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Anesth Analg 2004;99:1141-1146 © 2004 International Anesthesia Research Society doi: 10.1213/01.ANE.0000130618.99860.48
Steven J. Barker Section Editor |
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Abstract |
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In 21 patients given sevoflurane anesthesia, we simultaneously compared the abilities of Bispectral Index (BIS) and rapidly extracted auditory evoked potentials index (AAI) to display the effect of an increasing cerebral concentration of sevoflurane, with and without noxious stimulation. In addition to BIS/AAI, hemodynamic variables were monitored. After titrating sevoflurane to BIS = 50–55 during 15 min, the end-tidal concentration of sevoflurane (1.46% ± 0.20%) was doubled followed by a noxious stimulus, laryngoscopy, applied at random time points within the following 15 min. After the end-tidal concentration of sevoflurane was doubled, a substantial reduction in BIS was observed, whereas only a slight reduction in AAI was seen (P < 0.0001). BIS/AAI responses to laryngoscopy were not attenuated with increasing wash-in of sevoflurane. After noxious stimulation, AAI exceeded the highest recommended value, 25, in 3 cases, whereas BIS did not exceed the recommended threshold, 60, in any of the patients. Response times for BIS and AAI were 44.5 ± 26 and 47 ± 31 s, respectively. These results suggest that, at a hypnotic level associated with surgical sevoflurane anesthesia, BIS better displays drug-related alterations in the level of hypnosis than AAI or hemodynamic variables but there is no difference between BIS and AAI in the time to response to a noxious stimulus.
IMPLICATIONS: At a hypnotic level associated with surgical sevoflurane anesthesia, the data in this study suggest that Bispectral Index (BIS) better displays drug-related alterations in the level of hypnosis than auditory evoked potentials index (AAI) or hemodynamic variables and that there is no difference between BIS and AAI in the response time to a noxious stimulus.
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Introduction |
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The incidence of explicit recall during general anesthesia for various types of general surgery is approximately 0.2% (1). Intense noxious stimulation during laryngoscopy and intubation are important reasons for awareness, and this probably also applies to other situations in which the degree of noxious stimulation is suddenly increased (1). The Food and Drug Administration has recently approved Bispectral Index (BIS) for reducing the incidence of awareness. BIS is a derived parameter from the electroencephalogram (EEG) used for monitoring the level of hypnosis during anesthesia (2). Another commercialized cerebral monitor uses rapidly extracted auditory evoked potentials to calculate an index, the A-line ARX index or AAI (3). The Food and Drug Administration has previously approved both BIS and AAI for reducing the amount of administered anesthetics. However, individualized delivery of anesthetics is possible only if the displayed indices clearly show the effects of alterations in drug delivery and in the degree of noxious stimulation (4). It is also desirable that the true response to noxious stimulation be displayed with minimal delay. Previous studies on the relation between drug concentration and indices from cerebral monitoring have mainly been done with propofol using steady-state concentrations. The present study was done to mimic the dynamic clinical situation when the sevoflurane concentration is increased to meet anticipated surgical stimulation, to simultaneously compare how BIS, AAI, and commonly used hemodynamic variables display increasing, nonsteady-state sevoflurane concentrations, and to determine how these measures respond to a sudden noxious stimulation (laryngoscopy) at various time points during 15 min of increased sevoflurane wash-in.
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Methods |
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Patients
IRB approval and informed consent were obtained before the study. Twenty-one patients with ASA physical status I, aged 20–40 yr, scheduled for elective knee arthroscopy with general anesthesia were enrolled (Table 1). The study was done before surgery. Exclusion criteria were body mass index >30, neurological disorders, hearing disorders, and use of active psychotherapeutics. No premedications were given. Before induction of anesthesia, the patients were hydrated with 5–10 mL/kg of a balanced electrolyte solution (Ringer-Acetat®; Baxter Medical AB, Kista, Sweden). The patients were randomly assigned to noxious stimulation (laryngoscopy) at 1 of 7 predefined time points (3 patients at each time point) after the change in sevoflurane concentration (see protocol and Fig. 1). In the postanesthesia care unit, and a second time 1–3 weeks postoperatively, the patients were questioned for explicit recall according to Brice et al. (5).
