1Department of Anaesthesia, 2Departments of Health Economics and Anaesthesia and 3Department of Medical Engineering, Teikyo University, School of Medicine, Ichihara Hospital, Ichihara-shi, Japan
Accepted for publication: April 15, 2000
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Br J Anaesth 2000; 85: 35963
Keywords: anaesthesia, general; anaesthetics, gases, xenon; anaesthetics, volatile, isoflurane; monitoring, electroencephalography; measurement techniques, spectroscopy
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Xenon is an inert gas with many favourable characteristics as an anaesthetic,4 including a low blood/gas partition coefficient (0.12),5 a minimal alveolar concentration (MAC; 71%)6 that is lower than that of nitrous oxide but analgesic properties similar to those of nitrous oxide,7 8 a lack of toxicity, and harmlessness to the environment. However, xenon was not considered when the algorithm for the BIS was formulated, and whether the BIS appropriately reflects the depth of anaesthesia produced by this gas has not been investigated. Therefore, we performed a randomized prospective study to characterize how the BIS changes as the concentration of xenon is decreased during emergence from anaesthesia until the patient awakens and regains responsiveness to verbal command.
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The unpremedicated patients had an extradural catheter placed at the L2/3 interspace, and after a 3 ml test dose, 10 ml of mepivacaine 1.5% with 1:200 000 epinephrine was administered. If the sensory level of T10 or higher to pinpricks was not obtained within 15 min, the extradural catheter was judged to be functioning inadequately and the patient was not included in the study.
In addition to routine monitoring devices, the EEG signal was acquired using four electrodes (ZipprepTM; Aspect Medical Systems, Natick, MA, USA) applied to the forehead, with one on each outer malar bone, one at the centre of the forehead and one (ground) on either side of the centre electrode. The BIS (version 3.22) value and the 95% spectral edge frequency (SEF95) were displayed using an Aspect EEG monitor (Model A-1050; Aspect Medical Systems) and were stored every 5 s on a personal computer for later off-line analysis throughout the study.
The patients were assigned randomly to receive either xenon (n=11) or isoflurane (n=9) for maintenance of anaesthesia. After a stable baseline EEG had been obtained with the patients eyes closed, those who were to receive xenon and isoflurane received propofol 2.5 mg kg1 intravenously (i.v.) and an inhalation of 5% sevoflurane, respectively, for induction of anaesthesia. The larynx and upper trachea were sprayed with 4% lidocaine 3 ml, and the trachea was then intubated with the aid of vecuronium 10 mg i.v. In the xenon group, anaesthesia was maintained with 56% xenon (0.8 MAC) in oxygen using a closed breathing system (all concentrations of inhalational anaesthetics are end-tidal). The isoflurane group received isoflurane 1.01.5% in a 6 litre min1 flow of oxygen, which was reduced to 0.92% (0.8 MAC) at least 15 min before the end of surgery. All patients also received a continuous extradural infusion of 1.5% mepivacaine containing 1:200 000 epinephrine at 68 ml h1 to maintain the mean arterial pressure and heart rate within 20% of the preoperative values. The lungs were ventilated mechanically to maintain the end-tidal concentration of carbon dioxide (CO2) at 3035 mm Hg, and additional doses of vecuronium were administered if clinically indicated. The body temperature, measured with an oesophageal sensor, was maintained by the use of a warming mattress placed on the operating table. Intravenous fluids were also warmed.
The end-tidal concentration of xenon was monitored continuously using a xenon analyser (Anzai Medical, Tokyo, Japan), the effective working range of which was 1100% with error <1% and 90% response time less than 1 s. This device measures absorption by the gas mixture of a characteristic x-ray, which is proportional to the concentration of xenon in the gas mixture. The end-tidal concentrations of carbon dioxide and isoflurane were measured using an infrared analyser (Capnomac Ultima; Datex, Helsinki, Finland). In the xenon group, an in-line infrared capnogram (Hewlett-Packard, Waltham, MA, USA) was used instead. These analysers were calibrated before each use according to the manufacturers instructions.
