yearperiod
(approximately12,000deliveries)withclinicalimprovement,althoughthedataonallwomenwith
lowfibrinogenwasnotcollectedatthistime24Theseearlyreportsreflectedareactiveratherthan
preventativestrategytohaemostaticimpairment.Morerecentstudiesfromothergroupshave
reportedimprovementsinhaemostasiswiththeuseoffibrinogenconcentratetotreat
hypofibrinogenaemia.27;28
Thesecasereportsareselectiveandpronetoreportingbias,butwere
sufficientlyencouragingtopromotefurtherinvestigation.
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TheroleofStandardCoagulationTestsandClaussFibrinogenforDetectionofCoagulopathyinPPH
Toinvestigatetheeffectofseverityofbleedingonstandardcoagulationtests,weevaluateda
consecutivecohortof18,501womenwhodeliveredatourunitover3years.WomenwithPPH
>1500mL(n=456,2.5%)hadtheirbloodtestresultsreviewed.PTandaPTTusuallyremainedwithin
thenormalrangeuntilbloodlossreached4000-5000mL.29Thisreflectedsufficientcoagulation
factorsforhaemostasisuntilthebleedvolumereached4000-5000ml,andinfusionofFFPuptothat
timewasunlikelytohaveimprovedhaemostasis.Incontrast,fibrinogenfellrapidlyasbloodvolume
lossincreased,suchthatby2000mLthemajorityofcaseshadafibrinogenbelowthenormalrange
forterm(4g/L),andat4000mLmostwomenhadafibrinogen<2g/L.29AUKObstetricSurveillance
System(UKOSS)surveyofwomentransfused≥8unitsofRBC(averagebloodloss6000mL)also
foundthatmanymorewomenhadafibrinogen<2g/LthananabnormalPToraPTTbothatfirst
presentationandwhencoagulationwasatitsworst.30Thelikelihoodofhypofibrinogenaemia
dependedonthecauseofbleedingandwasmostoftenassociatedwithplacentalabruption.14;30
Takentogether,thesestudiesindicatethatthestandardcoagulationtestsPTandaPTTshowthat
earlydepletionofcoagulationfactorsisuncommoninobstetrichaemorrhage,andthatplasma
fibrinogenlevelmaybeamoreimportanttherapeutictarget.
FibrinogenandFibtemasbiomarkerstopredictseverityofprogressionofpostpartumhaemorrhage
Inaninfluentialpaper,Charbitetalmeasuredmultiplecoagulationfactorsinwomenexperiencing
PPH.FibrinogenlevelwastheonlyindependentpredictorofprogressiontoseverePPHanda
fibrinogen<2g/Lhadhada100%positivepredictivevalueforprogressionfrommoderatetosevere
PPH.31Thisfindinghasbeenconfirmedbyusinretrospectiveandprospectivestudiesandbyother
groupsinvestigatingPPHinmultiplecohortsusingdiversemethodologies(Table1).14;31-35
These
studiesnowshowconvincinglythatplasmaClaussfibrinogen,measuredearlyduringPPH,isa
biomarkerforpredictingprogressiontoseverePPH.
