CHEMICAL,CLINICAL,ANDIMMUNOLOGICALSTUDIESONTHEPRODUCTSOFHUMANPLASMAFRA - PDF document

CHEMICAL,CLINICAL,ANDIMMUNOLOGICALSTUDIESONTHEPRODUCTSOFHUMANPLASMAFRACTIONATION.XXI.THEUSEOFFIBRINFOAMASAHEMOSTATICAGENTINNEUROSURGERY:CLINICALANDPATHOLOGICALSTUDIES12ByORVILLET.BAILEYANDFRANCD.INGRAHAM(FromtheDepartmentsofPathologyandSurgery,HarvardMedicalSchool,andtheSurgicalServicesofthePeterBentBrighamandTheChildren'sHospitals,Boston)(ReceivedforpublicationFebruary17,1944)Inneurosurgery,thereareseveraltypesofbleedingforwhichthehemostaticagentsnowingeneralusearenotsatisfactory.Byfarthemostcommoniscapillaryoozing.Thecontrolofsuchoozinginthedura,brain,spinalcord,andespeciallythebedsofintracranialtumors,fre-quentlyprolongsneurosurgicalproceduresandattimesisdifficult,ifnotimpossible,tostopcompletely.Anothertypeofbleedingforwhichthecommonhemostaticagentsarenotsatisfac-toryisthatfromtheduralsinusesandotherlargevenouschannelswhereligaturecannotbeap-plied.Thevarioussubstanceswhichhavebeenemployedinthesesituationsuptothepresenttimehavebeendiscussedelsewhere(1,2).WhenfibrinfoamwaspreparedbyBering(1)fromtheproductsoflargescaleplasmafrac-tionation(2,3),theinvestigationofitsusesinneurosurgerywasundertaken,alongwithastudyofthetissuereactionstoitspresence.Therearenowavailableforevaluationbothclinicalmaterialandaseriesofexperimentalstudiesinmonkeys.CLINICALMATERIALFibrinfoamandthrombinhavebeenusedforthecontrolofbleedingin170neurosurgicalpa-tientsatthePeterBentBrighamHospitalandTheChildren'sHospital,Boston.IThisworkhasbeencarriedoutundercontract,recom-mendedbytheCommitteeonMedicalResearch,betweentheOfficeofScientificResearchandDevelopmentandHarvardUniversity.2ThispaperisNumber26intheseries"StudiesonPlasmaProteins"fromtheHarvardMedicalSchool,Bos-ton,Massachusetts,onproductsdevelopedbytheDepart-mentofPhysicalChemistryfrombloodcollectedbytheAmericanRedCross.Thethrombinisdissolvedin30cc.ofsalinesolutionatroomtemperatureandfoamsoakedinthissolutionafewminutesbeforeuse.Thetechnicofapplicationtothebleedingpointneces-sarilyvarieswiththecircumstances.Ingeneral,theareahasbeendriedbysuction,themoistfoamapplied,andacottonpattieheldoverthefoamuntilithasbecomeadherent.Thefoam,appliedinthisway,hasprovedtobeveryeffectiveincontrollingoozingfromtheoutersurfaceofthedura,bleedingfromthesubstanceoftumors,andfromthetumorbedafterremoval,aswellasfromlargervessels,suchaslargesuperficialcor-ticalveinsandevenfromduralsinuses.Thematerialhasbeenleftinplaceinallofthesepatientsinamountsvaryingfromsmallfragmentstoamassthesizeofagolfball.Innoinstancehastherebeenanyclinicalevidenceofcorticalirritation.Furthermore,inthosepa-tientsinwhomtheoperativefieldwasseenafter14hoursto81days,eitheratsecondaryopera-tion(15patients)oratautopsy(4patients),therewasnoevidenceofaninflammatoryreactionorotherunfavorableresult.Thefollowingcasehistoryisgiventoillustrateitsuse:A36-year-oldhousewifewasadmittedOctober16,1943becauseoffailingvision.Twoyearsandfourmonthspreviouslyglasseshadbeenfittedbutshewasnotawareoflossofvisualacuityuntil5monthsago.Therehadbeenamildpersonalitychange,ofwhichthepatientwasnotaware,througha2-yearperiod.Mildheadacheshadbeenassociatedwithmensesformanyyears.Examina-tionshowedalmosttotallossofvisionintherighteyeandabilitytocountfingersatonefootwiththelefteye.Roentgenogramsrevealederosionofthesellaturcicaandslightthickeningoftherightfrontalbone.Adiagnosisofmeningiomawasmadeandarightfrontalboneflapwasturneddown.Thetumorinvolvedthefrontalboneand591 ORVILLET.BAILEYANDFRANCD.INGRAHAMduradowntoandintotherightfrontalsinus.Thein-volvedboneanddurawereresectedandthelargevesselsaroundthetumorclippedorcoagulated.Amassfillingtheentirefossaanddisplacingthefalxtotheleftofthemidlinewasthenmobilizedandliftedout.Alargeballoffoamwasimmediatelyplacedinthetumorbedwhichwasbleedingfreelyfromnumerouspoints.Thiswasheldinplacewithapieceoflintine(cotton)forseveralminutesandthecentralportionofthefoammassthenpulledgentlyoutleavingathinshellofthematerialliningthebed.Atthispointtherewasnobleeding.Thecavitywasfilledwithsaline,theduraldefectreplacedwithfibrinfilm(de-scribedbelow)andtheflapclosed.Recoverywasun-eventful.Histologicaldiagnosis:Meningioma.(Note:Thereisnoreasonwhytheentiremassoffoamshouldnothavebeenleftinplaceifnecessary.Theuseofthefoammadeitpossibletoremovetheentiretumoratonetimeandtoleavethetumorbedentirelyfreefromoozing.Thiswas,moreover,accomplishedinamuchshortertimethanwouldhavebeenpossiblewithouttheuseofthefoam.)TISSUEREACTIONSOFFIBRINFOAMSINHUMANPATIENTSFibrinfoamsbeforeimplantation.SamplesoffibrinfoamswerefixedinZenker'sfluid,em-beddedinparaffin,cut,andstainedwithphloxine-methyleneblue.Underthesecircumstances,thefoamwasfoundtoconsistofanetworkofdarkbluefiberswithclearinterstices.Thisisatwo-dimensionalpicture;inthreedimensions,thestructureofthefoamwouldbemorelikeahoneycomb.Therewasaclosesimilarityinstainingreactionbetweenthefibersofthefoamandthefibrinofspontaneousbloodclots.How-ever,thefibersofthefoamwerecoarserandmorehomogeneousthanwerethefibersoffreshlyclottedblood.Tissuereactionsinhumanpatients.WehaveFIG.1.LowPOWERPHOTOMICROGRAPHSHOWINGFIBRINFOAMONTHESUPERIORSURFACEOFTHEDURAThespecimenwasobtainedatautopsy,14hoursafteroperation.Theillustrationshowsthehistologicalappearanceofthefoamandthelackofimmediatereactioninthispatient.592 FIBRINFOAMASAHEMOSTATICAGENTINNEUROSURGERYFIG.2.PHOTOMICROGRAPHSHOWINGASMALLFRAGMENTOFFOAMINASPECIMENOBTAINEDATSECONDARYOPERATION24DAYSAFTERTHEORIGINALOPERATIONThiswastheonlyfragmentoffoamidentified.hadtheopportunitytostudythetissuereactionstofibrinfoamsin19humanpatients.Inthesepatients,foamswereremovedatsecondaryoper-ationsor(in4instances)atautopsy.Thelengthoftimethatthefoamhadbeenincontactwiththetissuesvariedfrom14hoursto81days.Figure1showstheappearanceoffoam,whichhadbeenappliedtotheduraatoperation,14hoursbeforedeath.Theappearanceofthefibersofthefoamwasessentiallythesameasbeforeithadbeenincontactwiththetissues.Theinterstices,however,hadbecomefilledwithclottedblood.Therewasnoreactioninthetissues.Thecompleteabsenceoftissuereactioninthisspecimenmaybedueinparttothepoorgeneralconditionduringthe14hoursthatthefoamwasincontactwiththedura.Inaspecimenoffoamobtained3daysafterithadbeenleftonthedura,thetotalamountoffoamwasmuchlessthanthatoriginallyplacedthereatthetimeoftheoperationbutconsider-ablenumbersoffiberswereeasilyidentified.Thefoambecameeosinophilicattheperipherywhereitwasincontactwithlivingtissues;exceptforthisnarrowzone,thefoamretainedthesameappearanceasithadbeforeitwasplacedinthepatient.Aboutthefoam,thereweremoderatenumbersofpolymorphonuclearleukocytesandlymphocytes.Alsopresentwerescatteredmono-nuclearcellswhichcontainedhomogeneouseosin-ophilicmaterial,judgedtobeminutefragmentsoffoam.Nolargefragmentsofthefoamwerefoundinanyofthespecimensexceptthoserecoveredat14hoursandat3days.Inspecimensobtainedfrom7to24daysaftertheyhadbeenleftinplaceatoperation,eitherafewverysmallfragmentswerepresentornotraceoffoamwasfound.Figure2illustratestheonlyremnantofthefoamwhichcouldbeidentified24daysafteralargeamounthadbeenusedtocontroloozingfromthedura.Therewasasmallmatoffibrous593 ORVILLET.BAILEYANDFRANCD.INGRAHAMtissueaboutthefragmentandafewmononuclearcellswereseen.Thematerialaboutthefrag-mentwasmostlyfreshbloodfromthesecondoperationatwhichthetissueswereremoved.Sincethefoamwasusedtocausethecoagulationofblood,itwasinevitablethatthefoamshouldatoncebesurroundedbybloodclot.Therewouldbeaconsiderablenumberoffibroblastsproducedintheorganizationofthebloodclot.Hence,itwasimpossibletodeterminehowmanyofthefibroblastswereduetothepresenceofthefoamandhowmanytothebloodclot.Itap-pearedfromthisandotherspecimens,thatthetissuereactiontothefoamwaslessthantoabloodclotofcomparablesize.Figure3showsaportionofcerebralcortexonwhichfibrinfoamhadbeenusedasahemostaticagent81dayspreviously.Notraceoffoamre-mained.Whilethefibroustissueofthearach-noidwassomewhatincreased,thiswasnotinexcessofthatexpectedfromtheoperativepro-cedurealone.Therewerenotissuechangeswhichcouldbedefinitelyrelatedtothefibrinfoamanywhereinthespecimen.ANIMALEXPERIMENTSAseriesofanimalexperimentswasalsocarriedouttodeterminethelocalreactionofcerebraltissuestofoamandthrombin.Forthisstudy,37monkeys(Macacamulatta)wereusedtotest6standardconditions.Thesenotonlyprovidedanopportunitytostudythetissuereactionstofibrinfoambutalsoincludedanopportunitytocomparethetissuereactionduetofoamwiththatduetosolublecellulose.Ineachanimal,A:,,!7'A4;&#x~~~~;&#x Tj ;&#x/F1 ;$.3;� Tf;&#x 47.;t T;&#xz 4.; T;&#xs 66;&#x.24 ;� Td;&#x 000;*^SA-1-1v.%**.P..~~*SSFIG.3.PHOTOMICROGRAPHOFMENINGESANDCEREBRALCORTEXSHOWINGTHESITEATWHICHFIBRINFOAMHADBEENPLACED81DAYSPREVIOUSLY.NoRESIDUALFoAMWASIDENTIFIED.Whilethefibroustissueofthemeningeswasincreased,theamountwasnotinexcessofthatwhichcouldbeaccountedforbytheoperativeprocedurealone.5940.