Proposal: A crossover study comparing the efficacy of the Buteyko breathing method with continuous positive airway pressure (CPAP) in obstructive sleep apnea

Abstract

This proposed study aims to evaluate the success of Buteyko Breathing Method (BBM) for sleep apnea considering BBM's positive effects on asthma

Full text

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Acrossoverstudycomparingtheefficacy
oftheButeykobreathingmethodwith
continuouspositiveairwaypressure(CPAP)
inobstructivesleepapnea
ShariCheves,StacyMorrow,JohnBienvenida
PH206Epidemiology•December2,2014
UniversityofCalifornia,Irvine

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Abstract
Prevalenceofsleepapneaaffectsbetween2and10%oftheglobalpopulation,showingstrong
associationswithobesity,hypertension,cardiovascularmorbidityandmortality.Whileitisnot
clearifsleepapneaplaysacausalroleindisease,treatmentwithCPAPhasimprovedcertain
aspectsofOSAanddiseaseriskinsomecases.Yetduetocomplexfactorsincluding
convenienceandcomfort,patientadherencetoCPAPtreatmentispooracrossallages,and
successinfindingeffectivealternativetherapieshasbeenlimited.
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Asdiscoveredinathletictrainingandmyofunctionaltherapy,nasalbreathingandverymild,
controlledhypoxiacanpotentiallyimproverespiratoryfunctionandperformance.Buteyko
BreathingMethod(BBM)isasimpletechniquethatfeaturesdaily“underbreathing”thathas
beenclinicallyshowntoimproveasthma,aconditioncomorbidwithOSA.Observationalstudies
haveindicatedthatBBMmayimprovesymptomsofsleepapnea,thoughpotentialmechanisms
ofsuccessareunclear.

ThiscrossoverstudyaimstoevaluatetheefficacyofBBMonindicatorsofobstructivesleep
apnea(OSA)comparedtobaselineandstandardtreatmentwithcontinuouspositiveairway
pressure(CPAP).InthisSouthernCaliforniastudy,subjectswithnewlydiagnosedmildto
moderatesleepapneawillberandomlyassignedtooneoftwosequencesoftreatments.
Measurementsofpolysomnography,respiratoryplasticity,andcapnometrywillhelpquantify
resultsofeachtreatment.Qualitativeanalysisincludingselfreportedhealthchangesand
experienceswithtreatmentswillalsobecompared.
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Overview
Obstructivesleepapnea(OSA)isthemostcommonsleepdisorderedbreathingconditionthat
preventsadequateairflowduringsleep.Upperairwaysareblockedwhensoftmusclescollapse
duringsleepbetween10and30seconds.Thesepausesresultinintermittenthypoxiawith
significantdropsinbloodoxygenlevelsthatassociatewithmanydifferentdiseases.Individuals
withuntreatedsleepdisorderedbreathingexperienceare5.2timesmorelikelythanothersto
experiencecardiovascularmortalityindependentofsex,gender,orBMI.(1)PrevalenceofOSA
issimilarbetweenmajorcountries,rangingbetween3and7%formenand2to5%for
women.(2)AvastmajorityofOSAcasesremainundiagnosed.
AlthoughOSAmostsignificantlyassociateswiththeriskofheartdisease,researchhasrevealed
otherassociationswithdiabetes(3),cancer(4),stroke(5),dementiainolderwomen(6),adverse
pregnancyoutcomes(7),pneumonia(8),certainautoimmunediseases(9),andmotorvehicle
crashes.ThepresenceofOSAinREMsleepsignificantlyassociateswiththedevelopmentof
hypertensioninlongitudinalanalysis.(10)Anincreasingnumberofstudieslinksleepdisordersto
ADHDinchildren.(11)Weightgainappearstoincreasemarkersofsleepapneawhileweight
lossseemstodecreasethem.(12)PatientswithOSAalsohavemorecomplicationsaftersurgery.
(13)
BackgroundandRationale
Themostcommontreatmentforsleepapneaiscontinuouspositiveairwaypressure(CPAP).Use
ofCPAPassociateswithlowerriskofcardiovasculardisease,withastrongereffectformen.(14)
TreatmentwithCPAPmayalsorelievedaytimesleepinessandsubsequentriskoftraffic
accidents.(15)Inwomen,CPAPappearstoreducetheriskofstroke.(16)CPAPtherapyalso

