Rev. bras. ortop. vol.52 número5

SOCIEDADE BRASILEIRA DE ORTOPEDIA E TRAUMATOLOGIA

w w w . r b o . o r g . b r

Original

Article

Comparative

study

of

topical

vs.

intravenous

tranexamic

acid

regarding

blood

loss

in

total

knee

arthroplasty

夽

Ari

Zekcer

,

Ricardo

Del

Priori

,

Clauber

Tieppo

,

Ricardo

Soares

da

Silva

,

Nilson

Roberto

Severino

a_{ClínicaOrtopédicaTatuapé,GrupodeCirurgiadeJoelho,SãoPaulo,SP,Brazil} b_{ClínicaSantaMaria,SãoPaulo,SP,Brazil}

c_{InstitutodeOrtopediaCampoBelo,SãoPaulo,SP,Brazil}

d_{FaculdadedeCiênciasMédicas,SantaCasadeMisericórdiadeSãoPaulo,DepartamentodeOrtopediaeTraumatologia,SãoPaulo,SP,}

Brazil

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received13August2016 Accepted20September2016 Availableonline30August2017

Keywords:

Tranexamicacid Arthroplasty

Replacementarthroplasty Knee

Fibrinmodulatingagents Antifibrinolytic

a

b

s

t

r

a

c

t

Objective:Tocomparetopicalvs.intravenoustranexamicacid(TA)intotalkneearthroplasty regardingbloodlossandtransfusion.

Methods:NinetypatientswererandomizedtoreceiveTAintravenously(20mg/kgin100mL ofsaline;groupIV),topically(1.5gin50mLofsaline,sprayedovertheoperatedsite,before releaseofthetourniquet;topicalgroup),orintravenoussaline(100mL withanesthesia; controlgroup).Thevolumeofdrainedbloodin48h,theamountoftransfusedblood,and theserumlevelsofhemoglobinandhematocritbeforeandaftersurgerywereevaluated.

Results:The groups were similar for gender, age, weight, laterality, and preoperative hemoglobinandhematocritlevels (p>0.2).Thehemoglobinlevel droppedinallgroups whencomparingthepreoperativeandthe48-hevaluations:thecontrolgroupdecreased 3.8mg/dLonaverage,whiletheIV_{grouphadadecreaseof3.0,andthetopicalgroup,of3.2} (p=0.019).ThedifferencebetweenthecontrolandIV_{groupswasconfirmedbyBonferroni} test(p=0.020).Thedifferencebetweenthecontrolgroupandthetopicalgroupwasnot sig-nificant(p=0.130),althoughtherewaslessreductioninhemoglobininthetopicalgroup;the comparisonbetweentheIV_{groupandthetopicalgroupwasalsonotsignificant(p=1.000).}

Conclusion: UsingtopicandIV_{tranexamicaciddecreasedbloodlossandtheneedfor} transfu-sionintotalkneearthroplasty.TopicalapplicationshowedresultssimilartoIVuseregarding theneedforbloodtransfusion,butwithoutthepossiblesideeffectsofIV_{administration.}

©2017SociedadeBrasileiradeOrtopediaeTraumatologia.PublishedbyElsevierEditora Ltda.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://

creativecommons.org/licenses/by-nc-nd/4.0/).

夽

PaperdevelopedatAACD,SãoPaulo,SP,Brazil;andFaculdadedeCiênciasMédicas,SantaCasadeMisericórdiadeSãoPaulo,SãoPaulo, SP,Brazil.

∗ _{Correspondingauthor.}

E-mail:ariz@uol.com.br(A.Zekcer).

http://dx.doi.org/10.1016/j.rboe.2017.08.005

Estudo

comparativo

com

uso

do

ácido

tranexâmico

tópico

e

intravenoso

em

relac¸ão

à

perda

sanguínea

na

artroplastia

total

do

joelho

Palavras-chave:

Ácidotranexâmico Artroplastia

Artroplastiadesubstituic¸ão Joelho

Moduladoresdefibrina Antifibrinolíticos

r

e

s

u

m

o

Objetivo: Compararousodeácidotranexâmico(AT)tópicoeintravenosonaartroplastia totaldejoelhocomrelac¸ãoàperdadesangueenecessidadedetransfusão.

