BJA Advance Access originally published online on October 24, 2007
British Journal of Anaesthesia 2007 99(6):858-863; doi:10.1093/bja/aem300
Differential electroencephalographic response to tracheal intubation between young and elderly during isoflurane– and sevoflurane–nitrous oxide anaesthesia
1 Department of Anesthesiology and Intensive Care Medicine
2 Department of Public Health, Graduate School of Medicine, Osaka City University, 1-5-7 Asahimachi, Abeno-ku, Osaka 545-8586, Japan
* Corresponding author. E-mail: odayou{at}msic.med.osaka-cu.ac.jp
Accepted for publication August 27, 2007.
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Abstract |
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Background: Age-associated differences in the electroencephalographic (EEG) response to noxious stimuli with the presence of nitrous oxide (N2O) are unknown. We compared the EEG response with tracheal intubation between young and elderly.
Methods: Sixty young (<40 yr) and elderly (>70 yr) patients were randomly allocated to one of the four groups. Anaesthesia was induced with 66% N2O and isoflurane in oxygen (Young-isoflurane and Elderly-isoflurane groups) or 66% N2O and sevoflurane in oxygen (Young-sevoflurane and Elderly-sevoflurane groups). Inhaled isoflurane and sevoflurane concentrations were gradually increased and the end-tidal concentrations were maintained at 1.1% and 1.7%, respectively. Tracheal intubation was performed 12 min after induction of anaesthesia.
Results: There were significant differences in the overall changes in bispectral index (BIS) and 95% spectral edge frequency (SEF95) between young and elderly (P<0.001 for both), but not between patients receiving isoflurane and sevoflurane (P=0.4 and 0.3, respectively). Both BIS and SEF95 were significantly decreased after tracheal intubation in Young-isoflurane and Young-sevoflurane groups (P<0.05 for all). In sharp contrast, BIS and SEF95 remained unchanged in Elderly-isoflurane and Elderly-sevoflurane groups (P>0.7 for all). These results suggest that both BIS and SEF95 significantly decreased, despite the presence of increased sympathetic activity after tracheal intubation in young patients.
Conclusions: A significant difference was detected in EEG response to tracheal intubation between young and elderly. BIS does not reflect the depth of anaesthesia after tracheal intubation during anaesthesia with isoflurane or sevoflurane with 66% of N2O in young patients.
Keywords: anaesthetics volatile, isoflurane; anaesthetics volatiles sevoflurane; intubation; monitoring, bispectral index; monitoring, electroencephalogram
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Introduction |
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Increasing age is associated with a decrease in the minimum alveolar concentration (MAC) of volatile agents.1 Age also decreases the MAC to suppress patients’ response to commands (MAC-awake).2 When combined, it can be hypothesized that the required concentrations of anaesthetics to suppress the cerebral cortex activity and body movement in response to surgical stimulation are lower in elderly than in young patients. Bispectral index (BIS) is a reliable marker indicative of the depth of anaesthesia and the levels of sedation, thereby being widely used.3 4 Taken together with BIS being calculated based on the electroencephalogram (EEG), there would be differences in BIS between young and elderly patients even at the same alveolar concentration of volatile agents. In addition, BIS response to noxious stimuli might also be different between these two patient subgroups. Although there have been several studies examining the haemodynamic differences in response to noxious stimuli between young and elderly patients,5 there have been, to our knowledge, no studies examining the age-related difference in BIS response to noxious stimuli. Tracheal intubation is well known as one of the most intense noxious stimuli and will significantly affect EEG.6 7 Despite a significant EEG change after tracheal intubation by adding N2O during isoflurane and sevoflurane anaesthesia,8 effect of age on those changes is not clear. In the present study, we hypothesized that BIS and haemodynamic parameters in response to tracheal intubation would be different between young and elderly patients during anaesthesia with isoflurane, sevoflurane, and nitrous oxide (N2O).
