Journal of Biomedical SciencesISSN 2254-609X

2017Vol. 6 No. 2:16

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Research Article

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DOI:10.4172/2254-609X.100060

Aidah Alkaissi1, Tasneem Tarayra2 and Abdelbaset Nazzal3

1 An-NajahNationalUniversity,Nursing&MidwiferyDepartment,FacultyofMedicineandHealthSciences,Nablus,Palestine

2 FacultyofGraduateStudies,An-NajahNationalUniversity,Nablus,Palestine

3 An-NajahNationalUniversityHospital,Nablus,Palestine

Corresponding author: Dr.AidahAlkaissi

aidah@najah.edu

AssistantProfessorinanesthesiology,An-NajahNationalUniversity,FacultyofMedicineandHealthSciences,NursingandMidwiferyDepartment,P.O.Box7,Nablus,Palestine.

Tel:00972(0)597395520Fax:00972(0)92342910

Citation:AlkaissiA,TarayraT,NazzalA.TheClinicalEffectivenessoftheBispectralIndex(BIS)ToReducetheRiskofAwarenessforElectiveSurgicalPatientsUndergoingGeneralAnesthesia:AProspective,Randomized,Double-Blind,ControlledTrial.JBiomedicalSci.2017,6:2.

The Clinical Effectiveness of the Bispectral Index (BIS) To Reduce the Risk of Awareness

for Elective Surgical Patients Undergoing General Anesthesia: A Prospective,

Randomized, Double-Blind, Controlled Trial

AbstractBackground: Unintended intra-operative awareness is a serious complicationof general anesthesia. The incidence of such awareness has been reported tobeabout0.1-0.6%ofpatientsundergeneralanesthesia.Reminiscenceofwhatoccurredduringtheoperationcanbefeltbypatients,whichcanbestressfulandleavelastingmentalsufferingafterwardtheoperation.Patientsthatexperienceunintended intra-operativeawarenessmayhavesomecombinationofauditoryfunction, tactual feeling, a sense of weakness, an inability tomove, pain, anddread.BispectralIndex(BIS)monitoringhasbeenshowntodecreaseawarenessandboost recoverytime fromanesthesia.Aimsof the study is toevaluate theclinical impact of BISmonitoring to reduce the incidenceof awareness and itsimpactonhemodynamicparameters,drugconsumption,therecoverytimeandtheend-tidal concentrationofvolatileanesthetics inadultpatientsundergoingvarioustypesofsurgeryundergeneralanesthesia.

Methods: Thedesignadoptedforthisstudyisaprospective,randomized,double-blindtrial.Thestudyinvolvedfifty-nineadultpatientswithAmericanSocietyofAnesthesiologists (ASA)physical status I-III, aged18 to72 years. 41males and18femalesscheduledfordifferenttypesofoperationsundergeneralanesthesiaparticipatedinthestudy.PatientswererandomizedforinclusionintheBIS-handledanesthesiagroup(n=30),withtheBISvaluecontrolledbetween40and60,whichisconsideredconvenientforsurgicalanesthesia;ortheregularcare(RC)groupwithoutBIS-control(n=29).ABISsensorwasplacedontheforeheadofpatients.Hemodynamicspecificationswererecordedbefore inductionofanesthesiaandeveryfiveminutesduringsurgeryuntiltheremovaloftheendotrachealtube.Thepatientswereinterviewedbyablindedobserverat24-36hoursafteroperationthrough the use of a structured questionnaire. Two independent endpointadjudicationcommitteesblindedtogroupidentityassessedtheinterviewresultsandidentifiedtheconfirmedawarenesscases.

Findings:Therewerenosignificantdifferencesbetweenthetwogroupsinallthegeneralcharacteristicsofthepatients.Regardinganesthetictime,themean±SDintheRCgroupwas76.6±84.3minutes,and124.2±124.4minutes intheBISgroup;thedifferencewasnotsignificant.Surgicaltimewas73.8±85.8minutesintheRCgroupand116.4±106.2minutesintheBISgroup;thedifferencewasnotsignificant.Ofthetotal59patients29patientswereassignedtotheroutinecontrolgroupand30patientstotheBISgroup.NocaseofawarenesswasreportedintheBIS-guidedgroupbut4reports(13.8%)inthecontrolgroup(P=0.035),BIS-guidedanesthesiadecreasedawarenessby13.8%(95%CI(1.3%-26.4%).Themostcommonformsofawarenesswasauditoryperceptions,tactileperceptionandthesenseofparalysis.

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TherewasastatisticallysignificantdifferenceinthemeandoseofinhaledanestheticagentsbetweentheRCgroup(0.029±0.008%)andtheBISgroup(0.025±0.009%),P=-0.023,whichindicatesthatBISmonitoringcouldreducetheneededuseofinhalationanesthesia.RegardingtheopioidfentanyltherewasalsoasignificantdifferenceintheuseddoseoffentanylfortheBISgroup(115.56±94.18mcgandtheRCgroup(77.76±40.52mcg),P=0.035.TherewasfoundtobeadifferenceinthepropofoldosagebetweentheBISgroup(474.07±711.3mg)andtheRCgroup(230±59.938mg),P=0.235.ItisclearthatpatientsintheRCgrouphadalowerdosageofpropofolthanpatientsintheBISgroup,butthedifferencewasnotsignificant.LowdosesoffentanylandpropofolmaybeoneofthecausesofawarenessintheRCgroup.Wefoundnosignificantdifferencesinsomaticresponsesofsweating,tearing,pupildilationandcoughingintra-operativelybetweenBIS-monitoredandRCpatients.However,asignificantreductioninintra-operationaljerkingwasrecordedforthefavorofBISgroup.Thepercentageofpatientswhoexperiencedjerkingmovementsintra-operativelywas27.6%intheRCgroupand6.9%intheBISgroup,P=0.037.

Therewerenostatisticallysignificantdifferencesbetweenthetwostudygroupsinanyofthetimemeasuresunderstudywhichare: time from cessation of inhalational agents to eye opening; time to respond to commands; time to eye opening (eitherspontaneouslyorinresponsetocommand,timetofirstmovementresponse;andtimetoextubation.ThetimetophonationfortheRCgroupwas12.82±6.11minutesandonly10.21±5.127minutesfortheBISgroup,P=0.026,thisoccursforthefavorofBISgroup.

There isastatisticallysignificantdifferencebetweenthetwogroups inthetimetodischargefromthePACUat12.38±4.989minutesfortheRCgroupand9.23±3.819minutesfortheBISgroup,P=0.007.Inotherwords,patientsintheBIS-monitoredgroupweredischargedearlierfromthePostAnestheticCareUnit(PACU)thantheRCpatients.

Conclusions:BIS-guidedanesthesiawhere theBISscore iskeptbetween40and60, reducedtheriskofawarenesscomparedtoroutinecare.ThemainreasonfortheoccurrenceofawarenessintheRCgroupcouldbeduetoalightgeneralanesthetic.Inaddition,BISmonitoringreducestheusageofvolatileanesthesiaandthetimeofdischargefromthePostAnestheticCareUnit.

Keywords: Awareness;Generalanesthesia;BIS;Monitoring

Received: February25,2017; Accepted: March27,2017; Published: April03,2017

IntroductionItisnecessarythatthelevelofgeneralanesthesia(GA)issuitablefor the individual patient undergoing surgery. If anesthesia isdeeperthanrequiredtokeepapatientunconscious,itcouldtiltthe riskof anesthesia-relatedmorbidity, suchaspostoperativenausea,vomiting,andcognitivedivergence.Thiscanalsoextendrecoverytimesandrisehealthcarecosts.Ifanesthesiaistoolight,thepatientmaynotbetotallyunconsciousandcanleadtointra-operativeawareness.Intra-operativeawarenessisaratherrarecircumstancewithanincidenceofoccurrenceinapproximately1-2patientsperevery1,000.Lyonsdeclaredthat,Awarenessisknownto triggerdepression,anxietyandpost-traumaticstressdisorder(PTSD)[1].

