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RESEARCHOpenAccessPreventiveeffectofulinastatinonpostoperativecomplications,immunosuppression,andrecurrenceinesophagectomypatientsLingminZhang1,NingWang2,SunaZhou3,WenguangYe4,QinglinYao4,GuixiaJing1*andMingxinZhang4*AbstractBackground:Toevaluatethepotentialefficacyofpreventiveeffectofulinastatininesophagectomypatients.
Methods:Eightypatientswithesophagealcancerwerepreoperativelyallocatedatrandomintotwoequalgroups.
Ulinastatinwasadministeredtothetreatmentgroup(U)whereasthecontrolgroup(C)receivedaplacebo.
Thearterialoxygentensionandcarbondioxidetensionweremeasuredandtherespiratoryindex(RI)wascalculated.
PlasmalevelsofcirculatingTlymphocytesubsetsandinterleukin6(IL-6)weremeasuredandclinicalcoursesofpatientsinthetwogroupswerecompared.
Results:RIintheUgroupwassignificantlylowerthanthatintheCgroup.
TherateofpostoperativecomplicationsandthedurationofICUstayweresignificantlylowerintheUgroup.
UlinastatinsignificantlyincreasedtherateofCD3+andCD4+cells,andratioofCD4+/CD8+,butdecreasedtherateofCD8+cellsandreleaseofIL-6comparedtotheCgrouponpostoperativedays1and3.
PatientswithintheCgroupshowedworserecurrencefreesurvival.
Multivariateanalysisrevealedthatulinastatinadministrationsignificantlydecreasedtheincidenceofrecurrence.
Conclusions:Ulinastatinhadapreventiveeffectonpostoperativecomplicationsandimmunosuppressioninesophagectomypatients,therebyprolongingrecurrencefreesurvival.
Keywords:Esophagectomy,Immunosuppression,Postoperativecomplications,Recurrence,UlinastatinBackgroundSurgeryremainsthemosteffectivetreatmentforsolidtumorsincludingesophagealcancer.
However,esopha-gectomy,oneofthemostinvasiveproceduresamonggastrointestinaloperations,hasahighfrequencyofpost-operativecomplications[1].
Severalresponsibleback-groundfactorshavebeenproposedtoexplainthebroadspectrumofpostoperativecomplicationsaftersuchin-vasiveprocedures.
Themostimportantonesaresyste-micinflammatoryresponsesyndromeandcompensatoryanti-inflammatorycytokineresponsesyndrome[2-4].
Moreover,surgicalstresscancauseimmunosuppres-sioninresponsetothecomplexinteractionofvarioushormones,cytokines,andacutephasereactants[5].
Ithasbeenreportedthatperioperativeandpostoperativeimmunosuppressionincreasestheratioofrecurrenceandadverselyaffectstheprognosisofcancerpatients[6,7].
Therefore,itisdesirabletofindaneffectivecountermeasureagainsttheoverproductionofproin-flammatorycytokines,postoperativecomplications,andimmunosuppression.
Ulinastatinisaserineproteaseinhibitorwithamo-lecularweightof~67,000foundinhealthyhumanurine.
Itisusedworldwideforpatientswithinflammatorydis-orders,includingdisseminatedintravascularcoagulation,shock,andpancreatitis[8-10].
Furthermore,ulinastatinadministrationcanhelpreducethesurgicalstress,pre-ventradiation-inducedlunginjury,andmodulateim-munefunctions[11-13].
Theaimofthepresentstudywastoevaluatethepotentialefficacyofpreventiveeffectofulinastatinon*Correspondence:jgx666@126.
com;zmx3115@163.
comEqualcontributors1DepartmentofAnesthesiology,FirstAffiliatedHospital,MedicalSchool,Xi'anJiaotongUniversity,Xi'an710061,ShaanxiProvince,China4DepartmentofGastroenterology,TangduHospital,FourthMilitaryMedicalUniversity,Xi'an710038,ShaanxiProvince,ChinaFulllistofauthorinformationisavailableattheendofthearticleWORLDJOURNALOFSURGICALONCOLOGY2013Zhangetal.
