GENERAL ANESTHESIA 439 Midazolam prcmcdica- tion reduces propofol Oliver H.G. Wilder-Smith MBCHB MD,* dose requirements for Patrick A. Ravussin MD,{ Laurent A. Decosterd PhD,$ multiple anesthetic Paul A. Despland MD,§ Bruno Bissonnette MD~[ cndpoints Purpose: This study investigatesthe interactions between midazo- Objectif : Examiner les interactions entre la pr~m~dication avec du lam premedication and propofol infusion induction of anesthesiafor midazolam et I'induction de I'anesth~sie avec une perfusion de propofol multiple anesthetic endpoints including: loss of verbal contact (LVC; en regard de divers param~tres comprenant " la perte du contact verbal hypnotic), dropping an infusion flex (DF; motor), loss of reaction to (PCV; hypnotique), le relSchement de la main (RM; moteur), I'absencede painful stimulation (LRP; antinociceptive) and attainment of elec- r~action 8 une stimulation douloureuse (ARD; antinociceptif) et la sup- troencephalographic burst suppression (BUR; EEG), pression des salves d'activit~ ~lectroenc~phalographiques(SUP; EEG). Methods: In a double blind, controlled, randomized and prospec- M~thodes : L'&ude prospective, contr61&, randomis& et 8 double insu tive study, 24 ASA I-II patients received either midazolam 0,05 conceme 24 patients ASA I-II qui ont re,u, soit 0,05 mgkg~1 de mida- mgkg I (PH; n 13) or saline placebo (P0; n I I)ivas premedica- zolam (PM; n 13), soit une solution sal& placebo (PO; n I I) iv tion. Twenty minutes later, anesthesia was induced by propofol comme pr~m~dication. L'anesth~sie a ~t~ induite, 20 rain plus tard, infusion at 30 mgkg ~ hr ~. ED~0, EDg~ and group medians for avec une perfusion de propofol 8 30 mgkg I" hr I. Les ED50, ED95 et times and doses were determined and compared at multiple anes- les m~dianes pour les temps et les doses dans chaque groupe ont ~t~ thetic endpoints. d&ermin&s et compar&s pour divers param~tres anesth~siques. Results: At the hypnotic, motor and EEG endpoints, midazolam R~sultats : Pour les variables hypnotique, motrice et EEG, la pr~m~di- premedication significantly and similarly reduced propofol ED~0 cation au midazolam a r~duit pareillement et de fa~on signiflcative la (reduction: 18%, 13% and 20% respectively; P <0.05 vs ED5o de propofol (r~duction : 18 %, 13 % et 20 % respectivement; P unpremedicated patients) and EDg~ (reduction: 20%, I1% and <0,05 vs les patients sans pr~m~dication) et la ED95 (r~duction: 20 %, 20% respectively; P <0.05 vs unpremedicated patients). For I 1% et 20 % respectivement; P <0,05 vs les patients sans pr~m~di- antinociception (LRP), dose reduction by premedication was cation). Concemant I'antinociception (ARD), la r~duction de la dose par greater for propofol EDg~ (reduction: 41%; P <0.05 vs unpremed- la pr~m~dication a ~t~ plus importante pour la ED95de propofol (r~duc- icated patients) than ED~0 (reduction: 18%; P <0.05 vs unpremed- tion : 41%; P <0,05 vs les patients sans pr~m~dication) que pour la icated patients). Hemodynamic values were similar in both groups ED5o (r~duction : 18 %; P <0,05 vs les patients sans pr~m~dication). at the various endpoints. Les valeurs h~modynamiques ont ~t~ similaires chez les patients des Conclusions: Hidazolam premedication 20 rain prior to induction deux groupes quant aux divers param~tres &udi~s. of anesthesia reduces the propofol doses necessary to attain the Conclusions : La pr~m~dication avec du midazolam, 20 min avant multiple anesthetic endpoints studied without affecting hemody- I'induction de I'anesth~sie, permet de r~duire les doses de propofol namics in this otherwise healthy population. The interaction differs n&essaires 8 I'atteinte des divers objectifs anesth~siques &udi~s sans for different anesthetic endpoints (e.g., antinociception vs hypnosis) modifier I'h~modynamie chez une population de patients en bonne and propofol doses (e.g., ED~0 vs EDge). sant& Les interactions diff&ent en fonction des param~tres anesth~siques (ex., I'antinociception vs I'hypnose) et selon les doses de propofol (ex., ED5o vs ED95). From the Nociception Research Group Berne University, Berne,* the Department ofAnaesthesiology Sion Hospital, t the Division of Clinical Pharmacology,:~ the Depamnent of Nettrology,§ Lausanne University Hospital (CHUV), Lausanne, Switzeflaald and the Depamnent of Anaesthesia,¶ University of Toronto, Toronto, Canada. Address corresposdesce t#. Dr. Oliver H.G. Wilder Smith, The Pain Centre, University Department ofAnaesfllesiology, Academisch Ziekeiflmis Nijmegen, P.O. Box 9101, NL 6500 HB Nijmegen, The Netherlands. Phone: +31 24 361 44 06; Fax: +31~4 361 35 85; E mail: [email protected] Work was carried out at the Department of Anaesthesiology, Lausanne University Hospital (CHUV), Lausanne, Switzerland. Part of file study was presented at the 1995 Aflama ASA meeting. FhDalcial Support: Partially supported by a grant from Roche Pharma (Switzerland) A.G. Accepted for psblicatios Jassary 11, 2001. 