Agitation and changes of Bispectral IndexTM and electroencephalographic-derived variables during sevoflurane induction in children: clonidine premedication reduces agitation compared with midazolam{dagger}

I. Constant*,1, Y. Leport1, P. Richard1, M.-L. Moutard2 and I. Murat1

1 Service d’Anesthésie-Réanimation, Hopital d’enfants Armand Trousseau, Assistance-Publique, Hôpitaux de Paris, Paris VI University, France. 2 Service de Neurologie pédiatrique, Hopital Saint Vincent de Paul, Assistance-Publique, Hôpitaux de Paris, France*

*Corresponding author. E-mail: isabelle.constant@trs.ap-hop-paris.fr
{dagger}Presented in part at the annual meeting of the European Society of Anaesthesiologists, Nice, France, April 6–9, 2002.

Accepted for publication: November 14, 2003


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. This double-blind randomized study was undertaken to assess agitation, Bispectral IndexTM (BISTM) and EEG changes during induction of anaesthesia with sevoflurane in children premedicated with midazolam or clonidine.

Methods. Children were allocated randomly to receive rectal midazolam 0.4 mg kg–1 (n=20) or oral clonidine 4 µg kg–1 (n=20) as premedication. Rapid induction of anaesthesia was achieved with inhalation of sevoflurane 8% in nitrous oxide 50%–oxygen 50%. After tracheal intubation, the children’s lungs were mechanically ventilated and the inspired sevoflurane concentration was adjusted to achieve an end-tidal fraction of 2.5%. The EEG and BISTM were recorded during induction until 10 min after tracheal intubation. The EEG was analysed using spectral analysis at five points: baseline, loss of eyelash reflex, 15 s before the nadir of the BISTM (BISnadir), when both pupils returned to the central position (immediately before intubation), and 10 min after intubation.

Results. Agitation was observed in 12 midazolam-treated and five clonidine-treated patients (P=0.05). At baseline, EEG rhythms were slower in the clonidine group. Induction of anaesthesia was associated with similar EEG changes in the two groups, with an increase in total spectral power and a shift towards low frequencies; these changes were maximal around the end of the second minute of induction (BISnadir). When the pupils had returned to the central position, fast EEG rhythms increased and BISTM was higher than BISnadir (P<0.05). In both groups, agitation was associated with an increase in slow EEG rhythms at BISnadir.

Conclusions. Compared with midazolam, clonidine premedication reduced agitation during sevoflurane induction. During induction with sevoflurane 8% (oxygen 50%–nitrous oxide 50%), the nadir of the BISTM occurred at the end of the second minute of inhalation. Agitation was associated with a more pronounced slowing of the EEG rhythms at BISnadir compared with inductions in which no agitation was observed. The BISTM may not follow the depth of anaesthesia during sevoflurane induction in children.

Br J Anaesth 2004; 92: 504–11

Keywords: anaesthetic techniques, induction; anaesthetics volatile, sevoflurane; brain, electroencephalography; monitoring, bispectral index; complications, agitation; children


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Sevoflurane is becoming very popular for inhalational induction of anaesthesia in children. However, we demonstrated that agitation occurred in 60% of children during sevoflurane induction.1 Clonidine given orally at a dose of 4 µg kg–1 is an effective premedicant in children.2 It has sedative properties and prevents emergence agitation after sevoflurane anaesthesia.3 We speculated that premedication with clonidine may decrease the incidence of agitation during sevoflurane induction in children. In an attempt to understand more precisely the phenomenon commonly observed during induction, we recorded the electroencephalogram (EEG) continuously.

The second goal of this study was to investigate the general agreement of Bispectral IndexTM (BISTM) measurements with the frequency of the EEG during sevoflurane induction in children. The BISTM has been shown to be a quantifiable measure of the hypnotic effect of anaesthetic drugs on the central nervous system.4 6 This EEG-based monitor of anaesthetic effect integrates various EEG descriptors into a single dimensionless, empirically calibrated number. Although a BISTM/anaesthetic concentration relationship similar to that seen in adult patients6 may exist in paediatric patients during sevoflurane sedation,7 there are no data describing the BISTM changes during sevoflurane induction in children.

