Obstruction Event Severity in Diagnostics of Sleep Apnea

Publications of the University of Eastern Finland Dissertations in Health Sciences

isbn 978-952-61-1465-1

Publications of the University of Eastern Finland

Dissertations in Health Sciences

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Anu Muraja-Murro

Obstruction Event Severity in

Diagnostics of Sleep Apnea

Anu Muraja-Murro

Obstruction Event Severity in

Diagnostics of Sleep Apnea

most common sleep disorder, is characterized with repeated epi-sodes of blockage of upper airway during sleep. Currently, diagnosis and classification of OSA is based on the number of apnea and hypopnea events or desaturation events per hour. The purpose of this study was to create a novel diagnostic param-eter containing information on se-verity of individual obstruction and desaturation events. Adjusted AHI parameter was introduced and shown to improve the recognition of the patients with the highest risk of the severe health consequences of OSA.

ANU MURAJA-MURRO

Obstruction

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Event

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Severity

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in

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Diagnostics

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of

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Sleep

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Apnea

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ToȱbeȱpresentedȱbyȱpermissionȱofȱtheȱFacultyȱofȱHealthȱSciences,ȱUniversityȱofȱEasternȱ

Finlandȱȱ

forȱpublicȱexaminationȱinȱAuditoriumȱ2,ȱKuopioȱUniversityȱHospital,ȱȱ

onȱFridayȱtheȱ13th_{ȱJuneȱ2014,ȱatȱ12ȱnoonȱ} ȱ

ȱ ȱ

PublicationsȱofȱtheȱUniversityȱofȱEasternȱFinlandȱ ȱDissertationsȱinȱHealthȱSciencesȱȱ

Numberȱ233ȱ ȱ ȱȱ

DepartmentȱofȱClinicalȱNeurophysiologyȱ

InstituteȱofȱClinicalȱMedicineȱ

SchoolȱofȱMedicineȱ

FacultyȱofȱHealthȱSciencesȱ

UniversityȱofȱEasternȱFinlandȱ

ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ KopijyväȱOyȱ Kuopio,ȱ2014ȱ ȱ SeriesȱEditors:ȱȱ

ProfessorȱVeliȬMattiȱKosma,ȱM.D.,ȱPh.D.ȱ

InstituteȱofȱClinicalȱMedicine,ȱPathologyȱ

FacultyȱofȱHealthȱSciencesȱ ȱ

ProfessorȱHanneleȱTurunen,ȱPh.D.ȱ

DepartmentȱofȱNursingȱScienceȱ

FacultyȱofȱHealthȱSciencesȱ ȱ

ProfessorȱOlliȱGröhn,ȱPh.D.ȱ

A.I.ȱVirtanenȱInstituteȱforȱMolecularȱSciencesȱ

FacultyȱofȱHealthȱSciencesȱ ȱ

ProfessorȱKaiȱKaarniranta,ȱM.D.,ȱPh.D.ȱ

InstituteȱofȱClinicalȱMedicine,ȱOphthalmologyȱ

FacultyȱofȱHealthȱSciencesȱȱ ȱ

LecturerȱVeliȬPekkaȱRanta,ȱPh.D.ȱ(pharmacy)ȱ

SchoolȱofȱPharmacyȱ

FacultyȱofȱHealthȱSciencesȱ ȱ

Distributor:ȱȱ

UniversityȱofȱEasternȱFinlandȱ

KuopioȱCampusȱLibraryȱ

P.O.Boxȱ1627ȱ FIȬ70211ȱKuopio,ȱFinlandȱ http://www.uef.fi/kirjastoȱ ȱ ISBNȱ(print):ȱ978Ȭ952Ȭ61Ȭ1465Ȭ1ȱ ISBNȱ(pdf):ȱ978Ȭ952Ȭ61Ȭ1466Ȭ8ȱ ISSNȱ(print):ȱ1798Ȭ5706ȱ ISSNȱ(pdf):ȱ1798Ȭ5714ȱ ISSNȬL:1798Ȭ5706ȱ

III

ȱ ȱ

Author’sȱaddress:ȱ DepartmentȱofȱClinicalȱNeurophysiologyȱȱ

KuopioȱUniversityȱHospitalȱandȱ

InstituteȱofȱClinicalȱMedicineȱ

SchoolȱofȱMedicineȱ

UniversityȱofȱEasternȱFinlandȱ

KUOPIOȱ

FINLANDȱ ȱ

Supervisors:ȱ Professor,ȱChiefȱPhysicistȱJuhaȱTöyräs,ȱPh.D.ȱ

DiagnosticȱImagingȱCentreȱȱ

KuopioȱUniversityȱHospitalȱandȱ

DepartmentȱofȱAppliedȱPhysicsȱ

UniversityȱofȱEasternȱFinlandȱ

KUOPIOȱ

FINLANDȱ ȱ

Professor,ȱChiefȱPhysicianȱEsaȱMervaala,ȱM.D.,ȱPh.D.ȱ

DepartmentȱofȱClinicalȱNeurophysiologyȱȱ

DiagnosticȱImagingȱCentreȱ

KuopioȱUniversityȱHospitalȱandȱ

InstituteȱofȱClinicalȱMedicineȱȱ

SchoolȱofȱMedicineȱ

UniversityȱofȱEasternȱFinlandȱ

KUOPIOȱ

FINLANDȱ ȱ

Reviewers:ȱ DocentȱTapaniȱSalmi,ȱM.D.,ȱPh.D.ȱ ȱ DepartmentȱofȱClinicalȱNeurophysiologyȱ ȱ HelsinkiȱUniversityȱCentralȱHospitalȱandȱ ȱ UniversityȱofȱHelsinkiȱ

HELSINKIȱ

FINLANDȱ ȱ

ProfessorȱHannuȱEskola,ȱPh.D.ȱ

DepartmentȱofȱElectronicsȱandȱCommunicationsȱEngineeringȱ

TampereȱUniversityȱofȱTechnologyȱ

TAMPEREȱ

FINLANDȱ ȱ

Opponent:ȱ DocentȱEsaȱRauhala,ȱM.D.,ȱPh.D.ȱ

DepartmentȱofȱClinicalȱNeurophysiologyȱȱ

SatakuntaȱCentralȱHospitalȱandȱ

UniversityȱofȱTampereȱ

PORIȱ

FINLANDȱ

V

MurajaȬMurro,ȱAnuȱ

ObstructionȱEventȱSeverityȱinȱDiagnosticsȱofȱSleepȱApneaȱ

UniversityȱofȱEasternȱFinland,ȱFacultyȱofȱHealthȱSciencesȱ

PublicationsȱofȱtheȱUniversityȱofȱEasternȱFinland.ȱDissertationsȱinȱHealthȱSciencesȱ233,ȱ2014,ȱ61ȱp.ȱ

ȱ ISBNȱ(print):ȱ978Ȭ952Ȭ61Ȭ1465Ȭ1ȱ ISBNȱ(pdf):ȱ978Ȭ952Ȭ61Ȭ1466Ȭ8ȱ ISSNȱ(print):ȱ1798Ȭ5706ȱ ISSNȱ(pdf):ȱ1798Ȭ5714ȱ ISSNȬL:1798Ȭ5706ȱ ȱ ABSTRACT

Obstructiveȱ sleepȱapneaȱ(OSA)ȱisȱtheȱ mostȱcommonȱsleepȱrelatedȱbreathingȱ

disorderȱinȱadults.ȱCurrently,ȱtheȱdiagnosisȱandȱclassificationȱofȱOSAȱisȱbasedȱonȱ

theȱnumberȱofȱapneaȱandȱhypopneaȱeventsȱorȱdesaturationȱeventsȱperȱhour,ȱi.e.ȱtheȱ

apneaȬhypopneaȱindexȱ(AHI)ȱorȱtheȱoxygenȱdesaturationȱindexȱ(ODI)ȱdetectedȱinȱ

polygraphicȱrecordings.ȱUnfortunately,ȱAHIȱandȱODIȱdoȱnotȱprovideȱdetailedȱ

informationȱonȱtheȱseverityȱofȱindividualȱobstructionȱevents.ȱȱ

Theȱaimȱofȱthisȱthesisȱwasȱtoȱinvestigateȱmorbidityȱandȱmortalityȱrelatedȱtoȱ

obstructiveȱ sleepȱ apneaȱ andȱ toȱ introduceȱ novelȱ diagnosticȱ parametersȱ

incorporatingȱ informationȱ onȱ morphologyȱ andȱ durationȱ ofȱ obstructionȱ andȱ

desaturationȱevents.ȱTheȱmostȱpromisingȱofȱtheȱnewȱparametersȱwasȱobstructionȱ

severity,ȱwhichȱincorporatesȱtheȱdurationȱofȱobstructionȱandȱtheȱareaȱofȱtheȱrelatedȱ

desaturationȱevent.ȱTheseȱissuesȱwereȱinvestigatedȱinȱretrospectiveȱstudiesȱwithȱ

ambulatoryȱ polygraphicȱ recordingsȱ ofȱ menȱ (nȱ =ȱ 226Ȭ1068)ȱ referredȱ toȱ theȱ

DepartmentȱofȱClinicalȱNeurophysiologyȱatȱKuopioȱUniversityȱHospitalȱdueȱtoȱaȱ

suspicionȱofȱsleepȱdisorderedȱbreathingȱduringȱtheȱyearsȱ1993Ȭ2007.ȱInȱadditionȱtoȱ

reȬanalyzingȱambulatoryȱpolygraphicȱrecordings,ȱinformationȱwasȱcollectedȱonȱ

morbidityȱ andȱ mortalityȱ ofȱ patients.ȱ Finally,ȱ anȱ adjustedȱ AHIȱ parameterȱ

connectingȱAHIȱandȱobstructionȱseverityȱwasȱintroducedȱtoȱallowȱtheȱuseȱofȱtheȱ

AmericanȱAcademyȱofȱSleepȱMedicineȱ(AASM)ȱGuidelinesȱinȱtheȱdiagnosticsȱofȱ

theȱseverityȱofȱtheȱdisease.ȱ

TheȱpatientsȱwithȱmoderateȱtoȱsevereȱOSAȱhadȱsignificantlyȱhigherȱmortalityȱ

ratesȱasȱcomparedȱtoȱthoseȱwithoutȱOSA.ȱTheȱseverityȱofȱindividualȱobstructionȱ

eventsȱshowedȱsignificantȱvariationȱbetweenȱpatientsȱhavingȱsimilarȱAHI.ȱTheȱ

obstructionȱseverityȱparameterȱwasȱfoundȱsuperiorȱtoȱAHIȱonȱitsȱownȱinȱdetectingȱ

patientsȱatȱtheȱhighestȱriskȱofȱsufferingȱcardiovascularȱmortalityȱorȱmorbidity.ȱ

AdjustedȱAHIȱwasȱfoundȱtoȱbeȱeasilyȱapplicableȱandȱpotentiallyȱsuitableȱforȱ

clinicalȱuse.ȱ

Theȱ novelȱ parametersȱ introducedȱ inȱ thisȱ thesisȱ provideȱ importantȱ

supplementaryȱinformationȱtoȱAHIȱwhenȱassessingȱtheȱseverityȱofȱOSAȱandȱ

improveȱtheȱrecognitionȱofȱthoseȱpatientsȱwhoȱcarryȱtheȱhighestȱriskȱofȱsufferingȱ

severeȱhealthȱconsequencesȱofȱOSA.ȱ ȱ

NationalȱLibraryȱofȱMedicineȱClassification:ȱWFȱ143,ȱWFȱ141ȱ

MedicalȱSubjectȱHeadings:ȱ Sleepȱ Apnea,ȱObstructive/diagnosis;ȱ Sleepȱ Apnea,ȱObstructive/ȱ

VII

MurajaȬMurro,ȱAnuȱ

Hengityskatkostenȱvaikeudenȱmerkitysȱuniapneanȱdiagnostiikassaȱȱ

ItäȬSuomenȱyliopisto,ȱTerveystieteidenȱtiedekuntaȱ

PublicationsȱofȱtheȱUniversityȱofȱEasternȱFinland.ȱDissertationsȱinȱHealthȱSciencesȱ233,ȱ2014,ȱ61ȱp.ȱ

ȱ ISBNȱ(print):ȱ978Ȭ952Ȭ61Ȭ1465Ȭ1ȱ ISBNȱ(pdf):ȱ978Ȭ952Ȭ61Ȭ1466Ȭ8ȱ ISSNȱ(print):ȱ1798Ȭ5706ȱ ISSNȱ(pdf):ȱ1798Ȭ5714ȱ ISSNȬL:ȱ1798Ȭ5706ȱ ȱ ȱ TIIVISTELMÄ

Obstruktiivinenȱ uniapneaȱ onȱ yleisinȱ aikuistenȱ unenȱ aikainenȱ hengityshäiriö.ȱ

Nykyinenȱ obstruktiivisenȱ uniapneanȱ diagnostiikkaȱ jaȱ luokitusȱ perustuvatȱ

poikkeavienȱhengitysȬȱjaȱhappidesaturaatiotapahtumienȱlukumääräänȱtunnissaȱ

unenȱaikana.ȱKäytetyimmätȱdiagnostisetȱindeksitȱovatȱapneaȬhypopneaȱindeksiȱ

(apneaȬhypopneaȱindex,ȱAHI)ȱjaȱhappidesaturaatioȱindeksiȱ(oxygenȱdesaturationȱ

index,ȱODI).ȱValitettavastiȱAHIȱjaȱODIȱeivätȱsisälläȱtarkempaaȱtietoaȱyksittäistenȱ

poikkeavienȱhengitystapahtumienȱvakavuudesta.ȱ

Tässäȱ väitöskirjassaȱ tutkittiinȱ uniapneaanȱ liittyvääȱ sairastavuuttaȱ jaȱ

kuolleisuuttaȱ sekäȱ kehitettiinȱ uusiaȱ diagnostisiaȱ parametreja.ȱ Uusistaȱ

parametreistaȱlupaavimmaksiȱosoittautuiȱobstructionȱseverityȱ Ȭparametri,ȱjokaȱ

huomioiȱ poikkeavienȱ hengitystapahtumienȱ kestonȱ jaȱ niihinȱ liittyvänȱ

happidesaturaationȱpintaȬalan.ȱTutkimuksessaȱkäytiinȱläpiȱtakautuvastiȱKuopionȱ

Yliopistollisessaȱsairaalassaȱvuosinaȱ1993Ȭ2007ȱtutkittujaȱpotilaitaȱ(nȱ=ȱ226Ȭ1068),ȱ

jotkaȱ oliȱ lähetettyȱ uniapneaȬepäilynȱ vuoksiȱ ambulatoriseenȱ yöpolygrafiaan.ȱ

