Prevention
of
adhesion
formation
in
Wistar-albino
rats
by
increased
bowel
movements
achieved
with
oral
Ricinus
oil
use
for
8
days
postoperatively:
an
experimental
study
Serkan
Kahyaoglu
a,*
,
Hakan
Timur
a,
Metin
Kaba
a,
Inci
Kahyaoglu
b,
Levent
Sirvan
c,
Mahmut
Nedim
Cicek
da
DepartmentofHighRiskPregnancy,ZekaiTahirBurakWomen’sHealthEducationandResearchHospital,Ankara,Turkey
b
DepartmentofObstetricsandGynecology,FacultyofMedicine,UfukUniversity,Ankara,Turkey
cDepartmentofPathology,ZekaiTahirBurakWomen’sHealthEducationandResearchHospital,Ankara,Turkey d
DepartmentofGynecology,ZekaiTahirBurakWomen’sHealthEducationandResearchHospital,Ankara,Turkey
1. Introduction
Adhesionformationisagreatchallengethatcausessignificant
morbidityincluding infertility,chronicpelvic pain,smallbowel
obstruction,complicated repeat surgery and surgical
complica-tionslikeprolonged operationtime,and intestinaland urologic
injuries among women. Prevention of adhesion formation by
effectivetreatmentmodalitiesandmaterialsnecessitates
under-standingthepathogenesisofadhesionformation.Ninetypercent
ofpatientsundergoingabdominalsurgeryand55–100%ofwomen
experiencingpelvic surgery develop adhesions [1].Fortunately,
mostpatientswithintra-abdominaladhesionsareasymptomatic
[2].
Adhesion-relateddisorders(ARD)consistofchronicpelvicpain,
bowel obstruction,ectopic pregnancy, infertility due to
periad-nexaladhesions,dyspareuniaand difficultiesduringsubsequent
surgical procedures leading to increased reoperation time and
frequencyofvisceralinjuries.Inalargeretrospectivestudy,50%of
hospitalre-admissionsaftersurgerywereduetoARD[3].
Humanperitoneumconsistsofamesotheliallayerandvascular
stroma which is in close contact with peritoneal fluid that
facilitatesmotilityoftheabdominopelvicorgans.Peritonealfluid
contains a surfactant that lowers friction between the visceral
tissues [4]. Following surgery, fibrin deposits take place in the
surgically damagedareasoftissues.Fibrinresorption asnormal
physiological repairororganizationtofibrousadhesionaretwo
consequencesofthiscomplexandpathogeneticallyunclearevent
ARTICLE INFO
Articlehistory:
Received13March2012 Receivedinrevisedform7July2012 Accepted4August2012 Keywords: Adhesions Surgery Ricinusoil Animalmodel ABSTRACT
Objective:Adhesionformationfrequentlyoccursafterabdominopelvicsurgeryandcancausesignificant morbidityfor patients.Meticulous hemostasis, minimalaccess surgeryand utilization ofsurgical adjuvants intraoperatively are clinically useful measures to minimize adhesion formation. We investigatedtheclinicalefficiencyoforalRicinusoiltreatmentfor8dayspostoperativelytodecrease adhesionformationinthiscase–controlstudyinaratmodel.
Study design: Following computer-generated randomization, 24 female Wistar-albino rats were operatedon,with10standardcauterylesionsontherightuterinehornandtwosimplesuturelesions onleftuterinehorngeneratedwithabsorbablematerial.Half(n=12)theratsreceived0.13g(0.2ml) Ricinusoilemulsion(40g/60ml)viatheoralrouteduringthefirst8dayspostoperatively,andthe remainingrats(n=11)wereconsideredascontrols.Theextent,severity,degree,totaladhesionscores andhistopathologicalfeaturesoftheadhesionswerethemainoutcomemeasures.
Results:ThedegreeandtotaladhesionformationscoresintheRicinusoilgroupandcontrolgroup revealedsignificantdifferencesinadhesionextentandseverity.ThetotaladhesionscoresoftheRicinus oilandcontrolgroupswere3.002.21and5.182.78respectively(P<0.05).Differencesintypeof inflammation,extentofinflammationandvascularizationwerestatisticallyinsignificantforsutureand cauterylesionsindividually(P>0.05).