4
reducestheriskofhypertensioninOSApatients,(17)thoughresearchindicatesthatitmayonly
protectcardiovascularpatientswhoalsoundergoprimarypreventiontherapy.(18)
WhileCPAPhasbeentherecommendedtreatmentforsleepapneainmostindividuals,the
devicescanbeuncomfortableandinconvenient.Approximately1530%ofpatientsdonot
acceptCPAPtreatment,while2040%discontinueafterthreemonths.Recentstudiessuggest
increasednasalinflammationinsomeCPAPpatientsthatassociateswithdaytimesleepiness.(19)
OthermetabolicfactorsinCPAPcompliancemayincludelowlevelsmalonyldialdehydethat
playanimportantroleinnitricoxideproduction.(20)Furthermore,whileCPAPimproves
measurementsofOSA,itdoesnotappeartoimprovemetabolicorinflammatorymarkers
associatedwithOSA(21)andmortalityrisksarenotconsistentlyimproved.Findingsare
complicatedbyfactorsofcompliance,age,andcomorbidityamongCPAPusers.Alackof
protectionisparticularlynotableinmoreseverecasesofOSAsuchasobesityhypoventilation
syndrome.(22)Newresearchsuggeststhattheindividualdifferencesinphysiologicalresponses
toOSAandhypoxiamayplayanimportantrole.(23)
DozensofmeasurementshelpdiagnoseOSAthroughpolysomnography,theindustry’s
resourceintensive“goldstandard.”TheseverityofOSAisdeterminedbythepopular
apneahypopneaindex(AHI)whichdividestheapneabreathingpausesbythehoursofsleep.
NormalAHIlevelsarefrom04.Insomecases,severityofhypoxiaismorecloselyassociated
withdiseaseoutcomethantheAHI.(24)

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UnderlyingconditionsplayasignificantroleinOSAandlikelyinfluencetheeffectivenessof
anyOSAtreatment.Inonestudy,asthmapredictedan8yearriskofdevelopingOSA,(25)while
anotherstudyshowed38%ofOSApatientswithunderdiagnosedallergicrhinitis.(26)
Nasalobstructionisofteninvolvedinallergicconditions,possiblycontributingtopoortolerance
ofCPAP.Nasalobstructionalsoleadstomouthbreathing.Interestingly,onestudyfoundthat
nasalbreathingwasmorecommoninwomenthanmen.(27)Sleepdisordershavelongbeen
associatedwithmouthbreathingandstudiestypicallyignoreitspresentation.(28)
Mouthbreathingcanresultfromnasalobstructionsaswellasabnormalorofacialmuscletone.
Myofunctionaltherapyhasbeenusedtoimprovemusclefunctionofthetongue,lips,andjaw.In
fact,myofunctionaltherapytoretrainmusclesofthefaceandtonguedecreasesAHIby50%in
adultsand62%inchildren.(29)Onemajorgoalofmyofunctionaltherapyispropernasal
breathing.Whilethecompletemechanismsremainunclear,nasalbreathingencouragesthe
importantreleaseofnitricoxide(NO)inthenasalpassages.Extremelyhighconcentrationsare
releasedintheepithelialcellsofupperairways,andprotectiveeffectsinvolvebloodpressure,
tumorsuppression,andvasculartone.Serumandalveolarlevelsofnitricoxidemaybereduced
inOSA(30),whilefractionalexhalednitricoxide(FeNO)maybeincreased.(31)Lownasalnitric
oxidelevelsalsoassociatewithuncontrolledasthma.(31)CPAPtreatmentmayresolvecertain
FeNOlevels,evenaftershorttermtreatment,(32)(31)butotherfactorsofNOproductionareat
work.ResearchersspeculatethatreducedexpressionofendothelialNOsynthase(eNOS),the
enzymesupportingNOproduction,contributestoendothelialdysfunctionunderlyingsleep
apnea.(33)GeneticpolymorphismsthatcontrolNOproductionmayexplainthisdeficiencyand
untreatablesusceptibilityinmanycases.(34)ItisnotablethatdecreasedNOproductionand