Métodos: Foramrandomizados90pacientesparareceberATporviaintravenosa(20mg/kg em100mLdesoluc¸ãosalina;grupoIV_{),tópico(1,5gem50mLdesoluc¸ãosalina,antes} desoltarotorniquete;grupotópico)ousoluc¸ãosalinaintravenosa(100mLcomanestesia; grupocontrole).Ovolumedesanguedrenadoem48horas,aquantidadedesangue trans-fundidoeasconcentrac¸õessériasdehemoglobinaehematócritoforamavaliadosantese depoisdacirurgia.

Resultados: Osgruposeramsemelhantesquantoasexo,idade,lateralidadeeconcentrac¸ões pré-operatóriasdehemoglobinaehematócrito(p>0,2).Aconcentrac¸ãodehemoglobina diminuiuemtodososgruposquandoasavaliac¸õespré-operatóriaeem48horasforam comparadas:ogrupocontroletevereduc¸ãomédiade3,8mg/dL,enquantoogrupoIV_teve diminuic¸ãode3,0eogrupotópico,de3,2(p=0,019).Adiferenc¸aentreosgruposcontrole eIV_{foiconfirmadapelotestedeBonferroni(p=0,020).Adiferenc¸aentreosgrupos} con-troleetópiconãofoisignificativa(p=0,130),apesardehaverumamenordiminuic¸ãoda hemoglobinanogrupotópico;acomparac¸ãoentreosgruposIV_{etópicotambémnãofoi} significativa(p=1,000).

Conclusão: OusodeATtópicoeIVreduziuasperdassanguíneaseanecessidadede trans-fusãonaartroplastiatotaldojoelho.OusotópicomostrouresultadosemelhanteaousoIV emrelac¸ãoànecessidadedetransfusãosanguínea,porémsemospossíveisefeitoscolaterais daadministrac¸ãoIV_.

©2017SociedadeBrasileiradeOrtopediaeTraumatologia.PublicadoporElsevier EditoraLtda.Este ´eumartigoOpenAccesssobumalicenc¸aCCBY-NC-ND(http://

creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Totalkneearthroplastyisamajororthopedicoperation involv-ing considerablelossofblood.Despite the commonuse of tourniquets,itisestimatedthatthevolumeofbloodloss dur-ingthissurgeryisbetween800and1200mL.1–5

Bleedingduringsurgicaltraumainducesactivationofthe coagulationcascade3,6_{andthenfibrinolysis.}1,7–9_Tranexamic acid,anantifibrinolytic agent,has demonstrated inhaving the abilityofreducing blood loss, but there isstill contro-versyregardingthe dosageandthe typeofadministration. Tranexamicacidinhibitsfibrinolysisbycompeting withthe lysinemolecule atfibrinogen binding sites.7,10,11 _{Itis used} successfullyinheartsurgery,organtransplantsand gyneco-logicalsurgery,proceduresinvolvingalargeamountofblood loss.10–14 _{In kneearthroplasty, intravenoustranexamicacid} hasbeenshowntoreducebloodlossandtheneedforblood transfusion.1,15–19_{However,thedosageandtypeof} adminis-trationare stillcontroversial,andpossiblesideeffectssuch as nausea, headache and hypercoagulation, although rare, may occur.18,20–22 _{A study measuring the plasma levels of} plasminogeninperipheralbloodsuggests thattheeffectof tranexamicacidisgreateratthesiteofthesurgicalwound thanintheperipheralblood.7

Wedesignedthisrandomizedcontrolledtrialtoobserveif therewasanydifferencebetweenthetopicalandintravenous administration of tranexamic acid in total knee arthro-plastyregardingthevolumeofbloodlossand theneedfor

transfusion.Thehypothesestestedherewere:(1)the blood losswouldbehigherinthecontrolgroupwhencomparedto theothers;(2)topicalandintravenousadministrationsofthe drugshouldbeequallyeffectiveinreducingbloodlossandthe needforbloodtransfusion.