Therefore, this double-blinded randomized study was designed to assess clinical, EEG and BISTM changes during sevoflurane induction in children premedicated with midazolam or clonidine.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patients and study design
The study was approved by our institutional ethics committee (CCPPRB Saint-Antoine, Paris, France) and written informed consent was obtained from parents. We studied 40 children ASA PS I aged 2–10 yr who were scheduled for elective tonsillectomy. They were allocated randomly to one of two treatment groups using a prospective randomized design. Patients and investigators were blinded to the premedicant and the code was broken after completion of the study. Patients in the clonidine group received oral clonidine 4 µg kg–1 with a small amount of water (total volume of 2 ml) 1 h before induction and 2 ml of saline by the rectal route 30 min before induction. Patients in the midazolam group received 2 ml of water administered by the oral route 1 h before induction and our standard premedication with intrarectal midazolam 0.4 mg kg–1 with a small amount of saline (total volume of 2 ml) 30 min before induction.

Anaesthesia was induced with sevoflurane 8% in a mixture of oxygen and nitrous oxide (50–50), and this inspired concentration was maintained up to tracheal intubation. The circuit was primed with sevoflurane 8% and mask induction was performed using an open circuit at high fresh gas flow (8 litres min–1). Expired gases and oxygen saturation were recorded continuously (Capnomac Ultima; Datex, Instrument Corporation, Helsinki, Finland). The time to loss of eyelash reflex and the time for the pupils to return to the central position were recorded. In addition, the degree of airway obstruction and the time when the oral airway was inserted if required were recorded. Ventilation of the lungs was manually assisted before tracheal intubation at a rate close to 20 min–1. Tracheal intubation was performed using a preformed oral cuffed tracheal tube after placement of an i.v. line, and just after visualization of the pupils in the central position. After placement of the tracheal tube, the lungs were mechanically ventilated with a tidal volume of 10 ml kg–1 at the rate of 20 min–1 (Aestiva; Datex-Ohmeda, Helsinki, Finland). The inspired concentration of sevoflurane was reduced to obtain an end-tidal fraction (SD) of 2.5 (0.1)% and this expired concentration was maintained for 10 min. Surgery started after completion of the study, and anaesthesia was maintained with sevoflurane in all children.

The induction period until 10 min after placement of tracheal tube was videotaped and reviewed by a blinded, independent paediatric neurologist (MLM) in order to assess the presence of agitation. Agitation was defined as involuntary movements of upper and/or lower limbs during induction and before tracheal intubation that excluded involuntary movements related to mask placement or venous puncture. The time of the beginning and end of the agitation phase was recorded.

Analysis of BISTM data
The disposable BisSensor (Aspect Medical Systems, Newton, MA, USA) was applied to the forehead of each child before induction of anaesthesia and was connected to an Aspect Medical Systems Model A-2000 BIS Monitor 2.10. The adult sensor was used for all patients. The skin was prepared to ensure low impedance and a good quality of signal. The smoothing window was set at 15 s and the values of BISTM were downloaded online onto a computer for later analysis (sample time 5 s). BISTM values at loss of eyelash reflex and when the pupils returned to the central position were noted. The other values of BISTM were extracted retrospectively from the file downloaded for each patient, as follows: the BISTM at baseline was calculated as the mean of BISTM values recorded during the 60 s period preceding induction, the nadir of the BISTM was the lowest value of BISTM detected from the start of induction to the time when the pupils returned to the central position (the corresponding time was also noted), the BISTM at 2.5 (0.1)% end-tidal sevoflurane was calculated as the mean of BISTM values recorded during the tenth minute after tracheal intubation.

Analysis of EEG data
Independently from the BISTM monitor, the EEG was recorded continuously in awake children before anaesthesia, during induction until 10 min after tracheal intubation. A single channel was recorded from Ag–AgCl electrodes placed on the forehead and left mastoid, with the right mastoid as the common electrode. The electrode impedance was checked automatically and maintained at less than 5 k{Omega}. The EEG signal was acquired (256 Hz) on a microcomputer (Compaq) using the Brain-QuickTM program stem II, (Micromed, Merignac, France) and stored on hard disk. Bandpass filters were set at 0.5–30 Hz.8

The EEG was analysed in the frequency domain. Spectral analysis of the EEG signal was performed using fast Fourier transformation (FFT) (Acqknowledge v3.25; Biopac Systems, Santa Barbara, CA, USA) on 8-s epochs.9 The following variables were calculated:10 total spectral power (TSP), defined as the area under the curve of the spectrum (µV2), spectral edge frequency 95 (SEF95 = the frequency below which 95% of the EEG power is located) and median power frequency (MPF = the frequency below which 50% of the EEG power is located). Spectral bands of 0–4 Hz (delta), 4–8 Hz (theta), 8–13 Hz (alpha) and 13–30 Hz (beta) were analysed and the power of the spectral bands was calculated and expressed as a percentage of total spectral power. The delta ratio (ratio of the power in the 8–30 Hz band to power in the 0–4 Hz band) was calculated. These EEG-derived variables were calculated at baseline, at loss of eyelash reflex, when the pupils returned to the central position, at 2.5 (0.1)% end-tidal sevoflurane and 15 s before the occurrence of the nadir of BISTM (BISnadir).

