Short term olfactory memory and olfactory function after inhalation anesthetic agents: a randomized clinical trial

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SCIENTIFIC ARTICLE

Short term olfactory memory and olfactory function after inhalation anesthetic agents: a randomized clinical trial

Huseyin Sari

^a^,∗

, Yavuz Atar

^a

, Tarkan Mingir

^b

, Tolgar Lutﬁ Kumral

^a

, Muhammed Fatih Akgun

^a

, Esmail Abdulahi Ahmed

^a

, Imran Aydogdu

^a

, Ziya Salturk

^a

, Guler Berkiten

^a

, Yavuz Uyar

^a

aOkmeydanıTrainingandResearchHospital,DepartmentofOtorhinolaryngology-HeadandNeckSurgery,Istanbul,Turkey

bOkmeydanıTrainingandResearchHospital,DepartmentofAnesthesiology,Istanbul,Turkey

Received24March2019;accepted1December2019 Availableonline8February2020

KEYWORDS Olfactorymemory;

Inhalationanesthesia;

Desﬂurane;

Sevoﬂurane

Abstract

Backgroundandobjectives: This clinical trial aimed to evaluate the effects of two different inhalationanesthetic agents on postoperative olfactory memoryand olfactory function inpatientswhounderwentmicrolaryngealsurgery.

Methods: Thisrandomizedprospectivecontrolledstudyconsistedof102consecutivepatients withavoicedisorder.Thepatientsunderwentmicrolaryngealsurgeryforvoicedisordersunder generalanesthesia.Patientswho didnot meet inclusioncriteria and/ordeclinedto partic- ipate (n= 34) were excluded from thestudy. Patientswere divided into two groups. Four patientsfromGroup1andfourpatientsfromGroup2werelosttofollow-up.Group1(n=30) receivedsevoﬂurane,andGroup2(n=30)receiveddesﬂuraneduringanesthesia.Wecompared theresultsbyperformingthepre-opandpost-opConnecticutChemosensoryClinicalResearch CenterOlfactorytest.

Results: Thirty-threepatients(55%)weremaleand27(45%)werefemale.Themeanagewas 48.18±13.88years(range:19---70years).Preoperativeandpostoperativeolfactoryfunctions didnotshowasigniﬁcantdifferencewithinthegroupspostoperatively(p>0.05).Preoperative andpostoperativeolfactorymemoryshowedasigniﬁcantdecrease3hoursafterthesurgery(p

<0.05).

Conclusions: Olfactoryfunctionsandmemorywerenotaffectedbydesﬂuraneintheearlypost- operativeperiod.Althoughsevoﬂuranedidnotaffectolfactoryfunctions,ithadatemporary negativeeffectonolfactorymemoryintheearlypostoperativeperiod.

by-nc-nd/4.0/).

∗Correspondingauthor.

E-mail:[email protected](H.Sari).

https://doi.org/10.1016/j.bjane.2020.02.009

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PALAVRASCHAVE Memóriaolfativa;

Anestesiainalatória;

Desﬂurano;

Sevoﬂurano

Memóriaolfativadecurtadurac¸ãoefunc¸ãoolfativaapósanestésicosinalatórios:

estudoclínicorandomizado

Resumo

Introduçãoeobjetivos: Oestudoavaliouoefeitopós-operatóriodedoisagentesanestésicos inalatóriosdistintonamemóriaolfativadecurtaduraçãoenafunçãoolfativaem pacientes submetidosàmicrocirurgiadelaringe.

Método: O estudo prospectivo controlado randomizado avaliou, consecutivamente, 102 pacientescomalteraçãovocalsubmetidosàmicrocirurgiadelaringesobanestesiageral.Trinta equatro pacientesnãoobedeceramaoscritérios deinclusãoe/ounão aceitaramparticipar doestudoeforamexcluídos.Ospacientesforamdivididosemdoisgrupos.Quatropacientes doGrupo 1equatro doGrupo 2foramperdidosduranteoseguimento.OGrupo 1(n=30) recebeusevofluranoeoGrupo2(n=30)desfluranoduranteaanestesia.Comparamosresul- tadospréepós-operatóriosdememóriaolfativaefunçõesolfativas,realizandooConnecticut ChemosensoryClinicalResearchCenterOlfactorytest.