- FIBRINFOAMNASAHEMOSTATICAGENTINNEUROSURGERYbilateralcraniotomieswereperformed,theduraopenedandtheparietallobeexposed.Foamandthrombinwereplaced(1)onthenormalcortex,(2)oncortexdamagedbymultipleneedlewoundswhichproducedbleeding,and(3)withinthesubstanceoftheparietallobeatadepthof3to4mm.Sinceitwouldobviouslybedesirabletousethematerialincompoundheadinjurieswithgrosscontamination,particularlyunderwarconditions,thesameprocedureswerecarriedoutusingfoamandthrombinincombinationwithsulfadiazineandagainwithpenicillin.Theani-malsweresacrificedatperiodsvaryingfrom3hoursto3months.Therewasnophysiologicalevidenceofcorticalirritationorotheruntowardeffectsinanyoftheseanimals.Whenthemonkeysweresacrificed,theskullswerefixedin10percentformalinafterexcesstissuehadbeentrimmedawav.Theskullwasthendissectedawaysothattherelationshipofmeningesandcerebralcortexcouldbestudiedwvithoutdistortion.Blocksoftissuewerethencut,embeddedinparaffin,andstainedwithhematoxylinandeosin.Theearliesttissuereactioninthemeningeswastheappearanceofsmallnumbersofmononuclearcellsandpolymorphonuclearleukocytes.Thiswasfollowedbyarapiddisappearanceofthefoamwithcondensationintoamorecompactmass.Thecellularinfiltration,neverextensive,becameminimalandtherewasaslightprolifera-tionoffibroustissue.Onlyverysmallbitsoffoamwerepresentafter1weekandnofragmentsatallcouldbeidentifiedat3weeks.Whenrelativelylargepiecesoffibrinfoam(4X4X6mm.)wereinserteddirectlyinthesubstanceofthecerebralcortex,thesedisap-pearedatleastasrapidlyasonthemeninges.Themaximumtissuereactionnotedinanyofthesemonkeyswasaslightgliosisatthesiteofimplantationofthefoam.Someoftheexperimentswereplannedtopro-videabasisforcomparisonofthetissuereactionsoffibrinfoamandofsolublecellulosesoakedinhumanthrombinsolution.Allthemonkeysinthisgrouphadidenticaloperativeproceduresoneachsideoftheskullasoutlinedabove,butfibrinfoamwasimplantedononesideandsolublecellulosesoakedinthrombinontheother.In2monkeys,therewereadhesionsbetweenthearachnoidandduraonthesideonwhichsolublecellulosesoakedinthrombinhadbeenplacedbutnoadhesionsontheoppositeside,wherefibrinfoamhadbeenimplanted.Theextentoftissuereactionandrateofabsorptionwereother-wisequitesimilarwiththetwohemostaticagents.Whensulfadiazinewasplacedinexperimentalwoundscontainingfibrinfoam,therewerenodetectablechangesinthephysicalcharacteristicsofthefoamorinthecharacterorextentofthetissueresponse.Inexperimentalwoundscon-tainingbothfibrinfoamandpenicillin,theprop-ertiesofthefoamwereunchangedandthetissueresponsewasnotaltered.3COMMENTFromtheclinicalpointofview,fibrinfoamhasprovedtobeavaluablehemostaticagentinneurosurgicalprocedures.Itisreadilypreparedfromthedrystateintheoperatingroomandthethrombindissolvesquickly.Verylittledelay,therefore,isoccasionedinpreparingthematerialevenwhenvigorousbleedingisencounteredun-expectedly.Bytheuseofthefoamandthrombin,asout-linedinprecedingparagraphs,completecontrolofoozingissecured.Thisappliesnotonlytobleedinginsuchsituationsasthedurawherethemoreconventionalmethodsareadequatebuttimeconsuming,butalsotosuchlocationsasthebedsofneoplasms,wheretheconventionalagentsarenotalwayssatisfactory.Itisalsoofgreatassistanceincontrollingmorevigorousbleedingfromlargevenouschannels,suchastheduralsinusesandcerebralveins.Fibrinfoam,how-ever,isseldomeffectiveinthemanagementofbleedingfromlargearteries.Thematerialhasaconspicuousadvantageovermuscleinthatitcouldbemadeeasilyavailableinanydesiredquantityandinthatitcauseslesstissuereactionthandoesmuscle.Inthisseriesofcases,thefoamhasfrequentlysavedconsiderabletimeandhasmadeitpossibletoaccomplishcompleteextirpationofatumorwhichmightotherwisehavebeenimpossibleorIThepenicillinwasprovidedbytheOfficeofScientificResearchandDevelopmentfromsuppliesassignedbytheCommitteeonMedicalResearchforclinicalinvestigationsrecommendedbytheCommitteeonChemotherapeuticandOtherAgentsoftheNationalResearchCouncil.595 ORVILLET.BAILEYANDFRANCD.INGRAHAMwouldhavehadtobedividedintotwoormorestage.Thetissuereactionstothefoamareminimalbutnotentirelyabsent.Notonlyaretheyslighterthanthereactioncausedbyhumanmusclewhenusedasahemostaticagent,buttheyarealsoconsiderablylessthanthosecausedbysilkandcatgutsuturesorbonewax.Theamountoffibroustissueproducedismorenearlycomparabletothatresultingfromtheorganiza-tionofasmallbloodclot.Asamatteroffact,itisdifficulttodeterminewhetherthesmallamountoffibroustissueleftatthesiteofim-plantationoffoamisduetothefoamitselfortoorganizationofthebloodclotwhichthefoamhasinduced.Itispossiblethattheseminimaltissuereactionsmaybefurtherreducedbychangesinthemethodsofpreparationofthefoamssothattheyareabsorbedevenmorequickly.Theexperimentalevidenceindicatesthatthefoammaybeusedinwoundstreatedwithsulfa-diazineandpenicillinwithoutchangeintissuereaction.Clinicalexperienceinafewinstancesisinaccordwiththeexperimentalstudiesonthispoint.Additionalillustrationanddiscussionoftheutilityoffibrinfoamhasbeenpresentedelse-where(1,4).SUMMARYFibrinfoamhasbeentestedunderavarietyofexperimentalconditionsinaseriesofmonkeys.Thetissuereactionswereminimalinallanimals,includingthoseinwhichthefoamwasimplantedinconjunctionwithsulfadiazineandpenicillin.Thefoamwasusedin170neurosurgicalpa-tients,undervaryingconditions.Itsrapidhemostaticactionhasshortenedmanyopera-tions.Insomeinstances,ithasmadesuccessfuloperationpossiblewhenotherhemostaticagentswouldhavebeeninadequate.BIBLIOGRAPHY1.Bering,E.A.,Jr.,Chemical,clinical,andimmunologicalstudiesontheproductsofhumanplasmafractiona-tion.XX.Thedevelopmentoffibrinfoamasahemostaticagentandforuseinconjunctionwithhumanthrombin.J.Clin.Invest.,1944,23,586.2.Edsall,J.T.,Ferry,R.M.,andArmstrong,S.H.,Jr.,Chemical,clinical,andimmunologicalstudiesontheproductsofhumanplasmafractionation.XV.Theproteinsconcernedinthebloodcoagulationmechanism.J.Clin.Invest.,1944,23,557.3.Cohn,E.J.,Oncley,J.L.,Strong,L.E.,Hughes,W.L.,Jr.,andArmstrong,S.H.,Jr.,Chemical,clinical,andimmunologicalstudiesontheproductsofhumanplasmafractionation.I.Thecharacterizationoftheproteinfractionsofhumanplasma.J.Clin.Invest.,1944,23,417.4.Ingraham,F.D.,andBailey,0.T.,Theuseofproductspreparedfromhumanfibrinogenandthrombininneurosurgery.Fibrinfoamsashemostaticagents;fibrinfilmsinrepairofduraldefectsandinpre-ventionofmeningocerebraladhesions.J.Neuro-surg.,1944,1,23.596