Analyysejäȱ vartenȱ potilaistaȱ kerättiinȱ sairastavuusȬȱ jaȱ kuolleisuustiedot.ȱ

VäitöskirjassaȱesiteltiinȱobstructionȱseverityȱȬparametriinȱperustuvaȱadjustedȱAHIȬȱ

parametri,ȱjokaȱmahdollistaaȱAmericanȱAcademyȱofȱSleepȱMedicine:nȱ(AASM)ȱ

suositustenȱmukaisenȱuniapneanȱvakavuudenȱluokittelun.ȱȱ

Kohtalaistaȱtaiȱvaikeaaȱuniapneaaȱsairastavillaȱpotilaillaȱtodettiinȱmerkittävästiȱ

korkeampiȱ kuolleisuusriskiȱ verrattunaȱ potilaisiin,ȱ joillaȱ eiȱ oleȱ uniapneaa.ȱ

Yksittäistenȱhengitystapahtumienȱvakavuudessaȱhavaittiinȱmerkittävääȱvaihteluaȱ

samanȱ AHI:nȱ omaavienȱ potilaidenȱ välillä.ȱ Obstructionȱ severityȱ Ȭȱ parametriȱ

osoittautuiȱ paremmaksiȱ kuinȱ AHIȱ selviteltäessäȱ suurimmassaȱ terveysriskissäȱ

oleviaȱ uniapneapotilaita.ȱ Adjustedȱ AHIȱ todettiinȱ mahdollisestiȱ sopivaksiȱ

kliiniseenȱkäyttöön.ȱ

UudetȱparametritȱparantavatȱkorkeimmassaȱsydänȬȱjaȱverisuonitaudinȱriskissäȱ

sekäȱ kuolleisuusriskissäȱ olevienȱ potilaidenȱ tunnistamista.ȱ Adjustedȱ AHIȱ

parametrinȱkäyttöȱvoiȱparantaaȱuniapneataudinȱvakavuudenȱarviointiaȱkliinisessäȱ

työssä.ȱ ȱ

Luokitus:ȱWFȱ143,ȱWFȱ141ȱ

YleinenȱSuomalainenȱasiasanasto:ȱobstruktiivinenȱuniapnea;ȱuniapneaȬoireyhtymä;ȱdiagnostiikka;ȱ

indeksit;ȱkuolleisuusȱ

IX

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ȬȱFaith,ȱHopeȱandȱLoveȱmakeȱmiraclesȱȬȱ

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ToȱAlpo,ȱJuho,ȱLaura,ȱJuusoȱandȱMetteȱ

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XI

Acknowledgements

ȱȱ

ThisȱstudyȱwasȱcarriedȱoutȱinȱDepartmentȱofȱClinicalȱNeurophysiology,ȱKuopioȱ

UniversityȱHospitalȱduringȱtheȱyearsȱ2011Ȭ2014.ȱȱ ȱ

IȱwishȱtoȱexpressȱmyȱdeepȱgratitudeȱtoȱmyȱmainȱsupervisorȱProfessorȱJuhaȱTöyräs,ȱ

Ph.D.ȱforȱhisȱsupportȱandȱunbelievableȱguidance.ȱJuhaȱintroducedȱmeȱtoȱtheȱ

fascinatingȱlifeȱofȱscienceȱandȱtaughtȱmeȱhowȱtoȱbeȱaȱresearcher.ȱThereȱisȱaȱphraseȱ

thatȱ“youȱcan’tȱteachȱanȱoldȱdogȱnewȱtricks”,ȱbutȱJuhaȱprovedȱthisȱwrong.ȱHeȱhasȱ

shownȱamazingȱpatienceȱinȱteachingȱnewȱthingsȱaboutȱscienceȱtoȱme,ȱ“anȱoldȱ

dog”.ȱȱ ȱ

IȱoweȱmyȱsincereȱgratitudeȱtoȱmyȱsupervisorȱProfessorȱEsaȱMervaala,ȱM.D.,ȱPh.D.ȱ

forȱtheȱinspiringȱcoȬoperationȱandȱtheȱencouragementȱwhichȱbeganȱalreadyȱatȱtheȱ

beginningȱofȱmyȱcareerȱinȱclinicalȱneurophysiology.ȱForȱtheȱpastȱ17ȱyearsȱEsaȱhasȱ

beenȱguidingȱmeȱinȱtheȱinterestingȱfieldȱofȱclinicalȱneurophysiologyȱandȱinȱlaterȱ

yearsȱ alsoȱ inȱ science.ȱ Heȱ hasȱ alwaysȱ supportedȱ me,ȱ showingȱ boundlessȱ

enthusiasm,ȱalwaysȱwithȱaȱpositiveȱattitudeȱinȱveryȱdifferentȱkindȱofȱsituations.ȱ ȱ

Iȱwishȱtoȱthankȱtheȱofficialȱreviewersȱofȱtheȱthesis,ȱDocentȱTapaniȱSalmiȱM.D.,ȱ

Ph.D.ȱandȱProfessorȱHannuȱEskolaȱPh.D.ȱforȱtheirȱpromptȱcommunicationsȱandȱ

valuableȱcomments.ȱIȱenjoyedȱmyȱdiscussionsȱwithȱProfessorȱHannuȱEskola,ȱhisȱ

preciseȱquestionsȱandȱcommentsȱhaveȱmadeȱthisȱthesisȱsoȱmuchȱbetter.ȱWithȱtheȱ

helpȱofȱDocentȱTapaniȱSalmi’sȱexpertȱinsightsȱandȱcomments,ȱthisȱthesisȱimprovedȱ

significantly.ȱIȱwantȱtoȱexpressȱmyȱgratitudeȱtoȱDocentȱEsaȱRauhala,ȱM.D.,ȱPh.D.ȱ

forȱacceptingȱtheȱinvitationȱofȱbeingȱtheȱopponentȱforȱtheȱpublicȱexaminationȱofȱ

myȱdoctoralȱthesis.ȱIȱamȱalsoȱgratefulȱtoȱEwenȱMacDonald,ȱD.Pharm.ȱforȱtheȱ

linguisticȱrevisionȱofȱtheȱthesis.ȱIȱalsoȱwantȱtoȱthankȱTuomasȱSelander,ȱM.Scȱforȱ

statisticalȱadvice.ȱ ȱ

IȱdeeplyȱthankȱphysicistsȱPekkaȱTiihonen,ȱPh.D.ȱandȱAnttiȱKulkas,ȱPh.D.ȱforȱtheirȱ

helpȱinȱdataȱanalysis,ȱimageȱprocessingȱandȱtextȱediting.ȱIȱwantȱalsoȱthankȱtheȱ

otherȱcoȬauthorsȱforȱtheirȱcontributionsȱtoȱthisȱstudy:ȱTainaȱHukkanenȱB.Sc.,ȱKeijoȱ

EskolaȱB.M.,ȱTuukkaȱKolariȱM.D.,ȱJoukoȱNurkkalaȱM.D.,ȱHenriȱTuomilehtoȱM.D.,ȱ

Ph.D.,ȱJoukoȱKokkarinenȱM.D.,ȱPh.D.,ȱProfessorȱMarkkuȱPeltonenȱPh.D.ȱandȱ

physicsȱstudentsȱMikkoȱHiltunenȱandȱSallaȱKupari.ȱȱ ȱ

IȱwishȱtoȱthankȱMerviȱKönönenȱM.Sc.ȱforȱherȱfriendshipȱandȱtheȱenjoyableȱ

discussionsȱaboutȱscienceȱandȱonȱnonȬscientificȱtopics.ȱIȱalsoȱwishȱtoȱexpressȱmyȱ

thanksȱtoȱAnneȬMariȱKantanenȱM.D.ȱforȱnumerousȱdiscussionsȱaboutȱprofessionalȱ

andȱdayȬtoȬdayȱthings,ȱyouȱhaveȱalwaysȱsupportedȱme,ȱduringȱscientificȱandȱshopȱ

stewardȱactivities.ȱ

Iȱ expressȱ myȱwarmȱ thanksȱtoȱ allȱmyȱ colleaguesȱinȱ Departmentȱ ofȱ Clinicalȱ

Neurophysiology,ȱ Kuopioȱ Universityȱ Hospital;ȱ Susannaȱ WesterenȬPunnonenȱ

M.D.,ȱSaraȱMäättäȱM.D.,ȱPh.D.,ȱTuulaȱOjalaȱM.D.,ȱAndreȱOunȱM.D.,ȱPh.D.ȱandȱ

LiisaȱTeriöȱM.D.,ȱyouȱhaveȱalwaysȱsupportedȱmeȱandȱshownȱaȱpositiveȱattitudeȱ

towardȱmyȱscientificȱstudyȱinȱspiteȱofȱyourȱbusyȱdailyȱwork.ȱWeȱhaveȱhadȱmanyȱ

goodȱlaughsȱtogetherȱduringȱtheȱyearsȱandȱIȱbelieveȱthatȱweȱwillȱhaveȱmanyȱmoreȱ

happyȱtimesȱinȱtheȱfuture.ȱIȱalsoȱwishȱtoȱthankȱallȱtheȱstaffȱinȱourȱClinic,ȱIȱhaveȱ

beenȱprivilegedȱtoȱworkȱwithȱwonderfulȱpeopleȱforȱsoȱmanyȱyears,ȱIȱconsiderȱthatȱ

ourȱ workȱ community,ȱ allȱ theȱ nurses,ȱ physicists,ȱ medicalȱ technologists,ȱ

departmentalȱsecretariesȱandȱmedicalȱdoctorsȱareȱoneȱbigȱfamily,ȱfacingȱtogetherȱ

theȱgoodȱandȱbadȱtimes.ȱȱȱȱȱ ȱ

Iȱwarmlyȱthankȱallȱmyȱfriendsȱfromȱnearȱandȱfarȱforȱsharingȱmyȱlifeȱoutsideȱofȱ

scienceȱandȱwork.ȱEspecially,ȱIȱamȱthankfulȱtoȱmyȱdearȱfriends,ȱSussuȱ&ȱPekkaȱandȱ

Mallaȱ&ȱOlliȱforȱallȱtheȱrelaxingȱeveningȱgatheringsȱandȱunforgettableȱtripsȱweȱ

haveȱmadeȱtogetherȱinȱFinlandȱandȱbeyond;ȱyouȱhaveȱhelpedȱmeȱfeelȱthatȱ“theȱ

worldȱisȱaȱbetterȱplace”.ȱIȱwishȱtoȱthankȱmyȱoldestȱfriendȱPirkkoȱforȱallȱtheȱ

momentsȱweȱhaveȱsharedȱtogetherȱsinceȱchildhood.ȱItȱisȱwonderfulȱtoȱknowȱthatȱ

youȱwillȱalwaysȱbeȱthereȱforȱmeȱandȱtheȱotherȱwayȱround.ȱ ȱ

Iȱdedicateȱmyȱdearȱthanksȱtoȱmyȱparents,ȱmyȱdeceasedȱmotherȱLiisaȱandȱmyȱfatherȱ

Paavoȱforȱtheirȱloveȱandȱencouragementȱinȱmyȱlife.ȱIȱcarryȱtheȱlovingȱmemoryȱofȱ

myȱmotherȱinȱmyȱheartȱandȱwishȱthatȱsheȱwouldȱhaveȱhadȱopportunityȱtoȱattendȱ

thisȱevent.ȱIȱamȱgratefulȱtoȱmyȱaunts,ȱPaulaȱforȱbeingȱmyȱspareȱmotherȱinȱaȱtimeȱofȱ

happinessȱandȱsorrowȱinȱadulthood,ȱandȱAstaȱandȱMirjaȱforȱtheȱmemorableȱ

discussionsȱaboutȱeverythingȱinȱlife.ȱIȱalsoȱexpressȱmyȱthanksȱtoȱmyȱparentsȬinȬlawȱ

MarjattaȱandȱHeimoȱforȱallȱpracticalȱhelpȱweȱhaveȱneededȱinȱeverydayȱlife.ȱThisȱ

alsoȱinȱFinnish:ȱIsotȱKiitoksetȱMarjattaȱjaȱHeimoȱkaikestaȱavustaȱarjessa.ȱȱ ȱ

Iȱwarmlyȱthankȱmyȱfourȱchildren,ȱJuho,ȱLaura,ȱJuusoȱandȱMetteȱforȱbeingȱinȱmyȱ

lifeȱandȱgivenȱmeȱsoȱmuchȱhappinessȱandȱrevealingȱtoȱmeȱwhatȱcomesȱfirstȱinȱlife.ȱ

Itȱhasȱbeenȱaȱgreatȱprivilegeȱtoȱseeȱalreadyȱtwoȱofȱyou,ȱJuhoȱandȱLaura,ȱtoȱgrowȱupȱ

intoȱadults;ȱhowever,ȱyouȱalwaysȱwillȱbeȱmyȱpreciousȱlittleȱchildren.ȱItȱhasȱbeenȱ

andȱwillȱbeȱaȱdidacticȱjourneyȱwithȱJuuso,ȱwhoȱhasȱtaughtȱmeȱpatienceȱandȱrespectȱ

toȱeveryȱgoodȱmomentȱinȱlife.ȱIȱhopeȱthatȱyouȱwillȱfindȱyourȱplaceȱinȱthisȱworld.ȱ