Under GA, the patient is routinely monitored for signs ofpotential intra-operative awareness, including rapid heartbeat,highbloodpressure,sweating,tearproduction,motion,grimacesandrapidbreathing. Inpatientsreceiving inhaledGA,end-tidalvolatileanestheticconcentrationcanbeassessedtomeasuretheprofundityofanesthesia.However,clinicalobservationaloneisnotadequateforunderstandingthedepthofanesthesia.Electro-encephalography (EEG) has been developed to measure andinterprettheelectricalactivityinthebraintoprovideameasureofconsciousness.MostEECunitsincludeamodulethatcollectsand analyzes raw data from sensors placed on the patient'sforehead.Theoutputisthendisplayednumericallyonamonitortobeobservedbytheanesthesiologisttoevaluatethedeepness

ofunconsciousness.Oneof theseEEGdevices is theBispectralIndex(BIS)[2-4].

Aims of the study is to evaluate the clinical impact of BISmonitoringtoreducetheincidenceofawarenessanditsimpactonhemodynamicparameters,drug consumption, the recoverytime and the end-tidal concentration of volatile anesthetics inadultpatientsundergoingvarioustypesofsurgeryundergeneralanesthesia.

BackgroundAwarenessduringanesthesiaisaseriouscomplicationofpotentiallong-term psychological consequences. Use of the BispectralIndex (BIS), can reduce the incidence of anesthesia awarenessforthepatient.IgorKaganshowedthatawarenessandmemoryofsurgicaleventsduringanesthesiaaresideeffectsthatcanleadtomentaldisordersincludingPTSD.Awarenessduringanesthesiacannotalwaysbecompletelyprevented.Apatientmaybeawareforanumberofreasons, including:thelevelofanesthesia,thetypeofanesthesia,inadequatemonitoringandanesthesiologisterrors. However, there aremeasures taken to reduce the riskofawareness.BISmonitoringappearstobeapromisingtoolinhelpingtoreduceintra-operativeawareness[5].

Bispectral Index (BIS)monitoring system allows the anestheticprofessionalstoaccessprocessedEEGinformationasameasureof the effect of certain anesthetics under the care of patientstheyselecttomonitor.BISisastatisticalindicatorwhichinvolves

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amergeroftherepetitionsphere,timesphereandthehighorderof the spectral parameters. TheBIS algorithmwas attainedbydocumentingEECwavedata fromhealthypatientsundergoingevolutionperiodsbetweenunconsciousnessandconsciousnessafteradministrationofvariousimpressivemethods[6].TheBISratioisasumbetweenzero(absenteeismofbrainreaction,EEGisoelectric), and one hundred (patient attentive). A preferredquotafortheallotmentofanesthesiashouldbefrom40-60[7].

It has become a well-known fact that patients who haveexperienced awareness are reluctant to talk about it if notdirectlyasked.Interviewmethodsfordetectingexperiencesofawareness have been developed, first by Brice, et al. [8] andlatermodified by Liu, et al. [9]. Themodified Brice interviewhas beenwidely adopted and is nowused inmost studies fordetectingawareness.

Theprimarycharacteristicsofawarenessvarybetweenpublishedreports.Inastudyof26patientswithintra-operativeawareness,Moerman,etal.[10]foundthatthemostcommonformofrecallwashearingsounds,reportedby89%ofthepatients.Paralysiswas the secondmost common feeling, recalled by 85%of thestudy population, while pain was reported by 39% of thoseincluded in the study. Cobcroft and Forsdick found pain to bethe most common recollection reported by 39% of patientsexperiencingrecallinter-operatively.Recollectionofsoundswasreportedby31%ofthisstudypopulation[11].

Ghoneim,etal.studiedcasesofawarenesspublishedbetween1950and2005, andanalyzed the risk factors and causes. Twohundred and seventy-one cases of awareness were expressedand these were compared with control patients from twolarge groups of surgical patients. Themain element related tooccurrence of awarenesswas light anesthesia. Aware patientswere more prone than controls to be younger, female, andundergoing obstetrical or cardiac surgery. Thirty-eight percentofpatientsdisclosedpainduringtheepisode.Otheraccusationsincluded hearing voices (66%), feel helpless or worried (34%),andtheinabilitytomove(34%).Delayedpsychologicaldisorderswererecordedin22%ofpatients[12].

Mylesetal.conductedastudytoassessifBIS-guidedanesthesiadiminishedtheincidenceofawarenessduringsurgeryinadults.The method was a prospective, randomized, double-blind,multicenterstudy.AdultpatientswithahighriskofawarenesswererandomizedtoBIS-guidedanesthesiaorroutinecare.Thepatientswereassessedbyablindedobserverforawarenessat2-6hours,24-36hoursand30daysaftersurgery.Anon-partisancommittee blinded to group character reviewed the existenceof awareness at each reporting phase. The primary endpointwasprovedawarenessunderanesthesiaatanytime.Thestudyincluded 2,463 eligible and consenting patients, 1,225 in theBISgroupand1,238intheroutinecaregroup.Thereweretworeports of awareness in the BIS-guided group and 11 reportsin the routine care group (P=0.022). BIS-guided anesthesiadiminishedtheriskofawarenessby82%(95%CI17-98%).Theauthors concluded that BIS-controlled anesthesia diminishesthe risk of occurrence of awareness in adult surgical patientsreceivinggeneralanesthesia[13].

Objectives(1) To evaluate if the introductionof BISmonitoring in clinicalpractice for the administrationof anaesthesia reduces the riskof intra-operative awareness in surgical patients undergoinggeneral anaesthesia. (2) To examine whether BIS monitoringreduces pharmaceutical expenditure, recovery time, and end-tidal volatile anesthetic concentration in patients undergoinggeneral anaesthesia. (3) To discover the possible risks of BISmonitoringinpatientsundergoinggeneralanaesthesia.

MethodologyStudy designThisstudyisaprospective,randomized,double-blind,controlledstudy. Patients were randomized to one of two groups: BIS-guidedanesthesiaandroutinecare.Thepatientswereappraisedbyablindedviewerforawarenessat24-36hours.Aftersurgery,a blinded separate panel unaware of group identity evaluatedeachawarenessreport.

The study populationThe study groups subsisted ofmen (n=41) andwomen (n=18)older than18 years, going throughdifferent typesof electoralsurgery under general anesthesia between September andDecember,2015.

Sampling of the studyThestudysamplesubsistedof60patientsrandomizedtoeither:Group (1), n=30 patients who had BIS-monitored generalanesthesia.Group(2)n=30patientswhohadroutinecareundergeneralanesthesia.Note,onepatientwithdrewfromthestudy;thus,Group(2)isn=29patients.Responseratewas98%.

Anesthesia protocolAnesthesia system thoroughly checked (evaporator, infusionpumps,freshgasflowandintravenouslines).Thisprotocolhasbeen regulated to decrease the insecurity of intra-operativeawareness.Patientsarepre-medicatedwithmidazolam (2mg)intravenously. Anesthetic induced with fentanyl® (2 mcg/kg),propofol® (2mg/kg), and Norcuron® (rocuronium bromide) (1mg/kg)wasgiventofacilitateintubationderivedbyconservancytherapy with O2, N2O and sevoflurane® is administered. Atthe end of surgery, Atropine sulfate® (0.5 mg) is given priorto a Neostigmine Methylsulfate® injection to lessen the riskof bradycardia. Neostigmine Methylsulfate® (0.04 mg/kg) isadministeredforreversaloftheeffectofneuromuscularblockingagents (NMBA). ECG, heart rate, blood pressure, SpO2, end-tidal sevoflurane concentration, BIS value, and clinical signs ofinadequacy of deepness of anesthesia (movement, sweating,tearing, coughing, and jerking) are monitored and recorded.Bispectral index (BIS) commercialized by Covidien BIS loc 2channelsis linkedviaelectrodestothepatient'sforeheadafterpreparationoftheskinofthepatientbycleaningthepadwiththe alcohol to provide good electrical contact and a signal istranscribe from the electro-encephalographic activity of thepatient.BISvaluerangesfrom0-100.ABISvalueof(0)indicates

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EEC silence, while close to (100) is the value of a fully awakeadult.Valuesbetween40and60 indicateanadequate levelofanesthesiarecommendedbythemanufacturer.BISsignalisnearto100atthestartoftheoperationwhenthepatientisconsciousandfallstoabout50aftertheinductionstagewhenthepatientlosesconsciousness.

