Disorders of Adhesions or AdhesionRelated Disorder Mon - PDF document

DisordersofAdhesionsorAdhesion-RelatedDisorder:MonolithicEntitiesorPartofSomethingBigger—CAPPS?DavidM.Wiseman,Ph.D.,M.R.Pharm.S.Thepurposeofthisarticleistoreviewprogressintheeldofabdominopelvicadhesionsandthevalidityofitstwounderlyingassumptions:(1)Theformationof 700%)ofinitiatingconditionsinpatientswithHCthaninthosewithoutHC.TogetherwithndingsrelatedtothetoxicityofIntergel,thesendingsraisethepossibilitythatheterozygotesforgenesregulatingoxidativestressareatgreaterriskofdevelopingsurgicalcomplicationsaswellasmoresevereandprogressiveconditionssuchasCAPPS.Adhesions,adhesion-relateddisorder,complexabdominopelvicandpainsyndrome,chronicpelvicpain,hysterectomy,ironoverload,hemochromatosishehistoryofadhesionpreventionhasbeenanalyzedintermsofsixepochsdividedprincipallyaccordingtothelevelofsophisticationoftheapproachesused.Theperiodreferredtoas‘‘TheIndustrialRevolu-tion’’startingaround1989wasmarkedbytheintroduc-tionofInterceed(1989;Ethicon,Inc,Somerville,NJ),Sepralm(1996;GenzymeCorp;Cambridge,MA),Preclude(ca.1990;WLGore&Associates,Flagstaff,andAdept(2007;BaxterHealthcareCorporation,Deereld,IL).Hyaluronicacid,Flogel(poloxamer;Alli-ancePharmaceuticalCorp.,SanDiego,CA),tolmetin,Focalgel(Focal,Inc.,Lexington,MA),andtissue-typeplasminogenactivatorwereallevaluatedforadhesionprevention,butdidnotreachthepointofregulatorysubmission.Sepracoat(1997;GenzymeCorp,Cam-bridge,MA)wasdeniedapproval,andIntergel(2002;Ethicon,Inc.,Somerville,NJ)wasapprovedbutwith-drawnforsafetyreasons.Adcon-L(1998;Gliatech,Inc.,Cleveland,OH)wasapprovedforspinalsurgerybutlaterwithdrawn.SepralmIIwasbrieyavailableinEuropebutdiscontinued,andSprayGel(Covidien,Manseld,MA),andHylagel(FidiaAdvancedBiopolymers,s.r.l.AbanoTerme,Italy)remainavailableonlyoutsidetheUnitedStates.This‘‘IndustrialRevolution’’hasfueledanexplo-sioninourgraspofabdominopelvicadhesionsanditsetiology,epidemiology,preventioninhumanandanimalmodels,aswellasitsclinicalmanifestationsofpain,infertility,andbowelobstruc-Twoassumptionsunderlyingthecontem-porarystudyofadhesionsandtheirpreventionarethefollowing:1.Theformationofadhesionsresultsininfertility,bowelobstruction,orothercomplications.Reducingoravoidingadhesionswillcurbthesesequelae.2.‘‘Adhesions’’isamonolithicentitytobetackledwithoutregardtoanyothercondition.Thepurposeofthisarticleistoreviewourprogressintheeldanditsunderlyingassumptions.DOESREMOVALORAVOIDANCEOFADHESIONSIMPROVEPATIENTOUTCOMES?Ithaslongbeenarguedthatthecollectionofoutcome-baseddataforregulatorypurposeswouldbeimpracticalduetothemultifactorialnatureofpainandinfertilityortheprolongedfollow-uprequiredinlargenumbersofpatientstoevaluatebowelobstruction.Nonetheless,studieshaveemergedthatpermitustotestourhypoth-esesthattheremoval(i.e.,adhesiolysis)oravoidanceofadhesions(i.e.,useofadhesionbarriers)willresultinclinicalbenets.AdhesionReductionandSurgicalComplicationsThatthereductioninadhesionformationwouldresultintheoverallreductionofsurgicalcomplicationsisobviousfromtheseveralepidemiologicstudiesndingthatapproximatelyonethirdofpatientsundergoingabdominalorpelvicsurgerywereadmittednearlytwiceinthenext10yearsforaproblemrelatedtoadhesionsorthatcouldbecomplicatedbyadhe-sions.13,23Thesameargumentisjustiedfromthenumerousstudiesshowingthereductioninincidence,extent,orseverityofadhesionsusingavarietyofadhesionbarriers.Moredirectevidencecomesfromasmallretrospectivestudyinvolving52patientsundergoingasecondcesareansection,whichfoundthatdeliverytimesandoperativetimeswerereducedinpatientshavingSepralmplacedatarstcesareansectioncomparedwiththoseinpatientswhereSepra-lmwasnotused.Bloodlosswasalsoreducedbutdidnotreachsignicance.RelaparotomytimewasalsoreducedinchildrentreatedwithSepralm(undergoingabdominalsurgerycomparedwiththatofcontrolpatients.Aprospectiverandomizedstudyfailedin191patientstodemonstrateanysignicantdifferencesinthetimetoclosealoopileostomyifSepralmhadbeenusedatthetimeofileostomycreation.Thisfailurewasattributedtothevariabilityintechniquesusedbythelargenumberofsurgeons(29)participatinginthestudy.AdhesionReductionandInfertilityTheAmericanFertilitySociety(AFS)classicationofadnexaladhesionsinherentlyacknowledgesaninverserelationshipbetweenadhesionsandfertilityhasbeenconrmedintwoways.First,pregnancyrateshavecorrelatedwithAFSscores(beforeadhesiolysis)inprospectivesettingsbybothlaparotomyandlaparo-Second,thepregnancyratesamonginfertile DISORDERSOFADHESIONSORARD otherinpatientdiagnosesofperitonealandpelvicadhe-sionsareadded,thenancialcostofadhesionseasilyexceeds$5billion,andthatisbeforeoutpatientcostsandlossofworkareconsidered.Theuseofadhesionbarriersasevidencedfromcode99.77isalsoverylow.Thisisalmostcertainlyanunderestimate.Basedonestimatedsalesofadhesionbarriersof$100million,anaveragepriceperunitof$200,andanaverageusageof1unitperprocedure,adhesionbarriersareonlyused,conservatively,in500,000proceduresannually.Toestimatetheirpotentialusage,assumingthatobstructionduetoadhesionsrep-resents1%ofgeneralsurgicaladmissionsin1year,thenthegureof99,075dischargesforintestinaladhe-sionswithobstructionrepresentssome9.9millionpro-cedureswherebarriersmightbeused.Thepercentageofproceduresinwhichadhesionbarriersareusedisatbestalittleover5%.Solvingtheproblemofadhesionsmaybebrokendownintofourmaintasks:1.Developmoreeffectiveantiadhesionagentsforavarietyofindicationsbothbylaparotomyandlaparo-2.Expandbasicresearchbeyondthatcurrentlycon-ductedbyahandfuloflaboratories.3.Increasephysicianandpatientawarenessaboutadhesionsandtheirpreventiontoimprovetheuseofadhesionbarriersandothertechniques,leadingtomorechancesforimprovedoutcomes.4.Challengetheparadigmsonwhicharebasedcon-temporaryeffortsinadhesionprevention.Isittimeforadifferentlook?Thedevelopmentofmoreadvancedantiadhesionagentshasbeendiscussedelsewhere,andothercon-tributionsinthisissueofSeminarsinReproductiveMedicineprovideaglimpseoftheexcellentbasicresearchbeingconductedintheeld.Thelasttwoitemswillbediscussedfurtherhere.IMPROVINGPHYSICIANANDPATIENTAWARENESSABOUTADHESIONSTheramicationsofphysicianandpatientignoranceaboutadhesionshaslongbeenthesubjectofdebateintheboardroomsofmedicalproductcompaniesandthebarroomsofconferencesonadhesions.Corporateadver-tisingaswellassponsorshipofseveralexcellentstudiessuchasthoseanalyzingdatafromtheScottishNationalHealthServicehasgreatlyincreasedawarenessofadhesions.Revolutionizingpatients’accessanduseofmedicalinformation,theInternethasspawnedtheproliferationofWebsitespromotingresearchandawarenessandprovidinginformationandsupporttofamiliesandpatientsaffectedwithallmannerofconditions,particularlythoseheretoforerelegatedtoobscurityinmedicaltextbooks.Accordingly,in1996