DearȱMette,ȱyouȱbringȱsunshineȱintoȱmyȱeverydayȱlife.ȱIȱloveȱallȱofȱyouȱandȱhopeȱ

weȱhaveȱplentyȱofȱyearsȱtoȱenjoyȱeachȱotherȱandȱtheȱsmallȱthingsȱinȱlife.ȱ ȱ

Finally,ȱmyȱlovingȱthanksȱgoȱtoȱmyȱhusbandȱAlpoȱforȱhisȱendlessȱsupportȱandȱhisȱ

beliefȱinȱme.ȱHeȱhasȱalwaysȱbeenȱthereȱwhenȱneededȱtoȱshareȱallȱmyȱjoysȱandȱ

worries.ȱYearsȱago,ȱwhenȱweȱmet,ȱitȱwasȱLOVEȱatȱfirstȱsight,ȱbutȱitȱisȱamazingȱtoȱ

realizeȱthatȱitȱisȱpossibleȱtoȱfallȱinȱloveȱwithȱyouȱallȱoverȱagain,ȱdayȱafterȱday.ȱIȱ

can’tȱimagineȱlifeȱwithoutȱyou.ȱYouȱmakeȱmyȱday!ȱȱ

ȱ

XIII

ThisȱdoctoralȱstudyȱhasȱbeenȱfinanciallyȱsupportedȱbyȱStateȱResearchȱFunding,ȱ

TheȱResearchȱFoundationȱofȱAiliȱandȱAarneȱTurunen,ȱTheȱResearchȱFoundationȱofȱ

UniversityȱofȱEasternȱFinlandȱandȱResearchȱFoundationȱofȱtheȱKuopioȱUniversityȱ

Hospital.ȱ ȱ ȱ ȱ Kuopio,ȱMayȱ2014ȱ ȱ ȱ ȱ ȱ

XV

List

ȱ

of

ȱ

the

ȱ

original

ȱ

publications

ȱȱ

Thisȱdissertationȱisȱbasedȱonȱtheȱfollowingȱoriginalȱpublicationsȱreferredȱinȱtheȱtextȱ

byȱtheirȱromanȱnumerals:ȱȱ ȱ

ȱ ȱ ȱ

Iȱ MurajaȬMurroȱ A,ȱ Eskolaȱ K,ȱ Kolariȱ T,ȱ Tiihonenȱ P,ȱ Hukkanenȱ T,ȱ

TuomilehtoȱH,ȱPeltonenȱM,ȱMervaalaȱE,ȱTöyräsȱJ.ȱMortalityȱinȱmiddleȬ

agedȱmenȱwithȱobstructiveȱsleepȱapneaȱinȱFinland.SleepȱandȱBreathing,ȱ

17(3):ȱ1047Ȭ1053,ȱ2013.ȱȱ ȱ

IIȱ MurajaȬMurroȱA,ȱNurkkalaȱJ,ȱTiihonenȱP,ȱHukkanenȱT,ȱTuomilehtoȱH,ȱ

Kokkarinenȱ J,ȱ Mervaalaȱ E,ȱ TöyräsȱJ.ȱ Totalȱ durationȱ ofȱ apneaȱ andȱ

hypopneaȱeventsȱandȱaverageȱdesaturationȱshowȱsignificantȱvariationȱinȱ

patientsȱ withȱ aȱ similarȱ apneaȬhypopneaȱ index.ȱ Journalȱ ofȱ Medicalȱ

Engineeringȱ&ȱTechnology,ȱ36(8):ȱ393Ȭ398,ȱ2012.ȱ ȱ

IIIȱMurajaȬMurroȱ A,ȱ Kulkasȱ A,ȱ Hiltunenȱ M,ȱ Kupariȱ S,ȱ Hukkanenȱ T,ȱ

TiihonenȱP,ȱMervaalaȱE,ȱTöyräsȱJ.ȱTheȱseverityȱofȱindividualȱobstructionȱ

eventsȱisȱrelatedȱtoȱincreasedȱmortalityȱrateȱinȱsevereȱobstructiveȱsleepȱ

apnea.ȱJournalȱofȱSleepȱResearch,ȱ22:ȱ663Ȭ669,ȱ2013.ȱ ȱ

IVȱMurajaȬMurroȱ A,ȱ Kulkasȱ A,ȱ Hiltunenȱ M,ȱ Kupariȱ S,ȱ Hukkanenȱ T,ȱ

TiihonenȱP,ȱMervaalaȱE,ȱTöyräsȱJ.ȱAdjustmentȱofȱapneaȬhypopneaȱindexȱ

withȱseverityȱofȱobstructionȱeventsȱenhancesȱdetectionȱofȱpatientsȱwithȱ

highestȱriskȱofȱsevereȱhealthȱconsequences.ȱSleepȱandȱBreathing,ȱDOI:ȱ

10.1007/s11325Ȭ013Ȭ0927Ȭz,ȱ2014.ȱ

ȱ

ȱ

ȱ ȱ

Theȱoriginalȱpublicationsȱhaveȱbeenȱreproducedȱwithȱtheȱkindȱpermissionȱofȱtheȱ

copyrightȱholders.ȱ ȱ

XVII

Contents

ȱ

2ȱOBSTRUCTIVEȱSLEEPȱAPNEAȱȱ...ȱȱ 3ȱ

2.1ȱPathophysiologyȱandȱetiologyȱȱ...ȱȱ 3ȱ

2.2ȱRiskȱfactorsȱȱ...ȱȱ 5ȱ

2.3ȱClinicalȱfeaturesȱȱ...ȱȱ 7ȱ ȱ 2.3.1ȱDiurnalȱsymptomsȱȱ………..ȱ 8ȱ

2.3.2ȱNocturnalȱsymptomsȱ………..ȱ 9ȱ

2.4ȱDiagnosticsȱofȱobstructiveȱsleepȱapneaȱȱ...ȱȱ 9ȱ ȱ 2.4.1ȱPolysomnographicȱandȱambulatoryȱrecordingsȱȱ 12ȱ

2.5ȱOSAȱandȱcoȬmorbiditiesȱȱ...ȱȱ 15ȱ ȱ 2.5.1ȱCardiovascularȱcoȬmorbidities………...ȱ 16ȱ ȱ 2.5.2ȱNonȬcardiovascularȱcoȬmorbiditiesȱ………..ȱ 20ȱ

2.6ȱTreatmentȱȱ...ȱȱ 21ȱ ȱ

3ȱOBJECTIVESȱOFȱTHEȱTHESISȱȱ...ȱȱ 25ȱ ȱ

4ȱPATIENTSȱANDȱMETHODSȱȱ...ȱȱ 27ȱ

4.1ȱPatientsȱandȱfollowȬupȱȱ...ȱȱ 27ȱ

4.2ȱEquipmentȱȱ...ȱȱ 28ȱ

4.3ȱParametersȱandȱsignalȱanalysisȱȱ...ȱȱ 29ȱ

4.4ȱStatisticalȱanalysesȱȱ...ȱȱ 31ȱ ȱ

5ȱRESULTSȱȱ...ȱȱ 33ȱ

5.1ȱEstimationȱofȱsleepȱapneaȱseverityȱwithȱAHIȱȱ...ȱȱ 33ȱ

5.2ȱConnectionȱbetweenȱdurationȱandȱmorphologyȱofȱobstructionȱandȱȱ ȱȱȱȱȱȱdesaturationȱeventsȱandȱseverityȱofȱOSAȱȱ...ȱȱ 34ȱ ȱ

6ȱDISCUSSIONȱȱ...ȱȱ 39ȱ ȱ

7ȱSUMMARYȱANDȱCONCLUSIONSȱȱ...ȱȱ 45ȱ ȱ REFERENCESȱȱ...ȱȱ 47ȱ ȱ ȱ ORIGINALȱPUBLICATIONSȱIȬIVȱȱ ȱ ȱ

Abbreviations

ȱ

ȱ

AȬAHIȱ AdjustedȬapneaȬhypopneaȱindexȱ

AASMȱ AmericanȱAcademyȱofȱSleepȱMedicineȱȱ

AFȱ Atrialȱfibrillationȱ

AHDIȱ ApneaȬhypopneaȬdesaturationȱindexȱ

AHIȱ ApneaȬhypopneaȱindexȱ

ApDurȱ Durationȱofȱaȱsingleȱapneaȱeventȱ

ASDAȱ AmericanȱSleepȱDisorderȱAssociationȱ

AVȬȱblockȱ Atrioventricularȱblockȱ ȱ

BMIȱ Bodyȱmassȱindexȱ(kg/m2_)ȱ CHDȱ Coronaryȱheartȱdiseaseȱ

CO2ȱ Carbonȱdioxideȱ

COPDȱ Chronicȱobstructiveȱpulmonaryȱdiseaseȱȱ

CPAPȱ Continuousȱpositiveȱairwayȱpressureȱȱ

DesAreaȱ Areaȱofȱaȱsingleȱdesaturationȱeventȱ

ECGȱ Electrocardiogramȱ

EEGȱ Electroencephalogramȱ

EMGȱ Electromyogramȱȱ

EOGȱ ElectroȬoculogramȱȱ

GERȱ Gastroesophagealȱrefluxȱȱ

HFȱ Heartȱfailureȱ

HypDurȱ Durationȱofȱaȱsingleȱhypopneaȱeventȱ

kgȱ Kilogramȱ

LVEFȱ Leftȱventricularȱejectionȱfractionȱȱ

m2_{ȱ Squareȱmeterȱ} mthsȱ Monthsȱ

MRAȱ Mandibularȱrepositioningȱapplianceȱ nȱ Numberȱofȱpatients/samplesȱ

NIDDMȱ NoninsulinȬdependentȱdiabetesȱmellitusȱ

NRȱ Notȱreportedȱ

ODIȱ Oxygenȱdesaturationȱindexȱȱ

OSAȱ Obstructiveȱsleepȱapneaȱȱ

pȱ Probabilityȱofȱrejectingȱtheȱnullȱhypothesisȱ

PaCO2ȱ Partialȱpressureȱofȱcarbonȱdioxideȱinȱarterialȱbloodȱȱ PaO2ȱ Partialȱpressureȱofȱoxygenȱinȱarterialȱbloodȱȱ PSGȱ Polysomnographyȱȱ

QOLȱ Qualityȱofȱlifeȱ

rȱ Correlationȱcoefficientȱ

REMȱ Rapidȱeyeȱmovementȱȱ

RERAȱ RespiratoryȱeffortȬrelatedȱarousalȱȱ

XIX

SCSBȱ Staticȱchargeȱsensitiveȱbedȱȱ

SDȱ Standardȱdeviationȱ

SpO2ȱ Saturationȱofȱperipheralȱoxygenȱȱ SPSSȱ StatisticalȱPackageȱforȱSocialȱSciencesȱ

TAD%ȱ Totalȱapneaȱdurationȱasȱaȱpercentageȱofȱsleepȱtimeȱ

TAHD%ȱ Totalȱ combinedȱ cumulativeȱ apneaȱ andȱ hypopneaȱ durationȱ asȱ aȱ

percentageȱofȱsleepȱtimeȱ

THD%ȱ Totalȱhypopneaȱdurationȱasȱaȱpercentageȱofȱsleepȱtimeȱ

TIAȱ Transientȱischemicȱattackȱȱ

UPPPȱ Uvulopalatopharyngoplastyȱ ȱ

ȱ ȱ

1

ȱ

INTRODUCTION

ȱȱ

Obstructiveȱsleepȱapneaȱ(OSA)ȱisȱtheȱmostȱcommonȱadultȱsleepȱdisorderȱandȱanȱ

importantȱfactorȱdecreasingȱqualityȱofȱlifeȱ(Youngȱetȱal.,ȱ2002).ȱTheȱdiseaseȱisȱ

characterizedȱbyȱrepeatedȱmechanicalȱobstructionȱofȱtheȱupperȱairwayȱduringȱ

sleepȱ(Kriegerȱetȱal.,ȱ2002).ȱOSAȱwasȱmentionedȱinȱliteratureȱforȱtheȱfirstȱtimeȱasȱ

earlyȱasȱinȱmidȬ1800ȬcenturyȱinȱtheȱPickwickȱPapersȱbyȱCharlesȱDickens.ȱInȱmidȱ

1960s,ȱtheȱfirstȱmedicalȱstudiesȱonȱsleepȱapneaȱwereȱpublishedȱ(Gastautȱetȱal.,ȱ1966,ȱ

JungȱandȱKuhlo,ȱ1965).ȱInȱ1976ȱGuilleminaultȱtogetherȱwithȱDementȱproposedȱaȱ

measureȱforȱtheȱclinicalȱclassificationȱofȱOSA,ȱtheȱapneaȬhypopneaȱindexȱ(AHI)ȱ

(personalȱ communicationȱ withȱ Professorȱ Guilleminault).ȱ Theȱ mostȱ effectiveȱ

treatmentȱ forȱ theȱ diseaseȱ i.e.ȱ continuousȱ positiveȱ airwayȱ pressureȱ (CPAP)ȱ

treatmentȱwasȱintroducedȱbyȱSullivanȱetȱal.ȱinȱAustraliaȱ(Sullivanȱetȱal.,ȱ1981).ȱ ȱ

OSAȱisȱestimatedȱtoȱaffectȱ9Ȭ24%ȱofȱallȱmiddleȬagedȱindividualsȱ(Youngȱetȱal.,ȱ

1993).ȱInȱaddition,ȱOSAȱhasȱbeenȱassociatedȱwithȱanȱincreasedȱriskȱofȱmortality,ȱ

especiallyȱdueȱtoȱcardiovascularȱmorbidityȱ(Heȱetȱal.,ȱ1988,ȱMarinȱetȱal.,ȱ2005,ȱWonȱ

etȱal.,ȱ2013).ȱSinceȱOSAȱisȱanȱimportantȱpublicȱhealthȱissue,ȱtheȱdiagnosisȱshouldȱbeȱ

achievedȱasȱearlyȱasȱpossibleȱandȱtheȱpatientsȱwithȱtheȱhighestȱriskȱneedȱtoȱbeȱ

identifiedȱ reliably.ȱ Theȱ goldȱ standardȱ forȱ diagnosisȱ ofȱ OSAȱ isȱ fullȱ nightȱ

polysomnographyȱ (PSG)ȱ includingȱ theȱ followingȱ parameters:ȱ

electroencephalogramȱ(EEG),ȱelectroȬoculogramȱ(EOG),ȱelectromyogramȱ(EMG),ȱ

oronasalȱ airflow,ȱ chestȱ wallȱ movementȱ efforts,ȱ bodyȱ position,ȱ snoring,ȱ

electrocardiogramȱ (ECG)ȱ andȱ saturationȱ ofȱ peripheralȱ oxygenȱ (SpO2).ȱ

Unfortunately,ȱconductingȱsuchȱelaborateȱPSGȱrecordingsȱareȱexpensiveȱandȱnotȱ

availableȱforȱallȱpatients.ȱHowever,ȱambulatoryȱpolysomnographyȱdevicesȱwithȱaȱ

limitedȱamountȱofȱrecordedȱbiosignalsȱareȱgenerallyȱacceptedȱinȱtheȱdiagnosticsȱofȱ

