Auricular Acupressure on Specific Points for Hemodialysis Patients with Insomnia

13 Pages·2015·0.42 MB·English

RESEARCHARTICLE
Auricular Acupressure on Specific Points for
Hemodialysis Patients with Insomnia: A Pilot
Randomized Controlled Trial
ChuanZou1☯,LihongYang2☯,YuchiWu1,GuobinSu1,ShuhuiChen2,XinfengGuo2,
XiuqingWu1,XushengLiu1,QizhanLin1*
1 NephrologyCenter,GuangdongProvincialHospitalofChineseMedicine,Guangzhou,Guangdong
province,P.R.China,2 Evidence-basedMedicineandClinicalResearchServiceGroup,Guangdong
ProvincialHospitalofChineseMedicine(TheSecondAffiliatedHospital/ClinicalCollege,Guangzhou
UniversityofChineseMedicine,GuangdongProvincialAcademyofChineseMedicalSciences),Guangzhou,
Guangdongprovince,P.R.China
☯Theseauthorscontributedequallytothiswork.
* [email protected]
Abstract
OPENACCESS
Citation:ZouC,YangL,WuY,SuG,ChenS,Guo
Objectives
X,etal.(2015)AuricularAcupressureonSpecific
PointsforHemodialysisPatientswithInsomnia:A Toassessthefeasibilityandacceptabilityofarandomizedcontrolledtrialcomparedauricu-
PilotRandomizedControlledTrial.PLoSONE10(4):
laracupressure(AA)onspecificacupointswithAAonnon-specificacupointsfortreating
e0122724.doi:10.1371/journal.pone.0122724
maintenancehemodialysis(MHD)patientswithinsomnia.
AcademicEditor:KathrinEller,MedicalUniversityof
Graz,AUSTRIA
Methods
Received:November5,2014
Sixtythree(63)eligiblesubjectswererandomlyassignedintoeitherAAgroupreceivedAA
Accepted:February11,2015
onspecificacupoints(n=32),orshamAA(SAA)groupreceivedAAonpointsirrelevantto
Published:April15,2015 insomniatreatment(n=31)foreightweeks.Allparticipantswerefollowedupfor12weeks
Copyright:©2015Zouetal.Thisisanopenaccess aftertreatments.Theprimaryoutcomewasclinicalresponseateightweeksafterrandomi-
articledistributedunderthetermsoftheCreative zation,definedasareductionofPittsburghSleepQualityIndex(PSQI)globalscoreby3
CommonsAttributionLicense,whichpermits
pointsandmore.
unrestricteduse,distribution,andreproductioninany
medium,providedtheoriginalauthorandsourceare
Results
credited.
DataAvailabilityStatement:Allrelevantdataare Fifty-eight(58)participantscompletedthetrialandfivedroppedout.Twentyparticipantsin
withinthepaperanditsSupportingInformationfiles. AAgroup(62.5%)andteninSAAgroup(32.3%)respondedtotheeight-weekinterventions
Funding:ThisworkwassupportedbytheProjectof (χ2=5.77,P=0.02).PSQIglobalscoredeclined3.75±4.36(95%CI-5.32,-2.18)and2.26±
ResearchStudioofFamousOldTCMPractitioners 3.89(95%CI-3.68,-0.83)inAAgroupandSAAgrouprespectively.Threeparticipantsdied
ExperienceHeritage,StateAdministrationof
duringthefollow-upperiod.NoevidencesupportedtheirdeathswererelatedtotheAAinter-
TraditionalChineseMedicine(GrantNo.
vention.Nootheradverseeventwasobserved.
2012KT1301);andResearchProjectforPractice
DevelopmentofNationalTCMClinicalResearch
Bases,P.R.China(GrantNo.201007005).The Conclusion
fundershadnoroleinstudydesign,datacollection
Feasibilityandlogisticsofpatientrecruitment,randomizationprocedure,blinding
andanalysis,decisiontopublish,orpreparationof
themanuscript. approach,interventionsapplicationandoutcomeassessmenthadbeentestedinthispilot
PLOSONE|DOI:10.1371/journal.pone.0122724 April15,2015 1/13
SpecificAuricularAcupressureImprovesSleepQuality
CompetingInterests:Theauthorshavedeclared trial.ThepreliminarydataappearedtoshowafavorableresultonAAtreatment.Afull-scale
thatnocompetinginterestsexist. trialiswarranted.
