REVISTA
BRASILEIRA
DE
ANESTESIOLOGIA
OfficialPublicationoftheBrazilianSocietyofAnesthesiologywww.sba.com.br
SPECIAL
ARTICLE
Plasma
levels
of
interleukin-10
and
nitric
oxide
in
response
to
two
different
desflurane
anesthesia
flow
rates
Dilek
Kalaycı
a,
Bayazit
Dikmen
a,
Murat
Kac
¸maz
b,
Vildan
Tas
¸pınar
a,
Dils
¸en
Örnek
a,∗,
Özlem
Turan
aaDepartmentofAnaesthesiaandReanimation,AnkaraNumuneTrainingandResearchHospital,Ankara,Turkey bKırıkkaleUniversity,MedicalBiochemistryDepartment,Kırıkkale,Turkey
Received27February2013;accepted10June2013 Availableonline17October2013
KEYWORDS Generalanesthesia; Interleukin; Surgery; Nitricoxide; Desflurane
Abstract
Objective:This study investigated interleukin-10 and nitric oxide plasma levels following
surgerytodeterminewhetherthereisacorrelationbetweenthesetwovariablesandif dif-ferentdesfluraneanesthesiaflowratesinfluencenitricoxideandinterleukin-10concentrations incirculation.
Materialsandmethods: Fortypatients between18and70yearsandASAI---IIphysicalstatus
whowerescheduledtoundergothyroidectomywereenrolledinthestudy.
Interventions:Patients were allocated into two groups to receive two different desflurane
anesthesiaflowrates:highflow(GroupHF)andlowflow(GroupLF).
Measurements:Bloodsamples were drawnatthe beginning(t0) andend(t1) ofthe
opera-tionandafter24h(t2).Plasmainterleukin-10andnitricoxidelevelsweremeasuredusingan
enzyme-linked-immunosorbentassayandaGriessreagentskit,respectively.Hemodynamicand respiratoryparameterswereassessed.
Results:Therewasnostatisticallysignificantdifferencebetweenthetwogroupswithregard
to interleukin-10levels atthe times ofmeasurement. Interleukin-10levels wereincreased equallyinbothgroupsattimest1andt2comparedwithpreoperativeconcentrations.Forboth
groups,nitric oxidecirculatingconcentrations weresignificantly reducedattimest1andt2
compared with preoperativeconcentrations. However, the nitric oxidevalue was lower for GroupHFcomparedtoGroupLFatt2.NocorrelationwasfoundbetweentheIL-10andnitric
oxidelevels.
Conclusion:Clinicalusageoftwodifferentflowanesthesiaformswithdesfluranemayincrease
interleukin-10levelsbothinGroupHFandGroupLF;nitricoxidelevelscirculating concentra-tionsweresignificantlyreducedattimest1andt2comparedwithpreoperativeconcentrations;
however, at 24h postoperatively they were higher inGroup LF compared to Group HF. No correlationwasdetectedbetweeninterleukin-10andnitricoxidelevels.
©2013SociedadeBrasileiradeAnestesiologia.PublishedbyElsevier EditoraLtda.Allrights reserved.
∗Correspondingauthor.
E-mail:[email protected](D.Örnek).
PALAVRAS-CHAVE Anestesiageral; Interleucina; Cirurgia; Óxidonítrico; Desflurano
Níveisplasmáticosdeinterleucina-10eóxidonítricoemrespostaaduastaxasde fluxoemanestesiacomdesflurano
Resumo
Objetivo: esteestudoinvestigouosníveisplasmáticosdeinterleucina-10eóxidonítricoapós
cirurgiaparadeterminarsehácorrelac¸ãoentreessasduasvariáveisesediferentestaxasde fluxo deanestesia comdesflurano influenciam as concentrac¸õesde interleucina-10e óxido nítriconacirculac¸ão.
Materiaisemétodos: quarentapacientes,entre18e70anosdeidade,estadofísicoASAI---II,
programadosparatireoidectomiaforamincluídosnoestudo.
Intervenc¸ões:ospacientesforamdivididosemdoisgruposparareceberdoisfluxosdiferentes
deanestesiacomdesflurano:fluxoalto(GrupoFA)efluxobaixo(GrupoFB).