Resultados: Foramincluídosumtotalde33(55%)homense27(45%mulheres.Aidademédia foi48,18±13,88anosvariação:19---70anos).Asfunçõesolfativaspréepós-operatóriasnão apresentaramdiferençaestatisticamentesignificantedentrodosgruposnopós-operatório(p

> 0,05).A memóriaolfativa prée pós-operatória não mostrou diminuic¸ão estatisticamente signiﬁcantequandoavaliadatrêshorasapósacirurgia(p< 0,05).

Conclusões: Memóriaefunçõesolfativasnãoforamalteradaspelodesfluranonopós-operatório imediato.Emboraosevofluranonãotenhaalteradoasfunçõesolfativas, causouefeitotem- porárionegativonamemóriaolfativanopós-operatórioimediato.

by-nc-nd/4.0/).

Introduction

Olfactory dysfunction occurs in approximately 5% of the general population.^1,2 It has been reported that patients withsmellingdisordershavealsoseriousproblemsregarding safety, eating,and personal hygiene.³ Olfactory disorders are frequently seen in the general population, and they have a negative effect on the patients’ quality of life.⁴ The main causes of olfactory disordersare upperrespira- tory infections, systemic disorders, nasal disorders (e.g.

sinusitis, nasal polyps), head trauma, neurodegenerative diseasesandmedicaldrugs.⁵

Olfactory memory is a crucial cerebral function in mammals.Itspurposesincludedefense,reproduction,for- aging,andinfant-motherbonding.⁶Postoperativecognitive dysfunctionisaclinicallyrecognizedphenomenonfollowing surgery; it is related to problems in daily performance andimprovedmorbidityandmortality.⁷Generalanesthesia causesareversibledecreasein short-termmemory,which is quickly resolved following the cessation of anesthetic drugaction.⁸

Inhalationalanestheticsarecommonlyusedforalltypes ofsurgicalprocedures.Anestheticdrugshavebeenblamed forpostoperativeolfactorydysfunction,buttheyhave not been shown to cause hyposmia or anosmia.¹ There have beenseveralscientiﬁcstudiesaboutthenegativeeffectsof anestheticdrugsonolfactoryfunctioninanimals.⁹However, theeffectofinhalationalanestheticsonearlypostoperative olfactoryfunctionshasnotbeenproperlyexplored.

The aim of this study was to examine the effects of two different inhalational anesthetics on post-operative

olfactorymemoryandolfactoryfunctioninpatientswhohad undergonemicrolaryngealsurgery.

Methods

This study was carried out at a tertiary hospital on 102 patientswhohadundergonemicrolaryngealsurgerywitha voicedisorderdiagnosis. Allstudy protocolsand informed consentformswereapprovedandcollectedbytheinstitu- tionalreviewboard. The dataretrievedfromthe medical records included patient age, sex and presenting com- plaints.

Patientswhohadbenignvocallesionswereacceptedfor the study. Exclusion criteria included nasal septal deviation,previousnasalsurgery,tonsillectomy,nasalpolyposis, preexistingsinusdisease,nasalallergies,preexistingsubjec- tiveolfactorydisturbancesuchasintranasaldrugabusers, systemicdiseasessuchasdiabetesmellitus,rheumatologic disordersandoncologicaldiseases.Thepatientswhodidnot meetthe inclusioncriteriaand/or declined toparticipate (n=34)wereexcludedfromthisstudy.Arandomizationpro- gram generated a randomallocationsequence.¹⁰ Patients weredividedintotwogroups. FourpatientsfromGroup1 andfourpatientsfromGroup2werelostduringthefollow- up.Group1(n=30)receivedsevoﬂuraneagent,andGroup 2(n=30)receiveddesﬂuraneagentduringtheanesthesia.

