REVISTA
BRASILEIRA
DE
ANESTESIOLOGIA
OfficialPublicationoftheBrazilianSocietyofAnesthesiologywww.sba.com.br
SCIENTIFIC
ARTICLE
Comparison
of
effects
on
the
oxidant/antioxidant
system
of
sevoflurane,
desflurane
and
propofol
infusion
during
general
anesthesia
Mesut
Erbas
a,
Yavuz
Demiraran
b,∗,
Hayriye
Ak
Yildirim
c,
Gulbin
Sezen
b,
Abdulkadir
Iskender
b,
Ibrahim
Karagoz
b,
Hayati
Kandis
daDepartmentofAnesthesiologyandReanimation,MedicalFaculty,C¸anakkaleOnsekizMartUniversity,Canakkale,Turkey bDepartmentofAnesthesiologyandReanimation,MedicalFaculty,DuzceUniversity,Duzce,Turkey
cDepartmentofBiochemistry,MehmetAkifErsoyThoracicandCardiovascularSurgeryTrainingandResearchHospital,Istanbul,
Turkey
dDepartmentofEmergencyMedicine,MedicalFaculty,DuzceUniversity,Duzce,Turkey
Received12February2014;accepted2May2014
Availableonline3June2014
KEYWORDS
Oxidant; Antioxidant; Propofol;
Generalanesthesia
Abstract
Backgroundandobjectives: Desfluraneandsevoflurane arefrequently usedfor maintenance ofanesthesiaandstudieshaveshownthattheseanestheticscauseavarietyofchangestothe oxidativestressandantioxidativedefensemechanisms.Thisstudyaimstocomparetheeffects ofsevoflurane, desflurane andpropofol infusion anesthesiaon theoxidant andantioxidant systemsofpatientsundergoinglaparoscopiccholecystectomy.
Methods:45 patients between 18 and50 years with planned laparoscopic cholecystectomy undergeneralanestheticwereincludedinthestudy.Patientsweredividedintothreegroups onthewaytosurgery:propofol(groupPn:15),sevoflurane(groupSn:15)anddesflurane(group Dn:15).Allgroupsweregivenhypnotic2mg/kgpropofolIV,1mcg/kgfentanylIVand0.1mg/kg vecuroniumIVforinduction.FormaintenanceofanesthesiagroupSwereventilatedwith2% sevoflurane,groupDcasesweregiven6%desfluraneandgroupPweregivenpropofolinfusions of12mg/kg/hforthefirst10min,9mg/kg/hforthesecond10minand6mg/kg/hafterthat. Before inductionandafter theoperationvenousbloodsamples weretaken toevaluatethe levelsofglutationperoxidase,totaloxidantsandantioxidants.
Resultsandconclusions: The45 patientsincludedinthestudywere 22maleand23female patients. The demographic characteristicsof thegroups were similar. In the postoperative periodweobservedthatwhilesevofluraneandpropofolincreasedantioxidantsbyastatistically significantlevel,desfluraneincreasedthetotaloxidantslevelbyasignificantamountcompared tolevelsbeforetheoperation.
©2014SociedadeBrasileiradeAnestesiologia.PublishedbyElsevier EditoraLtda.Allrights reserved.
∗Correspondingauthor.
E-mail:demiraran@gmail.com(Y.Demiraran). http://dx.doi.org/10.1016/j.bjane.2014.05.004
PALAVRAS-CHAVE
Oxidante; Antioxidante; Propofol; Anestesiageral
Comparac¸ãodosefeitosdaperfusãodesevoflurano,desfluranoepropofolsobreo sistemaoxidante/antioxidanteduranteanestesiageral
Resumo
Justificativaeobjetivos: Desflurano e sevoflurano são usados com frequência para a manutenc¸ãodaanestesia,eestudosmostraramqueessesanestésicoscausamalterac¸ões vari-adas nosmecanismos dedefesa antioxidante contrao estresseoxidativo. Este estudoteve como objetivocompararosefeitosdeanestesias comperfusão desevoflurano,desfluranoe propofolsobreossistemasoxidante/antioxidantedepacientessubmetidosàcolecistectomia laparoscópica.
