Braz. j. . vol.83 número3

www.bjorl.org

Brazilian

Journal

of

OTORHINOLARYNGOLOGY

ORIGINAL

ARTICLE

Obstructive

sleep

apnea

in

postmenopausal

women:

a

comparative

study

using

drug

induced

sleep

endoscopy

夽

Soo

Kweon

Koo

,

Gun

Young

Ahn

,

Jang

Won

Choi

,

Young

Jun

Kim

,

Sung

Hoon

Jung

_,

_Ji

_Seung

_Moon

_,

_Young

_Il

_Lee

a_{BusanSaintMary’sHospital,DepartmentofOtorhinolaryngology,Busan,SouthKorea} b_{UlsanHanaENTHospital,Ulsan,SouthKorea}

c_{GoodSamsunHospital,DepartmentofOccupationalandEnvironmentalMedicine,Busan,SouthKorea}

Received2December2015;accepted23March2016 Availableonline25April2016

KEYWORDS Sleepapnea syndrome; Endoscopy; Gender; Menopause

Abstract

Introduction:ThekeytosuccessfultreatmentofOSASistoindividuallytailorsuchtreatment. Thus,itisveryimportanttodeterminetheseverity ofOSAS,itspattern,andtheextentof collapse,bygender,age,andBMI.

Objective: Theobjectiveofthestudywastounderstandthecharacteristicsofobstructivesleep apneainpostmenopausalwomenbycomparingpostmenopausalandpremenopausalsubjects, andmen,usingDISE.Wehopethatourworkwillhelpthemedicalcommunitytoconsulton, diagnose,andtreatOSASmoreeffectively.

Methods:A total of 273 patients (195 males and 78 females) diagnosed with OSAS were enrolled. Female patients were divided into pre-menopausal (n=41) and post-menopausal patients(n=37).Thegroupofpost-menopausalfemalepatientswasmatchedwithagroupof malepatientswithsimilarageandbodymassindex(BMI).DISEfindingswerecomparedbetween pre-menopausalfemalepatientsandpost-menopausalfemalepatients,andalsobetween post-menopausalfemalepatientsandmalepatientsmatchedforageandBMI.

Results:UponPSGexamination,post-menopausalpatients(whohadasignificantlyhigherBMI thandidpre-menopausalpatients;25.6kg/m2_vs.23.5kg/m2_{;p=0.019)tendedtohaveahigher}

AHIandalowerlowestSaO2,butthedifferencesdidnotattainstatisticalsignificance.With

DISEanalysis,post-menopausalfemalepatientsshowedhighervaluesinallobstructionsites, withsignificantlyhighervalueinlateraldiameterofretropalatal(1.49vs.0.90;p=0.001)and retrolinguallevels(1.14vs.0.61;p=0.003)comparedtopre-menopausalfemalespatients. Post-menopausalfemalepatientsshowedsignificantlymoreretrolingualcollapse(antero-posterior,

夽 _{Pleasecitethisarticleas:KooSK,AhnGY,ChoiJW,KimYJ,JungSH,MoonJS,etal.Obstructivesleepapneainpostmenopausalwomen:}

acomparativestudyusingdruginducedsleependoscopy.BrazJOtorhinolaryngol.2017;83:285---91.

∗_{Correspondingauthor.}

E-mail:[email protected](S.K.Koo).

PeerReviewundertheresponsibilityofAssociac¸ãoBrasileiradeOtorrinolaringologiaeCirurgiaCérvico-Facial.

http://dx.doi.org/10.1016/j.bjorl.2016.03.011

AP,p≤0.0001, andlateral diameter,p=0.042) inthelower BMIgroup (BMI<25)and more concentricretropalatalcollapse(lateraldiameter,p=0.017andtonsillarobstruction,p=0.003) inhigherBMIgroup(BMI≥25)thanBMIandagematchedmalepatients.

Conclusion:Post-menopausalfemalepatientsshowedadifferentpatternofairwayobstruction comparedtopre-menopausalfemalepatientsandmalepatientsmatchedforageandBMIbased onDISEfindings.

