EarlyBloodBasedResuscitationafterTraumaticInjury:theGood,theBadnotsoUgly?

ScottC.BrakenridgeMD
UTSouthwesternMedicalCenter,Dallas,TX

Introduction

Controlofhemorrhageandappropriatevolumeresuscitationfromhemorrhagicshock

arethecornerstonesofinitialtreatmentfortheseverelyinjuredtraumapatient.Therapid
identificationofsourcesofhemorrhagenecessitatingsurgicalcontrol,andsubsequenttimely
initiationofoperativeintervention,areunarguablytheprimaryconcernsforthesurgeon
evaluatingtheseverelyinjuredpatient.Theprimarygoalsofacutevolumeresuscitationfrom
hemorrhagicshock,restorationofintravascularvolumeandoxygencarryingcapacity,have
remainedunchangedsincetheVietnamWarera.However,whathasshiftedoverthepast20
yearsistheroleofbloodproductsinearlypostinjuryresuscitation.
Earlyphysiologicexperimentsandclinicalexperiences,includingworkpublishedby
AlfredBlalock,suggestedthatwholebloodisindeedthebestresuscitativefluidfor
hemorrhagicshock.13However,acombinationofissuesincludingriskoftransfusionreactions,
transmissionofinfectiousagentsandthecostandlogisticaldifficultiesofstorageanddelivery
ledtoanisotoniccrystalloidbasedresuscitationstrategysincetheVietnamWarera.In
addition,overthepast20yearsmultiplestudieshaveshownanassociationoftransfusionwith
increasedmortality,infectionandriskofmultipleorgandysfunction(MOD)ininjuredpatients.

Thesefindingshaveledseveralauthorstoadvocateavoidanceoftheuseofbloodproductsin
injuredpatientswheneverpossible.4,5
Despitethenumerousconcernsregardingbloodproductusageinthetrauma
populationtherehasbeenarekindlingofinterestinearlybloodbasedresuscitation.Recent
evidencefromthetheatresoftheIraqandAfghanistanconflictshavesuggestedthatashift
fromcrystalloidtobloodbasedresuscitationfromhemorrhagicshockshowsimproved
survival.68Thesefindingshaveacceleratedtheinvestigationofsocalleddamagecontrol
resuscitation,whichfocusesontheearlyandaggressiveutilizationofbloodcomponent
therapyincombinationsapproachingthatofwholeblood,primarilytoaddressearly
coagulopathy.Interestingly,therehavebeenanecdotalreportsthatpatientsreceivingthistype
ofresuscitativetherapyhaveclinicalevidenceofalessvigoroussystemicimmuneresponse,
includinglesspulmonarydysfunctionandfasterweaningfrommechanicalventilation.9These
conflictingoutcomesresultsraiseaseriousdilemmaregardingourapproachtowardstrauma
resuscitation.Thequestionthathasyettobecompletelyansweredremainshowdowebest
resuscitatepatientswithseveretraumaticinjuryfromhemorrhagicshockandpreventtrauma
associatedearlycoagulopathywithoutexacerbatingtheposttraumaticsystemicinflammatory
responseorincreasingtheriskformultipleorganfailure?

ThepastTheBad

Transmissiblediseases&Transfusionreactions
Whiletheoreticallyconsideredthemostphysiologicallyeffectivemethodof
resuscitationfromacutehemorrhagicshock,therehavebeenseveralhistoricallimitationsand
risksthathavelimiteditsuseasaprimaryresuscitativefluid.Transfusiontransmitteddiseases
remainasmall,butnonethelessreal,riskassociatedwithtransfusionofbloodproducts.The
recognitionoftransfusionassociatedhepatitisandHIVtransmissionduringthe1980shada
profoundimpactontheoverallutilizationofallogeneicbloodproducttransfusionintheUnited
States.Bothcollectionsandtransfusionsdecreasedsignificantlyfromthelate1980stothe
mid1990s,reachinganadirin1996.10Themostrecentestimatesforriskoftransmissionof
HepatitisB(1:350,000),HepatitisC(1:1,800,000)andHIV(1:2,300,00)perunittransfusedinthe
UnitedStatesremainextremelylowasaconsequenceofdonorscreeningmechanismsthat
havebecomestandardpractice.11Whilepositivebacterialculturesofapheresisplateletunits
havebeenreportedashighas1:5000,septiccomplicationsarealsoextremelyrareat
approximatelyonefatalcasepermillion.11TransmissionofemergingdiseasessuchasWest
Nilevirusandpriondiseasesremainanecdotalatthistime,butmayposelargerrisksinthe
futureasourunderstandingofthesediseasesevolves.
Whiletransmissionofinfectiousdiseasesmayhavehadamorevisceralemotional
impactontransfusionpracticeinthepast,noninfectiouscomplicationssuchasacute
hemolyticreactions,andespeciallytransfusionrelatedacutelunginjurycontinuetoposea
muchmoresignificantrisktothetransfusedtraumapatient.Themajorityofacutehemolytic
reactionsareprovokedbyABOincompatibilities,whicharetheresultofavoidablesystems