Statistical analysis
A previous study showed that 60% of children premedicated with midazolam demonstrated agitation during sevoflurane induction.1 In addition, compared with placebo, clonidine (2 µg kg–1, i.v.) has been demonstrated to reduce postoperative sevoflurane-induced agitation by more than 80% in children premedicated with midazolam.3 Therefore, we calculated the sample size according to an expected reduction of 60% of agitation in children premedicated with oral clonidine vs midazolam. We estimated that 20 subjects were required per group (power of 80% and P<0.05).

Data for the two groups (clonidine and midazolam) were analysed using non-parametric repeated measures analysis of variance (Friedman’s test). Incidence of agitation was compared between the two groups using the {chi}2 test. A non-parametric equivalent of the unpaired Student’s t test (Mann–Whitney U test) was performed for comparison of EEG data between children showing agitation during induction and the other subjects (Statview version 5.0, Abacus Concept, Berkeley, CA). P<0.05 was considered significant. Clinical and EEG data are expressed as mean (SD) and BIS data are expressed as median (range).


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Clinical data (Table 1)
Twenty children were enrolled in each group. The two groups were comparable regarding age and weight. The time to obtain loss of eyelash reflex was similar in the two groups, but the pupils were centred earlier in the clonidine group (P=0.027). In all children the trachea was intubated successfully at the first attempt (at central pupils).

Most of the children required insertion of an oral airway within the first 3 min of induction to relieve partial airway obstruction (12 in the clonidine group vs 11 in the midazolam group). Peripheral oxygen saturation was maintained above 96% throughout the study in all children. In the two groups, respiratory frequency increased significantly at loss of eyelash reflex compared with control awake values (20.6 (2.9) in the midazolam group, and 19.2 (2.8) in the clonidine group at baseline vs 30.5 (8.2) in the midazolam group and 28.1 (7.1) in the clonidine group at loss of eyelash reflex). This increase was not significantly different between the two groups. No hypercarbia (defined as end-tidal carbon dioxide >48 mm Hg) or hypocarbia (defined as end-tidal carbon dioxide <30 mm Hg) was observed.

Agitation
Agitation occurred in 12 midazolam-treated and five clonidine-treated children (P=0.05). This transient agitation started earlier (45 (7) vs 57 (15) s, P=0.04) and lasted longer (56 (24) vs 28 (14) s, P=0.03) in the midazolam group compared with the clonidine group.

BISTM and EEG data (Table 2)
The BISTM was similar in the two groups throughout the study period. Induction of anaesthesia was associated with a rapid decrease of BISTM values, reaching the value of about 50 at loss of eyelash reflex. The maximal depression of BISTM (nadir of BISTM) occurred at the end of the second minute of induction (126.0 (35.7) s in the midazolam group vs 130.7 (22.7) s in the clonidine group, not significant). From the nadir, the BISTM increased rapidly to stabilize at around 40 within the third minute of induction. Consequently, the BISTM was higher when the pupils returned to the central position than at the end of the second minute (BISnadir). An example of the time course of BISTM is shown in Figure 1.



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Fig 1 Example of time course of BISTM during sevoflurane induction in a 5-yr-old child premedicated with midazolam. The agitation period is shown.

 
Regarding the EEG data, the baseline EEG patterns were different in the clonidine group compared with the midazolam group. The slow waves (delta and theta) were more prominent and the fast rhythms (beta) were less pronounced, as reflected by a lower delta ratio and median power frequency after clonidine premedication compared with midazolam. These differences disappeared when sevoflurane was introduced. Induction of anaesthesia was associated with an increase in the total spectral power of the EEG signal in all children and a shift towards the low-frequency spectral bands (Table 2); these changes were maximal at BISnadir. In the third minute, the relative contribution of fast oscillations (alpha and beta) increased. When the pupils returned to the central position, the SEF95 was markedly increased compared with the end of the second minute of induction (BISnadir) (Table 2). This change was associated with a significant shift of the EEG oscillations towards high frequencies (Table 2, Fig. 2).


