DTIC ADA480289: Fresh Frozen Plasma Should be Given Earlier to Patients Requiring Massive Transfusion

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TheJournalofTRAUMA(cid:1)Injury,Infection,andCriticalCare
Fresh Frozen Plasma Should be Given Earlier to Patients
Requiring Massive Transfusion
Ernest A. Gonzalez, MD, Frederick A. Moore, MD, John B. Holcomb, MD, Charles C. Miller, PhD,
Rosemary A. Kozar, MD, PhD, S. Rob Todd, MD, Christine S. Cocanour, MD, Bjorn C. Balldin, MD,
and Bruce A. McKinley, PhD
Background: Acidosis, hypothermia, 2003)andresuscitatedusingourstandardized 1.4 (cid:1) 0.03 within 8 hours and remained
andcoagulopathywereidentifiedmorethan ICU shock resuscitation protocol received nearly constant for the remaining 16
20 years ago as a deadly triad for patients MT (>10 units packed red blood cells hours of ICU resuscitation, indicating
presenting with exsanguinating hemorrhage. [PRBC]) during hospital day 1 (age, moderatecoagulopathy.Statisticalanal-
This led to fundamental changes in initial 39(cid:1)2;ISS,29(cid:1)1;survival,70%.)All ysis found severity of coagulopathy
managementofseverelyinjuredpatients.De- patients required emergency operating (INR) at ICU admission associated with
spitemajoradvances,hemorrhageremainsa room and/or interventional radiology survival outcome (p (cid:2) 0.02; area under
leading cause of early death in trauma pa- proceduresandarrivedintheICU6.8(cid:1) receiver operator curve [ROC] (cid:2) 0.71.)
tients.Recentstudiesreportmostseverely 0.3 hours after admission. Coagulopa- Conclusion:These data indicate aci-
injuredpatientstobecoagulopathicatadmis- thy, present at hospital admission (pre- dosisandhypothermiatobewellmanaged.
sion, before resuscitation interventions, and ICU INR, 1.8 (cid:1) 0.2), persisted at ICU CoagulopathywasnotcorrectedintheICU
that traditional massive transfusion practice admission (initial ICU INR, 1.6 (cid:1) 0.1). despiteadherencetopre-ICUMTandICU
grosslyunderestimatesneeds.Thehypothesis Pre-ICU resuscitation, 9 (cid:1) 1 L crystal- protocols,likelybecauseofinadequatepre-
for this study is that our pre-intensive care loid fluid, 12 (cid:1) 1 units PRBC, 5 (cid:1) 0.4 ICUintervention.Moreaggressivepre-ICU
unit(ICU)massivetransfusion(MT)protocol units fresh frozen plasma (FFP), was interventiontocorrectcoagulopathymaybe
doesnotadequatelycorrectcoagulopathy,and consistent with our MT protocol by effective in decreasing PRBC requirement
thatearlyuncorrectedcoagulopathyispredic- which FFP was not given until after 6 during ICU resuscitation, and, because of
tiveofmortality. units PRBC. ICU resuscitation involved the association with increased mortality,
Methods: Data maintained in our 11(cid:1)1LlactatedRinger’ssolution(LR) could improve outcome. We have revised
TraumaResearchDatabasewerereviewed. and 10 (cid:1) 1 units PRBC. Mean pH was our pre-ICU MT protocol to emphasize
Univariate logistic regression analysis was normal within 8 hours. Mean tempera- earlyFFPinaFFP:PRBCratioof1:1.We
usedtoanalyzetheassociationofearlyICU ture increased from (cid:1)35 °C to >37 °C thinkthattreatmentofcoagulopathycanbe
international normalized ratio (INR) and within4hours.IntheICUduringresus- improved with the development of stan-
outcomes,includingsurvival. citation, patients received 10 (cid:1) 1 units dardized protocols, both empiric and data
Results: Ninety-seven of 200 patients FFPforcoagulopathy;theratioofFFP: driven.
admittedduring51months(endingJanuary PRBC was 1:1. Mean INR decreased to
JTrauma.2007;62:112–119.
A
cidosis,hypothermia,andcoagulopathywereidentified spreadrecognitionprovidedtobearationaleforfundamental
more than 20 years ago as a deadly triad for patients changesintheinitialmanagementofseverelyinjuredpatients
presenting with exsanguinating hemorrhage.1 Wide who present with exsanguinating hemorrhage. Regional
traumasystemsnowtriagethesecriticallyinjuredpatientsto
Level I trauma centers, where prevention of hypothermia,
SubmittedforpublicationMarch31,2006.
damagecontrolsurgery,massivetransfusion(MT)protocols,
AcceptedforpublicationOctober6,2006.
and early intensive care unit (ICU) triage for optimized re-
Copyright©2007byLippincottWilliams&Wilkins,Inc.
From the Department of Surgery, University of Texas Houston Medical suscitation are standards of care. Despite these major ad-
School(E.A.G.,F.A.M.,C.C.M.,R.A.K.,S.R.T.,C.S.C.,B.C.B.,B.A.M.),andthe vances,hemorrhageremainsaleadingcauseofearlydeathin
USArmyInstituteofSurgicalResearch(J.B.H.),FortSam,Houston,Texas. both civilian trauma and military combat casualty care.2
PresentaddressforF.A.M.,S.R.T.,B.A.M.:TheMethodistHospital,
Recognizing that acidosis, hypothermia, and coagulopathy
DepartmentofSurgery,DivisionofSurgicalCriticalCareandAcuteSur-
are physiologic derangements likely to complicate early man-
gery,HoustonTX.
