Rev. bras. ortop. vol.52 número2

(1)

SOCIEDADE BRASILEIRA DE ORTOPEDIA E TRAUMATOLOGIA

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

Original

article

Evaluation

of

serum

levels

of

C-reactive

protein

after

total

knee

arthroplasty

夽

João

Maurício

Barretto

∗

_,

_Fabrício

_Bolpato

_Loures,

_Rodrigo

_Sattamini

_Pires

_e

_Albuquerque,

Filipe

das

Neves

Bezerra,

Rafael

Vinagre

Faro,

Naasson

Trindade

Cavanellas

InstitutoNacionaldeTraumatologiaeOrtopedia(Into),RiodeJaneiro,RJ,Brazil

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received2March2016 Accepted17May2016 Availableonline6March2017

Keywords:

C-reactiveprotein PCR

Knee Osteoarthritis Arthroplasty

a

b

s

t

r

a

c

t

Objective:ToevaluatethebehaviorofC-reactiveprotein(CRP)levelsinthefirstthreeweeks aftertotalkneearthroplasty(TKA)anddefinethefactorsrelatedtoitsvariation.

Methods:WeevaluatedtheCRPvaluesin103patientsundergoingprimaryTKA.SerumCRP wasmeasuredonthedaybeforesurgery,andonthethirdandtwenty-firstdaysafterthe procedure.

Results:PCRshowedsuddenincreaseonthethirddayaftersurgery,reachingthemeanvalue of111.9mg/L,median75.9mg/L.Onlyone-thirdofthepatientsreturnedtonormallevelsin thethirdweek.Intheimmediatepostoperativeperiod,CRPwasnotcorrelatedwithbody massindex(BMI),age,gender,bloodtransfusion,orcomplications.

Conclusion:SerumCRPremainshighinthethirdweekafterTKAinmostpatients,andthis changeisprimarilyrelatedtosurgicaltrauma.

Avaliac¸ão

dos

níveis

séricos

da

proteína

C

_-reativa

_após

_artroplastia

_total

do

joelho

Palavras-chave:

ProteínaC-reativa PCR

Joelho Osteoartrite Artroplastia

r

e

s

u

m

o

Objetivo:AvaliarocomportamentodaproteínaC-reativa(PCR)séricanastrêsprimeiras sem-anasapósartroplastiatotaldojoelho(ATJ)edefinirosfatoresrelacionadosasuavariac¸ão.

Métodos:ForamavaliadososvaloresdaPCRem103pacientessubmetidosàATJprimária.A PCRséricafoidosadanavésperadacirurgia,noterceiroeno21◦_dia_após_o_{procedimento.}

Resultados:APCR apresentou elevac¸ão súbitano terceirodia apósa cirurgia, atingiuo valormédiode111.9mg/L,commedianade75,9mg/L.Somenteumterc¸odospacientes

夽

StudyconductedattheInstitutoNacionaldeTraumatologiaeOrtopedia(Into),CentrodeCirurgiadoJoelho,RiodeJaneiro,RJ,Brazil.

∗ _{Corresponding}_author_.

E-mail:joao.barretto1@gmail.com(J.M.Barretto).

http://dx.doi.org/10.1016/j.rboe.2016.05.009

(2)

apresentounormalizaçãonaterceirasemana.Nopós-operatórioimediato,nãofoi encon-tradacorrelaçãodaPCRcomíndicedemassacorporal(IMC),idade,gênero,hemotransfusão oucomplicaçõesdospacientes.

Conclusão: APCRséricapermaneceelevadanaterceirasemanaapósATJnamaioriados pacienteseessaalterac¸ãoestárelacionadaessencialmenteaotraumacirúrgico.

Introduction

Osteoarthritis(OA)istheleadingcauseofmusculoskeletal dis-abilityworldwide,1_and_the_main_physical_limitation_factor_in

theelderlypopulation.2_This_serious _public_health_problem

affectsapproximately12.4millionBrazilians.3_Due_to

anatom-icalandbiomechanicalfactors,themostcommonlyaffected jointistheknee.1

Theincreasedlifeexpectancyanddesireforgreater activ-ityhaveexponentiallyincreasedthedemandfortotalknee arthroplasty (TKA).4 _It _represents _one _of _the _most

suc-cessful orthopedic procedures of the century. Despite the successofTKA,post-operativeinfectionremainsa devastat-ingcomplication.5_Early_diagnosis_is_difficult,_as_the_signs_of

physicalexamination and serological markers can present alterationsduetosurgicaltrauma.6