6
assumedcardiovascularriskarelinkedtopolymorphismsintheeNOSgeneassociatedwith
methylmercuryexposure.(35)
Trainingthatincorporatesslowernasalbreathingwithreducedventilationhasbeenreportedto
improveasthmasymptoms.(36)(37)Onestudyoncontrolledbreathingshowedimprovementsin
certainaspectsofsleepqualityandbloodpressure.(38)Controlledbreathing,particularly
throughbreathholding,forcesamildhypoxicstatewhichappearstobebothprotectiveand
damagingbasedonshortorlongtermexposure,respectively.Hypoxictraining,forinstance,is
commonlyusedwithcertainathletes.Onestudyproposedthatbenefitswereconferredbymodest
amountsofhypoxiaequatedto916%inspiredoxygen,andlowcyclesequatedto3to15
episodesperday.(39)ModerateaerobicexercisealsoreducesAHI,thoughmoreresearchis
neededtodeterminelevelsofhypoxiaachievedfordifferenttypesandintensitiesof
exercise.(40)
Thedualityofhypoxiaiscomplicatedbythebody’sfunctionofrespiratoryplasticity,theability
fortheupperairwaytoadjustitselfandavoidcollapseduringsleep.Measuresofrespiratory
plasticityincludehypoxicventilatoryresponse(HVR)andventilatorylongtermfacilitation
(LTF).ResearchershavedeterminedthatintermittenthypoxiaenhancesthemagnitudeofHVR
andLTF,thoughthelongtermhealthconsequencesofthesechangesareunclear.(41)Recent
investigationsofrespiratoryplasticityinOSAcautionthatintermittenthypoxiamayresultin
detrimentaltypesofrespiratoryplasticitywhencarbondioxidelevelsarenotmaintained.(42)
Consequently,therapiesthatcanmanipulaterespiratoryplasticitybasedonindividualconditions
mightproducebetteroutcomes.

7
Controlledbreathingexerciseshavebeenusedforthousandsofyearstotreatrespiratory
conditions.Onetechniquewasdefinedinthe1950swhenaUkrainianphysicianKonstantin
Buteykonotedthatasthmawasworsenedwithhyperventilationandimprovedwithexercises
featuring“underbreathing.”TheButeykoBreathingMethod(BBM)slowlyspreadtodifferent
countrieswithclaimsofbenefittingsleepdisorders,anxiety,andfatigue.ThebenefitsofBBM
onasthmahavebeenpublishedinclinicaltrials,butsupportforOSAislimitedtoacase
study(43),smallsurvey,(44)andobservationsamongtrainingpractitioners.Thesimple
techniquesinBBMincludebreathholdingandnasalbreathingthroughcontrolledexercises.
Indeed,breathholdingaswellasnasalbreathinghavebeenassociatedwithsignificantlyhigher
levelsofNOreleasedfromnasalpassages.(45)ItissuggestedthatBBMelicitsaverymild
intermittenthypoxiaandhasbeensuccessfullyusedtocontrolasthmasymptoms.(46)Studiesare
neededtoidentifyhowBBMcompareswithCPAPtreatmentinbothquantitativeandqualitative
aspectsofsleepapnea.
Hypothesis
Ourapriorihypothesisisthatshortterm,dailyuseofBBMcansignificantlyimprovebaseline
AHIandothermeasurementsofrespiratoryplasticityinmildtomoderatecasesofOSA.Also,
wehypothesizethatshortterm,dailyuseofBBMtreatmentwillhavethesametreatmenteffects
asshortterm,dailyuseofCPAPtreatment.
Method
StudyDesign
ThirtytwosubjectswithnewlydiagnosedmildtomoderateOSAwillbeanalyzedusinga2x2
crossoverstudydesignwithtwotreatments,twoperiodsand2sequencestoanalyzetheefficacy