SupportedbyNIGMSGrantsP50-GM38529andT32-GM008792. agement of severely injured patients, we prospectively record
Presentedatthe65thAnnualMeetingoftheWesternTraumaAssoci- variables describing these potential complications in high-risk
ation,February26–March3,2006,BigSky,Montana.
patientsaspartofstandardizedICUshockresuscitation.Aspart
Addressforreprints:BruceAMcKinley,PhD,TheMethodistHospital,
of ongoing performance improvement, we implemented a for-
DepartmentofSurgery,DivisionofSurgicalCriticalCareandAcuteSur-
gery, 6550 Fannin Street, Smith Tower 1661, Houston, TX 77030; email: malMTprotocolinthelate1990s.Ourprotocolwastotransfuse
[email protected]. freshfrozenplasma(FFP)afterthepatienthadreceived6units
DOI:10.1097/01.ta.0000250497.08101.8b ofpackedredbloodcells(PRBC).3Thisdelayinadministering
112 January2007
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MAR 2006 2. REPORT TYPE 00-00-2006 to 00-00-2006
4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER
Fresh Frozen Plasma Should be Given Earlier to Patients Requiring
5b. GRANT NUMBER
Massive Transfusion
5c. PROGRAM ELEMENT NUMBER
6. AUTHOR(S) 5d. PROJECT NUMBER
5e. TASK NUMBER
5f. WORK UNIT NUMBER
7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION
U.S. Army Institute of Surgical Research (USAISR),3400 Rawley E. REPORT NUMBER
Chambers Avenue,Fort Sam Houston ,TX,78234-6315
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Standard Form 298 (Rev. 8-98)
Prescribed by ANSI Std Z39-18
EarlyFFPtoMassiveTransfusionTraumaPatients
FFPisstandardofcareinmanyUStraumacenters,andisbased continuous cardiac output monitoring capability and an arte-
on the traditionally held belief that posttraumatic coagulopathy rial catheter were placed. Hemoglobin concentration ([Hb])
develops over time because of acidosis-, hypothermia-, and was monitored at bedside using a point-of-care analyzer
resuscitation-relatedhemodilutionandconsumptionoffactors. (HemoCue;HemoCueInc,LakeForest,Calif.).[Hb],cardiac
Recent studies challenge this traditional thought and re- index(CI),andpulmonarycapillarywedgepressure(PCWP)
port that most severely injured patients are coagulopathic at were the key measurement variables that were used to guide
emergencydepartment(ED)admissionandbeforeaggressive protocol logic. The process involves maintenance of oxygen
resuscitationinterventions.4–6Hirshbergetal.7describedde- deliveryindex(DO I)(cid:1)500mL/min-m2((cid:1)600mL/min-m2
2
velopment of coagulopathy in trauma patients using a com- before January 2001) with interventions of PRBC if [Hb] (cid:2)
puter model with data from patients at Ben Taub Hospital 10g/dLandDO I(cid:2)500;crystalloidfluidbolus(1LLR)if
2
(Houston,TX).Therationaleforacomputermodelwastheir [Hb](cid:1)10,PCWP(cid:2)15mmHg,andDO I(cid:2)500;PCWP-CI
2
observation that previous hemodilution models used to de- optimization (“Starling curve”) if [Hb] (cid:1) 10, PCWP (cid:1) 15,
velop recommendations for MT grossly underestimate clot- and DO I (cid:2) 500; inotrope infusion (milrinone) if PCWP-CI
2
ting factor needs, and that MT protocols based on these optimized, [Hb] (cid:1) 10, PCWP (cid:1) 15, and DO I (cid:2) 500; and
2
earliermodelswerevalidatedinthe1980swhenwholeblood vasopressor infusion (norepinephrine) if inotrope infusion
transfusion(notPRBCandcomponenttherapy)wasstandard ongoing, PCWP-CI optimized, Hb (cid:1) 10, PCWP (cid:1) 15,
of care. In their analysis, they identified that (1) early pro- DO I(cid:2)500andmeanarterialpressure(cid:2)60.Thisstandard-
2
longation of prothrombin time (PT) is the sentinel event; (2) ized shock resuscitation protocol directs the above interven-
early administration of FFP is key in preventing coagulopa- tions during the first ICU day. Data describing acidosis,
thy; and (3) the optimal replacement ratio of FFP:PRBC is hypothermia, and coagulopathy were obtained prospectively
2:3.Theyrecommendthat2unitsFFPbegivenwiththefirst asapartofthisprocess.Atthestartoftheshockresuscitation
unit of PRBC in patients who are at high risk of requiring protocol, baseline body core temperature (T), arterial blood
MT. After this report and similar observations at our trauma gas, and coagulation profile comprising PT, international
center by intensive care fellows with previous military com- normalized ratio (INR), platelet count ([plt]), partial throm-
batcasualtyexperience,weundertookthisstudytoascertain boplastin time (PTT), and fibrinogen concentration ([fib])
whetherourstandardofcareMTprotocolshouldbechanged. wereobtainedandrepeatedevery4hoursforthedurationof
Based on recently published data, we hypothesize that our the 24 hour process. Additional data characterizing the pre-
MT protocol does not adequately prevent or correct coagu- ICU course were recorded retrospectively, and these data
lopathy,andthatearlyuncorrectedcoagulopathyispredictive were recorded in a Trauma Research Database. The Trauma
of mortality. Research Database is maintained with approval of the Com-
mittee for the Protection of Human Subjects (Institutional
METHODS Review Board) of the University of Texas Health Science
High-risk patients who were admitted to the Shock Center at Houston.