failures.12,13Transfusionrelatedlunginjury(TRALI)isdefinedastheonsetofAcuteLungInjury
(acuteonset,bilateralradiographicinfiltrates,hypoxemiaandlackofpulmonaryvasculature
overload/congestion)withinsixhoursofatransfusion.14TRALIisthoughttobemediatedby
donorantigranulocyteantibodieswhichtriggerpulmonaryinflammation,pulmonaryvascular
permeabilityandultimatelypulmonaryedema.Contrastedagainsttherisksoftransmissible
infectiousdiseases,TRALIposesamuchlargerstatisticalrisk,estimatedatapproximately
1:5000ofallbloodproductunitstransfused.15WhileTRALIisawelldescribedentityinthe
overalltransfusionpopulation,theactualincidenceinthesubpopulationoftraumaand
criticallyillpatientsremainsanunresolvedquestion.Arecentmulticenterretrospective
analysisof1351intensivecareunitpatientsreceivingtransfusionrevealedsuspectedTRALI(ALI
withoutothersuspectedsources)ratesof1:1271unitstransfused,possibleTRALI(ALIwith
otherpossibleriskfactorsforlunginjury)at1:534unitstransfused,andtransfusionassociated
circulatoryoverload(TACO)at1:356unitstransfused.16Whilethesenumbersappearstriking,
theyalsoillustratethepointthatisolatingTRALIasthecauseofpulmonaryfailureinthe
criticallyillandinjuredpatientpopulationismadeextremelydifficultbyotherpossiblecauses
ofpulmonarydysfunctionsuchasresuscitativevolumeoverload,injuryorsepticrelated
systemicinflammation,andthoracicinjuries.Thereiscurrentlynoliteratureontheincidence
ofTRALIspecificallyaddressingthetraumapopulation.

Mortality

Oneofthemajorpredictorsofmortalityafterinjuryistransfusionofbloodproducts.

Thishasbeenshownrepeatedlyinbothretrospectiveandprospectivestudiesattemptingto
identifyriskfactorspredictiveofmortalityafterinjury.Injuredpatientsrequiringblood
transfusionhavebeenfoundtohavebetween3to5foldincreasedoddsofdeathcomparedto
thosenotrequiringtransfusion.4,1719Inaddition,therealsoappearstobeadosedependent
associationbetweentransfusionrequirementsandmortality.Inasinglecenter,4year
retrospectiveanalysisof316patientswithbluntliverand/orsplenicinjurytheoverallriskof
deathincreasedwitheachunitoftransfusedPRBC(OR1.16,95%CI1.101.24).17Not
surprisinglythen,requirementofmassivetransfusion,mostoftendefinedas>10UnitsPRBC
within24hoursofinjury,isanevenstrongerpredictorofmortality.2022
Pooroutcomesaftertransfusionhavealsobeenwelldescribedinthegeneralcritical
carepopulation.2325Asinglecenterprospectivecohortstudyof248patientsadmittedtoboth
surgicalandmedicalintensivecareunitsmeetingthe1994AmericanEuropeanConsensus
Conferencecriteriaofacuterespiratorydistresssyndrome(ARDS)showedsimilarfindingsto
therisksreportedinthetraumapopulation.Theyreportedthatthesepatientshadan
approximate3foldincreasedoddsofmortalitywithtransfusionof1unitofPRBC(OR3.12,
95%CI1.287.58)afteradjustingforage,gender,APACHEIIIscore,andincitingeventoflung
injury.24TheyalsofoundadosedependentrelationshipofPRBCwithmortalityshowinga5%
increasedadjustedoddsofdeathperunitofPRBCtransfused(OR1.06,95%CI1.041.09).
Interestingly,insubgroupmultivariateanalysis,transfusionafteronsetofARDSwasassociated
withanoddsratioformortalityof1.13(95%CI1.07to1.29),whiletransfusionpriortoonsetof
ARDSwasfoundnottobeariskfactorformortality.24