8
ofBBMtreatmentandtocompareitsefficacywithCPAPtreatment.Thecrossoverstudydesign
willreducethepatientvariabilitythatappearstoimpactOSAandCPAPtreatmentandallowfor
acomparisonoftreatmentswhilecontrollingforvariablessuchasgender,age,BMI,anddisease
severity(47).Thesequence(XorY)willberandomlyassignedtoeachpatient.Thetablebelow
illustratesourstudydesign:
2x2Design
Period1
(2Weeks)
Period2
(2Weeks)
SequenceX
CPAP
BBM
SequenceY
BBM
CPAP
ForBBMtreatment,subjectswillreceiverealtimeoneononedailyBBMvideotraining
interventionwiththefollowingfeatures:trainingsessionsconductedfor20minutesinthe
morningeverydayforatotalof14sessionswithinthetreatmentperiodmeasuringthesubjects’
controlpauseslowlyincreasingeachsubjects’controlpauseovertime,withanidealdurationof
40+secondsandawarenessandparticipationinexclusivenasalbreathing.Thecontrolpauseis
definedastheamountoftimeapersoncancomfortablyholdtheirbreathafterexhaling,andthis
canincreaseby34secondsperweekwithregulartraining.AccordingtotheButeykoClinic,the
mostaccuratereadingofthecontrolpauseistakenrightafterwaking.Physicalexercisewith
correct,nasal,calmbreathingisnecessaryforincreasingthecontrolpausefrom2040seconds.
SubjectsusingBBMtreatmentwillnotbeabletocrossovertoCPAPtreatmentduringthestudy
withoutdroppingoutofthestudy.

9
ForCPAPtreatment,subjectswillreceiveadeviceandmaskthat,whenproperlyworn,createa
positivepressurethatpreventsairwaysfromcollapsingincasesofOSA.TheCPAPdevicewill
betitratedfortheproperpressureforeachsubjectbasedontheinitialbaselineevaluation.
EachofthetwotreatmentperiodswillspanfortwofullweeksstartingonaTuesday,and
measurementsofsleepquality(polysomnography)andrespiratoryfunction(AHI,capnometry,
oxygensaturation)willbeobtainedatthebeginningandendofeachstudyperiod.Qualitative
evaluationswillalsobeconductedusingsurveystoevaluatetheparticipants’experienceand
symptomsattheendofeachperiod.
Awashoutperiodofoneweekwillseparateeachperiod,andparticipantswillbeinstructedto
terminateallBBMtechniquesandCPAPusagetopreventcarryovereffects.Thiswashoutperiod
wasdeterminedbasedonresearchindicatingthatmildormoderateOSApatientsusingCPAP
treatmentfor4monthswillreturntopretreatmentlevelsexcludingoxygendesaturationand
airflowobstructionaftertwodaysofCPAPwithdrawal.(48)Theoutcomevariablesinthisstudy
willbethepolysomnography,capnometry,andrespirationmeasurementsforeachmethod.
Thoughacrossoverdesignrequirestwiceasmanymeasurementsperpatientasaparallelgroup
study,thesamplesizeismuchlessinordertomeetcriteriainavoidingtypeIandtypeIIerrors.
Participantswillalsobenefitfromtheexperienceofcomparingtwotreatments,andthe
measurementswillbesharedafterthestudyiscomplete. 