OSAȱ(Collop,ȱ2008).ȱCurrently,ȱtheȱdiagnosisȱandȱclassificationȱofȱtheȱdiseaseȱisȱ

basedȱonȱOSAȬrelatedȱsymptomsȱandȱtheȱnumberȱofȱapneaȱandȱhypopneaȱeventsȱ

orȱdesaturationȱeventsȱperȱhour,ȱi.e.ȱtheȱapneaȬhypopneaȱindexȱ(AHI)ȱorȱtheȱ

oxygenȱdesaturationȱindexȱ(ODI)ȱasȱassessedȱinȱpolygraphicȱrecordingsȱ(Iber,ȱ

2007).ȱUnfortunately,ȱneitherȱAHIȱnorȱODIȱprovideȱinformationȱonȱtheȱseverityȱofȱ

theȱevents.ȱHowever,ȱitȱisȱpossibleȱtoȱuseȱmoreȱsevereȱODIȬvaluesȱ(e.g.ȱODI10ȱandȱ

ODI20),ȱbutȱevenȱwithȱtheseȱvalues,ȱtheȱcombinationȱbetweenȱapnea/hypopneaȱ

eventsȱandȱdesaturationȱwillȱbeȱmissedȱandȱneitherȱtheȱlengthȱnorȱtheȱdepthȱofȱtheȱ

desaturationȱeventsȱisȱevaluated.ȱInȱaddition,ȱaȱsimultaneousȱincreaseȱinȱtheȱ

durationȱandȱfrequencyȱofȱapneaȱandȱhypopneaȱeventsȱmayȱleadȱtoȱaȱparadoxicalȱ

situationȱ whereȱ theȱAHIȱ canȱnotȱincreaseȱanyȱ further.ȱ Thoseȱ patientsȱ withȱ

especiallyȱsevereȱ(i.e.ȱprolongedȱandȱdeep)ȱobstructionȱ(apneaȱandȱhypopnea)ȱandȱ

andȱtoȱdisplayȱanȱelevatedȱmortalityȱrate.ȱAlreadyȱinȱ1989,ȱSalmiȱetȱal.ȱreportedȱ

thatȱwhenȱconductingȱautomaticȱanalysis,ȱtheȱadditionȱofȱapneaȱpercentageȱvaluesȱ

(i.e.ȱpercentageȱofȱapneicȱtimeȱofȱrecording)ȱtoȱtheȱpolygraphyȱanalysisȱcouldȱ

provideȱmoreȱinformationȱthanȱAHIȱonȱitsȱownȱ(Salmiȱetȱal.,ȱ1989).ȱThus,ȱtheȱ

presentȱdiagnosticȱparametersȱAHIȱandȱODIȱmightȱnotȱrevealȱcompletelyȱtheȱ

overallȱseverityȱofȱtheȱdiseaseȱandȱtheȱphysiologicalȱstressȱthatȱitȱevokesȱ(Kulkasȱetȱ

al.,ȱ2013a,ȱOteroȱetȱal.,ȱ2010).ȱTherefore,ȱtheȱoverallȱseverityȱofȱdesaturationȱisȱ

clinicallyȱroutinelyȱevaluated,ȱforȱexample,ȱasȱtheȱtimeȱbelowȱ90%ȱsaturation.ȱ

Oteroȱetȱal.ȱalsoȱreportedȱthatȱsometimesȱAHIȱcanȱunderestimateȱtheȱseverityȱofȱ

theȱ patient’sȱ conditionȱ (Oteroȱ etȱ al.,ȱ 2010).ȱ Theyȱ studiedȱ recentlyȱ differentȱ

parametersȱofȱrespiratoryȱairflowȱandȱdesaturationȱinȱ274ȱpatientsȱandȱreportedȱ

thatȱtheȱcombinedȱpercentageȱofȱtheȱsleepȱtimeȱthatȱtheȱpatientȱhadȱbeenȱinȱapnea,ȱ

hypopneaȱ orȱ hypoxia,ȱ i.e.ȱ theȱ apneaȬhypopneaȬdesaturationȱ index,ȱ couldȱ

outperformȱtheȱAHIȱinȱtheȱdiagnosisȱofȱOSAȱ(Oteroȱetȱal.,ȱ2012).ȱȱȱ

ȱ

Basedȱonȱclinicalȱexperience,ȱwhenȱdiagnosingȱobstructiveȱsleepȱapneaȱitȱwouldȱ

beȱveryȱvaluableȱtoȱmeasureȱmultipleȱparameterȱvaluesȱwhenȱdiagnosingȱOSAȱinȱ

allȱpatientsȱreferredȱforȱpolysomnographyȱe.g.ȱdueȱtoȱdaytimeȱsomnolence.ȱForȱ

example,ȱthisȱwouldȱimproveȱtheȱidentificationȱofȱthoseȱpatientsȱwhoseȱindividualȱ

obstructionȱeventsȱareȱmoreȱsevere,ȱandȱinȱwhomȱtheȱclinicalȱdiseaseȱmayȱbeȱmoreȱ

devastatingȱthanȱexpected.ȱItȱisȱknownȱthatȱtheȱbeneficialȱtreatmentȱoptionsȱareȱ

alsoȱdifferentȱinȱindividualȱpatients.ȱInȱOSAȱpatientsȱwithȱmildȱdisease,ȱeffectiveȱ

treatmentȱmayȱultimatelyȱpreventȱtheȱpossibleȱappearanceȱofȱmanyȱsubsequentȱcoȬ

morbidities.ȱOtherwise,ȱeffectiveȱtreatmentȱofȱsevereȱOSAȱe.g.,ȱwithȱCPAPȱmayȱ

alleviateȱorȱevenȱpreventȱtheȱmostȱsevereȱhealthȱconsequencesȱrelatedȱtoȱOSA.ȱ ȱ

Oneȱcouldȱhypothesizeȱthatȱdevelopingȱnovelȱparametersȱthatȱwouldȱincludeȱ

informationȱonȱseverityȱofȱindividualȱobstructionȱeventsȱcouldȱprovideȱfeasibleȱ

toolsȱforȱestimatingȱmoreȱeffectivelyȱtheȱtrueȱseverityȱofȱtheȱdisease.ȱInȱthisȱthesis,ȱ

thisȱ hypothesisȱ hasȱ beenȱ testedȱ inȱ retrospectiveȱ studiesȱ withȱ ambulatoryȱ

polygraphicȱrecordingsȱofȱmenȱwhoȱhadȱbeenȱreferredȱtoȱtheȱDepartmentȱofȱ

ClinicalȱNeurophysiologyȱatȱKuopioȱUniversityȱHospitalȱdueȱtoȱaȱsuspicionȱofȱ

sleepȱdisorderedȱbreathing.ȱBasicȱanthropometricȱdataȱ(height,ȱweight,ȱBMI)ȱandȱ

informationȱonȱage,ȱsmoking,ȱtheȱuseȱofȱcontinuousȱpositiveȱairwayȱpressureȱ

(CPAP)ȱtreatmentȱandȱcardiovascularȱmorbidityȱwereȱcollectedȱfromȱtheȱmedicalȱ

recordsȱinȱKuopioȱUniversityȱHospital.ȱFurthermore,ȱtheȱprimaryȱandȱsecondaryȱ

causesȱofȱdeathȱwereȱobtainedȱfromȱStatisticsȱFinlandȱ(Helsinki,ȱFinland)ȱforȱ

deceasedȱpatients.ȱȱ ȱ

3

2

ȱ

Obstructive

ȱ

Sleep

ȱ

Apnea

ȱ

Obstructiveȱsleepȱapneaȱ(OSA)ȱisȱdefinedȱasȱrepeatedȱepisodesȱofȱcompleteȱorȱ

partialȱblockageȱofȱtheȱupperȱairwayȱduringȱsleep.ȱTheȱmusclesȱinȱtheȱupperȱ

airwayȱtemporarilyȱrelaxȱandȱtheȱairwayȱisȱnarrowedȱorȱclosedȱandȱbreathingȱ

momentarilyȱceases.ȱAnȱobstructiveȱapneaȱeventȱisȱdefinedȱasȱaȱcessationȱ(overȱ

90%ȱreductionȱinȱamplitude)ȱofȱairflowȱforȱǃȱ10ȱsecondsȱdespiteȱbreathingȱefforts.ȱ

Aȱhypopneaȱeventȱisȱdefinedȱasȱaȱreductionȱ(moreȱthanȱ30%)ȱinȱthoracoabdominalȱ

movementȱorȱairflowȱforȱmoreȱthanȱ10ȱsecondsȱwithȱrelatedȱoxygenȱdesaturationȱ

ofȱatȱleastȱ4%ȱ(aȱdesaturationȱeventȱhasȱtoȱoccurȱnoȱlaterȱthanȱ20ȱsecondsȱafterȱtheȱ

startȱofȱtheȱhypopnea)ȱorȱaȱ50%ȱreductionȱinȱthoracoabdominalȱmovementȱorȱ

airflowȱamplitudeȱconnectedȱwithȱanȱoxygenȱdesaturationȱofȱatȱleastȱ3%.ȱInȱbothȱ

scenarios,ȱatȱleastȱ90%ȱofȱtheȱevent’sȱdurationȱhasȱtoȱmeetȱtheȱamplitudeȱreductionȱ

criteriaȱforȱhypopneaȱ(Iber,ȱ2007).ȱTheȱapneaȬhypopneaȱindexȱ(AHI)ȱisȱdefinedȱasȱ

theȱtotalȱsumȱofȱtheȱapneaȱandȱhypopneaȱeventsȱdividedȱbyȱhoursȱofȱsleepȱ(AASM,ȱ

1999,ȱIber,ȱ2007).ȱ ȱȱ

Theȱprevalenceȱofȱobstructiveȱsleepȱapneaȱ(AHIȱǃȱ5)ȱinȱadultsȱisȱestimatedȱtoȱbeȱ

17%ȱȱ(Youngȱetȱal.,ȱ2005).ȱMoreover,ȱitȱhasȱbeenȱreportedȱthatȱ93%ȱofȱwomenȱandȱ

82%ȱofȱmenȱtoȱhavingȱmoderateȱtoȱsevereȱOSAȱhaveȱnotȱbeenȱclinicallyȱdiagnosedȱ

(Youngȱetȱal.,ȱ1997b).ȱInȱtheȱFinnishȱadultȱpopulation,ȱtheȱprevalenceȱofȱOSAȱhasȱ

beenȱreportedȱtoȱbeȱasȱhighȱasȱ8%ȱ(i.e.ȱ320ȱ000ȱindividuals)ȱ(Kronholmȱetȱal.,ȱ2009).ȱ

AlthoughȱOSAȱisȱalreadyȱaȱsevereȱthreatȱtoȱtheȱwellbeingȱofȱtheȱpopulation,ȱitȱhasȱ

beenȱpredictedȱtoȱbecomeȱevenȱmoreȱcommonȱinȱtheȱfutureȱ(Youngȱetȱal.,ȱ2002).ȱ

2.1 PATHOPHYSIOLOGY AND ETIOLOGY

TheȱpathophysiologyȱofȱOSAȱisȱcomplexȱandȱstillȱpartlyȱunresolved.ȱPharyngealȱ

anatomyȱandȱvariableȱvoluntaryȱcontrolȱinȱtheȱupperȱairwayȱdilatorȱmusclesȱareȱ

theȱprevalentȱcausesȱofȱpharyngealȱcollapseȱinȱmostȱcases.ȱOtherȱimportantȱcausesȱ

ofȱpharyngealȱcollapseȱareȱaȱreductionȱinȱtheȱcompetenceȱofȱmusclesȱofȱupperȱ

airwayȱtoȱrespondȱtoȱtheȱrespiratoryȱchallengeȱduringȱsleep,ȱanȱincreaseȱinȱarousalȱ

thresholdȱinȱresponseȱtoȱrespiratoryȱneuralȱand/orȱhumoralȱstimulation,ȱandȱ

instabilityȱofȱventilatoryȱcontrol.ȱTheȱupperȱairwayȱcanȱbeȱdividedȱintoȱthreeȱ

regions,ȱtheȱnasopharynx,ȱtheȱoropharynxȱandȱtheȱhypopharynxȱ(figureȱ1).ȱInȱanȱ

OSAȱ patient,ȱ upperȱ airwayȱ closureȱ duringȱ sleepȱ occursȱ mostȱ oftenȱ inȱ theȱ

oropharynxȱ(Remmersȱetȱal.,ȱ1978,ȱSchwabȱetȱal.,ȱ1995).ȱȱ ȱ

ȱ Figure 1.The upper airway may be divided into three regions, the nasopharynx, the oropharynx and the hypopharynx. In OSA, an obstruction of upper airway occurs most often in the oropharynx. (Figure modified from http://www.webmd.com/sleep-disorders/sleep-apnea/obstructive-sleep-apnea-blocked-upper-airway)