C-reactiveprotein(CRP)isanexampleofanacute-phase protein.Itissynthesized mainlybythe hepatocyte,andits functionistoactivatethecomplementsystemthroughthe classicalpathway.7_After_infectious_or_inflammatory_stimuli,

serumCRPlevelsmayriseabruptly,reachingupto1000times thebaselinevaluein48h.8

Thissubstancehasbeenusedinclinicalpracticeforover 70yearsasamarkerofinfectionand/orinflammation,butits serumvaluesanditsresponsetostimulivarywidely,andthe factorsassociatedwiththisoscillationarestilllittleknown.7

TheevaluationofserumCRPformsapartofthe propedeu-ticsforthediagnosisofperiprostheticinfection.9_The_test_has

highsensitivityandlowspecificity,10_and_may_be_influenced

byfactorssuchasage,gender,comorbidities,9_and_body_mass

index,11_in_addition_to_the_surgical_trauma.

ThisstudyaimedtoassessthebehaviorofserumCRPin thefirstthreeweeksafterTKAand toestablish thefactors relatedtoitsvariation.

Material

and

methods

AfterapprovaloftheprojectbytheInstitutionReviewBoard, undernumber 804.216,serum CRPwas measured prospec-tively and for convenience in 103 patients submitted to primaryTKAbetweenSeptember2014andMarch2015.

Thestudy includedallpatientswho underwentprimary TKA and accepted to participate by signing an informed consentform.Patientsundergoingrevisionarthroplastyand thosewithinflammatorydiseaseswereexcluded.

Onthedaybeforesurgery,thefirstsampleof2mLofvenous bloodwascollectedtodeterminethepreoperative quantita-tiveCRP(CRP0);assessmentwasmadeinthelaboratoryofthe

institution.ThebiochemistryanalyzerBT3000Plus® (Wiener Lab, Rosario,Santa Fe,Argentina) was used for the analy-sis withthe turbidimetricmethod, whose referencevalues inadultsis5mg/Lforinfectiousdiseases.Patientshadtheir statureandbodyweightmeasured.Weightwasdocumented inkilogramsandheightinmeters.Thesedatawereusedto calculatethebodymassindex(BMI)ofeachpatientinorder tocategorizethemaccordingtotheparametersoftheWorld HealthOrganization(WHO).12

Thesameimplantwasusedinallcases(PFCSigma® DePuy Synthes) andthe posteriorly stabilizedmodel withpatellar replacement waschosen. Intramedullary guides were used for the femoralcutand extramedullary guides for the tib-ialcut.Patientswereoperatedwiththeuseofperioperative ischemia;thecuffwasappliedatthethighlevel,witha pres-sure100mm/Hgabovethesystolicpressure.

Pre-anestheticassessment,filedinthemedicalrecord,was usedtodocumenttheunderlyingpathologiesandtheclinical statusofthepatients.

Onthethirddayafterthearthroplasty,whilepatientswere stillhospitalized, bloodcollectionprocedure forserumCRP wasrepeated(CRP3).

Patientsweredischargedaccordingtoclinicalcriteria,and anoutpatientfollow-upappointmentwasscheduledforthe 21stdayaftersurgery.Atthefollow-upappointment,before consultation orany manipulationof thesurgical wound,a blood samplewascollectedforthethirdCRPmeasurement (CRP21).

Aspreadsheetcontainingpatients’initials,medicalrecord number,age,gender,skincolor,primarykneepathology, later-ality,clinicalcomorbidities,bodyweightandheight,BMI,and CRP0,CRP3,andCRP21valueswascreated.

Fromthedatacollected,twofileswere createdandthen analyzed usingSPSS (StatisticalPackage forthe Social Sci-ences),version22.0,andMicrosoftExcel2007.

Descriptive analysis was presented as tables of the observed data, expressed as mean, standard deviation, median,andminimumandmaximumfornumericaldata,and frequency(n)andpercentage(%)forcategoricaldata,aswell asillustrativegraphs.CRP21wasconsiderednormalizedwhen

itreachedavaluelowerthanorequalto5mg/Lorlowerthan orequaltoCRP0.

(3)

Table1–Samplecharacterization.