;licenseeBioMedCentralLtd.
ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.
org/licenses/by/2.
0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
Zhangetal.
WorldJournalofSurgicalOncology2013,11:84http://www.
wjso.
com/content/11/1/84postoperativecomplications,immunosuppression,andrecurrenceinesophagectomypatients.
MethodsPatientsBetweenJanuary2007andDecember2007,patientswithlowerthoracicesophagealcancerrequiringsurgicalin-terventionattheFirstAffiliatedHospitalandSecondAffiliatedHospital,MedicalCollegeofXi'anJiaotongUniversity,wereenrolled.
Exclusioncriteria:priorche-motherapyorirradiationorimmunosuppressivedrugadministration;bloodloss≥1,000mL;ASAclassifica-tion≥III,histologicaltypeofadenocarcinoma.
Eightypatientsweresubsequentlyrandomizedintotwogroups:controlgroup(C,n=40)andulinastatingroup(U,n=40).
Theoperativeprocedureforremovalofthecancerwasperformedbyasinglesurgicalteamandthroughtheleftposterolateralthoracotomyapproachwithcombinedtho-racoabdominallymphaticdissection,proximalgastricre-sectionandmobilizationofthestomachforesophagealreplacement.
InstitutionalEthicsCommitteeapprovalforthisprojectwasobtained.
Writteninformedconsentwasobtainedfromeachpatientbeforerandomization.
Thestudywasdesignedasasingleblindedstudy.
Ulinastatin(Miraclid,MochidaPharmaceulinastatincal,Japan)wasadministeredtotheUgroupasabolusof200,000Udilutedin20mLofnormalsalineevery24hfrom3dayspre-operationuntil3dayspost-operation.
ClinicalcourseevaluationClinicalcoursewasevaluatedbasedonrateofpostope-rativecomplications,includingcardiovascularcomplica-tions(arrhythmia,pulmonaryembolism,andmyocardialinfarction),pulmonarycomplications(pneumonia,ate-lectasis,pulmonaryedema),andothers(esophagogastricanastomosisleakage,stenosis,andwoundinfection).
Thecriteriaofpostoperativecomplications,especiallyforpul-monarycomplications,weredescribedasbefore[14].
ThedurationofICUandhospitalstaywasalsodetermined.
Allpatientsreceivedcisplatin-basedpostoperativead-juvantchemotherapyorstandardradiotherapy,ifrequired.
Thefollow-upperiodrangedfrom1to48months(median,35.
7months).
Computedtomography(CT)wasperformedatleastevery6monthstodetectrecurrence.
SamplecollectionandassayArterialbloodwascollectedimmediatelyat10minutesafteroperationbegan(T1),1hourafterone-lungventila-tion(T2),andatthetimeofclosure(T3).
Arterialoxygentension(PaO2)andcarbondioxidetension(PaCO2)weremeasuredbybloodgasanalysis.
Therespiratoryindex(RI)wascalculatedasamarkeroflungdamageusingthefollowingformulas:RI=[FIO2*(760–47)-PaCO2/0.
8]/PaO2.
Peripheralwholebloodsampleswereobtained1hourbeforesurgery(D0)andonpostoperativedays1,3,and7(D1,D2,andD3).
LymphocytesubsetswerecountedbyaFACSCalibur(BectonDickinson,SanJose,CA,USA)flowcytometer.
Cytokinelevels(IL-6)weredeterminedbyELISA,usingcommerciallyavailablekits(R&DSystems,Minneapolis,MN,USA).
StatisticsDataareexpressedasmean±standarddeviation.
Sta-tisticalanalysiswasperformedwiththeSPSSsoftwarepackage(version13.
0,SPSSInstitute).
Continuousvari-ableswereanalyzedusingrepeatedmeasuresANOVAandcategoricaldatawerecomparedbytheχ2testorFisher'sexacttest.