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Methods |
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This study protocol was approved by the institutional ethics committee and written informed consent was obtained from all patients. Thirty young (<40 yr) and 30 elderly (>70 yr) patients with ASA physical status I or II, undergoing elective orthopaedic or gynaecological surgery, were randomized. Patients with abnormal ECG, cardiovascular, respiratory, or psychological diseases, or with predicted difficulty in tracheal intubation were excluded. Other exclusion criteria included a regular use of hypnotic medication, drug or alcohol abuse, and obesity with BMI >30 kg m–2. Patients were allocated to one of the following four groups according to age and the anaesthetics they received: Young-isoflurane, Young-sevoflurane, Elderly-isoflurane, and Elderly-sevoflurane groups (n=15 each). Random allocation to these groups was conducted using a computer-generated random number table.
Experiments were performed as described previously8 with small modifications. No premedication was used. Only isoflurane or sevoflurane, N2O, and vecuronium bromide were used during the study period. In brief, anaesthesia was induced with 66% of N2O and isoflurane in oxygen (Young-isoflurane and Elderly-isoflurane groups) or 66% of N2O and sevoflurane in oxygen (Young-sevoflurane and Elderly-sevoflurane groups) via a face mask using a semi-closed breathing circle system with a total gas flow of 6 litre min–1. After loss of consciousness, we started assisted ventilation followed by controlled ventilation. End-tidal carbon dioxide tension was maintained at 35–40 mm Hg. The concentrations of inhalation isoflurane and sevoflurane were initially 0.3 vol% and then increased slowly until the end-tidal concentrations reached 1.1 vol% and 1.7 vol%, respectively. Incidentally, the concentrations of these two anaesthetics were determined according to their MAC and our previous study,8 but not to the age-adjusted MAC.9–11 Induction of anaesthesia and tracheal intubation were performed by one of the authors (Y.O.) who was able to know only the end-tidal concentration of anaesthetics and carbon dioxide tensions but blinded as to EEG, BIS, arterial pressure, and heart rate (HR). Twelve minutes after induction of anaesthesia, the trachea was intubated and lungs were mechanically ventilated with the same concentrations of anaesthetics as before laryngoscopy. Mean arterial pressure (MAP), HR, BIS, and 95% spectral edge frequency (the frequency below which 95% of the EEG power is located, SEF95) were recorded from induction of anaesthesia (baseline) until 5 min after tracheal intubation. These values were recorded by other authors (T.M. and K.I.) who were blinded to group allocation.
EEG data were continuously observed by a monitor (A-2000, version 3.34; Aspect Medical Systems, Newton, MA, USA) using BisSensor strips (Aspect Medical Systems). The impedance of each electrode was maintained at <2 k
. The smoothing window was set at 15 s, which was taken into account for interpreting the data. All binary data packets, containing raw wave data and BIS and SEF95, were recorded on a personal computer (LB500/J2, NEC Corporation, Tokyo, Japan) using Bispectrum Analyzer for BIS developed by Hagihira and colleagues12 and analysed later by one of the authors who was unaware of the group allocation (T.M.).
Statistics
The number of patients in each group was determined based on our previous study to detect a 20% difference in BIS change compared with that before tracheal intubation with the assumption of a type I error protection of 0.05 and a power of 0.80.7 Patients’ characteristics, haemodynamic data, BIS, and SEF95 are expressed as the mean (SD). Statistical analyses were performed using SAS statistical software (Release 9.1, SAS Institute Inc., Cary, NC, USA) and Statistica (Advanced 06J, StatSoft, Tulsa, OK, USA). Differences in sex ratios among the four groups were examined by 
2 test. Overall differences in MAP and HR during the whole experiments, differences in BIS and SEF95 from 12 min after induction of anaesthesia (before laryngoscopy) to 5 min after tracheal intubation were examined by two-factorial analysis of variance (ANOVA) for repeated measurement using a general linear model (GLM). First of all, we supposed age (young or elderly) and anaesthetics (isoflurane or sevoflurane) as independent variables and MAP, HR, BIS, and SEF95 as dependent variables for examining the effect of age and anaesthetics on overall changes of dependent variables. Then, we have examined the differences of the dependent variables within the same study groups at different time points and between different groups at the same time points using Tukey’s honestly significant difference test, taking into account the number of measurements. Values were considered significant when P<0.05.