Material

and

methods

Studydesignandscenario

Thisisarandomized,single-blind,simulation-controlled clin-ical study performedin alargehospital betweenJune and November 2014. The Research Ethics Committeeapproved the study protocol (number 27270814.0.0000.0085) and the patients signedthe freeandinformed consentformbefore schedulingthedateofsurgery,afterbeingfullyinformedabout theproceduresanddesignofthestudy.Thestudyisenrolled inclinicaltrials.gov(protocolregisterNCT02323373).

Participantsandsurgicaltechnique

patientwassubmittedtolateralreleaseofthepatella. Exclu-sioncriteriawere:historyor identifiedriskofdeepvenous thrombosisor pulmonary embolism or history of coagula-tionorcardiovasculardisorders;vasculardiseasesorcurrent useofanticoagulantdrugs;orthopedicsurgeryinthelower limbs.

Thesame prosthesis was used in all cases (Genesys 2, Smith&Nephew,Memphis,USA).Tourniquetswereusedin all patients. All patientsreceived intravenousbolus hydra-tion(8mL/kg)immediatelypriortosurgeryand4mL/kg/hof salineduringtheoperation.Thesameanesthesiateam par-ticipatedinallsurgeries.Thesamekneesurgeryteam,with experiencedsurgeons(thatis,therewasnoresidentsurgeon orinteamtraining)performedalltheoperations.Hemostasis wasdoneaftertourniquetreleasebeforetissueclosure.A suc-tiondrainagedevicewasinstalledandusedfor48h(3.2mm, Portovac,Zammi),thedrainedvolumewasrecordedeverysix hours.

Patients received either regional (double-block) or gen-eral (when lumbarpuncture was not possible) anesthesia. The regional anesthesia protocol included spinal anesthe-sia(4mLof0.5%bupivacaine)andplacementofanepidural catheter.Apatient-controlledanalgesiapump(PAC)allowed paincontrolfor48haftersurgery,with165mLofsaline(0.9%), fentanyl(15mL)andropivacaine (20mL,1%)with adminis-trationof4mLperhour,6mLbolus,20-minrepeatinterval, andmaximumdoseof60mLin24h.Generalanesthesiawas performed withpropofol, fentanyl and cisatracurium besi-latefortrachealintubation.Intravenousinfusionpumpswere maintainedwithpropofol andopioids. PACforintravenous analgesia includedsaline solution(0.9%, 95mL,),morphine (50mL,1–2mL/h,bolusof1mgevery15min)andamaximum doseof6mL/h.

All patients of the three groups received the same postoperative care protocol, including physiotherapy with continuous passive movement equipment (for 1h, 3times a day), withgradual increase offlexion, initiatedwith 60◦

ofkneeflexion;preventionofvenousthrombosiswith elas-ticstockingsandsodiumenoxiparin(Clexane®,Sanofi)given subcutaneouslyoncedailyfor10days.

Outcomes

Theprimaryoutcomeanalyzedinthisstudywasthevolume ofbloodlossintotalkneearthroplasty.Thiswasdetermined by the suction drain, with recording of the total volume inmilliliters,measured48hafterthe endofsurgery,when drainagesystemswereremoved.Secondaryoutcomeswere: needfortransfusion(patientreceivedtwounitsofpackedred bloodcellseverytimehemoglobinlevelswerebelow8.0g/dL). Onemonthbeforesurgeryand24and48haftersurgery,all patientsunderwenthemoglobinandhematocritserum lev-els,and thenormalizedinternationalratioand coagulation timewere calculated.Theageandsexofthepatientswere alsorecorded.Therefore,thevariablesanalyzedinthisstudy were:hemoglobin level, hematocrit, partialthromboplastin time(PTT), internationalnormalized ratio (INR),volume of bloodlossthroughtheportovacdrainandneedfor transfu-sion.

Samplesize

Weusedtheprimaryparameterstodetectthedifferencesand toassumethestandarddeviationswithvalueof˛=0.05and withpowerof80%;thesamplesizeforeachgroupwas cal-culatedtobe26(Table1).Expectingwithdrawalandexitsof about10%,wedecidedtoenroll30patientsineachgroup.