SurvivalcurveswereestimatedbytheKaplan-Meiermethodwiththelog-ranktest.
Multivari-ateanalysiswasperformedusingtheCoxproportionalhazardregressionanalysis.
Pvalues<0.
05wereconsi-deredsignificant.
Table1Baselinecharacteristicsofthe80patientsControl(n=40)Ulinastatin(n=40)PAge56±1256±100.
861Gender(male/female)34/633/70.
762TNMstage(I/II/III)7/18/156/20/140.
897Lengthofresection(cm)10±4.
811±4.
00.
157Numberoflymphnodedissection11±4.
110±4.
60.
154Alcoholconsumption(yes/no)25/1523/170.
648Smoker(yes/no)21/1920/200.
823FEV1/FVC(%)85.
3±3.
385.
1±4.
30.
769ASAclassification(I/II)18/2217/230.
822Durationofoperation(min)206±44207±430.
918Durationofanesthesia(min)240±46242±440.
862Bloodlossduringoperation(mL)520±43518±620.
903Figure1Effectofulinastatinonrespiratoryindex.
Respiratoryindex(RI)intheulinastatingroup(U)wassignificantlylowerthanthatinthecontrolgroup(C)1hourafterone-lungventilation(T2)andthetimeofsternalclosure(T3;P<0.
05).
TheRIwascalculatedasamarkeroflungdamageusingthefollowingformulas:RI=[FIO2*(760–47)-PaCO2/0.
8]/PaO2.
Zhangetal.
WorldJournalofSurgicalOncology2013,11:84Page2of6http://www.
wjso.
com/content/11/1/84ResultsBaselinecharacteristicsofenrolledpatientsDuringaperiodof12monthsbetweenJanuary2007andDecember2007,80patientsundergoingesophagecto-mywereenrolledinthisstudy.
BackgroundfactorsforesophagealcancerpatientsarelistedinTable1.
Therewerenosignificantdifferencesbetweenthegroupsinaverageage,gender,TNMstage,lengthofresection,numberoflymphnodedissection,alcoholconsumption,smoking,ASAclassification,durationofoperation,dur-ationofanesthesia,andbloodlossduringoperation.
Typeofanesthesiawasthesamebetweenthetwogroups.
Therewerealsonosignificantdifferencesinperi-operativemanagement,includingtheusageofsteroidandelastaseinhibitor,infusionandnutritionalsupport,andNSAIDsandotheranalgesics,betweenthetwogroups.
EffectofulinastatinonrespiratoryindexRIbeforeoperationdidnotdiffersignificantlybetweenthegroups(groupUvs.
C,0.
29±0.
07vs.
0.
31±0.
06),andthereweresignificanttime-dependentchangesinRIvalueinbothgroups(P<0.
05,Figure1).
GroupUsho-wedsignificantlylowerRIvaluesthanthatofgroupC,bothat1hourafterone-lungventilation(T2)(0.
40±0.
09Table2EffectofulinastatinonpostoperativeclinicalcourseControl(n=40)Ulinastatin(n=40)PCardiovascularcomplications111Pulmonarycomplications810.
034Anastomosisleakage111Anastomosisstenosis101Woundinfection111Total1240.
034Death101DurationofICUstay(hours)45±2433±160.
01Lengthofhospitalstay(days)11±410±20.
170Figure2EffectofulinastatinonlymphocytesubsetsandIL-6.
Ulinastatin(U)administrationsignificantlyincreasedtherateofCD3+(A)andCD4+(B)cells,andratioofCD4+/CD8+(D),butdecreasedtherateofCD8+(C)cellsandreleaseofIL-6(E)comparedtocontrolgroup(C)onpostoperativedays1(D1)and3(D2;P<0.
05).
D0=1hourbeforesurgery,D3=Postoperativeday7.
Zhangetal.
WorldJournalofSurgicalOncology2013,11:84Page3of6http://www.
wjso.
com/content/11/1/84vs.
0.
53±0.
11,P<0.
05)andthetimeofsternalclosure(T3)(0.