Theȱupperȱairwayȱisȱcomposedȱofȱnumerousȱmusclesȱandȱsoftȱtissueȱbutȱlacksȱ

anyȱsupportȱfromȱbonyȱstructures.ȱAȱnarrowȱupperȱairwayȱisȱgenerallyȱmoreȱ

proneȱtoȱcollapseȱthanȱaȱlargerȱone.ȱOSAȱpatientsȱhaveȱbeenȱreportedȱ(asȱmeasuredȱ

byȱcomputedȱtomographyȱandȱmagneticȱresonanceȱimaging)ȱtoȱhaveȱaȱreducedȱ

crossȬsectionalȱareaȱofȱtheȱupperȱairwayȱwhenȱcomparedȱwithȱsubjectsȱwithoutȱ

OSAȱ(Burgerȱetȱal.,ȱ1992,ȱHaponikȱetȱal.,ȱ1983,ȱSchwabȱetȱal.,ȱ1995).ȱFurthermore,ȱitȱ

hasȱbeenȱreportedȱthatȱduringȱgeneralȱanesthesiaȱandȱrelatedȱmuscleȱrelaxation,ȱ

OSAȱpatientsȱexhibitȱaȱstructurallyȱmoreȱnarrowedȱandȱcollapsibleȱpharynxȱwhenȱ

comparedȱtoȱcontrolsȱ(Isonoȱetȱal.,ȱ1997).ȱȱ ȱ

Increasedȱnegativeȱairwayȱpressureȱstimulatesȱupperȱairwayȱmuscleȱactivity,ȱ

dilatingȱtheȱpharyngealȱairwayȱandȱmaintainingȱreasonableȱlevelsȱofȱairflowȱ

resistanceȱduringȱawake.ȱInȱcomparisonȱwithȱnormalȱsubjects,ȱOSAȱpatientsȱhaveȱ

higherȱactivityȱinȱtheirȱgenioglossusȱmuscleȱwhileȱawake,ȱbutȱnotȱduringȱsleepȱ

leadingȱtoȱpharyngealȱcollapseȱ(Mezzanotteȱetȱal.,ȱ1992).ȱȱ ȱ

ȱȱȱȱArousalȱisȱanȱimportantȱprotectiveȱmechanismȱenablingȱtheȱairwayȱtoȱreopenȱ

(Remmersȱetȱal.,ȱ1978).ȱItȱhasȱbeenȱreportedȱthatȱOSAȱpatientsȱexhibitȱmoreȱ

movementȱarousalsȱthanȱnormalȱsubjectsȱ(Collardȱetȱal.,ȱ1996).ȱThereȱisȱalsoȱaȱ

correlationȱbetweenȱtheȱseverityȱofȱabnormalȱrespiratoryȱeventsȱandȱarousals,ȱwithȱ

moreȱsevereȱ eventsȱ resultingȱinȱlongerȱ arousalsȱ (Nigroȱandȱ Rhodius,ȱ2005).ȱ

Increasingȱventilatoryȱeffortȱ(generatedȱbyȱvariousȱdifferentȱstimuli,ȱe.g.ȱhypoxia,ȱ

hypercapniaȱorȱrespiratoryȱloading)ȱisȱthoughtȱtoȱbeȱtheȱmostȱimportantȱstimulusȱ

5

higherȱthresholdȱforȱarousalȱ(Berryȱetȱal.,ȱ1996).ȱTheȱsleepȱapneaȱitselfȱmayȱbeȱtheȱ

reasonȱforȱtheȱincreasedȱthresholdȱ(Berryȱetȱal.,ȱ1996).ȱSleepȱapneaȱincreasesȱtheȱ

arousalȱ thresholdȱ relatedȱ toȱ airwayȱ occlusionȱ whileȱ nasalȬCPAPȬtreatmentȱ

decreasesȱtheȱarousalȱthresholdȱ(Berryȱetȱal.,ȱ1996,ȱHabaȬRubioȱetȱal.,ȱ2005).ȱKimoffȱ

etȱal.ȱreportedȱthatȱendingȱofȱobstructionȱwasȱmediatedȱthroughȱstimuliȱrelatedȱtoȱ

theȱlevelȱofȱinspiratoryȱeffortȱatȱendȬapnea,ȱwhichȱcausedȱarousalȱandȱreopeningȱofȱ

theȱairwayȱ(Kimoffȱetȱal.,ȱ1994).ȱȱ ȱ

Ventilatoryȱ controlȱ isȱ believedȱ toȱ beȱ anȱ importantȱ contributorȱ toȱ theȱ

pathogenesisȱofȱOSAȱ(EckertȱandȱMalhotra,ȱ2008).ȱPatientsȱwithȱOSAȱhaveȱlessȱ

stableȱventilatoryȱcontrolȱandȱduringȱwakefulness,ȱtheȱresponseȱofȱOSAȱpatientsȱtoȱ

hyperoxicȱCO2ȱisȱhigherȱthanȱinȱcontrolsȱ(Hudgelȱetȱal.,ȱ1998).ȱȱ

2.2 RISK FACTORS

ObesityȱisȱtheȱmostȱimportantȱsingleȱriskȱfactorȱofȱOSA.ȱHowever,ȱseveralȱotherȱ

factorsȱsuchȱasȱsmoking,ȱalcoholȱconsumption,ȱnasalȱcongestion,ȱmaleȱgenderȱandȱ

hormonalȱ changesȱ duringȱ menopauseȱ mayȱalsoȱ affectȱ theȱdevelopmentȱ andȱ

progressionȱofȱOSAȱ(tableȱ1).ȱFurthermore,ȱpatientsȱwithȱcardiovascularȱdiseaseȱ

haveȱaȱhighȱprevalenceȱofȱOSA.ȱConsequently,ȱpatientsȱwithȱcongestiveȱheartȱ

failure,ȱatrialȱfibrillation,ȱtreatmentȱresistantȱhypertension,ȱdiabetesȱtypeȱ2,ȱstroke,ȱ

nocturnalȱarrhythmiasȱandȱpulmonaryȱhypertensionȱareȱallȱhighȱriskȱpatientsȱifȱ

theyȱalsoȱsufferȱfromȱOSAȱ(tableȱ1).ȱ ȱ

AȱnumberȱofȱstudiesȱhaveȱreportedȱaȱsignificantȱassociationȱbetweenȱOSAȱandȱ

overweightȱ(Duranȱetȱal.,ȱ2001,ȱFeriniȬStrambiȱetȱal.,ȱ1994,ȱYoungȱetȱal.,ȱ1993,ȱ

Youngȱetȱal.,ȱ2002,ȱVgontzas,ȱ2008).ȱTheȱincreasedȱbodyȱweightȱimpairsȱbreathingȱ

inȱmanyȱways,ȱincludingȱalterationsȱinȱupperȱairwayȱstructureȱandȱfunction,ȱ

respirationȱdriveȱandȱobesityȬinducedȱhypoxemiaȱ(StrobelȱandȱRosen,ȱ1996).ȱItȱhasȱ

beenȱreportedȱthatȱespeciallyȱvisceralȱfatȱisȱsignificantlyȱcorrelatedȱwithȱsleepȱ

apneaȱ(Vgontzas,ȱ2008)ȱandȱthatȱwaistȱcircumferenceȱisȱaȱbetterȱpredictorȱforȱOSAȱ

thanȱneckȱcircumferenceȱorȱBMIȱ(Grunsteinȱetȱal.,ȱ1993).ȱNevertheless,ȱalsoȱgeneralȱ

obesityȱ(Newmanȱetȱal.,ȱ2001,ȱYoungȱetȱal.,ȱ1993)ȱandȱneckȱmorphologyȱ(Hoffsteinȱ

andȱMateika,ȱ1992,ȱMortimoreȱetȱal.,ȱ1998,ȱOlsonȱetȱal.,ȱ1995)ȱhaveȱbeenȱassociatedȱ

withȱOSA.ȱInȱseverelyȱobeseȱpopulations,ȱmoreȱthanȱeveryȱsecondȱindividualȱisȱ

sufferingȱfromȱmoderateȱtoȱsevereȱOSAȱ(Restaȱetȱal.,ȱ2001).ȱȱ ȱ

Smokingȱincreasesȱsleepȱinstabilityȱandȱcausesȱinflammationȱofȱtheȱairwayȱ

(Wetterȱetȱal.,ȱ1994).ȱCurrentȱsmokersȱareȱthreeȱtimesȱmoreȱlikelyȱtoȱexhibitȱOSAȱ

thanȱnonȬsmokersȱ(Wetterȱetȱal.,ȱ1994)ȱandȱsmokingȱhasȱbeenȱclaimedȱtoȱbeȱanȱ

independentȱriskȱfactorȱforȱOSAȱ(Kashyapȱetȱal.,ȱ2001).ȱHowever,ȱinȱaȱstudyȱwithȱ

associatedȱ(Newmanȱetȱal.,ȱ2001).ȱTheȱauthorsȱspeculatedȱthatȱsevereȱOSAȱpatientsȱ

mayȱhaveȱbeenȱproneȱtoȱquitȱsmoking,ȱwhichȱcouldȱexplainȱtheȱfindingsȱasȱcurrentȱ

smokingȱandȱOSAȱwereȱnotȱassociated.ȱ ȱ

Alcoholȱconsumptionȱisȱreportedȱtoȱdecreaseȱtheȱsizeȱofȱtheȱpharyngealȱairwayȱ

duringȱwakefulnessȱ (Robinsonȱetȱal.,ȱ1985)ȱ andȱtoȱincreaseȱtheȱincidenceȱofȱ

desaturationȱandȱapneaȱeventsȱduringȱsleepȱinȱasymptomaticȱvolunteersȱ(Taasanȱ

etȱal.,ȱ1981).ȱThisȱwasȱencounteredȱalsoȱinȱtheȱfollowingȱnight,ȱevenȱwhenȱnoȱ

alcoholȱ hadȱbeenȱ consumed.ȱFurthermore,ȱScanlanȱetȱ al.ȱreportedȱthatȱ evenȱ

modestȱalcoholȱconsumptionȱbeforeȱsleepingȱsignificantlyȱincreasedȱbothȱAHIȱandȱ

meanȱheartȱrateȱ(Scanlanȱetȱal.,ȱ2000).ȱHowever,ȱtheȱassociationȱbetweenȱlongȬtermȱ

alcoholȱuseȱandȱOSAȱstillȱneedsȱtoȱbeȱclarified.ȱ ȱ

Nasalȱ congestionȱ oftenȱ resultsȱ fromȱ allergicȱ rhinitisȱ andȱ anatomicȱ

abnormalities,ȱ suchȱ asȱ septalȱ deviation,ȱ nasalȱ polypsȱ andȱ hypertrophiedȱ

turbinates.ȱPatientsȱwhoȱreportedȱnasalȱcongestionȱdueȱtoȱallergyȱwereȱ1.8ȱtimesȱ

moreȱlikelyȱtoȱhaveȱmoderateȱtoȱsevereȱOSAȱasȱcomparedȱtoȱthoseȱwithoutȱnasalȱ

congestionȱ(Youngȱetȱal.,ȱ1997c).ȱHowever,ȱYoungȱetȱal.ȱalsoȱreportedȱthatȱtheȱ

strongestȱrelationshipȱwasȱfoundȱbetweenȱnasalȱcongestionȱandȱhabitualȱsnoringȱ

andȱnotȱwithȱAHIȱ(Youngȱetȱal.,ȱ1997c).ȱOSAȱhasȱbeenȱlinkedȱtoȱchronicȱnasalȱ

obstructionȱ alsoȱ inȱ otherȱ studiesȱ (Liistroȱ etȱ al.,ȱ 2003,ȱ Lofasoȱ etȱ al.,ȱ 2000).ȱ

Controversially,ȱinȱtheȱrecentȱreviewȱofȱKohlerȱetȱal.ȱchronicȱnasalȱobstructionȱwasȱ

postulatedȱtoȱplayȱonlyȱaȱminorȱroleȱinȱtheȱpathogenesisȱofȱOSAȱ(Kohlerȱetȱal.,ȱ

2007).ȱTheyȱconcludedȱthatȱaȱreductionȱinȱnasalȱresistanceȱ(byȱnasalȱdilators,ȱ

topicallyȱappliedȱsteroidsȱorȱnasalȱdecongestants)ȱwouldȱachieveȱonlyȱaȱminorȱ

improvementȱinȱOSAȱorȱinȱitsȱseverity.ȱȱ ȱ

MenȱhaveȱaȱtwoȱtoȱthreeȱfoldȱriskȱofȱOSAȱcomparedȱtoȱwomenȱ(Strohlȱandȱ

Redline,ȱ1996,ȱYoungȱetȱal.,ȱ1997d).ȱHowever,ȱthisȱdifferenceȱmayȱhaveȱbeenȱ

exaggeratedȱbyȱreferralȱandȱdiagnosticȱbiases.ȱStrohlȱandȱRedlineȱreportedȱinȱ1996ȱ

thatȱOSAȱisȱcommonȱinȱolderȱwomen,ȱespeciallyȱinȱmenopausalȱwomenȱ(Strohlȱ

andȱRedline,ȱ1996).ȱItȱhasȱbeenȱreportedȱthatȱwomenȱwithȱOSAȱdoȱnotȱcomplainȱ

aboutȱapneas,ȱarousalsȱorȱrestlessȱsleep,ȱinsteadȱtheyȱcomplainȱofȱfatigue,ȱinsomniaȱ

andȱmorningȱheadachesȱ(Ambrogettiȱetȱal.,ȱ1991,ȱAlotair,ȱ2008).ȱMenopauseȱisȱtheȱ

mostȱimportantȱendocrinologicalȱriskȱfactorȱforȱOSAȱinȱwomenȱ(Bixlerȱetȱal.,ȱ2001,ȱ

Youngȱetȱal.,ȱ2003)ȱandȱhormonalȱsubstitutionȱtherapyȱcanȱreduceȱthisȱriskȱfactor.ȱ