AlthoughplasmaClaussfibrinogenlevelsyieldsusefulinformation,ittakesatleastanhourfora
resulttobeavailable,limitingitsutilitytodirectpracticeduringPPH.VE-POCTsgenerateasurrogate
measureoffibrinogenwithresultsavailablewithin10minutesofvenipuncture.36-38
Weinitiatedthe
ObstetricBleedingStudy1(OBS-1)toinvestigatewhetheraFibtem®assay,performedontheRotem®
machine(Werfen,Barcelona,Spain),couldpredictprogressionfromearlytoseverePPH.A
consecutivecohortof346womenwithPPH>1000mLwasenrolled.AtrecruitmentbaselineFibtem
wasperformedconcurrentlywithaplasmaClaussfibrinogen,whilstallotherroutinePPH
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managementwasprovided.ClinicianswereblindedtotheFibtemresultbutdidknowthe
laboratoryfibrinogenwhenitbecameavailable(Fig.1).14
DespiteonlyamoderatecorrelationbetweenClaussfibrinogenandFibtem(r=0.59)thetwo
parametershadanalmostidenticalvalueforpredictingprogression.AstheClaussfibrinogenor
FibtemfelltheneedforanyRBCtransfusion,≥4unitsRBC,≥8unitsofbloodproducts
(RBC+FFP+platelets),useofaninvasiveprocedureorableed>2500mLincreased.Thelowerthe
fibrinogenorFibtemA5thehighertheproportionofwomenwithpooroutcomes(Fig.2).For
example,themedian(IQR)fibrinogenandFibtemA5ofwomenwhoreceived≥8unitsofblood
productswas2.1(1.8-3.4)g/Land12(7-17)mm,respectively,comparedwith3.9(3.2-4.5)and19
(17-23)inthosewhodidnot.FibtemA5<10mmwasassociatedwithmoreprolongedbleeding
(median127versus65minutes,p=0.02),longerinlevel2care(patientsneedingextendedpost-
operativecarewithenhancedinterventionsandmonitoring)(median24versus11hours,p<0.001)
andshortertimetofirstRBCtransfusion(p<0.001).Inaddition,thecombinationofalow
fibrinogen/Fibtem,withtheclinicalobservationthattherewason-goingPPHatrecruitment,wasa
strongerpredictorofthesepooroutcomesthaneitheralone.14
OBS-1confirmedthatalowfibrinogenorFibtemA5,measuredearlyduringaPPHwasassociated
withprogressionofPPH,howeveritremainedunknownwhethercorrectionoftheseparameters
wouldimproveoutcome.Furthermore,theappropriateclinicaltargetforfibrinogenorFibtemA5to
maintainhaemostasis,andthereforewhenfibrinogencontainingproductsshouldbeinfused,was
unknown.
AppropriateTriggersforFibrinogenreplacementduringPPH
InanauditreportcomparingaRotem-basedalgorithm(thatinfused3goffibrinogenconcentrateif
theFibtemwas<7mm,or<12mmwithseverebleeding,andFFPiftheExtemCTwas>100s)with
theUnit’spreviouspracticeoftreatingmajorPPHwithshockpacks(consistingof4RBC,4FFPand1
poolofplatelets):TheRotem-basedalgorithmwasassociatedwithalargereductioninFFP,
cryoprecipitateandplateletusage,fewerwomenneeded>5unitsRBC,orhadtransfusion
associatedcirculatoryoverloadoradmissiontoITU.39;40
Whilethesedatawereretrospectiveandun-
randomized,theiroutcomesindicatethatROTEM-guidedtransfusionmanagementmaybesuperior
toanempiricmassivetransfusionapproachforPPH.Thereisnoinformationinthepaperabout
responsetimestoadministrationofbloodproductsafteradoptionoffibrinogenconcentrate
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infusions,althoughimmediateavailabilityoffibrinogenconcentratestoredontheirdeliverysuite
mayhavereducedresponsetimeandthereforeimprovedclinicaloutcomes.
Aprospective,double-blind,randomisedcontrolledtrial(RCT)ledbyWikkelsoeinvestigated
whetherinfusing2goffibrinogenconcentrateafter500-1000mLbloodloss,irrespectiveofplasma
fibrinogenlevel,reducedtheneedforRBCtransfusionandbloodloss.Nodifferenceinoutcomes
wasachievedwiththeempiricadministrationof2GfibrinogenconcentrateforPPHshowingthat
earlypre-emptive,formulaicfibrinogenreplacementwasnotindicated.Analysisfoundthatthe
averagefibrinogenlevelwhenfibrinogenconcentratehadbeeninfusionwasabout4.5g/Linboth
armsofthestudy,demonstratingthatthislevelisadequateforhaemostasisduringPPH.41The
resultsprovidegoodevidenceagainsttheuseofempiricfibrinogenreplacementduringPPHinthe
absenceofamonitoredlowplasmafibrinogenlevel,whileexposingmanywomentoplasma-derived
bloodproductsunnecessarily.