TraumaICUatMemorialHermannHospital(LevelIregional Althoughpreventionand/ortreatmentofacidosis,hypo-
traumacenterservingsoutheastTexasandapopulationof(cid:1)4 thermia, and coagulopathy were recognized as an important
million) and who met specific criteria underwent a 24-hour adjunctofshockresuscitationduringthedevelopmentofthat
standardizedshockresuscitationprocessdirectedbycomput- protocol, these aspects of care were not rigorously managed
erized decision support. This protocol has been described bycomputerizeddecisionsupport.AsspecifiedbyourLevel
previously.8–10 Data describing the patients’ clinical course I Trauma Center standards of care, documentation and pre-
andresuscitationprocesswereobtainedprospectively.Crite- vention of hypothermia began by measuring T in the ED
riafortheresuscitationprotocolwere(1)majortorsotrauma, using a urinary catheter T sensor and, after initial trauma
defined as injury of two or more abdominal organs, two or evaluationwascomplete,theexposedbodywascoveredwith
morelongbonefractures,complexpelvicfracture,flailchest, warmedblanketsandfluids,andbloodproductswereinfused
ormajorvascularinjury;(2)metabolicstress,definedasbase viafluidwarmingdevices(e.g.,LevelIfluidinfusor).Inthe
deficit (BD) (cid:1) 6 mEq/L within 12 hours of hospital admis- operatingroom(OR),forcedwarmairblankets(BairHugger,
sion;and(3)anticipatedtransfusionrequirementof(cid:1)6units Arizant Healthcare Inc, Eden Prairie, MN) were applied, the
PRBCs within 12 hours of hospital admission, or age (cid:1) 65 headwascoveredwithaheatreflectingcap,andmechanical
yearswithanytwoofthethreepreviouscriteria.Patientswith ventilation was provided with warm (38° C), humidified air.
these criteria who also incurred severe brain injury, defined Fluid warmers (e.g., Level I fluid infusor) were also used
asGlasgowComaScalescore(cid:2)8intheICUandabnormal together with these interventions in the ICU as needed to
brain computed tomography scan finding, were not resusci- normalize T. T data in the ICU were obtained prospectively
tated by this standardized protocol unless the patient’s brain using the pulmonary artery catheter. Acidosis was managed
injury was assessed by the attending neurosurgeon to be at by resuscitation and mechanical ventilation. Patients requir-
lowriskofworseningcerebraledemawithcrystalloidvolume ing shock resuscitation were intubated and ventilated to nor-
loading.AtICUadmission,apulmonaryarterycatheterwith malize PaCO2. Metabolic acidosis responded to resuscitation
Volume 62 • Number 1 113
TheJournalofTRAUMA(cid:1)Injury,Infection,andCriticalCare
interventions and was not specifically treated with intrave- RESULTS
nous buffer administration. We did not advocate sodium Duringa51monthperiodendingJanuary2003,97patients
bicarbonate therapy in the ED, OR, or ICU unless arterial were resuscitated using our ICU protocol and received MT.
pH(cid:2)7.20.Ourresponsetocoagulopathyinpre-ICUsettings Table 1 depicts the cohort as severely injured (Injury Severity
was according to an empiric MT protocol that was initiated Score [ISS], 29 (cid:4) 1); relatively young (age, 39 (cid:4) 2 years);
bythetraumasurgeon.After6unitsPRBCweretransfusedin mostly men (62%) who predominantly incurred blunt injury
ED, OR, or interventional radiology facilities, the hospital (73%);anddemonstratingshockathospitaladmission(EDBD,
blood bank was notified. The blood bank then sent 6 units 10 (cid:4) 1 mEq/L). All patients required emergency OR and/or
PRBC and 4 units FFP in an insulated container, and these interventionalradiologyproceduresandarrivedattheICU6.8(cid:4)
components were transfused upon receipt and type/cross 0.3hoursafterEDadmission.AtstartofICUresuscitation,BD
match check. After these components were given, additional was7(cid:4)1mEq/L.Ofnote,coagulopathywaspresentathospital
admission (ED INR, 1.8 (cid:4) 0.2). In the ED, INR was obtained
containerswereprovidedbythebloodbankasneededwith6
for77(79%)ofthesepatientsand,ofthese,57patients(74%)
units PRBC, 6 units FFP, and a number of platelet 6-packs
had INR (cid:3) 1.2. At ICU admission, INR was obtained for all
equal to the number of 12 unit quantities of PRBC that had
patients; INR was (cid:3) 1.2 in 82 patients (85%). Comparison of
been transfused, and these components were transfused.
‘lived’ and ‘died’ subgroups showed that only severity of co-
When the patient arrived in the Shock Trauma ICU, this
agulopathy at ICU admission, indicated as INR, differed (p (cid:2)
empiric protocol was stopped by the bedside ICU physician.
0.05;seeTable1).EDINRof‘lived’and‘died’subgroupswere
Component therapy (FFP, plt, cryoprecipitate) were admin-
notsignificantlydifferent.Pre-ICUresuscitationincluded12(cid:4)
istered to correct abnormal PT and maintain [plt] (cid:1)100
1unitsPRBC,9(cid:4)1Lcrystalloidfluid,and5(cid:4)0.4unitsFFP.