Variable Number Percentage

Gender

Male 24 23.3

Female 79 76.7

Laterality

Right 60 58.3

Left 43 41.7

Ethnicity

White 35 34

Mixed-race 51 49.5

Black 17 16.5

Source:Datafromtheinstitutionmedicalrecords.

50

45

40

35

30

25

20

Females

BMI

Males

Fig.1–Bodymassindex(BMI)distributionaccordingto gender.

Mann–Whitney test was used. Comparison between more

than two independent groups was conducted using the

Kruskal–Wallistest.Thequantitativevariableswereanalyzed

bytwoapproaches:bycalculatingPearson’slinearcorrelation

coefficientfornormaldistributionsandSpearman’s

correla-tioncoefficientfornon-normal.A5%significancelevelwas

adoptedforrejectingthenullhypothesis.

Results

Thestudy included 103 knees of 117 patients who

under-wentprimaryTKA;24patientsweremaleand79werefemale.

Table1presentsthedistributionofthesampleregardingsex, operatedside,andethnicity.

Meanageofpatientswas68.9years(±6.4),rangingfrom 55 to91. Meanage offemale patients was 69 years (±6.3) andmalepatients,68.3(±6.9).TheMann–Whitneytest indi-catedthatbothgroupsweresimilarregardingage(p=0.910). Therewasnoassociation betweenageandCRP0 (p=0.688),

CRP3(p=0.455),andCRP21(p=0.831).

Patients had a mean BMI of 31.4 (±5.8); 32.7 (±5.8) for femalesand27(±3.2)formales.Student’st-testshowedthat BMIwassignificantlyhigherinthefemalegroupthaninthe malegroup(p=0.000).ThisdifferenceisshowninFig.1.

SAH

0.00% 20.00%

Total Females Males

40.00% 60.00% 80.00% 100.00% DM

Heart disease Hypothyroidism

Comorbidities

Fig.2–Incidenceofcomorbidities.DM,diabetesmellitus;

SAH,systemichypertension.

Source_:_Data_from_the_institution.

Only15.3%ofthepatientswereeutrophic.Remainingof thesamplewasoverweight(31.6%)orobese(53.1%).TheCRP21

normalizationratewasnotcorrelatedwithBMI(p=0.516). All patients had gonarthrosis inthe operated knee;100 hadprimarygonarthrosisandthreehadsecondary gonarthro-sis. Only 10.7% ofthe patients did notpresent a systemic pathology.Amongthe89.3%ofpatientswithcomorbidities, systemic arterial hypertension (SAH) was the most preva-lent, followedbydiabetesmellitus(DM),heartdisease,and hypothyroidism.Thedistributionofthemostfrequentclinical comorbidities,dividedbygenderandtotalsample,isshownin

Fig.2.

Postoperativecomplicationsoccurredintencases(9.7%), comprisingninefemalepatients(11.4%)andonemale(4.2%). Skinnecrosiswasthemostfrequentcomplication,observed insixpatients,followedbydeepveinthrombosis(DVT;three cases)andpostoperativerigidity(onecase);14patients(13.6%) receivedpostoperativebloodtransfusion,allredcell concen-trates(RCC).

The CRP values were submitted to the Shapiro–Wilk normality test; the null hypothesis was rejected (p=0.000) andanon-Gaussiandistributionwasdemonstrated.Table2

presentsthesevaluesinthetotalsampleandtheirstatistical variables.

TherateofCRPnormalizationbythethirdweekwas28.2% inthetotalsample;26.6%infemalesand33.3%inmales.There wasnosignificantdifferencebetweengenders(p=0.520).

Table3presentstherateofnormalizationafterthethird weekinthetotalsampleanddividedbygender.

TheevolutionofthemeanserumCRPfromthe preopera-tiveperiodtothe21stdayisshowninFig.3.

TherateofCRP21 normalizationwasnotcorrelatedwith

BMI (p=0.516) or patient’s age (p=0.831). The group that receivedbloodtransfusionpresentednormalizationin14.3% ofthecases.Amongthosewhodidnotreceivetransfusion, thisratereached30.3%.Despitethediscrepancy,Fisher’sexact testshowednostatisticallysignificantdifferencebetweenthe twogroups(p=0.339).

The rateofCRP21 normalizationfor patientswith

(4)

Table2–C-reactiveprotein(CRP)values.