IntheObstetricBleedingStudy2(OBS-2)weusedFibtemA5andobservationofongoingbleedingto
guidefibrinogenandFFPreplacement.InOBS-1,aFibtemA5<16mm(fibrinogenabout3g/L),ina
womanwithongoingbleeding,hadbeenassociatedwithprogressiontomultiplepooroutomes14
andthiswassupportedbyotherobservationalstudies(Table1).OBS-2wasadouble-blind,placebo
controlledRCTwhichenrolledwomenwithPPH>1000-1500mL.Thestudyinvestigatedwhether
infusingfibrinogenconcentrate42ifFibtemA5was<16mmandbleedingwasongoingreducedblood
productusage.OBS-2alsoinvestigatedwhetheritwassafetowithholdFFPifFibtemA543was≥15
mmontheassumptionthatanormalfibrinogenwasasurrogateforadequatelevelsofother
coagulationfactors(Fig.3a).14;29;31
Therewasnostatisticallysignificantdifferenceinanyoutcomebetweenthefibrinogenandplacebo
(Normalsaline)groups,demonstratingthatafibrinogenofaround3g/Lisadequateforhaemostasis
duringPPH.44Pre-specifiedsubgroupanalyses
43showedthatfibrinogen>2g/LorFibtemA5>12mm
wereadequateforhaemostasisdespiteseverePPH.However,ifFibtemA5orfibrinogenwas<12
mmor<2g/Latthetimeofrandomisation,womeninthefibrinogengroupreceivedfewerblood
productsandhadlowerbloodlossafterstudymedicationcomparedtoplacebo.44Theseexploratory
subgroupanalysesdidnotreachstatisticalsignificancepossiblyduetothesmallnumberofwomen
randomisedwithafibrinogen<2g/L.Howevertheseresults,inconjunctionwiththedatafrom
Mallaiah39,suggestthatanappropriateinterventionpointforinfusionoffibrinogenisaFibtemA5
<12mmorfibrinogen<2g/L,andastudyinvestigatingthisiswarranted.
Inourexperienceafibrinogenlevelbelow2g/Lisuncommonduringobstetrichaemorrhage.
Combiningdatafromconsecutivestudiesandobservationfromourinstitutionoverthelast8years
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showsarateof1-2/1000deliveriesandasimilarincidencehasbeenobservedacrossallunitsin
Wales.InOBS-2,irrespectiveofbloodloss,womenwithaFibtemA5>15mmorwhohadstopped
bleeding,hadFFPwithheld(n=605).Median(IQR)bloodlosswas1500ml(1300-2000ml)andnone
ofthewomendevelopedhaemostaticimpairment21suggestingthathaemostaticimpairmentduring
PPHcanbeassessedaccuratelyusingVE-POCTs.
Thrombocytopeniaandplatelettransfusionduringpostpartumhaemorrhage
IthasbeensuggestedthatamassivetransfusionprotocolusedforPPHshouldinclude
platelets.18;20;45;46
Guidelinesrecommendmaintainingtheplateletcountabove75x109/Lduring
PPH.8;9TherearelimiteddataontheincidenceandcausesofthrombocytopeniaduringPPH,
thereforeweanalysedthewomenrecruitedtotheOBS-1study.InmoderatetoseverePPH,
thrombocytopeniawasuncommon,with8/347(2.3%)womenhavingaplateletcount<75x109/L.
Twelvewomen(3.4%)receivedaplatelettransfusionandthesefellintotwogroups.Firstly,women
whowerethrombocytopenicbeforedeliveryduetopre-eclampsiaorpre-existingdiseasessuchas
immuneorinheritedthrombocytopeniaandsecondly,womenwithinitiallynormalplateletcounts
whoeitherhadaplacentalabruptionorbleeds>5000mL.47Thesefindingsweresupportedbythe
UKOSSsurveyofwomenwhoreceived≥8unitofRBC(medianbloodloss6000mL)wherethe
medianfirstplateletcounttakenduringthebleedwas131x109/Landlowestwas68x10
9/L,77%of
thesewomenreceivedaplatelettransfusion.Placentalabruptionwasassociatedwiththelargestfall
inplateletcount(137to54x109/L).
30Thesereportssuggestthattheplateletcountisadequate
duringPPHinthevastmajorityofcases,andinclusionofplateletsinshockpackswouldresultin
manywomenreceivingunnecessaryplateletinfusions.
MeasurementofbloodlossafterdeliveryandduringPPH
EarlyrecognitionofPPHwithmeasuredratherthanestimatedbloodlossiscriticalbecauseclinicians
oftenunderestimatethevolumeofbleeding.48Measurementofbloodlossismoreaccurateandis
feasibleinroutinepractice,shouldbestartedaftereverydeliveryeveniftheinitiallossseems
normal49andisakeyrecommendationinRCOGguidance.
