40

Antagonism of benzodiazepine-fentanyl anaesthesia with flumazenil The specific benzodiazepine antagonist flumazenil (Ro 15-1788) (Ro) was given in a double-blind study to 40 adult orthopaedic patients in order to determine if it shortens the immediate recovery time after benzodiazepine-fentanyl anaesthesia. On the evening before operation the patients were premedicated orally with 1-2 mg offlunitrazepam and 30 rain before the induction of anaesthesia with 7.5 mg midazolam. Induction of anaesthesia was carried out with flunitrazepam 0.03-0.04 mg" kg -j and fentanyl 0.1 mg IV. Anaesthesia was maintained with fentanyl (5.9 Ixg "kg-j "h -j ) and nitrous oxide.After the reversal of muscle relaxation, 20 patients received a placebo and 20 patients Ro, as boluses up to 10 ml, until the effect of awakening was noticed. The dose of Ro (0.1 mg. ml -j ) required was 6.8 +2.9 txg" kg -j and that of placebo 10 + 0 ml. Patients given Ro woke up faster than patients given placebo. Ro patients were more alert than patients given placebo until 120 rain after the injection or the test drug. After this patients in both groups behaved similarly. Eight patients given Ro and one given placebo showed some mild adverse reaction for 5-60 rain after the administration of Ro or placebo (e.g., nausea, shivering). This study indicates that flumazenil speeds up awakening after benzodiazepine-fentanyl anaesthesia. Dans une dtude d double insu, 40patients orthopEdiques adultes recevaient le flumaz~nil spdcifique antagoniste de la benzodiazEpine (Ro 15-1788) (Ro). La veille de l' op~ration, les patients ont refu, par la voie buccale, une prdmEdication avec I d 2 mg de flunitrazEpam et, 30 minutes avant l' induction de l'anesth~sie, avec 7,5 mg de midazolam. L' induction de r anesthEsie a ~tE rEalisEe avec flunitrazEpam 0,03-0, 04 mg . kg-t etfentanyl O,1 mg intraveineux. L'anesth~sie a dt~ maintenue avec fentanyl

Key words ANAESTHETIC TECHNIQUES" ANALGESICS:

intravenous;

fentanyl;

nVI'NO~CS: benzodiazepines, midazolam, flunitrazepam, benzodiazepine antagonist, flumazenil. From the Department of Anaesthesia, Tampere University Central Hospital, SF-33520 Tampere 52, Finland. Address correspondence to: Dr. S. Kaukinen. C A N J A N A E S T H 1990 / 37: I / p p 4 0 - 5

Seppo Kaukinen Mo, Jukka Kataja MD, Liisa Kaukinen MD

(5,9 I~g. kg -1. h -t ) ainsi qu'avec hEmioxyde. La relaxation des muscles disparue, 20 patients ont refu un placebo et 20 patients le Ro en forme de bolus (1 ~ 2 ml). Les bolus (quantitE totale de 10 ml max.) ont dtE administrds d intervalles d'une minute, jusqu' d ce que l'effet sur le rdveil ait EtEaperfu. La dose requise deRodtaitde4,8 +- 1,6(SD)ml(6,8 +. 2,91xg. kg-I )etcelledu placebo de 10 +- 0 ml. Les patients Rose rdveiUaient plus vite que les patients du placebo. Les patients Ro dtaient consid&ablement moins sous l' effet du tranquillisant jusqu'~ 60 minutes aprEs l'injection du mddicament d'essai ; ils faisaient preuve d'une meilleure capacitd de comprehension et de collaboration jusqu'd 30 minutes ; ils dtaient mieux orientals dans le temps et dans l' espace jusqu ' ti 30 minutes, et ils avaient moins d'amnEsie antErograde jusqu'd 120 minutes que les patients du placebo. Ces temps Ecoul(s, les patients Ro et du placebo se comportaient de la mEme mani&e. Huit patients Ro et un patient du placebo montraient quelque IEgdre r(action adverse pendant de 5 ~ 60 minutes apr~s l'administration du Ro ou du placebo (par example nausEe, fiissons). Cette ~tade indique la capacitE du flumazEnil d' accdl&er le rdveil aprds l' anesthdsie benzodiazEpine fentanyl.

