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T.SAKAI，H. SINGH，W. D. MI，T. KUDO and A. MATSUKI

Department of Anaesthesiology & Pain Management， University of Hirosaki School of Medicine， Hirosaki， Japan

　　Background：We studied the effect of variable doses of ketamine on the endpoints of hypnosis，e.g. unresponsiveness to verbal commands （UVC），loss of eyelash reflex （LER），and inhibition of body movement response with or without sneezing to nasal membrane stimulation （INBMR）， and processed EEG variables，e.g. bispectral index （BIS），95％ spectral edge frequency （SEF） and median frequency（MF）during propofol infusion.

　　Methods： Forty－eight patients received either propofol infusion， 30 mg kg^－１ h^－１ （Group P； n＝12） or ketamine bolus， 0.25， 0.5 or 0.75 mg i.v. followed by propofol infusion， 30mg kg^－１ h^－１variable dose ketamine infusion， 0.25， 0.5 or 0.75mg kg^－１ h^－１（Groups PK_0.25， PK_0.5 and PK_0.75； n＝12 each） until UVC， LER and INBMR. BIS， 95％ SEF and MF values were monitored and recorded at the endpoints of hypnosis. Propofol and ketamine concentrations were measured at INBMR.

　　Results：Propofol infusion， 30 mg kg^－１ h^－１， induced UVC， LER and INBMR at BIS： 65±2， 63±9 and 33±7； 95％ SEF： 17±3，17±4 and 14±3； and MF values of 5±2，5±3 and 3±2， respectively. With adjunctive ketamine （Groups PK_0.5 and PK_0.75），the hypnotic endpoints were achieved at higher BIS and 95％ SEFvalues and lower propofol doses and concentrations as comparedto Groups P and PK_0.25（9.9±5.8 and 9.4±3.4 vs. 13.4±4.5 and 14±5.8 mg　ml^－１）.

　　Conclusions： Our results suggest additive interaction between propofol and ketamine （Groups PK_0.5 and PK_0.75） for achieving the hypnotic endpoints； however， ketamine did not depress the EEG variables in proportion to its hypnotic effect. The paradoxically higher BIS and 95％ SEF values at the hypnotic endpoints may be due to lower propofol concentrations and/or no effect of ketamine on the EEG variables.

　　Received 28 April， accepted for publication 6 August 1998

　　Key words：Anesthetics， intravenous： propofol， ketamine； monitoring， electroencephalogram： bispectral index，95％ spectral edge frequency，median frequency；reflex：eyelash， nasal.

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　　CLINICAL responses to different stimuli have beenstudied to predict the adequacy of anaesthesia^[1，2].Mechanical stimulation of nasal mucous membrane（via the trigeminal nerve） leads to body movementand/or sneezing ^[3－6].In this study，we utilizedbody movement and/or sneezing in response tomechanical stimulation of nasal mucous membrane inaddition to two other commonly tested endpoints ofhypnosis，e.g.response to verbal commands and eyelashreflex，to assess adequacy of anaesthesia.

　　Co－administration of propofol and ketamine resultsin enhanced hypnosis，better haemodynamic stability，analgesia and reduced incidence of adverse centralnervous system effects of ketamine ^[7－10].ProcessedEEG variables，e.g.bispectral index （BIS），95％ spectraledge frequency （SEF） and median frequency （MF），have been studied for their efficacy in predicting theadequacy of propofol i.v. anaesthesia ^[2，11].Ketamineincreases the d，q and b activity of the EEG ^[10，12]；however，a recent report suggested no effect of a bolusdose of ketamine，0.25?0.5 mg kg^－1 i.v，on the BISvalues^[13].

　　In spite of the additive hypnotic effect，there havebeen no reports of the effects of variable doses of ketamineon processed EEG variables at the endpoints ofhypnosis during propofol infusion. This study was，therefore，designed to study the effects of variabledoses of ketamine on the processed EEG variables atthe clinical endpoints of hypnosis，e.g. unresponsivenessto verbal commands （UVC），loss of eyelash reflex（LER） and inhibition of nasal body－movement responseand/or sneezing （INBMR） during propofol infusion.

　　Methods

　　Patients：After obtaining approval from the InstitutionalEthics Committee，48 ASA 1 or 2 patients，20－55 years，scheduled for elective non－cranialsurgery were recruited into the study. Written informed consent was obtained from all the patientsprior to participation in the study. Patients withneurolgical or psychiatric disease，smoking （±10cigarettes/day），excessive alcohol intake（±30 g/day） or intranasal pathology were excluded. Patientsdid not receive any premedication prior to inductionof anaesthesia.