TheBISmonitorallowstheanesthesiologisttodetectexcessivelyhighorlowhypnosisandconsequentlytoadaptthetitrationoftheanestheticagentstoavoidunsafestates.ChangesinanestheticdeliveryareledbythepresenceofclinicalsignsinrelationtotheBISvalue.IfthepatienthashypertensionortachycardiaandtheBISvalue is>60,sevofluranelevelsare increased. IfBISvaluesareinthetargetrangeof50-60,thenfentanylisadministered.IftheBISvalueis<50,thensevofluraneisreducedandthepatientismonitored fora lackofpain relief. In thecontrolgroup, theanesthetist could change anesthesia management at his/herdiscretion,basedon thepatient's needs.BISMonitoring startsbefore anesthesia induction and lasts throughout surgery.Monitoring is discontinuedwhenpatients aredischarged fromtheoperatingroom.Anend-tidalagentmonitorisused.

Primary outcome measure Incidenceofintra-operativeawareness.

Secondary outcome measures (1) Intra-operative inhalation anesthesia consumption (2)

Intra-operative anestheticmedicationsconsumption(3)Recovery outcomes (time to eye opening, time to firstmovementresponse,timetoresponsetocommands,timetophonation,andtimetoextubation)(4)Postoperativenauseaandvomiting (PONV ) (5)PostoperativePain (6)timeuntildischargefromthePACU.

Questionnaire

Eachstudysubjectwasinterviewedatthe24-36hbyablindedobserveraftersurgery.Twoindependentendpointadjudicationcommitteeswere part of anesthesiologists and certified nurseanesthetics (CRNA), blinded to group identity, be assessedindependentlyofeachreportingawareness.

Thequestionnaire includeddemographic information includinggender, age, BMI, smoking, previous surgery, previousmedications, and chronic diseases. Interview questions forpostoperative assessment of awareness were chosen fromquestionnaires in previous studies of awareness (Appendix 1) [14-16].

Validity of the interview toolThevalidityoftheinterviewtoolwassubstantiatedbyateamoffive arbitrators (two anesthetists, two anestheticnurses and astatistician)afterallmembersoftheteamcollectivelyprovidedinputonthequestions.

Reliability of the interview toolThereliabilityofthe interviewtoolwasprovedoutrightbythereliability coefficient using the ChronbachAlpha Equation. Thereliabilitywasupto70.0%.

Study instrumentAldreteScoreisasystemformeasuringrecoveryafteranesthesia.ThenumericalrangefortheAldretescoringsystemis0to10.Twopointsarepossibleineachoffivecategories:activity,breathing,consciousness,bloodcirculationandcolor,andpulseoximetry,according to calculation. The system determines a patient'scandidacytoleavethepost-anesthesiacareunit.Apatientmustreceiveatleast9ofthe10pointsontheAldretescoringsystemtobeconsideredfordischarge[17].

Variables of the study Age,gender,smoking,ASAstatus,weight,height,BISvalue,SBP,DBP,MAP,HR,andSPO2weredeliberatedandregisteredbeforeinduction (control value), after intubation, after incision, andevery5minutesduringtheoperationuntiltheextubation(whentheoperationiscompleteandtheadhesivebandageisappliedto the surgical site, it is time for extubation which is definedas the period from this moment until the endotracheal tubeis extubated).Consumption of anesthetic agents, lacrimation,coughing,sweating,andmovementweremeasuredthroughoutthedurationofanesthesiaandsurgery,andthetimeofdischargefromthePACUwasrecorded.

Randomization and blindness Following signing of consent, patients were randomized toreceiveBIS-guidedanesthesia(BISgroup)orroutineanesthesiacare (routine care group). All other settings peri-operativepersistedconstantlybetweenthetwogroups.IntheBISgroup,the obligated anesthesiologist had continued access to BISinformation.Inthecontrolgroup,theanesthetistcouldchangeanesthesia management at his/her discretion, based on thepatient'sneeds.Postoperatively, the careproviderandpatientwereblindedtothetypeofgroupthepatientwasassignedintra-operative. Random assignment to study groups was achievedthrough envelopes containing random numbers formerlyarranged by a person who is not convoluted with any othercomponentofthestudy.

Procedure AfteracquiringendorsementfromtheInstitutionalReviewBoard(IRB) and the attainment ofwritten informed consent fromallpatients,60patientswithAmericanSocietyofAnesthesiologists[ASA]physicalstatusI-III, foreseenforvarioustypesofelectivesurgery under general anesthesia were enrolled in the study.After 3-5 minutes of preoxygenation in a 10-15° inclinedposition, anesthesia was administered at 2 μg/kg of fentayl,2 mg/kg of propofol and 1 mg/kg of Norcuron to facilitateendotracheal intubation. Anesthesia was maintained by O2,N2OandSevoflurane(1-1.5%).ECG,BP,HR,SpO2,andBISweremonitored regularly all through the surgical procedure. End-tidal seveflurane, N2O and CO2 concentration was measuredunder anesthesia. Patients received fentanyl (1microgram/kg)intravenously if there were clinical signs suggestive of a lackof depth of anesthesia, including an increase of >20% of pre-anesthetic values inHRandMAP, tearing, coughing, sweating,andmovement.Alldatawereregisteredbyaperson,whowas

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not knowledgeable of anesthesia management protocol andtechnique. BIS, HR and BP were measured and documentedat designated points during anesthesia: before induction, 30secondsafterlaryngoscopyandintubation,andevery5minutesuntilextubationofthepatient.

Sevofluraneandnitrousoxidewerestoppeduponthestartandcompletion of skin closure, respectively. Reversal of musclerelaxation by (atropine and neostigmine) was administratedduring skin closure. Patients were requested to open theireyesatone-minute intervalsafterextubation.Thetimeperiodfromtheterminationoftheinhalationalagentstoeyeopeningwas noted. All patients were interviewed 24-36 hours aftersurgerytodetermineawareness.Theprimaryendpointwastheconfirmationofawareness,asdefinedbythepatient'smemoryofintraoperativeevents,determinedbyinterview.Eachmemberof the review committees reviewed the interview results, andthe independent coded each report with "awareness" or "noawareness". Accepted awarenesswas defined as a unanimouscoding of “awareness” or two committee members codingas “awareness”. The recovery time was measured from thecompletionofwounddressingsand formostpatients includedeyeopeningandqualificationfordischarge.

Inclusion criteria for subjects in the study group (1) 18yearsofageandolder(2)Males&females(3)Elective

surgeryofdifferenttypes(4)Generalanesthesia.

Exclusion criteria for study group (1) Use of beta-blockers: Patients on beta blockers that

provide muscle relaxants during surgery, in that beta-blockersmaymaskfastheartrate,physicalmovements,orhemodynamicchanges[18](2)Patientswithtraumaticbrain injury, memory impairment, psychosis, or knownor suspected electroencephalograph abnormality (e.g.,epilepsy,previousbrainresection,orscarring).(3)Patientswithahistoryofmentaldisease(4)Uncooperativepatients(5) Patientswith languagebarrier problems (6) Patientswith a history of awareness (7) Patients with opiumaddiction(8)Patientswithneuromusculardisorders.

Statistical analysisThe statistical analyses were performed by SPSS software 21.A statistical power analysis was performed to determine thesize of study required to show that the BIS monitor reducesintra-operative awareness. We took 30 patients for eachgroup. Statistical measures calculated were: frequencies andpercentages, mean and standard deviation, Chronbach alphacoefficient,Mann-WhitneyTestofdifferencesinallquantitativevariablesunderstudyduetothegrouptype(RoutineCaregroupand BIS group), Chi Square Test of association between eachcategorical variable under study and the group type (RoutineCaregroupandBISgroup).

Ethical considerationTheethicalprinciples followedare: respect, informedconsent,charity, no harm done, truth and justice, and explanation of

researchprotocols to thepatient.Thestudy followstheWorldMedicalAssociationDeclarationofHelsinkiEthicalPrinciplesforMedicalResearchonHumans[19].Priortothecommencementofdatacollection,approvalforthisstudywasobtainedfromtheAn-NajahNationalUniversityInstitutionalReviewBoard(IRB).

To mitigate bias and ensure the confidentiality of all studyparticipants, identification numbers were assigned to eachpatienttoavoidusinganypatientinformationthatwouldidentifythepatient.Nohazardstoparticipationwereidentifiedforthisstudy.The researchersconciliatedwithallpatientsundergoingsurgerywithgeneralanaesthesiainthepreoperativeholdingareaonthedayofthescheduledsurgicalprocedure.Theresearcherselucidated theobjectivesof the study, theparticipant's role inthe study, privacy concerns, and participation as voluntary. Atthattime,allpatientswhofitthecriteriawererequestedtobeengagedinthestudy.