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Protocol
Anesthesia was induced with 8% sevoflurane in oxygen/air (inspired fraction of oxygen [FIO2] = 0.5) for 2 min followed by 4% until tracheal intubation (Fig. 1). After 1 min at the reduced sevoflurane concentration (4%), the patients received 0.6 mg/kg rocuronium immediately followed by 1 µg/kg remifentanil. Two minutes later tracheal intubation was performed by one of the authors (AE) who also did all trial laryngoscopies (see below). Ventilation was assisted to keep the arterial oxygen saturation (SpO2) >95%. Fresh gas flow was initially set to >8 L/min and was adjusted to 3 L/min after intubation. Controlled mechanical ventilation in a semiclosed anesthesia circle was used, keeping end-tidal CO2 (ETCO2) between 4.5–5.5 kPa and FIO2 at 0.4. After tracheal intubation, 15 min was allowed for obtaining a "steady-state" BIS value of 50–55 by continuously adjusting the inspired fraction of sevoflurane. After a twofold increase in the end-tidal sevoflurane concentration (Etsev), the patients were subjected to a noxious stimulus (laryngoscopy for 30 s) at 1 of the 7 predefined time points (0, 2, 4, 6, 9, 12, or 15 min). The twofold increase in Etsev was obtained by increasing the inspired fraction of sevoflurane to 8% for 30 s and thereafter by continuous adjustment of the vaporizer setting to get an end-tidal reading that was twice the Etsev needed for BIS 50–55 (Fig. 1). The anesthesiologist was blinded to monitoring indices during the 30-s laryngoscopy. Heart rate (HR) and noninvasive systolic blood pressure (SBP) were monitored with Datex Ohmeda ADU 98/S5 (Helsinki, Finland).
Monitoring and Data Acquisition
Standard monitoring (electrocardiogram, SpO2, SBP, Etsev, ETO2, and ETCO2) was applied. The EEG was recorded using an Aspect A-2000 BIS® monitor (BIS version 4.0; Aspect Medical Systems, Newton, MA). Electrodes (BIS-sensor XP) were applied on the forehead as recommended by the manufacturers. Electrode impedances were accepted if the impedance was <7.5 k
(default settings). The smoothening time of the BIS monitor was set to 15 s. BIS is an index ranging from 100 to 0 and the recommended value for surgical anesthesia is between 40–60. The mid-latency auditory evoked potentials (MLAEP) were recorded using the A-Line® monitor (version 1.4; Danmeter A/S, Odense, Denmark.). Three electrodes (A-line AEP electrodes; Danmeter A/S) were positioned at mid-forehead (+), left forehead (reference), and left mastoid (–). Electrode impedances were accepted if <5 k (default settings). The AAI was calculated from the MLAEP as described elsewhere (6,7). AAI is an index ranging from 99 to 0. The recommended value for surgical anesthesia is 15–25. The MLAEP was elicited with bilateral click stimuli of 70-dB intensity and 2-ms duration. There are at least two studies reporting no interference of auditory click stimuli with BIS values (8,9).
From induction and until 1.5 min after the laryngoscopy, BIS, AAI, and the hemodynamic variables were followed and recorded on a personal computer. Values of BIS and AAI were collected every 5 s as well as HR and Etsev. SBP was automatically monitored every minute. The changes in BIS and AAI and latency to peak values after the stimulus were recorded. After termination of the study protocol, BIS was not collected and stored on the computer during surgery for technical reasons.
Values immediately before noxious stimulation are denoted by preS (e.g., BISpreS; AAIpreS), and after stimulation by postS (e.g., BISpostS; AAIpostS). Time (t) to stimulation was measured from the onset of the increase in sevoflurane concentration to noxious stimulation (predefined as 0, 2, 4, 6, 9, 12, and 15 min) and response time was measured from the onset of the stimulation to the earliest maximum of BIS or AAI. Similar definitions were used for HR and SBP.
A step increase in delivery of anesthetic gas leads to a rapid increase in blood concentration followed by a blood/multicompartment equilibration. As shown in Figure 2, where data for the 21 patients have been normalized to t = 0, BIS decreases in a nonlinear way whereas the decrease in AAI is linear when anesthetic gas delivery is increased. BIS has previously been shown to follow a power function (Hill equation) (10,11) with effective site concentration (Ce) as independent variable. Ce, in turn, is obtained by solving the first-order differential equation dCe/dt = ke0(Etsev – Ce), where Etsev is assumed to equalize blood concentrations. To describe the time course of Ce and BIS, we solved the differential equation numerically using the measured gas concentration (Etsev), where an average t1/2ke0 for sevoflurane of 3.5 min (10) was assumed, followed by a nonlinear regression to fit the BIS data to Hill equation. Note that t1/2ke0 is not able to be calculated as proposed by Olofsen and Dahan (10) in this particular setting and Hill equation was, therefore, replaced by an exponential function (Const + exp[–kt]) (Fig. 3A) when analyzing non-normalized data. This exponential function and Hill equation differ mainly during the first minute only, and is a good estimate of the time response of BIS on the step increase of sevoflurane delivery.