Shortly before the end of surgery, residual neuromuscular blockade was reversed with neostigmine 2.5 mg and atropine 1.0 mg i.v. and recovery was verified by the train-of-four response to ulnar nerve stimulation. When surgery was complete, a designated investigator, blinded both to the anaesthetic administered and to the EEG data, asked the patient in a normal tone to open her eyes and to squeeze and release the investigators hand. If the patient failed to follow both of these commands, the end-tidal concentration of xenon or isoflurane was reduced by 7 or 0.12%, respectively (both approximately 0.1 MAC). The new concentration was maintained for 15 min. During this period, the patients ability to respond to verbal commands was checked every 5 min and whenever clinical signs of imminent awakening, such as coughing, bucking and frowning, were noted. If no response was observed for the entire 15 min period, the concentration of anaesthetic was reduced again. This process was repeated until an alveolar concentration was reached at which the patient responded appropriately to either one of the commands. This concentration was termed the awakening concentration. Care was taken to minimize stimuli other than verbal commands during the entire wake-up period. Mechanical ventilation was continued during the entire period. When coughing or bucking hindered effective ventilation with positive pressure, the patient was allowed to breathe spontaneously.
The BIS and SEF95 values at each concentration at which no response to verbal command was observed during the entire 15-min equilibration period were calculated by averaging the values obtained over the last 3 min of that period. At the awakening concentration, the values displayed at the time of the patients response were recorded. The data from right- and left-sided electrodes were averaged.
Fifteen minutes after tracheal extubation, the extradural block level to pinpricks was examined, and the patient was asked to rate her incisional pain using a verbal rating scale of 010, values of 0 and 10 representing no pain and the worst pain imaginable, respectively. All patients were asked 2 h after the operation if they remembered being called by their name when they woke up.
The BIS values, the postoperative pain ratings and the extradural analgesia levels are reported as median (range) and were analysed using Mann-Whitney U-tests. Other data are presented as mean (SD) and were analysed using unpaired t-tests. A P value less than 0.05 was considered statistically significant.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
Xenon was markedly different from isoflurane in the BIS value on awakening. Four patients in the xenon group awoke while their BIS values were less than 50 (45 (4149)) and had not appreciably increased from those observed at higher concentrations of xenon (Fig. 1, lower panel). The remaining seven patients awoke with the BIS greater than 80 (96 (8298)), but in four of them the BIS value was no greater than 50 when the concentration of xenon was only 0.1 MAC (7%) higher than the awakening concentration (Fig. 1, lower panel).
The SEF95 values of the xenon group changed similarly to the BIS (Fig. 2, lower panel). Thus, all four patients who awoke with their BIS below 50 and one who did so at a BIS of 82 showed relatively low SEF95 values on awakening (11.1 (2.9) Hz, range 6.714.0 Hz). On the other hand, the remaining six patients awoke at a SEF95 value of 25.0 (3.2) Hz, but in three of them the SEF95 value was relatively low (<12 Hz) when the xenon concentration was only 0.1 MAC higher than that associated with awakening.
No subject experienced major anaesthesia-related adverse events. When interviewed postoperatively, none of the four patients who awoke with the BIS below 50 remembered that they were called by their name when they were waking up, while two of the seven patients who awoke with the BIS greater than 80 remembered it vaguely.
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Two issues need to be addressed when considering the validity of our data. First, one may argue that the behaviours we used as the end-point of awakening (eye-opening and hand-squeezing) were too simple to distinguish a non-specific or reflexive reaction to hearing a voice from a conscious and deliberate response to the command. However, a recent investigation11 that evaluated the level of hypnosis using graded and varied stimuli and multiple verbal commands demonstrated that the participants either responded fully to all the stimuli and commands or showed no responses at all. Intermediate levels of responsiveness were observed rarely. This strongly suggests that a positive response to a simple verbal command is sufficient evidence that the subject is awake.
The second issue involves a computational delay of the BIS monitor device. The BIS value reported by the monitor represents an average value derived from the previous 60 s of usable EEG data.1 Therefore, it is possible that the patients whose BIS values on awakening were less than 50 had experienced an increase in the BIS within the 60 s preceding awakening and that their BIS values at the exact moment of awakening were actually greater than 50. However, we believe this is unlikely because we provided a quasi-stable level of anaesthesia for 60 s preceding the moment of awakening by maintaining the end-tidal concentration of xenon constant, except for stepwise reductions at every 15 min, and by leaving the patients undisturbed as much as possible. Moreover, even if this increase actually occurred, this does not invalidate our conclusion that the low BIS may be associated with the near-awakening state during xenon anaesthesia, because the BIS stayed low until less than 60 s before awakening.