Results Datawere collected froma total of 59patients agedbetween18 and 72 years and enrolled in the study, with 30 patientsrandomizedto theroutinecontrolgroup(onepatientdroppedoutbywithdrawinghisconsentform)and30patientstotheBISgroup.41patientsweremaleand18patientswerefemale,andallunderwentdifferenttypesofsurgery.PatientswererandomizedintwogroupswiththeBISgroupreceivingtitratedanesthetictomaintainBISvaluesbetween40and60,whiletheconventionalgroup received anesthetic without the use of BIS monitoringduringoperation.ThemajorityofpatientswereASAI-IIIstatus.18patients (64.3%) in theRC groupand18 (62.1%) in theBISGrouphadprevioussurgeryand11(37.9%)intheRCgroupand10 (34.5%) in the BIS group have chronic diseases; 11 (37.9%)intheRCgroupand15(51.7%)weresmokers(Table1).Patientdemographicsandclinicalcharacteristicsofthetwostudygroupsare shown in Table 1. There were no significant differencesbetween the two groups in all the general characteristics ofpatients.

There is a statistically significant difference in the inspiredconcentrationoftheanestheticbetweenthetwogroupsunderstudy.FortheRCgroup,themeanvaluewas0.0282%whichwaslowerat0.024%intheBISgroup,P=0.043.Thedataalsoshowastatisticallysignificantdifferenceinthemeandoseof inhaledanesthetic agents between the two groups: for the RC group,themeanvaluewas0.029%andwas0.025%`fortheBISgroup,P=0.023.Thereisastatisticallysignificantdifferenceintheend-tidalsevofluraneconcentration:themeanvaluewas0.054forRCgroupand0.018fortheBISgroup,P=0.004.Thereisastatisticallysignificant difference in sevoflurane dosage between the twogroups:fortheRCgroupthemeanvaluewas0.028and itwas0.023fortheBISgroup,P=0.023(Table 2).ThisgenerallymeansthattheconsumptionofinhaledanesthesiawassignificantlylessintheBISgroupcomparedtotheRCgroup.Theseresultsconfirmthat usingBISmonitoring reduces consumptionof inhalationalanesthesia.

There is a statistically significant difference in the fentanyldosage between the two groups: for the BIS group, themean

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valuewas115.56,whileitwas77.76fortheRCgroup,P=0.035(Table 2).ItisclearthatpatientsintheRCgroupgotsignificantlylessamountsoffentanylintra-operativelycomparedwiththeBISgroup.Theremayhavebeeninsufficientdoses.

There is a difference in the propofol dosage between the twogroups: for theBISgroup, themeanvaluewas474.07±711.3whichwas reduced to230±59.938 for theRCgroup,P=0.235(Table 2). It is clear thatpatients in theRCgrouphada lowerpropofoldosethanpatientsintheBISgroup,butthedifferencewasnotsignificant.

There is statistically significant difference between the grouptype and intra-operative jerking with the percentage of intra-operative jerking reduced from f(%) 8(27.6%) in the RC groupto 2(6.9%) in the BIS group, P=0.037 (Table 3). There are nostatisticallysignificantdifferencesbetweenthegrouptypesandintra-operative sweating, intra-operative lacrimation, pupillarydilatation,andintra-operativecoughing(Table 3).

Regardinganesthetictime,76.6±84.3minwasrecordedintheRCgroupand124.2±124.4mininBISgroup;thedifferencewasnotsignificant (P=0.207).Thesurgicaltimewas73.8±85.8minintheRCgroupand116.4±106.2minintheBISgroup,andthedifference was not significant (P=0.194).There is a statisticallysignificantdifferenceintimetophonationbetweenthetwostudygroupswiththemeantimetophonationoftheRCgroupat12.82minandfortheBISgroupequalto10.21minutes,P=0.026(Table 4).Therearenostatisticallysignificantdifferencesbetweenthetwostudygroupsinanyoftheremainingtimemeasuresunderstudythatare:timefromcessationofinhalationalagentstoeyeopening, time to response to commands, time to eyeopening(eitherspontaneouslyorinresponsetocommand),timetofirstmovementresponse,andtimetoextubation(Table 4).

Therearestatisticallysignificantdifferencesinperceptionofpainbetweenstudygroups.25%ofpatientsintheRCgroupexpressedmildlevelsofpainwhile0%intheBISgroupdid.ThishappenedbecausetheBISgrouphadmildpainlessthanexpected(count=0

andtheexpectedcount=3.4),whiletheRCgrouphadmildpainmorethanexpected(count=7andtheexpectedcount=3.6).Ontheotherhand,7.1%oftheRCgroupexpressedmoderatelevelsofpain,while23.1%oftheBISgrouphadmoderatelevelsofpain.ThishappenedbecausetheBISgrouphadmoderatepainmorethan expected (count=6 and expected count=3.9), while theRC grouphadmoderatepain less thanexpected (count=2 andexpectedcount=4.1),P=0.011(Table 5).

There is a statistically significant difference in the time todischarge from the PACU between the two study groups: themeantimetodischarge fromthePACUwas12.38minutes fortheRCgroupand9.23minutesfortheBISgroup,P=0.007(Table 6).ItisevidentthatthepatientsintheBISgroupweredischargedfromPACUearlier thanpatients in theRCgroup.Therearenostatistically significant differences in all other variables beingstudied,suchasrecoverytimeandAldreteScore(Table 6).

There is a statistically significant difference between the twostudygroupsinthepreoperationrespiratoryrate(RR).ThepreoperationRRperminfortheBISgrouphadameanvalueof15.13±2.013andforRCgroup13.93±2.071min,P=0.033.ValuesofPre-OperativeRRsforbothgroupsarewithinthenormalrange,sothereisnoclinicalimportancetothisdifference.Therearenostatisticallysignificantdifferencesbetweenthetwogroupsinthevariables:SAT,CO2,HR,SBP,DBP,MAPPreandPostoperation(Table 7).

There are statistically significant differences between the BISand Routine Care groups in SAT at the following time pointsduring operations: 35 min. (Routine Care mean=98.32%,BIS mean=99.08%), 40 min. (Routine Care mean=98.21, BISmean=98.96%), 45 min. (Routine Care mean=98.11, BISmean=99.05%), 50 min. (Routine Care mean=98.32, BISmean=99.10), but this data has no clinical relevance becauseall values are within the normal range. There are statisticallysignificant differences between the two study groups in SBPduringoperationatthefollowingtimepoints:50min.(Routine

Variable Routine Care group N=29 BIS group N=30 P-valueMeanAge 41.11±18.892 43.34±16.363 0.571

MeanWeight 77.17±17.994 75.79±14.369 0.889MeanHeight 170.25±7.347 169.97±8.695 0.955

PatientMetabolicIndex 26.62±4.70 26.14±4.00 0.690Gender-male 20(69%) 21(70%) 0.931Gender-female 9(31%) 9(30%)

Previoussurgery-Yes 18(64.3%) 18(62.1%) 0.862Previoussurgery-No 10(35.7%) 11(37.9%)

Previousmedication-Yes 6(22.2%) 5(17.2%) 0.639Previousmedication-No 21(77.8%) 24(82.8%)

Smoking-Yes 11(37.9%) 15(51.7%) 0.291Smoking-No 18(62.1%) 14(48.3%)

Chronicdiseases-Yes 11(37.9%) 10(34.5%) 0.785Chronicdiseases-No 18(62.1%) 19(65.5%)

*Significantat0.05level.DataareMean±SDwithP-valuesderivedfromMann-WhitneyUtestorFrequenciesandPercentages(%)withP-valuesderivedfromChiSquaretest.

Table 1 Comparisonofdemographicvariablesandclinicalcharacteristicsbetweenstudygroups(RoutineCareandBIS).

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Care mean=109 mmHg, BIS mean=128.45 mmHg), 55 min.(Routine Caremean=103.75mmHg, BISmean=122.25mmHg),60min. (Routine Caremean=100.08mmHg, BISmean=126.29mmHg),but,again,thisresulthasnoclinicalrelevancesinceallvaluesareinthenormalrangeforbothgroups(Table 8).