10
StudyPopulation
UponapprovalbytheHumanSubjectsInstitutionalReviewBoardatUCIrvine,subjectswillbe
recruitedfromlocalcareprovidersaswellasonlineadvertisementsandnewsletterpostings.
CandidateswillbefirstscreenedbyphoneinterviewtoconfirminterestandOSAsymptoms
suchasdaytimesleepiness,daytimefatigue,andsnoring.Durationoftherecruitmentphasewill
befromthefirstofthemonthtothelastdayofthemonth.Participantsmaybeasthmaticbutthey
mustindicatetheirasthmaticconditionatthebeginningofthestudy.Additionalcriteriawill
include:successfulcompletionofanightlongpolysomnographywithresultsindicativeofOSA
aqualifiedotolaryngologistmustassesstheparticipant’snasalairflowcapacityandapprovethe
participantfortreatmentstablemedicalhistoryasevidencedbymedicalrecordsnohistoryof
treatmentforsnoringwillingnesstoengageinbothtreatmentscurrentmedicationregimenmust
notcontainnarcoticorpsychedelicdrugsandabstinencefromdailyalcoholuse.
ContraindicationsfortheButeykomethodinclude:cancerbraintumorkidneydiseasediabetes
chestpainsicklecellanemiaepilepsyschizophreniahyperthyroidismrecentheartproblems
(withinthelastsixmonths)arterialaneurysmandthrombosis.ContraindicationsfortheCPAP
(continuouspositiveairwaypreassure)include:persistentnauseaand/orvomitinghypotension
uppergastrointestinalbleedingorrecentsurgerysuspectedpneumothoraxandanyserious
allergyorblockageofnasalpassages.
Allpotentialparticipantswillfilloutconsentforms,demographicquestionnaires,andsleep
qualityquestionnairesassessingbothnighttimeanddaytimesleepcomplaints.Aphysicianwill
intervieweachsubjectformedicalandotolaryngologichistoryandperformmedicaland
otolaryngologicexaminations.Medicationhistorywillbeassessedforpertinentprescription

11
drugsandherbalsupplements.Thepolysomnographusedtomeetcriteriaforthestudywillalso
serveasbaselinemeasurementstocomparetoposttreatmentAandpretreatmentB
measurements.Furthermore,duringthispolysomnograph,technicianswillalsoperformCPAP
titrationtodeterminethecorrectairpressuresettingsforCPAPtherapy.Titrationinvolves
gradualincreasesinairpressureuntilmanifestationsofapneadisappear.Technicianswill
monitorforchangesassociatedwithadjustmentofbodypositionorprogressionofsleepcycle
andregulateairpressureasneeded.
DuetodifferencesinCPAPefficacyinolderadults,onlyadultsnewlydiagnosedwithmildand
moderateOSAages2165willbeincluded.
ProposedMeasures
Polysomnogramsandmeanapneahypopneaindex(AHI)readingswillbetakenatthebeginning
andendofeachtreatmentatthesleepcenter.IntegratednocturnalCO2(capnometry)willbe
measuredaswell.Datawillbescoredbyapolysomnographerinablindtotreatmentfashion,
meaningsleeptechniciansandpolysomnographerswillhavenoknowledgeoftheparticipant’s
assignedsequence.
Polysomnographs(PSGs)willbeperformedusingthefollowing:respiratoryinductive
plethysmograph(RIP)electroencephalography(referredtoasEEG,C3A2)an
electrooculogram(EOG)chinelectromyogram(EMG)electrocardiogram(EKG)oraland
nasalairflowmeasures(thermistors)andpulseoximeter(rightindexfinger).Equipment
operationandcalibrationwillbeperformedbytrainedvasculartechniciansandexperienced