kcells/mm3. Before 2002, this was done at the discretion of
ThisisconsistentwiththeMTprotocolbywhichFFPwasnot
the Shock Trauma ICU critical care team. Typically, FFP (2
givenuntilafter6unitsPRBC,andthefirstbloodbankresponse
units), plt (6 pack), and/or cryoprecipitate (10 pack) were
given and coagulation measurements were rechecked. In
2002, we began development of a rule-based, data-driven Table 1 Description of Shock Resuscitation Massive
protocol for coagulopathy prevention and correction in the Transfusion Cohort* (†p < 0.05)
shock Trauma ICU, and implemented this at bedside as a
All Lived Died
paper protocol to more rigorously control this process of
care.6 For purposes of this protocol, we chose INR (cid:3) 1.3 as Number 97 68 29
Age(yr) 39(cid:4)2 38(cid:4)2 42(cid:4)3
a threshold for FFP administration to correct coagulopathy
Men(n(cid:5)%(cid:6)) 61(62) 39(40) 22(23)
during shock resuscitation of the actively bleeding patient. ISS 29(cid:4)1 28(cid:4)1 32(cid:4)2
For purposes of this study, we defined coagulopathy as INR Bluntmech(n(cid:5)%(cid:6)) 71(73) 48(50) 23(24)
(cid:3)1.2, moderate coagulopathy as 1.4 (cid:2) INR (cid:2) 1.8, and EDINR 1.8(cid:4)0.2 1.9(cid:4)0.2 1.5(cid:4)0.1
severe coagulopathy as INR (cid:3) 1.8. EDBD(mEq/L) 10(cid:4)1 10(cid:4)1 11(cid:4)1
Pre-ICUcrys(L) 9(cid:4)1 8(cid:4)1 11(cid:4)3
During the 51 months ending January 2003, there were Pre-ICUPRBC(unit) 12(cid:4)1 11(cid:4)1 13(cid:4)2
200 shock resuscitation protocol patients, of which 97 re- Pre-ICUFFP(unit) 5(cid:4)0.4 6(cid:4)1 4(cid:4)0.4
ceivedMT,definedas(cid:1)10unitsPRBCinthefirst24hospital IRembolization(n(cid:5)%(cid:6)) 16(17) 10(10) 6(6)
Emergencysurgery(n(cid:5)%(cid:6)) 94(97) 66(68) 28(29)
hours.DatawereextractedfromtheTraumaResearchDatabase
ICUadmitINR† 1.6(cid:4)0.04 1.5(cid:4)0.1 1.7(cid:4)0.1
forthisstudycohortdescribingdemographics,pre-ICUcourse, ICUadmitBD(mEq/L) 7(cid:4)1 6(cid:4)1 8(cid:4)0.2
ICU resuscitation, and outcomes, with the focus on hypother- ICUadmitT(°C) 35.4(cid:4)0.1 35.4(cid:4)0.2 35.3(cid:4)0.2
mia,acidosis,andcoagulopathy. ICULOS(dg) 13(cid:4)1 15(cid:4)2 9(cid:4)2
Dataarepresentedasmean(cid:4)SEMintablesandfigures. *This cohort comprised of 97 patients. The data presented
Analysisofvariancewasusedtodetectchangesinavariable includeinterventionsbeforeICUadmission.Severityofcoagulopathy
atICUadmission(indicatedasINR)wasgreaterforthesubgroupof
with time. Student’s t tests were used to compare measure-
patientswhodiedthanthesubgroupofpatientswholived(p(cid:2)0.05).
mentsofthesameparametricvariablebetweensubgroups.(cid:3)2
ISS,injuryseverityscore;Bluntmech,bluntmechanismofinjury;
tests were used to compare categorical variables, e.g., the ED INR, international normalized ratio in emergency department at
number of patients in ‘lived’ and ‘died’ subgroups. Coagu- hospitaladmission;EDBD,basedeficitinemergencydepartmentat
hospital admission; pre-ICU crys, crystalloid fluid volume infused
lation variables were analyzed using logistic regression to
fromhospitaltoICUadmission;pre-ICUPRBC,packedredbloodcell
assessassociationofcoagulopathyseverityandsurvivalout-
volume infused from hospital to ICU admission; pre-ICU FFP, fresh
come.Univariatelogisticregressionwasusedtoidentifyrisk frozen plasma volume infused from hospital to ICU admission; IR
factor variables having significant association with survival embolization, interventional radiology embolization procedure; ICU
admitINR,internationalnormalizedratioatICUadmission;ICUadmit
outcome. Analyses were done using SAS software, version
BD,BDinintensivecareunitatadmission;ICUadmitT,bodycore
9.1 SP3 (SAS Institute Inc., Cary, NC). p (cid:2) 0.05 was con-
temperature in intensive care unit at admission; ICU LOS, intensive
sidered significant. careunitlengthofstay.
114 January2007
EarlyFFPtoMassiveTransfusionTraumaPatients
wasacontainerwith4unitsFFPand6unitsPRBC.Forty-nine
patients(51%)received(cid:1)10unitsPRBCduringED,ORand/or
interventional radiology procedures. Mean ICU length of stay
(LOS) was 13 (cid:4) 1 days. Twenty-nine patients (30%) did not
survive hospitalization. Six (6%) died during the 24-hour ICU
resuscitation (three from exsanguination and three from fulmi-
nant early adult respiratory distress syndrome) and four (4%)
diedduringICUday2(twofromexsanguinationandtwofrom
early fulminant adult respiratory distress syndrome). Nineteen
latedeaths(20%)occurredduetomultipleorganfailure/sepsis
(n (cid:7) 11; ICU LOS 15 (cid:4) 3 days), adult respiratory distress
syndrome (n (cid:7) 4; ICU LOS 12 (cid:4) 5 days), withdrawal of
support(n(cid:7)3;ICULOS20(cid:4)4days),andpulmonaryembolus
(n(cid:7)1;ICULOS,22days).Abdominalcompartmentsyndrome
occurred in seven of the patients who died. Overall, 5 of 29
deaths (17%) were due to hemorrhage during the first two
hospital days. This subgroup with early death caused by hem-
orrhage did not differ from the overall group in ISS, ED INR,
Fig. 2. (A) Acidosis (arterial pH, base deficit [BD]) response to
pre-ICUcrystalloidfluid,PRBCorFFPvolume,orEDtoICU
standardized ICU shock resuscitation, showing normalization
admittime;however,theydidhavepre-ICU[Hb]lessthan[pre
ICU[Hb](cid:7)7.0(cid:4)1.1v10.3(cid:4)0.3g/dL(p(cid:2)0.05)]andinitial withinthefirst8hoursintheICU.(B)Coretemperature(T)during
ICUINRgreaterthan[initialICUINR(cid:7)2.1(cid:4)0.2versus1.6(cid:4) resuscitation,indicatingnearnormaltemperatureatICUadmission
0.04(p(cid:2)0.05)]thatoftheoverallgroup;indicatingworsening andrapidwarmingtoT(cid:3)37°Cduringthefirst4hoursintheICU.