Randomization,allocationandinterventions

Randomizationwasperformedbytheanesthesiologist draw-inglotsofsealedenvelopes,previouslyplacedinacontainer with 90 similar envelopes (30 in each group) prepared in advancewithanallocationratioof1:1:1.

Each patient was allocated to one of three groups: the topical group consisted ofpatients receiving a solution of 1.5gtranexamicacid(50gmg/mL,Transamin®,ZydusNikkho) diluted in50mL saline (at 0.9%),which coveredthe entire operatedarea,andmaintainedfor5minforabsorptionbefore tourniquetrelease.Theintravenousgroupreceived20mg/kg oftranexamicaciddilutedin100mLat0.9%salinesolution, administeredwithanesthesiain10min.Finally,thecontrol consistedofpatientswhoreceivedonly100mLofsaline,also administeredatthetimeofanesthesiarunningin10min.

Statisticalanalysis

Forstatisticalanalysis,SPSSsoftwareversion13.0wasused. Significance was set at 5%. We used the t-test for the pairedanalyses,theChi-squaretestandthenon-parametric Kruskal–Wallis and Mann–Whitneytests. Wealsoused the analysis of variance (Anova) with the Bonferroni multiple comparisonsmethod.

Results

During the study period, 102 patients were invited to par-ticipate. However,we had to excludefour patients due to cardiomyopathy,fiveduetopreviouseventsof thromboem-bolism,andthreepreviouslysubmittedtotibialosteotomies (Fig. 1). Therefore, we concluded the evaluations with 90 patients,30ineachgroup.Ofthesepatients,80wereoperated with regional anesthesia (double block) and 10 with gen-eral anesthesia (duetoprevious spinearthrodesisorother anatomicalproblemsthathinderedtheperformanceofanew puncture).Therewerenosurgicalcomplications,nolesionsor sideeffects,andnopatientperishednorwherethereareany withdrawals.

Table1–Parametersforcalculatingsamplesize.

Parameters Hb Ht PTT INR

Difference 1 10 3.5 0.06

Deviation 1.2 4 6 0.10

Alpha 5% 5% 5% 5%

Testpower 80% 80% 80% 80%

Sample 14 4 26 24

Hb,hemoglobin;Ht,hematocrit;INR,normalizedinternationalratio;PTT,partialthromboplastintime. Pairtedttest(comparisonofmeans).

30 topic 30 controls

30 intravenous 30 topic

30 intravenous

R A N D O M I Z E D

90 included

Previous thrombosis (n = 5)

Cardiomiopathy (n = 4)

30 controls

102 patients with

total knee

replacement

Tibial osteotomy (n = 3)

E X C L U D E D A S S E S S E D

E V A L U A T E D

Fig.1–Flowchartforpatientenrolment.Onehundredandtwopatientswithtotalkneeprosthesiswereevaluated.

international ratio was significantly different between the controland intravenousgroups(p=0.008)and betweenthe intravenousandtopicalgroups(p=0.042),butitwassimilar incomparisontothe topicaland controlgroups (p=0.470). HematocritandPTTwerenotsignificantlydifferentbetween groups.Table2showsthemeanvaluesatthebeginningofthe studyandthestandarddeviationsineachgroup.

Hemoglobinconcentrationdecreasedinall groupswhen thepreoperativeevaluationswerecompared,andin48hours: therewasareductionof27.40%inthecontrolgroup,23.18% inthe topical group, and 22.30% inthe intravenousgroup (p=0.001 for all). The difference between the groups was

significant:thecontrolgroupdecreasedby3.8mg/dLon aver-age,whiletheintravenousgrouphadareductionof3.0andthe topicalgroup,3.2(p=0.019).AnotherBonferronicomparison showedthattherewasasignificantdifferencebetweenthe controlandintravenousgroups(p=0.020),whereastherewas nodifferencebetweencontrolandtopicalgroups(p=0.130), andintravenousandtopicalgroups(p=1.000).Fig.2showsa boxdiagramwithsuchcomparisons.