There are statistically significant differences between the twostudygroups(BISandRoutineCare)inDBPduringoperationatthe following time points: 50 min. (Routine Care mean=61.18mmHg, BIS mean=76), 55 min. (Routine Care mean=62.33mmHg,BISmean=72.68mmHg).Again,thisresulthasnoclinicalrelevancesinceallvaluesareinthenormalrangeforbothgroups(Table 8).

There are statistically significant differences between the twostudy groups inMAP during operation at the 90minute timepoint(RoutineCaremean=77.56mmHg,BISmean=92.57mmHg).Finally,therewerenostatisticallysignificantdifferencesbetweenthe two study groups for all other variables of blood pressureandtimepoints,aswemeasuredbloodpressureevery5minutesintra-operatively(Table 8).

Ofthetotal59patients29patientswereassignedtotheroutinecontrol group and 30 patients to the BIS group. No case of

awareness was reported in the BIS-guided group but 4 reports(13.8%) in the control group (P=0.035), BIS-guided anesthesiadecreasedawarenessby13.8%(95%CI(1.3%-26.4%)(Table 9).Themostcommonformsofawarenesswasauditoryperceptions,tactileperception and the sense of paralysis. Patients with awarenessof the RC group, two patients undergoing cholecystectomy, onepatientundergoingstrabismussurgeryandonepatientundergoingSubmucosalResectionofthenose(SMR).

Table 10 shows that there are no statistically significantassociationatthesignificancelevelα=0.05betweenawarenessmeasurementandgender,surgicaltimeandagecategories(allP-Values>0.05).

Figure 1showsariseinSATlevelsfortheRCgroupovertheSATlevelsfortheBISgroupafter60minutesofoperationduration.Thedifferencesweresignificantonlyattheminutes35,40,45,and50infavoroftheBISgroup.Thisresulthasnoclinicalrelevancesinceallvaluesareinthenormalrangeforbothgroups.

Figure 2 exhibits that end-tidal CO2 parameters do not differbetweenthetwostudygroupsoverdurationofoperation.Therewerenosignificantdifferencesbetweeneachtwocorrespondingpoints.

Induction Agent Routine Care group N=29 BIS group N=30 P-valuePropofolmg 230±59.938 474.07±711.3 0.235

Midazolammg 1.17±0.408 1.5±1 0.648Fentanyl(µg) 77.76±40.523 115.56±94.18 0.035*

InspiredconcentrationoftheSevoflurane% 0.028±0.007(0.011-0.04)

0.024±0.013(0.0-0.07) 0.043*

Meandoseofi.v.anestheticagent(mg) 221.07±56.197 260.67±243.678 0.936

Meandoseofinhaledanestheticagents 0.029±0.008(0.012-0.04)

0.025±0.009(0.01-0.035) 0.023*

End-tidalsevofluraneconcentration% 0.054±0.166(0.008-0.9)

0.018±0.012(0.006-0.06) 0.004*

*Significantat0.05level.DataareMean±SDwithP-valuesderivedfromMann-WhitneyUtestorFrequenciesandPercentages(%)withP-valuesderivedfromChiSquaretest.

Table 2 Comparisonofinductionagentlevelsbetweenstudygroups(RoutineCareandBIS).

Variable Categories Routine Care group N=29 BIS group N=30 P-valueIntra-operativeSweating No 29(100%) 26(96.3%) 0.296

Yes 0(0%) 1(3.7%)Missing 0 3

Intra-operativelacrimation No 24(85.7%) 25(89.3%) 0.686Yes 4(14.3%) 3(10.7%)

Missing 1 2PupillaryDilatation No 27(96.4%) 26(92.9%) 0.553

Yes 1(3.6%) 2(7.1%)Missing 1 2

Intra-operativeCoughing No 28(96.6%) 29(100%) 0.313Yes 1(3.4%) 0(0%)

Missing 0 1Intra-operativeJerking No 21(72.4%) 27(93.1%) 0.037*

Yes 8(27.6%) 2(6.9%)Missing 0 1

*Significantat0.05level.DataareFrequenciesandPercentages(%)withP-valuesderivedfromChiSquaretest.

Table 3 Differencebetweenintra-operativephysiologicalvariablesbetweenstudygroups(RoutineCareandBIS).

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Variable Routine Care group N=29 M( ± SD) BIS group N=30 P-valueTimeofsurgery(minutes) 73.8±85.8 116.4±106.2 0.194

LengthofProcedure(minutes)Anesthesiatime 76.6±84.3 124.2±124.4 0.207

Timefromcessationofinhalationalagentstoeyeopening(minutes) 7.32±4.643 5.19±3.462 0.087

Timetoresponsetocommands(minutes) 10.03±5.335 8.11±4.516 0.205Timetoeyeopening(eitherspontaneouslyorin

responsetocommand)(minutes) 10.81±5.955 8.24±4.833 0.086

Timetofirstmovementresponse(minutes) 7.69±6.03 5.31±3.878 0.174Timetophonation(minutes) 12.82±6.11 10.21±5.127 0.026*Timetoextubation(minutes) 8.64±4.775 7.25±4.106 0.278

*Significantat0.05level.DataareMean±SDwithP-valuesderivedfromMann-WhitneyUtest.

Table 4 Differencesinanesthesiamanagementtimevariablesbetweenstudygroups(RoutineCareandBIS).

Variable Categories Routine Care group N=29 F(%) BIS group N=30 F(%) P-value

Nausea(yes/no)Nonausea 29(100%) 26(100%)

-----Missing 0 4

Pain 0(no pain) 1-3(Mild)

4-6(Moderate) 7-8(Severe)

9(Very Severe) 10(Worse Possible)

NoPain 19(67.9%) 20(76.9%)

0.011*

Mild 7(25%) 0(0%)

Moderate 2(7.1%) 6(23.1%)

Severe 0(0%) 0(0%)

VerySevere 0(0%) 0(0%)

WorsePossible 0(0%) 0(0%)

Missing 1 4

*Significantat0.05level.DataareFrequenciesandPercentages(%)withP-valuesderivedfromChiSquaretest.

Table 5 Differencesinnauseaandpainbetweenstudygroups(RoutineCaregroupandBISgroup).

Variable Routine Care group N=29 Mean ± S.D BIS group N=30 Mean ± S.D P-valueRecoverytime(minutes) 11.64±5.09 9.95±4.261 0.210

DischargeCriteriaScoreAldreteScore 9.72±0.75 9.7±1.67 0.185TimetoDischargefromthePACU(minutes) 12.38±4.989(6-26) 9.23±3.819(4-20) 0.007*

*Significantat0.05level.DataareMean±SDand(Minimum-Maximum)withP-valuesderivedfromMann-WhitneyUtest.

Table 6 DifferencesinRecoverytime,DischargeCriteriaScore,TimetoDischargefromthePACUbetweenStudyGroups(RoutineCaregroupandBISgroup).

Figure 3 shows thatHR levelsdonotdifferbetweenthestudygroupsthroughthedurationoftheoperation,exceptatthefinaltimerange(100min.andafterward),butitisnotsignificant.Therewerenosignificantdifferencesbetweeneachtwocorrespondingpoints.

Figure 4exhibitsthatthedifference inSBP levelsforthestudygroups does not differ through the duration of the operation.Thedifferencesweresignificantonlyattheminutes50,55,and60,P˂0.05 in favorof theBISgroup.This resulthasnoclinicalrelevancesinceallvaluesareinthenormalrangeforbothgroups.

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Figure 5exhibitsdifferencesinDBPlevelsforthestudygroups,withtheDBPoftheBISgrouphigherthanfortheRCgroupatthe50and55minutetimeframes.Thedifferencesweresignificantonlyattheminutes50and55,P˂0.05infavoroftheBISgroup.This result has no clinical relevance since all values are in thenormalrangeforbothgroups.

Figure 6 shows differences in MAP for the study groups. Thedifferences were significant only at the minute 50, P˂0.05 infavoroftheBISgroup.Thisresulthasnoclinicalrelevancesinceallvaluesareinthenormalrangeforbothgroups.

DiscussionBISmonitoring has been introduced to the operating room toreduce the incidence of awareness, improve anesthesiologistabilitytoadministeranestheticsandimproveoutcomesinearlydischarge from the recovery room.Of the total59patients29patients were assigned to the routine control group and 30patients to theBISgroup.Nocaseofawarenesswas reported inthe BIS-guided group but 4 reports (13.8%) in the control group(P=0.035), BIS-guided anesthesia decreased awareness by 13.8%(95%CI(1.3%-26.4%).Themostcommonformsofawarenesswasauditoryperceptions,tactileperceptionandthesenseofparalysis.