8Weadoptedthepracticeofgravimetric
measurementofbloodlossonswabsandpadswiththeadditionofmeasuredbloodlossinconical
underbuttockdrapesandsuctionbottlesduringourstudiestostandardisepatientrecruitmentand
ensuretimelyescalationofcare.Measurementofbloodlossalonedoesnotleadtoimproved
outcomesduringPPH,50butwhenintegratedintoapathwaycanaidescalationofcare.
20Inaddition,
escalationofcarealsoneedstotakeintoaccountotherfactorssuchasmaternalvitalsignsas
bleedingcanbeconcealedandtheapparentrateofbloodloss,althoughspecificguidanceisnot
available.
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ImpactofObstetricBleedingStudiesonpracticeandevolvingqualityimprovement
Between2013and2015womenrecruitedtoOBS-2followedthestudybloodproductalgorithm(Fig
2a)andthosenotrecruitedweretreatedusingthelocalmajorobstetrichaemorrhageROTEM
algorithm(Fig3b).Since2010PPHoutcomedatahasbeencollectedatourinstitutionaspartofa
qualityimprovementinitiative.DuringOBS-2,RBCusagedecreasedby32%,FFPusageby86%and
thenumberofwomenreceiving5ormoreunitsRBCfellby86%(Fig4).Inaddition,bleeds≥2500ml
fellby83%andlevel3ITUadmissions(womenrequiringadvancedrespiratorysupport)duetoPPH
decreasedfromabout4/yeartononein3years(Fig4).Althoughtemporallyrelated,itisunlikely
thattheinterventionoffibrinogenadministrationwassolelyresponsiblefortheseimproved
outcomesasonly7womentreatedintheinterventionalarmhadafibrinogen<2g/L.Thisimplies
thatotherfactorsassociatedwithrunningthestudyandcomplyingwithprotocolswereinfluencing
maternaloutcomes.Inordertostandardiserecruitmenttothestudy,womenwereriskassessed,
bloodlosswasmeasuredratherthanestimatedandobstetriciansandanaesthetistsattendedthe
mother’sbedsidetoobtainconsentandtakestudybloodsasspecifiedinthestudyprotocol.
WhenOBS-2endedinNovember2015,itwasexpectedthatimprovedoutcomeswouldcontinue.
However,itrapidlybecameapparentthatthiswasnotthecaseandtheendofthestudycoincided
withanincreaseinlargehaemorrhagestoratessimilartobeforethestudy(Fig4).Asystematic
reviewof16largebleedsovera6monthperiodidentifiedcommonthemesincludingareturnto
estimatingbloodloss,themultidisciplinaryteamnotattendingthemother’sbedsideinatimely
fashionandPOCTsnotbeingperformedearlyinthecourseofthehaemorrhage.Thisresultedin
delayedrecognitionofadeterioratingpatientanddelayedescalationofobstetricintervention.
Qualityimprovementinitiativesinpostpartumhaemorrhage
In2011ShieldsdescribedaqualityimprovementprogrammethatstandardisedcareduringPPH.This
includedriskassessmentfollowedbyanescalating3-stageapproachbasedon500,1000and1500
mLbloodlossand/orclinicalsigns.Thisstepwise,prescriptiveapproachrequiredaccurate
contemporaneousmeasurementratherthanestimationofbloodlossandwasinitiatedafterevery
delivery.Theprotocolstipulatedthataseniormidwife,obstetricianandanaesthetistshouldattend
themother’sbedsidewhenbloodlossreached1000mL.At1500mLbloodloss,empiricalfixed-ratio
bloodproducttransfusionwasstartedbasedondataderivedfromtraumastudies.Thegroupnoted
thatPPHprogressedinfewerwomen,thenumberofbloodproductsusedfellandfewerwomen
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developedcoagulopathy.19TheprotocolwasrolledoutacrossaregionbytheCaliforniaMaternal
QualityCareCollaborative(CMQCC)withsimilarresults.20Asimilarqualityimprovementprogramme
wasinitiatedbyTheAssociationofWomen’sHealth,ObstetricandNeonatalNurses(AWHONN).
BothCMQCCandAWHONNhaveextensiveinformationavailableontheirwebsites
(http://www.awhonn.org/?page=PPHandhttps://www.cmqcc.org/resources-tool-kits/toolkits/ob-
hemorrhage-toolkit).