Table2–Meanbasalvaluesandstandarddeviation(SD)foreachgroupandcomparisonamonggroups.

Variable Group Mean Median SD Minimal Maximum p

Hb Control 13.5 13.5 1.1 10.7 15.3 0.549a

IV _{13.9 13.5 1.2 11.9 16.7}

Topical 13.8 13.7 1.3 10.6 16.5

Ht Control 41.1 41.2 3.0 32.3 46.2 0.295a

IV _{42.1 42.3 3.8 30.9 50.5}

Topical 42.5 42.6 3.3 35.5 48.4

PTT Control 28.2 27.5 3.8 23.4 37.1 0.143a

IV _{29.8 29.5 3.3 24.7 40.0}

Topical 29.9 29.3 3.8 24.4 39.4

INR Control 1.01 1.01 0.07 0.80 1.20 0.020b

IV _{1.07 1.07 0.08 0.99 1.32}

Topical 1.03 1.02 0.06 0.86 1.18

INR,normalizedinternationalratio;IV_{,intravenousgroup;Hb,hemoglobin;Ht,hematocrit;PTT,partialthromboplastintime.} a _{Varianceanalysis–Anova.}

b _{Kruskall–Wallistest.}

Table3–Meanvolumeofblooddrainedandstandarddeviation(SD)foreachgroupandcomparisonamongthegroups (varianceanalysisandBonferronimultiplecomparisonstest).

Test Group Mean Median SD Minimal Maximum p

Anova Control 609 595 203 260 1.000 0.001

IV _{421 340 246 150 990}

Topical 409 400 213 70 850

Bonferroni Controlvs.IV _0.004

Controlvs.topical 0.004

IV _{vs.topical 1.000}

IV_{,intravenousgroup.}

18

16

14

12

10

8

6

Control IV Topic

Hb (dl/g)

Hb PRE Hb 48h

Fig.2–Graphshowsthecomparisonofhemoglobinlevels preoperatively(blueboxes)and48haftersurgery(green boxes).

1000

800

600

400

200

0

Control IV Topic

Drain (ml)

Fig.3–Graphshowingthecomparisonofdraineffective outputinthethreegroups.

intravenous groups, and between the control and topical groupswassignificant,butthedifferencebetweenthetopical andintravenousgroupswasnotsignificant.Thisisillustrated inFig.3.

Discussion

Most bleeding after total knee arthroplasty occurs after tourniquetremoval.9,23–26_{Despitethecontroversiesregarding} postoperativeoutcomes,suchasfunctionandpain, tourni-quetsarewidelyusedintotalkneearthroplastyandactually reducebloodlossbyhalf.27_{Buttheystillcarryrisksofnerve} damageandoptionsforreducingbloodlossarebeing investi-gated.

Weconductedarandomized,controlledstudyinaBrazilian populationstudygroupthatcomparedthetopicaland intra-venousadministrationofanantifibrinolyticagent,tranexamic acid,whichinsomestudiesisadministeredpriorto tourni-quet application to slow the onset of fibrinolysis,17 _and has been shown to reduce postoperative blood loss in orthopedicsurgerywithoutthromboemboliceventsorother complications.17,28–31_{ThedrugwasalsostudiedintheCrash} seriesofmulticenterstudieswithtraumapatients;itreduced the risk of death due to hemorrhage when administered withinthreehoursofthetrauma.17,29,32,33

In this study, we were able to confirm the hypothesis that blood loss would begreater inthe control group, not treatedwithtranexamicacid,comparedtotwoothergroups that usedthe drug. Thisfinding is consistentwith the lit-erature, confirmingthe antifibrinolyticeffectoftranexamic acid.1,15–19,30,34,35 _{In addition, we also confirm the second} hypothesis: we haverevealed that topicaland intravenous administrationsofthedrugareequallyeffectiveinreducing bloodloss.

Thetopicaladministrationoftranexamicacid hassome advantages,themainonebeingthepossibilityofusinglower dosage.36_{Inaddition,itavoidstherisksassociatedwiththe} systemic absorption of the medication, with the possible riskofhypercoagulation,37_{withtheuseonlyoflocalaction,} andalsoslowstheonsetoffibrinolysis.9,21_{Theycanalsobe} administeredbyintra-articularinjectionthrough thedrain, shortly afterclosure, withclear effects on totalblood loss and knee joint edema.38 _{However,our study isone ofthe} firsttodirectlycompareintravenousdrugadministrationwith localadministrationintotalkneearthroplastyinaBrazilian populationgroup. Ourstudy demonstratedthat the topical dose of 1.5g was as effective as the intravenous dose of 20gmg/kgoftranexamicacidinrelationtotheneedforblood transfusion.

Maniaretal.22 _{conductedarandomized,controlledtrial} comparing various tranexamic acid dosage schedules and included a group receiving a single local dose application of 3g/100mL saline solution in patients undergoing total kneearthroplasty.Theauthorscomparedlocalvs.intravenous administrationofthedrug,butitwasadosagestudyinwhich variousintravenousadministrationschemeswerecompared withonlyonelocaladministrationregimenanddosage.The resultofthisstudy reportedthattobeeffective,the useof IVtranexamicacidshouldbegiveninoneinitialdoseatleast duringanestheticinduction.Asinourstudy,theyfound signif-icantdifferencesbetweenlocaladministrationoftranexamic acidandcontrols.

Options for minimizing bleeding in total knee arthro-plasties are described inthe literature, amongthem: local

adrenalineuse,theuseofanavigationsystemforbonecuts and/ortheuseofhemostaticagents(Floseal®,Baxter).39

One of the limitations of our study is that it was not double-blind.Anotherlimitationwasthepreoperative evalu-ationsperformedbydifferentlaboratories,butwiththesame methodology.

Conclusions

Thisrandomizedandcontrolledclinicalstudydemonstrated thattheIVuseoftranexamicacidhadthelowestbloodloss regardingtopicalandcontrolgroups,butthetopicalusewas sufficienttoreducetheneedforbloodtransfusions,without thepossiblesideeffectsoftheIVuseinthetotalknee arthro-plasty.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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1.BenoniG,FredinH.Fibrinolyticinhibitionwithtranexamic

acidreducesbloodlossandbloodtransfusionafterknee

arthroplasty:aprospective,randomised,double-blindstudy

of86patients.JBoneJointSurgBr.1996;178(3):434–40.

2.CushnerFD,FriedmanRJ.Bloodlossintotalknee

arthroplasty.ClinOrthopRelatRes.1991;(269):98–101.

3.HiippalaS,StridL,WennerstrandM,ArvelaV,MäntyläS,

YlinenJ,etal.Tranexamicacid(Cyklokapron)reduces

perioperativebloodlossassociatedwithtotalknee

arthroplasty.BrJAnaesth.1995;74(5):534–7.

4.LotkePA,FaralliVJ,OrensteinEM,EckerML.Bloodlossafter

totalkneereplacement.Effectsoftourniquetreleaseand

continuouspassivemotion.JBoneJointSurgAm.

1991;73(7):1037–40.

5.SehatKR,EvansR,NewmanJH.Howmuchbloodisreallylost

intotalkneearthroplasty?Correctbloodlossmanagement

shouldtakehiddenlossintoaccount.Knee.2000;7(3):151–5.

6.ZoharE,FredmanB,EllisM,LubanI,SternA,JedeikinR.A

comparativestudyofthepostoperativeallogeneic

blood-sparingeffectoftranexamicacidversusacute

normovolemichemodilutionaftertotalkneereplacement.

AnesthAnalg.1999;89(6):1382–7.

7.BenoniG,LethagenS,FredinH.Theeffectoftranexamicacid

onlocalandplasmafibrinolysisduringtotalknee

arthroplasty.ThrombRes.1997;85(3):195–206.

8.KambayashiJ,SakonM,YokotaM,ShibaE,KawasakiT,Mori

T.Activationofcoagulationandfibrinolysisduringsurgery,

analyzedbymolecularmarkers.ThrombRes.