Conclusions: Ricinusoiltreatmentfollowingabdominopelvicsurgeryforthe8-dayperiodthatcovers thecompletionoftissuehealingprocessmaybeapromising,cheapandcost-effectivetreatmentstrategy forpatients.
ß2012ElsevierIrelandLtd.Allrightsreserved.
*Correspondingauthorat:Gn.Dr.TevfikSaglamCaddesiEmlakbankasıEvleri, SehitVeliKaraSokakC3BlokNo:32Etlik,Ankara,Turkey.Tel.:+905058868040.
E-mailaddress:mdserkankahyaoglu@gmail.com(S.Kahyaoglu).
ContentslistsavailableatSciVerseScienceDirect
European
Journal
of
Obstetrics
&
Gynecology
and
Reproductive
Biology
j o urn a l hom e pa ge : ww w. e l s e v i e r. c om/ l o ca t e / e j ogr b
0301-2115/$–seefrontmatterß2012ElsevierIrelandLtd.Allrightsreserved. http://dx.doi.org/10.1016/j.ejogrb.2012.08.010
thatoccurinthebaredtissueareasafterperitonealinsultcaused
bysurgicalornonsurgicaltrauma.Peritonealmesothelialcells
re-epithelialize the surface defect from its floor that requires
approximately 8 days for complete regeneration during the
normalhealingprocess.
Thealteredmechanismofperitonealhealingcausesadhesion
formation by triggering the release of vasoactive kinins and
histamine that convert inactive fibrinogen into a fibrin matrix
withinthedamagedperitonealsurfaces.Insufficientlocal
fibrino-lysis by the action of tissue plasminogen activator (t-PA) and
urokinase-likeplasminogenactivator(u-PA)leadstoorganization
offibrinmatrixthatresultsinadhesionformation[5].Adhesions
formasameansof preventingischemic injuryafteroperations
during which the tissues are aggressively damaged, crushed,
sutured, cauterized and devascularized to provide new blood
supply [6]. Foreign materials like sutures, talc powder, fecal
material and/or bacterial infection induce an inflammatory
responsethatleadstoadhesionformation.Rough manipulation
of tissues during surgery, excessive devascularization, blunt
dissectionofformer adhesions, serosaltissuedrying, infections
such as peritonitis, peritoneal endometriosis and free
intra-abdominalbloodclotsareotherriskfactorsthathavebeenrelated
toadhesionformation[7].
Methods of adhesion prevention include the least invasive
surgical approach (laparoscopy versus laparotomy), meticulous
surgical technique and proper utilization of surgical adjuvants
(barrier agents). Oxidized regenerated cellulose (Interceed),
chemicallymodifiedsodiumhyaluronate/carboxymethylcellulose
(Seprafilm) and polytetrafluoroethylene (Gore-Tex) are well
knownand widely usedbarrieragents for preventing adhesion
formation after surgical procedures. However, there remains
limitedevidenceaboutthebeneficialeffectofbarrieragents on
long-termclinicaloutcomessuchas chronicpelvic pain,bowel
obstructionandinfertility[8].
Previously, in two experimental studies conducted on rats,
Chunxiaetal.andWangetal.usedchangtongoralliquid(CTOL)
forincreasingtheintestinalperistalsistoovercomepostoperative
adhesion formation. CTOL has been found to be effective to
decrease the graded scores of intestinal adhesion significantly
[9,10].Zhangetal.investigatedtheclinicaleffectoforalTaozhi
Zhipu Mixture (TZM) in preventing postoperative intestinal
adhesion in a case–control study. TZM was found to increase
postoperative gastro-intestinal peristalsis and significantly
re-ducedtheoccurrenceofpostoperativeintestinaladhesions[11].In
anexperimentalanimalmodelstudy,Boveetal.demonstratedthe
efficiencyof mechanical visceral mobilizationon postoperative
adhesionscoresduetoanatomicallybasedvisceralmobilization.In
thatstudy,continueddailyeffortsbytheinvestigatorsfor7days
withdigital palpation ofviscera,manuallylysedand prevented
surgically induced adhesions and weremore effectivethan no
intervention[12].