Métodos: Foramincluídosnoestudo45 pacientesentre18 e50anos, agendadospara cole-cistectomialaparoscópicasobanestesiageralforamincluídosnoestudo.Ospacientesforam divididosem trêsgruposparareceberempropofol(GrupoP,n:15),sevoflurano(GrupoS,n: 15)edesflurano(GrupoD,n:15).Todososgruposreceberam2mg/kgdepropofolIV,1mcg/kg de fentanilIVe 0,1mg/kg devecurônioIV para induc¸ão.Para manutenc¸ãodaanestesia, o GrupoSrecebeuventilac¸ãocomsevofluranoa2%,oGrupoDrecebeudesfluranoa6%eoGrupo Precebeupropofolemperfusõesde12mg/kg/hnosprimeiros10min,9mg/kg/hnos10min seguintes e6mg/kg/h subsequentemente.Antesda induc¸ão edepoisda cirurgia,amostras desanguevenosoforamcolhidasparaavaliarosníveisdeglutationaperoxidaseeototalde oxidanteseantioxidantes.
Resultadoseconclusões: Dos45pacientesincluídosnoestudo,22eramdosexomasculinoe 23dosexofeminino.Ascaracterísticasdemográficasdosgruposeramsemelhantes.Noperíodo pós-operatório,observamosqueenquantosevofluranoepropofolaumentaramosantioxidantes a um nível de significância estatística,desflurano aumentou onível total deoxidantes em quantidadesignificativa,emcomparac¸ãocomosníveispré-operac¸ão.
©2014SociedadeBrasileira deAnestesiologia.PublicadoporElsevierEditoraLtda.Todosos direitosreservados.
Introduction
Free oxygen radicals, on the one hand while they oxi-dizebiologicalmoleculessuchasthebody’sbuildingblocks of protein, lipid and DNS, on the other hand they can work against this oxidation as part of the body’s natural antioxidantdefensesystem.Thissituationisbalancedunder normalphysiological conditions.Howeverinasituationof meetinganystress,asaresultofincreasingantioxidant con-sumptionor freeradicalcreation,manyoxidative stresses increase.1,2 Many antioxidant molecules are found in the
bloodtopreventorinhibittheharmfuleffectsoffree oxy-genradicals.Measurementoftotalantioxidantandoxidant levels in plasma can be used to determine the oxidative stress reactionofthe organism.3,4 Desfluraneand
sevoflu-ranearefrequentlyusedformaintenanceofanesthesiaand studieshave shownthat theseanestheticscausea variety ofchangestotheoxidativestressandantioxidativedefense mechanisms.5Thechemicalstructureofpropofolissimilar
tosomefreeradicalconsumerssuchasendogenousvitamin Eandbutylatedhydroxenetoluene.6---8
Inthisstudyweaimedtocomparetheeffectsof sevoflu-rane, desflurane and propofol infusion anesthesia on the oxidant and antioxidant systems of patients undergoing laparoscopiccholecystectomy.
Methods
Afterpermissionwasgivenby2009/12no.decisionofDuzce UniversityMedicalFacultyClinicalStudyEthicsCommittee
and informed patient consent was obtained, 45 patients ASAI---IIbetween18and50yearswithplannedlaparoscopic cholecystectomyundergeneralanestheticwereincludedin thestudy.Patientswere dividedinto threegroups onthe waytosurgery:TIVA(groupPn:15),sevoflurane(groupSn: 15)anddesflurane(groupDn:15).Patientswithendocrine dysfunction,bloodtransfusionintheprevious2weeks,signs ofinfectionandinflammation,historyofpreoperative med-icationuse,anemia,andhemorrhagerequiring transfusion duringtheoperation wereexcluded fromthestudy.After fasting for 8h all patients in the study were given 1mg midazolamIV for premedication 30min beforethe opera-tion.Patientswere taken tothe operatingroom.Routine monitoring withelectrocardiogram (ECG), peripheral oxy-gensaturation(SPO2),andnon-invasivebloodpressurewere done.Laterbeforetheoperationvenousbloodwastakento evaluatetotaloxidantstatus,totalantioxidantstatusand glutationperoxidaselevels.
aftertidalvolumewasdeterminedtobe6---8mg/kgand res-pirationratewas12,ventilationwasbegunwithanAvance S/5anesthesiadevice.Tenminutesbeforetheexpectedend ofsurgerypropofolinfusionwasended.Whenthelastskin suturewasbeingmadeinhalationagentswereshutoff. Man-ualventilationwith100%O2wasundertaken.Inthisperiod allparametricreadingsweretaken.Afterspontaneous respi-rationbegan,neuromuscularantagonizationwascompleted with0.01mg/kgatropineand0.03mg/kgneostigmine.After extubationthepatientwastakentorecovery.Latervenous blood was taken to evaluate total oxidant status, total antioxidantstatusandglutationperoxidaselevelsafterthe operation.