Statistics CRP0(mg/L) CRP3(mg/L) CRP21(mg/L) 1CRP(%) 2CRP(%)

Mean 15.1 111.9 27.4 3118.6 −47.5

95%CI 10.519.6 94.2129.6 20.134.6 2048.24189.0 −70.4−24.6

Median 6.4 75.9 15.4 1051.9 −73.6

Standarddeviation 23.2 90.4 36.9 5476.9 117.1

Minimum 0.6 4.8 0.7 −62.8 −99.1

Maximum 132.5 384.0 263.9 25,242.5 962.5

Rawvariation 131.9 379.2 263.2 25,305.3 1061.6

Correlationcoefficient 1.5 0.8 1.4 1.8 −2.5

1CRP,variationbetweenCRP0andCRP3;2CRP,variationbetweenCRP3andCRP21.

Table3–RateofC-reactiveprotein(CRP)normalization.

Classification Gender Total

Female Male

CRP21was

normalized

21 8 29

26.6% 33.3% 28.2%

CRP21upto

10mg/L>CRP0

29 7 36

36.7% 29.2% 35.0%

CRP21from10to

20mg/L>CRP0

14 3 17

17.7% 12.5% 16.5%

CRP21from20to

50mg/L>CRP0

8 4 12

10.1% 16.7% 11.7%

CRP21from50to

100mg/L>CRP0

4 1 5

5.1% 4.2% 4.9%

CRP21morethan

100mg/L>CRP0

3 1 4

3.8% 4.2% 3.9%

Total 79 24 103

100% 100% 100%

15 112

27

0 20 40 60 80 100 120 140

21 18 15 12 9 6 3 0

Days after surgery

Total Females Males

CRP value

Fig.3–VariationofthemeanC-reactiveprotein(CRP)from thepreoperativeassessmenttothe21stday.

Discussion

CRPisanacute-phaseproteinthathasbeenusedas

inflam-matoryorinfectionmarkersince1930.Inthelastdecade,it

hasreceivedspecialattentionduetoitspredictiverolein

sev-eraldiseases.1_It_has_an_important_role_in_orthopedics,_being

usedinthediagnosisandcontrolofinfections.13

Withthe increase in lifeexpectancy and the growth of obesity,theratesofOAhaveincreasedexponentially,since thesefactorsaredirectlylinkedtothegenesisofthedisease.14

TKA promotes an effective relief of pain and improves function.15_Projections_suggest_that_{approximately}_3.5_million

kneearthroplastieswillbeperformedintheUnitedStatesin 2030.16_Despite_being_a_safe_surgery,_infection_is_a_potentially

devastating complication,ranging between0.4%and 2%of patients.17_Diagnosis_in_the_acute_phase_allows_treatment_with

debridement,implantretention,andantibiotictherapy;1_the

successratescanbeashighas36%,18_as_long_as_the_treatment

isinitiatedbeforethethirdweek.1

Theworkupofperiprostheticinfectionsisbasedon clin-icalandlaboratoryfindings.13_The_early_{identification}_of_this

complication is difficult because the signs of the physical examinationarenotreliableandserologicalmarkersare ele-vatedintheimmediatepostoperativeperiod.6_CRP_can_be_a

usefultool;itpresentshighsensitivity,butlowspecificity.10

UnderstandingCRPbehaviorintheimmediatepostoperative periodiscriticaltoincreasingthereliabilityoftheuseofthis markerfordiagnosis.

TherateofCRPnormalizationafterthethirdpostoperative weekwas28.2%;26.6%amongwomenand33.3%amongmen. Thesamplepresentedaratioof3.29femalesforeverymale, which is consistent with the literature.4,19 _No _differences

were observedinCRPvariationregardinggender(p=0.520), althoughKrausetal.20_and_Choi_et_al.21_have_demonstrated

significantlyhighervaluesinwomen.