Anassistantdoctorwhowasblindedtothestudyenrolled thedataoftheparticipants.

Thepatientsunderwentmicrolaryngealsurgeryfortheir voicedisordersundergeneralanesthesia.Allpatientshada

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completeearnoseandthroatexamination.Thedaybefore the operation, a ﬂexible nasopharyngoscope and strobo- scope wereused toevaluate their vocal cord lesionsand nasalpathologies.Inaddition,thepatientswhodecidedon surgeryreceivedapreoperativeevaluationattheanesthesia clinic.

Anesthesiaprocedure

All patients underwent surgery under general anesthesia withendotrachealintubation.Patientswithoutanypremed- icationweretakenintotheoperationroomanddemographic datawas recorded.Standard electrocardiography, peripheral oxygen saturation, and non-invasive blood pressure monitoring wereperformed. Afterperipheral venous can- nulation,anesthesiainductionwasachievedwith2␮g.kg⁻¹ fentanyl,2mg.kg⁻¹propofol,and0.6mg.kg⁻¹ rocuronium viaendotrachealintubation,andintermittentpositivepres- sureventilationwasinitiated.Thetidalvolumewassetto 8mg.kg⁻¹,andthefrequencywassettobeend-tidalcar- bon dioxide 35 ± 5 mmHg. Anesthesia was performed by givingsevofluranetothefirstgroupand desfluranetothe secondgroup.Thedosesofinhaledanestheticagentswere adjustedtoachieve 1MACend tidalreadingof theagent (e.g.2%forsevofluraneand6%fordesflurane).Itwascontin- uedwitha40%O2/airmixtureand0.15---0.25␮g.kg⁻¹.min⁻¹ remifentanilinfusion.Allcasesweretreatedwithparaceta- mol10mg.kg⁻¹and1 mg.kg⁻¹ tramadolhydrochloricacid intravenouslyforpostoperativeanalgesiaabout15minutes beforethe end of the operation. Finally, a muscle relax- anteffectwasantagonizedwith0.04mg.kg⁻¹neostigmine and0.02mg.kg⁻¹atropine.Vasoconstrictoragentswerenot appliedtothe surgical area.Cases withadequate muscle strengthwere transportedtothepostoperative collection unit by the standard procedure, and the internship was donewhenthemodifiedAldretescorewas9orgreater.All thesurgerieslastedbetween40---60minutes.Therewasno sideeffectandcomplicationrelatedtoanestheticagentson patients.

Olfactory functions were assessed preoperatively and postoperativelyusingthe Connecticut ChemosensoryClin- icalResearchCenter (CCCRC) smelltest. The CCCRC test includesabutanolthresholdtestforolfactoryfunctionand asmellidentiﬁcation test forolfactory memory.Aspecial dietprogramwasnotappliedtoallpatients.

Olfactorymemorytest

TheCCCRCtest wasconductedinan odorlessroom under standard conditionsusing a commerciallyavailable smell- testkit.Forbothpartsofthetest,eachnostrilwastested separatelybyhavingthesubjectoccludetheoppositenos- tril. There were seven olfactory stimuli (baby powder, chocolate,cinnamon,coffee,mothballs,peanutbutterand soap)andonestimulus(VicksVapoRub,EczacıbasıDrugCom- pany,Turkey)usedtotesttrigeminalnervesensoryfunction.

ThecapabilitytosenseVicksshowsintacttrigeminalnerve function. It was recognized by all subjects and was not involvedintheﬁnalscore.Olfactorytestswereconducted individuallyandwerescoredoutof7(0:worstolfaction,7:

bestolfaction).