Mensurac¸ões:amostrasdesangueforamcolhidasnoinício(t0)efinal(t1)dacirurgiaeapós
24h(t2).Osníveis plasmáticosdeinterleucina-10eóxidonítrico forammedidosusandoum
ensaioimunossorventeligadoàenzimaumestojodereagentesdeGriess,respectivamente.Os parâmetroshemodinâmicoserespiratóriosforamavaliados.
Resultados: nãohouvediferenc¸aestatisticamentesignificanteentreosdoisgruposemrelac¸ão
aosníveisdeinterleucina-10níveisnostemposdemedic¸ão.Osníveisdeinterleucina-10 aumen-taramigualmenteemambososgruposnostempost1et2emcomparac¸ãocomasconcentrac¸ões
nopré-operatório.Emambososgrupos,asconcentrac¸õescirculantesdeóxidonítricoestavam significativamentereduzidasnostempost1et2emcomparac¸ãocomasconcentrac¸õesno
pré-operatório.Noentanto,ovalordeóxidonítricofoimenornoGrupoFAquenoGrupoFBnot2.
Nãohouvecorrelac¸ãoentreosníveisdeIL-10eóxidonítrico.
Conclusão:ousoclínicodedoisfluxosdiferentesemanestesiacomdesfluranopodeaumentaros
níveisdeinterleucina-10tantonoGrupoFAquantonoGrupoFB;osníveisdasconcentrac¸ões cir-culantesdeóxidonítricoestavamsignificativamentereduzidosnostempost1et2emcmparac¸ão
comasconcentrac¸õesnopré-operatório;contudo,24hapósacirurgia,essesníveisestavam maioresnoGrupoFBemrelac¸ãoaoGrupoFA.Nãofoidetectadacorrelac¸ãoentreosníveisde interleucina-10eóxidonítrico.
©2013SociedadeBrasileira deAnestesiologia.PublicadoporElsevierEditoraLtda.Todosos direitosreservados.
Introduction
Immune response against surgery is known to be benefi-cialfor defense mechanisms of the body, wound healing, and prevention of antibody formation against tissues.1,2
Cytokinesplayaremarkableroleincontrollingand modulat-ingthereactionsoftheorganismagainstforeignantibodies and agents as well as in local and systemic inflamma-toryresponsesbyregulatingtheintercellularinteractions. Majorityofthecytokinessecretedfromtheimmunesystem areinterleukinsandtheirmainfunctionistostimulatethe immunesystemcells.3Thereisaconstantbalancebetween
the proinflammatory and anti-inflammatory cytokines. By
in vivo and in vitro studies, anesthetic agents and tech-niqueshavebeenshowntohaveaninfluenceovercytokine production.4,5 However, there is no adequate number of
studiesfocusingontheinfluenceofdesfluraneovercytokine release.6 Interleukin-10 (IL-10), known as the cytokine
synthesis inhibitory factor, is one of the most potent immunosuppressive agents. During the surgical and anes-thetictrauma,IL-10andNOproductionshavebeenreported tochange.7ItisbelievedthatIL-10mayalsobeanimportant
factorinregulationofNOmechanism.8
NO is produced in the vascular endothelium from l
-arginineasaresponsetophysicalandreceptorstimulation, by nitric oxide synthase (NOS) which is known to be a
calcium/calmodulin-dependent enzyme.9 NO is a radical
compound due to having a single unmatched electron in itsouter shell.Itisnottoxicinlowconcentrations.While NOplaysanimportant roleinthe managementof cardio-vascularfunction,neurotransmission,andbloodpressure,10
italsobearsimportancewithregard toimmune system.11
Volatileagents have been reported to inhibit endothelial andneuronalNOSbywayofinhibitingintracellularcalcium mobilization.11
Lowflowanesthesiaisatechniquethatisgainingin pop-ularitybecauseitconsumeslessanesthetic gas,hasalow cost,andreducesenvironmental pollution.To thebestof ourknowledge,thereisnostudyfocusingontherelationship betweenlowflowanesthesiaandcytokinerelease.