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AAI appeared to be linear (Fig. 2) and a linear regression was therefore made using time as the independent variable (Fig. 3B).
In addition, correlations between changes in HR and SBP were tested by nonparametric tests (Spearman rank correlations). A commercial statistical software was used (Statistica; StatSoft®, Tulsa, OK) and a P value of < 0.05 was considered statistically significant.
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Results |
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Response to Increasing Ce Before Noxious Stimulation (Unstimulated Patients)
BIS/AAI.
When an Etsev titrated to BIS = 50–55 (AAI 16 ± 5; mean Etsev 1.46% ± 0.20%) was doubled, there was a decrease in BIS from 50–55 to a new constant level, BIS = 25–30 (Fig. 2). When data were normalized (Fig. 2; n = 191, r = 0.98, and P < 0.0001), this decrease closely fitted to the model used by Olofsen and Dahan (10). A monoexponential fit, using individual BIS values for singular time points just before the stimulation, gave a statistically significant decrease in BIS to the new constant level; t1/2 = 0.99 min (n = 20, r = 0.93, and P < 0.003), k = –0.697 (Fig. 3A). For AAI, a linear slightly decreasing trend with increasing Etsev (Fig. 2) was evident. AAI decreased with time from a normalized index value of 18.6–10.5 (n = 179, r = 0.88, and P < 0.0001) during the 15 min studied (0.54 index units/min; Fig. 2). Individual response data and pooled AAI data did not exhibit any significant change (Fig. 3B).
Central Hemodynamics.
There was a statistically significant increase in HR with time after increasing sevoflurane concentration (linear regression; P < 0.04). SBP decreased although not statistically significantly (Table 2).
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Response to Noxious Stimulation
BIS/AAI.
The average ± SD increases in BIS and AAI after laryngoscopy were 6.3 ± 6.6 and 6.4 ± 7.1, respectively (Fig. 3). There were large interindividual differences in the response to stimulation. The stimulus response was not dependent on prestimulus value, i.e., increased wash-in time of sevoflurane did not attenuate the magnitude of the response. AAI exceeded the highest recommended value, 25, in 3 patients, 1 at time 0 (AAIpreS 17; AAIpostS 26), 1 after 2 min (AAIpreS 13; AAIpostS 26), and in 1 patient after 6 min (AAIpreS 17; AAIpostS 48). BIS did not exceed the highest recommended value, 60, in any of the patients. Twenty of 21 patients responded with increased BIS and 19 of 21 patients responded with increased AAI after stimulation (Fig. 3). The response time from prestimulus value to earliest maximum value after stimulation was 44.5 ± 26 s for BIS, and 47 ± 31 s for AAI.
Central Hemodynamics.
There were large interindividual differences in the responses to the noxious stimulus. The stimulus response was not dependent on the prestimulus value and there was no significant correlation between the hemodynamic response and the BIS/AAI response except for a weak correlation between SBP increase and increase in BIS (r = 0.48; P < 0.03, Spearman rank order correlation). Although all patients showed a significant increase in HR within the 90 s after the laryngeal stimulation (Table 2), 10 of the patients reacted initially with a transient decrease in HR.
Patients’ Subjective Experience
No patient reported awareness with explicit recall.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We compared the abilities of BIS and AAI to display increasing hypnotic action in an already anesthetized patient, and how these monitoring techniques respond to a noxious stimulus at different time points during a gradual increase in the cerebral concentration of sevoflurane. This was done to simulate the situation when the anesthetic concentration is increased to meet anticipated surgical stimulation. Both BIS and AAI decreased significantly during the 15-minute trial period, although in markedly different ways. Using the t1/2ke0 for BIS found by Olofsen and Dahan (10), we found the inhibitory sigmoid Emax model to adequately fit the wash-in time/BIS relationship in our data set, that is, at a level normally considered to be at, and in excess of, what is needed for surgical anesthesia (corresponding to Etsev 1.5%–3.0%; BIS 50–25). However, the AAI did not fit the sigmoid Emax model at this level of anesthesia. The AAI was best described by a straight line with a difference of only 8 index units over the 15-minute trial period of increased sevoflurane delivery, which is a very small difference in comparison with the interindividual variability and intraindividual "spontaneous" fluctuations. This is in agreement with Alpiger et al. (12) who did not find any graded response of AAI with stepwise transitions from end-tidal steady-state concentrations of sevoflurane in the 1%–2% concentration range, and according to Kalkman and Drummond (13), MLAEP are almost completely suppressed soon after loss of consciousness. However, when smaller doses of anesthetics affect the brain (BIS values between 50 and 95), the sedative effect evaluated by the Observer’s Assessment of Alertness/Sedation Scale was better correlated to AAI than to BIS (14), and other studies have suggested that derivatives of MLAEP are better discriminators than BIS in tracing the transition from awake to the anesthetized state (15–17). Thus, titration of sevoflurane may be easier with BIS than with AAI at the hypnotic level investigated in this study. This is probably because the BIS algorithm, at "deeper" levels of hypnosis, is more discriminating than evoked potentials.