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Similar patient characteristics among the four groups with respect to sex ratios, weight, height, and baseline haemodynamics were found (Table 1 and Fig. 1). Similar age distribution was found between Young-isoflurane and Young-sevoflurane groups, and between Elderly-isoflurane and Elderly-sevoflurane groups. End-tidal carbon dioxide tensions and isoflurane or sevoflurane concentrations before and after tracheal intubation were comparable. No differences between Young-isoflurane and Elderly-isoflurane or between Young-sevoflurane and Elderly-sevoflurane groups were observed (Table 2). Concentrations of end-tidal isoflurane and sevoflurane, expressed as multiples of the age-adjusted MAC, in Elderly-isoflurane and Elderly-sevoflurane groups were significantly higher than that in Young-isoflurane and Young-sevoflurane groups, respectively (P<0.01 for both). No patients had a systolic arterial pressure <80 mm Hg nor a HR slower than 50 beats min–1. No cardiovascular agents were required. None complained of awareness during anaesthesia when questioned after operation. Laryngoscopy and tracheal intubation were performed within 20 s in all patients, and there were no differences in the time required for these procedures among the groups (data not shown).
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P<0.05 and 
P<0.01 compared with the value before tracheal intubation within the study group.
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Although both MAP and HR were significantly increased after tracheal intubation compared with baseline and compared before laryngoscopy in all groups (P<0.01 for all), we found similar overall changes in MAP or HR between young and elderly patients, or between patients receiving isoflurane and sevoflurane, with the exception that there were significant differences in HR between young and elderly (P=0.03, Fig. 1).
Electromyographic activity was present at induction of anaesthesia, as indicated by the BIS monitor algorithm, but it disappeared after the administration of the neuromuscular blocking agent. There were no decreases in the BIS signal quality index. BIS was between 96 and 98 at baseline and decreased during induction of anaesthesia, dropping below 50 in all patients before laryngoscopy (12 min after induction) (Fig. 2). Both BIS and SEF95 were stable for 5 min before tracheal intubation and there were no differences in BIS or SEF95 before laryngoscopy among the four groups (Fig. 2). There were significant differences in overall changes of BIS and SEF95 between young and elderly patients (P<0.001 for both), but no differences in BIS and SEF95 between patients receiving isoflurane and sevoflurane from 12 min after induction of anaesthesia until 5 min after tracheal intubation (P=0.4 and 0.3, respectively). Age nor anaesthetic choice influenced the BIS or SEF (P=0.8 and 0.7, respectively).
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BIS values in both Young-isoflurane and Young-sevoflurane groups were significantly lower at 1 and 2 min after tracheal intubation compared with those before laryngoscopy (P<0.01 and 0.05 for Young-isoflurane and Young-sevoflurane groups, respectively). There were no changes of BIS after tracheal intubation compared before laryngoscopy in the Elderly-isoflurane and Elderly-sevoflurane groups. BIS in both Young-isoflurane and Young-sevoflurane groups was significantly lower than that in the Elderly-isoflurane and Elderly-sevoflurane groups, respectively, at 1 and 2 min after tracheal intubation (P<0.05 for all). SEF95 at 1 and 5 min after tracheal intubation in Young-isoflurane group was significantly lower than the value before laryngoscopy (P<0.01 for all). SEF95 at 1 and 2 min after tracheal intubation in Young-sevoflurane group was significantly lower than the value before laryngoscopy (P<0.05 for both), although there were no differences between Young-isoflurane and Elderly-isoflurane nor between Young-sevoflurane and Elderly-sevoflurane groups. In Young-isoflurane and Young-sevoflurane groups, EEG was characterized by high amplitude (> approximately 100 µV), low frequency (<3 Hz) waves with a significant decrease in both BIS and SEF95 after tracheal intubation, which were not seen in elderly patients (Fig. 3).