Olfactoryfunctiontest

For every trial, two glass bottles were presented to the patient. One of them contained water and the other a diluteconcentrationofbutanol.Thebottleswereidentical inappearanceandwerepresentedsimultaneously.Subjects were asked to keep one nostril obstructed while sniffing the bottlewiththeirother nostril. Patientswereasked if therewasanythingotherthanwaterinthebottles.Iftheir selection waswrong, a stronger concentration of butanol wasgivenalongsidethebottlecontainingonlywater.Ifthe subjectcorrectlyidentifiedthesamebutanolconcentration fivetimesbacktoback,thescorewasdocumentedforthat nostril. The other nostril wasthen tested separately, and thescoresforbothnostrilswereaveragedtogettothefinal score.The strongest butanolconcentration (bottle0)was 4%butanolindeionizedwater.Eachfollowingdilution(bot- tles1---9)wasa1:3dilution withdeionizedwater.Possible scoresrangedfrom0to9,butallscores7andgreaterwere scoredas7bytheCCCRCtest.^11,12

Fortheevaluationofolfactorymemoryandfunction,the CCCRC olfactory test scoresmeasured the day beforethe surgerywere consideredasabaselineandcomparedwith thescores3hoursand5weeksaftersurgery.

Dataanalysis

Statistical analysis of the data were conducted using IBM SPSSStatistics22(IBMSPSS,Turkey).Thedatawereanalyzed using descriptive statistical methods (mean and standard deviation), and theShapiro Wilks test was usedto assess thenormaldistributionoftheparameters.Student’st-test wasusedforthecomparisonof quantitativedatashowing theparametersofthenormaldistribution,andChi-squared test wasusedfor the comparisonof thequalitative data.

Repeated ANOVA tests were used to compare parametric dependent groups. Mauchly’s sphericity test was used to evaluatetheassumptionofsphericityfortherepeateddata and‘‘sphericityassumed’’p-valuewasreported.Post-Hoc Bonferroni correction test was used to compare the differences.Resultswereevaluatedusingthe95%Conﬁdence Intervals (CI),andthelevel ofsigniﬁcance wassetat p <

0.05.

Results

Thestudygroupcomprised60consecutivepatients.Thirty- threeofthem(55%)weremaleand27(45%)werefemale.

The mean age was 48.18 ± 13.88 years (range: 19---70 years). No signiﬁcant difference was observed regarding age and gender between groups (p = 0.162; p = 0.795);

(Tables1and2).

Preoperativeandpostoperativeolfactoryfunctionswere compared between and withinthe groups. NeitherGroup 1 nor Group 2 showed a signiﬁcant difference within the group postoperatively (p = 0.508; p = 0.715). Postopera- tivethreehoursandﬁrstweekmeasurementsdidnotshow anydifferencebetweenthegroups (p =0.494;p=0.431);

(Table3).

Preoperative and postoperative olfactory memory was comparedbetweenandwithinthegroups.Therewasasig-

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Table1 Descriptivestatisticsofageandsexbetweenthegroups.

Total(n=60) Group1(Sevoﬂurane)

(n=30)

Group2(Desﬂurane) (n=30)

p

Age Min---Max(Median) 19---70(50) 19---70(54) 19---70(47) t:−1.416

Mean±Sd 48.18±13.88 50.70±14.15 45.66±13.36 0.162^a

Gender Female 27(45.0) 13(43.3) 14(46.7) ␹²:0.067

Male 33(55.0) 17(56.7) 16(53.3) 0.795^b

a Studentt-Test.

b Chi-SquareTest.

Table2 Descriptivestatisticsofagebysex.

Sex Age

Min---Max Mean±SD/%

Female 16---65 47.35±12.66

Male 19---70 48.51±14.47

niﬁcantdifferenceamongtheresultsofGroup1(p=0.019).

Apost-hocBonferonniwasusedtocomparethedifferences.

Therewasasignificantdecreasethreehoursaftertheoper- ation(0.001). However,there wasnodifferencebetween preoperativeandfirstweekresults(p>0.05).Group2did not show significant differences withinthe group postoperatively (p = 0.804). Postoperative three hours and first weekmeasurementsdidnotshowanydifferencebetween thegroups(p=0.943;p=0.967);(Table4).