TrialRegistration
ChineseClinicalTrialRegistryChiCTR-TRC-12002272.
Introduction
Sleepproblemsareamongthemostfrequentcomplaintsindialysisunits.Approximately50–
80%ofpatientswithend-stagerenaldisease(ESRD)complainofinsomnia[1–4],whichis
nearlytwo-foldmorethangeneralpopulationsdo[5].Previousresearcheshaveshowedthat
poorsleepqualityislinkedtothedurationofdisability,highhealth-careutilization,poorquali-
tyoflifeandmortalityinmaintenancehemodialysis(MHD)patients[6,7].Self-reportedsleep
qualityinMHDpatientsisassociatedwithhypertensionandnon-dippingbloodpressure[8,9],
indicatingthatpoorsleepmaybeoneoftheimportantfactorscontributingtothehighpreva-
lenceofcardiovasculareventsobservedinMHDpatients.
Theetiologyofinsomniainpatientswithchronickidneydisease(CKD)ismultifactorialand
complicated.Pathophysiologicabnormalities,psychologicalproblems,lifestyle,andtreatment-
relatedfactorsleadtothissleepproblem.Pathophysiologicconditionsincludeanemia[2,10],
hypoproteinemia[11],hyperphosphatemia[2,10],secondaryhyperparathyroidism[2,12],
micro-inflammatorystate[10,11,13],andimbalanceofautonomicnervousactivity[14].Psycho-
logicalfactors,likeanxietyanddepression[4]anduremicsymptomsincludinglimbpain[15]
andpruritus[12]alsoplayaroleinsomeindividuals.Prevalenceofsleepproblemsdecreases
afterrenaltransplantation[16,17],dailynocturnaldialysis[18]andparathyroidectomy[19].
Untilnow,onlyalimitednumberofpharmacologicstudiesandevenlessnon-pharmaco-
logicstudieshavefocusedonthetreatmentofinsomniainCKDpatients.Consequently,treat-
mentsuggestionsaremainlybasedonresultsobtainedfromnon-CKDpopulations[20].
BenzodiazepinereceptoragonistsaretheonlyagentscurrentlyapprovedbytheUSFoodand
DrugAdministration(FDA)fortreatinginsomnia.Althoughinsomniaisoftenachroniccon-
dition,theUSFDAhasonlyapprovedeszopicloneforclinicalusewithoutaspecifiedtime
limit.Othersleepmedicationshavebeenapprovedtousenolongerthan35days.Thelimited
durationonprescriptionofthesemedicationsisduetothepotentialabuse,dependenceand
adverseeffects,suchasresidualdaytimesedation,cognitiveimpairmentandpoormotorco-
ordination[21].
Owingtolimitationsofcurrenttreatment,manyalternativetherapieshavebeenusedtotreat
insomnia.InChina,acountrywithalonghistoryofapplyingMeridianTheoryinhealthcare,
acupuncture,auricularacupunctureandauricularacupressurearecommonalternativethera-
piesforinsomnia.Auriculartherapy,originallyderivedfromauricularacupuncture,involves
stimulationatspecificacupointsontheouterearwithneedles,pellets(Semenvaccariae),mag-
neticpearlsandelectricity[22].Auricularacupressure(AA)isoneofthetypicaltypesappliedin
diverseclinicalconditionsincludingsleepproblems.OurpreliminaryworkshowedthatAA
addingtobasiccare(includingsleephygieneandsleepmedicationsifnecessary)achievedim-
provementsonsleepquality,efficacyanddurationinhemodialysispatientswithsevereinsom-
nia[23].WealsofoundthatpatientsconsumedlesssleepmedicationsafterreceivingAA
treatment.However,arecentmeta-analysisofrandomizedcontroltrials(RCT)andquasi-RCTs
comparedAAwithshamcontrolforinsomniacsshowedequivocalresults[24].Therefore,we
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SpecificAuricularAcupressureImprovesSleepQuality
plannedtodesignasham-controldouble-blindRCTtoassesstheefficacyandsafetyofAAfor
insomniainthedialysispopulation.