12
polysomnographers.Recordingswillbedigitizedusinga44channelpolygraph(Compumedics
44Eseries,Australia).
Arespiratoryinductiveplethysmographrecordsdisplacementofsensorbandsandthisrepresents
changesintidalvolume.Thisdata,expressedaspercentageofbaselinetidalvolume,willbe
usedtomeasurerespiratoryplasticity(vLTFandHVR).Ventilatorylongtermfacilitationis
definedasdeeperbreathsafterareturntonormaloxygenlevelswhereasHVRischaracterized
bydeeperbreathsduringhypoxia(49).EEGsinvolvecarefulplacementofelectrodesonthe
scalptorecordbrainwaveswhicharemeasuredinHertz(Hz)orcyclespersecond.Deltawaves
(<4Hz),thetawaves(47Hz),alphawaves(813Hz),andbetawaves(>13Hz)correspondto
differentstagesofthesleepcycle(50).EOGsrecordeyemovementsbydetectingvoltage
changesthatoccurwhentheeyemovesinrelationtotheattachedEOGelectrode(51).Eye
movementslastinglessthan500millisecondsthatareirregularandhavedrasticpeaksare
indicativeofREMsleep(52).EMGsmonitormusclemovementsasinfrequentchinmuscle
movementsthatcorrespondtotheonsetofREMsleep(53).
EKGswillmonitorheartrateandrhythmthroughelectrodesplacedonthechestwhichdetect
electricalsignalsemittedfromtheheart.Thermistors(Alice2builtinoral/nasalthermistor)will
trackairflowbysensingchangesintemperaturearoundthenoseandmouth.Inhalationis
indicatedbyalowtemperaturewhilewarmertemperaturesareassociatedwithexhalation,anda
lackofvariationintemperaturewillbeindicativeofanapneaevent(54).Bloodoxygenlevels
willbeassessedusingapulseoximeter.Thisdevicewillbeattachedtotherightindexfinger,
utilizingredandinfraredlighttodeterminebloodoxygenation.Anoxygenlevelof95100%is
considerednormalwhereasalevelbelow90%isconsideredhypoxemic(55).Finally,a

13
capnometerdevicewillmeasuretheamountofcarbondioxideinthesubject’sexhaledbreaths.
Thismeasurementisknownasendtidalcarbondioxide(ETCO2).AnETCO2valuebetween
3545mmHgisconsiderednormalwhereasavaluebelow35mmHGisindicativeofhypocapnia
(56).IntegratednocturnalCO2willbecalculatedbysumminguptheproductsoftheaverage
ETCO2ineachtimeintervalandthepercentsleepofeachtimeinterval. 
Polysomnographerswillmeasuresleeprecordingsin30secondepochs.OSAeventswillbe
describedasairflowcessationofthenoseandmouthwithaminimum10secondduration.
Eventsresultinginaminimum50%decreaseinairflowandassociatedwithelectrophysiologic
evidenceofarousalwillbeconsideredhypopneic.CombinedAHIs,apneaindexes,and
hypopneaindexeswillbecalculatedbydividingthenumberofeventsbythehoursofsleep
experienced.Participantswillbeaskedtonotsmokeatleast30minutespriortothebeginningof
testingasthismaycorrupttestresults.At9pm,participantswillreporttothesleepcenterafter
consumingalightmeal.SedativesandhypnoticswillnotbeadministeredasthismayalterPSG
measurements.Subjectswillbeallowedtorelaxintheirroomandreadanovelorenjoy
televisionentertainmentonthescreenprovided.Oncetheyarereadytobeginsleep,the
participantwillnotifythesleeptechnician.
Apulseoximeterwillthenbeattachedtotherightindexfingerinordertomonitorbloodoxygen
levelsduringtesting.RIPbandswillbesecuredtothethorax(nipplelevel)andabdomen
(umbilicuslevel)usingadhesivetape.EEGelectrodeswillbeplacedaccordingtothe1020
system.TwoEOGelectrodeswillbeattachedtoeachsubject.Anelectrodewillbelocated
approximately1cmupand1cmoutfromtheoutercanthusoftherighteye.Theotherelectrode
willbeplaced1cmdownandonecmoutfromtheoutercanthusofthelefteye.Adhesivetape