Oneofthemostinfluentialstudieschangingthepracticeofcriticalcaremedicinewas
theCanadianCriticalCareTrialsGroupmulticenterrandomizedcontrolledtrialoftransfusion
requirementsintheintensivecareunitpopulation.TheTransfusionRequirementsinCritical
Care(TRICC)trialrandomized838intensivecareunitpatientstoeitherarestrictive(transfusion
triggerHgb<7g/dL)oraliberalPRBCtransfusionstrategy(transfusiontriggerHgb<10g/dL)
poweredfortheirprimaryoutcomeof30dayallcausemortality.Whiletherewasno
significantdifferenceinoverall30daymortality,subgroupanalysissuggestedlessillpatients
(APACHEIIscore20)andpatientsovertheageof55showedlowermortalityrates.26In
hospitalmortality,asecondaryendpoint,waslowerintherestrictivestrategygroup(22%vs.
28%).27Alsonotpoweredforadefinitiveanalysis,asubsequentretrospectivestudyofthe
subsetof203criticallyillinjuredpatientsfromtheTRICCcohortfoundnosignificantdifference
betweenrestrictiveandliberalstrategiesfor30dayallcausemortality,multipleorgan
dysfunction,andlengthofhospitalandICUstay.26TheoverallapplicabilityoftheTRICCtrial
dataspecificallytothetraumapopulationremainsunknown.

Infectiouscomplications
Asuspectedadverseimmunosuppressiveeffectofallogenictransfusionofpackedred
bloodcellsmanifestingasincreasedratesofpostoperativewoundinfectionhasbeendescribed
inseveraldifferentsurgicalsettingsincludingaftercardiac,colorectalandgeneralsurgical
procedures.2830Theassociationbetweenbloodproducttransfusionandinfectious
complicationshasalsobeenshowninthecriticalcarepopulation.Tayloretaldescribeda

retrospective2yearcohortof1,717intensivecareunitpatientsandshowedthosereceiving
transfusionofgreaterthan1unitofPRBChadagreaterrisk(15.4%vs.2.9%)ofnosocomial
infection.31BloodproductsotherthanPRBCshavealsobeenassociatedwithinfectious
complications.InanontraumasurgicalICUpopulation,analysisofa380patientretrospective
cohortrevealedfreshfrozenplasma(FFP)asanindependentriskfactorforinfectious
complicationsaftercontrollingfortransfusionofPRBCsandillnessseverity(APACHEII).32
Interestingly,inthisstudytherewasnoassociationbetweenFFPandinfectiouscomplications
inthosereceivingbothFFPandPRBCs.
Anassociationbetweentransfusionofbloodproductsandinfectiouscomplicationshas
alsobeendescribedspecificallywithinthetraumaliterature.Thisassociationwasfirst
describedinaposthocanalysisofarandomizedcontrolledtrialcomparingtheeffectivenessof
singlevs.dualagentantibioticprophylaxisforpostoperativesepticcomplicationsinpatients
withintestinalperforationafterpenetratingabdominaltrauma.33Inthisstudy,receiving
greaterthan10UnitsofPRBCswasasignificantpredictorofinfectiouscomplications.Many
subsequentretrospectivedescriptiveandprospectivecohortstudieshavealsoshownan
associationbetweentransfusionandinfectiouscomplicationsafterbothpenetratingandblunt
injury.3437Ina5yearprospectivecohortof482patientswithbothbluntandpenetratingliver
injuries,FabianshowedtheAbdominalTraumaIndexScoreandnumberofunitsoftransfused
PRBCstobeindependentlyassociatedwithincreasedriskofperihepaticabcess.35
Subsequently,ina1yearprospectivecohortstudyofalltraumapatientswithalengthofstay
greaterthan3days,Edna&Bjerkesetnotedasixfoldgreateroddsofinfectiouscomplications
(urinarytractinfection,pneumoniaand/orpneumonia)inpatientsreceiving>4unitsPRBCs.36

Inanotherlargeretrospectivecohortstudy,Agarwalnotedthatinjuryseverityscore(ISS)and
thenumberofunitsofPRBCstransfusedastheonlyindependentpredictorsofoccurrenceof
infectiouscomplications.37