© 2016 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Published by Elsevier Editora Ltda. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

PALAVRAS-CHAVE Síndromedaapneia dosono;

Endoscopia; Gênero; Menopausa

Apneiaobstrutivadosonoemmulheresnapós-menopausa:estudocomparativo usandoendoscopiadosonoinduzidoporfármaco

Resumo

Introduc¸ão:Achaveparaosucessodotratamentodasíndromedaapneiaobstrutivadosono (SAOS)éadaptarindividualmenteessetratamento.Assim,émuitoimportantedeterminara gravidadedaSAOS,seupadrãoeamedidadocolapso,porsexo,idadeeIMC.

Objetivo:O objetivo doestudo foicompreender ascaracterísticas daapneia obstrutiva do sonoemmulheresnapós-menopausa,comparandoestascaracterísticasentremulheresna pós-menopausaepré-menopausa,ehomens,utilizandoendoscopiadosonoinduzidoporfármacos (DISE).Esperamos queonossoestudoajude acomunidademédicaadiagnosticaretratara SAOSdemaneiramaiseficaz.

Método: Foramrecrutados273pacientes(195dosexomasculinoe78dofeminino)com diag-nósticodeSAOS.Aspacientesdosexofemininoforamdivididasempacientesnapré-menopausa (n=41)enapós-menopausa(n=37).Ogrupodepacientesdosexofemininonapós-menopausa foipareadacomumgrupodepacientesdosexomasculinocomidadeeÍndicedeMassaCorporal (IMC)semelhantes.OsachadosdaDISEforamcomparadosentreaspacientesdosexofeminino napré-menopausaeaspacientesdosexofemininopós-menopausaetambémentrepacientes dosexofemininonapós-menopausaepacientesdosexomasculinopareadosporidadeeIMC.

Resultados: AoexamedePSG,aspacientesnapós-menopausa(quetinhamumIMC significativa-mentemaiordoqueaspacientesnapré-menopausa;25,6vs23,5kg/m2_{;p=0,019)tenderama}

terumIAHsuperioreumasaturac¸ãoarterialdeoxigênio(SaO2)mínimamenor,masasdiferenc¸as

não atingiram significânciaestatística.NaanálisedoDISE, pacientesdosexo feminino pós-menopausaapresentaramvaloresmaiselevadosemtodososlocaisdeobstruc¸ão,comumvalor significativamentemaiordediâmetrolateraldosníveisretropalatal(1,49vs.0,90;p=0,001) eretrolingual(1,14 vs.0,61; p=0,003)emcomparac¸ão compacientesdo sexofemininona pré-menopausa.Aspacientesdosexofemininonapós-menopausaapresentaramcolapso signi-ficativamentemaisretrolingual(anteroposterior,AP,p≤0,0001ediâmetrolateral,p=0,042) nogrupodeIMCmenor(IMC<25)ecolapsoretropalatalmaisconcêntrico(diâmetro lateral,

p=0,017eobstruc¸ãotonsilar,p=0,003)nogrupodemaiorIMC(IMC≥25)doquepacientesdo

sexomasculinopareadosporIMCeidade.

Conclusão:CombasenosachadosdoDISE,aspacientesdosexofemininonapós-menopausa apresentaram umpadrão diferentede obstruc¸ão dasviasrespiratóriasemcomparac¸ãocom pacientesdosexofemininonapré-menopausaecomospacientesdosexomasculinopareados poridadeeIMC.

© 2016 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Publicado por Elsevier Editora Ltda. Este ´e um artigo Open Access sob uma licenc¸a CC BY (http:// creativecommons.org/licenses/by/4.0/).