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　　Anaesthesia：Patients were randomly assigned to receiveone of the following four treatments untilachieving the clinical endpoints of UVC，LER and INBMR：

　　Propofol infusion，30 mg kg^－1 h^－1 （Group P，n＝12）；Ketamine bolus，0.25 mg kg^－1 i.v. 1 min priorto propofol infusion，30 mg kg^－1 h^－1 ketamineinfusion，0.25 mg kg^－1 h^－1 （PK_0.25，n＝12）；Ketaminebolus，0.5 mg kg^－1 i.v. 1 min prior to propofolinfusion，30 mg kg^－1 h^－1 ketamine infusion，0.5 mg kg^－1 h^－1 （PK_0.5，n＝12）；Ketamine bolus，0.75 mg kg^－1 i.v. 1 min prior to propofol infusion，30 mg kg^－1 h^－1 infusion with or without ketamineinfusion，0.75 mg kg^－1 h^－1 （PK_0.75，n＝12）.

　　Measurements：Electrocardiogram （ECG），arterialoxygen saturation （SpO₂） and mean arterial pressure（MAP） were monitored continuously. After commencingi.v. propofol infusion with or without ketamine infusion，responses to verbal commands and eyelash reflexwere assessed every 30 s until inhibition of theseresponses. Thereafter，nasal body－movement responseand/or sneezing was assessed every minute by stimulatingthe nasal mucous membrane with a rotatingsoft brush （radius：1.5 mm，length：1.2 cm） mountedon a 1－mm radius stiff rod until inhibition of this response.The brush was inserted 3 cm past the nasalorifice after application of 0.1％ tramazoline hydrochlorideto reduce nasal bleeding due to its vasoconstrictoreffect. The rotating stimulus was applied at100±10 Hz for three 2－s durations over a period of 10s. A positive response was defined as any visible motor（muscle） movement and/or sneezing during orimmediately following stimulation. If positive nasalbody－movement response and/or sneezing persistedon three consecutive attempts，propofol boluses，30mg i.v. were administered every minute prior to nasalstimulation until inhibition of this response. AfterINBMR，patients were intubated with vecuroniumand maintained on propfol¹fentanyl¹ketamine i.v.anaesthesia to facilitate the surgical procedure.

　　After skin preparation，four disposable silver－silverchloride electrodes were placed （2 negatives：one eachabove the outer malar bones，one reference：4 cmabove the nasion and one ground：left forehead） asper 2－channel referential BIS montage. Impedance ofthe electrodes was below 2000 W. BIS，95％ SEF andMF were monitored continuously using a microprocessor－based，2－channel A－1050 EEG monitor （AspectMedical Systems，Inc.，Natick，MA）. The EEG variableswere calculated at 5－s epochs and recorded at15－s intervals. BIS，95％ SEF and MF values，and totaldoses of propofol were monitored and recorded ateach clinical endpoint of hypnosis. Radial arterialblood samples for measurement of propofol and ketamineconcentrations were withdrawn at INBMR. Fivemilliliters of blood sample was centrifuged at 3000rpm for 15 min and separated plasma was stored at 70 C. Plasma propofol and ketamine concentrationswere analysed using high－performance liquid chromatographyat 270 and 250 nm UV，respectively.

　　Data analysis：Data are presented as mean ±SD andwere analyzed using Statview version II （Macintosh）.Multiple analysis of variance （ANOVA） was used forcomparisons between the four treatment groups. Repeated－measures ANOVA was applied for changesover time within the same treatment groups. ScheffeF post hoc test was used after ANOVA and P＝0.05 wasconsidered statistically significant.

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　　In conclusion，ketamine supplementation of propofol （Groups PK_0.5 and PK_0.75） reduced the propofol dose requirement for achieving the clinical endpoints of hypnosis，suggesting additive interaction between propofol and ketamine. The decreases in the BIS and 95％ SEF values were less in patients receiving adjunctive ketamine with propofol as compared to propofol alone. For comparable degree of hypnosis，propofol and ketamine co－administration does not lead to proportionate reduction of the EEG variables.

　　Acknowledgement

　　The authors thank the residents and faculty members of the Department of Anaesthesiology and Pain Management for their assistance with this study.

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