Theobjectiveofthisstudywastoinvestigateplasma con-centrationsofNOandIL-10intheperioperativeperiodand evaluatewhetherdifferentdesfluraneanesthesiaflowrates couldinfluence systemicNOandIL-10responses. Further-more,weexploredthepossibilityofacorrelationbetween circulatingNOandIL-10concentrations.
Materials
and
methods
Table1 Patientcharacteristics,surgeryduration,andanesthesiaflowtype.
GroupHF(n=20) GroupLF(n=20) p
Age(years) 43.25±14.54 44.65±11.17 0.735
Height(cm) 167±12 168±15 0.200
Weight(kg) 63.95±12.31 69.25±10.91 0.158
Gender(F/M) 15/5 14/6 0.500
ASAI/II 15/5 13/7 0.366
Lengthofanesthesia(min) 128.15+21.23 114.25+28.34 0.087
Lengthofoperation(min) 114.65±21.43 99.25±28.34 0.060
Dataareexpressedasmean±SDornumberofpatients.
committee and acquisition of informed consent from patients. Criteria for exclusion were: age <25 or >75 years, pregnancy, renal and liver insufficiency, oncologic disease,infection, including HIV infection, immunological dysfunctionandtreatment withnitro-derivate compounds or immunosuppressivedrugs. Patientswereallocated ran-domlyintotwogroupsusingthesealedenvelopetechnique. Patients who received no premedication were taken to the operating room and monitored for heart rate, noninvasivearterialblood pressure,andoxygensaturation (JulianPlus,Drager,Lübeck,Germany).Anintravenousline wasopenedwithan18Fcatheterinthebackofthehand andanesthesiainductionwasperformed.
Anesthesiainductionwasconductedwith1---2g/kg
fen-tanyl (Fentanyl, Janssen-Cilag, Belgium) and 2---3mg/kg propofol(Pofol,Dongkook,Pharm.Co.Ltd.,Korea)untilthe eyelashreflexdisappeared.Musclerelaxationwasachieved with 0.1mg/kg vecuronium bromide (Norcuron, Organon, Oss,Holland).
Group HF (n=20) received 6---8% desflurane (Suprane, Baxter,USA)inamixtureof2L/minO2+2L/min air
intra-operatively,whereas Group LF(n=20)received amixture of 1.4L/min O2+3.0L/min air for 10min followed by a
reduction to 0.5L/min O2+0.5L/min air in the fresh gas
flow,while 6---8% desfluranewasdeliveredthroughout the entire operation independently of flow rate. Patients in bothgroups were properlyextubated. The concentrations of propofolused for the induction, and fentanylused for inductionandmaintenance,werenoted.
Heart rate, blood pressure (mmHg), oxygen saturation (%),inhaled oxygenconcentration(%) (FiO2),inhaled
des-fluraneconcentration(%)(FiDes),endtidaldesfluranerate (%), minimal alveolar concentration (MAC), and end-tidal CO2(%)(etCO2)valuesweremonitoredandnotedat5,10,
15,20,30,45,60,75,and90minintraoperatively,andafter extubation.
Patients’ temperature was kept approximately 36◦C
and operation room temperature were approximately 25◦C. Patients in both groups received 75mg diclofenac
sodium intramuscularly for postoperative pain manage-ment and 4mg ondansetron intravenously for nauseaand vomitingprophylaxis30min priortotheendofthe opera-tion.
Thebloodspecimenswerecentrifugedat1500×gforat least10min andtheserumsamplestransferred to Eppen-dorf tubes for storage at −80◦C until measurement of
IL-10and NO. SerumIL-10 levels were measured using a solidphasesandwichELISA(HumanIL-10ImmunoassayKit;
BiosourceInternationalInc.,Camarillo,CA,USA).The cali-brationcurvewaspreparedwithIL-10standardsof1,7.8, 15.6,31.25,62.5,125,250,500pg/mL.Theresultsaregiven aspg/mL.Nitrite/nitratelevelsweremeasuredasdescribed by Tsuei etal.8 Nitratewasreduced tonitrite with
vana-dium(III)andnitritelevelsmeasuredusingGriessreagents, which reflect the total amount of nitrate and nitrite in the sample. Serial dilutionsof 0.5---250Msodiumnitrate
(Merck, Germany)were usedasstandards andthe results wereexpressedasmol/L.