Introduction

Severalpopulationbasedstudies acrossvarious geographi-calregionsandethnicgroupshavereportedtheprevalence ofsleepdisorderedbreathing(SDB)fromobstructivesleep apneasyndrome(OSAS).OSASisadiseasethatisrelatively morecommoninmenthanwomen,especiallymiddle-aged men.1_{Andaccordingtovariousstudies,incidenceofOSASin}

womenincreasesaftermenopause.1,2_{Thusbesidesgender} differences,incidenceofOSASmaybeduetotheinfluence ofhormones changingwithage,racialmakeupand differ-encesindiet.

according togender andage,determination ofthe sever-ityofOSAS,patternanddegreeofairwaycollapsearevery importantinindividuallytailoringatreatment.A compara-tivestudyofOSASbetweenmenandwomenbasedonthe naturalphysiologicsleepstateofthesubjectshasnotbeen conductedyet.Sleepnasoendoscopyordruginducedsleep endoscopy(DISE), firstintroducedbyCroftandPringle3_in 1991, is a procedure that uses a flexible nasoendoscope tovisualize the upperairway undersedation. DISE evalu-atesthelocalizationofflutterandcollapseinpatientswith SDB.SeveralcentersarenowavailablethatperformDISEis nowavailableinmultiplesleepstudyclinics.AlthoughDISE hassomelimitationssuchaslimitedperiodof observation andmultiple classificationsystems,it addressesthe natu-ralphysiologicstateofsleepmorethananyothercurrently availablediagnostictool.4

The keyto successfultreatment of OSAS is to individ-ually tailor suchtreatment. Thus, it is very important to determinetheseverityofOSAS,itspattern,andtheextent of collapse, by gender, age, and BMI; then it is possible toconstructa personalizedtreatment plan. Menopauseis associated withimportant physical andhormonal changes infemales,andthusmustbeconsideredwhentherapeutic approachesareplanned.Wesoughttounderstandthe char-acteristics of obstructive sleep apnea in postmenopausal women by comparingpostmenopausal andpremenopausal subjects,andmen,usingDISE.Wehopethatourworkwill help themedicalcommunitytoconsult on,diagnose, and treatOSASmoreeffectively.

Methods

Patientsselectionandoutcomeassessment

Theretrospectiveobservationalstudywasconductedatour ENTDepartmentwhereDISEwasperformedbyoneexaminer in273subjects(195males,meanage41.1yearsold;and78 females,meanage46.0yearsold)consecutiveOSASpatients from2013to2014.

BeforeDISE,allpatientsreceivedathoroughear,nose, andthroatexamination, focusingonnasalpathology, ton-sil size, uvula and palate aspect and tongue size. Their medicalhistorywastaken.Allpatientsunderwentfullnight polysomnography(PSG,WEE-1000K,NihonKohden,Japan). To minimize morphological bias, we excluded patients withskeletal frameworkanomalies such assevere retrog-nathia or jaw retrusion patients. In addition, to exclude bias introduced by tonsil size, we excluded patients with tonsils of grades III and IV. Patients who had undergone prior surgery of the soft palate or tongue were also excluded. Post-menopause was defined as a patient who did not have menstruation for more than a year and post-menopausal women receiving hormonal replacement therapywerealsoexcluded.Thefemalegroupsconsistedof 41pre-menopausal(meanage,36.7yearsold)and37 post-menopausalfemalepatients(meanage,56.3yearsold).All post-menopausal femalepatients were over 50 yearsold. Individuals with a BMI of 25---29.9 were considered over-weight,while individuals witha BMI 30 were categorized asobese.5 _{The matching limitswere 50yearsor olderfor} age,and25kg/m2_{orhigherforBMIinourstudy.}

According to these criteria, we compared DISE find-ingsbetweenpre-menopausalfemaleandpost-menopausal female patients or between post-menopausal female and malespatientsmatchedforage(over50yearsold)andBMI.

Druginducedsleependoscopyandclassification system

AllDISEprocedureswereperformedby thesameENT sur-geonin a semi-dark and silent operation roomwith each patient lying supine. Sleep was induced by intravenous administrationof midazolam with respiratory monitoring. Theanesthesiologistslowlytitratedthedrugto0.07mg/kg perpatient;bolusesof1---2.5mgweregiven(toamaximum of7.5mgperpatient)usingatarget-controlledinfusion sys-tem. An extra bolus was often required by patients who wereextremelynervous.Oncethepatientwasdeeplyasleep enough to snore, show obstructions and responded slug-gishtoalightglabellaorloudauditorystimulus(Ramsay’s levelofsedationscale5),6_{a4mm-diameterflexiblevideo} laryngoscopewasgentlyintroducedthroughthenose.Video images of all DISE procedures were later evaluated by a singleotolaryngologist.