75±0.
16vs.
0.
90±0.
17,P<0.
05).
EffectofulinastatinonpostoperativeclinicalcourseThepostoperativeclinicalcourseofeachpatientwascare-fullymonitoreddaily,andcomplicationswerechecked(Table2).
Postoperativecomplicationswereobservedin12patients(30%)intheCgroupand4patients(10%)intheUgroup,respectively(P<0.
05).
AsignificantdecreaseinpulmonarycomplicationswasobservedintheUgroup(P<0.
05),andonepatientintheCgroupdiedofpul-monaryoedema.
Althoughlengthofhospitalstayshowednosignificantdifferencesbetweenthetwogroups,thedurationofICUstaywassignificantlyshorterintheUgroup(P<0.
05).
AscanbeseenfromFigure2,ulinastatinadministra-tionsignificantlyincreasedtherateofCD3+andCD4+cells,andratioofCD4+/CD8+,butdecreasedtherateofCD8+cellsandreleaseofIL-6comparedtotheCgrouponD1andD2(P<0.
05).
SideeffectsNopatientexperiencedsideeffectsrelatedtoulinastatinadministration;namely,shock,itching,rash,nausea,vo-miting,orneutropenia.
SurvivalanalysisOf80patientsinthedatabase,onepatientdiedintheCgroupduringtheperioperativeperiod,and3werelosttofollow-up.
Asaresult,76patientswereenrolledforsurvivalanalysis.
TherecurrencerateoftheUgroupwas57.
5%comparedto72.
5%intheCgroup.
Themostcommonrecurrencepatternwaslocoregionalrecurrence(60%intheUgroupand72%intheCgroup),whileotherpatientsdevelopedsystemicrecurrenceoracom-binationofboth.
Recurrence-freesurvivalofallpatientswas33.
8±1.
7months,anditwasstatisticallybetterfortheUgroup(39.
4±2.
2)comparedtotheCgroup(27.
8±2.
4)byKaplan-Meieranalysis(P<0.
05,Figure3).
Multivariateanalysisrevealedthatulinastatinadminis-trationsignificantlydecreasedtheincidenceofrecur-rence(Table3).
DiscussionMajorstressfulsurgeryincludingesophagectomyalwayscausedoverproductionofproinflammatorycytokines.
Theinitialproinflammatoryresponsemaybeuncon-trolledcausinganimbalancebetweeninflammatoryre-sponsesyndromeandcompensatoryanti-inflammatorycytokineresponsesyndrome,whichledtopostoperativecomplications[15].
Forthespecialsurgicalprocedures,theriskofpulmonarycomplicationsafteresophagec-tomyishigherthananyothercommonoperation[16].
Moreover,surgicalstresscancauseimmunosuppressionFigure3Kaplan-Meiersurvivalanalysis.
CumulativerecurrencefreesurvivaldifferencesbetweenpatientsintheCandUgroups.
PatientswithintheCgroupshowedworserecurrencefreesurvival.
Pvaluewasobtainedusingthelog-ranktestofthedifference.
Table3MultivariatecoxproportionalhazardsanalysisforrecurrencefreesurvivalVariablesRecurrencefreesurvivalPRR95%CIUlinastatinadministration0.
1490.
063-0.
351<0.
05TNM1.
8120.
652-5.
0380.
254Alcoholconsumption2.
0660.
909-4.
3440.
757Smoking1.
0880.
534-2.
2170.
817Gender0.
9160.
425-1.
9730.
822Zhangetal.
WorldJournalofSurgicalOncology2013,11:84Page4of6http://www.
wjso.
com/content/11/1/84inresponsetooverproductionofproinflammatorycytoki-nes.
Inesophagealcancer,aprognosticrelationbetweenthepresenceofcomplicationsandimmunosuppressionafteresophagectomyandsurvivalhaspreviouslybeenreported[17,18].
Thesedatasuggestthataneffectivecountermeasureagainstpostoperativecomplicationsandimmunosuppressionisdesirable.