coagulopathy during pre-ICU procedures for reasons that are
unclearfromclinicaldata. Coagulation data during ICU resuscitation are shown in
Figure 1 summarizes ICU resuscitation interventions. All Figures3(INR,PTT)and4([plt],[fib]).AtthestartofICU
patientsreceivedLRandPRBC.Totalvolumeswere11(cid:4)1L resuscitation, (cid:1)7 hours after hospital admission, moderate
LRand10(cid:4)1unitsPRBC.Twenty-sixpatients(27%)received coagulopathy persisted with INR (1.6 (cid:4) 0.1). At the start of
(cid:1)10 units PRBC during ICU resuscitation. Figure 2 shows ICU resuscitation, INR was (cid:3)1.2 in 74 patients (76%) and
arterial pH and BD during ICU resuscitation. Severe acidosis INRwas(cid:1)1.4in55patients(57%).MeanINRdecreasedto
wascommonatthestartofresuscitation,with7.00(cid:2)pH(cid:2)7.20 1.4 (cid:4) 0.03 within 8 hours and remained nearly constant for
in26(27%)patientsandpH(cid:2)7.00in3patients(2%),and8(cid:2) the remaining 16 hours of ICU resuscitation. PTT was 58 (cid:4)
BD (cid:2) 10 in 25 patients (26%) and BD (cid:3) 10 in 25 patients 4secatthestartanddecreasedtoastableplateauof36(cid:4)1
(26%).BothmeanpHandBDwerewithinnormalrangewithin sec within 12 hours during resuscitation. [plt] was 95 (cid:4) 9
8 hours. Figure 2 also shows T during ICU resuscitation. Of kcells/mm3 at the start and, with the exception of a transient
note, hypothermia was not a significant problem. At ICU ad- increase between 4 and 12 hours, tended to decrease during
mission, T was 35.4 (cid:4) 0.1 °C, with 32 (cid:2) T (cid:2) 35 °C in 27 resuscitation. Severe thrombocytopenia was uncommon dur-
patients (28%) and T (cid:2) 32 °C in 1 patient (1%). Mean T ing the first 4 hours in the ICU, with 30 (cid:2) [plt] (cid:2) 50
increased rapidly to (cid:3) 37 °C during the first 4 hours, and kcells/mm3in12patients(13%)and[plt](cid:2)30kcells/mm3in
remainednearlyconstantforthedurationofresuscitation. 4 (4%) of these patients. [fib] was 143 (cid:4) 8 at the start and
mean values increased in near linear fashion to 386 (cid:4) 17
mg/dL during resuscitation. During the first 4 hours in the
ICU, [fib] less than normal limits (100 to 450 mg/dL) was
uncommon, with 50 (cid:2) [fib] (cid:2) 80 mg/dL in 11 (11%) and
[fib] (cid:2) 50 mg/dL in 3 (3%) of these patients.
Interventions for coagulopathy during ICU resuscitation
areshowninTable2.FFPwasthemostfrequentintervention
for coagulopathy, and 81 (84%) of these patients received
10 (cid:4) 1 units FFP. Fewer patients (57 [59%]) received plt
componenttherapy.Cryoprecipitatewasgivento20(21%)of
these patients.
Fig. 1. Cumulativevolumesofpackedredbloodcells(PRBC)and In this study cohort, univariate logistic regression anal-
lactated Ringer’s solution (LR) given during ICU day 1 as part of ysisfoundseverityofcoagulopathy(indicatedbyINR)mea-
standardizedshockresuscitationtoattainandmaintainO delivery sured at arrival in the ICU to be associated with survival
2
indexgoal(600mL/min-m2;500afterJanuary2001). outcome (see Table 3; area under ROC, 0.71). Figure 5
Volume 62 • Number 1 115
TheJournalofTRAUMA(cid:1)Injury,Infection,andCriticalCare
Table 2 Interventions for Coagulopathy During
Standardized ICU Shock Resuscitation*
Intervention Patients(n(cid:5)%(cid:6)) Volume†
FFPfirst12ICUhrs 78(80) 8(cid:4)1units
FFPsecond12ICUhrs 43(44) 5(cid:4)1units
pltfirst12ICUhrs 48(50) 3(cid:4)0.46pk
pltsecond12ICUhrs 29(30) 3(cid:4)16pk
cryofirst12ICUhrs 19(20) 2(cid:4)0.410pk
cryosecond12ICUhrs 4(4) 2(cid:4)110pk
*Numberofpatients(majortorsotraumawithexsanguinatinghem-
orrhage) who received intervention for coagulopathy and volumes of
bloodcomponentstransfusedtopatientswhoreceivedeachcompo-
nentinfirstandsecond12hoursofstandardizedICUresuscitation.
†Approximate volume per unit of coagulation factor replace-
mentcomponents:FFP(cid:1)250mL/unit;plt(cid:1)300mL/6pk;cryo(cid:1)120
mL/10pk.
FFP,freshfrozenplasma;plt,platelets;cryo,cryoprecipitate.
Table 3 Potential Risk Factors Tested for Association
With Mortality Using Univariate Logistic Regression*
(†p < 0.05)
Fig. 3. (A)Internationalnormalizedratio(INR)duringICUday1, RiskFactor OR p
indicatingmoderatecoagulopathy(INR,1.6(cid:4)0.1)atICUadmis-
Age 1.02 0.13
sion and incomplete correction (INR, 1.4 (cid:4) 0.03) by the end of Malegender 0.91 0.08
resuscitationandICUday1.(B)Partialthromboplastintime(PTT) ISS 1.03 0.13
during ICU day 1, indicating coagulopathy (PTT, 58 (cid:4) 4 sec) at EDBD(mEq/L) 1.07 0.18
ICUadmissionandincompletecorrection(PTT,36(cid:4)2sec)bythe ICUadmitBD(mEq/L)† 1.14 0.04
EDINR 0.74 0.38
endofresuscitation.