Bixlerȱetȱal.ȱreportedȱthatȱtheȱprevalenceȱofȱsymptomaticȱOSAȱinȱpostmenopausalȱ

womenȱwithȱandȱwithoutȱhormoneȱreplacementȱtherapyȱwasȱ0.6%ȱandȱ2.7%,ȱ

respectivelyȱ(Bixlerȱetȱal.,ȱ2001).ȱPremenopausalȱwomenȱwithȱpolycysticȱovaryȱ

syndromeȱhaveȱanȱincreasedȱprevalenceȱofȱOSAȱ(Fogelȱetȱal.,ȱ2001).ȱInȱtheȱstudyȱofȱ

Vgontzasȱetȱal.,ȱwomenȱwithȱpolycysticȱovaryȱsyndromeȱwereȱ30ȱtimesȱmoreȱlikelyȱ

toȱsufferȱfromȱOSAȱthanȱtheȱpremenopausalȱcontrolsȱ(Vgontzasȱetȱal.,ȱ2001).ȱ

Patientsȱwithȱpolycysticȱovaryȱsyndromeȱhaveȱhighȱlevelsȱofȱandrogenȱsecretion,ȱaȱ

7

endocrinologicalȱdisorders,ȱsuchȱasȱacromegaly,ȱhypothyroidismȱandȱCushing’sȱ

syndrome,ȱareȱriskȱfactorsȱofȱOSAȱ(SaaresrantaȱandȱPolo,ȱ2003).ȱȱ Table 1. Reported risk factors of OSA

ȱ

Risk factor Relative risk References

Obesity ++++ (Peppard et al., 2000a, Strobel and Rosen, 1996)

Male gender +++ (Schwab, 1999, Young et al., 1993) Congestive heart failure +++ (Herrscher et al., Javaheri, 2006, Zhao et

al., 2007, Ferreira et al., 2010)

Hypertension ++ (Somers et al., 2008, Fletcher et al., 1985) Atrial fibrillation ++ (Braga et al., 2009, Gami et al., 2004) Diabetes type 2 ++ (Foster et al., 2009, Resnick et al., 2003,

Einhorn et al., 2007)

Stroke ++ (Bassetti and Aldrich, 1999, Dyken et al., 1996, Good et al., 1996, Mohsenin and Valor, 1995, Wessendorf et al., 2000) Pulmonary

hypertension ++ (Dumitrascu et al., 2013, Sajkov and McEvoy, 2009) Nocturnal arrhythmias + (Javaheri et al., 1998, Lattimore et al.,

2003)

2.3 CLINICAL FEATURES

TheȱmostȱcommonȱsymptomȱinȱOSAȱisȱexcessiveȱdaytimeȱsleepiness.ȱBedȱpartner’sȱ

reportsȱonȱsnoring,ȱgaspingȱorȱinterruptionsȱinȱbreathingȱduringȱsleepȱareȱalsoȱ

commonlyȱrelatedȱtoȱOSA.ȱOtherȱrelatedȱclinicalȱfeaturesȱareȱlistedȱinȱtableȱ2.ȱInȱaȱ

recentȱreviewȱnocturnalȱgaspingȱorȱchokingȱwereȱreportedȱtoȱbeȱtheȱmostȱreliableȱ

indicatorsȱforȱOSAȱ(Myersȱetȱal.,ȱ2013).ȱ ȱ

Table 2. Symptoms of OSA

Nocturnal Diurnal Awakenings with choking Excessive sleepiness

Snoring Morning headaches

Nocturnal restlessness Changes in mood

Insomnia Lack of concentration

Increased perspiration during sleep Cognitive deficits, (e.g. memory impairment) Gastroesophageal reflux Impotence, decreased libido

Nocturia Cough Mouth dehydration Impaired overall quality of life (QOL)

2.3.1ȱDiurnalȱsymptomsȱ

Excessiveȱdaytimeȱsleepinessȱcausedȱbyȱsleepȱfragmentationȱisȱaȱcentralȱfeatureȱofȱ

OSAȱ(Bennettȱetȱal.,ȱ1999,ȱSullivanȱandȱIssa,ȱ1985).ȱCPAPȬtreatmentȱreducesȱtheȱ

numberȱofȱapneaȱandȱhypopneaȱeventsȱthusȱdecreasingȱtheȱarousalȱindexȱandȱ

relievingȱtheȱclinicalȱsymptomsȱ(Ballesterȱetȱal.,ȱ1999,ȱGuilleminaultȱetȱal.,ȱ1991).ȱ

However,ȱitȱhasȱbeenȱclaimedȱthatȱdifferencesȱinȱtheȱfrequencyȱofȱarousalsȱcanȱnotȱ

explainȱtheȱvariationȱinȱresultantȱsleepinessȱasȱfoundȱinȱtheȱSleepȱHeartȱHealthȱ

Studyȱ(Gottliebȱetȱal.,ȱ1999).ȱDespiteȱthisȱresult,ȱGottliebȱetȱal.ȱreportedȱaȱsignificantȱ

associationȱbetweenȱtheȱrespiratoryȱdisturbanceȱindexȱandȱsleepinessȱ(Gottliebȱetȱ

al.,ȱ1999).ȱExcessiveȱsleepinessȱisȱassociatedȱwithȱsignificantȱmorbidityȱandȱadverseȱ

effectsȱonȱworkingȱperformanceȱ(DawsonȱandȱReid,ȱ1997,ȱMitlerȱetȱal.,ȱ1988)ȱfamilyȱ

relationshipȱandȱqualityȱofȱlifeȱ(Brionesȱetȱal.,ȱ1996,ȱRothȱandȱRoehrs,ȱ1996,ȱYoungȱ

etȱ al.,ȱ 2002).ȱ Furthermore,ȱ OSAȱ patientsȱhaveȱ beenȱ reportedȱ toȱdisplayȱ anȱ

increasedȱriskȱofȱmotorȱvehicleȱandȱoccupationalȱaccidentsȱ(Georgeȱetȱal.,ȱ1987,ȱ

Lyznickiȱetȱal.,ȱ1998,ȱUlfbergȱetȱal.,ȱ2000,ȱYoungȱetȱal.,ȱ1997a,ȱVoronaȱandȱWare,ȱ

2002,).ȱItȱmustȱalsoȱbeȱnotedȱthatȱOSAȱpatient’sȱbedȱpartner’sȱsleepȱmayȱalsoȱbeȱ

disturbed,ȱaffectingȱalsoȱhis/herȱqualityȱofȱlifeȱ(McArdleȱetȱal.,ȱ2001).ȱȱ ȱ

Snoringȱandȱexcessiveȱdaytimeȱsleepinessȱhaveȱbeenȱshownȱtoȱbeȱmutuallyȱ

associatedȱtogetherȱ(Gottliebȱetȱal.,ȱ2000,ȱGuilleminaultȱetȱal.,ȱ1991,ȱYoungȱetȱal.,ȱ

1993,ȱZielinskiȱetȱal.,ȱ1999).ȱFurthermore,ȱalmostȱallȱpatientsȱwithȱsevereȱOSAȱ

exhibitȱsnoringȬlikeȱsymptomsȱ(Restaȱetȱal.,ȱ2001).ȱHowever,ȱinȱaȱrecentȱreview,ȱ

snoringȱwasȱnotȱreportedȱtoȱbeȱusefulȱforȱestablishingȱtheȱdiagnosisȱofȱOSA,ȱ

althoughȱaȱpatientȱwithȱmildȱsnoringȱandȱnormalȱweightȱwasȱconsideredȱunlikelyȱ

toȱhaveȱmoderateȱorȱsevereȱOSAȱ(Myersȱetȱal.,ȱ2013).ȱȱȱ ȱ

OSAȱandȱmorningȱheadachesȱareȱknownȱtoȱbeȱassociated.ȱTheȱprevalenceȱofȱ

morningȱheadachesȱhasȱbeenȱreportedȱtoȱvaryȱfromȱ11.8%ȱtoȱ74%ȱinȱOSAȱpatientsȱ

(Albertiȱetȱal.,ȱ2005,ȱBoutros,ȱ1989,ȱGuilleminaultȱetȱal.,ȱ1977,ȱKristiansenȱetȱal.,ȱ

2011,ȱLohȱetȱal.,ȱ1999).ȱHowever,ȱmorningȱheadachesȱhaveȱalsoȱbeenȱlinkedȱtoȱ

otherȱsleepȬrelatedȱdisordersȱ(AldrichȱandȱChauncey,ȱ1990,ȱPocetaȱandȱDalessio,ȱ

1995,).ȱInȱOSAȱpatients,ȱheadachesȱhaveȱbeenȱlinkedȱtoȱtheȱcerebralȱvasodilationȱ

triggeredȱbyȱ oxygenȱ desaturationȱ(Lohȱ etȱal.,ȱ1999).ȱInȱfact,ȱtheȱ mechanismȱ

responsibleȱforȱmorningȱheadachesȱisȱcomplexȱandȱinvolvesȱalsoȱhypercapnia,ȱ

sleepȱfragmentationȱandȱanȱincreaseȱinȱintracranialȱpressureȱ(JennumȱandȱJensen,ȱ

2002).ȱImportantly,ȱtheȱseverityȱofȱOSAȱisȱcorrelatedȱwithȱtheȱoccurrenceȱofȱ

morningȱheadachesȱ(Albertiȱetȱal.,ȱ2005,ȱLohȱetȱal.,ȱ1999)ȱandȱCPAPȬtreatmentȱhasȱ

beenȱreportedȱtoȱrelieveȱthisȱsymptomȱ(Lohȱetȱal.,ȱ1999,ȱNeauȱetȱal.,ȱ2002).ȱȱ ȱ

Cognitiveȱ dysfunctionȱ hasȱ beenȱ associatedȱ withȱ OSAȱ andȱ especiallyȱ anȱ

impairmentȱofȱexecutiveȱfunctionȱandȱattentionȱhasȱbeenȱdescribedȱbyȱmanyȱ

authorsȱ(Bedardȱetȱal.,ȱ1991b,ȱBerryȱetȱal.,ȱ1986,ȱFindleyȱetȱal.,ȱ1986,ȱKimȱetȱal.,ȱ

9

wasȱreportedȱtoȱexhibitȱsomeȱdegreeȱofȱneurocognitiveȱdysfunctionȱ(Antonelliȱ

Incalziȱetȱal.,ȱ2004).ȱAdamsȱetȱal.ȱfoundȱthatȱevenȱafterȱexcludingȱcomorbidȱ

conditions,ȱ impairmentȱ ofȱworkingȱ memory,ȱdeclarativeȱmemoryȱ andȱsignalȱ

discriminationȱwereȱdirectlyȱrelatedȱtoȱtheȱloweredȱnocturnalȱoxygenȱsaturationȱ

(Adamsȱ etȱal.,ȱ2001).ȱTheȱcognitiveȱdysfunctionȱisȱthoughtȱ toȱbeȱcausedȱ byȱ

hypoxemiaȱduringȱsleepȱorȱtoȱexcessiveȱdaytimeȱsleepinessȱ(Lalȱetȱal.,ȱ2012,ȱ

Verstraeten,ȱ2007).ȱSurprisingly,ȱitȱseemsȱ thatȱ CPAPȬtreatmentȱonlyȱpartiallyȱ

improvesȱtheȱcognitiveȱdysfunctionȱevenȱafterȱcompleteȱrecoveryȱfromȱdaytimeȱ

sleepinessȱ(FeriniȬStrambiȱetȱal.,ȱ2003).ȱȱ 2.3.2ȱNocturnalȱsymptomsȱ

NocturiaȱisȱcommonȱinȱpatientsȱwithȱOSAȱ(Pressmanȱetȱal.,ȱ1996)ȱwithȱ47.8%ȱofȱ

patientsȱsufferingȱfromȱitȱ(Hajdukȱetȱal.,ȱ2003).ȱHajdukȱetȱal.ȱstatedȱthatȱwomenȱ

sufferȱnocturiaȱmoreȱthanȱmenȱ(60.0%ȱvs.ȱ40.9%)ȱandȱtheȱseverityȱofȱOSAȱisȱlinkedȱ

toȱtheȱseverityȱofȱnocturiaȱ(Hajdukȱetȱal.,ȱ2003).ȱInȱOSA,ȱtheȱincreasedȱintrathoracicȱ

pressureȱcausedȱbyȱhypopneasȱorȱapneasȱleadsȱtoȱincreasedȱvenousȱreturnȱandȱ

atrialȱstretchȱwhichȱinducesȱfalseȱsignalsȱofȱfluidȱvolumeȱoverload.ȱInȱtheȱkidneys,ȱ

thisȱtriggersȱincreasedȱsecretionȱofȱatrialȱnatriureticȱpeptideȱandȱasȱaȱconsequence,ȱ

theȱurineȱproductionȱisȱincreasedȱ(Umlaufȱetȱal.,ȱ2004).ȱThereȱareȱonlyȱaȱfewȱ

studiesȱonȱtheȱeffectȱofȱCPAPȬtreatmentȱonȱnocturia.ȱHowever,ȱCPAPȬtreatmentȱ

hasȱbeenȱshownȱtoȱreduceȱtheȱnocturiaȱassociatedȱwithȱOSAȱ(Margelȱetȱal.,ȱ2006).ȱȱȱ ȱ

Nocturnalȱgastroesophagealȱrefluxȱ(GER)ȱhasȱbeenȱlinkedȱtoȱOSA,ȱandȱ54Ȭ76%ȱ

ofȱOSAȱ patientsȱsufferȱfromȱ itȱ (ZanationȱandȱSenior,ȱ2005).ȱ Inȱ theȱ generalȱ

populationȱtheȱoccurrenceȱofȱGERȱisȱaroundȱ10%ȱ(ZanationȱandȱSenior,ȱ2005).ȱ

NasalȱCPAPȬtreatmentȱhasȱbeenȱshownȱtoȱreduceȱtheȱgastroesophagealȱrefluxȱ

(Kerrȱetȱal.,ȱ1992).ȱȱ ȱ

ȱȱȱȱWithinȱtheȱlastȱtenȱyears,ȱnumerousȱstudiesȱhaveȱreportedȱaȱhighȱprevalenceȱ(39Ȭ