14
willbeusedtoattachatotalofthreeEMGelectrodestothementalisandsubmentalismusclesof
thechintomonitormusclemovement.ThesixEKGleadswillbeattachedtothechestaccording
tostandardprocedure.Oronasalthermistorsensors(Compumedics,Melbourne,Australia)will
beattachedaroundthenoseandmouth.Acapillarytubewillbeattachedtothesubject’sairway
andwillcontinuouslycollectairsamples.Theseairsampleswilltravelupthetubetothe
sidestreamcapnometerwhereH2Oparticleswillberemovedinawatertrap.Theremaininggas
willthenbeassessedwithaninfraredlightforETCO2levels.Interviewswilltakeplaceatthe
beginningandendofeachtreatmenttoallowforqualitativeanalysisincludingselfobserved
changesinhealth,sleepinessandfatigue,adherencetotreatment,preconceptionsoftreatments,
andchallengeswithtreatments.
Statisticalmethods
Wefirstperformatesttovalidatetheassumptionsofourcrossoverdesign.Inorderforthis
methodtobevalid,wemustruleoutthepossibilityofacarryovereffectbetweenthetwo
treatments.Wewilltestthisusingatwosidedunpairedttestsofthewithinsubjectsums(47).
Wewillusean =0.05levelofsignificancetodetermineiftherearesignificantdifferencesα
betweentheperiods.Alowpvalue(p<0.05)foreithertstatisticwillbeevidenceofa
significantcarryovereffect. 
WeuseaonesidedpairedttesttotestthehypothesisthatBBMwillsignificantlydecreasethe
outcomemeasurements.
Ho: =0μBBM 
Ha:  <0μBBM 
where isthemeaneffectofBBMtreatmentμBBM 

15
ThetstatisticisastandardizedmeasureoftheaverageeffectoftheBBMtreatmentonthe
outcomemeasure.Weusean =0.05levelofsignificancetodetermineifthereisasignificantα
decreaseforeachmeasure.Alowpvalue(p<0.05)willbeevidenceofasignificantdifference
andthatBBMtreatmentsignificantlydecreasestheoutcomemeasure.
WeuseatwosidedpairedttesttotestthehypothesisthattheBBMtreatmentwillhavethesame
treatmenteffectsasCPAPtreatment.Wewanttotestforanysignificantdifferencebetweenthe
twotreatments.
Ho: =0μCPAP − μBBM 
Ha: 0μCPAP − μBBM =/ 
where isthemeaneffectofCPAP,andμCPAP 
isthemeaneffectofBBM.μBBM
ThetstatisticisastandardizedmeasureofthedifferenceinaverageeffectoftheBBMtreatment
andtheCPAPtreatmentontheoutcomemeasure.Wewillusean =0.05levelofsignificanceα
todetermineifthereisasignificantdifferencebetweenthetwotreatments.Alowpvalue(p<
0.05)willbeevidencesupportingthealternativehypothesisthatthereisasignificantdifference
betweenthetwotreatments.Ahighpvalue(p>0.05)wouldgivenoevidenceagainstthenull
hypothesisthatthetreatmenteffectsarethesame.
Inthecasethatourdataarenotnormallydistributed,thenanonparametricWilcoxonranksum
testwillbeusedtotestforcarryovereffectsandthehypothesis(47).AWilcoxonranksumtest
firstrankstheoutcomemeasurementsforeachtreatmentandthensumstheranksforeach