Theseinitiativesoverlappedwithourexperiencesintermsofriskassessment,measuredbloodloss
andearlyescalationofobstetriccarebyseniorclinicians.Themaindifferencewastheapproachto
bloodproductreplacement,liberalfixed-ratioinfusionofbloodproductsbasedondataderivedfrom
trauma19;20
versusVE-POCTstotargethaemostatictherapybasedonourprogrammeofresearch.It
isnotknownwhichoftheseapproachesresultsinbetteroutcomesandclinicaltrialsspecifically
addressingthevalueofVE-POCTsarerequiredtoaddressthis.
Understandingtheimpactofpointofcaretestsofcoagulationinpostpartumhaemorrhage
DuringOBS-2Rotem-guidedbloodproductreplacementwasintroducedintoroutinepracticeatour
centreforallpatients..Asexperienceincreasedandcliniciansacceptedtheresultsasclinically
reliable,managementofPPHchanged.IfearlyinthebleedtheRotemresultswerenormal,the
bleedingmustbeduetoaphysicalcause(atony,traumaorretainedplacentaltissue)andnot
coagulopathy.Thisknowledgefacilitatedearlytargetedescalationofobstetriccareand,ifnecessary,
involvementofamoreexperiencedcolleague.Ifcoagulationwasabnormalearlyinthebleedthe
motherwasimmediatelyidentifiedashighrisk.Earlycoagulopathyinsuchcasesraisessuspicionof
delayedresuscitation,placentalabruptionoramnioticfluidembolus.Themotherrequiredurgent
treatmentforcoagulopathy,almostalwayswithfibrinogenreplacement,andescalationofobstetric
managementtoaddresstheunderlyingcauseofbleeding.Thisbinaryclassificationhelpedtheteam
focusonthemostimportantclinicalproblemandourimpressionwasthatVE-POCTsfacilitated
behaviouralchangeofthemultidisciplinaryteam.
ANationalInstituteforHealthandCareExcellencereviewofVE-POCTduringPPHfocusedonlyon
bloodandbloodproductusage(https://www.nice.org.uk/guidance/dg13).Ourexperienceisthat
VE-POCTscanactasatriggeraroundwhichcarecanbestructuredbyencouragingcliniciansto
attendthebedsideearly.TheVE-POCTresultsinfluencedecisionmakingand,ifnormal,allowthe
obstetriciantofocusonmanagingtheobstetriccauseofbleedingwhiletheanaesthetist
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concentratesonappropriateresuscitationandbloodproductreplacement.Ourobservation,
supportedbythefindingsfromOBS-2andotherretrospectiveobservationalstudies,27;28;39;40;44
isthat
inthesmallnumberofwomenwhoareidentifiedashavingafibrinogen<2g/LorFibtemA5<12mm,
rapidcorrectionofhypofibrinogenaemiawithfibrinogenconcentrateimproveshaemostasisandis
advantageous,althoughlargeprospectivetrialsareneededtoverifythesefindings.
Localqualityimprovementinitiatives
Improvedlocalclinicaloutcomesmaybeaconsequenceofmultipleinter-relatedfactors.These
includedriskassessmentofallwomen,cumulativemeasurementofbloodlossandensuringthatan
experiencedmidwife,obstetricianandanaesthetistattendthemotherat1000mLbloodlosswith
ROTEMassessmentofcoagulationforallwomenweathertheywereenrolledintotheOBS-2study
ornot.Wedonotknowwhichoneoftheseinterventionsimprovesoutcomesanditislikelytobea
combinationofallofthesefactors.Overaoneyearperiod(2017,18monthsafterfinishingtheOBS
2trial)inourtertiaryreferralcentre,2.8/1000womenhadaPPH>2500mL,abloodtransfusionof≥5
unitsRBCorreceivedFFP.WhencomparedwiththepublisheddatafromHealthcareImprovement
Scotland,whereanoverallrateof6/1000wasreported,ourresultsfallbelow3standarddeviations
fromthemean.2WearecurrentlyseekingtoreplicatetheseimprovementsacrossWales.
AllWalesqualityimprovementprogramme:OBSCymru(ObstetricBleedingStrategyforWales
(Cymru))
OBSCymru(http://www.1000livesplus.wales.nhs.uk/obs-cymru)isaregisteredqualityimprovement
initiativethataimstoreducematernalmorbidityduetoPPHacrossWales.Waleshasapopulation
of3.1millionanddelivers30,000womenayearin12consultantledunits(CLU),withbetween500-
6000deliveriesperannumineachCLU.TheprojectaimstoreduceratesofmajorPPHandblood
transfusion,level3ICUcareandhysterectomyduetoPPH.