50%ȱvs.ȱ9Ȭ15%ȱinȱgeneralȱpopulation)ȱofȱinsomniaȱsymptomsȱinȱOSAȱpatientsȱ

(Chung,ȱ2005,ȱKrakowȱetȱal.,ȱ2001,ȱSmithȱetȱal.,ȱ2004).ȱThisȱseemsȱparadoxicalȱasȱ

theȱsameȱpatientsȱsufferȱalsoȱfromȱexcessiveȱdaytimeȱsleepiness.ȱ

2.4 DIAGNOSIS OF OBSTRUCTIVE SLEEP APNEA

TheȱdiagnosisȱofȱOSAȱisȱbasedȱonȱinterviewȱandȱclinicalȱexaminationȱofȱtheȱpatientȱ

andȱsupportingȱabnormalȱresultsȱinȱaȱpolygraphicȱrecording.ȱTheȱseverityȱofȱtheȱ

diseaseȱisȱjudgedȱbasedȱonȱclinicalȱsymptoms,ȱespeciallyȱdaytimeȱsleepiness,ȱandȱ

findingsȱinȱpolygraphicȱrecording.ȱMoreȱspecifically,ȱtheȱclinicalȱdiagnosticsȱaboutȱ

theȱseverityȱisȱbasedȱonȱtheȱmostȱsevereȱfindingsȱofȱsleepiness,ȱSpO2ȱduringȱsleepȱ

symptomsȱ ofȱsleepinessȱatȱ aȱlowȱactivityȱlevel,ȱ thenȱtheȱseverityȱwouldȱbeȱ

classifiedȱasȱmoderateȱOSA.ȱ

Table 3. Criteria for clinical classification of the obstructive sleep apnea* Severity

of disease Sleepiness SpO2during sleep (%) AHI Mild manifestation only when

non-active, not necessarily daily, minimal

disadvantages in social and working life

average mean • 90 and

minimum • 85 5 ” AHI < 15

Moderate daily symptoms, when low activity level and only

little concentration is needed (e.g. attending a

meeting, watching a movie)

average mean < 90 and

minimum • 70 15 ” AHI < 30

Severe daily symptoms in situations which require

more attention and concentration (e.g.

driving, conversation, eating)

average mean < 90 and

minimum < 70 30 ” AHI

*Modified from The Report of American Academy of Sleep Medicine Task Force (1999) and Obstructive sleep apnea syndrome (online), Current Care Summary, 2010.

Theȱ goldȱ standardȱ inȱ diagnosingȱ ofȱ OSAȱisȱ overnightȱ polysomnographyȱ

(Douglasȱetȱal.,ȱ1992),ȱwhichȱinvolvesȱrecordingȱofȱe.g.ȱsleepȱstages,ȱrespirationȱandȱ

bloodȱoxygenȱsaturation.ȱHowever,ȱpolysomnographicȱrecordingsȱinȱspecializedȱ

sleepȱcentersȱareȱrelativelyȱexpensive,ȱrequireȱtrainedȱtechniciansȱand,ȱthus,ȱareȱ

notȱavailableȱforȱallȱpatients.ȱEffectiveȱscreeningȱofȱsleepȱapneaȱrequiresȱsystemsȱ

thatȱareȱcheaperȱandȱsimplerȱthanȱthoseȱusedȱforȱstandardȱpolysomnography.ȱForȱ

thisȱreason,ȱtheȱintroductionȱofȱsimpleȱportableȱdevicesȱledȱtoȱaȱmajorȱincreaseȱinȱ

theȱdiagnosticsȱofȱsleepȱapneaȱinȱtheȱlateȱ1990’s.ȱȱ ȱ

Recordingȱforȱaȱsingleȱnightȱisȱtheȱnormalȱclinicalȱpractice,ȱalthoughȱitȱisȱknownȱ

thatȱtheȱqualityȱofȱsleepȱandȱresultsȱofȱnightȱpolygraphyȱmayȱvaryȱbetweenȱnights.ȱ

TheȱfirstȬnightȱeffectȱisȱaȱwellȬknownȱphenomenon,ȱwhichȱisȱbelievedȱtoȱresultȱ

fromȱsleepingȱinȱtheȱunfamiliarȱenvironmentȱofȱaȱhospital.ȱThisȱphenomenonȱisȱ

characterizedȱwithȱlessȱtotalȱsleepȱtime,ȱaȱlowerȱsleepȱefficiencyȱindex,ȱmoreȱawakeȱ

timeȱafterȱsleepȱonset,ȱlessȱREMȬsleepȱandȱlongerȱREMȬlatencyȱcomparedȱtoȱtheȱ

followingȱnightsȱ(LeȱBonȱetȱal.,ȱ2003).ȱRecently,ȱNewellȱetȱal.ȱreported,ȱhowever,ȱ

thatȱtotalȱsleepȱtimeȱdidȱnotȱdifferȱsignificantlyȱbetweenȱtwoȱconsecutiveȱrecordingȱ

nights,ȱandȱinȱtheȱOSAȬsuspectedȱgroupȱnoȱstatisticallyȱsignificantȱdifferencesȱ

wereȱdetectedȱinȱAHIȬvaluesȱbetweenȱconsecutiveȱnightsȱ(Newellȱetȱal.,ȱ2012).ȱ

11

individually,ȱ40.9%ȱofȱpatientsȱwouldȱhaveȱbeenȱmisdiagnosedȱinȱtermsȱofȱOSAȱ

severityȱifȱtheȱAHIȱofȱoneȱofȱonlyȱtheȱtwoȱnightsȱhadȱbeenȱusedȱinsteadȱofȱbothȱ

nights.ȱThisȱisȱaȱgoodȱexampleȱofȱtheȱimpactȱofȱnightȬtoȬnightȱvariability.ȱInȱ

addition,ȱLeȱBonȱetȱal.ȱreportedȱthatȱfirstȱnightȱrecordingȱshowedȱsignificantlyȱlessȱ

severeȱAHI,ȱwhileȱmeanȱO2ȱsaturationȱandȱmaximumȱO2ȱwereȱstableȱacrossȱnightsȱ (LeȱBonȱetȱal.,ȱ2000).ȱTheyȱconcludedȱthatȱitȱwouldȱbeȱworthwhileȱrecordingȱaȱ

secondȱpolygraphyȱnightȱifȱtheȱresultȱofȱtheȱfirstȱoneȱwasȱnegativeȱinȱpatientsȱwithȱ

clinicalȱsuspicionȱand/orȱsymptomsȱsuggestingȱofȱOSA.ȱHowever,ȱLojanderȱetȱal.ȱ

examinedȱ dataȱfromȱ twoȱ polygraphicȱassessments,ȱtheȱfindingsȱwereȱratherȱ

similar,ȱthereȱwereȱnoȱsignificantȱdifferencesȱforȱexampleȱinȱtimeȱspentȱinȱtheȱ

supineȱpositionȱorȱinȱtheȱclassificationȱofȱOSAȱandȱtheyȱproposedȱthatȱinȱroutineȱ

clinicalȱworkȱoneȱnightȱpolygraphyȱisȱadequateȱ(Lojanderȱetȱal.,ȱ1998).ȱInȱtheȱdayȬ

toȬdayȱroutineȱinȱtheȱclinic,ȱalmostȱeveryȱpatientȱisȱsubjectedȱtoȱonlyȱoneȬnightȱ

polygraphyȱforȱseveralȱreasonsȱ(e.g.,ȱcostsȱandȱfeasibility).ȱHowever,ȱtheȱfirstȬnightȱ

effectȱ shouldȱ beȱ takenȱ intoȱ accountȱ byȱ theȱ individualsȱ whoȱ analyzeȱ theȱ

polygraphicȱdata.ȱInȱpracticeȱandȱinȱtheȱoptimalȱsituation,ȱrepeatingȱtheȱsleepȱ

recordingȱmayȱbeȱsuggestedȱbyȱtheȱanalyzer.ȱȱ ȱ

Inȱclinicalȱpractice,ȱpulseȱoximetryȱisȱoftenȱusedȱinȱmeasuringȱoxygenȱsaturationȱ

inȱpolygraphicȱrecordings.ȱHowever,ȱthatȱmethodȱsuffersȱfromȱtheȱlimitationȱthatȱ

theȱrelationshipȱbetweenȱpulseȱoximetryȱvaluesȱandȱpartialȱpressureȱofȱoxygenȱisȱ

notȱlinear.ȱIfȱaȱpatient’sȱbaselineȱpartialȱpressureȱofȱoxygenȱisȱlow,ȱthenȱanȱ

obstructiveȱeventȱ(apnea/hypopnea)ȱwillȱevokeȱdeeperȱdesaturationȱ(figureȱ2).ȱOnȱ

theȱotherȱhand,ȱpatientsȱwhoseȱbaselineȱO2ȱlevelsȱareȱmoreȱphysiologicalȱtolerateȱ

obstructionȱeventsȱbetterȱandȱsufferȱonlyȱmilderȱdesaturations.ȱTheȱliteratureȱ

containsȱseveralȱstudiesȱsuggestingȱthatȱpulseȱoximetersȱareȱrelativelyȱaccurateȱinȱ

theȱclinicallyȱrelevantȱrange,ȱbutȱthatȱtheyȱexperienceȱlimitationsȱwhenȱtheȱvaluesȱ

fallȱbelowȱ80%ȱ(Fanconi,ȱ1989,ȱNickersonȱetȱal.,ȱ1988).ȱ ȱ

ȱ

Figure 2. Dissociation curve of oxygen –hemoglobin, the relationship between partial pressure of oxygen in arterial blood (PaO2) and saturation of peripheral oxygen (SpO2)

100 95.8 50 0 SpO 2 (%) PaO2(mmHg) 26.8 40 80 120 0

ȱȱȱȱHowever,ȱCO2ȱisȱaȱmoreȱpotentȱregulatorȱofȱrespiratoryȱdriveȱthanȱoxygenȱ

(DeanȱandȱNattie,ȱ2010).ȱ ȱDuringȱsleep,ȱhypercapniaȱisȱmoreȱlikelyȱtoȱdriveȱ

breathingȱthanȱhypoxia.ȱItȱhasȱbeenȱreportedȱthatȱduringȱanȱobstructiveȱapneaȱ

eventȱȬȱandȱespeciallyȱwithȱrepetitiveȱlongȱapneasȱ–ȱtheȱtranscutaneousȱCO2ȱȱlevelȱ

isȱslightlyȱincreasedȱ(Gislasonȱetȱal.,ȱ1989).ȱRauhalaȱetȱal.ȱreportedȱthatȱtheȱ

transcutaneousȱCO2ȱlevelȱincreasedȱduringȱflowȱlimitation,ȱbutȱduringȱapneaȱorȱ

hypopneaȱepisodesȱthereȱwereȱnoȱsignificantȱelevationsȱ(Rauhalaȱetȱal.,ȱ2007).ȱ

Theyȱstatedȱthatȱtheirȱpatientsȱwereȱeucapnic,ȱonlyȱmoderatelyȱobeseȱandȱalsoȱthatȱ

theirȱOSAȱwasȱmoderate,ȱandȱthatȱtheseȱreasonsȱmayȱhaveȱinfluencedȱtheȱresults.ȱ

Rimpiläȱetȱal.ȱhaveȱveryȱrecentlyȱreportedȱthatȱaȱnocturnalȱtargetȱCO2ȱlevelȱisȱ

dependentȱ onȱ bothȱ perfusionȱ andȱ ventilation.ȱ Thisȱ levelȱ isȱ believedȱ toȱ beȱ

determinedȱbyȱseveralȱfactors,ȱe.g.ȱtheȱdegreeȱofȱrespiratoryȱdriveȱ(Rimpiläȱetȱal.,ȱ

2014).ȱ However,ȱ theȱtranscutaneousȱ CO2ȱ measurementȱ isȱrarelyȱ includedȱ inȱ polygraphicȱrecordingsȱinȱclinicalȱpractice.ȱ

ȱ

2.4.1ȱPolysomnographicȱandȱambulatoryȱrecordingsȱ

AmbulatoryȱsleepȱrecordingȱdevicesȱhaveȱbeenȱusedȱinȱtheȱdiagnosticsȱofȱOSAȱ

sinceȱtheȱlateȱ1980’sȱ(Penzelȱetȱal.,ȱ1990).ȱInȱtheȱearlyȱdevicesȱonlyȱheartȱrateȱandȱ

breathingȱi.e.ȱsnoringȱwereȱrecorded.ȱInȱFinland,ȱtheȱStaticȬChargeȱSensitiveȱBedȱ

(SCSB)ȱwasȱintroducedȱinȱ1979ȱ(Alihankaȱetȱal.,ȱ1981).ȱThisȱmethodȱenabledȱ

recordingȱ ofȱ bodyȱ movements,ȱ theȱ ballistocardiogramȱ andȱ breathingȱ effortsȱ

(Alihankaȱ etȱ al.,ȱ 1981).ȱ Althoughȱ interpretationȱ ofȱ SCSBȱ recordingsȱ wasȱ

challenging,ȱitȱwasȱusedȱinȱFinlandȱinȱdiagnosticsȱofȱsleepȱapneaȱuntilȱlateȱ1990s.ȱȱȱ ȱȱ

ȱȱȱȱȱTaskȱForceȱofȱtheȱStandardsȱofȱPracticeȱCommitteeȱofȱtheȱAmericanȱSleepȱ

DisorderȱAssociationȱdistinguishedȱfourȱtypesȱofȱsleepȱmonitoringȱdevicesȱ(ASDA,ȱ

1994)ȱandȱlistedȱtheirȱspecificationsȱasȱsummarizedȱinȱtableȱ4.ȱ ȱ

ȱȱȱȱȱTheȱclinicalȱvaluesȱofȱambulatoryȱ recordingȱforȱdiagnosticsȱofȱOSAȱ wereȱ

systematicallyȱ evaluatedȱ byȱ Flemonsȱ etȱ al.ȱ (2003).ȱ Theyȱ reportedȱ thatȱ theȱ

ambulatoryȱrecordingsȱexhibitȱvariableȱsensitivitiesȱ(31Ȭ100%)ȱandȱspecificitiesȱ(48Ȭ