Discussion

Olfactorymemoryisimportantforthemaintenanceofdaily physiologicalfunctionsandcontributesgreatlytothequal- ity of life.¹³ In this study, we investigated the effects of desﬂuraneandsevoﬂuraneonearlypostoperativeolfactory memoryandolfactoryfunctioninpatientswhounderwent microlaryngealsurgeryundergeneralanesthesia.

Olfactoryimpulses aredetectedin theolfactoryregion ofthenose.Smellmolecules dissolveinthemucusonthe

olfactory epithelium and connect with olfactory receptor cells. In this way, chemical information from the smell molecules causes an action potential in smell receptor cells.Theseimpulsesarethencarriedtothebulbusolfac- torius in the brain. After that, they are carried via the tractus olfactorius and stria olfactorius to the olfactory cortex.¹⁴ Olfactory memory is found in the piriform cortex, the amygdala and entorhinal cortex.¹⁵ Smell is the onlyoneoftheﬁvesensesthatiscarrieddirectlyintothe cortical regions of the brain without passing through the thalamus.¹⁶ Therelatedneurotransmissionsystems(adren- ergicandgamma-aminobutyricacid)areknowntargets of anestheticdrugs.¹⁷

Volatileanesthetic agents are commonly usedin anes- thesiaandaregenerallywell-toleratedbypatientswithout systemicdiseases,butveryrarelyunplannedcomplications can be seen. Sevoflurane, isoflurane and desflurane now constitutethefundamental halogenatedvolatileanesthet- icsusedindevelopedcountries.¹⁸ Post-anesthesiaanosmia cases have been little reported in the literature. Kon- stantinidis et al. reported the presence of anosmia in a 60 year-old female patient who had undergone urologi- cal surgery.¹⁹ The patient was given general anesthesia using fentanyl, propofol and sevoflurane; it was thought thatthedevelopmentofanosmiamightoriginatefromthe directeffectofsevofluraneontheolfactoryepitheliumwith resultant peripheral-type olfactory dysfunction.^19,20 Vari- ous scientific studies have indicated that among general anestheticdrugs,fentanylandpropofoldepressedolfactory

Table3 Comparisonofthepreoperativeandpostoperativeolfactoryfunction (butanolthresholdtest)betweengroups and withingroups.

Olfactoryfunction(Butanol ThresholdTest)

1Preop ²Postop3^rd hour

3Postop1 week

First-last change

Post-hoc Bonferronitest Mean±SD

(CI95%)

Mean±SD (CI95%)

p^b p^c

Group1(Sevoﬂurane) 8.30±2.95 (7.9---9.40)

8.20±2.76 (7.17---9.23)

8.10±2.56 (7.15---9.05)

0.508 1---2p:1.000 1---3p:1.000 2---3p:1.000 Group2(Desﬂurane) 8.33±2.90

(7.75---9.92)

8.7±2.87 (7.63---9.77)

8.63±2.66 (7.64---9.63)

0.715 1---2p:1.000 1---3p:1.000 2---3p:1.000

p^a 0.483 0.494 0.431

a Studentt-test.

b RepeatedMeasuresANOVAtest.

c Adjustmentformultiplecomparisons:Bonferronitestp<0.05.

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Table4 Comparisonofthepreoperativeandpostoperativeolfactorymemory(identiﬁcationtest)betweengroupsandwithin groups.