WeoftenperformedDISEpostoperativelytoobservethe extentof improvementaftersurgery; preoperative proce-dureswereprincipallydiagnosticinnature.

Each procedure took 20---30min. When possible, we performedonlyonecycle,aftercarefulpreparation,to min-imizetheriskofrespiratorycomplications.

We divided the pharynx into two portions: the retropalatal level (the region of posterior to the soft palate)andtheretrolinguallevel(the regionof the phar-ynx posterior to the vertical portion of the tongue). We madetheclassification systemaccording toourpublished procedures.4,7 _{Briefly, our classification system included} the following: the obstruction site, degree of SDB, and the anatomical structure contributing the most to sleep apnea. The retropalatal level was subdivided into palate (antero-posterior diameter), lateral pharyngeal wall (lat-eraldiameter), and tonsil (specific structure contributing to obstruction). The retrolingual level was divided into tonguebase(antero-posteriordiameter),lateralpharyngeal wall (lateral diameter), and epiglottis (specific structure contributingtoobstruction). Degreeof airwayobstruction was categorized as no obstruction (rated as 0), partial obstruction(ratedas1;50---75%obstruction),andcomplete obstruction(ratedas2,>75%)(Table1).

Statisticalanalysis

We evaluated the difference between female and male patientgroups accordingtoDISEfindings. Student’st-test was used to compare BMI, AHI, and lowest arterial oxy-gensaturation (SaO2) betweenmaleand femalepatients. Mann---Whitney U test was used if the data was not nor-mallydistributed.Allstatisticaltestswereperformedusing SPSSversion 18.0 (SPSS Inc., Chicago IL, USA). Statistical significancewasmetwhenp-valuewaslessthan0.05.

Table1 DISEclassificationsystem.

Obstructionlevel Configurationa

APdiameter Lateraldiameter Contributingstructure

Retropalatal PalateAP LPW Tonsil

0/1/2 0/1/2 0/1/2

Retrolingual TonguebaseAP LPW Epiglottis

0/1/2 0/1/2 0/1/2

AP,anteroposterior.

a_{Degreeofobstructionhasonenumberforeachstructure:0,noobstruction(novibration);1,partialobstruction(vibration,50---75%);} 2,completeobstruction(collapse,>75%).

AdaptedfromKooetal.7

Table2 Demographyandpatient’scharacteristicsofPSGfinding.

Sex Number Age(yr) BMI(kg/m2_{) AHI(events/h) LowestSaO} 2(%)

Male 195 41.1 26.0 23.2 79.6

Female 78 46.0 24.5 13.9 83.2

pa _0.005c _0.001c _0.001c _0.026c

Female

Pre-menopausalfemalepatients 41 36.7 23.5 12.8 85.0

Post-menopausalfemalepatients 37 56.3 25.6 15.0 81.2

pb _<0.0001c _0.019c _{0.630 0.130}

PSG,polysomnography;BMI,bodymassindex;AHI,apnea/hypopneaindex;SaO2,arterialoxygensaturation. a_{Student’st-testbetweenmaleandfemale.}

b _{Student’st-testbetweenpre-menopausalandpost-menopausalfemalepatients.}

c _{Statisticallysignificantdifferencesbetweengroupsregardingage,BMI,AHIandlowestSaO} 2.

Results

Demography of patients used in this study is summarized inTable 2. Total273 subjects (195males, meanage 41.1 years old; and 78 females, mean age 46.0 years old). Male patients had significantly higher BMI (26.0 vs. 24.5;

p=0.001),higherAHI (23.2vs.13.9;p=0.001),andlower lowest SaO2 (79.6 vs. 83.2; p=0.026). The average ages of pre-menopausal and post-menopausal female patients

were 36.7 and 56.3years, respectively. Upon PSG exami-nation, post-menopausalpatients (whohad a significantly higher BMI than did pre-menopausal patients; 25.6kg/m2 vs.23.5kg/m2_{;p=0.019)tendedtohaveahigherAHIand} alowerlowestSaO2,butthedifferencesdidnotattain sta-tisticalsignificance(Table2).