Beforeconductingafull-scaleRCT,somecriticalissuesregardingfeasibilityassessment
shouldbeevaluatedbyperformingapilotstudy.Consequently,weconductedapilottrialcom-
paredgenuineAAwithshamAA(SAA)presentingasAAonnon-specificacupointsforMHD
patientswithinsomnia,whichaimedtoassessthefeasibilityofrecruitment,randomization,al-
locationconcealment,blinding,interventionprotocols,outcomeassessmentproceduresand
acceptabilityofAAtreatment.
Methods
TheprotocolforthistrialandsupportingCONSORTandSTRICTAchecklistsareavailableas
supportinginformation;seeS1CONSORTChecklist,S2STRICTAChecklistandS1Protocol.
Studydesign
Thispilotstudywasdesignedtobeatwo-arm(allocationratio1:1),double-blind,sham-
controlled,randomizedtrial,andregisteredonChineseClinicalTrialRegistry(ChiCTR-TRC-
12002272).
Ethicsapproval
ThistrialwascarriedoutaccordingtotheprinciplesoftheDeclarationofHelsinki(Version
Edinburgh2000).ThestudyprotocolandwritteninformedconsentwereapprovedbyInstitu-
tionalEthicsReviewBoardsofGuangdongProvincialHospitalofChineseMedicine(B2011-
28-01).Allparticipantsprovidedwritteninformedconsent.
Participants
Participantswererecruitedthroughinvitationletters,informationpamphletsandpostersinHemo-
dialysisCenterofGuangdongProvincialHospitalofChineseMedicine(Guangzhou,P.R.China).
Patientswhometallofthefollowinginclusioncriteriawereinvitedtoparticipateinthetrial.
Inclusioncriteria.
a. Underregularmaintainhemodialysistreatment(weeklytreatmenthour(cid:1)10)for12to120
months;
b. Aged18~75years;
c. ChronicprimaryinsomniadiagnosedaccordingtoDiagnosticandStatisticalManualof
MentalDisordersfourthedition-TextRevision(DSM-IV-TR)[25];
d. GlobalscoreofPittsburghsleepqualityindex(PSQI)>7;
e. Freeofhypnoticsuseorusingaminimummaintainingdoseofestazolam((cid:3)1mg/d)during
thepastthreemonths;
f. Informedconsentprovided.
Exclusioncriteria. Thosewithanyofthefollowingconditionswereexcluded.
a. Presenceofco-morbiditiesincludingcancer,congestiveheartfailure,connectivetissuedis-
easeandhematologicdiseases;
b. Inadequatelydialyzed,indicatingbyureaclearanceindex(Kt/V)<1.20;
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SpecificAuricularAcupressureImprovesSleepQuality
Fig1.Flowchartofparticipantsenrollment,assignmentandfollow-up.
doi:10.1371/journal.pone.0122724.g001
c. Presenceofseverephysicalsymptomssuchasbonepain,itchyskin,sleepapneaandrestless
legswhichareobviouslycausativeforinsomnia,andfatiguecausedbysevereanemia
(hemoglobin<60g/L)ormalnutrition(serumalbumin<30g/L).
Interventions
Thistrialincludedaneight-weektreatmentperiodanda12-weekpost-treatmentfollow-uppe-
riod.EligibleparticipantswererandomlyassignedtoreceiveAAeitheronspecificacupointsor
onshamacupoints(Fig1).
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SpecificAuricularAcupressureImprovesSleepQuality
Fig2.Auricularacupoints.a:Auricularacupointsusedintreatmentandcontrolgroup.b:Codesfortheacupointsused.
doi:10.1371/journal.pone.0122724.g002
AcupointsusedinAAgroup. ParticipantsinAAgroupreceivedAAonfiveactiveacu-
pointsincludingShenmen(TF4),Sympatheticautonomic(AH6a),Subcortex(AT4),Heart
(CO15),andEndocrine(CO18),asillustratedinFig2.