StatisticalanalyseswereconductedwithSPSS13for Win-dows.Theresultswereexpressedasmean±SDandnumber of patients. The statistical differencebetween IL-10 and NOlevels,continuousvariablesacquiredbymeasurement, drug consumption, and length of anesthesia and opera-tionwereanalyzedwithindependentt-test,whereascount data concerning categorical variables were evaluated by chi-square test. Correlation between plasma NO and IL-10 changes at the different time points was performed using Bravais---Pearson’s correlation coefficient. Statistical differences between the mean values of hemodynamic parameters,saturation, FiO2,FiDes, expiratorydesflurane
concentration, and MAC were evaluated by dependent t -test. p<0.05 wasrecognized asstatistically significant in alltheanalyses.
Results
The patientcharacteristics of the two groups, as well as anesthesiaandsurgerydurationaresummarizedinTable1. There were no significant differences between the two groups. Propofol and fentanyl concentrations delivered in the Group HF 163.00±25.77mg, 123.75±42.51g and
Group LF 165.00±29.46mg, 151.25±44.77g (p=0.821,
p=0.054, respectively). There wasno statistically signifi-cantdifferencebetweengroups.
Therewasnostatisticallysignificantdifferencebetween heartrate,meanarterialbloodpressure,oxygensaturation, inhaledoxygenconcentration,andetCO2values(p>0.05).
The high flow group (Group HF) demonstrated signifi-cantly higher FiDess (%) at intraoperative times of 5, 10, 20minandsignificantlyhigherexpiratorydesflurane concen-trations(%)(Fig.1).MACvalueswerehigheratall measure-menttimesexcept30mininthehighflowgroup(p>0.05).
PlasmaIL-10concentrationsshowedsignificantelevation at t1 and t2 compared with baseline values. No
5 6 7 8 9
AE 5 min. 10 min. 15 min. 20 min. 30 min. 45 min. 60 min. 75 min. 90 min.
%
Inspired desflurane concentration Group HF Inspired desflurane concentration Group LF
Expired desflurane concentration Group HF Expired desflurane concentration Group LF
Figure 1 Inspired and expireddesflurane concentration in thegroups (AE,after intubation; Group HF, highflow desflurane anesthesia;GroupLF,lowflowanesthesia).
observedbetweenthetwogroupsthroughoutthestudytime (Fig.2).
NOcirculatingconcentrationsweresignificantlyreduced at times t1 and t2 compared with pre-operative time in
bothgroups.Furthermore,therewasasignificantdifference betweenGroupsHFandLFwithrespecttomeanNOvalues recorded at thet2 time point (Fig.3). The NOvalue was
lowerinGroupHFcomparedtoGroupLFatt2.
Finally,wefoundthattherewasnocorrelationbetween thedecreaseofcirculatingNOatt1andt2andtheelevation
inplasmaIL-10concentrations.
Discussion
We demonstrate that in patients undergoingsurgery with general anesthesia, clinical usage of two different flow
anesthesiaforms with desflurane may increase IL-10 lev-elsboth in Group HF and Group LF, NO levelscirculating concentrations weresignificantly reduced at timest1 and
t2comparedwithpreoperativeconcentrations;however,at
24hpostoperativelytheywerehigherinGroupLFcompared toGroupHF.NocorrelationwasdetectedbetweenIL-10and NOlevels.Wealsofoundthatthehighflow group demon-stratedasignificantlyhigherFiDesatintraoperativetimesof 5,10,20min,aswellassignificantlyhigherexpiratory des-fluraneconcentrationsandMACvaluesatallmeasurement times.
Surgicaltraumaandanesthesiaareknowntoaffectmany functionsoftheimmunesystemthroughvariousfashions.12
Althoughmajorityofstudiesshowthatimmunedepression observedduringthepostoperativeperiodmaybeprimarily stemmingfromsurgery-relatedstress,someinvitrostudies demonstratethatanestheticagentsalsohavearoleinthis
IL-10 (pg/mL)
Group HF; High flow desflurane anesthesia, Group LF; Low flow anesthesia. 1.44
2.00 1.96
1.34
2.41
3.52
0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00
t0 t1 t2
GroupHF GroupLF
NO (µmol/L.)