Comparisons between pre-menopausal and post-menopausal female patients accordingto DISEfindingare summarized in Table 3. In DISE finding, post-menopausal

Table3 ComparisonofDISEscorebetweenpre-menopausalandpost-menopausalfemalepatients.

Retropalatallevel Retrolinguallevel

APdiameter Lateral diameter

Tonsillar obstruction

APdiameter Lateral diameter

Epiglottic obstruction

Pre-menopausalfemale patients(41)

1.73 0.90 0.49 1.49 0.61 0.39

Post-menopausalfemale patients(37)

1.76 1.49 0.59 1.62 1.14 0.62

pa _{0.847 0.001}b _{0.568 0.424 0.003}b _0.227

(),numberofpatients;DISE,drug-inducedsleependoscopy;AP,anteroposterior. a_{Student’st-test.}

Table4 ComparisonofDISEscorebetweenpost-menopausalfemalepatients(BMI<25)andmen(age≥50;BMI<25).

Retropalatallevel Retrolinguallevel

APdiameter Lateral diameter

Tonsillar obstruction

APdiameter Lateral diameter

Epiglottic obstruction

Men(26) 1.81 0.88 0.31 0.85 0.81 0.62

Post-menopausalfemale patients(17)

1.88 1.24 0.35 1.76 1.24 0.71

pa _{0.710 0.166 0.935 <0.0001}b _0.042b _0.716

(),numberofpatients;DISE,drug-inducedsleependoscopy;AP,anteroposterior. a _{Mann---Whitneytest.}

b _{Statisticallysignificantdifferencesbetweengroups.}

Table5 ComparisonofDISEscorebetweenpost-menopausalfemalepatients(BMI≥25)andmen(age≥50;BMI≥25).

Retropalatallevel Retrolinguallevel

APdiameter Lateral diameter

Tonsillar obstruction

APdiameter Lateral diameter

Epiglottic obstruction

Men(31) 1.68 1.19 0.16 1.10 0.87 0.52

Post-menopausalfemale patients(20)

1.65 1.70 0.80 1.50 1.05 0.55

pa _{0.882 0.017}b _0.003b _{0.057 0.461 1.000}

(),numberofpatients;DISE,drug-inducedsleependoscopy;AP,anteroposterior. a _{Mann---Whitneytest.}

b _{Statisticallysignificantdifferencesbetweengroups.}

femalepatientsshowedhighervaluesinalltheobstruction sites.Significantdifferencewasseenforbothlateral diame-terofretropalatal(0.90vs.1.49;p=0.001)andretrolingual levelmeasures(0.61vs.1.14;p=0.003)(Table3).

IncomparisontoDISEfindingbetweenpost-menopausal femalepatients(n=37)andmalepatientsmatchedforage (over 50 years old) and BMI, the total number of male patients was 195, of these, 26 and 31 were matched for age(over50years)andBMI(BMI<25kg/m2_{),andage(over} 50 years) and BMI (BMI≥25kg/m2), with females.

Post-menopausalfemalepatientshadsignificantlyhighervalues inAP(p<0.0001)andlateraldiameterofretrolinguallevel (p=0.042)inlowerBMIgroup(BMI<25)(Table4).Inhigher BMIgroup(BMI≥25),post-menopausalfemalepatientshad

significantly higher values in lateral diameter (p=0.017) and tonsillar obstruction (p=0.003) of retropalatal level (Table5).

Discussion

OSAS is generally more common and severe in men and than women when matched for BMI and PSG parameters suchasAHIandlowestSaO2saturation.1Thesefindingsare in agreement with our resultand previous reports in the literature about sleep apnea patients of different ethnic origins.8---10 _{However, women experience hormone-related} changessuchasmenopauseandpregnancythathaveagreat

influenceonincidenceOSAS.Therefore,genderdifferences areveryimportantinexamination andtreatmentof sleep disorders.