Multipleorgandysfunction

Thepreviouslymentionedrisksassociatedwiththeutilizationofbloodproductsfor

traumaticresuscitationhavenodoubthadsignificantimpactontheresuscitationpracticeof
traumasurgeons.However,someofthemostvigorousinvestigation,aswellasdebate,within
thetraumacommunityoverthepasttwodecadeshascenteredaroundtheassociationofblood
producttransfusionwithposttraumaticmultipleorgandysfunction.Thedevelopmentof
multipleorgandysfunction(MOD)isassociatedwithsignificantlyincreasedmorbidityand
mortalityaftersevereblunttraumaticinjury.38,39MODmanifestsasprogressivedysfunctionof
multipleorgansystems(pulmonary,renal,cardiacandhepatic)incriticallyinjuredandseptic
patients.Advancesintraumasystems,volumeresuscitation,damagecontrolsurgical
proceduresandadvancedcriticalcaresupportivemeasuresoverthepastfivedecadescontinue
tocontributetothesurvivalofpatientswithprogressivelyincreasingseverityofinjuries.
However,evenastheseinterventionsimproveuponsurvivalintheimmediatepostinjury
period,MODcontinuestoimpactthelongtermmorbidityandmortalityofseverelyinjured
patients.Despitebeinganareaofintenseactiveinvestigation,MODremainstheleadingcause
oflatepostinjurydeathsintheintensivecareunit.4042

Multipleorgandysfunctionisassociatedwithanearly,systemichyperinflammatory
responsetosevereinjuryknownasthesystemicinflammatoryresponsesyndrome(SIRS).
Almostimmediatelyaftersevereinjurythereisactivationoftheimmunologiccascadeleading
tosignificantelevationinproinflammatorycytokines,suchasTNF,IL1andIL6,inboth
animalmodelsandinjuredpatients.4346Insomeinstances,systemicinflammationissosevere
thereisprogressiontoearlyMODwithinthefirst23days.Inothers,thisdysfunctional,robust
inflammatoryresponseiscounteredbyadelayedcompensatoryantiinflammatoryresponse
(CARS)associatedwithantiinflammatorycytokinessuchasTGF,IL4andIL10.47,48This
leadstothedevelopmentofanextendedperiodofposttraumaticimmunosuppressionwhichis
associatedwithincreasedriskofinfection,sepsisandsubsequentlateMOD.4850Despite
continuingactiveinvestigation,thetriggersofthisimmunologicresponseandwhyitoccursin
somepatients,butnotothers,remainunknown.
GiventhehypothesisofdysfunctionalinflammationasthedrivingforceoftheSIRS
responseandMOD,thesuspectedimmunomodulatoryeffectsofallogenicbloodtransfusion
madeitanearlysuspectasapotentialcontributortocomplicationsaftertraumaassociated
withimmunedysfunction.Sincetheearly1990s,thetransfusionofbloodproductsafter
traumaticinjuryhasrepeatedlybeenshowntobeassociatedwiththesubsequentonsetof
MOD.5153Mostprominently,Mooreandhiscolleagueswereabletoconsistentlyreportan
associationbetweentransfusionandMODinaseriesofstudiesfromanongoingprospective
cohortofseverelyinjuredpatientsspanningovermorethantenyears.39,42,5255Inmultiple
differentanalysesoftheirongoingprospectivecohortofseverelyinjuredpatients,thisgroup
consistentlyshowedthat>6UnitsofPRBCstransfusedwithinthefirst24hoursofresuscitation

afterinjurywasaindependentpredictorofmultipleorganfailure.Inthefirstofthesestudies,
Sauaiaperformedaretrospectivecohortanalysisof394traumapatientsovera3yearperiod
withaninjuryseverityscore(ISS)>15andfoundthatagegreaterthan55years,InjurySeverity
Score(ISS)25and>6UnitsofPRBCinthefirst12hoursafterinjurywereindependent
predictorsofMOD.52Theywerealsosubsequentlyabletoshowthatthetransfusionof>6units
PRBCwithinthefirst12hoursafterinjuryremainedanindependentpredictorofMODwhile
controllingforinjuryseverity(ISS)andseverityofshock(basedeficit,lactate).53Asour
understandingofthenaturalhistoryofMODprogressed,attentionalsoturnedtoevaluating
theassociationoftransfusionwithAcuteRespiratoryDistressSyndrome(ARDS)aspulmonary
dysfunctionisoftenabellwetherofprogressiontoMOD.SimilartothepreviousMODdata,
SilverboarddescribedadoseeffecttypeassociationbetweentransfusionofPRBCand
occurrenceofARDSinaprospectivecohortanalysisof102severelyinjuredpatientsrequiring
intubation.56