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Table 2 EEG data (mean (SD) and BISTM data (median [range]). Asterisks indicate significant differences between clonidine and midazolam groups (*P<0.05; ***P<0.001); {dagger}significant differences between BISnadir and central pupils ({dagger}P<0.05; {dagger}{dagger}P<0.01; {dagger}{dagger}{dagger}P<0.001). BISnadir is 15 s before the time of occurrence of the nadir of BISTM
 


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Fig 2 Examples of EEG tracings recorded during induction of anaesthesia with sevoflurane in children premedicated with midazolam or clonidine at baseline (left), 15 s before the occurrence of the nadir of BISTM (BISnadir) (middle) and at central pupils (right), with the corresponding power spectra and BISTM values.

 
Burst suppressions were observed in four out of 20 patients in each group. Burst suppression occurred in all cases after centralization of the pupils.

From our systematic clinical observations, we noted that the nadir of the BISTM occurred at the end of the agitation period (Figs 1 and 3).



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Fig 3 Mean values of BISTM as a function of time, measured during sevoflurane induction in children who demonstrated agitation and those who demonstrated no agitation (mean and 95% confidence interval). These traces are synchronized from the beginning of sevoflurane inhalation. Individual agitation periods are represented by black marks.

 
When the children demonstrating agitation during induction were taken together whatever the premedication group, they showed a lower mean value of BISTM and a different EEG profile at BISnadir compared with the children in whom agitation was not observed. The slow waves (delta) were more prominent and the faster rhythms (alpha and beta) were less pronounced, as reflected by lower delta ratio and median power frequency (Table 3, Fig. 3).


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Table 3 Comparison of EEG and BISTM data calculated at BISnadir from children showing agitation during induction of anaesthesia [agitation (+)] vs those showing no agitation [agitation (–)]. EEG data are mean (SD). BISTM data are median [range]. BISnadir is 15 s before the time of occurrence of the nadir of BISTM (median [range])
 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Clonidine premedication compared with midazolam reduced the incidence of agitation during sevoflurane induction and reduced the time to obtain centralized pupils in children. During rapid induction with sevoflurane 8% in a 50–50 mixture of nitrous oxide and oxygen, the nadir of BISTM occurred at the end of the second minute of inhalation and corresponded to a noticeable shift to lower frequency bands of the EEG tracing. Whatever the premedication group, children who demonstrated agitation during induction showed slower EEG traces during the second minute of induction compared with those who did not demonstrate agitation.

Clonidine premedication vs midazolam premedication
In our institution, sevoflurane induction of anaesthesia is performed using high inspired concentrations of sevoflurane (8%) to speed up loss of consciousness and to reduce the child’s distress scores.11 12 In these conditions we found that the time required to obtain the clinical end-point of centralization of the pupils is reduced in children premedicated with clonidine compared with midazolam. These results are in accordance with the shortening of induction time when anaesthesia is induced with 5% sevoflurane using the triple-breath method in adults premedicated with clonidine compared with placebo.13 This speeding-up of sevoflurane induction may be explained by the decrease in anaesthetic requirement induced by clonidine.

Agitation is not uncommon during induction of anaesthesia with sevoflurane in children, whatever the induction technique.14 15 Agitation usually occurs after loss of consciousness and lasts about 45 s when sevoflurane 7% is administered in a mixture of oxygen and nitrous oxide in children premedicated with midazolam.1 Clonidine premedication was associated with a reduced incidence and a shorter duration of agitation than that observed with midazolam. This is in agreement with previous adult and paediatric studies. Indeed, in adult intensive care patients, clonidine is effective in preventing and treating clinical excitement.16 Moreover, compared with placebo, i.v. clonidine prevents sevoflurane-induced postoperative clinical excitement in children premedicated with midazolam.3

Both midazolam and clonidine are known to have specific effects on EEG tracings. Intravenous clonidine administration increases delta band activity and decreases alpha band activity,17 whereas the EEG effects of midazolam are mainly characterized by an increase in beta activity.18 The EEG patterns observed at baseline in the two groups of children premedicated with clonidine or midazolam are similar to those described in previous adult studies, suggesting that an effective plasma concentration was achieved. These EEG differences were not associated with similar differences in BISTM values at baseline. This discrepancy between the BISTM and EEG data may suggest that the algorithm of the BISTM has low sensitivity in this range of frequencies in an awake patient. However, the differences between the two EEG profiles disappeared as soon as the induction began. The EEG effects of sevoflurane seem to override the effects of premedication on EEG tracings.