TheOBSCymruintervention
ThekeytoOBSCymruistolimitthenumberofmoderatebleedsthatprogresstosevere
haemorrhageandsoreducematernalmorbidity.Theprojectfocusedon4keyelementswhichdraw
onthequalityimprovementworkfromothergroups19;20
andthelessonslearntfromourresearch
programme.
11
1. Riskassessmentofallwomen:potentialriskfactorsforPPHareflaggedonadmissionto
deliverysuiteandwithon-goingriskassessmentduringlabour.
2. Cumulativegravimetricmeasurementofbloodlossaftereverydelivery:tofacilitate
escalationofcarewithspecificactionsrequiredat500,1000and1500mLbloodloss.
3. Multidisciplinarycarewithaseniormidwife,obstetricianandanaesthetistattendingthe
bedsideat1000mLbloodloss.
4. Rotem-guidedbloodproductreplacementusinganalgorithmderivedfromtheresultsof
OBS-2.
Thesethemesareembeddedintoclinicalpracticeusinganumberofinterventionsandtools
(availableathttp://www.1000livesplus.wales.nhs.uk/obs-cymru).APPHproformadescribingan
escalating4-stageapproachwasdevelopedandisplacedinallmothers’notesonadmissionto
deliverysuite.(Specificpaperworkwhichdescribesallactionsandinterventionswhichshouldoccur
asPPHprogressesandalsoactsasatemplateforscribingtheevents).
• Stage0:riskassessmentforallwomeninlabour(onadmissionandaslabourprogresses).
• Stage1:at>500mLafteravaginalbirthaseniormidwifeisinformed,thecauseofbleeding
assessedandinitialtreatmentinstituted.
• Stage2:at>1000mLaseniormidwife,obstetricianandanaesthetistattendthebedsideto
assessandescalatemanagementasappropriate.SamplesforRotem,bedsidelactateand
haemoglobin,FBCandcoagulationscreenaretakenandtranexamicacidisgiven.
• Stage3:at>1500mLwithon-goingbleedingtheconsultantobstetricianandanaesthetistare
informed.ThemajorobstetrichaemorrhageprotocolisactivatedandRotem-guidedblood
productreplacementinstitutedwhilstmedicalandsurgicaltreatmentsarecontinued.
ThisisacomplexinterventionandsoitsimpactisbeingassessedaccordingtoMedicalResearch
Councilguidance.51Thestep-wiseinterventionshavebeenincorporatedintoanallWalesPPH
guideline
(http://www.wisdom.wales.nhs.uk/sitesplus/documents/1183/Post%20Partum%20Haemorrhage_M
aternity%20Network%20Wales%20All%20Wales%20Guidelines_2017.pdf)andisbasedontheRoyal
CollegeofObstetricsandGynaecology(RCOG)green-topguidance8andincorporatingtheOBSCymru
approach.
DataarecollectedprospectivelyonallPPHs>1000mlinWalestobecomparedwithretrospective
datacollectedfromtheunits.ItistooearlytoassesswhetherkeymarkersofseverePPHare
changing;thisinformationwillbereportedatthecompletionoftheprojectin2019.
12
OBSCymruRotemguidedalgorithm
TheOBSCymruRotem-guidedbloodproductalgorithmisshowninfigure5http://www.oaa-
anaes.ac.uk/assets/_managed/cms/files/Guidelines/ROTEM%20Protocol.pdf.At1000mLbloodloss
withongoingbleedingFibtemA5andExtemCT,bedsidevenouslactateandhaemoglobinare
performedandFBCandcoagulationsenttothelaboratory.Intravenoustranexamicacidisgiven.The
WOMANtrialshowedthattranexamicacid,givenwithin3hoursofdelivery,reduceddeathdueto
bleedingwithoutanincreaseinthromboticorotheradverseevents,52ouralgorithmtherefore
infusestranexamicacidassoonasPPHisrecognisedoratthelatest1000mL.Therationaleforearly
Rotemtestingisnotonlytorapidlyidentifythesmallnumberofwomenwhoneedhaemostatic
support,buttoreassuretheobstetricianthatcoagulationisnormalandfocustreatmentonobstetric
causesofbleeding.Haemostaticbloodproductreplacementinitiallyfocusesonfibrinogen.IfFibtem
A5is≤12mmorClaussfibrinogen<2g/L,fibrinogenconcentrateisgiven.Fibrinogenconcentrateis
notlicensedforthisindicationintheUKandanalternative,asrecommendedbyRCOG,istoinfuse
cryoprecipitate.8TherecommendationsonfibrinogenreplacementarebasedondatafromOBS-2
andtheLiverpoolPPHalgorithm.39;40;44
Thetargetistomaintainthefibrinogen>2g/Lwhichis
supportedinthe2016RCOGguideline.8;9IftheExtemCTisprolongedabovethenormalrange(75
secbasedonlocalvalidation)orthePT/aPTTisabovethenormalrange,afterfibrinogen
replacement,15ml/kgFFPisinfusedbasedonRCOGguidanceandOBS-2data.8;44
Plateletsare
transfusedif<75x109/LbasedonRCOGguidance.