16
treatment.TheWstatisticifthesmallerofthetwosums.WecompareWstatistictoWcritical
whichcanbefoundusingaWilcoxonranksumtableusingan =0.05levelofsignificance(forα
twotailtest).If|Wstatistic|isgreaterthanWcritical,thenwerejectthenullhypothesisand
concludethatthereissignificantevidenceinfavorofthenull.(57)
Wedeterminedasamplesizeofapproximately32participantsbasedonasamplesizecalculation
forouronesamplepairedttestforthesecondhypothesistest(58).Thiscalculationusedan
estimatedmeandifferenceinoutcomeofAHIof6.6withanestimatedstandarddeviationof9.3
basedonapreviousstudycomparingtheefficacyofCPAPwithmandibularadvancementdevice
(MAD)therapy(59).Weusean =0.05levelofsignificanceand =0.80statisticalpower.α β 
Belowistheequationusedforcalculatingthesamplesizeusing(59).
N= )(
sd
μdiff
2(Z+Z)
β 1−α 2
where =estimatedmeandifferenceinAHIoutcomevariableandμdiff 
sd=estimatedstandarddeviationofthereductionintheAHIoutcomevariable
LimitationsandAlternateApproaches
Thereareafewlimitationswhenusingacrossoverdesign.First,itisverydifficulttoassume
absolutelynocarryovereffectbetweenthesequencesandthatthewashoutperiodwill
completelyabolishanyeffect.Itisalsodifficulttoassumethatthereisnodifferenceineffect
betweensequenceXandsequenceY(47).Lastly,acrossoverstudydesignwiththreeorfour
periodsisrecommendedforgreaterefficiency(60).

17
ArandomizedcontrolledparallelgroupdesignforcomparingBMMandCPAPwouldavoidany
carryovereffectsinthecrossoverdesign,butvariabilitybetweensubjectscouldstrongly
influencetheresults.Sufficientrandomizationinsubjectswouldberequiredyetchallengingwith
thesmallersamplesizesdesiredwithsleepstudiesthatinvolvenumerous,costly
polysomnographs.Evenwiththiscrossoverstudy,therelianceonmeasurementsof
polysomnography,capnometry,andrespirationmaynotbeadequatetofullyevaluatethe
effectivenessofBMMorevenCPAPwithrespecttoOSAandsubsequentriskofdiseaseand
mortality.ElevatedlevelsofFeNOinOSA,forexample,requirelongtermuseofCPAPto
decline.Longerstudyperiodsmighthelpconfirmefficacyoftreatments.
TheprospectofusingdailybreathingexerciseswithBMMasasupplementarytreatmentfor
CPAPisalsonotexaminedinthisstudy.Inaddition,morecomprehensive,comparativestudies
ofotherlessinvasivetreatmentssuchasavoidanceofthesupinesleepingposition,(61)
oropharyngealexercises,(62),andmyofunctionaltherapywouldbeasignificantadditiontosleep
research.NewstudiesrevealnovelassociationsbetweenOSAandenhancedbonedensity,(63)
reducedmortalityincertaincases,(64)andreducedcardiovascularinjury.Furtherresearchneeds
toexplorehowOSAmayhavedevelopedasaprotectivemechanismincertainstagesortypesof
disease.Comparingothertreatmentsthatcomplementthetheoreticallyprotectivehypoxicroleof
OSAcouldenhancenaturalprocessesofrespirationandmetabolicbalanceforlongtermhealth.

18
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BackgroundonButeykobreathingmethodswassupportedbyJanLeuken,certifiedButeyko
trainerinCulverCity,CA.ProfessorBehrouzJafari,MDandDirectoroftheVALongBeach
HealthcareSystemSleepCenter,providedtipsonthehypothesisandrelevantbiomarkers. 
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
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StacywasresponsiblefortheHypothesisandStudyDesign,StatisticalMethods,andthe
LimitationsandAlternateApproachessections.JohnwasresponsiblefortheStudy
PopulationandProposedMeasuressectionsaswellasorganizingthereferences.Shari
wasresponsibleforBackgroundandRationaleandStudyDesignsections,project
guidance,andcorrespondencewithprofessionaladvisors.
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