1990;60(2):157–67.

9.PetäjäJ,MyllynenP,MyllyläG,VahteraE.Fibrinolysisafter

applicationofapneumatictourniquet.ActaChirScand.

1987;153(11–12):647–51.

10.DunnCJ,GoaKL.Tranexamicacid:areviewofitsusein

surgeryandotherindications.Drugs.1999;57(6):1005–32.

11.EubanksJD.Antifibrinolyticsinmajororthopaedicsurgery.J

AmAcadOrthopSurg.2010;18(3):132–8.

12.MonganPD,BrownRS,ThwaitesBK.Tranexamicacidand

aprotininreducepostoperativebleedingandtransfusions

duringprimarycoronaryrevascularization.AnesthAnalg.

13.BoylanJF,KlinckJR,SandlerAN,ArellanoR,GreigPD,

NierenbergH,etal.Tranexamicacidreducesbloodloss,

transfusionrequirements,andcoagulationfactorusein

primaryorthotopiclivertransplantation.Anesthesiology.

1996;85(5):1043–8,discussion30A–31A.

14.WellingtonK,WagstaffAJ.Tranexamicacid:areviewofits

useinthemanagementofmenorrhagia.Drugs.

2003;63(13):1417–33.

15.CamarasaMA,OlléG,Serra-PratM,MartinA,SánchezM,

RicósP,etal.Efficacyofaminocaproic,tranexamicacidsin

thecontrolofbleedingduringtotalkneereplacement:a

randomizedclinicaltrial.BrJAnaesth.2006;96(5):576–82.

16.GoodL,PetersonE,LisanderB.Tranexamicaciddecreases

externalbloodlossbutnothiddenbloodlossintotalknee

replacement.BrJAnaesth.2003;90(5):596–9.

17.JansenAJ,AndreicaS,ClaeysM,D’HaeseJ,CamuF,Jochmans

K.Useoftranexamicacidforaneffectivebloodconservation

strategyaftertotalkneearthroplasty.BrJAnaesth.

1999;83(4):596–601.

18.TanakaN,SakahashiH,SatoE,HiroseK,IshimaT,IshiiS.

Timingoftheadministrationoftranexamicacidfor

maximumreductioninbloodlossinarthroplastyoftheknee.

JBoneJointSurgBr.2001;83(5):702–5.

19.RalleyFE,BertaD,BinnsV,HowardJ,NaudieDD.One

intraoperativedoseoftranexamicAcidforpatientshaving

primaryhiporkneearthroplasty.ClinOrthopRelatRes.

2010;468(7):1905–11.

20.EngelJM,HohausT,RuwoldtR,MengesT,JürgensenI,

HempelmannG.Regionalhemostaticstatusandblood

requirementsaftertotalkneearthroplastywithandwithout

tranexamicacidoraprotinin.AnesthAnalg.2001;92(3):775–80.

21.WongJ,AbrishamiA,ElBeheiryH,MahomedNN,Roderick

DaveyJ,GandhiR,etal.Topicalapplicationoftranexamic

acidreducespostoperativebloodlossintotalknee

arthroplasty:arandomized,controlledtrial.JBoneJointSurg

Am.2010;92(15):2503–13.

22.ManiarRN,KumarG,SinghiT,NayakRM,ManiarPR.Most

effectiveregimenoftranexamicacidinkneearthroplasty:a

prospectiverandomizedcontrolledstudyin240patients.Clin

OrthopRelatRes.2012;470(9):2605–12.

23.FahmyNR,PatelDG.Hemostaticchangesandpostoperative

deep-veinthrombosisassociatedwithuseofapneumatic

tourniquet.JBoneJointSurgAm.1981;63(3):461–5.

24.KlenermanL,ChakrabartiR,MackieI,BrozovicM,StirlingY.

Changesinhaemostaticsystemafterapplicationofa

tourniquet.Lancet.1977;1(8019):970–2.

25.NakaharaM,SakahashiH.Effectofapplicationofa

tourniquetonbleedingfactorsindogs.JBoneJointSurgAm.