8Becausecoagulopathycanevolverapidlyduring
PPHwerepeatRotemandlaboratorytestingevery500mLorevery30minutesduringongoing
bleeding,oratanytimeforclinicalconcern.Testsarerepeatedafterbloodproductsaregivento
assessresponse.
TheFuture–questionstobeaddressed.
TheroleofVE-POCTsinthemanagementofPPHremainsdebated53;54
anddefinitiveevidenceis
lacking.Wehypothesisethatitisthecombinedeffectoftheearlyrecognitionofbleedingtriggering
timelyinterventionsincorporatingVE-POCTsandamanagementstrategyinvolvingthewhole
multidisciplinaryteamthatiskeytopreventingprogressionofPPHandminimisingmorbidity.A
studycomparingsuchanapproachutilisingearlyVE-POCT,withacceptedstandardcarebasedon
laboratorytestsofcoagulationisnownecessaryalthoughthiswouldnecessitatelargemulti-centre
studies.Itmayalsobepossibletopartiallyaddresssomeofthesequestionsbyspecificallystudying
highrisksurgicalproceduressuchaswomenhavingaCaesareansectionforplacentapreviaor
womenwhopresentwithabruption.
13
Dataonthecosteffectivenessofsuchanapproachisimportantifthisistobeusedmoregenerally
withinavarietyofhealthcaresettings.Wesuggestthatqualitativeassessmentoftheimpactofthe
interventiononteamdynamicsandbehaviourshouldalsobestudied.Amultinationalgroupof
interestedresearchersmayberequiredtoaddresstheseissues.
Funding
Thisreviewwaspreparedwithoutexternalfundingsupport.
Acknowledgements
Theauthorsthankthewomenwhohaveagreedtotakepartinthestudiesdescribedandthe
midwives,anaesthetistsandobstetricianswhohavehelptoenrolthesubjects.Theroleofeveryone
involvedinOBSCymruisgratefullyacknowledged.
Declarationsofinterest
PWChasreceivedresearchsupportfromCSLBehring,Werfen/TemInternationalandHaemonetics.
HehasactedasapaidconsultanttoCSLBehringandWerfen/TemInternational.
SFBhasreceivedsupportforqualityimprovementinitiativesfromWerfen/TemInternationaland
WelshGovernment.
LdeLhasreceivedresearchsupportfromWerfen/TemInternationalandHaemonetics.
REChasreceivedresearchsupportfromCSLBehring,Werfen/TemInternationalandHaemonetics.
ShehasreceivedsupportforqualityimprovementinitiativesfromWerfen/TemInternationaland
WelshGovernment.ShehasactedasapaidconsultanttoCSLBehringandWerfen/Tem
International.