Inthiscase–controlanimalstudy,weevaluatedtheeffectofthe
ingestion of Ricinus oil for 8 days, which is the period for
completion of peritoneal healing, on adhesion formation by
increasedbowelmovementspostoperativelytoimpedethebared
areasoftissuesfrombecomingadjacenttooneanother.Themain
outcomemeasureofthisstudywasthemeasurementofthetotal
adhesionformationscore,whichwasdefinedasthesumofextent,
severityanddegreepointsoftheadhesions[6].
2. Materialsandmethods
Twenty-fournon-pregnant,femaleWistaralbinorats,weighing
200–240g, were used to constitute a model for postoperative
adhesionformation by three surgeons (SK, HT, MK) who were
experiencedin experimentalanimalstudies.Thenumberof the
subjectsnecessaryforstatisticalsignificancewithapoweranalysis
of0.80(
b
:0.20anda
:0.05)wasdeterminedas12foreachgroup.TheanimalexperimentalstudiescommitteeofAnkaraEducation
andResearchHospitalapprovedthisstudy,whichwasconducted
atAnimalResearchCenteroftheAnkaraEducationandResearch
Hospital,Ankara,Turkey.
Theratswereacclimatizedinthevivariumfor10daysbefore
the study and were individually housed. A single injection of
ketaminehydrochloride(40mg/kg;i.m.ofalfamin10%,100mg/
ml,Woerden,TheNetherlands)andxylazinehydrochloride(2mg/
kg;i.m.ofalfazyne2%,20mg/ml,Woerden,TheNetherlands)was
utilizedforanesthesiaoftherats.Allsurgicalinterventionsthat
wereappliedtotheanimalswereperformedbytwosurgeons(HT,
MK).Theabdominalskinoftheratswasshavedandpreparedwith
povidone-iodinescrub. A lowermidlineincision,approximately
4cminlengthwasmade.Tenstandardlesionswereappliedonthe
serosal surface of the right uterine horn by using bipolar
cauterization with a power setting of 10W for two seconds.
Twosimplesuturesweremadeontheserosalsurfaceoftheleft
uterinehornbyusing3/0polyglactinabsorbablesuturematerial
takingintoaccountnottodamageuterinevasculature(Fig.1).The
abdominal incision wasclosed in two layers. The
musculoper-itoneumandfasciaweresuturedwithcontinuoussuturesof2/0
polyglactin absorbable suture. The skin was also continuously
closedwith3/0polyglactinsuture.
Afterthefullrecoveryoftheratstheywerehousedseparately
for14days.Duringthefirst8dayspostoperatively,12oftherats
weregiven0.13g(0.2ml)Ricinusoilemulsion(40g/60ml)viathe
oralrouteinthemorningbeforetheirmealbyusingafeedingtube.
Theremaining12ratswerecontrolsandwerefedwiththesame
ratmealbesidesadministrationof0.2mlnormalsalinebyusinga
feedingtubeinthemorningbeforethemealinsteadofreceiving
Ricinusoil.Oneoftheratsfromthecontrolgroupwasfounddead
duringthe1stpostoperativeday,probablyrelatedtoanesthesia.
Twoweekslater,theanimalsweresacrificedwithalethaldose
ofpentobarbitalsodium.Atransversesubcostalincisionwasmade
and the intraabdominal cavity was evaluated for adhesion
formation. One of the authors (SK), who was blinded to case
andcontrolgroupassignment,performedtheadhesionscoringby
usingthesamecriteriainthestudyofLeachetal.[7].Theextentof
adhesionstotheuterinehorndefectswasscoredasfollows:0no
uterineadhesion;11–25%involvement;226–50%involvement;3
Fig.1.Theviewoftencauterylesionsgeneratedontherightuterinehornandtwo simplesuturesappliedontheserosalsurfaceoftheleftuterinehorn.
51–75%involvement,and476–100%involvement.Adhesionswere
furtherclassifiedbasedongrossexaminationaccordingtoseverity
asfollows:0noadhesion;1filmyavascular;2vascularoropaque,
and3cohesiveattachmentofuterinehorntoipsilateralabdominal
sidewall.Thedegreeofadhesionformationgradedasfollows:0no
adhesion;1theadhesioncouldbeseparatedfromthetissuewith
gentletraction;2theadhesioncouldbeseparatedfromthetissue
with moderate traction, and 3 requiring sharp dissection for
adhesiolysis.Thesumofthethreeparameterswasconsideredas
theoveralltotaladhesionformationscore.