Group HF; High flow desflurane anesthesia, Group LF; Low flow anesthesia. 38.50
27.75
16.22 45.83
23.85
28.13
0.00 5.00 10.00 15.00 20.00 25.00 30.00 35.00 40.00 45.00 50.00
t0 t1 t2
GroupHF GroupLF
Figure3 Nitricoxidelevelsrelativetomeasurementtime.
depression.Therefore, the numberof studies focusing on therelationshipbetweenanesthesiaandimmunesystemhas increased.
Volatile anesthetics have been reported to suppress cytokine releasefrommononuclear cells, reduce lympho-cyteproliferation,leadtolymphocyteapoptosis,andinhibit neutrophil functions in a dose-dependent way.12---15
More-over, they have been shown to cause proinflammatory gene expression in the alveolar macrophages.16 However,
studies focusing on the influences of volatile anesthetics overcytokineproductionreportdifferingresults.17---20
Desflurane may increase proinflammatory cytokine expressioninthealveolarmacrophages.21,22Desfluranehas
beennotedtoproducemoreproinflammatoryresponse com-paredwiththesevoflurane.23Moreover,desfluraneisknown
tohavenoeffectoverIL-6releaseinendotoxemicratsand itisreportedtocauseconsiderabledecreasesinthelevels ofotherproinflammatorycytokinessuchasTNF-␣andIL-10.
While researching the effects of anesthesia over the immune system, responses against different anesthesia techniques have been studied as well.24,25 Although the
definitivemechanismconcerningtheinfluenceof anesthet-icsover cytokineproductionis notunderstood, calciumis knowntoplayanimportantroleincytokineregulation.26
To the best of our knowledge, there is no study focusing on the relationship between low flow anesthe-siaand cytokine release,particularlyconcerninglow flow desfluraneand cytokinerelease. In thecurrent study,we investigatedtheeffectsofdesflurane,deliveredattwo dif-ferentflowrates,overIL-10andNOlevels.
High flow desfluranewas found toincrease IL-10level at the end of the operation and this increase was shown to be continuing with a mild drop during the postopera-tiveperiod. Low ratedesflurane wasobserved toelevate theIL-10levelattheendoftheoperationaswellandthis elevationwasshowntocontinue duringthepostoperative period.While therewas nostatistically significant differ-encebetweenthetwogroupswithregardtotheincreases, theelevationinthelowflowdesfluranegroupwashigher. IncreasesinIL-10levelmaybeinfluencedbymanyfactors
such as surgical stress, anesthetic drugs, blood loss, and stresshormones.27,28
Whiletherearestudiesindicatingthatdesfluranecauses ahigherincreaseinproinflammatorycytokines,inthe cur-rentstudy,desfluraneelevatedanti-inflammatorycytokine levels in both of the groups and contributed to the proinflammatory/anti-inflammatory balance in a positive way. This influence occurs to be more remarkablein the low rate anesthesia group which may be secondary to generation of more physiological conditions in the respi-ratory tract by low flow anesthesia. Nonetheless, further studies focusing onthe influence of desflurane over anti-inflammatory cytokines,andparticularlythoseconcerning the effects of low flow anesthesia over cytokine release, arerequired.