Olfactorymemory (IdentiﬁcationTest)

1Preop ²Postop3^rd hour

3Postop1 week

First-last change

Post-hoc Bonferronitest Mean±SD

(95%CI)

Mean±SD (95%CI)

p^b p^c

Group1(Sevoﬂurane) 7.70±3.44 (6.41---8.98)

6.57±1.25 (6.10---7.03)

7.57±2.98 (6.45---8.67)

0.019* 1---2p:0.001 1---3p:1.000 2---3p:0.129 Group2(Desﬂurane) 7.37±3.37

(6.10---8.562)

7.63±3.53 (6.31---8.95)

7.53±3.19 (6.34---8.72)

0.804 1---2p:1.000 1---3p:1.000 2---3p:1.000

p^a 0.706 0.943 0.967

aStudentt-test.

b RepeatedMeasuresANOVAtest.

c Adjustmentformultiplecomparisons:Bonferronitest*p< 0.05.

response.⁷However,inourstudywedidnotencounteranos- miainthepostoperativeperiod.

Intheliterature,limiteddatacanbefoundregardingthe effectofanestheticagentsandmethodsonolfactorymem- ory.Severalstudieshaveshownthatthepopularinhalational anesthetic isoﬂurane may cause neurotoxicity connected withcognitivedysfunctionorlearning/memoryimpairment.

Meanwhile,desflurane,anotherpopular inhalationalanes- thetic,does nothavethesekindsofeffects.On theother hand,oneclinical studyindicated thatgeneral anesthesia withisoflurane1.2% hasno significant effectonolfactory memory.²¹

AnotherstudywithsevofluraneperformedbyKostopana- giotou et al. demonstrated that sevoflurane impaired post-operativeolfactorymemorybutolfactoryfunctionwas preserved.⁸TheUniversityofPennsylvaniaSmellIdentifica- tionTest(UPSIT)wasusedintheirstudywithinthefirstthree hoursaftersurgery.ACCCRtestwasusedinourstudy,and twodifferentanesthetic agents were studied. In addition totheirmeasurement,theresultsafterthefirstpostoper- ative week were alsoconsidered. Our study showed that thenegativeeffectofsevofluraneonolfactorymemorywas completelyresolvedbytheendofthefirstweek.

Yildiz et al. analyzed the effect of desflurane 6% on postoperative olfactory memory by Brief-Smell Identifica- tionTest TM (B-SIT).²² Theyfound that desfluranehad no effecton short-term olfactory memory. This is similar to ourresultsregardingdesflurane.Inadditiontotheirresults, weaddedfirst-weekdatatoourstudyandfoundnodiffer- ence.

Michael et al. evaluated the effects of five inhala- tionalanestheticsonthelearningcapabilitiesandmemory of rats.²³ They found that larger doses of sevoflurane, halothane, and desflurane had negativeeffects onlearn- ing,while 0.44%desfluranehadsignificant adverseeffects onmemory.Callaway etal. studied theeffects of desflu- raneanesthesiainrats.Theydemonstratedthattheeffects ofdesfluraneonlearningandmemorywereageanddose- dependent.²⁴ Those studies were performed with varying dosages on animals, but our study was performed with standard therapeutic doses on human patients. Minimum

alveolarconcentrationwaskeptover1inourstudybyusing sevoﬂuraneconcentrationof2%anddesﬂuraneof6%.

Thelimitations of ourresearchcanbelisted asadefi- ciencyinourpatientpopulationandalackofinvestigation ofdifferentdosesofdesfluraneandsevofluraneoverlonger periodstodeterminetheirlong-termpostoperativeeffects.

Conclusion

Olfactoryfunctionandmemorywerenotaffectedbydesﬂu- raneintheearlypostoperativeperiod.Althoughsevoﬂurane didnot affectthe olfactoryfunctions, ithad atemporary negative effectonolfactory memory in the early postop- erativeperiod.In ordertomakemorereliablecomments, furtherstudieswithlargercohortsarerequired.

Conﬂicts of interest

Theauthorsdeclarenoconﬂictsofinterest.

References

1.AdelmanBT.Alteredtasteandsmellafteranesthesia:causeand effect?Anesthesiology.1995;83:647---9.

2.BramersonA,JohanssonL,EkL,etal.Prevalenceofolfactory dysfunction:theSkovdepopulation-basedstudy.Laryngoscope.

