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TECHNOLOGY, COMPUTING, AND SIMULATION

Electroencephalographic Mapping During Routine Clinical Practice: Cortical Arousal During Tracheal Intubation?

Wolfgang J. Kox, MD^*, Christian von Heymann, MD, Judith Heinze, Leslie S. Prichep, PhD, E. Roy John, PhD, and Ingrid Rundshagen, MD

*University Hospital of Muenster, Muenster, Germany; Department of Anesthesiology, University Hospital Charité, Humboldt University of Berlin, Campus Charité Mitte, Berlin, Germany; Brain Research Laboratories, NYU School of Medicine, New York, NY; Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY

Address correspondence and reprint requests to Ingrid Rundshagen, MD, Department of Anesthesiology, University Hospital Charité, Campus Charité Mitte, Schumannstr. 20/21, D-10117 Berlin, Germany. Address e-mail to ingrid.rundshagen{at}charite.de.

	Abstract

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We used quantitative analysis of the electroencephalogram (EEG) in 42 patients to assess the effect of tracheal intubation after induction of anesthesia with etomidate and sufentanil using standard clinical practice. The EEG was recorded from eight bipolar electrode derivations and Z-transformed relative to age expected normative data for relative power in the delta, theta, alpha, and beta frequency bands. Tracheal intubation resulted in classical cortical arousal, as indicated by acceleration of the EEG frequencies. Significant effects were seen in all frequency bands, most pronounced in the alpha frequency band, with the largest increase bilaterally in the fronto-temporal regions (F-values: Delta – 9.592, P < 0.001; theta – 1.691, P < 0.001; alpha – 18.439, P < 0.001; beta – 4.504, P < 0.001). Changes in alpha and delta power during induction of anesthesia were correlated with the dose of etomidate (P < 0.05). Changes in alpha after tracheal intubation were correlated at the parietooccipital brain regions to the dose of sufentanil (P < 0.05). Individual titration of the dose of etomidate and sufentanil, as during routine clinical practice, is not sufficient to block the strong noxious stimulation of tracheal intubation and results in cortical arousal. The clinical impact of this cortical wake-up phenomenon is undetermined.

	Introduction

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A major goal of general anesthesia is to achieve an adequate level of hypnosis and analgesia during tracheal intubation and noxious surgical procedures (1). However, the clinical assessment of the grade of anesthesia is often limited because the classical signs of an inadequate level might be absent as a result of the effects of other drugs. For example, muscle responses could be missed because of muscle relaxants, the pupillary size might be altered by the use of opioids or catecholamines, and changes in heart rate (HR) might be blocked by beta receptor antagonists or increased to compensate hypovolemia intraoperatively. There is a need to quantify the cerebral electrical activity with variables other than clinical variables. Electroencephalography (EEG) has been described as one of the most sensitive methods to detect pharmacodynamic effects in brain electric activity but experts disagree about which aspects of anesthetic depth are reflected in the EEG (2–4).

Most of the EEG studies in the literature, however, used standardized protocols with fixed doses of anesthetics, which do not always reflect clinical practice. Therefore, in this study the EEG was used to measure cerebral activity when anesthetics were administered during routine clinical conditions. We used multichannel EEG recordings in combination with power spectrum analysis, which have been shown to quantify changes in brain function related to different states of alertness, sleepiness, and anesthesia (5–6). However, little is known about the topographic pattern of cortical electrical activity during noxious stimulation, such as tracheal intubation or surgical stimulation (7,8).

The present study focuses on a subgroup of patients who received sufentanil and etomidate for induction of general anesthesia using standard clinical practice. EEG was recorded during the awake state, during induction of anesthesia, and after tracheal intubation, to evaluate alterations of regional cerebral activity in the presence of noxious stimulation. The aims of this study were 1) to assess the significance of the topographic changes in EEG power after induction of anesthesia with etomidate/sufentanil during standard clinical practice and 2) to analyze the modifications in this power distribution during laryngoscopy and tracheal intubation. Our hypotheses was that tracheal intubation would not result in significant EEG changes because the anesthetic depth would be adequate when the anesthetic dose was not fixed by protocol but selected by the anesthesiologist.

	Methods

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After approval from the Institutional Ethics Committee and written informed patient consent had been obtained, 42 patients (35 ± 13 yr, 74 ± 12 kg, height 1.76 ± 0.09 m [mean ± sd], ASA physical status I-II, 32 males, 10 females) scheduled for elective surgery were enrolled in the study. All patients were free from neurological or psychiatric diseases and none were taking medication.