ThePresentTheGood
Damagecontrolresuscitation

Damagecontrolsurgeryisnowawelldescribedandwidelypracticedconceptintrauma

andemergencygeneralsurgery.Thisstrategyconsistsofimmediatelimitedsurgical
interventionincludingcontrolofhemorrhageandentericspill,temporaryshuntingofcomplex
vascularinjuries,debridementofdevitalizedtissueandtemporaryabdominalclosure,withthe
goalofexpeditedtransfertotheintensivecareunitforphysiologicresuscitation.Definitive

surgicalrepairsarethendeferredfor2472hoursafterresuscitationiscompleteandthe
patientsphysiologyhasbeenstabilized.5760Recently,datafromthetheatresofconflictinIraq
andAfghanistanhavesparkedanewinterestinaggressivebloodbasedresuscitationfor
hemorrhagicshock.68,6164Thisconceptofdamagecontrolresuscitationconsistsof
resuscitationfromhemorrhagicshockwithpackedredbloodcells,freshfrozenplasmaand
plateletsinratiosapproachingthecompositionofwholeblood.7,9,62,65Infact,severalreports
frommilitarysurgeonsinthecombattheatredescribedthesafeandefficacioususeofdonated
freshwholeblood,primarilydrivenbyshortagesofbloodproductcomponents.6,8,64,65Theuse
ofisotoniccrystalloidsolution,themainstayoftraumaticvolumeresuscitationsincethe
VietnamWar,isminimized.
AdvocatedbyHolcomb,amongothers,thedrivingthoughtprocessbehinddamage
controlresuscitationistoaddresstheearlycoagulopathyoftraumathoughttobeattributedto
thedilutionofclottingfactorsbyresuscitationwithcrystalloidsolutionsandpackedredblood
cells,compoundedwithhypothermiaandacidosis.9,66,67Datafrombothcivilianandmilitary
literaturehaveshownthatthelethaltriadofcoagulopathy,hypothermiaandacidosisafter
injuryisassociatedwithincreasedmortality.9,63,68Inanefforttoevaluatetheconceptof
damagecontrolresuscitation,Borgmanandcolleaguesperformedaretrospectivecohort
analysisof246traumapatientsadmittedovera2yearperiodtoacombatsupporthospitalin
Iraq.Theyreportedthatinpatientsrequiringmorethan10unitsofPRBCovera24hour
period,thosereceivingahighratioofplasmatopackedredbloodcells(median1:1.4)had
significantlylowerratesofoverall(19%vs.65%)andhemorrhagerelatedmortality(37%vs.
92.5%)comparedtothosewithlowerratios(median1:8).6Afterimplementationofdamage

controlresuscitationclinicalpracticeguidelinesinIraqin2006,FoxandHolcombperformeda
retrospectivecohortanalysiscomparingoutcomesinpatientsrequiringextremity
revascularizationbeforeandafterinitiationoftheprotocol.Theyfoundthatwhilethetwo
cohortsweresimilarwithregardstoinjuryseverityandphysiologicparameters,patients
resuscitatedafterimplementationofthedamagecontrolresuscitationguidelineshadmore
completepostoperativephysiologicrecoveryasmeasuredbypostoperativeheartrate,
systolicbloodpressure,basedeficitandinternationalnormalizedratio(INR).62

Followingcloselyinthefootstepsofthemilitary,civiliantraumacentershavealsonow

startedtoreportonoutcomesafterinitiatingtheirowndamagecontrolresuscitationprotocols.
Afterimplementingchangesintheirmassivetransfusionprotocolstoadopttheconceptof
damagecontrolresuscitation,Cottonalsoperformedaretrospectivehistoricalcohortanalysis
tocompareoutcomesbeforeandafterinitiationofthedamagecontrolresuscitationprotocol.
Theyfoundthatpatientsresuscitatedundertheirtraumaexanguinationprotocol,whileusing
moreintraoperativebloodproductsandlesscrystalloidsolution,hadsignificantlylower
amountsoftotal24hourbloodproductutilization(31.2vs.38.7Units).Theseseverelyinjured
patientsalsohadsignificantlylower30daymortality(37.6%vs.56.8%),aswellaslowerrates
ofcomplicationsthoughttobecausedbydysfunctionalinflammationincludingabdominal
compartmentsyndrome(0%vs.9.9%),sepsis(10.0%vs.19.8%),ventilatorassociated
pneumonia(27.2%vs.39.0%),andmultipleorgandysfunction(15.6%vs.37.2%).69