Biochemicalanalysis
Bloodsamplestakeninanticoagulantfreevacuumgeltubes werecentrifugedat2000×gfor15min.Theserumwas por-tioned into clean tubes. For glutation studies the serum separated in the tube was deproteinized. Forthe depro-teinizationprocedure5gmetaphosphoricacidwasdissolved in50mLdistilledwaterand200Lsamplesweremixedwith
200L metaphosphoric acid solution and vortexed. They
wererestedat roomtemperature for5minandwere cen-trifugedat2000×gfor4min.Thesupernatantwascarefully separated to a different tube. This supernatant to mea-sureglutationandtheserumportionsdesignatedtomeasure otherparameterswerestoredat−80◦Cuntilmeasurements couldbemade.Glutationwasmeasuredbasedonenzymatic measurementsusingCayman (CaymanInc.,AnnArbor,MI, USA)commercialkits,whichuse5-thio-2-nitrobenzoicacid (TNB)toreactwiththeDTNB(5,5′-dithio-bis-2-nitrobenzoic acid) of the sulfhydryl group in GSH glutation reductase formingayellowcolor.Onthedayofmeasurement,samples werethawedandmixed,thenprepared4Mtriethanolamine solutionof10Lwasaddedto200Lsamplesandvortexed.
Aftersamplesweredilutedat1:2(v/v)ratiowithMESbuffer, standardswerepreparedaccordingtotheprospectus.They wereaddedto50mwells,andtheplatewascoveredwith
thelid fromwithinthekit.Atthisstage,accordingtothe prospectusanassaycocktailofMESbuffer(11.25mL),GSH co-factormixture(0.45mL),GSHenzymemixture(2.1mL), distilledwater(2.3mL),andGSHDTNB(0.45mL)was pre-paredand150Lfreshly-preparedassaycocktailwasadded
toall wells, the plate wascovered and incubated on an orbitalmixerinthedarkfor25min.Inthe25thminute mea-surementwastakenusingaBio-Rad680Microplatereader at414nm.TotalantioxidantmeasurementsusedaCayman (CaymanInc.,AnnArbor,MI,USA)commercialkitbasedon oxidationinhibitionofABTS•+bythemetmyoglobininABTS (2,2′-azino-di-[3-ethylbenzthiazoline sulphonate]). On the dayofmeasurementsampleswerethawedandmixed,then forantioxidantmeasurementsthesamplesweredilutedwith assay buffer at 1:19 (v/v) and standards were prepared accordingtotheprospectus.After10Ltroloxstandardor
10L sample was added to all wells 10L metmyoglobin
and 150L chromogen solutionwere added and to begin
the reaction immediately 40L 441M antioxidant assay
hydrogenperoxidewasadded.The platewascoveredand incubatedonamixeratroomtemperaturefor5min. Mea-surementwasmadeusingaBio-Rad680Microplatereader
at405nm.TotaloxidantcapacitymeasurementsusedaRel Assaykit(RelAssayDiagnostics, MegaTıpSanandTicLtd Sti, Turkey) developed by Erel.9 This method is based on
oxidants inthesample turningaferrousironchelatorinto ferricions,whichinanacidenvironmentformacolor com-plex with chromogen and this complex is then measured spectrophotometrically. Stabilized stock standard solution (SSSS) was diluted 40,000 times by deionized water then 150Lor the sample wasmixed with1000L reactive I.
First absorbance was measured using a spectrophotome-terat530nmwavelength.FiftyLprochromogensolution
wasadded,mixedandincubatedat roomtemperaturefor 10min.Secondabsorbancewasmeasuredat530nm.
Forcalculationsthefollowingformulaewereused:
TOS=
Absorbancesample
Absorbancestandard
×standardvalue
Absorbance sample=2nd absorbance sample−1st absorbancesample,
Absorbance standard=2nd absorbance standard−1st absorbancestandard,
Standardvalue:20molH2O2equiv./L.