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In the present study, BIS was significantly decreased after tracheal intubation in young patients irrespective of receiving isoflurane or sevoflurane. In sharp contrast, BIS was not affected by tracheal intubation in elderly patients, and there were significant differences compared with young patients. Since SEF95 was also decreased after tracheal intubation, a decrease in the EEG frequency would account for the significant decrease in BIS in young patients after tracheal intubation. This is, to our knowledge, the first study showing the differential response of EEG to noxious stimuli between young and elderly patients. Such a decrease in BIS in young patients apparently suggests that the depth of anaesthesia was augmented after tracheal intubation. On the other hand, an abrupt increase in MAP and HR indicates an increased sympathetic response, and there is discordance between BIS and the depth of anaesthesia in young patients.
An abrupt decrease in BIS in response to noxious stimuli has been referred to as a ‘paradoxical arousal’.12–14 Paradoxical arousal is characterized by a shift of dominant frequency of EEG to slow waves in combination with increased sympathetic response and attributable to intense noxious stimuli such as tracheal intubation and surgical incision.12–14 Those previous findings and the observed EEG characterized by slow delta waves suggest that the decrease in BIS observed only in young patients in the present study also results from paradoxical arousal, and EEG parameters such as BIS and SEF95 do not reflect the depth of anaesthesia correctly. Although we could not determine whether paradoxical arousal has never emerged in elderly patients, relatively small inter-individual differences in BIS and SEF95 after tracheal intubation permit us to anticipate that it was unlikely indeed.
Although the reason why such a decrease of EEG frequency and BIS occurred only in young patients remains unclear, significant differences in the potency of anaesthetics shown by the different end-tidal concentrations expressed as multiples of the age-adjusted MAC between young and elderly may account for this (Table 2). These results indicate that the degree of sympathetic blockade could also be different between young and elderly patients, since concentrations of anaesthetics required for blunting adrenergic response are also different between them.15 16 Age-related differences in the activity of reticular neurons or in the intracerebral neurotransmission might also be related to the differences in the frequency ranges of the EEG.17 18
In the absence of noxious stimuli, N2O does not affect EEG frequency or BIS when used alone or in combination with i.v. agents.19 20 In contrast to those studies, both of these parameters significantly decreased in the presence of N2O by tracheal intubation. Since no groups were studied without N2O, its role on a potential reason for these findings cannot be proven in this study. However, results of our previous studies suggest a possible contribution of N2O to the EEG changes observed in the present study. We noted a significant decrease in BIS after tracheal intubation by accidentally adding N2O to sevoflurane in our previous study.7 This finding promoted a study to examine the effect of N2O at different concentrations, and we proved that N2O contributes to the decrease of EEG frequency range and BIS after tracheal intubation during isoflurane and sevoflurane anaesthesia in middle-aged patients.8 However, the effect of age on N2O-induced decrease in EEG still remained unclear. In the present study, we have examined the effect of age on N2O-induced EEG changes. These results are consistent with other reports,13 14 and suggest a remarkable difference between i.v. and volatile agents in their effects on EEG. A significant decrease of EEG frequency with a decrease of BIS is also reported in children with agitation during induction of anaesthesia with sevoflurane 8% and N2O 50%, which supports the disparity between the level of sedation and EEG frequency observed in the present study.21
In addition to the concentrations of anaesthetics not adjusted to age, another major limitation of the present study is that EEG was examined at a single concentration of isoflurane and sevoflurane. However, with lower concentrations, tracheal intubation would have induced more remarkable increase in arterial pressure, HR, and BIS, leading to cardiovascular complications or intraoperative awareness, particularly in elderly patients. We performed tracheal intubation 12 min after induction of anaesthesia. BIS and SEF95 and end-tidal concentrations of anaesthetics were almost stable during the last 5 min before tracheal intubation (Fig. 2); however, it is not clear whether equilibration was established in the concentration of anaesthetics between alveolar and effect site. Further study with a single anaesthetic agent at various concentrations will be required to elucidate the age-associated difference of EEG.
In summary, BIS was significantly decreased after tracheal intubation in young, but not in elderly patients. Since the increase in arterial pressure and HR was commonly observed in both of these patients, paradoxical arousal might be one of the explanations for the EEG changes observed in these young patients. In young patients, the decrease of BIS in response to noxious stimuli could be more commonly induced than in elderly patients, and therefore, careful observation of EEG and haemodynamic response is strongly recommended.
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