TheFutureTheUnknown

Limitationsofexistingoutcomesdata

Thelargebodyofliteraturedescribedabovehasclearlyshownanassociationofblood

productadministrationafterinjurywithadverseoutcomessuchasmultipleorganfailureand
death.However,therearesignificantlimitationstotheseobservationalstudiesthatpreclude
theassumptionthatbloodproductsaretheactualcausativefactorforthesepooroutcomes.
Manyofthestudieslinkingbloodproducttransfusiontotheseoutcomesfailedtocontrolfor
oneormoreobviousconfoundingfactorssuchasseverityofshock,injuryorillnessseverityand
patientage.18,23,31,3337,51,70Whilethemostprominentstudieshaveutilizedadvanced
multivariatestatisticalanalysestoattempttocontrolfortheseobviousconfounders,thereisno
waytoaccountforunknownorunmeasuredconfounderswhichcouldhaveasignificanteffect
onoutcomesinthesetypeofobservationalstudies.Consistently,indicesofshockseveritysuch
asbasedeficitandlactateareamongthestrongestriskfactorsassociatedwithoutcomessuch
asmortalityandmultipleorganfailure.However,inmanyofthesestudiesthereisasignificant
amountofmissingdatafortheseshockindicatorsandthetimingoftheirmeasurementis
highlyvariable.5254Additionally,themethodsutilizedtodealwithmissingdatainseveralof
thesestudiesaredebatableandthecombinationofthesefactorscouldhaveleadtobiased
results.21,5254Also,thesestudiesfailtocontrolforothercomponentsutilizedinvolume
resuscitationsuchascrystalloidandcolloid.Thismakesitimpossibletodetermineifblood
productsaretrulycausativefactorsoftheseadverseoutcomesastheirusemaymerelybean
indicatorofthosepatientswithincreasedresuscitationrequirements.Finally,whilestatistically
significant,theoddsratiosforbloodproductsasapredictiveriskfactorarerelativelymodest,
andmuchtoosmalltodrawcausativeconclusionsfromthesetypesofobservationalstudies.

Analysesoflargemultiinstitutionalprospectivecohortstudiessuchasthetraumagluegrant
(InflammationandtheHostResponsetoInjury)andPROMMTT(ProspectiveObservational
MulticenterMassiveTransfusionsTudy)studygroupswillhopefullybeabletomore
comprehensivelyteaseaparttheserelationships.

Leukoreduction

Overthepastdecadetherehasbeenmuchinterestinwhetherornotprestorage

leukoreductionofpackedredbloodcellsimprovesoutcomesintraumapatientsrequiring
transfusion.Levelsofinflammatorymediatorssuchasbioactivelipidsandcytokineshavebeen
foundtoincreaseafterroutinebloodproductstorage.71,72Thesefindingsledsometo
hypothesizethatmediatorsreleasedfromresidualleukocytesmayberesponsibleforthe
detrimentalimmunologicsequelaeassociatedwithtransfusionofpackedredbloodcells.
Leukoreductionhasbeenshowntosignificantlyreducebioactivelipids,cytokines,andto
attenuateprimingofrecipientneutrophils.73,74However,observationalstudiesassessinghow
theselaboratoryfindingstranslatetoclinicaloutcomessuchasARDS,infectiouscomplication,
multipleorgandysfunctionandmortalityhaveyieldedmixedresults.7579Theonlyrandomized
controlledtrialofleukoreducedbloodtransfusionintraumapatientsfoundnodifferenceon
incidenceofinfectiouscomplicationswithin28daysofinjury.80Whilethedebateover
whetherleukoreductionimprovesoutcomesremainscontentious,itmaybemootintheUnited
Statesgiventhetrendtowarduniversalleukoreduction.In2006thepercentageof

leukoreducedwholebloodandPRBCunitstransfusedwasreportedatgreaterthan70%and
continuesonanupwardtrend.10

Bloodstorageage

Thetimebloodproductsremaininstoragepriortotransfusionhasalsobeenanareaof

recentinterest.Severalobservationalstudieshaverevealedanassociationbetweenpacked
redbloodcellsthathavebeenstoredlongerthan14to28dayswithworseoutcomesafter
injury,includinginfection,multipleorganfailure,increasedICUlengthofstay,andmortality.81
84

Aleadinghypothesiswasthatthiswasprimarilyduetoreleaseofinflammatorymediators

fromresidualleukocytes.Recently,Weinbergreportedresultsonaretrospectivecohortstudy
of2,062transfusedtraumapatientsthatsuggeststheremaybeothermechanismsinvolved.
Theyfoundthatovera7.5yearperiodthatPRBCunitsstored14daysorlongerremaineda
significantpredictorofmortalitydespiteuniversalleukoreduction.85Thissuggeststhatthere
arefactorswithinstoredbloodproductsotherthanleukocyticmediatorswhichmayhave
detrimentaleffectsonclinicaloutcomes.Prospectiveinterventionalstudiesarenecessaryto
determinewhethertheutilizationoffreshlycollectedbloodproductseffectsoutcomesin
injuredpatientsrequiringtransfusion.