1967;49(7):1345–51.

26.TsumaraN,YoshiyaS,ChinT,ShibaR,KohsoK,DoitaM.A

prospectivecomparisonofclampingthedrainor

post-operativesalvageofbloodinreducingbloodlossafter

totalkneearthroplasty.JBoneJointSurgBr.2006;88(1):

49–53.

27.EjazA,LaursenAC,KappelA,LaursenMB,JakobsenT,

RasmussenS,etal.Fasterrecoverywithouttheuseofa

tourniquetintotalkneearthroplasty.ActaOrthop.

2014;85(4):422–6.

28.WangQ,LiuJ,FanR,ChenY,YuH,BiY,etal.Tranexamicacid

reducespostoperativebloodlossofdegenerativelumbar

instabilitywithstenosisinposteriorapproachlumbar

surgery:arandomizedcontrolledtrial.EurSpineJ.

2013;22(9):2035–8.

29.RobertsI,PerelP,Prieto-MerinoD,ShakurH,CoatsT,HuntBJ,

etal.Effectoftranexamicacidonmortalityinpatientswith

traumaticbleeding:prespecifiedanalysisofdatafrom

randomisedcontrolledtrial.BMJ.2012;345:e5839.

30.CharoencholvanichK,SiriwattanasakulP.Tranexamicacid

reducesbloodlossandbloodtransfusionafterTKA:a

prospectiverandomizedcontrolledtrial.ClinOrthopRelat

Res.2011;469(10):2874–80.

31.LinPC,HsuCH,ChenWS,WangJW.Doestranexamicacid

savebloodinminimallyinvasivetotalkneearthroplasty?Clin

OrthopRelatRes.2011;469(7):1995–2002.

32.RobertsI,ShakurH,CoatsT,HuntB,BalogunE,BarnetsonL,

etal.TheCRASH-2trial:arandomisedcontrolledtrialand

economicevaluationoftheeffectsoftranexamicacidon

death,vascularocclusiveeventsandtransfusionrequirement

inbleedingtraumapatients.HealthTechnolAssess.

2013;17(10):1–79.

33.KerK,KiriyaJ,PerelP,EdwardsP,ShakurH,RobertsI.

Avoidablemortalityfromgivingtranexamicacidtobleeding

traumapatients:anestimationbasedonWHOmortality

data,asystematicliteraturereviewanddatafromthe

CRASH-2trial.BMCEmergMed.2012;12:3.

34.SinghJ,BallalMS,MitchellP,DennPG.Effectsoftranexamic

acidonbloodlossduringtotalhiparthroplasty.JOrthopSurg

(HongKong).2010;18(3):282–6.

35.HynesMC,CalderP,RosenfeldP,ScottG.Theuseof

tranexamicacidtoreducebloodlossduringtotalhip

arthroplasty:anobservationalstudy.AnnRCollSurgEngl.

2005;87(2):99–101.

36.Sa-NgasoongsongP,WongsakS,ChanplakornP,Woratanarat

P,WechmongkolgornS,WibulpolprasertB,etal.Efficacyof

low-doseintra-articulartranexamicacidintotalknee

replacement;aprospectivetriple-blindedrandomized

controlledtrial.BMCMusculoskeletDisord.2013;14:340.

37.ZuffereyPJ,MiquetM,QuenetS,MartinP,AdamP,Albaladejo

P,etal.Tranexamicacidinhipfracturesurgery:arandomized

controlledtrial.BrJAnaesth.2010;104(1):23–30.

38.IshidaK,TsumuraN,KitagawaA,HamamuraS,FukudaK,

DogakiY,etal.Intra-articularinjectionoftranexamicacid

reducesnotonlybloodlossbutalsokneejointswellingafter

totalkneearthroplasty.IntOrthop.2011;35(11):1639–45.

39.HelitoCP,GobbiRG,CastrillonLM,HinkelBB,PécoraJR,

CamanhoGL.ComparisonofFloseal®andelectrocauteryin

hemostasisaftertotalkneearthroplasty.ActaOrtopBras.