AcupointsusedinSAAgroup. ParticipantsinSAAgroupreceivedAAonfiveHelix
points(HX5–9),whichwereclearlyremotefromtheinnereararea.(Fig2)
StandardprocedureforAAmanipulation. AAwasprovidedwhenparticipantswereon
hemodialysisinastateofrelaxation.Bothinterventionsweredeliveredbyatrainednurseprac-
titioner(Z.C.Zhong),whohadnopriorexperienceonAAbeforeandwasunawareofthe
groupallocation.Acupointareasweredisinfectedwith75%isopropylalcoholbeforeattaching
a1.0cm×1.0cmadhesiveplasterwithonebead(SemenVaccariae,globesofaround2.0mmin
diameter;surface:smooth;color:black;TaichengTechnology&Developmentco.,LTD,Shang-
hai,China)imbedded.Participantswereinstructedbythetrainednursetopressthebeadswith
continuousandappropriatefingerstrengthinthreetofourkgandwiththerateofonetotwo
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SpecificAuricularAcupressureImprovesSleepQuality
perseconduntilahotsensationandslightsorenessonthepointswerefelt[26].Eachacupoint
shouldbemanipulatedthreetofivetimesinthedaytimeandevening.Wedidnotrecommend
pressingatlatenight,especiallyonehourbeforegoingtosleep.Theplastersweresuperseded
everytwotothreedays(usuallyontheirdialysisday)andacupointsontwoearswereusedal-
ternately.Iftheplastersorbeadsdetached,thepatientswereaskedtocometohospitaltore-
ceivefreshplasters.
Rationaleforacupointselection
Auricularacupointswereselectedbecauseofthefollowingreasons:(1)Accordingtotraditional
Chinesemedicine(TCM)pathologyofinsomnia[27],treatmentsshouldfocusonregulating
theimbalancedyinandyangoftheHeart.Shenmen(TF4)andHeart(CO15)arerelatedtothe
Heartandabletocalmthespirit.Theotheracupointshelpself-modulatingthefunctionsofin-
ternalorgans.(2)Hyperarousalisdeemedtobeapathophysiologicalfactorininsomnia
[28,29].Acupointslocatingatthetriangularfossaandcavumconchaearelikelytostimulate
thevagusnerve,thusmodulatingautonomicnervoussystem(ANS)[30,31].(3)Aprescription
ofAAcontainedacupiontTF4,AT4,AH6a,CO15andCO18hadbeenappliedtoinsomnic
MHDpatients.Encouragingresultswasobtainedinourpreliminarystudy[23].
Outcomemeasurements
Feasibility. Feasibilityofthistrialwasassessedbythepercentageofrecruitment,retention,
attendanceandadherence.
Effectiveness. SleepqualitywascharacterizedwiththeChineseversionofPSQI[32].PSQI
containssevendomainsscoringfrom0to3,withatotalscorerangingfrom0to21.Thehigher
scoreindicatestheworsesleepquality.ThepermissionofusingPSQIwasobtainedfromProf.
Buysseviaemail.ThereliabilityandvalidityofitsChineseversionhadbeenproved[33,34].
PSQIwasassessedatbaseline,4,8weeksafterrandomizationand4,8,12weekspost-
treatment.
(1)Primaryoutcome
Theprimaryoutcomewastheclinicalresponseateightweeksafterrandomization.Re-
sponsewasdefinedasareductionofPSQIglobalscoreby3pointsandmoreaccordingtoliter-
aturereview[35].
(2)Secondaryoutcomes
SecondaryoutcomeswerePSQIglobalscore,andscoresofeachdomainincludingsleepdu-
ration,sleepdisturbance,sleeplatency,daydysfunction,sleepefficiency,overallsleepquality
andsleepmedication.Allparticipantsunderwentbloodbiochemicaltestsbeforerandomiza-
tionandattheendoffollow-up.Parametersincludingserumcreatinine(SCr),bloodureani-
trogen(BUN),totalcarbondioxide(TCO ),potassium(K+),calcium(Ca2+),phosphate
2
(PO 3-),parathyroidhormone(PTH),albumin(Alb),hemoglobin(Hb)andKt/Vwerealles-
4
sentialformonitoringthecomplicationsforMHDpatientsandadequacyofdialysis.Ifpartici-
pantsrequiredhypnoticagentsduringthestudybecauseofunbearablesleepdisorders,they
wereallowedtotakehypnoticsinitiatingfromtheminimumdoseandencouragedtocomplete
thetrial.Theweeklydoseofhypnoticagentswasrecorded.Adverseeventsthroughoutthe
treatmentandfollow-upperiodsweredocumentedanddealtwithbyappropriatemeasures.
Randomizationandallocationconcealment
ArandomsequencegeneratedbyMicrosoftExcelsoftware2003,wasproducedbyaninvesti-
gatornotinvolvedinrunningthetrial.Therandomsequencewaskeptbyhimandtheassign-
mentwasunawaretootherresearchstaffs.