ComponentRatios&wholebloodutilization

Whiletheoverallconceptofbloodbaseddamagecontrolresuscitationisbecoming

accepted,theoptimalratioofbloodproductcomponentsutilizedintheseprotocolsisstill
widelydebated,andundercontinuinginvestigation.Asmentionedpreviously,recentmilitary
datahasreportedthattheutilizationofbloodproductcomponentresuscitationinratios
approachingthatofwholebloodwasfoundtobeassociatedwithimprovedoutcomes.69,64
Holcombfoundsimilarresultsinaretrospectiveanalysisof466injuredpatientsat16LevelI
civiliantraumacentersreceivingmassivetransfusion(>10UnitsPRBC1st24hrs.).Inthisstudy
bothplasmaandplatelettoPRBCratioswereclassifiedaseitherlow(<1:2)orhigh(1:2).
Shownbysurvivalanalysis,patientswithhighFFP:PRBCandhighplatelet:PRBCratioshad
significantlyhigher24hourand30daysurvivalratesthanthosewithlowFFPandplateletto
PRBCratios.86Otherauthorshavehadsimilarfindingsinsubsequentretrospectivestudies.
Zinkandcolleaguesreportedina6yearsingleinstitutionreviewthathigher6hourratiosof
FFP:PRBCandplatelet:PRBCratioswasassociatedwithimproved6hourandinhospital
mortality.87Inanotherlargemulticenterretrospectiveanalysis,Teixeirareportedthatin
patientsreceiving>10unitsPRBCs,mortalitydecreasedsignificantlywithincreasedratioof
FFP:PRBC.However,theyfailedtofindanyadditionalsurvivaladvantageonceaFFP:PRBCratio
of1:3wasreached.88ThepreviouslymentionedPROMMTTstudywillhopefullyyielddatato
builduponthecurrentretrospectiveliteratureandbethefoundationforcontrolledclinical
trialsinthisarea.

Giventhatratiosofbloodproductsapproachingwholebloodareassociatedwith

improvedoutcomes,alogicalnextstepisconsiderationofwholebloodresuscitation.The
militaryhashadsignificantinterestinthisareagivenacommonsituationoflimitedcomponent

supplyinthemidstofmasscasualtyscenarios.Recently,Spinellareportedthataretrospective
analysisofcombatcasualtiesbetween2004and2007requiringtransfusionrevealedthat
patientsreceivingwarmfreshwholebloodinadditiontocomponenttherapywereassociated
withimproved24hourand30daysurvivalcomparedtothosereceivingcomponenttherapy
alone.8Proponentsarguethatutilizationoffreshwholebloodmayallowforefficient
correctionofcoagulopathywhileminimizingtheamountoftransfusionofcomponentswith
advancedstorageage.Whilethistypeofutilizationofwholebloodappearsadvantageousat
multiplelevelstherearestillmanyoutstandingissuesregardingsafetyandfeasibilitywhich
needtobeaddressedbeforeitsutilizationcanbetransferredtothecivilianrealm.Civilian
bloodbanksandtraumacenterswouldrequireasignificantinvestmentincapital,personnel
anddonorrecruitmenttodealwithissuessuchasrapidinfectiousdiseasescreening.
Significantadvancementsinstoragetechnologyanddonorrecruitmenttomaintainsupply
wouldalsoberequiredgiventhecurrent72houraveragestoragelifeoffreshwholeblood.

LogisticalConstraints&Utilization

Limitedsupply,logisticalconstraintsincomponentproductionandstorage,and

increasingcosts,havecomplicatedtheutilizationofbloodproductsbothhistoricallyandinthe
presentera.Ingeneral,overallbloodcomponentdemandisgreaterthanavailablesupply.
Whilebloodcollectionsareincreasing,between2000and2006approximate10%ofhospitalsin
theUnitedStatesreportedhavingtocancelelectivesurgeriesatsecondarytobloodbank
inventoryshortages.10MosturbanLevelOnetraumacentershaveprotocolsinplacekeeping