Midazolam (0.1 mg/kg orally) was given 45 min preoperatively. On arrival in the operating room, an 18-gauge catheter was inserted in a peripheral forearm vein. Anesthesia was induced by bolus injection of sufentanil followed by etomidate. Nondepolarizing muscle relaxants were used to facilitate tracheal intubation, after patients became unresponsive. The induction dose, the injection speed or the times to intubation were not standardized by protocol. It was up to the anesthesiologist to determine the level of anesthesia individually and when to perform laryngoscopy and intubation. The anesthesiologist was blinded to the EEG.

All recordings were made using a Spectrum 32 EEG data acquisition system (Cadwell Laboratories, Kennewick, WA). Nineteen electrodes were pasted on the scalp, at positions corresponding to the International 10/20 system, referenced to linked ears. A ground electrode was placed on the cheek. In addition, electrodes for recording the electrooculogram were placed diagonally above and below the orbit of the eye for detection of eye movement artifact. An electrocardiogram electrode was placed on the thorax. Eight bipolar derivations were constructed. The bipolar EEG montage is shown in Figure 1.

View larger version (23K): [in this window] [in a new window]   Figure 1. Electrode positions according to the International 10-20 system. Black circles indicate the electrodes of the bipolar electroencephalogram montage used in this study.

Amplifiers had a bandpass from 0.5 to 70 Hz, with a 50 Hz notch filter. All impedances were kept below 5 k and were checked regularly throughout the procedure. The A/D converter sampled at 200 Hz per channel with 12-bit resolution. The data were reduced to 100 Hz before analysis, using Fant's resampling algorithm, which minimizes aliasing (9). All EEG data were edited visually by an experienced EEG technician, augmented by an automatic EEG artifact detection algorithm. At each state defined below, an artifact-free sample was selected for quantitative ana-lysis containing 24–48 segments, each of 2.5 s in duration, with the exception of induction in which only the last 12 segments before loss of consciousness (LOC) were used because induction often occurred quickly and its duration varied widely.

Baseline (BL) EEG recordings were performed in the awake state the day before surgery. The patients rested comfortably with closed eyes during the recording procedure. EEG recording was performed continuously throughout the delivery of anesthesia. From these recordings the following segments were selected for further analysis: 1) Premed, approximately 45 min after premedication; 2) Induction, after bolus injection etomidate; 3) LOC, after loss of consciousness; defined as stopping counting and being unable to respond to verbal command; and 4) Intubation, immediately after tracheal intubation.

During induction of anesthesia HR, noninvasive systolic, diastolic and mean arterial blood pressures and pulse oxymetric oxygen saturation (Spo₂) were registered simultaneously. The total amounts of etomidate (mg/kg body weight) and sufentanil (µg/kg body weight) each patient received during induction were documented.

The artifact-free EEG was converted from the time to the frequency domain via a Fast Fourier Transform (FFT) for each epoch. These power spectra were averaged across the set of artifact-free segments (for Induction only 12–24 EEG 2.5-s segments [30–60 s] were used because of variation in time losing consciousness) to yield measures of power in each of the 4 frequency bands for every electrode position: Delta (1.5–3.5 Hz), theta (3.5–7.5 Hz), alpha (7.5–12.5 Hz), and beta (12.5–25 Hz). Each EEG feature was then transformed for Gaussianity and expressed as standard scores (z-score) relative to the mean and sd of the EEG feature obtained from an age-appropriate normal database (9). This paper will concentrate on the z-scores of relative power in each frequency band.

The distribution of data was tested using the Kolmogoroff-Smirnoff test. The changes in EEG data in each frequency band and the vital variables were analyzed using a multivariate analysis of variance (Hotelling's T-square; repeated measurement design). To analyze topographic changes during anesthetic induction, data at BL, Induction, and LOC were included in the overall multivariate analysis resulting in a full 2-factor within design, separately conducted for each frequency band (8 EEG derivations x 3 time points). Similarly data at LOC and Intubation were included for analyzing changes induced by stimulation. Post hoc comparison was performed using the dependent Student's t-test. Correlations (Pearson) were calculated for the induced EEG changes during induction (BL-LOC) and intubation (LOC-INTUBATION) and the total dose of etomidate and sufentanil. P values less than or equal to the 0.05 level were considered significant.

	Results

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Significant F values were obtained from the multivariate analyses of variance for each frequency band, revealing the biggest changes for delta and alpha power, when BL, LOC, and Intubation were included in the analysis comparing EEG activities in different brain regions over time (F-values: Delta – 24.210, P < 0.001; theta – 5.730, P < 0.001; alpha – 23.725, P < 0.001; beta – 13.502, P < 0.001).