ICUadmitINR† 9.25 0.02
ICUPRBC(unit) 1.03 0.23
ICUFFP(unit) 1.03 0.28
*INRatstartofICUresuscitationearlyafterICUadmission(ICU
admit INR) was found to be predictive of death (area under ROC,
0.71).AssociationwasalsofoundforBDatstartofICUresuscitation
and mortality (ICU admit BD; area under ROC, 0.64), but multivariate
analysisfoundcolinearity,indicatingprobableeffectofacidosisonINR.
OR,oddsratio/unitchangeinriskfactorvariable;p,probabilityofa
type1statisticalerror,ISS,injuryseverityscore;EDBD,basedeficit
inemergencydepartmentathospitaladmission;ICUadmitBD,BDin
intensivecareunitatadmission;EDINR,internationalnormalizedratioin
emergencydepartmentathospitaladmission;ICUadmitINR,INR
in intensive care unit at admission; ICU PRBC, cumulative PRBC
volume transfused in ICU during 24-hour standardized shock re-
suscitation; ICU FFP, cumulative FFP volume transfused in ICU
during24-hourstandardizedshockresuscitation.
depictsthisrelationship,withseverecoagulopathy(INR(cid:1)2.0)
associatedwith(cid:1)50%probabilityofdeath.Anassociationwas
alsofoundforseverityofshockatICUadmission(indicatedby
BD)andmortality(areaunderROC,0.64);however,colinearity
of INR and BD was apparent with multivariate analysis, indi-
catingprobableeffectofacidosisonINR.
Fig. 4. (A) Platelet count ([plt]) during ICU day 1, showing ade- DISCUSSION
quate platelet concentration at ICU admission and maintenance It has long been recognized that the “bloody vicious
(cid:3)85kcells/mm3,buttendencytodecrease.(B)Fibrinogenconcen- cycle” of acidosis, hypothermia, and coagulopathy is an im-
tration ([fib]) during ICU day 1, showing uniform, near-linear portant factor in the early death of bleeding trauma patients
increaseduringICUday1. who survive long enough to arrive at hospitals capable of
116 January2007
EarlyFFPtoMassiveTransfusionTraumaPatients
pre-ICUMTprotocol(pre-ICUPRBC,12(cid:4)1units;pre-ICU
FFP, 5 (cid:4) 0.4 units), ICU admission INR was 1.6 (cid:4) 0.04.
Additionally, despite routine serial coagulation analyses and
interventions directed by the bedside ICU physician, coagu-
lopathy was not definitively corrected. INR decreased to a
stableplateauof1.4(cid:4)0.03within8hours,andthismoderate
coagulopathy persisted for the remaining 16 hours of resus-
citation (see Fig. 3). Transfusion of FFP was the primary
intervention for coagulopathy correction (see Table 2). The
ratioofunitsofFFP:PRBCduringICUresuscitationwas1:1,
Fig. 5. Univariate logistic regression analysis shows that severity whichexceedspublishedrecommendations.7,15Thestandard
ofcoagulopathy,indicatedasinternationalnormalizedratio(INR),
of care throughout the study period was to maintain [plt]
earlyafterICUadmissionispredictiveofmortality(p(cid:7)0.02;area (cid:1)100 k cells/mm3 during active resuscitation. Forty-two pa-
underROC,0.71). tients (43%) had [plt] (cid:2)100 k cells/mm3 during the first 4
hoursintheICUand,afteratransientincreasebetween4and
providing life-saving hemorrhage control interventions.1,11 12 hours, mean [plt] tended to decrease as resuscitation pro-
Despite tremendous advances in care at now-specialized ceeded(seeFig.4).Mean[fib]increasedsteadilyduringICU
Trauma Centers, hemorrhage remains the leading cause of resuscitation with remarkable uniformity and remained
earlydeath.2,12Aswecontinuetostudytheepidemiologyof within normal range of 100 to 450 mg/dL (see Fig. 4).
patients who arrive with exsanguinating hemorrhage, it is Appropriately, few patients received cryoprecipitate, a more
apparentthatasubsetofthesepatientsdonotrespondwellto definitive intervention to increase [fib] than FFP (see Table
standard of care interventions. Because resuscitation is an 2).Thischallengestherecentemphasisforearlycryoprecip-
obligatory intervention, we have focused our efforts on con- itate administration. Although Fries et al.16 reported that
trollingICUresuscitationbyutilizingcomputerizeddecision increasing[fib]togreaterthannormalrangedecreasesblood
support. With ongoing analyses of prospectively collected loss in an animal model of liver injury, clinical data are
data, we have progressively refined this process of care and lacking.
determined that the clinical trajectory of the nonresponder WethinkthatfailuretocorrectcoagulopathyduringICU
declares itself early in pre-ICU care.13 Therefore, we have resuscitation was largely attributable to inadequate pre-ICU
developed several pre-ICU protocols to hasten identification intervention. The patients who arrived with obvious coagu-
andtreatmentoflife-threateninghemorrhageandtooptimize lopathy required ongoing transfusion and received FFP and
pre-ICUresuscitation.Thisanalysiswasundertakentoassess PRBC according to our standard of care both pre-ICU (MT
how well our empiric pre-ICU MT protocol is working in protocol, FFP withheld until after 6 units PRBC) and during
patientswhoareenteredintoourICUresuscitationprotocol. ICUresuscitation(FFP:PRBCgiven1:1).DuringICUresus-
This study cohort was severely injured patients with citation, however, these patients had ongoing blood loss as
severeshockevidentintheEDandpersistentatICUarrival. indicatedbyongoingPRBCtransfusionrequirements.Super-
ICU resuscitation was effective. Mean CI increased to (cid:1)4 position of INR and PRBC transfusion data during ICU
L/min-m2 within 4 hours, [Hb] (cid:1) 11 g/dL remained stable, resuscitation, shown in Figure 6, clearly shows that signifi-
andBDwascorrectedwithin(cid:1)8hours.Althoughsignificant cant coagulopathy was present and that these patients were
acidosis was present at ICU admission, it was reliably cor- receivingvigorousPRBCtransfusiontomaintainhemoglobin
rected with resuscitation.8,9,14 Together with BD, pH was concentration. These observations suggest that more aggres-
normalized within 8 hours (see Fig. 2). To our surprise,
severe hypothermia was uncommon at ICU admission. Only
onepatientarrivedintheICUwithT(cid:2)32°C.Atthetimeof
Shock Trauma ICU admission, T was 35.5 (cid:4) 0.1 °C and nor-
malizedwithin4hoursdespitecontinuedneedforlargevolume
resuscitationandlackofactiveinternalrewarminginterventions
(seeFig.2).