Changes observed in the IL-10 and NO concentrations during anesthesia and surgical trauma raise the question whetherIL-10hasanyinfluenceoverNOmetabolismornot. In thestudy of Ochoa etal.,elevated IL-10wasfound to haveanimportantroleinNOproductionfollowingtrauma, which wasassociatedwiththearginase activity.26 Whilea
relationshipbetweenIL-10andNOSinsepticanimalmodels under surgicalstress wasshown by one study,27 no
corre-lation could be found between IL-10 and NO by another study.7
While basal NO is required for many normal functions of the body, NO released upon stimulation may lead to variousdamages.TNF-␣,IL-4,IL-10,andmacrophage
differ-entiationinducingfactorinhibitinducibleNOS.29Infaceof
trauma,NOsynthesisisreducedbecauseofincreasesinthe extrahepaticarginaseIactivation.ReducedNOlevelsallow maintenanceofbloodflowintheorgansfollowingtrauma.27
Duringthepostoperativeperiod,reducedNOlevelsin the circulation may be secondary to various factors. Fujioka et al. proposed that hypoperfusion couldlead todefects inNOproductionandtheyfoundlowerpostoperativeserum nitrite and nitrate values in patients who receivedmajor surgery.30
has been shown topromote NO production in the animal trials.31 In a similar study, following induction of sepsis,
urinarynitrateconcentrationwasincreasedandplasma argi-ninelevelwasdecreased.32NOissynthesizedfrom
l-arginine
by NOS. The most important function of NOproduced by iNOSis toinduce acytotoxiceffectover the tumorcells. In addition to its antimicrobial influence, NO also plays a role in the cytokine production, apoptosis, and signal transduction.33
NOisanimportantmoleculethatalsotakespartinthe anestheticprocessandcontributestomechanismsofaction concerningcertainanestheticagents.WhileNOplaysapart inexcitatorysynaptictransmissionviaglutamate,inhibition of excitatory transmissionmaysuppress NOproduction or influence.34
Johns et al. showed that beforehand delivery of NO-synthase inhibitors reduced MAC value of halothane.27
Halothane, isoflurane, and sevoflurane have been shown to inhibit endothelial NOS35 along with NMDA-mediated
neurotransmission and neuronalNOS in rats.36,37 NOplays
a significant part in the regulation of vascular tonus. Halothane, isoflurane, enflurane, and sevoflurane have beenshowntoreducethelevelofendothelium-dependent relaxants.38,39 Inthestudy ofBlaise, halothanewasfound
toslowly,butremarkably suppressthe relaxationinduced by exogenous NO.40 Halothane has been shown to
atten-uate the hemodynamic changes caused by NOS inhibitor, whereasisofluranehasbeen showntohavealowereffect in this aspect comparedwith the halothane.41 Wei et al.
reportedthatisofluraneprevented changesinthe arterial bloodpressureandcerebralvascularresistanceinducedby NOSinhibitors.42
Tschaikovskyetal.reportedthat halothane,enflurane, isoflurane,sevoflurane,anddesfluranereducednitrite pro-duction in a doze and time dependent fashion,11 and
observedahigheramountofnitriteproductiondueto com-bined usageofLPS+TNF-␣comparedwiththe soleusage.
Boostet al.showed that desfluraneincreased NOrelease fromalveolarmacrophages.6
In this study,NOshoweda decreaseat the end of the operationamongthelowflowgroupwhichwasstillpresent at 24h postoperatively,whereasNOexhibitedareduction attheendoftheoperationbutstartedtoriseagainat24h postoperatively.
Presentstudyresultssuggestthatdesflurane,similarto othervolatileanesthetics,reducesNOrelease.This conclu-sionwasnotconsistentwiththestudyofBoostetal.which hasshownthatdesfluraneincreasedNOrelease.6This
incon-sistency may be arisingfrom the differencebetween the times of measurement, becausein our study,NOlevel at 24hpostoperativelyapproachedthebasalvalueinthelow flowgroup.
Deloguetal.conductedastudywithpropofol---fentanyl andsevofluraneinwhichtheyfoundanincreaseinIL-10level andadecreaseinNOlevelpostoperatively;nocorrelation wasreportedbetween thechanges.7Inthe present
inves-tigation we were unable to demonstrate any relationship betweencirculatingIL-10andNOinbothgroupstested.
Inconclusion,inthisstudydesfluranebyitselfincreased theplasmalevelofIL-10inpatients.However,therateof desfluraneflowdidnotchangetheIL-10level.Desfluraneby itselfdecreasedNOlevelsinpatients.Moreover,therateof
desfluraneflowchangedNOlevels.Inaddition,no relation-shiplinkedtheincreaseincirculatingIL-10withalteredNO production.ThoseresultssuggestthatiNOSisinfluencedby factorsotherthanIL-10aswell.
Conflicts
of
interest
Theauthordeclaresnoconflictsofinterest.
References
1.StevensonGW,HallSC,RudnickS,etal.Theeffectof anaes-theticagentsonthehumanimmuneresponse.Anaesthesiology. 1990;72:542---52.