Significant interactions were found between time and topography for all frequency bands but were most pronounced for alpha (F-values: Delta - 3.850, P < 0.001; theta – 0.814, P = 0.002; alpha – 5.250, P < 0.001; beta – 4.738, P < 0.001). Although delta and theta increased at all electrode positions, alpha and beta decreased in all brain regions (P < 0.001). For alpha, the most pronounced topographic changes occurred in temporal and parietooccipital regions. The largest decrease in beta was found bilaterally in frontotemporal regions. Means and sd of the z-scores and results of the post hoc comparisons are given in Table 1.

EEG changes in the delta and alpha band were significantly correlated with the total dose of etomidate during induction of anesthesia. Correlation coefficients are given in Table 2.

With respect to changes induced by tracheal intubation, significant changes were seen in all frequency bands, most significant for alpha (F-values: Delta – 9.592, P < 0.001; theta – 1.691, P < 0.001; alpha – 18.439, P < 0.001; beta – 4.504, P < 0.001). The largest changes in alpha were observed bilaterally in the fronto-temporal regions (Fig. 2). In general, the following changes were observed during Intubation: 1) delta activity decreased in comparison with LOC in all electrode positions (P < 0.05; Fig. 3); 2) theta returned to baseline levels in the central leads; 3) the anesthetic-induced loss of alpha and beta activity was partially reversed in all brain regions (P < 0.001).

View larger version (20K): [in this window] [in a new window]   Figure 2. Z-transformed bipolar relative power for delta. Measurements were performed (bars from left to right) in the awake state baseline (BL), after premedication with midazolam, after induction of anesthesia with etomidate/sufentanil, during loss of consciousness (LOC), and after tracheal intubation. Electrode montage according to the international 10-20 system: T3T5, T4T6. *P < 0.001 versus BL; P < 0.001 LOC versus intubation.

View larger version (18K): [in this window] [in a new window]   Figure 3. Z-transformed bipolar relative power for alpha. Measurements were performed (bars from left to right) in the awake state baseline (BL), after premedication with midazolam, after induction of anesthesia with etomidate/sufentanil, during loss of consciousness (LOC), and after tracheal intubation. Electrode montage according to the international 10-20 system: F7T3, F8T4. *P < 0.001 versus BL; P < 0.001 LOC versus intubation.

EEG changes in delta (at C3Cz) and in alpha (at P3O1 and P4O2) were correlated with the dose of sufentanil, i.e., the larger the dose of sufentanil, the smaller the EEG changes.

The vital variables are shown in Table 3. HR, systolic, diastolic and mean arterial blood pressure and Spo₂ remained unchanged when tracheal intubation was performed.

LOC occurred after 40 s (median; range, 14–83 s) and tracheal intubation was performed after 279 s (range, 73–960 s). The amounts of drugs the patients received during induction of anesthesia differed markedly: etomidate 0.3 (range, 0.2–0.8 mg/kg); sufentanil 0.5 (range, 0.2–0.6 µg/kg). There were no significant correlations with the total amounts of sufentanil and etomidate (r = 0.08; P = 0.57).

	Discussion

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This study demonstrates that multichannel EEG can be used during standard clinical administration of anesthesia to evaluate cerebral electrical activity in the unstimulated and stimulated states in the anesthetized patient. Changes in alpha frequencies showed the most significant topographic alterations during both conditions. Further, EEG changes in alpha and delta during LOC were correlated to the total dose of the given hypnotic. In contrast to our hypothesis "during clinical practice individual titration of anesthetics sufficiently blocks the cortical response to intubation," it was demonstrated that classical cortical arousal, defined as an increase in EEG frequencies, followed tracheal intubation. Changes in EEG alpha activity at both occipital brain regions were correlated with the dose of sufentanil. The vital variables remained unchanged and did not correspond to cortical arousal. Our study replicates and extends the results of a recent study to other agents; we recently reported using multichannel quantitative EEG during induction with thiopental and fentanyl (10).

With respect to the findings during induction of anesthesia, our results are in line with earlier studies using visual analysis of multichannel EEG signals or processed EEG variables, which report a shift from alpha and beta power to the lower frequencies during deep stages of etomidate anesthesia (11–13). A biphasic EEG response is an initial increase of power followed by a decrease; this has been interpreted by some as a possible marker for the transitional state between consciousness and unconsciousness (14). We did not demonstrate this biphasic EEG effect in any of the frequency bands, perhaps as a result of the combination of drugs used and the rapidity of induction of anesthesia by bolus injection. Lallemand et al. (15) studied the bispectral index (BIS), a computerized EEG parameter, during orotracheal intubation when patients randomly received etomidate 0.2 mg/kg, 0.3 mg/kg, or 0.4 mg/kg. Similar to our study, time to loss of eyelash reflex and time to tracheal intubation showed a large interindividual variability (time to LOC: range, 10–295 s; time to intubation: range, 86–420 s). The interindividual variability of plasma concentration of etomidate was large (range, 29–998 ng/mL). Intubation was performed when the BIS had decreased to 50. No changes in BIS and hemodynamics were documented 30 s after intubation. The authors concluded that performing tracheal intubation is possible without purposeful movement and without cortical arousal when BIS levels are lower than 50. In contrast, we demonstrated classical cortical arousal after tracheal intubation even when opioids were administered in addition to etomidate. Hagihira et al. (16) reported that the BIS and the spectral edge frequency 95 showed variable changes to noxious stimulation during isoflurane and sevoflurane anesthesia. Thus, BIS did not always adequately reflect cortical activation during noxious stimulation. More sensitive EEG variables were changes of the peak heights of the EEG bicoherence. Moreover, BIS values below 40 have been shown in fully awake, paralyzed volunteers, showing the complexity of the interpretation of the BIS (17).