Ininvestigatingtheabdominopelviccavitiesofthe23rats,the
adhesion-carryingtissuesincludinguterinehorns,bowel,bladder
and peritoneal surface were excised en-bloc and fixed in the
formaldehyde solution. Histopathological examination of the
specimenswasperformedbyapathologistblindedtothegroups.
Prepared fromthe adhesion-containing tissues,sections witha
5
m
mthickness were preparedand stainedwith hematoxylin–eosinandMallorytrichromeforlightmicroscopeexaminationand
pathologicalevaluationofthetypesandextentofinflammation
and vascularity. Three inflammation classifications were made
according to the majority of the cell types surrounding the
arterioles. Polymorphonuclear leucocyte (PMNL) domination
demonstratesacute,plasmocytedominationdemonstrateschronic
and PMNL+plasmocytes+eosinophils without any domination
demonstrate active-chronic inflammation process respectively
[15]. Under high power magnification (HPX10) by light
micro-scope, the extentof the inflammation was considered as focal
whenrestrictedtoa certainarea,anddiffusewhenallthearea
underthemicroscopeiscoveredwithinflammatoryprocess.The
areas with inflammationwere also evaluated according to the
numberofcapillaries andclassifiedas: <3 and3–10capillaries
within the same adhesion-containing tissue specimens. Blood
capillarieswereidentifiedbyusingaFactorVIIIimmunolabeling
technique.Theextent,severity,degree,totaladhesionscoresand
histopathologicalfeaturesoftheadhesionsconstitutedthemain
outcomemeasuresofthiscase–controlstudy.
StatisticalanalysiswasperformedbyusingIBMSPSSStatistics
Software (19.0, SPSS Inc., Chicago, IL, USA). The results were
presentedasmeanadhesionscoresstandarddeviationvaluesand
comparedbyusingtheIndependentSamplesTestandPairedSamples
Test.Thecomparisonofhistopathologicaldatawasaccomplishedby
usingtheChi-squaretest.Fisher’sexacttestwasusedtocompare
categoricalvariables. P values<0.05were consideredstatistically
significant.
3. Results
Alltheanimalstoleratedthesurgicalprocedureswellexcept
one from the control group. No surgical site infections and/or
incisionalherniawereseen.AlltheanimalswhichreceivedRicinus
oilfor8dayspostoperativelyexperienceddiarrheathroughoutthe
drugadministrationperiodasobservedfromtheirstoolsbythe
authors;on thecontrary, none oftheanimalsfrom thecontrol
group experienced diarrhea postoperatively. The preoperative
meanvalues of weightfor controland Ricinusoil groups were
22711and2279grespectively(P>0.05;IndependentSamples
Test). The postoperative mean values of weight for control and
Ricinus oil groups were 22610 and 22510g respectively
(P>0.05;IndependentSamples Test).The weightchanges within
thebothcontrolandRicinusoilgroupsseparatelywerealsofoundto
bestatisticallyinsignificant(P>0.05;PairedSamplesTest).
Statisti-calanalysisforextent,severity,degreeandtotaladhesionformation
scoresamong theRicinus oilgroup andcontrol group revealeda
prominentbutinsignificantdifferenceforadhesionextent(P=0.05),
asignificant differenceforadhesiondegree (P<0.05),butnot for
adhesionseverity (P>0.05) asshown in Table1. Total adhesion
scores oftheRicinusoilandcontrolgroupswere 3.002.21and
5.182.78respectively(P<0.05).
AsshowninTable2,whencomparedwiththecontrolgroup,
theRicinusoilgroup’shistopathologicalcharacteristicsofuterine
hornswithsuturelesionswithrespecttotypeofinflammation,
extent of inflammation and vascularization were found to be
statisticallyinsignificant(P>0.05)(Figs.2and3).
Table1
ComparisonofRicinusoilgroupandcontrolgroupaccordingtoadhesionformation scoresintheratuterinehornmodel.
Adhesion Ricinus(n=12) Control(n=11) Pvalue* Extent 1.000.73 1.641.20 0.050 Severity 1.000.73 1.640.80 0.062 Degree 1.000.85 1.911.04 0.032 Total 3.002.21 5.182.78 0.049 ValuesarecomparedasmeanSD.