2.Salo M. Effects of anaesthesia and surgery on the immune response.ActaAnaesthesiolScand.1992;36:201---20.
3.BaykalY,KaraayvazM,KutluM,etal.MedSci.1998;18:77---83. 4.CrozierTA,MüllerJE,QuittkatD,etal.Effectofanaesthesia onthecytokineresponsestoabdominalsurgery.BrJAnaesth. 1994;72:426.
5.Pirttkangas CO, Salo M, Mansikka M, et al. The influence ofanaesthetic technique upon theimmuneresponse to hys-terectomy:acomparisonofpropofol infusionandisoflurane. Anaesthesia.1995;50:1056---61.
6.BoostAK,HofstetterC,FlondorM,etal.Desflurane differen-tiallyaffectsthereleaseofproinflammatorycytokinesinplasma andbronchoalveolarfluidofendotoxemicrats.IntJMolMed. 2006;17:1139---44.
7.DeloguG,AntonucciA,SignoreM,etal.PlasmalevelsofIL-10 andnitricoxideundertwodifferentanaesthesiaregimens.Eur JAnaesth.2005;22:462---6.
8.Tsuei BJ, Bernard AC, Shane MD, et al. Surgery induces human mononuclear cell arginase I expression. J Trauma. 2001;51:497---502.
9.GalleyH,NelsonLR,WebsterNR.Anaestheticagentdecreases theactivityofnitricoxidesynthasefromhuman polymorphonu-clearleucocytes.BrJAnaesth.1995;75:326---9.
10.GalleyHF.Anaesthesiaandthenitricoxide-cyclicGMPpathway inthecentralnervoussystem.BrJAnaesth.2000;84:141---3. 11.TschaikowskyK,RitterJ,SchroppelK,etal.Volatileanesthetics
differentiallyaffectimmunostimulatedexpressionofinducible nitricoxidesynthase.Anesthesiology.2000;92:1093---102. 12.KelbelI,WeissM.Anaestheticsandimmunefunction.CurrOpin
Anaesthesiol.2001;14:685---769;
MoudgilGC,AllanRB,RussellRJ,WilkonsonPC.Inhibitionby anaesthetic agents of human leucocyte locomotion towards chemicalattractants.BrJAnaesth.1997;49:97---105.
13.MoudgilGC.Effect orpremedicants,intravenous anaesthetic agents an local anaesthetics on phagocytosis in vitro. Can AnaesthSocJ.1981;28:597---602.
14.Brand JM, Kirchner H, Poppe C, et al. The effects of general anesthesis on human peripheral immune cell distri-butionandcytokineproduction.ClinImmunolImmunopathol. 1997;83:190---4.
15.MatsuokaH,KurusawaS,HorunouchiT,etal.Inhalation anes-theticsinduceapoptosis innormalperipherallymphocytesin vitro.Anesthesiology.2001;95:1467---72.
16.Giraud O, Seince PF, Rolland C, et al. Halothane reduces the early lipopolysaccharide-induced lung inflammation in mechanically ventilated rats. Am J Respir Crit Care Med. 2000;162:2278---86.
18.SchneemilchCE,HachenbergT,AnsorgeS,etal.Effectsof dif-ferentanaestheticagentsonimmunecellfunctioninvitro.Eur JAnaesthesiol.2005;22:616---23.
19.Bahadır B, Bas¸gül E, C¸eliker V, et al. Halotan, ˙Izofluran ve Sevoflurananestezilerininimmuneyanıtaetkisi.Anestezi Der-gisi.2003;11:260---4.
20.KotaniT,HashimotoH, SesslerDI,etal.Intraoperative mod-ulationofalveolarmacrophagefunctionduringisofluraneand propofolanesthesia.Anesthesiology.1998;89:1125---30. 21.Mitsuhata H, Shimizu R, Yokoyama MM. Suppressive effects
ofvolatile anestheticson cytokine releaseinhuman periph-eral blood mononuclear cells. Int J Immunopharmacol. 1995;17:529---34.
22.KoksalGM,SayilganC,GungorG,etal.Effectsofsevoflurane and desflurane on cytokine response during tympanaoplasty surgery.ActaAnaesthesiolScand.2005;49:835---9.