Meanagewas68.9years(±6.4),reachingpatientsinthe seventhdecadeoflife.Theincidenceofgonarthrosisincreases withaging, reaching49.7%ofpeopleover 65years.19 _CRP’s

behaviorintheacutepostoperativeperiodshowedno correla-tionwithage,althoughParvizietal.9_and_Choi_et_al.21_reported

(5)

Mostpatientswereoverweightorobese,whichconfirms theroleofobesityinthegenesis14_and_progression_of_OA.22

Theadiposetissueproducesinflammatoryagents,including CRP.Excessbodyfatperpetuatesasubclinicalinflammatory statethatmayraisethebaselineCRPlevelsinthisgroup.23_No

differencesintherateofCRP21normalizationwereobserved

between obese and nonobesepatients (p=0.704). However, the present sample consisted of only15.3% normotrophic patients,which hinderedthis comparison.Liuet al.11

ana-lyzedtheCRPvaluesof1571patientsundergoingTKArevision anddividedthemintofourgroupsforthepresenceof infec-tionandobesity.TheyfoundnodifferenceintheCRPvalue between obese and non-obese patients (p=0.23); nonethe-less,theseauthorssuggestthatincreasingthecutoffpointfor obesepatientswouldincreasethespecificityofthistestforthe diagnosisofinfection.Choietal.21_found_a_direct_relationship

betweenBMIandCRP,butstrongerinfemalepatients. Theincidenceofcomorbiditiesinthesamplewas consis-tentwiththedistributioninthepopulationatthesameage range24_and_was_not_associated_with_the_rate_of_CRP

21

normal-ization(p=0.739).

Complicationswereobservedin9.7%ofpatients,andthere wasnodirectrelationshipwiththerateofCRP21

normaliza-tion(p=0.462).Nopatientpresentedinfectiouscomplications, whichmayhaveinfluencedtheabsenceofrelation.Therate ofbloodtransfusioninthepresentsamplewasinagreement withnationalliterature25_and_did_not_influence_the_CRP_curve

intheacutephase.

Thepresent study revealed twoimportant findings:the variationofCRPintheimmediatepostoperativeperiod(CRP3),

whichreachedthemeanvalueof111.9mg/L(CRP0),andthe

rateofnormalizationafterthethirdweek(CRP21),whichis

expectedinonlyone-thirdofpatients.Thisrapidincreasein CRP3aftertissueinjurydemonstratestheparticipationofthis

proteininthehost’sdefensesystem.Regardlessofthe nor-malization,afurtherincreaseinCRPafterthefirstweekis suggestiveofinfection.26_Since_there_were_no_cases_of

infec-tioninthepresentsample,thisincreasewasdueexclusively totissuedamage.

Shenetal.26_suggest_that_CRP_levels_after_arthroplasty_are

directlylinkedtotheregionand extentofsurgicaltrauma, regardlessof blood transfusion, age, or sexof the patient, which is consistent with the present findings. Thienpont etal.27_found_no_difference_in_the_CRP_values_after

conven-tionalorminimallyinvasiveTKAanddemonstratedthatthe elevationoftheproteinisrelatedtobonemarrowtrauma.

Conclusion

The value ofserum CRP shows a sudden increase on the thirddayaftertotalkneearthroplasty.Two-thirdsofpatients remainwithelevatedCRPinthethirdweekaftersurgery,and thischangeisessentiallyrelatedtosurgicaltrauma.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

r

e

f

e

r

e

n

c

e

s

1.ScottWN.Insaal&Scottsurgeryoftheknee.5thed. Philadelphia:Elsevier/ChurchillLivingstone;2012.

2.CentersforDiseaseControlandPrevention(CDC).Prevalence ofdoctor-diagnosedarthritisandarthritis-attributable activitylimitation.UnitedStates,2007–2009.MorbMortal WklyRep.2010;59(39):1261–5.

3.CoimbraIB,RezendeMU,PlaperPG.Osteoartite(artrose)– CenárioatualetendênciasnoBrasil.SãoPaulo:Limay;2012.

4.LouresFB,GóesRFA,PalmaIM,LabroniciPJ,GranjeiroJM,Olej B.Anthropometricstudyofthekneeanditscorrelationwith thesizeofthreeimplantsavailableforarthroplasty.RevBras Ortop.2016;51(3):282–9.

5.SharkeyPF,LichsteinPM,ShenC,TokarskiAT,ParviziJ.Why aretotalkneearthroplastiesfailingtoday–hasanything changedafter10years?JArthroplasty.2014;29(9):1774–8.

6.YiPH,CrossMB,MoricM,SporerSM,BergerRA,DellaValleCJ. The2013FrankStinchfieldAward:diagnosisofinfectionin theearlypostoperativeperiodaftertotalhiparthroplasty. ClinOrthopRelatRes.2014;472(2):424–9.

7.AblijH,MeindersA.C-reactiveprotein:historyandrevival. EurJInternMed.2002;13(7):412.