It has been shown that hemodynamics, intracranial pressure, and cerebral perfusion pressure remained constant when a burst suppression EEG pattern during etomidate-based anesthetic induction was achieved before tracheal intubation (18–19). The etomidate dose required to reach burst suppression was 1.28 ± 0.11 mg/kg, and in the other study it was 1.15 ± 0.09 mg/kg. Both studies were performed in patients with intracranial pathologies and procedures. However, during clinical routine for standard surgical procedures the dose of etomidate, if used in combination with an opioid, is much lower, as we demonstrated. As a consequence, cortical arousal follows tracheal intubation in clinical practice.

Kochs et al. (7) showed with topographical EEG analysis that surgery resulted in increases in delta activity and decreases in alpha activity predominantly at frontal leads. The delta shift was attenuated in the group with a larger concentration of isoflurane (0.6% versus 1.2% isoflurane). The authors interpreted their findings to be related to intraoperative "paradoxical" arousal phenomena. The difference between the present findings and their results are explained to some extent by the use of sufentanil. Opioids have been shown to block or diminish the cortical response to tracheal intubation in a dose-dependent fashion (20,21).

The physiologic basis of the EEG response to noxious stimulation during anesthesia is complex. The extralemniscal reticular activating system has been shown to be essential for EEG arousal (22). There is evidence from animal studies that both synchronized and desynchronized EEG responses to noxious stimulation may occur when the depth of anesthesia is changed (23,24). Moreover, depth of anesthesia depends on the intensity of the noxious stimulation (25). Kiyama and Takeda (26) reported a paradoxical arousal in patients receiving general anesthesia, whereas this response was blocked in patients who received a combination of balanced and extradural anesthesia. They suggested that surgical stimuli in the absence of adequate analgesia induced a paradoxical arousal response. Freye et al. (27) concluded, from a study in cardiac patients receiving fentanyl (7 µg/kg) or sufentanil (1 µg/kg), that an increase in power of the alpha band after tracheal intubation seemed to be closely correlated with cortical reactivation and reduction of hypnosis. In conclusion, the selective action of anesthetics on neurons involved in the complex multisynaptic organization mediating arousal, in combination with the intensity of the stimulation, adds to the different electrical response of the brain measured with the EEG.

Multivariate analysis of variance is a reliable statistical approach to analyze related variables (28). Another interesting multivariate statistical approach was used by Bischoff et al. (5), who investigated the topography of clonidine-induced EEG changes in volunteers. Principal component analysis was used for data reduction to identify a small numbers of components to explain most of the variance observed in a much larger number of variables (26 EEG leads, 4 frequency bands). Thereby the most prominent effects of clonidine were increases in the delta band over centroparietooccipital areas and decreases in alpha band over parietooccipital regions. Administration of clonidine resulted in subjective drowsiness assessed by visual analog scales. The authors pointed out that the principal component analysis technique does not clarify the physiological relations but only exposes statistical correlation between data.

In conclusion, we documented cortical arousal during tracheal intubation during routine clinical conditions with multichannel quantitative EEG mapping. The change in alpha power was identified as the most sensitive EEG measure to reflect the modulation of cerebral electrical activity during laryngoscopy and tracheal intubation. It is not possible in these analyses to correlate this shift in EEG frequencies directly to cortical or subcortical origins. Future studies combining multichannel EEG with source localization algorithms or other functional neuroimaging techniques could further enhance the understanding of the anesthetized brain and its modulation by noxious input. In addition, studies combining EEG mapping with cognitive assessment and measuring stress response, e.g., catecholamine or neurotransmitter release, are warranted to address the question of clinical relevance of the EEG findings presented herein.

	Footnotes

 
Accepted for publication October 25, 2005.

Supported, in part, by Physiometrix.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kox, W. J. Articles by Rundshagen, I. Search for Related Content PubMed PubMed Citation Articles by Kox, W. J. Articles by Rundshagen, I. Related Collections Airway Monitoring (Non-cardiac)