weformedTheInternationalAdhesionsSociety,anditsadhesions.orgWebsitenowreceivesmorethan100,000visitorsmonthly.Ignoranceaboutadhesionsamongpatientsandphysiciansisfrequentlyreportedtous,arguablydelayingdiagnosisandtreatmentandinictingadditionalsufferingonpatientsshunnedbytheirphysi-cians,employers,andfamiliesasmalingerers.Tocharacterizethecausesofthisignorance,patientswhohadabdominalorpelvicsurgeriesweresurveyedviatheInternetaboutinformationgiventhempriortosurgeryregardingadhesionsandadhesionbarriers.Fivehundredseventy(43male,527female)patientsrespondedconcerning952procedures.Patientsreportedbeinginformedaboutadhesionspriorto27%oftheprocedurestheyunderwent.Inonly122(12.8%)ofthesewereadhesionsmentionedaspartoftheinformed Table1HospitalDischargeDataforTwoAdhesion-RelatedCodesandUseofBarriers20012002200320042005ICD-9-CMDiagnosisCode568.0PeritonealAdhesionsAllDiagnoses—DischargesAlldischarges156,621168,154172,935180,806186,387Femalepercentoftotal(%)7473727372ICD-9-CMDiagnosisCode560.81,IntestinalAdhesionswithObstructionAllDiagnoses—DischargesAlldischarges89,04891,66488,96594,70899,075Femalepercentoftotal(%)6362626262PrincipalDiagnosisOnly—DeathsAll22192366231121402118Female13961404141812641285Femaledeathsaspercentoffemaledischarges(%)3.253.193.362.812.7899.77ApplicationofAdhesionBarrier——23,81330,105:HealthcareCostandUtilizationProject,AgencyforHealthcareResearchandQuality. DISORDERSOFADHESIONSORARD ireallydon’tknowwhattodoanymore...iiamtoscaredtoaskforhelpbutireallywantitIamsoreadytojustcommitsuicidebutineversucceed(10/9/.feelsuicidaltryingtocopewithARD(3/6/IlostanotherARDpatientthispastweekendtosuicide.Herfamilyandfriendswerenosupportforher.He[rhusband]wastoldheronlyproblemwasaddictiontopainmeds.Thatwasthelaststraw,(fromanARDvolunteer10/2/2006).IhadafullhysterectomyIaminconstantpelvic/abdominalpain.had.additionalsurgeriesforadhesions.Iamstillinconstantpain24–7.Iamsodepressedwiththoughtsofsuicide,however,mydeepfaithwillalwayspreventmefromdoingthis(12/Basedonanecdotalreports,patientswerealsoaskedabouttheiruseofphysicaltherapy.Inthe26%ofpatientsusingit,29%beneted.Suchtherapyhasbeenwidelyreportedtobenetpatientswithadiagnosisofchronicpelvicpain.Fortypercentofpatientsreportedthattheirphysicianwasabletohelptheirconditionsomewhat,withanother51%reportingthattheirphysi-ciansacknowledgedtheirproblembutwereunabletohelp.Contrarytoearlierimpressions,only9%ofpatientsreportedthattheirphysiciansdeniedtheirproblemandwereunwillingtohelp.ViewingARDintheContextofComplexAbdominopelvicandPainSyndrome(CAPPS)Thetermstillleavesthesamefrustratedanddesperatepatienttraversingcontinentsandoceansinthehopeofndingthatonephysicianwith‘‘thesecret’’totheirsuffering.Continuingtopuzzleusareobser-vationsthatsevereARDpatientsaretemporarilyre-lievedofpainafteradhesiolysis,andwhenpainrecurstheyareadhesion-free(andfreeofotherpathology)atlaparoscopy.EquallypuzzlingistheimprovementinpainafterdiagnosticlaparoscopyaloneinpatientswithIfbyusingthetermwehavesuc-ceededinacknowledgingtheexistenceofARDpa-tients’numeroussymptoms,wecontinuetofailpracticallybyassumingthattheyareallrelatedbythecommondenominatorofadhesions.Aswillbeex-plained,amoresuccessfulapproachmaybederivedbyexaminingtheproblemofARDinthecontextofamuchlargerproblemofwhatwehavetermedabdominopelvicandpainsyndrome(CAPPS)denedoperationallyas:asyndromeofnonmalignantoriginconsistingofacomplexofsymptomsoftheabdomenorpelvisthatincludespain,bowel,orbladderdysfunctionofatleast6monthsduration.Bothsidesofthedebateaboutwhetheradhesionscausepainhavefailedtoconsiderneurologicchangesthatoccurinchronicpain.Althoughacuteorsubchronicpainmaybeduetosurgicallycorrectiblepathology(i.e.,adhesions,endometriosis,etc.),oncepainhasbecomechronic(e.g.,6months),changesinthespinalcordanddorsalrootgangliaresultinthetransmissionofunsolicited,inappropriate,anduncontrolledimpulsestothepaincentersofthebrain.Painitselfbecomesthediseasestateratherthanalocalcause.Althoughpaincanbetemporarilyarrestedbytheremovaloftriggerssuchasendometriosisandadhesions,painmayinevitablyreturnbecausetheneuralchangesthemselveshavenotbeenaddressed,akintothephenomenonofphantomlimbpain.Indeed,phantombladderpainhasbeenreportedinpatientsaftercystectomy.Butthestorycontinues.Thecomplexneuroanat-omyofsacral,lumbar,hypogastric,andpelvicplexiaffordsmanyopportunitiesforcross-talkbetweenthenervesofabdominalandpelvictissues.Impulsesonceappropriatefromoneorganmaytriggerimpulsesinanearbypathway,deceivingthebrainintobelievingthattheyhaveoriginatedelsewhere.Further,pathologyinoneorgan(e.g.,uterus,bladder,bowel)mayinduceorhypersensitivityinanother.Thus,apatientinwhomonlyoneorganwasaffectedinitiallymaydevelopaprobleminanother.Manystudiesattesttothecoprevalencebetweenvariousabdominalandpelvicdisorders76,77includingadhesions.Asimilarpatternoforganinvolvementappearstoexistfromourpreliminaryanalysisof687femaleARDpatientsfromtheUnitedStatesrespondingtoourInternet-basedsurvey(Table2).Focusingonadhesionsandcalculatingthecumulativecoprevalenceofthevemostfrequentdiagnosesor Table2ConditionsandDiagnosesReportedbyU.S.WomenVisitinganAdhesions-OrientedWebSiteConditionorDiagnosisPercentofTotal(%)AllU.S.women687100Adhesions:abdominal53277Adhesions:pelvic43363Adhesions:abdominalorpelvic58285Chronicabdominal(notpelvic)pain38356Chronicpelvic(notabdominal)pain38356Chronicpain:abdominalorpelvic47169Irritablebowelsyndrome37655Recurrentbowelobstruction29944Endometriosis27040Interstitialcystitis19729Fibroids18327PelvicInammatoryDisease(PID)9814Hemochromatosisorironoverloaddisorder477Previoushysterectomy38756 DISORDERSOFADHESIONSORARD patientwhohasenteredtheworldofCAPPS,itmaymatterlittlethattheyenteredthroughthedoorofIC,IBS,endometriosis,orARD,anewopportunityexiststolearnfromCAPPSpatientsby:1.AdaptingtherapiesusedinonevariantofCAPPSinpatientswithadifferentvariant.Forexample,sacralnervestimulationhasbeenshowntobeeffectiveintreatingICandisalsousefulintreatingotherCAPPScomponentssuchaschronicpelvicpain.2.Learninghowtopreventpatientssufferingfromthe‘‘monolithic’’varietiesofindividualdiseasesfromprogressingtothemultifactorialcondition.IDENTIFYINGRISKFACTORSFORPROGRESSIONTOCAPPSFROMTHEPERSPECTIVEOFARDGeneticFactorsTherehaslongbeenspeculationaboutgeneticfactorsinARD.Therelativeinabilitytolysebrinmaypredisposeapatienttoadhesions.Hypobrinolysis,associatedwithanalleleoftheplasminogenactivatorinhibitor-1(PAI-1)gene,wasfoundmoreofteninwomenwithendome-triosisthanincontrols.Moredirectlyrelatedtoadhe-sions,carriersoftheIL-1RN*2alleleareatgreaterriskforadhesionformation.MultipleSurgeriesAprimaryoccurrenceofadhesivesmallbowelobstruc-tion(ASBO)isitselfariskfactorforfutureobstruction.TherateofrecurrenceafterarstASBOwascalcu-as16%after41months(range,1to75months),18%at10years,and29%at30years.TheriskofrecurrentASBOincreasedwithincreasingnumberofpriorSBOepisodesandreached81%forpatientswith4ormoreadmissionsduetoASBO.Age40years,typeofadhesion,andpresenceofpostoperativecomplicationswerealsoidentiedasriskfactorsforASBO.TheeffectofmultiplesurgerieshasbeennotedinotherCAPPS-relatedareas.WomenwithIChadsignicantlymorepelvicsurgeriesthandidcontrols,oftenperformedbeforeICwasdiagnosedandpossiblyforpainrelatedtoundiagnosedIC.Oneoverlookedconsequenceofmultiplesurgeryistheaccumulationofscartissuewithinperitonealtissue(asopposedtobetweenperitonealtissue,i.e.,adhesions)andtheeffectthismayhaveinentrappingsensorynerves,givingrisetopainandrelatedsequelae.Perhapsoneeffectofrepeatedsurgeriesistoincreasethepopulationofbroblastsofthe‘‘adhesionphenotype,’’makingtherecurrenceofadhesionsevermorelikely.HysterectomyHysterectomyisassociatedwithseveralCAPPS-relatedconditions.WomenwithIC(215)hadahigher(42%)prevalenceofhysterectomiesthandidcontrolsAdiagnosisofICwasmade1to5yearsafterhysterectomyinmostofthe68%ofthepossiblecases.HysterectomyisalsoassociatedwithahighrateofSBO.Sixty-sevenpercentofpatientsadmittedforSBOhadhadahysterectomy.Therateofadhesion-relatedobstructionaftergynecologicsurgeryforbenignconditionswithouthysterectomyhasbeenestimatedat0.3%.Withhysterectomy,thisratemaybe2to3%andwithradicalhysterectomyashighas5%.Some56%ofourownsampleof687U.S.womenhadhadhysterectomies(Table2),muchhigher0.01)thanthereportedfrequenciesof21to Table4FractionofPatientsReportingVariousConditionswithorwithoutHysterectomyorHemochromatosis/Iron-OverloadDisorder38730047640Adhesions:abdominalorpelvic0.970.691.401.000.841.20Chronicpelvicorabdominalpain0.840.481.760.980.661.47Endometriosis0.530.212.550.850.362.37Interstitialcystitis0.410.123.350.830.253.36IBS0.710.342.080.980.521.90Recurrentobstruction0.550.291.860.890.402.23Fibroids0.380.123.280.870.223.93PID0.220.045.070.810.098.62Hemochromatosis/iron-overloaddisorder0.110.0138.33Hysterectomy0.910.541.70Geometricmeanoffractions/ratios0.440.162.820.900.362.47Hyst,hysterectomy;H-I,hemochromatosisoriron-overloaddisorder. DISORDERSOFADHESIONSORARD pathologicentity.Ratherthanusetermsthatconstraintheapproachtothesepatientsbytheparadigmsofthespecialtyrelatedtothepatient’sinitialsymptomset,itisproposedthatatermsuchascomplexabdominopelvicandpainsyndrome(CAPPS)beusedtoallowtheunencumbereddevelopmentofamultidisciplinarybiop-sychosocialapproach.Itisessentialtounderstandnotonlythepatho-genesisofthe‘‘initiating’’conditionsbutalsohowtheyprogresstoCAPPS.Inthecaseofadhesions,wehavesomeunderstandingofhowadhesionsformandthebreadthofproblemsexperiencedbythesevereadhesionspatient.Butwehavelittleunderstandingofhowadhe-sionsbecomeARDandhowARDbecomesCAPPS.Onthepositiveside,wecanbegintoapplywhatwehavelearnedaboutthetreatmentofCAPPSstemmingfromotherpathologiestothetreatmentofCAPPSstemmingfromadhesions.Theauthorgratefullyacknowledgesthemanythousandsofpatientswhosepersonalcommunicationshavegivenafacetothesufferingofadhesionsandasenseofurgencyinourquesttosolvetheproblem.Theauthoralsothanksthenumerousmedicalandpatientvolunteersaroundtheworldwhohaveprovidedhelpandassistancetotheadhesions.orgWebsite,especiallyRobertaandBruceSpeyerofOBGYN.netformakingtheworkofadhe-sions.orgpossible.ABBREVIATIONSAFSAmericanFertilitySocietyARDadhesion-relateddisorderASBOadhesivesmallbowelobstructionCAPPScomplexabdominopelvicandpainsyndromeCOMTcatechol--methyltransferaseCPPchronicpelvicpainGCH1GTPcyclohydrolaseHChemochromatosisHHChereditaryhemochromatosisIBSirritablebowelsyndromeICinterstitialcystitisIODiron-overloaddisorderPAI-1plasminogenactivatorinhibitor-1PIDpelvicinammatorydiseasepIRSpossibleIntergelreactionsyndromeSBOsmallbowelobstruction1.WisemanDM.Adhesionprevention:pastthefuture.In:diZeregaG,DeCherneyA,DiamondM,etal,eds.PeritonealSurgery.NewYork,NY:Springer-Verlag;2000:401–4182.WisemanDM,TroutJR,FranklinRR,DiamondMP.Metaanalysisofthesafetyandefcacyofanadhesionbarrier(InterceedTC7)inlaparotomy.JReprodMed1999;44:3.BeckDE,CohenZ,FleshmanJW,KaufmanHS,vanGoorH,WolffBG.Aprospective,randomized,multicenter,controlledstudyofthesafetyofSepralmadhesionbarrierinabdominopelvicsurgeryoftheintestine.DisColonRectum2003;46:1310–13194.DiamondMP.ReductionofadhesionsafteruterinemyomectomybySepralmmembrane(HAL-F):ablinded,prospective,randomized,multicenterclinicalstudy.Sepra-lmAdhesionStudyGroup.FertilSteril1996;66:904–9105.HaneyAF,HeslaJ,HurstBS,etal.Expandedpolytetra-uoroethylene(Gore-TexSurgicalMembrane)issuperiortooxidizedregeneratedcellulose(InterceedTC7)inpreventingadhesions.FertilSteril1995;63:1021–10266.DiamondMPandtheSepracoatAdhesionStudyGroup.Reductionofdenovopostsurgicaladhesionsbyintra-operativeprecoatingwithSepracoat(HAL-C)solution:aprospective,randomized,blinded,placebo-controlledmulti-centerstudy.TheSepracoatAdhesionStudyGroup.FertilSteril1998;69:1067–10747.JohnsDB,KeyportGM,HoehlerF,diZeregaGS.ReductionofpostsurgicaladhesionswithIntergeladhesionpreventionsolution:amulticenterstudyofsafetyandefcacyafterconservativegynecologicsurgery.FertilSteril8.WisemanDM.PossibleIntergelreactionsyndrome(pIRS).AnnSurg2006;244:630–6329.HolmdahlL.Mechanismsofadhesiondevelopmentandeffectsonwoundhealing.EurJSurgSuppl1997;579:7–910.PracticeCommitteeoftheAmericanSocietyforRepro-ductiveMedicine.Pathogenesis,consequences,andcontrolofperitonealadhesionsingynecologicsurgery.FertilSteril11.LiakakosT,ThomakosN,FinePM,DervenisC,YoungRL.Peritonealadhesions:etiology,pathophysiology,andclinicalsignicance.Recentadvancesinpreventionandmanagement.DigSurg2001;18:260–27312.LowerAM,HawthornRJ,ClarkD,etal.Adhesion-relatedreadmissionsfollowinggynaecologicallaparoscopyorlapa-rotomyinScotland:anepidemiologicalstudyof24046patients.HumReprod2004;19:1877–188513.LowerAM,HawthornRJ,EllisH,O’BrienF,BuchanS,CroweAM.Theimpactofadhesionsonhospitalread-missionsovertenyearsafter8849opengynaecologicaloperations:anassessmentfromtheSurgicalandClinicalAdhesionsResearchStudy.BJOG2000;107:855–86214.IvarssonML,HolmdahlL,FranzenG,RisbergB.Costofbowelobstructionresultingfromadhesions.EurJSurg1997;163:679–68415.JeekelH.CostimplicationsofadhesionsashighlightedinaEuropeanstudy.EurJSurgSuppl1997;579:43–4516.RayNF,DentonWG,ThamerM,HendersonSC,PerryS.Abdominaladhesiolysis:inpatientcareandexpendituresintheUnitedStatesin1994.JAmCollSurg1998;186:1–917.FarquharC,VandekerckhoveP,WatsonA,VailA,WisemanD.Barrieragentsforpreventingadhesionsaftersurgeryforsubfertility.CochraneDatabaseSystRev2000:18.WisemanDM.Correlationsbetweenanimalandhumanmodelsofadhesions.DiamondMP,DeCherneyAH,eds. 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