8.GabayC,KushnerI.Acute-phaseproteinsandothersystemic responsestoinflammation.NEnglJMed.1999;340(6): 448–54.

9.ParviziJ,ZmistowskiB,BerbariEF,BauerTW,SpringerBD, DellaValleCJ,etal.Newdefinitionforperiprostheticjoint infection:fromtheWorkgroupoftheMusculoskeletal InfectionSociety.ClinOrthopRelatRes.2011;469(11):2992–4.

10.JacovidesCL,ParviziJ,AdeliB,JungKA.Molecularmarkersfor diagnosisofperiprostheticjointinfection.JArthroplasty. 2011;266Suppl,99-103.e1.

11.LiuJZ,SalehA,KlikaAK,BarsoumWK,HigueraCA.Serum inflammatorymarkersforperiprosthetickneeinfectionin obeseversusnon-obesepatients.JArthroplasty.

2014;29(10):1880–3.

12.Obesity:preventingandmanagingtheglobalepidemic. ReportofaWHOconsultation.WorldHealthOrganTechRep Ser.2000;894,i-xii,1-253.

13.ParviziJ,GehrkeT.Consensointernacionaleminfecc¸ões articularesperiprotéticas.Accessedin18/01/2016.Available in:http://www.rbo.org.br/pdf/consensos/consensosciiap.pdf. 14.FelsonDT.Theepidemiologyofkneeosteoarthritis:results

fromtheFraminghamosteoarthritisstudy.SeminArthritis Rheum.1990;203Suppl.1:42–50.

15.ChengCK,LungCY,LeeYM,HuangCH.Anewapproachof designingthetibialbaseplateoftotalkneeprostheses.Clin Biomech(Bristol,Avon).1999;14(2):112–7.

16.KurtzSM,LauE,OngK,ZhaoK,KellyM,BozicKJ.Future youngpatientdemandforprimaryandrevisionjoint replacement:nationalprojectionsfrom2010to2030.Clin OrthopRelatRes.2009;467(10):2606–12.

17.CarvalhoJúniorLH,TemponiEF,BadetR.Infectionaftertotal kneereplacement:diagnosisandtreatment.RevBrasOrtop. 2013;48(5):389–96.

18.OdumSM,FehringTK,LombardiAV,ZmistowskiBM,Brown NM,LunaJT,etal.Irrigationanddebridementfor

periprostheticinfections:doestheorganismmatter?J Arthroplasty.2011;266Suppl.:114–8.

19.CentersforDiseaseControlandPrevention(CDC).Arthritis: NationalStatistics.Accessedin20/01/2016.Availablein:

http://www.cdc.gov/arthritis/data statistics/national-statistics.html.

(6)

disease,bodymassindex,gender,andosteoarthritis. OsteoarthritisCartilage.2007;15(8):966–71.

21.ChoiJ,JosephL,PiloteL.ObesityandC-reactiveproteinin variouspopulations:asystematicreviewandmeta-analysis. ObesRev.2013;14(3):232–44.

22.LouresFB,GóesRFA,LabroniciPJ,BarretoJM,OlejB.Avaliac¸ão doíndicedemassacorporalcomofatorprognósticona osteoartrosedojoelho.RevBrasOrtop.2016;51(4):400–4.

23.NazmiA,OliveiraIO,GonzalesDA,GiganteDP,HortaBL, VictoraCG.DifferentialandcumulativeimpactofBMIand centralobesityonC-reactiveproteinlevels:findingsfroma Brazilianbirthcohort.AmJEpidemiol.2009;169Suppl.11:S83.

24.SouzaARA,CostaA,NakamuraD,MochetiLN,Stevanato FilhoPR,OvandoLA.Umestudosobrehipertensa˜oarterial

sisteˆmicanacidadedeCampoGrande,MS.ArqBrasCardiol. 2007;88(4):441–6.

25.CardozoRT,SouzaJúniorEF,AlvesWC,BarbiFilhoF. Artroplastiatotaldojoelho:indicaçãodetransfusão sanguíneadeacordocomavariaçãohematimétricaeos sintomasclínicosdehipoperfusaõ.RevBrasOrtop. 2014;49(5):507–12.

26.ShenH,ZhangN,ZhangX,JiW.C-reactiveproteinlevelsafter 4typesofarthroplasty.ActaOrthop.2009;80(3):330–3.