23.SchillingT,KozianA,KretzschmarM,etal.Effectsof propo-fol and desflurane anaesthesiaon thealveolar inflammatory response to one-lung ventilation. Br J Anaesth. 2007;99: 368---75.
24.Schneemilch CE, Hachenberg T, Ansorge S, et al. Effect of 2 anesthetic techniques on the postoperative pro-inflammatoryandantiinflammatorycytokineresponseand cel-lularimmunefunctiontominorsurgery.JClinAnesth.2005;17: 517---27.
25.BlerkmanD,JonesMV,HarrisonNL.Theeffectsoffourgeneral anestheticsonintracellular[Ca] inculturedrathippocampal neurons.Neuropharmacology.1995;34:541---51.
26.OchoaJB,BernardAC,MystrySK,etal.Traumaincreases extra-hepaticarginaseactivity.Surgery.2000;127:419---26.
27.JohnsRA,MoscickJC,DifazioCA.Nitricoxidesynthaseinhibitor dose-dependently and reversibly reduces the threshold for halothaneanaesthesia.Arolefornitricoxideinmediating con-sciousness?Anesthesiology.1992;77:779---84.
28.KatoM,HondaI,SuzikiH,etal.Interleukin-10productionduring upperabdominalsurgery.JClinAnaesth.1998;10:184---8. 29.DaviesMG,FultonGC,HagenPO.Clinicalbiologyofnitricoxide.
BrJSurg.1995;82:1598---610.
30.FujiokaS,MizumotoK,OkadaK.Adecreasedserum concen-trationofnitrite/nitratecorrelateswithanincreasedplasma concentrationoflactateduringandaftermajorsurgery.Surg Today.2000;30:871---4.
31.OudonhovenIM,KlaasenHL,lapreJA,etal.Nitricoxide-derived urinarynitrateasamarkerintestinalbacterialtranslocationin rats.Gastroenterology.1994;107:47---53.
32.KomarovAM,ReddyMN.Effectofsepticshockonnitrate,free aminoacids,andureainmurineplasmaandurine.ClinBiochem. 1998;31:107---11.
33.GunnettCA,ChuY,HeistadDD,etal.VasculareffectsofLPS inmicedeficientinexpressionofthegeneforinduciblenitric oxidesynthase.AmJPhysiol.1998;275:H416---21.
34.GalleyHF,LeCrasAE,LoganSD,etal.Differentialnitricoxide synthaseactivity,cofactoravailabilityandcGMPaccumulation inthecentralnervoussystemduringanaesthesia.BrJAnaesth. 2001;86:388---94.
35.NakamuraK,TerasakoK,TodaH,etal.Mechanismsofinhibition ofendothelium-dependentrelexationbyhalothane,isoflurane, andsevoflurane.CanJAnaesth.1994;41:340---6.
36.Pearce RA, Stringer JL, Lothman EW. Effect of volatile anestheticsonsynaptictransmissioninthehippocampus. Anes-thesiology.1989;71:591---8.
37.YamamotoT,ShimoyamaN,MizuguchiT.Nitricoxidesynthase inhibitorblocksspinalsensitizationinducedbyformalin injec-tionintotheratpaw.AnesthAnalg.1993;77:886---90.
38.Muldoon SM, Hart JL, Bowen KA, et al. Attenuation of endothelium-mediatedvasodilatationbyhalothane. Anesthesi-ology.1988;68:31---7.
39.Uggeri MJ,ProctorGJ, Johns RA. Halothane, enflurane,and isoflurane attenuate both receptor and non-receptor medi-ated EDRF production in rat thoracic aorta. Anesthesiology. 1992;76:1012---7.
40.BlaiseGA.Effectofvolatileanestheticagentsonendothelium dependent relaxation. In: Blanck TJJ, Wheeler DM, editors. Mechanisms of anesthetic action in skeletal, cardiac, and smoothmuscle.Advancesinexperimentalmedicineandbiology, vol.301.NewYork:PlenumPress;1991.p.229---35.
41.GreenblattEP,LoebAL,LongneckerDE.Endotheliumdependent circulatorycontrol a mechanism for the differingperipheral vasculareffectsofisofluraneversushalothane.Anesthesiology. 1992;77:1178---85.