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SpecificAuricularAcupressureImprovesSleepQuality
Blinding
Boththeparticipantsandtheresearchnursewereblindedtothetreatmentprotocol.Because
acupointnamesinChineseoftenreflecttheeffectsofthepoint(e.g.Shenmenreferstotran-
quilization),allpointsusedinthestudyweregivenacodetoavoidbreakingtheblinding
(e.g.1A,1B,seeFig2).ThenurseselectedforthisstudydidnothavepreviousAAtraining
orexperience.HewasmadeawarethatthestudywasgoingtocomparetwodifferentAA
protocols,andwasaskednottoreadtheAAchartduringthestudy.Hewastrainedtoapply
bothtreatmentprotocols,andinstructednottodiscussthedifferenceoftreatmentswiththe
participants.ToavoidtheHawthorneandRosenthaleffects,hewasrequiredtolimitthein-
teractionwiththeparticipants.Hewouldnotaskparticipantswhethertheyfeltsorewhen
placingtheseedsontheacupoints(acommonpracticeforconfirmingtheaccuracyofpoint
location).Theparticipantswouldnotaskhimanyquestionaboutthemanipulationandre-
portanyresultstohim.Anyquestionregardingmanipulationwasdirectedtoanother
investigator(X.Q.Wu)whomwasresponsibleforteachingtheparticipantshowtoapply
thesqueezingmethod.Allresultswerereportedtotheinvestigator(Y.C.Wu)whomwas
responsibleforrecordingresultsinaclinicalinterview.Anotherinvestigator,who
conductedthestatisticalanalysis,didnotknowthegroupassignmentuntiltheanalyses
completed.
Samplesize
Asthispilotstudywasanexploratorystudyandundertookforthefeasibility,samplesizecal-
culationwasnotperformed.
Statisticalanalysis
Adescriptiveanalysiswasperformed.Meanandstandarddeviations(SD)werecalculatedfor
thequantitativevariablesandfrequencydistributionsforthequalitativeones.Outcomeofclin-
icalresponsewasanalyzedbyChi-squaredtestorFisher’sexact.Repeated-measuresanalyses
ofvariancewereconductedtocomparechangesonPSQIglobalscoreandeachdomain.Limit-
edtothenatureofpilotstudy,therewasnotadequatepowertodetectstatisticaldifference,and
thereforedatawereonlyanalyzedtoindicatethedirectionofeffectofAAtreatment.Allanaly-
seswereperformedontheintentiontotreat(ITT).Weassumedthattheunobserveddatawere
missingcompletelyatrandombasedonlittle’sMCARtest(χ2=18.03,P=0.978).Imputation
ofmissingdatawascarriedoutwiththelastobservationcarriedforward(LOCF).Theoutcome
valuesateightweeksaftertreatmentwerethebaselinevaluesoftheparticipantswhomwith-
drewordroppedout.Inthiscase,thewithdrawalsordropoutswereconsideredtobetheinef-
fectivecases,anditprovidedaconservativeestimation.Statisticalanalysiswasprocessedusing
thePredictiveAnalyticsSoftwarepackage(PASWStatistics18).
Results
Twohundredandeight(208)patientswerescreenedforeligibilityfromSeptembertoNovem-
ber2012.Ofthese,35(16.8%)declinedtoparticipateinthetrial,68(32.7%)didnotfulfillthe
inclusioncriteria,42(20.2%)mettheexclusioncriteria.Eventually,63(30.3%)patientswere
included,with32randomlyassignedtoreceiveAAonspecificacupointsand31onshamacu-
points(Fig1).Fiveparticipants(7.9%)withdrewduringthestudy.ThreeparticipantsinSAA
groupandoneinAAgroupwithdrewatfourweeksaftertreatments,duetocomplainingof
lackingineffect.OneparticipantinAAgroupdiscontinuedduetotransferringtoanotherhe-
modialysisunit(Fig1).
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SpecificAuricularAcupressureImprovesSleepQuality
Asweappliedinterventionsontheirdialysisday,allparticipantsexceptthewithdrawals
completedalltreatmentsessionsandreportedthattheyself-administeredaccordingto
ourinstruction.