440 CANADIANJOUP,2qAL OF ANESTHESIA D RUG combinations are used frequently chosen to simulate typical iv premedication (as in clinical anesthesia. As well as widening opposed to co-induction) at our institution and also the spectrum of action of anesthesia, the permitted us to obtain a stable baseline EEG under use of combinations can also decrease the influence of midazolam. Neither the investigator side effects, mainly by reducing the doses of individual nor the person interpreting the EEG knew whether drugs necessary via synergism. the patient had been premedicated or not. The EEG Because anesthesia is the result of several different was interpreted by an experienced electroencephalog- actions, such as hypnosis, antinociception or myorelax- rapher, present throughout the study period. ation, studies of anesthetic drug interactions should Monitoring devices were next installed and the ideally include multiple endpoints involved in anesthe- patient pre-oxygenated by face mask. Lung ventilation sia. However, most studies involving anesthetic drug was assisted or controlled from induction onwards to interactions have so far investigated only single clinical maintain normal respiratory values (FiC~=I.0; SpO2 endpoints, usually the hypnotic endpoint of loss of ver- >95%; ETCO2=4-5 kPa). Anesthesia was induced by a bal contact or eyelash reflex, using single iv bolus tech- continuous iv infusion of propofol 1% solution by niques. Infusion induction titration models 1 3 syringe pump (Perfusor®, Braun Melsungen, Germany) represent an interesting and increasingly validated at 30 mg.kg 1.hr 1until the appearance of burst suppres- alternative to bolus models for the study of drug inter- sion on the EEG. actions. They permit the evaluation of multiple end- Continuous EEG recording (standard 10-20 system points in one patient and session, include the clinically 16 channel montage, Medilog®, Oxford, UK) was important time element and are easy to apply to clini- started five minutes before iv premedication and cal practice. Using such a model, we have recently been acquired until the end of the study. Arterial blood pres- able to show that for thiopental, the interaction with sure (non-invasive, automated oscillometry) and heart midazolam premedication differs according to the rate (ECG monitor) were measured at one-minute anesthetic endpoint studied. 3 intervals and recorded specifically at four endpoints. Midazolam is a popular adjuvant drug for iv anes- The following endpoints were determined and docu- thesia. It has been demonstrated to be hypnotically mented on the EEG record: 1) hypnotic: loss of verbal synergistic with propofol as a premedicant or co- contact (LVC), by questioning every ten seconds inductant during induction using bolus techniques. ~6 "please open your eyes"; 2) motor: drop flex (DF), time To our knowledge, the interactions ofmidazolam pre- at which a 500-ml plastic infusion bag held in the hand medication with propofol have not been studied for was dropped; 3) antinociceptive: loss of reaction to pain multiple anesthetic endpoints. This investigation is (LRP), time at which purposeful somatic movement to designed to quantify the interaction of midazolam transcutaneous constant current tetanic electric stimula- with propofol at multiple anesthetic endpoints using tion by a nerve stimulator ceased (Digistim®, Biometer an infusion induction titration model. A/S, Copenhagen, DK; stimulation started after LVC and DF was applied via self adhesive electrodes on the Methods side of the index finger at 100 Hz/40 mA/0.2 msec After institutional Review Board and Ethics and avoided stimulating major nerves); and 4) elec- Committee approval as well as written informed troencephalographic: burst suppression (BUR) (first patient consent, 24 ASA physical status I-II patients occurrence of three seconds isoelectricity between scheduled for elective back surgery were prospectively bursts in the dominant side, fronto-parietal channel). included in the study. Exclusion criteria comprised car- The times and cumulative propofol doses at each diovascular and neurological disease, diabetes mellitus, endpoint were recorded. Vecuronium 0.1 mg.kg 1 to chronic hypnotic or analgesic medication and abnor- facilitate intubation was given only after the patient mal body weight (over 20% deviation from ideal). ceased reacting to painful stimulation. On reaching In the operating room, the electrodes for the elec- EEG burst suppression, the trachea was intubated and troencephalogram (EEG) were applied to the the study ended. unpremedicated patients, an awake EEG obtained, and the patients allocated to receive either midazolam Statistical analysis 0.05 mg.kg 1 iv (PM; n=13) or placebo (NaC1 0,9%) Using data from bolus studies by Short4,Sand Vinik6 (P0; n=11) by use of a random number table. Twenty and infusion model data from Peacock, 7 we estimated minutes before anesthesia induction a person not the group size necessary to detect a clinically relevant involved in the study performed slow iv premedication difference of 20% in ED50values for loss of verbal con- (injection over 30 sec) of the patients.