Statisticalanalysis
Data were analyzed using the SPSS v 11.5 (SPSS, Inc., Chicago,IL,USA)computerprogram.Distributionof numer-ical data within the groups was evaluated using the Shapiro---Wilktest.Datawithnormaldistributionaregiven asmean±standarddeviation(SD);categoricalvariablesare givenasfrequencies.Todetermineanydifferencesin aver-agenumericaldatabetweenthegroupstheone-wayANOVA wasused.Tofindgroups responsible forsignificant differ-encesmultivariateanalysisusedtheScheffetest.Beforeand aftermeasurementswereanalyzedwiththepairedsamples
t test as they had normal distribution. Categorical varia-bleswerecomparedbetweenthegroupswiththechi-square test. Ap value <0.05 wasaccepted asstatistically signifi-cant.
Results
Ourstudycomprisedatotalof45 patients:15weregiven sevoflurane, 15 were given desflurane and 15 were given propofolinfusion.Ofthe45patients22weremaleand23 were femalepatients. Therewasnostatistical difference betweenthepatientsinthegroupsintermsofaverageage, weight,andanesthesiaduration(Table1)(p>0.05).
Hemo-Table1 Demographiccharacteristicsofpatients. GroupS GroupD GroupP p
Age(years) 35±8 36±8 34±8 0.84 Heavy(kg) 69±9.3 68±8.8 67±8.6 0.92 Sex(M/F) 9/6 7/8 6/9
Anesthesiatime(min) 106±13 113±18 107±10 0.43
68
Group S
Group D
Group P
Pre-op 1. min 5. min 15. min 30. min 60. min
Post-op 1. minPost-op 5. minPost-op 15. min
70 72 74 76 78 80 82 84
Figure1 Hemodynamicdatafromthegroups.
Table2 TAS,TOSandGSH-PXlevelsofpatients. PREOP POSTOP p TAS(mmol/L)
GroupS 0.6±0.1 0.8±0.2 0.02a
GroupD 0.8±0.2 0.7±0.2 0.24
GroupP 0.6±0.1 0.7±0.1 0.04a
TOS(mol/L)
GroupS 7.1±4.5 10.5±6.4 0.07
GroupD 9.1±4.6 12.6±4.1 0.03b
GroupP 8.4±6.3 6.4±4.2 0.10
GSH-PX(mmol/L)
GroupS 0.7±0 0.7±0.1 0.42
GroupD 0.7±0.1 0.7±0.1 0.89
GroupP 0.8±0.1 0.7±0.1 0.79
a Thereisstatistically significantdifferenceinTASbetween thepreoperativeandpostoperativeperiodingroupsSandP.
b ThereisstatisticallysignificantdifferenceinTOSbetween thepreoperativeandpostoperativeperiodingroupD.
dynamicmonitoring of patientswascompletedduring the operation. During this monitoring the patients’ preopera-tive,intraoperativeandpostoperativemeanbloodpressure (MBP) was recorded (Fig. 1). The MBP values of patients in groups S, D and P were similar. It was observed that sevoflurane and propofol significantly increases the total antioxidantcapacity.Furthermorewefoundthatdesflurane significantlyincreasesthetotaloxidantcapacity.
TheTAS,TOSandglutationperoxidaselevelsofpatients beforeandaftertheoperationareshowninTable2.
Discussion
In this study we reached the conclusion that sevoflurane andpropofolhave antioxidantpropertieswhile desflurane increasedoxidativestress.
The aimof generalanestheticapplicationsis tocreate anesthesiaeffectivelywhilereducingtominimallevelsthe conditionsthatmay harmtheorganism. Anesthetic mate-rial appropriate for this aim should be pure and stable chemically, have quickonset andslowend to effect,and notcreateany unwantedeffects onvitalfunctions during andafteradministration.10Infactanestheticmaterialsand
anesthetic duration used in general anesthesia, together withthestressofsurgicaltrauma,areimportantfactorsthat disruptthe body’simmunologicaland antioxidantdefense systems.11 Laparoscopicsurgeryexposes theparietal
peri-toneumandvisceralperitoneumtoischemictrauma.Studies have shown that if intraabdominal pressure is held at 15mmHgduringlaparoscopy,bloodflowtotheparietal peri-toneumreducesbyasignificantamount,whileat10mmHg there is no change. For this reason pneumoperitoneum maypotentially cause ischemia and increase free oxygen radicals.12 General anesthesia disruptsthe immunological
defense mechanisms and induces an inflammatory reac-tionin alveolarmacrophages.Ingeneralizedinflammatory reactionsincludingproductionofleukocytes,inflammation mediatorsandfreeoxygenradicalsarereleased.Membrane damagecaused byfree radicalsduringgeneral anesthesia presentsasobservedlipidperoxidationproducts.13 Studies
haveshownthatavarietyofmedicationsusedin anesthe-siahaveeffectsontheoxidant-antioxidantsystem.However theeffectontheantioxidantsystemoftheinhalation anes-theticdesfluranehasnotbeenfullystudied.Knowledgeof theinteractionsofinhalationagentusedonpatientsunder oxidativestresscarriesclinicalimportance.14Baysaletal.15
examinedthetotaloxidativestatusandantioxidativestatus levelsofpediatricpatientsundergoinglaparoscopicsurgery andconcludedthatthesurgicalstressoflaparoscopy with inhalationanestheticsincreasedtotaloxidantcapacityand reducedtotalantioxidantcapacity.