*
IndependentSamplesTestPvalue.
Table2
Histopathologicalcharacteristicsofuterinehornswithsuturelesions.
Parameter Ricinus group, n(%) Control group, n(%) Pvalue* Typeofinflammation Acute 4(33%) 2(18%) 0.40 Chronic 1(9%) 2(18%) 0.48 Active-chronic 7(58%) 7(64%) 0.79 Extentofinflammation 0.30 Focal 4(33%) 6(54%) 0.30 Diffuse 8(67%) 5(46%) 0.30 Vascularization(numberofcapillaries) 0.75 <3 8(67%) 8(73%) 0.75
3–10 4(33%) 3(27%) 0.75
*
PearsonChi-squarevalue.
Fig.2.Postoperativesecondlooksurgicalviewofoneofthecontrolgrouprats demonstratinglowadhesionscore.
AsshowninTable3,whencomparedwiththecontrolgroup,
theRicinusoilgroup’shistopathologicalcharacteristicsofuterine
hornswithcauterylesionswithrespecttotypeofinflammation,
extent of inflammation and vascularization were not found
statisticallysignificant(P>0.05).Neovascularization withinthe
adhesionsand chronicactiveinflammationcontainingscattered
leukocytesbetweendenseeosinophilleucocytesaredemonstrated
inFigs.4and5.
4. Comment
Adhesionformationrequiresthebaredareasofsurgerytocome
closetogetherfora whiletofacilitatetheorganizationoffibrin
exudateresultinginadhesion[13].Inapreviousreviewstudy,a
reduction inperitoneal fibrinolytic activityfollowing peritoneal
trauma was thought to be of key importance in adhesion
formation, and suppression of inflammation, manipulation of
coagulationaswellasdirectaugmentationoffibrinolyticactivity
were found to be promising antiadhesion treatment strategies
[14].Theresultsofthepresentstudydemonstratethatincreased
bowelmovementsfor8dayspostoperativelybyusingapurgative
agentlikeRicinusoilviatheoralrouteasasimpleandrelatively
cheaptreatment modalitydecreasedadhesionformation
signifi-cantly.
Surgical adjuvants, fibrinolytic agents, anticoagulants,
anti-inflammatoryagents,antibiotics,antihistaminics,corticosteroids
and peritoneal instillates have been used to prevent adhesion
formationwithvarioussuccessrates[5,15–17].Themosteffective
productforpreventionofpostoperativeadhesionformationinall
patientsisyettobediscovered.Currently,thereisnotreatment
protocolforanyoftheseadhesionformationpreventionmeasures
that promises todecreasetheadhesionrisk afteran individual
abdominopelvic surgical procedure. We demonstrated the
effi-ciencyofmechanicalseparationmethodinthisstudythatmightbe
anidealmethodtopreventpostoperativeadhesions[6].Itisnot
feasible for all patients to undergo reoperation for division of
freshlyformedadhesionsintheacutetimeperiodpostoperatively.
Wetriedtoachievethesameresultbyincreasingboththesmall
and thelarge bowelmovements toimpede theorganization of
fibrinexudatethatinducesadhesionformation.
Peritonealadhesions following abdominopelvicsurgeries are
common. Preventionof adhesionformationis thekeybehavior
ratherthantreatmentofformedadhesions[18,19].Althoughitis
notanadhesion-freeprocedure,thelaparoscopicapproachshould
beselectedforabdominopelvicsurgicalprocedureswhenclinical
Fig.3.Postoperativesecondlooksurgicalviewofoneofthecasegroup(Ricinusoil) ratsdemonstratinghighadhesionscore.
Fig.4.Neovascularizationwithintheadhesions.
Fig.5.Chronicactiveinflammationcontainingscatteredlenfocytesbetweendense eosinophilleucocytes.
Table3
Histopathologicalcharacteristicsofuterinehornswithcauterylesions. Parameter Ricinusgroup,n(%) Controlgroup,n(%) Pvalue* Typeofinflammation Acute 6(50%) 3(27%) 0.26 Chronic 2(17%) 2(18%) 0.92 Active-chronic 4(33%) 6(55%) 0.30 Extentofinflammation Focal 7(58%) 7(64%) 0.79 Diffuse 5(42%) 4(36%) 0.79 Vascularization(numberofcapillaries)
<3 8(67%) 5(45%) 0.30
3–10 4(33%) 6(55%) 0.30
conditionsallow.The questionof why aresomepatients more
susceptibletoadhesionformationthanothersstillremainstobe
answered.Anagentoractionthatshouldbeutilizedatthemost
appropriatestageofthehealingprocessforasufficienttimeperiod
toprevent adhesionformation effectively after abdominopelvic
surgeryisdefinitelyneededbythecliniciansattheexpenseofside
effects.