Ulinastatinhasmanyphysiologicaleffectsinsurgicalstress,includingthedecreaseoftheinflammatoryre-action,inhibitionofimmunosuppression,andmodifica-tionofthewaterbalance[13,19,20].
Moreover,previousstudieshaveshownthatulinastatininhibitshumanovar-iancancerandtheeffectcouldberelatedtodown-regulationofproteinkinaseC[21].
Studieshavealsofoundthatulinastatinenhancestheinhibitoryeffectofdocetaxelinbreastcancerbyamechanismconsistentwiththedown-regulatedexpressionofIL-6,IL-8,andTNF-α[22].
Sinceulinastatinhadapreventiveeffectonpostoperativecomplicationsandimmunosuppression,andmightinhibitthegrowthofcancercells,wechoseitforthecertainpurpose.
CD3+,CD4+,CD8+T-lymphocytepercentageandCD4+/CD8+ratiowerecloselyrelatedtothecellularim-munefunctionandpostoperativeanti-tumorimmunity[23-25].
Moreover,lowerCD3+,lowerCD4+andlowerCD4+/CD8+ratiowerefactorsindependentlyassociatedwithworseprognosisofesophagealcancerpatientsindifferentreports[26,27].
Therefore,weinvestigatedef-fectofulinastatinadministrationoncontentoflympho-cytesubsets.
Inthepresentstudy,itwasfoundthatulinastatinad-ministrationhadaprotectiveeffectonpulmonaryfunc-tionbydecreasingtheincreasingtrendofRIduringoperation.
Asaresult,thepostoperativecomplicationswerelowerthanthatintheCgroup,especiallyforpul-monarycomplications.
LowoccurrenceofpostoperativecomplicationsshortensthedurationofICUstayandde-creasedcostofcare.
Further,weinvestigatedtheeffectofulinastatinonreleaseofIL-6andcontentoflym-phocytesubsets.
Thechangeofpost-operativeIL-6andlymphocytesubsetsreflectedbeneficialeffectsofuli-nastatinonanti-inflammatoryaction,postoperativeim-munosuppression,andpostoperativeanti-tumorresponse.
Finally,weobservedthattheUgrouphadalongerrecur-rencefreesurvival.
ConclusionsFromtheseresultsweconcludedthatulinastatinhadapreventiveeffectonpostoperativecomplicationsandimmunosuppressioninesophagectomypatients,thereby,prolongingrecurrencefreesurvival.
Thepossiblereasonmaybethattheenhancedanti-tumorresponseinhibitedtumormetastasis[28,29].
However,thedetailedmecha-nismofactionofulinastatinshouldbefurtherstudiedatthemolecularbiologicallevel.
Evaluationofalargenum-berofcasesisalsonecessarytoassesstheclinicaluseful-nessofulinastatin.
AbbreviationsIL-6:Interleukin-6;RI:Respiratoryindex.
CompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.
Authors'contributionsLMandNWparticipatedinthedesignandconductionofexperiments,dataanalysis,andfinaldraftingandwritingofthemanuscript.
LM,NW,SZandWYallcontributedtotheseexperiments.
GJandMZwerecloselyinvolvedinresearchdesignanddraftingofthefinalmanuscript.
Allauthorsreadandapprovedthefinalmanuscript.
Authordetails1DepartmentofAnesthesiology,FirstAffiliatedHospital,MedicalSchool,Xi'anJiaotongUniversity,Xi'an710061,ShaanxiProvince,China.
2DepartmentofAnesthesiology,SecondAffiliatedHospital,MedicalSchool,Xi'anJiaotongUniversity,Xi'an710061,ShaanxiProvince,China.
3DepartmentofRadiotherapy,TangduHospital,FourthMilitaryMedicalUniversity,Xi'an710038,ShaanxiProvince,China.
4DepartmentofGastroenterology,TangduHospital,FourthMilitaryMedicalUniversity,Xi'an710038,ShaanxiProvince,China.
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doi:10.
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