BIS-guided Anesthesia can Reduce the Risk of Intra-operative Awareness Wehave found thatBIS-guidedanesthesia can reduce the riskof intra-operativeawareness in surgicalpatients.Weobserveda statistically significant difference in occurrenceof awareness

between patients undergoing routine care during surgery (4outof29,13.8%)andpatientsmonitoredbyaBISdeviceduringsurgery (0 out of 30, 0%) (P=0.035). BIS-guided anesthesiadecreased awareness by 13.8% (95% CI (1.3%-26.4%). Theseresultsareinagreementwithpreviousfindings[13,20].

Theresultsof thecurrentstudyareconsistentwith theearlierfindings of Chen et al. showed that the use of the BIS-guidedanesthesiasignificantlyreducedtheincidenceofawarenessfrom0.65%to0.14%whencomparedwiththecontrolgroup[21].

The risk of intra-operative awareness varies from country tocountry, depending on the anesthetic methods. Our studyis consistentwith a studyof Sebel, et al. from theUSwhichshowedthatanincidenceofintra-operativeawarenessofabout0.1% to 0.2% of patients undergoing general anesthesia [22].Our study isalso in linewitha study fromEurope thata largeprospectivestudyconductedbySamuelssonetal.whoexploredawareness of 11,785 patients undergoing general anesthesia.The incidence of intra-operative awarenesswith explicit recallwas 0.1% without the use of neuromuscular blocking drugs.Whentheyusedneuromuscularblockingdrugs,awarenesswas0.18%)[23].OurstudyalsoagreeswithanotherEuropeanstudybyLiuetal. thatreportedincidenceofrecallof intra-operativeeventsanddreamsduringnon-obstetricoperations,whichwas0.2%and0.9%respectively[9].

The results of the present study also agreewith Ekman et al.who reported that fewer patients in the BIS-monitored grouphad significant explicit recall compared to a control group(0.04% compared with 0.18%, P<0.038). This represents a

Parameter Routine Care group N=29 M ± SD BIS group N=30 M ± SD P-valueIntra-operativeSAT(SPO2)% 98.52±1.01 98.7±1.35 0.249

Intra-operativeEnd-tidalCO2(mmHg) 33.88±4.34 33.86±3.66 0.739Intra-operativeHR(beat/min) 78.77±12.37 77.25±13.27 0.544Intra-operativeSBP(mmHg) 112.64±19.13 116.91±21.82 0.458Intra-operativeDBP(mmHg) 69.9±16.15 70.2±13.39 0.779Intra-operativeMAP(mmHg) 83.38±14.79 84.87±14.86 0.514PreOperationHR(beat/min) 81.03±15.873 88.17±21.28 0.395

PreOperationSystolicBloodPressure(mmHg) 142.14±27.601 142.5±28.137 0.891

PreOperationDiastolicBloodPressure(mmHg) 87.28±20.32 86±16.233 0.976

PreOperationO2SAT% 98.48±2.011 99±1.857 0.330PreOperationRR(breath/min) 13.93±2.071 15.13±2.013 0.033*

PreOperationTEMP(°C) 36.643±0.2026 36.663±0.2883 0.514PostOperationHR(beat/min) 78.58±17.948 89.67±26.192 0.155

PostOperationSystolicBloodPressure(mmHg) 132.79±25.518 135.62±20.812 0.665

PostOperationDiastolicBloodPressuremmHg 86.53±17.36 84.62±16.963 0.776

PostOperationO2SAT(%) 99.05±1.682 99.19±1.078 0.755PostOperationRR(breath/min) 14.68±1.916 15±1.581 0.525

PostOperationTEMP(°C) 36.195±1.2782 36.455±0.4522 0.221

*Significantat0.05level.DataareMean±SDwithP-valuesderivedfromMann-WhitneyUtest.

Table 7 Differencesofanesthesiamanagementparameters(SAT,CO2,HR,SBP,DBP,MAPandPreandPostOperationParameters)betweenstudygroups(RoutineCareandBIS).

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reduction in the incidence of intraoperative awareness in theBIS-monitoredgroupby77%.Theauthorexplainedthat itmaybebecausethepatientswerekeptinadeepanestheticstate,andanesthesiologistsweretoldtoavoidBISvaluesabove60duringinduction and maintenance. The results showed that duringthemaintenance phase, the average BIS scorewas 38 (SD 8).AccordingtoBISmonitoringguidelines fromthemanufacturer,values below 40 indicate a deep hypnotic state, which is notrecommendedforsurgicalprocedures[20].

OurresultsarealsoinlinewithasystematicreviewconductedbyPunjasawadwongwhichprovidessufficientevidencetosupporttheuseofBIS-monitoringtoguideanesthesiaadministrationandtoprevent intra-operativeawareness [24].Alsoour resultsareconfirmedbythefindingsofSandinetal.whoreportedareducedriskofawarenessof13%overacontrolgroupwhenBISmonitoringwas used during general anesthesia [25]. The results of the

currentstudyareinaccordancewiththeB-AwaretrialconductedbyMyles, et al., a multicenter, double-blind, randomized trialthat evaluated the effectiveness of BISmonitoring in reducingawareness.Myles’studyreportedanawarenessriskreductionof82%whenBISmonitoringwasused[13].

TheresultsofthecurrentstudyarealsoconsistentwiththestudyofBergmanetal.,whichshowedthatof8,372patients,reportedincidentswere50casesofdefiniteawarenessand31casesofahighprobabilityawareness.Eachgroupwas furthersubdividedintoincidentswithnoapparentcauseofpreventableawareness,incidents with a clearly documented cause of awareness andincidentscausedbymedicationerrors.Therewere13cases(16%)withnoapparentcause.In36cases(44.5%),incidentswereduetoalowvolatileinspiredconcentrationorinsufficienthypnosis,and in32cases (39.5%), theeventwasdue to thedrug's fault[26].

Parameters at Specific Time Points-Minutes Routine Care group N=29 M ±SD BIS group N=30 M ±SD P-valueSAT_35(%) 98.32±1.145 99.08±1.1 0.014*SAT_40% 98.21±1.285 98.96±1.186 0.030*SAT_45% 98.11±1.823 99.05±1.046 0.046*SAT_50% 98.32±1.293 99.1±1.513 0.010*

SBP_50(mmHg) 109±28.08 128.45±25.482 0.016*SBP_55(mmHg) 103.75±20.722 122.25±27.34 0.028*SBP_60(mmHg) 100.08±28.268 126.29±32.031 0.034*DBP_50mmHg 61.18±15.593 76±15.922 0.008*DBP_55(mmHg) 62.33±15.656 72.68±16.62 0.039*MAP_50(mmHg) 77.56±17.494 92.57±19.836 0.012*

*Significantat0.05level.DataareMean±SDwithP-valuesderivedfromMann-WhitneyUtest.

Table 8 Differencesinanesthesiamanagementparameters(SAT,CO2,HR,SBP,DBPandMAP)acrosstimeforroutinecareandBISstudygroups.

Variable/CategoryGroup

P-valueRoutine Care (n=29) f(%) BIS (n=30) f(%)

IncidenceofAwarenessNo(n=55) 25(86.2%) 100(96.7%)

0.0.035*Yes(n=4) 4(13.8%)* 0(0%)*

*Significantat0.05level.DataareFrequenciesandPercentages(%)withP-valuesderivedfromChiSquaretest.

Table 9 Associationbetweenawarenessandstudygroup(RoutineCareandBIS).

Variable/CategoryAwareness

P-valueNo Yes

GenderMale(n=41) 39(95.1%) 2(4.9%)

0.578Female(n=18) 16(88.9%) 2(11.1%)

SurgicalTime

0-30minutes(n=10) 10(100%) 0(0%)

0.67531-60minutes(n=23) 20(87%) 3(13%)61-90minutes(n=10) 10(100%) 0(0%)

morethan90minutes(n=16) 15(93.8%) 1(6.3%)

AgeCategories

lessthan20(n=7) 5(71.4%) 2(28.6%)

0.235

20-29(n=7) 7(100%) 0(0%)30-39(n=14) 12(85.7%) 2(14.3%)40-49(n=6) 6(100%) 0(0%)50-59(n=14) 14(100%) 0(0%)60-69(n=7) 7(100%) 0(0%)

70ormore(n=2) 2(100%) 0(0%)

Table 10 showsfrequency,percentagesandtheP-valuesoftheChiSquaretestofassociationbetweenawarenessmeasurementandgender,surgicaltimeandagecategories.