Nosignificantdifferencewasfoundbetweentwogroupsonbaselinedemographicandclini-
calcharacteristics,includingage,gender,co-morbidities,sleepmedicationintake,anddialysis
adequacy(Table1).
MissingdataoffivewithdrawalswereimputedwithLOCF.Therefore,theywereconsidered
asnon-response.Twenty(20)participantsinAAgroup(62.5%)andten(10)inSAAgroup
(32.3%)respondedtotheeight-weekinterventions(χ2=5.77,P=0.02).ChangesofPSQIglob-
alscoreandofeachdomainwithinandbetweengroupsarepresentedinS1Table.PSQIglobal
scorehaddecreasedby3.75±4.36(95%CI-5.32,-2.18)and2.26±3.89(95%CI-3.68,-0.83)
aftertreatment,andby1.56±3.66(95%CI-1.15,-0.24)and1.26±2.97(95%CI-2.35,-0.17)at
theendoffollowup,inAAgroupandSAAgrouprespectively(seeFig3).Resultofrepeated-
measuresanalysesofvarianceforPSQIglobalscoreinTable2showsthatPSQIglobalscorede-
clinedovertimebothinAAgroup(F=8.47,P<0.01)andSAAgroup(F=4.09,P<0.01).
DecreasealsofoundinallsevendomainsexceptsleepdisturbanceaftertreatmentinAA
group.Decreaseofdayfunctionalanduseofsleepmedicationsweremaintainedtotheendof
followupinAAgroup(S1Table).NumberofparticipantstakingsleepmedicationsinAA
groupreducedfrom11(34.4%)to4(12.5%)aftereightweeksoftreatmentwhichmaintained
totheendoffollow-up,whilethenumberinSAAgroupincreasedfrom11(35.5%)to15
(48.4%)aftertreatment(χ2=9.63,P<0.01,Fig4).
ThreeparticipantsdiedinAAgroupduringthefollow-upperiod,onebecauseofmyocardi-
alinfarctionandtwobecauseofcardiacarrest.Noevidencesupportedtheirdeathswererelated
toAAintervention.Nootheradverseeventwasobservedinbothgroups.
Table1. BaselineCharacteristicofParticipants
AAgroup(n=32)Mean(SD) SAAgroup(n=31)Mean(SD)
Age(y) 53.28(12.68) 58.55(10.00)
Malesex(n,%) 17(53.1) 11(35.5)
Comorbidities(n,%)
Diabetes 3(9.4) 6(19.4)
Hypertension 21(65.6) 21(67.7)
Nocomorbidities 8(25.0) 4(12.9)
Takinghypnotic(n,%) 11(34.4) 14(45.2)
Dialysistimeperweek(hour) 11.0(1.02) 11.10(1.01)
SerumCreatinine(μmol/L) 1114.22(211.92) 1048.61(297.53)
Bloodurinenitrogen(mmol/L) 24.29(5.99) 22.15(6.35)
TCO (mmol/L) 19.95(3.32) 19.90(3.48)
2
Serumpotassium(mmol/L) 4.74(1.14) 5.06(0.67)
Serumcalcium(mmol/L) 2.19(0.24) 2.29(0.17)
Serumphosphorus(mmol/L) 2.20(0.60) 2.43(1.16)
PTH(pg/ml) 749.98(607.93) 978.22(666.23)
Albumin(g/L) 40.37(3.20) 39.62(2.89)
Hemoglobin(g/L) 112.47(12.03) 114.42(17.14)
KT/V 1.47(0.27) 1.44(0.28)
Abbreviations:TCO2:Totalcarbondioxidecontent,PTH:Parathyroidhormone,KT/V:ureaclearanceindex
doi:10.1371/journal.pone.0122724.t001
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SpecificAuricularAcupressureImprovesSleepQuality
Fig3.ChangeofPSQIglobalscoresintwogroups.
doi:10.1371/journal.pone.0122724.g003
Discussion
ThispilottrialaimedtoinvestigatethefeasibilityofaRCTcomparedAAonspecificpoints
withshamcontrolforinsomniacsinhemodialysiscenter.Thetrialwasimplementedsmoothly
inaccordancewiththestudyprotocol.
Randomizationproceduresandallocationconcealmentweresuccessful.Allinvestigators
excepttheonewhogeneratedandkepttherandomsequencewerenotawareofthegroupas-
signment.Theapproachofblindingofpersonnelandparticipantswasfeasibleandeffectivein
AAtreatmenttrial.Theresearchnursewouldnotbeallowedtoreadthestudyprotocoluntil
thefull-scaletrialcomplete.Usingnon-specificauricularpointsasshamcontrolwasaccepted.
Helix(HX)pointsareassumedappropriatelyasnon-specificpointsforinsomnia,astheyare
clearlyremotefromtheinnerearareaandoflittlerelevancewithneitherTCMtheoryonsleep
treatmentnorvagusnervedistribution[36].
InChina,MHDpatientsareregisteredandregularlydialyzeinoutpatienthemodialysiscen-
ter.Thus,wehadtheexactnumberofregisteredpatientstoscreenforpotentialparticipants.
Althoughtherecruitmentrateofthispilotstudywasjustaround30%,recruitmentwascom-
pletedinashortperiod.Sinceallparticipantsroutinelydialyzedinouroutpatienthemodialysis
Table2. Repeated-measuresanalysesofvarianceforPSQIglobalscoresanditscomponentsover
timeineachgroup.
Outcomes AAgroup(n=32) SAAgroup(n=31)
F P F P
PSQIscore 8.47 0.00 4.09 0.00
Durationofsleep 4.39 0.00 2.37 0.06
Sleepdisturbance 1.57 0.21 0.74 0.47
Sleeplatency 4.37 0.00 1.75 0.14
Daydysfunctionalduetosleepless 3.60 0.00 3.57 0.00
Sleepefficiency 2.11 0.08 2.30 0.06
Overallsleepquality 4.14 0.00 4.75 0.00
Useofsleepmedications 5.25 0.00 1.20 0.31
doi:10.1371/journal.pone.0122724.t002
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Fig4.Numbersofparticipantstakinghypnoticorhypnoticfree.Beforetreatmentbetweentwogroups(χ2=0.77,P=0.38).Aftertreatmentbetweentwo
groups(χ2=9.63,P<0.01).Endoffollow-upbetweentwogroups(χ2=4.59,P=0.03).
doi:10.1371/journal.pone.0122724.g004
centerandinterventionswereappliedduringtheirdialysis,allparticipantsexceptthewith-
drawalscompletedthefulltreatmentsessions.
Giventhenatureofapilotstudy,wedidnotcalculatethesamplesize,andthereforewehad
noadequatepowertodetectthestatisticaldifferencebetweentwointerventions.Nevertheless,
encouragingindicationswerefoundfromtheresultsoftheeffectivenessoutcomes.Ourdata
showed,eightweeksafterintervention,theresponserateofAAgroupwasalmosttwotimes
higherthanthatofSAAgroup(62.5%vs.32.3%).Besides,fewerparticipantsinAAgroupthan
inSAAgroupweretakinghypnotics(12.5%vs.48.4%)aftertreatment,aswellasattheendof
follow-up(12.5%vs.35.5%).CarryovereffectofAAtreatmentforinsomniawasobserved,in
termsofPSQIglobalscoreandthenumberofparticipantstoppedtakinghypnotics.Thisfind-
ingcoincidedwithanobservationalstudyontheelderlywithinsomnia[37].Theresultsen-
couragedustoconductalargefull-scaleRCTtoevaluatetheactualeffectofAAintreating
MHDpatientswithinsomnia.
Basedontheinformationgatheredfromthispilottrial,severalessentialsforconductinga
furtherRCTproperlywereidentified.
Withdrawalofhypnoticsmightbedifficult.Inviewoftheethicalissueandlowcompliance
withtheinterventions,werecruitedpatientswhomtookaminimumdoseofhypnotics(no
morethanonetabletofestazolampernight).Aboutone-thirdparticipantstookhypnoticsbe-
foreinterventionsineachgroup.Hypnoticagentssomewhatcontributedtothebeneficialac-
tivity.Inordertoavoidthisconfounding,athree-armtrialthatco-interventionswerenot
allowedtousecouldbeconsideredinfurtherstudydesign.Atrialwouldbecapabletocompare
AAwithshamcontrol,aswellasanactivecontrol(hypnotics).Consideringpatients’compli-
ance,aninequalityproportionofsamplesizesalsocouldbeconsideredinsamplesizecalcula-
tion,e.g.aproportionof3:3:2inAAgroup,SAAgroupandhypnoticsgroup.
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