These data indicate that, despite the absence of rigorous
protocols in the ED and OR settings, acidosis and hypother-
mia were reasonably well managed at our Level I trauma
center and did not seem to complicate our ICU resuscitation
process. Coagulopathy, however, remained a significant Fig. 6. Internationalnormalizedratio(INR)andcumulativePRBC
problem.Thesepatientsarrivedwithcoagulopathy(EDINR, transfusion during ICU resuscitation showing persistent moderate
1.8 (cid:4) 0.2). Despite receiving quantities of blood products coagulopathy (INR (cid:1)1.4) and concurrent ongoing transfusion
that were surprisingly consistent with our standard of care requirement.
Volume 62 • Number 1 117
TheJournalofTRAUMA(cid:1)Injury,Infection,andCriticalCare
sive pre-ICU intervention to correct coagulopathy may be death caused by exsanguination from 9% to 1%. Addition-
effectiveindecreasingPRBCrequirementduringICUresus- ally, a recent consensus conference to address issues related
citation and, because of the association with increased mor- toearlyMTafterinjuryconfirmedtheneedforearlierinter-
tality, could improve outcome.17 ventions in the massively injured patient who presents with
Recent publications from other Level I trauma centers shock,andconcludedthatthebloodproductscurrentlyavail-
also identify coagulopathy as a significant problem in the able to emergently support the severely injured patient are
early management of the trauma patient. Although tradition- inadequate and that focus needs to be on early coagulopathy
ally attributed to hemodilution, acidosis, and hypothermia, correction.15,17,20–23
tworecentstudiesindicatethatcoagulopathystartsverysoon Basedonourexperienceandtheabovecitedstudies,we
after trauma, independent of these aggravating events. A think that coagulopathy remains a significant problem with
retrospective trauma registry review from the Ryder Trauma severely injured patients and that it is present early after ED
Center (Miami, FL) documented 28% incidence of coagu- admission. The inciting mechanism for coagulopathy is not
lopathy (defined as PT (cid:1)14 sec) in trauma patients (median clear from the clinical data obtained, but the data do support
ISS, 9) at arrival to the trauma bay.5 A second report re- theneedforearlyrecognitionofcoagulopathyandcorrection
viewedhelicoptertransportsshortlyafterarrivaltotheRoyal before ICU admission, and possibly for new concepts to
LondonHospital(London,England,UK),andfound24%of address this issue.23
trauma patients (median ISS, 20) to be coagulopathic (de- Therefore, we are developing and implementing a stan-
fined as PT (cid:3) 18 sec in 16%, PTT (cid:3) 60 sec in 13%, and dardizedprotocolforpreventionandcorrectionofcoagulopa-
thrombin time (cid:3) 15 sec in 14%). These investigators also thy that starts in the ED. We have developed a multiple-tier
described a linear relationship between early coagulopathy, protocol.Thefirstinterventionsareempiricallydirectedbya
ISS, and mortality. Cosgriff et al.,18 from Denver Health pre-ICU MT policy. Our revised protocol emphasizes early
MedicalCenter(Denver,CO),analyzedatransfusionregistry FFP administration in a ratio of 1 unit FFP to 1 unit PRBC,
designedtodocumentcoagulopathyaspatientsproceedfrom beginning with the first unit of PRBC transfusion, and is
EDtoORandthentoICU.Intheseseverelyinjuredpatients invokedbythetraumasurgeoncallingthebloodbankassoon
(meanISS,31(cid:4)2)whoreceived(cid:3)10unitsPRBCinthefirst as severe bleeding is recognized and the need for MT is
24 hospital hours after injury, these researchers documented anticipated by the trauma surgeon. Our blood bank now
a 47% incidence of severe coagulopathy in the OR (defined maintains5unitsoffreshthawedplasmathatareimmediately
as PT and PTT 2 times clinical laboratory normal). Using availableforMTpatients.ThisMTprotocolremainsineffect
multiple logistic regression, these investigators identified untilthepatientarrivesintheShockTraumaICU,afterwhich
four independent risk factors for severe coagulopathy (with the empiric MT protocol is stopped by the bedside ICU
odds ratios): (1) pH (cid:2) 7.10 (12.3); (2) T (cid:2) 34 °C (8.7); (3) physician calling the blood bank, and coagulopathy correc-
ISS(cid:3)25(7.7);and(4)systolicbloodpressure(cid:2)70mmHg tionisthenbasedonanICUprotocolwithclinicallaboratory
(5.8). Hirshberg et al.7 reported a computer simulation using measurements and specified interventions for coagulation
data from exsanguinating patients treated at Ben Taub Gen- variables. We estimate the cost of the MT protocol to be
eralHospital(Houston,TX).Themodelaccountedforblood incidentaltoourTraumaCenterandtotheindividualpatient
componentreplacement,resuscitation-inducedhemodilution, because of the small percentage of patients admitted to a
bleeding, and hemodynamic status. These authors concluded Trauma Center who require MT and because of the poten-
that existing protocols underestimate the dilution of clotting tiallylife-savingearlypreemptiveintervention.Development
factorsinseverelybleedingpatients.Theyrecommendedthat oftheICUprocesshasproceededusingprinciplessetforthby