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Ti m e ( M i n u t e )

Routine Care group BIS group

0 5 10 15 20 25 30 35 40 45 50 55 60 65 7 75 80 85 90 95 100 105 110 115 120

Distribution of SAT Mean Values on Time1 0 0 . 0 0

9 9 . 5 0

9 9 . 0 0

9 8 . 5 0

9 8 . 0 0

9 7 . 5 0

9 7 . 0 0

9 6 . 5 0

9 6 . 0 0

9 5 . 5 0

SAT

Mea

n Va

lues

DistributionofSATmeanvaluesontime.Figure 1

Ti m e ( M i n u t e )

Routine Care group BIS group

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 110 115 120

Distribution of CO2 Mean Values on Time3 8 . 0 0

3 7 . 0 0

3 6 . 0 0

3 5 . 0 0

3 3 . 0 0

3 2 . 0 0

3 1 . 0 0

3 0 . 0 0

2 9 . 0 0

2 8 . 0 0

CO

2 M

ean

Valu

es

DistributionofCO2meanvaluesontime.Figure 2

Ti m e ( M i n u t e )

Routine Care group BIS group

0 5 10 15 20 25 30 35 40 45 50 55 60 65 7 75 80 85 90 95 100 105 110 115 120

Distribution of HR Mean Values on Time1 0 0 . 0 0

9 0 . 0 0

8 0 . 0 0

7 0 . 0 0

6 0 . 0 0

5 0 . 0 0

4 0 . 0 0

3 0 . 0 0

2 0 . 0 0

1 0 . 0 0

0 . 0 0

HR

Mea

n Va

lues

DistributionofHRmeanvaluesontime.Figure 3

Ti m e ( M i n u t e )

Routine Care group BIS group

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 110 115 120

1 4 0 . 0 0

1 2 0 . 0 0

1 0 0 . 0 0

8 0 . 0 0

6 0 . 0 0

4 0 . 0 0

2 0 . 0 0

0 . 0 0

Distribution of SBP Mean Values on Time

SBP

Mea

n Va

lues

DistributionofSBPmeanvaluesontime.Figure 4

T i m e ( M i n u t e ) Distribution of DBP Mean Values on Time8 0 . 0 0

7 0 . 0 0

6 0 . 0 0

5 0 . 0 0

4 0 . 0 0

3 0 . 0 0

2 0 . 0 0

1 0 . 0 0

0 . 0 0

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 110 115 120

T i m e ( M i n u t e )Routine Care group BIS group

DB

P M

ean

Valu

es

DistributionofDBPmeanvaluesontime.Figure 5

Ti m e ( M i n u t e )

Routine Care group BIS group

0 5 10 15 20 25 30 35 40 45 50 55 60 65 7 75 80 85 90 95 100 105 110 115 120

Distribution of MAP Mean Values on Time1 0 0 . 0 0

9 0 . 0 0

8 0 . 0 0

7 0 . 0 0

6 0 . 0 0

5 0 . 0 0

4 0 . 0 0

3 0 . 0 0

2 0 . 0 0

1 0 . 0 0

0 . 0 0

MA

P M

ean

Valu

es

DistributionofMAPmeanvaluesontime.Figure 6

Results of the current study do not agree with the study ofMozafari et al., who showed no evidence that BISmonitoringreduced awareness in patients undergoing abdominal surgeryunder general anesthesia compared to patients monitored by

routine anesthesia administration protocols [27]. Avidan et al.comparedaBIS-basedanesthesiaadministrationprotocolandaprotocolbasedonmeasurementofendtidalanestheticgas(ETA)and investigated reduction of anesthesia consciousness. They

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foundthatanesthesiaconsciousnesswassimilarbetweenbothgroups[28].

Respectively,ourstudydoesnotagreewithastudyfromSaudiArabiacarriedoutbyMessahelandAl-Qahtani,whichexaminedthe incidence of intra-operative awareness of 4,368 patientswho underwent surgery. In this study, all patients were givena premedication. This study reported no incidence of intra-operativeawareness[29].

Authors of the current study suggest that examining theanesthetic technique is important to understand the cause ofawarenessduringanesthesia.Patientsintheroutinecaregroupweregivenasmalleramountofpropofolthatproduceshypnosis,anda smalleramountof fentanyl to relievepainandsuppressmotion than patients in the BIS group. Thismay be the causeofthepatients intheroutinecaregrouphavingawarenessbutnotintheBISgroupinthecurrentstudy.Thissuggeststhatthepatientcanbeexposedtolightanesthesia.Whenanesthesia istoolight, itcanleadtorecalleventsorconversationsthattakeplace in the operating room. The cause is not clear. On theotherhand,monitoringthedepthofanesthesiausingBISshouldprevent intra-operative awareness and contribute to a precisedoseofanesthetic.

Inhalational Anesthetic Agent ConsumptionThe depth of anesthesia is measured by clinical parametersduring anesthesia (for example, blood pressure, heart rate, ordrug concentrations). These parameters become unreliablefor measuring depth of anesthesia over the term of titrationof anesthetic agents [30]. Monitoring of inhalation anestheticconcentration by observing minimum alveolar concentrationis part of routine anesthesia practice. It provides a methodfor monitoring the continuous brain concentration of volatileanesthetics. The BIS Index is a numerically treated, clinicallyvalidatedEEGparameterthatmeasurestheeffectsofanesthesiaandsedationonthebrain [31].Accordingto themanufacturerof the BIS, this monitoring function provides a vital tool thatallowsclinicianstodeliveranesthesiaappropriatetoapatient’sneeds,andtoassessandreactappropriatelytoapatient'sclinicalconditionduringsurgery.Overall, itcanbehelpfultomaintainsufficientdepthofanesthesia.

Our study showed a statistically significant reduction in themean dose of inhaled anesthetics when using BIS monitoringas compared with routine care and anesthesia monitoringprotocols.We also found a statistically significant reduction inend-tidalsevofluraneconcentrationwhenusingBISmonitoringascomparedwithroutinecareandanesthesiamonitoringprotocols.OurresultsareinagreementwithstudiesbyPunjasawadwong,et al.who showed that BIS-guided anesthesia can significantlyreduce anesthetic consumption [24] andwith Croci et al.whoshowed that BIS monitoring in women undergoing generalanesthesia for gynecological laparascopic surgery reduceddesflurane consumption by 34.6% [32].Our study shows thattheconsumptionof inhaledanesthesiawassignificantly less in

theBISgroupcomparedtotheRCgroup.Theseresultsconfirmthat usingBISmonitoring reduces consumptionof inhalationalanesthesia.

Anesthetic Drugs ConsumptionOur results showed a significant increase in fentanyl dose inthe BIS group as comparedwith the RC group and anesthesiamonitoringprotocols.Ourresultswerenotconsistentwithotherstudies[33-36].

Alkire, et al. showed that consumption of propofol duringinduction was significantly lower when using BIS monitoringas comparedwith routine care during general anesthesia.Ourresults are not consistentwith this study [37]. Our data showthat theconsumptionofpropofol for inductiondoesnotdiffersignificantlybetweenBISmonitoringandroutinecare.However,we observed that patients in the BIS group consumed morepropofolthanpatientsintheroutinecaregroup(Table 2).

Driessenetal.studiedtheapplicationofabalancedanesthesia(propofol,alfentanil,andN2O)underBISmonitoringandroutinecareandfoundthatpropofolconsumptionwaslowerintheBISgroup compared to the routine group [38]. Yili-Hankala et al.comparedpropofolandsevofluraneunderBISandroutinecareprotocols and found less consumption of both propofol andsevoflurane in the BIS monitored group. These studies showthat BIS monitoring is helpful for lowering the consumptionofpropofolduringanesthesia [39]which isnotthecase inourstudy.Friedbergetal.foundthatBISindexmonitoringdecreasedpropofolconsumptionby20%ascomparedtoroutinecare[40].Our results show increased the consumption of propofol andfentanylintheBISgroup,whichisnotconsistentwiththestudybyMunozGarciaetal.,whomentionsthatBISmonitoringallowsfor reduced consumptionofpropofol, fentanyl andmidazolam[41]. It isobvious thatpatients in the routinecaregrouphavebeen given a lesser amount of propofol and lesser amount offentanylthanpatientsintheBISGroup.Thishasledtoperforminglightanesthesiaandthismaybethecauseofthepatientsintheroutine care group having had more awareness than the BISgroupinthecurrentstudy.