Inrecentyearsmanystudiesontheantioxidantsystem havebeencompleted,thesestudiesfoundthatthe antiox-idant system has major effects on patient mortality and morbidity.16Antioxidantsystemsnormallyworkasawhole,
protectingcells fromthetoxiceffects ofoxygenradicals. Thismaintains theoxidant andantioxidantsystemsinthe organisminabalancedfashion.Insituationswherethis bal-anceisdisruptedtowardoxidation,inflammatorymediators andfreeoxygenradicalsareproducedbyleukocytes.These createlipidperoxidationincellmembranes,damagingDNA andcausingdisease.17
while antioxidant capacity was statistically significantly increased.Dikmenetal.18 lookedat theeffectof
sevoflu-raneon the enzymaticantioxidant defense system in the livers of rats and showed that sevoflurane produced an increase in lipid peroxidation before any insufficiency in the enzymatic antioxidant defense system. Allaouchiche et al.19 compared propofol (8mg/kg/h), desflurane (10%)
and sevoflurane (2.5%) to determine oxidative situation in pigs. Pigs were exposed to the anesthetic agents for about120min;propofolincreasedglutationperoxidase lev-els (GSH-Px) significantly in both bronchoalveolar lavage (BAL)fluidandincirculation.Desfluranecausedasignificant decreaseofGSH-PxinbothBALfluidandcirculation,while inthesevofluranegrouptherewerenosignificantchanges identifiedin BALfluidandincirculation. Theystatedthat oxidative stress due to desflurane anesthesia might be relatedtoextreme increasesinproinflammatorycytokines in alveolar macrophages. Sivaci et al.20 used sevoflurane
or desfluraneonpatients undergoinglaparoscopic surgery andobservedthatbothagentshadcytotoxiceffectsdueto freeradicalformation.Desfluranechangesoxidativestress and antioxidant mechanisms negatively; they stated that thenitrogen mixture usedwith desfluranemight increase thiseffectevenmore.Sivacietal.determinedthat desflu-ranereducedserumGSHlevels.Howeverwedidnotidentify anyeffectonserumGSHlevelsduetoeitherdesfluraneor propofol.
Propofol hasbeen found toincreasethe fluidityofthe erythrocytemembranepreventinghemolysis,similarto vita-min E, and shows antioxidant activity. Propofol protects erythrocytes from oxidative and physical stress. Ascorbic acidhasbeenshowntomakethiseffectmorepronounced. Inverselyvolatileanestheticsreduceerythrocytemembrane fluidity inducing hemolysis.21 In our study in the
propo-folinfusiongroup oxidativestressafterthe operationwas reducedcomparedtovaluesbeforeoperation,thoughnot significantly, while at the same time antioxidant capac-itywasstatisticallyincreasedafteroperation.In allthree groupsstatistically significantchanges inglutation peroxi-daselevelswerenotobserved.Inthepropofolinfusiongroup inthepostoperative periodtheywere alittlereduced,in thesevofluranegroupinthepostoperativeperiodtheywere alittleincreasedwhileinthedesfluranegroupnochanges wereobserved.Inourstudyinbothsevofluraneandpropofol infusiongroupsTASvaluesafteroperationwerestatistically significantlyincreasedcomparedtovaluesbeforesurgery.
Conclusion
Thisstudygivesanideathatingeneralanesthesia, neces-saryforavarietyofreasons,incasesunderoxidativestress theagentthatwillleastdamagetheantioxidantsystem,an importantcascadeinthehumoraldefensesystem,andthat willhaveleasteffectontheimmunesystemshouldbe cho-sen.Furtherresearchintotheimmunesituationofpatients receivinggeneralanestheticandtherelationshipbetween oxidant/antioxidantsystemsarerequired.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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