We can speculate how a level of xenon anaesthesia sufficiently light to permit a response to verbal command was associated with a BIS less than 50 in some patients, as the BIS computation algorithm has not been published. Our results demonstrated that, when the xenon patients awoke while their BIS were less than 50, their EEGs were always slowed, as indicated by the SEF95 values of no greater than 14 Hz. In marked contrast, isoflurane permitted our patients to awaken only after their SEF95 had increased to above 20 Hz. Because the BIS generally decreases as the power of the EEG high-frequency components declines,1 it is not surprising that the patients who awoke with low SEF95 also had low BIS values.
This study has several limitations. First, we used extradural analgesia, which may affect the sensitivity of the brain to general anaesthetics.12 Whether it disturbs the relationship between the BIS and the clinical level of hypnosis is unknown. Secondly, we studied only females, although the relationship between the dose of anaesthetics and the BIS may be sex-dependent.13 Thirdly, we studied only one end-point of hypnosis, i.e. the presence or absence of responses to verbal command, although other endpoints, especially memory formation, are also clinically relevant. It is reassuring that the four patients of the xenon group who awoke with BIS below 50 did not recall that they had been called by their names when waking up. However, the number of the patients studied was too small to draw any firm conclusion about whether low BIS values guarantee loss of memory formation during xenon anaesthesia.
In summary, we have demonstrated that BIS values less than 50 do not guarantee adequate hypnosis during xenon anaesthesia. Therefore, other modalities for monitoring the hypnotic level are required if xenon is to be used in clinical practice.
![]() |
Acknowledgements |
---|
![]() |
Footnotes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Morioka N, Ozaki M, Matsukawa T, Sessler DI, Atarashi K, Suzuki H. Ketamine causes a paradoxical increase in the bispectral index [abstract]. Anesthesiology 1997; 87: A502[ISI]
3 Suzuki M, Edmonds HL Jr, Tsueda K, Malkani AL, Roberts CS. Effect of ketamine on bispectral index and levels of sedation. J Clin Monit Comput 1998; 14: 373[ISI][Medline]
4 Dingley J, Ivanova-Stoilova TM, Grundler S, Wall T. Xenon: recent developments. Anaesthesia 1999; 54: 33546[ISI][Medline]
5 Goto T, Suwa K, Uezono S, Ichinose F, Uchiyama M, Morita S. The bloodgas partition coefficient of xenon may be lower than generally accepted. Br J Anaesth 1998; 80: 2556[ISI][Medline]
6 Cullen SC, Eger EI, Cullen BF, Gregory P. Observations on the anesthetic effect of the combination of xenon and halothane. Anesthesiology 1969; 31: 3059[ISI][Medline]
7 Yagi M, Mashimo T, Kawaguchi T, Yoshiya I. Analgesic and hypnotic effects of subanaesthetic concentrations of xenon in human volunteers: comparison with nitrous oxide. Br J Anaesth 1995; 74: 6703
8 Nakata Y, Goto T, Morita S. Effects of xenon on hemodynamic responses to skin incision in humans. Anesthesiology 1999; 90: 40610[ISI][Medline]
9 Glass PS, Bloom M, Kearse L, Rosow C, Sebel P, Manberg P. Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane, and alfentanil in healthy volunteers. Anesthesiology 1997; 86: 83647[ISI][Medline]
10 Rosow C, Manberg PJ. Bispectral index monitoring. Anesthesiol Clin N Am 1998; 2: 89107
11 Kearse LA Jr, Rosow C, Zaslavsky A, Connors P, Dershwitz M, Denman W. Bispectral analysis of the electroencephalogram predicts conscious processing of information during propofol sedation and hypnosis. Anesthesiology 1998; 88: 2534[ISI][Medline]
12 Inagaki Y, Mashimo T, Kuzukawa A, Tsuda Y, Yoshiya I. Epidural lidocaine delays arousal from isoflurane anesthesia. Anesth Analg 1994; 79: 36872[Abstract]
13 Gan TJ, Glass PS, Sigl J, Sebel P, Payne F, Rosow C, et al. Women emerge from general anesthesia with propofol/alfentanil/nitrous oxide faster than men. Anesthesiology 1999; 90: 12837[ISI][Medline]