OSASgenerallyoccursmore frequentlyandwithhigher severityinpost-menopausal femalesthan pre-menopausal females aspre-menopausal females have higher levels of circulatingprogesteronethatcouldpreventairwayclosure by reducing the collapsibility of genioglossus muscle.10---15 Other than that the reasons behind influence of gender andthe menopause status for females in occurrence and severity of OSAS are still not completely understood. It hasbeen estimated that the prevalence of this condition among women in their sixth or seventh decade of life rangesfrom4%to22%dependingonthedefinitionusedand thepopulation examined.11 _{Inourstudy,post-menopausal} femalepatientswithOSAShadasignificantlyhighervalueof BMI,higherAHIandlowerlowestSaO2_{saturation,although} the differences were not statistically significant. There-fore,post-menopausalfemalepatientstendedtoshowmore severeOSASthanpre-menopausalfemalepatients.Although noclear causes for thesechanges have been established, theageparametersformenopausalstatusandupperairway muscletonemighthavecontributed.

thelateralwalloftheairwayobstructionplaysasignificant roleforwomenaftermenopause.Thisisanimportantpoint fromthe therapeutic point of view. Other research stud-iesfrom DISE finding of obstructive sleep apnea patients showedsimilarresults,emphasizingtheimportanceofthe lateraldiameter.4,16,17_{InthecurrentstudyfromDISE} analy-sis,multileveland complete collapse wasmore prevalent in obese patients and in those with more severe OSA. Higher BMIvalueswere associated ahigher probabilityof complete concentric palatal collapse and also complete lateral hypopharyngeal collapse, which may be explained byfat accumulationat the lateral pharyngeal walls.16 _On thecontrary, lowerBMIvalue wasassociated withtongue base collapse,and thismay beresultof less fat accumu-lationinthelateralpharyngeal wall,possiblyallowing for more backward movement of the tongue.16 _{In our study,} post-menopausalfemalepatientsshowedmore concentric palatalcollapse(lateraldiameterandtonsillarobstruction ofretropalatal level) inhigherBMI groupand retrolingual collapse(AP and lateraldiameterof retrolinguallevel) in lower BMI group than male patients, and our result is in agreement with previous reports. These findings indicate that post-menopausal female patients have a higher ten-dencyofanatomicalchangeintheairwaythanmenofthe sameagegroupandlevelofobesity.Therefore,weshould pay more attention to anatomical changes when treating post-menopausalfemaleOSASpatients.

In general, a large upper airway soft tissuevolume in menmaycontributetoincreasedprevalenceofOSAS com-paredtowomen.Upperairwayresistanceisreportedtobe higherinmenthanthatinwomen.17,18_{But,post-menopausal} femalepatientsshowed moresevereclosure in ourstudy. Thismightbeduetothefactthatthemuscletoneof post-menopausalwomenisdecreased.However,furtherresearch isrequiredtoexplorethispossibility.

Ourstudyhassomelimitations.Thestudypopulationwas smallthusreducingthepowerofanalysis.Alsothepatients ofthis study werecandidates for obstructivesleepapnea surgery,sodidnotrepresentthegeneralOSASpopulation.As aresult,therewasaninherentbiasfordrugselection, pro-cedure,andclassificationfromDISE.Alarge-scalestudyof thegeneralOSASpopulationisrequired,asitwouldobviate thistreatmentbias.

Conclusion

In conclusion, post-menopausal female patients showed more severe sleep apnea than pre-menopausal female patients.InDISEfindings,post-menopausalfemalepatients showed a tendency with a more severe airway obstruc-tion,especiallyinthelateralwall.Post-menopausalfemale patientsshowedmoreconcentricpalatalcollapseinhigher BMIgroupandretrolingualcollapseinlowerBMIgroupthan themalepatients.Post-menopausalfemalepatientsshowed atendencywithmoresevereairwayobstructioninallparts oftheairwayinDISEfindingthanmenwithsimilarageand BMI. The key to successfully treating OSAS is individually tailoredtreatment.Inthisrespect,determiningthe sever-ity of OSAS, pattern and degree of collapse according to gender,ageandBMIareveryimportantforapersonalized

treatmentplan.Therefore,withinsomelimits,our compar-ativestudybetweenmenandwomenthroughDISEmayhelp themedicalcommunityconsult, diagnose,andtreat OSAS moreeffectively.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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