Opioid anaesthesia using fentanyl as the analgesic agent is a widely used anaesthetic technique. One of the side effects of fentanyl anaesthesia is patient awareness during surgery in spite of high-dose fentanyl. ~,2 To ensure sleep fentanyl anaesthesia is often supplemented with various psychotropic drugs, e.g., benzodiazepines. Although benzodiazepines allow reduction of the fentanyl dose, they prolong the recovery and may aggravate the postoperative respiratory depression caused by fentanyl.3 The recently developed imidazobenzodiazepine flumazenil (Ro 15-1788) has been shown to be a competitive inhibitor of benzodiazepines at the receptor level. 4 It binds selectively to central benzodiazepine receptors. 5 In studies in several animal species, flumazenil reversed the neurological and behavioural effects of different benzodiazepines. 6 In healthy volunteers, flumazenil has been found to reverse the effects of several benzodiazepines. 7-t~ Also, in clinical reports, flumazenil has

Kaukinen et al.: BENZODIAZEPINE ANTAGONISM WITH FLUMAZENIL TABLE I Patientcharacteristics Group

n

F/M

Age (yrs) mean • SD

Weight (kg)

Placebo Flumazenil

20 20

6/14 10/10

37 --- I1 36 • 12

77 --- 12 72 --- 12

been noticed to improve alertness and performance of patients when given after midazolam anaesthesia or sedation for short procedures, it. t2 However, the efficacy of flumazenil in reversing the effect of flunitrazepam, which exceeds the duration of the most operations, has been studied only scarcely. 13.~4 In the present study we have evaluated the efficacy and adverse effects of flumazenil in reversing the central effects of benzodiazepines, when the latter were given for premedication and for the induction of anaesthesia. Methods

The study was a double-blind investigation of 40 patients scheduled for minor orthopaedic knee or toe operations. It was accepted by the Committee of Ethics of the Hospital. Informed consent was obtained from every patient. The patients were divided according to random digits into two groups. After anaesthesia, placebo was given to the first group and flumazenil (Ro 15-1788) to the second group as test drugs. The patients were otherwise healthy and had not received any benzodiazepine therapy (Table I). As premedication, on the evening before surgery flunitrazepam 1-2 mg, and 30-45 min before the induction of anaesthesia midazolam 7.5 mg were given orally. Anaesthesia was induced with 0.1 mg fentanyl followed two minutes later with flunitrazepam 0.04 mg.kg -I. After disappearance of the lid reflex and appearance of dysarthria, pancuronium 0.1 mg. kg- l was given to facilitate tracheal intubation, and the lungs were ventilated with the gas mixture O2/NzO 1:2. Anaesthesia was maintained with fentanyl, 50-100 ixg, when needed, and pancuronium, 2 mg, was given as required. Muscle relaxation was reversed with neostigmine, 2.5 mg, and atropine, 1 mg. After spontaneous respiration had returned, the test drug flumazenil (Ro), 0.1 mg. ml -I, or placebo (P1) was given. The first dose of 2 ml was injected in 15 seconds. Thereafter, boluses of 1 ml were given at one-minute intervals until an effect of awakening was noticed. The total dose of the test drug was 10 ml. The efficacy of the test drug was judged by evaluating the degree of sedation, anterograde amnesia, comprehension and collaboration and orientation in time and space before giving the test drug, and at 5, 15, 30, 60, 120, 180 and 240 min afterwards. The evaluation was done by one of the authors who was not aware which of the test

41

solutions had been used. The degree of sedation was evaluated using a scale of 0 to 4: (0) patient awake and tense, (1) patient awake but not tense, (2) patient drowsy, (3) patient sleepy but arousable, and (4) patient sleepy and not arousable. Anterograde amnesia was tested by telling the patient the time just before induction of anaesthesia and after the anaesthetic, by showing the patient a small object such as a pencil, and asking later if she/he remembered the time or the object. Anterograde amnesia was coded from 0 to 2, (0) no anterograde amnesia, (1) partial anterograde amnesia, and (2) complete anterograde amnesia. Comprehension and collaboration were evaluated by asking the patient to raise one hand or leg. No response was scored 0 point, response by imitation 1 point, and response to order 2 points. Orientation in time and space was graded from 0 to 2, (0) total disorientation, (1) partial orientation, and (2) orientation in time and space. For statistical analysis of the results, Wilcoxon matchedpairs signed-ranks test and one-way analysis of variance were used. For heart rate and blood pressure a paired t test was used within the groups. A P value