FFP should be administered in a ratio of 2:3 with PRBC, or Morrisandcolleagues24andisbasedonliteraturereview,the
2unitsFFPshouldbeadministeredconcurrentlywiththefirst data presented here, a limited set of standard clinical measure-
units of PRBC if severe hemorrhage is anticipated. This ments able to be repeated, and our trauma team consensus
practice of early FFP administration is supported by another discussions. This ICU coagulopathy prevention and correc-
recent report from Denver Health Medical Center (Denver, tion decision support protocol uses thresholds and directs
CO),inwhichBiffletal.19describedtheongoingrefinement component therapy interventions to correct coagulopathy,
of a clinical pathway for management of hemodynamically indicated as INR, [plt], PTT, and [fib] as needed. ICU pro-
unstable patients with pelvic fractures. The initial protocol tocol development, begun in 2002, has undergone extensive
emphasized advanced trauma life support with early hemor- revision and is now being integrated with the standardized
rhagecontrolbyacombinationofexternalfixationandangio 24-hour ICU shock resuscitation protocol. The ICU coagu-
embolization. The next rendition, implemented 5 years later, lopathy correction protocol directs Factor VIIa as a final
emphasized earlier pelvic fracture stabilization by pelvic intervention on a compassionate-use basis if coagulopathy
binding, implemented a MT protocol that started FFP trans- and life-threatening bleeding persist despite traditional com-
fusion in the ED, and minimized indiscriminant crystalloid ponent interventions. Further clinical trial is needed for this
fluid infusion. After implementation of the refined protocol, intervention. Results of the recent European-South African
theauthorsreportedasignificantdecreaseintheincidenceof trial were mixed, with advantage shown for blunt but not
118 January2007
EarlyFFPtoMassiveTransfusionTraumaPatients
penetrating trauma victims,25and there is no US Food and 8. MarrAB,MooreFA,SailorsRM,etal.“Starlingcurve”generation
DrugAdministrationindicationforFactorVIIafortraumatic duringshockresuscitation:Canitbedone?Shock.2004;21:300–305.
shock.26FactorVIIaisavailableaccordingtohospital-specific 9. McKinleyBA,KozarRA,CocanourCS,etal.Normalvs.
supranormalO deliverygoalsinshockresuscitation:Theresponse
criteriaandafterconsultationwithanon-callhematologist. 2
isthesame.JTrauma.2002;53:825–842.
10. McKinleyBA,SailorsRM,GlorskySL,etal.Computerdirected
CONCLUSIONS
resuscitationofmajortorsotrauma.Shock.2001;15(Suppl):46.
This study indicates that coagulopathy is a problem that 11. MikhailJ.Thetraumatriadofdeath:hypothermia,acidosis,and
coagulopathy.AACNClinIssues.1999;10:85–94.
appears in severely injured patients at admission to the ED,
12. SauaiaA,MooreFA,MooreEE,etal.Multipleorganfailurecanbe
and is not corrected despite early correction of acidosis and
predictedasearlyas12hourspostinjury.JTrauma.1998;45:291.
hypothermia.Additionally,coagulopathyisnotcorrectedus-
13. BaloghZ,McKinleyBA,HolcombJA,etal.Bothprimaryand
ing current pre-ICU MT guideline therapy or by the bedside secondaryabdominalcompartmentsyndromecanbepredictedearly
clinician during ICU shock resuscitation despite identifica- andareharbingersofmultipleorganfailure.JTrauma.2003;
tion by serial clinical laboratory analyses and aggressive 54:848–859.
14. McKinleyBA,MarvinRG,CocanourCS,etal.Blunttrauma
component replacement. Reasons for this are unclear from
resuscitation:theoldcanrespond.ArchSurg.2000;48:637–642.
the data obtained, but may include the inability to correct
15. KetchumL,HessJR,HiippalaS.IndicationsforearlyFFP,
coagulopathy during ongoing resuscitation with crystalloid cryoprecipitateandplatelettransfusionsintrauma.JTrauma.2006;
fluid and PRBC, or that assessment by the bedside clinician 60(Suppl6):S51–S58.
is to accept moderate coagulopathy as an alternative to con- 16. FriesD,KrismerA,KlinglerA,etal.Effectoffibrinogenon
reversalofdilutionalcoagulopathy:aporcinemodel.BrJAnaesth.
tinuedaggressivebloodproductadministration.Development
2005;95:172–177.
of computerized decision support for this process will allow
17. NapolitanoL.CumulativerisksofearlyRBCtransfusion.JTrauma.
us to decipher this issue. 2006;60(Suppl6):S26–34.
Our data show that uncorrected coagulopathy at ICU ad- 18. CosgriffN,MooreEE,SauaiaA,etal.Predictinglife-threatening
missionisassociatedwithongoingtransfusionrequirementsand coagulopathyinthemassivelytransfusedtraumapatient:
hypothermiaandacidosisrevisited.JTrauma.1997;42:857–862.
that the severity of coagulopathy is directly associated with
19. BifflWL,SmithWR,MooreEE,etal.Evolutionofa
increased risk of death. For trauma patients presenting with
multidisciplinaryclinicalpathwayforthemanagementofunstable
exsanguinatinghemorrhage,coagulopathycorrectionbeginning patientswithpelvicfractures.AnnSurg.2001;233:843–850.
withaggressiveFFPadministrationpre-ICUmayimproveICU 20. HolcombJB,HessJR(eds.).Earlymassivetransfusion:stateofthe
resuscitationresponseandoutcome. art—ConferenceProceedings.USArmyInstituteofSurgical
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