2004;114:733---7.

3.DotyRL,McKeownDA,LeeWW,etal.Astudyofthetest-retest reliabilityoftenolfactorytests.ChemSenses.1995;20:645---56.

4.LandisBN,KonnerthCG,HummelT.Astudyonthefrequency ofolfactorydysfunction.Laryngoscope.2004;114:1764---9.

5.Doty RL. Studies of human olfaction from the University of Pennsylvania Smell and Taste Center. Chemical Senses.

1997;22:565---86.

6.FiresteinS.Howtheolfactorysystemmakessenseofscents.

Nature.2001;413:211---8.

7.Zhang B, Tian M, Zhen Y, et al. The effects of isoﬂurane anddesﬂuraneoncognitivefunctioninhumans.AnesthAnalg.

2012;114:410---5.

8.Jugovac I, Imas O, Hudetz AG. Supraspinal anesthesia:

behavioraland electroencephalographiceffects ofintracere-

(6)

broventricularlyinfusedpentobarbital,propofol,fentanyl,and midazolam.Anesthesiology.2006;105:764---78.

9.CainWS,GentJF,GoodspeedRB,etal.Evaluationofolfactory dysfunctionintheConnecticutChemosensoryClinicalResearch Center.Laryngoscope.1988;98:83---8.

10.Urbaniak GC, Plous S. http://www.randomizer.org/, 2013 (retrievedonJune22,2013).

11.LeonEA,CatalanottoFA,WerningJW.Retronasalandorthonasal olfactory ability after laryngectomy. Arch Otolaryngol Head NeckSurg.2007;133:32---6.

12.SpielmanAI.Chemosensoryfunctionanddysfunction.CritRev OralBiolMed.1998;9:267---91.

13.Leopold DA. The relationship between nasal anatomy and humanolfaction.Laryngoscope.1988;98:1232---8.

14.BrunjesPC,IlligKR,MeyerEA.Aﬁeldguidetotheanteriorolfac- torynucleus(cortex).BrainResBrainResRev.2005;50:305---35.

15.CullenMM,LeopoldDA.Disordersofsmellandtaste.MedClin NorthAm.1999;83:57---74.

16.VeyracA,NguyenV,MarienM,etal.Noradrenergiccontrolof odorrecognitioninanonassociativeolfactorylearningtaskin themouse.LearnMem.2007;14:847---54.

17.Michel F, Constantin JM. Sevoﬂurane inside and outside the operating room. Expert opinion on pharmacotherapy.

2009;10:861---73.

18.Konstantinidis I, Tsakiropoulou E, Iakovou I, et al. Anos- mia after general anaesthesia: a case report. Anaesthesia.

2009;64:1367---70.

19.DhananiNM,JiangY.Anosmiaandhypogeusiaasacomplication ofgeneralanesthesia.JClinAnesth.2012;24:231---3.

20.Bilgi M, Demirhan A, Akkaya A, et al. Effects of Isoﬂurane onPostoperativeOlfactoryMemory.ActaMedicaMediterranea.

2014;30:453---6.

21.KostopanagiotouG, KalimerisK, KesidisK,et al.Sevoﬂurane impairspost-operativeolfactorymemorybutpreservesolfac- toryfunction.EurJAnaesthesiol.2011;28:63---8.

22.YildizI,BayırH,SaglamI,et al.Theeffectofdesﬂuraneon postoperativeolfactorymemory. EurRevMedPharmacolSci.

2016;20:2163---7.

23.Alkire MT, Gorski LA. Relative amnesic potency of ﬁve inhalationalanestheticsfollowstheMeyer-Overtonrule.Anes- thesiology.2004;101:417---29.

24.CallawayJK,JonesNC,RoyseAG,etal.Memoryimpairmentin ratsafterdesﬂuraneanesthesiaisageanddosedependent.J AlzheimersDis.2015;44:995---1005.