Somatic Response and Clinical Signs of AwarenessLossofsomaticresponseduetopainfulstimuliisdefinedasnopurposefulmovement(twistingorjerkingofthehead,twitchingorgrimacing). Inourstudy,wefoundnosignificantdifferencesin somatic responses of sweating, tearing, pupil dilation andcoughing between BIS-monitored and routine care patients.Wedidnotea significant reduction in intra-operational jerkingbetweentheBIS-monitoredandroutinecarepatients.ThatBISishighlyusefultopreventpainfulstimuliandmaintaincompletelossofsomaticresponsetoanociceptivestimulus.

Time to ExtubationResults of this study show no significant difference in time toextubationbetweentheBIS-monitoredandroutinecaregroups.This observation is not consistent with previous studies that

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showedthatBISmonitoring isassociatedwithreducedtimetoextubation. Alkire et al. showed that time to extubation wassignificantly shorter under BIS monitoring than under routinecare [37]. Similar results were found by the following studies[35,39,42-44].OurresultsareconsistentwiththestudyofSadaqaetal.thatshowednosignificantdifferenceintimetoextubationofBISmonitoringandroutinecaregroupsinarandomizedcontrolstudyusingBispectralindexmonitoringduringcardiopulmonarybypasssurgery[45].

The Recovery TimeInourstudy,wehavebeenabletoreducetimetoeyeopeningbut thedifferencewasnot significantexcept in relation to thetimeofphonation(Table 4).Therefore,theresultsofthecurrentstudyarecongruentwithotherstudieswhichhaveshownthatBISmonitoringhad littleeffecton thetimeneeded to recoverfrom anesthesia, measured by eye opening [16,25]. Also, theresultsofthecurrentstudyareconsistentwiththoseshownbyLovemanetal.whostudiedcontrolledinfusionofpropofolandremifentanilunderBISmonitoringinneurosurgerypatientsandfoundthattheBISmonitoringdidnotimpactrecoverytime[46].

In contrast, in a systematic review study of Punjasawadwonget al. showed that regardless of the anesthetic used, BIS-guided anesthesia reduced all components of early recoverytimes,whichisthetimetoopeneyes,inresponsetothevoicecommand,extubationandorientation[24].WedonotalsoagreewiththestudyconductedbyKruereretal.whofoundthatthetimetoopeneyes,extubationandarrivaltoPostAnestheticCareUnit (PACU) significantly reduced by using the BIS monitoring[33]. Additionally, our results are not consistent with thoseofDagtekin et al.who reported that BISmonitoring facilitatesstablehemodynamicsandprovidesexcellentrecoverytimesforneuro-surgicalpatientsunderTotalIntravenousAnesthesia(TIVA[47].Theauthorsproposealimitationofthecurrentstudyisthetotalnumberofparticipants59,andmoststudiesof theBIS isperformedwithalargernumberofparticipants.Theremaybeasmallsamplesizehasaffectedthefindings.

Time to Discharge from PACU and Postoperative SymptomsWefoundasignificantreduction intimetodischargefromthePACUforBIS-monitoredpatientsascomparedtopatientsintheroutine care group. This result is consistent with the study ofPunjasawadwongetal.andRecartetal.,whichshowedthatBISmonitoringwasassociatedwithshorteneddurationinthePACU[44,48].

Ganetal.andSongetal.suggestthatcerebralmonitoringcanbeusefultoimprovethetitrationoftheanesthetic,which,inturn,leads toa faster recovery fromanesthesia [35,36]. Incontrast,previously-mentionedstudiesbyDroveretal.andRecartetal.didnotfindsignificantdifferences in lengthofstay inPACUorrecoverytimebetweenBIS-monitoredandroutinecarepatients[44,49].

Pavlin showed no impact of BIS-guided anesthesia on time tohome readiness after ambulatory surgery, despite a decline inPACU stay. They report that factors other than those relatedto anesthesia or surgery may have affected time of dismissalafter ambulatory surgery. These included fatigue, nausea andvomiting,pain,andlackofimmediateaccesstoanescort[50].

Ofnote,inourstudy,themildlevelofpain(25%)intheRCgroupascomparedwith0%fortheBISgroupmaybeassociatedwiththelowerdoseoffentanylusedforpainreliefintheRCgroupascomparedtotheBISGroup.

Theauthorssuggestthatitispossiblethatpainwasariskfactorthat led to the patients in the RC group taking longer to bereleasedfromthePACUthanthoseintheBISgroup.Tocomparetheresultsofthisstudywithpreviousstudiesofnausea,inthecurrent study, four patients in the BIS group complained ofnauseaaftersurgeryand0patientscomplainedofnauseaintheRCgroup.ThisresultisnotconsistentwithresultsfromCrocietal., which showed that the Bispectral Index-guided anesthesiacan reducepostoperativenauseaandvomiting [32].Ofnote isthatthenauseahadnoeffectonthetimeofdischargeofpatientsintheBISgroupfromthePACU.

Hemodynamic ParametersThisstudyshowedsignificantdifferences inSBP,DBPandMAPat different points of operation between the BIS-monitoredgroupandtheroutinecaregroup(Table 7).Ourresultsconfirmthe findings from Mozafari et al. who found that changes inhemodynamicparameterswerenotdependenton the typeofmonitoringtechnologyduringabdominalsurgery[27].OurresultsalsoagreewithPayneetal.whoreportedthatthehemodynamicresponsesduring surgerydonotdecreasewithBISmonitoring[51].TheauthorssuggestthatsignificantdifferencesinSBP,DBPandMAPatdifferentpointsofoperationbetweentheBISandroutinecaregroupwerenotclinicallyrelevant.

Awareness and Gender, Surgical Time and Age Thisstudyshowednostatisticallysignificantassociationbetweenawareness measurement and gender, surgical time and age.TheseresultsareinlinewithSebeletal.whoshowedthatageand gender did not affect the incidence of awareness [52]. Inthe contrary, a study of Katoh et al. found that age stronglyaffectedBISpoints.AthighervaluesofBIS,elderlysubjectshadhigherprobabilitiesofresponsecomparedtoyoungerpatients.Conversely,at lowervaluesofBIS,elderlypatientshadalowerprobability of response [53]. However, our findings are notconsistent with those found by Ghoneim, et al. who reportedthat conscious patientswere likely to be younger andwomen[12]. The authors proposed that, the limitation of the currentstudywitha small sample size that containsdifferent typesofsurgery that failed todetect therelationshipbetweenage,sexandtimeofsurgerywithawareness.Furtherresearchisneededwith a larger sample size that includes the general population

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of surgicalpatientsundergoingvarious typesof surgeryduringgeneralanesthesia.

ConclusionBIS-guided anesthesia (BIS kept at 40-60) reduced the risk ofawareness compared to routine care. The main reason forawareness of the RC group can considered a light generalanesthetic. In addition, BIS monitoring reduces the usage ofvolatileanesthesiaconsumptionandthetimeofdischargefromthePostAnestheticCareUnit.

Implications of BIS Monitoring for Anesthesia NursesUseofBISmonitoringisnotverypopularinalargernumberofanesthesia departments (AD) in our country, even though themajorityof anesthesiologists andanesthesianursesworking inAD are aware of the availability and function of BISmonitors.It is important that knowledge about improved anesthesiamanagement be moved into the AD setting. BIS monitoringbooststhequalityofpatientcareandshouldbeanelementofthestandardizedclinicalpracticeinoperatingroomsettings.

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Appendix I Interview Questions

Interview Questions Q1) Do you dream or have any other experiences while you were sleeping? Q2) What was the worst thing about your surgery? Q3) What was the next worse? Q4) Do you remember anything in between?(before you went to sleep, when you woke up)? Q5) What was the most unpleasant thing you remember from your operation and anesthesia? Q6) Could you alert anyone during surgery? Q7) Did you have any recall while surgery was being done? Q8) Were you feeling surgical instruments or dressing application? Q9) Were you hearing vague sounds? Q10) Have you felt an inability to move and feelings such as helplessness, or a sensation of weakness.