Intraoperativeorpostoperativemeasuresthatincrease
perito-neal fibrinolytic activity or bowel movements postoperatively
seemtobepromisingforpreventionofadhesionformation[11,14–
16]. Possibly, both intraoperative and postoperative clinical
practices during the time period of the healing process have
significanteffectsonadhesionformationpathogenesisfollowing
abdominopelvicsurgery.Todate,meticuloussurgicaltechniqueis
anadequateactionthatmaydecreasethelikelihoodofadhesion
formation. Surgeons should consider to use adhesion barrier
methods, especially for patients with endometriosis, pelvic
inflammatory disease or who are undergoing myomectomy
because of the increased risk of forming clinically apparent
adhesions.Furtherstudiesareneededtoevaluatethelong-term
benefitsofcommercialadhesionpreventionandbarriermethods
such as Interceed, Gore-Tex, and Seprafilm on fertility rates,
abdominaland/orpelvicpain.
Knowingthat theinflammatory processplays a keyrole for
adhesionformation,weselectedthehealthyandidenticalratsfor
conductionofthestudy,butthecurrentinflammatorystatusofthe
ratswasnotexactlyknownbytheauthors.Theclinicalreflectionof
thepromisingresultofthisstudythatdemonstratedthebeneficial
effectoforalRicinusoilutilizationfor8dayspostoperativelyon
reducing adhesion formation among rats may be a promising
methodtoreduceadhesionformationinhumans.However, the
possibleside effects like diarrhea,emesis, vomiting, electrolyte
imbalanceandcomplicationsbyincreasingbowelmotilityinthe
postoperative period caused by Ricinus oil utilization after
abdominopelvicsurgerymayhinderitsuseon humans.Further
randomizedcontrolledstudiesonhumansarerequiredtoevaluate
the effectiveness of Ricinus oil for decreasing postoperative
adhesionformationfollowingabdominopelvicsurgery.
In conclusion, reducing adhesionformation remains a great
challengeforsurgeons.Forpatientswithendometriosisorpelvic
inflammatory disease, it still remains a great challenge for the
clinicians to impede adhesion formation during these kind of
diseaseprocesses.Postoperativeadhesionformationseemstobe
amenable to prevention by utilization of expensive adhesion
barriermethodsorrelativelycheapmechanicallyeffectiveagents
on the bowel movements. In this study,we demonstrated the
adhesionformationpreventingeffectofapurgativeoralemulsion,
specificallyRicinusoil,onratswhichhadundergone
abdomino-pelvic surgery. Ricinus oil treatment following abdominopelvic
surgery forthe8-day periodthat coversthe completionof the
tissue healing process may be a promising, cheap and
cost-effectivetreatmentstrategytoimpedeadhesionformationprocess
forpatients.
Authors’roles
SK: Constitution of the hypothesis, performing the animal
experimentmodel,conception,design,acquisitionofdata,analysis
and interpretation of data, drafting and critically revising the
article,andapprovalofthefinalversion.
HT: Performing the animal experiment model, conception,
design, acquisition of data, analysis and interpretation of data,
draftingandcriticallyrevisingthearticle,andapprovalofthefinal
version.
MK: Performing the animal experiment model, conception,
design, acquisition of data,analysis and interpretation of data,
draftingandcriticallyrevisingthearticle,andapprovalofthefinal
version.
IK: Conception, design, acquisition of data, analysis and
interpretationofdata,draftingandcriticallyrevisingthearticle,
andapprovalofthefinalversion.
LS: Conception, design, acquisition of data, analysis and
interpretationofdata,draftingandcriticallyrevisingthearticle,
andapprovalofthefinalversion.
MNC: Conception, design, acquisition of data, analysis and
interpretationofdata,draftingandcriticallyrevisingthearticle,
andapprovalofthefinalversion.
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