EEG and BISTM data
Sevoflurane allows tracheal intubation to be performed without muscle relaxants in children.19 20 In our study the decision about when the child was ready for intubation was based on clinical indicators of depth of anaesthesia. Constriction and centralization of the pupils indicated that the level of surgical anaesthesia had been reached.

In adults, biphasic EEG changes with increasing drug concentration have been described for most hypnotic agents, including sevoflurane.21 These so-called biphasic effects are described as an increase in fast rhythms followed by a decrease in fast rhythms associated with a simultaneous increase in delta activity. They have been observed during incremental sevoflurane inhalation and they correspond to the sedative effects of hypnotic agents. In our study, using a high inspired sevoflurane concentration, the initial EEG changes were small in the first few seconds after the start of induction. Induction was associated with an increase in slow rhythms from loss of eyelash reflex to the end of the second minute of induction. From this point, the frequency of rhythms increased noticeably within the third minute, with a shift towards faster rhythms, and then remained unchanged until the time of tracheal intubation. The BISTM followed the EEG changes closely, with a short delay of ~15 s due to the calculation epoch. The nadir of BISTM observed at the beginning of the third minute may reflect the slow EEG frequency observed around the end of the second minute of induction. The subsequent increase in BISTM may reflect the shift of EEG rhythms towards faster frequencies. Consequently, the BIS was noticeably higher when the plane of surgical anaesthesia was reached, as attested by centralization of the pupils, compared with a few minutes sooner. It is interesting that during sevoflurane induction with nitrous oxide, when the clinically assessed depth of anaesthesia increases, BISTM values increased paradoxically. This discrepancy between the clinically assessed depth of anaesthesia and BISTM values during induction of anaesthesia may be explained by the calculation algorithm, which was essentially based on i.v. anaesthesia in adults. However, BISTM and EEG changes are very similar. Our findings are consistent with the paradoxical increase in BISTM values demonstrated in adults when isoflurane concentration was increased: this phenomenon has been explained by a pre-burst EEG state.22 In children this paradoxical increase in BISTM was also observed when the end-tidal sevoflurane concentration of 4% was compared with 3%.7

EEG effects of anaesthetics may vary according to the cortical topography of recording.23 Our findings result from frontal and cortical EEG data. This limited field of investigation may highlight a fast and transient pharmacodynamic effect of sevoflurane on the frontal cerebral cortex. However, this hypothesis requires further investigation.

Agitation and EEG-derived variables
Agitation phenomena have been reported in almost all studies designed to assess induction characteristics using sevoflurane in children. Agitation is described in most studies as the occurrence of non-purposeful movements requiring restraint during induction. In the present study, agitation was observed in 17 children out of 40. Because under sevoflurane anaesthesia we found similar EEG profiles in the two premedication groups, we analysed the children retrospectively according to the presence or absence of agitation during induction. Our results reveal that, whatever the premedication group, children who demonstrated agitation during induction exhibited lower EEG frequencies 15 s before the nadir of BISTM compared with children who remained quiet during induction. It is interesting to underline the fact that agitation was observed when BISTM values were at their lowest and EEG frequencies were slowest. These findings might suggest a relationship between the occurrence of agitation and the rapid increase in delta activity on EEG observed in the second minute of induction. Furthermore, the clinical and EEG events were transient and almost simultaneous in the first 2 min of induction. These observations might be explained by the rapid onset of cerebral effects of sevoflurane, which may affect cortical and subcortical area differently.24 25 However, further research would be needed to investigate the mechanisms of the sevoflurane-induced agitation.

In conclusion, we have demonstrated that clonidine premedication reduces the incidence of agitation compared with midazolam premedication during sevoflurane induction. Whatever the premedication group, during rapid induction with sevoflurane 8% in a mixture of nitrous oxide and oxygen (50–50), the nadir of BISTM occurred at the end of the second minute of inhalation and corresponded to a noticeable shift to lower frequency bands of the EEG tracing. This slowing was more pronounced when agitation was observed. In addition, our study demonstrated that the BISTM may not reflect the clinically assessed depth of anaesthesia during sevoflurane induction.


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Table 1 Population data. Mean (SD) (range). *Significant differences between the clonidine and midazolam groups (P<0.05)
 

    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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