14
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Table1:
Studiesinvestigatingtheassociationbetweenfibrinogenandprogressionofpostpartum
haemorrhage
Study N Studydesign Fibrinogeng/L
Timeof
fibrinogenassay
Outcomedefining
progressionof
PPH
Descriptive
statistic
reported
No
progression
ofPPH
Progression
ofPPH
ROC
AUC
(95%CI)
Charbit31 129 Infusionof
uterotonicafter
manualexploration
ofuterus
Invasiveprocedure
tocontrolbleeding,
fallinHb≥4g/Lor
≥4unitsRBC
Median(IQR)
4.4(3.7-5.1 3.3(2.5–4.2)
0.75(CInot
reported)
P<0.0001
Cortet32 738 DiagnosisofPPH Invasiveprocedure
tocontrolbleeding,
fallinHb≥4g/L,≥4
unitsRBCor
admissiontooITU
Mean(SD) 4.2(1.2) 3.4(0.9) 0.66
(0.64-0.68)
Poujade55 98 Variabletimebefore
embolisation
Successof
radiological
embolisation
Mean(SD) 2.9(1.3) 1.8(0.9) NR
Gayat34 257 Variabletimebefore
procedure
Invasiveprocedure
tocontrolbleeding
Median(IQR) 2.7(2.1-3.5) 1.8(1.1-2.5) 0.83
(±0.03)*
deLloyd33 240 Firstclinicalconcern
duringPPH
≥2500mLbloodloss Mean(SD) 4.4(1.1)
3.1(1.0) 0.85
(0.78-0.93)
Collins14 346 1000-1500mLblood
loss
Transfusionof≥8
unitsallogeneic
bloodproducts
Median(IQR) 3.9(3.2-4.5) 2.1(1.8-3.4) 0.82
(0.72-0.92)
Simon35 797 Beforebleeding
started
PPHrequiring
manualuterine
exploration,RBC
transfusionorfallin
Hb≥2g/L
Mean(SD) 4.9(1.0) 4.3(1.3) NR
StudiesareshownwhichinvestigatedtheassociationofClaussfibrinogen,takenearlyduringa
postpartumhaemorrhageorbeforebleedingstarted,withprogressionofbleeding.Variablestudy
designswereemployedbutinallcasesalowClaussfibrinogenwasassociatedwithastatistically
significantlyincreasedriskofprogression.Thisdemonstratesthatfibrinogenlevelisauseful
biomarkerforpredictingprogressionofpostpartumhaemorrhage,however,dothetimerequiredto
obtainaresultit’sclinicalutilityislimited.NRnotreported,CIconfidenceinterval,ROCreceiver
operatingcharacteristicscurve,IQRinter-quartilerangeandSDstandarddeviation.*,inthisstudy
theROCreferstoacompositepredictivetoolcombiningfibrinogen<2g/l,abnormalplacental
implantation,PTratio<50%,heartrate>115beatsperminute,troponinraised.
20
Legendsforfigures
Figure1:StudydesignforOBS-1
Figure2:
Theproportionofwomenprogressingto>2500mLbloodloss(red),redbloodcelltransfusion(dark
blue),atleast4unitsredbloodcelltransfusion(lightblue)oraninvasiveproceduretocontrolthe
bleed(green)dependentonClaussfibrinogen(Fig2a)orFibtemA5(Fig2b)takenat1000-1500
bloodlossisshown.DataarederivedfromtheOBS1study.
Figure3:Rotemguidedbloodproductalgorithms
Figure2ashowthestudydesignandbloodproductalgorithmusedforwomenrecruitedintoOBS-2.
Figure2bshowsthebloodproductalgorithmusedforwomenwhowerenotenrolled.
Figure4:ChangesintransfusionpracticeacrosstimeinCardiff
Figure4ashowsthenumberofunitsofredbloodcells(RBC)(grey)andfreshfrozenplasma(FFP)
(black)transfusedforeachyearbetween2010and2017.TheOBS2studywasassociatedwitha
reductioninRBCandFFPtransfusionwhichincreasedafterthestudyfinishedandfellagainonce
OBSCymruwasinitiated.Figure4bshowsdataforthenumberofwomenwhoreceivedatleast5
unitsofRBC,representingasubgroupofveryseverepostpartumhaemorrhage.Asimilartemporal
trendwasobserved.
Figure5:OBSCyrmubloodproductalgorithm.
Studyentry
1000mLPPH
measuredor
suspected
Perform
Fibtem,
APPT,PT,
Clauss
fibrinogen,
Hb
Fibtemperformedoutside
clinicalareasoclinicianswere
blindedtoresults
AllusualObstetric
interventions
Orderbloodand
bloodproductsif
PPH>1500mL
Reactto
laboratory
resultsasthey
became
available
Figure1
0
10
20
30
40
50
60
70
80
90
100
<2g/L 2-3g/L 3-4g/L >4g/L
%ofwomen
Concentrationoffibrinogen
>2500mLbloodloss
TransfusedanyRBC
Transfused≥4unitsRBC
Invasiveprocedure
Figure2b Figure2a
Figure3a
Figure3b
Figure4b Figure4a