100%)ȱ(Flemonsȱetȱal.,ȱ2003).ȱFlemonsȱetȱal.ȱ(2003)ȱdidȱnotȱfindȱthatȱanyȱgiven/oneȱ

deviceȱ typeȱ wasȱ superiorȱ toȱ theȱ others.ȱ However,ȱ alreadyȱ inȱ 1997ȱ AASMȱ

recommendedȱ thatȱ ambulatoryȱrecordingȱwithȱtheȱ typeȱIIIȱdeviceȱwouldȱbeȱ

appropriateȱforȱdiagnosticsȱofȱsleepȱapneaȱ(Chessonȱetȱal.,ȱ1997,ȱAASM,ȱ1997).ȱTheȱ

earlyȱdetectionȱofȱtheȱpatientsȱwithȱsevereȱOSAȱcanȱachieveȱmajorȱmedicalȱandȱ

economicalȱ benefitsȱ (PelletierȬFleuryȱ etȱ al.,ȱ 2004).ȱ Inȱ thatȱ study,ȱ significantȱ

improvementȱinȱdaytimeȱsleepiness,ȱqualityȱofȱlife,ȱandȱalsoȱcostȬeffectivenessȱofȱ

treatmentȱwereȱreportedȱwithȱanȱearlyȱdiagnosisȱofȱOSA.ȱFinally,ȱinȱ2007ȱAASMȱ

concludedȱthatȱambulatoryȱrecordingȱatȱhomeȱwouldȱbeȱsuitableȱforȱdiagnosticsȱofȱ

OSAȱ (Collopȱ etȱ al.,ȱ 2007).ȱ Manyȱ factorsȱ suchȱ asȱ lowerȱ costȱ ofȱambulatoryȱ

13

beenȱ reportedȱtoȱsleepȱbetterȱduringȱambulatoryȱ recordingsȱasȱtheyȱcanȱ beȱ

conductedȱ atȱ home.ȱ However,ȱ itȱ hasȱ toȱ beȱ keptȱ inȱ mindȱ thatȱ ambulatoryȱ

recordingsȱmayȱunderestimateȱAHI,ȱbecauseȱsleepȱtimeȱcannotȱbeȱ measuredȱ

accuratelyȱwithoutȱEEG.ȱFurthermore,ȱarousalsȱcannotȱbeȱidentifiedȱwithoutȱEEGȱ

data,ȱmakingȱtherebyȱdetectionȱofȱarousalȱrelatedȱhypopneasȱvirtuallyȱimpossible.ȱȱȱ ȱ

Table 4. Types of ambulatory devices as specified by the Task Force of the Standards of Practice Committee of the American Sleep Disorder Association and Task Force of the Standards of Practice Committee of the AASM

Device Number of channels

Biosignals Body

position recording Patient Description Type I • 7 EEG, EOG, EMG,

ECG or heart rate, airflow, respiratory movements, oxygen saturation

measured

objectively usually in sleep center (attended)

gold standard polysomnography recorded in a sleep

center

Type II • 7 EEG, EOG, EMG, ECG or heart rate,

airflow, respiratory movements, oxygen saturation

optional unattended complete polysomnography,

but ambulatory

Type III • 4 ECG or heart rate, airflow, respiratory movements, oxygen saturation

optional attended or

unattended ambulatory recording, only to diagnose

sleep apnea

Type IV 1-2 oxygen saturation and usually airflow

(can be also something else)

not

measured attended or unattended recording with ambulatory limited channels, not recommended EEG = electroencephalogram EOG = electro-oculogram EMG = electromyogram ECG = electrocardiogram ȱ

Theȱ Americanȱ Academyȱ ofȱ SleepȱMedicineȱ hasȱbeenȱ publishingȱupdatedȱ

detailedȱrecommendationsȱforȱrecordingsȱandȱanalysisȱofȱsleepȱstudies.ȱTheȱlatestȱ

recommendationsȱ wereȱ publishedȱ inȱ 2007ȱ andȱ 2012ȱ (tablesȱ 5ȱ andȱ 6).ȱ Theȱ

recommendationsȱpublishedȱinȱ2007ȱareȱmoreȱcommonlyȱappliedȱthanȱthoseȱ

publishedȱinȱ2012.ȱTheȱmostȱsignificantȱdifferenceȱbetweenȱtheȱrecommendationsȱ

isȱtheȱsimplificationȱofȱtheȱcriteriaȱdefiningȱhypopnea.ȱȱ ȱ

Table 5. Diagnostic criteria of respiratory events (AASM 2007) Event Sensor Drop of

amplitude (%) Duration (s) Associated SpO2 (%) Respiratory

effort based on Arousal EEG Apnea oronasal

thermistor

• 90 • 10

obstructive entire period

central absent

mixed second portion

of event Hypopnea nasal pressure • 30 • 10 • 4 Hypopnea nasal • 50 • 10 • 3 pressure • 50 • 10 yes RERA nasal pressure flattening • 10 effort-related RERA thoraco-abdominal RIP belts • 10 increasing respiratory effort effort-related RERA = respiratory effort-related arousal

RIP = respiratory inductance plethysmography

Table 6. Diagnostic criteria of respiratory events (AASM 2012) Event Sensor Drop of

amplitude (%) Duration (s) Associated SpO2 (%) Respiratory

effort based on Arousal EEG Apnea oronasal

thermistor

• 90 • 10

obstructive entire period

central absent

mixed second portion

of event Hypopnea nasal pressure • 30 • 10 • 3 Hypopnea nasal pressure • 30 • 10 yes RERA nasal pressure flattening • 10 effort-related RERA thoraco- abdominal RIP belts • 10 increasing respiratory effort effort-related RERA = respiratory effort-related arousal

15

2.5 OSA AND CO-MORBIDITIES

OSAȱpatientsȱoftenȱhaveȱmanyȱcoȬmorbidities,ȱmostȱimportantlyȱcardiovascularȱ

diseaseȱ(Peppardȱetȱal.,ȱ2000b,ȱShamsuzzamanȱetȱal.,ȱ2003,ȱYoungȱetȱal.,ȱ2004).ȱInȱ

OSA,ȱapneasȱandȱhypopneasȱcauseȱsympatheticallyȱmediatedȱvasoconstrictionȱandȱ

aȱ consequentȱ increaseȱ inȱ systemicȱ andȱ pulmonaryȱ pressure,ȱ elevatedȱ leftȱ

ventricularȱafterloadȱandȱbreathingȬrelatedȱchangesȱinȱcardiacȱoutput.ȱAllȱtheseȱ

togetherȱ withȱ suddenȱ intraȬthoracicȱ pressureȱ changesȱ causeȱ hypoxia,ȱ

reoxygenation,ȱhypercapnia,ȱarousalsȱandȱsleepȱdeprivation.ȱTheseȱsituationsȱcanȱ

induceȱintermediaryȱ mechanisms,ȱwhichȱareȱconnectedȱtoȱ cardiovascularȱ coȬ

morbiditiesȱ(figureȱ3).ȱȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ

Figure 3. Suggested mechanisms that participate to increase the risk of cardiovascular co-morbidities in patients with obstructive sleep apnea (Modified from Shamsuzzaman et al., 2003) ȱ ȱ Obstructive sleep apnea hypoxia reoxygenation hypercapnia intrathoracic pressure swings arousals sleep deprivation Intermediary mechanisms sympathetic excitation x vasoconstriction x increased catecholamines x tachycardia x impaired cardiovascular variability endothelial dysfunction vascular oxidative stress systemic inflammation increased coagulation metabolic dysregulation x obesity x leptin resistance x insulin resistance Cardiovascular co-morbidities hypertension stroke cardiac ischemia

x coronary artery disease x myocardial infarction x nocturnal ST-segment descent x nocturnal angina cardiac arrhythmia x bradycardia x A-V block x atrial fibrillation congestive heart failure

x systolic dysfunction x diastolic dysfunction cerebrovascular disease diabetes mellitus type 2

2.5.1ȱCardiovascularȱcoȬmorbiditiesȱ

Theȱ studiesȱ onȱ OSAȱ andȱ relatedȱ cardiovascularȱ eventsȱ andȱ allȬcauseȱ andȱ

cardiovascularȱmortalityȱareȱsummarizedȱinȱtableȱ7.ȱOSAȱpatientsȱoftenȱhaveȱ

coexistingȱdiseasesȱsuchȱasȱobesity,ȱhypertensionȱandȱdiabetes.ȱThereȱareȱstrongȱ

indicationsȱthatȱthereȱisȱaȱcausalȱinteractionȱbetweenȱOSAȱandȱcardiovascularȱ

diseaseȱ(Shamsuzzamanȱetȱal.,ȱ2003).ȱDuringȱsleep,ȱchangesȱinȱheartȱrateȱandȱbloodȱ

pressureȱusuallyȱappearȱ5Ȭ7ȱsecondsȱafterȱtheȱendȱofȱanȱobstructiveȱapneaȱevent.ȱInȱ

OSA,ȱ negativeȱ intrathoracicȱ pressure,ȱ hypoxiaȱ andȱ arousalsȱ areȱ theȱ mainȱ

pathophysiologicalȱfeaturesȱcausingȱcardiovascularȱconsequences.ȱȱ ȱ

Negativeȱintrathoracicȱpressureȱincreasesȱleftȱventricularȱtransmuralȱpressure,ȱ

andȱvenousȱreturnȱtoȱtheȱrightȱventricleȱcausingȱitsȱdilatation.ȱThisȱcanȱcomplicateȱ

theȱfillingȱofȱtheȱleftȱventricleȱ(Brinkerȱetȱal.,ȱ1980).ȱTheȱcombinationȱofȱanȱincreaseȱ

inȱleftȱventricleȱafterloadȱandȱaȱreductionȱinȱpreloadȱleadsȱtoȱaȱreductionȱinȱheartȱ

strokeȱvolumeȱduringȱobstructiveȱapneasȱ(Shamsuzzamanȱetȱal.,ȱ2003).ȱȱ ȱȱ

Inȱ OSAȱ patients,ȱtheȱ increaseȱ inȱsympatheticȱneuralȱ activityȱ triggeredȱbyȱ

repeatedȱhypoxiaȱandȱarousalȱeventsȱisȱthoughtȱtoȱbeȱtheȱmainȱmechanismȱbehindȱ

theȱ pathogenesisȱ ofȱ hypertension.ȱ Aȱ threeȬfoldȱincreaseȱ inȱriskȱ ofȱ deȱ novoȱ

hypertensionȱhasȱbeenȱfoundȱwithinȱfourȱyearsȱofȱfollowȬupȱofȱOSAȱpatientsȱ

havingȱAHIȱ ǃȱ15ȱ(Peppardȱetȱal.,ȱ2000b).ȱFurthermore,ȱtheȱincreaseȱinȱbloodȱ

pressureȱhasȱbeenȱreportedȱtoȱbeȱlinearȱasȱaȱfunctionȱofȱAHIȱ(Youngȱetȱal.,ȱ1997d).ȱ

Lavieȱetȱal.ȱfoundȱthatȱeachȱapneaȱevent/hȱincreasedȱtheȱriskȱofȱhypertensionȱbyȱ

1%ȱandȱaȱ10%ȱdecreaseȱinȱnocturnalȱoxygenȱsaturationȱfurtherȱelevatedȱtheȱriskȱbyȱ

13%ȱ(Lavieȱetȱal.,ȱ2000).ȱEvenȱwhenȱtakingȱaccountȱofȱpotentialȱconfoundersȱsuchȱ

asȱage,ȱgender,ȱobesity,ȱalcoholȱuseȱandȱsmoking,ȱitȱwasȱclaimedȱthatȱsleepȱapneaȱ

wouldȱbeȱassociatedȱwithȱhypertensionȱ(Nietoȱetȱal.,ȱ2000).ȱTheȱNationalȱHighȱ

BloodȱPressureȱEducationȱProgramȱincludedȱOSAȱasȱtheȱfirstȱonȱtheȱlistȱ ofȱ

identifiableȱprimaryȱcausesȱofȱhypertensionȱ(Chobanianȱetȱal.,ȱ2003).ȱThisȱisȱinȱlineȱ

withȱtheȱfactȱthatȱCPAPȬtreatmentȱreducesȱbloodȱpressureȱinȱOSAȱpatientsȱ(Beckerȱ

etȱal.,ȱ2003,ȱFaccendaȱetȱal.,ȱ2001,ȱKanekoȱetȱal.,ȱ2003a).ȱ ȱ

Snoringȱandȱischemicȱstrokeȱhaveȱbeenȱshownȱtoȱbeȱassociatedȱ(Huȱetȱal.,ȱ2000,ȱ

Jennumȱetȱal.,ȱ1994,ȱKoskenvuoȱetȱal.,ȱ1987,ȱPalomäki,ȱ1991,ȱSpriggsȱetȱal.,ȱ1992).ȱ

Yaggiȱetȱal.ȱreportedȱthatȱsleepȱapneaȱincreasedȱsignificantlyȱtheȱriskȱofȱstrokeȱ

(Yaggiȱetȱal.,ȱ2005).ȱBasedȱonȱaȱlargeȱcohortȱstudy,ȱtheyȱreportedȱthatȱpatientsȱwithȱ

sleepȱapneaȱhadȱanȱelevatedȱriskȱ(hazardȱratioȱ=ȱ1.97)ȱtoȱsufferȱanȱinitialȱstrokeȱorȱ

deathȱfromȱ anyȱ causeȱ comparedȱtheȱ controls.ȱ Theȱriskȱ wasȱreportedȱ toȱbeȱ

independentȱofȱotherȱcardiovascularȱandȱcerebrovascularȱriskȱfactors,ȱsuchȱasȱ

hypertensionȱ(Yaggiȱetȱal.,ȱ2005).ȱTheȱoccurrenceȱofȱsilentȱstrokeȱisȱalsoȱincreasedȱ

inȱOSAȱpatientsȱ(Minoguchiȱetȱal.,ȱ2007).ȱTheȱsoȬcalledȱsilentȱstrokeȱisȱassociatedȱ

withȱincreasedȱplateletȱactivationȱandȱsystemicȱinflammationȱ(Minoguchiȱetȱal