sufficientproductavailableforroutineemergentuse.Situationsofmasscasualtyorfacilitiesin
moreaustereenvironmentscanmaketheuseofanytypeofbloodproductproblematic.As
mentionedpreviously,combatsupporthospitalsinIraqandAfghanistanhavehadtoresortto
theuseoffreshlydonatedwholebloodwhendemandoutstripssupplyorcomponentproducts
areunavailable.64Inthecurrentareaoffiscallyconsciousmedicine,costsremainalegitimate
concern.In2006thereportedmeanamountpaidperunitofPRBC($213.94)increased
approximately6%whileaverageCMSreimbursementcoveredonly76%ofthesecosts.10As
mentionedpreviously,thelogisticalissuessurroundingpossibleutilizationoffreshwholeblood
intraumaresuscitationprotocolsareevenmorecomplex.Theimpactofcostandavailabilityof
allallogenicbloodproductsonthefeasibilityoffuturebloodbasedtraumaresuscitation
protocolsisyettobedetermined.

Hemoglobinsubstitutes

Withinthepast10yearstherehasbeenasignificantamountofexcitementand

enthusiasmforthepotentialuseofhemoglobinbasedoxygencarriers(HBOCs)asan
alternativetopackedredbloodcellstorestoreoxygencarryingcapacityafterhemorrhage.
Solutionscontainingpolymerizedpurifiedhumanhemoglobin(PolyHeme;Northfield
Laboratories,Inc.,Evanston,Illinois)andglutaraldehydecrosslinkedbovinehemoglobin
(HBOC201;BiopureCorporation,Cambridge,Massachusetts)havebeenthemostthoroughly
studiedoftheseagents.Thesesyntheticmoleculeshaveseveralpotentialtheoretical
advantagesoverhumanallogenicPRBCs.Theseincludetheavoidanceofinfectiousparticle

transmission,eliminationoftheneedforbloodtypingorcrossmatchpriortoadministration,
andalackofantigenicstimulusandpotentialimmunomodulationassociatedwithblood
transfusion.Theseformulationsalsohavethepotentialtobeeasilystoredforextended
periodsoftimeandcanbeimmediatelyavailableforuse.
However,thusfarresultsfromclinicaltrialsevaluatingtheseagentshavenotlivedupto
expectationsandconcernshavebeenraisedaboutseveralpotentialadverseeffects.Results
fromamulticenterphaseIIIclinicaltrialcomparingaPolyheme/crystalloidtoa
PRBC/crystalloidbasedinitialresuscitationprotocolfoundnosignificantdifferenceintheir
primaryendpointof30daymortality.89AlthoughtotalallogenicPRBCusewaslowerinthe
Polyhemegroup,MOFratesweresimilarbetweenthetwogroupsandseriousadversecardiac
eventsappearedtobegreaterinthePolyhemegroup.
AlthoughseveralanimalstudiesshowedpromisefortheutilizationofHBOC201after
hemorrhagicshock,resultsfromhumantrialshaveraisedconcernsaboutincreasesinsystemic
vascularandpulmonaryresistanceafteradministrationofthisagent.90Arecentmetaanalysis
of16randomizedcontrolledtrialsenrollingacombinationofsurgical,strokeandtrauma
patientsreinforcedtheseconcernsafterfindingasignificantlyincreasedriskofmortalityor
myocardialinfarctionassociatedwithHBOCadministration.91TheuseofHBOCsmaystillplaya
roleinaustereenvironmentsorsituationswherebloodproductsareunavailable,butfurther
technicaladvancementsandmorerobustclinicaldataisrequiredbeforeroutineallogenic
bloodproductuseissupplantedbythistechnology.

Conclusions

Theroleofbloodproducttherapyinresuscitationfromhemorrhagicshockcontinuesto

evolve.Resultsfromrecentdamagecontrolresuscitationprotocolsutilizingearlyand
aggressiveofbloodcomponenttherapyinratiosapproachingtheconsistencyofwholebloodto
combatearlytraumaassociatedcoagulopathyappearpromising.However,concernslinger
regardingthepossibleadverseeffectsassociatedwithbloodproductadministration.
Continuinginvestigationintothisareawillberequiredtodeterminewhetherornotblood
productsaretheactualcausativefactorleadingtoadverseoutcomessuchasinfectious
complicationsandmultipleorgandysfunction.Whiledevelopmentofbloodproduct
alternativessuchashemoglobinbasedoxygencarrierscontinues,theirroleinresuscitationof
thetraumapatientisyettobedefinedanditwillbesometimebeforetheirusebecomes
widespread.Althoughpromising,clinicaltrialsdeterminingtheefficacyofearlybloodbased
resuscitationfromhemorrhagicshockwillberequiredtofullydetermineitsroleinthecareof
theseverelyinjuredtraumapatient.


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