When we assessed the response to laryngoscopy at various time points during the 15 minutes of increased sevoflurane delivery we found no significant differences in the magnitude of the BIS and AAI responses. For BIS, as opposed to AAI, the increase in index value started from a gradually lower value with time (Fig. 3). After laryngoscopy, using the manufacturers’ threshold levels, the highest recommended AAI was exceeded slightly in 2 patients (1 at 0 minutes and 1 at 2 minutes, respectively). A significant increase of AAI was seen in a third patient (at 6 minutes), whereas the simultaneous BIS recordings did not exceed the highest recommended value in these or in any other patient. Whether AAI in these patients correctly identified significant cognitive capacity with amnesia or gave a false indication of wakefulness is not known.
However, in 1 patient the burst suppression ratio increased dramatically immediately before laryngoscopy giving BIS of 3. After stimulation, the increase in BIS in this patient far exceeded (to 34) that seen in any other patient. This indicates that a very low BIS value does not eliminate a significant arousing effect from noxious stimulation, although the response in this patient did not exceed the highest recommended value.
In one patient BIS did not increase, and in two patients AAI did not increase after laryngoscopy. Instead, the indices decreased in these patients. The reduction in BIS may have been caused by "paradoxical arousal," which is a pronounced 
activity of the EEG, sometimes seen after increased surgical stimulation and also after discontinuation of nitrous oxide, as described by Rampil et al. (18). The reduction in AAI still remains unclear to us.
The two monitors had similar response times after laryngoscopy in our study in contrast to what was found by Struys et al. (9), perhaps because they were using another stimulus, tetanic electrical stimulus (100 Hz, 50 mA) to the volar forearm level. Another explanation could be that they used a smoothening time of the BIS monitor of 30 seconds instead of the 15 seconds we used.
HR increased, and there was a trend toward decreased SBP with time from the change in Etsev. The hemodynamic response to laryngoscopy showed no correlation with time from the change in Etsev or with prestimulus values. This is in accordance with what Zbinden et al. (19) found when they assessed hemodynamic changes with different noxious stimuli at different end-tidal gas concentrations using isoflurane. We found no correlation between the arousal as indicated by BIS or AAI and the increase in HR. A weak correlation between increased BIS and increase in SBP was found, but not for AAI. However, we regard this weak correlation found for BIS as clinically insignificant, which is in accord with Mi et al. (20) who found that BIS could not predict hemodynamic responses to laryngoscopy. Their explanation for this was that the hemodynamic responses to laryngoscopy and intubation are mediated predominantly at the subcortical level (brainstem and hypothalamus). Even if increased HR was eventually evident in all patients during the first 90 seconds after laryngoscopy, a vagal response presumably accounts for an initial slowing of HR in 10 of the patients in our study. Even if our study contains a limited number of subjects, it indicates that the hemodynamic responses to noxious stimulation are poorly correlated with the level of hypnosis.
One limitation of our study is that our baseline (BIS = 50–55), which was chosen to avoid awareness, constitutes what is considered to be surgical anesthesia. If a higher baseline would have been acceptable, another time-AAI relationship may have been possible to demonstrate. Another limitation is that laryngoscopy, the noxious stimulus we used, is difficult to standardize in a repetitive manner. Yet another limitation is that new software versions for BIS and AAI have frequently been released and our result may be confined to the versions being used in this study (the most recent available when the study was conducted). Furthermore, because of our study design, we could not calculate individual ke0’s.
In summary, at a hypnotic level associated with surgical sevoflurane anesthesia, our data suggest that BIS better displays drug-related alterations in the level of hypnosis than AAI or hemodynamic variables but that there is no difference between BIS and AAI in the response time to a noxious stimulus. Sevoflurane, as the only anesthetic, did not attenuate the magnitude of BIS and AAI responses to laryngoscopy with increasing wash-in time. Thus, BIS and AAI represent the level of the functional integrity of the cerebral cortex, and also indicate arousal caused by persistent functional integrity of the subcortical structures, which are responsible for mediation of the pain-related reflexes.
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Acknowledgments |
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This study was supported by a grant from the Research Council of Southern Sweden (FORSS).
We thank Birgitta Törneke for recording and collecting the data, and Mats Johansson for computer support and technical assistance.
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Footnotes |
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An abstract was presented at the ESA meeting in Glasgow, May 31–June 3, 2003.
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References |
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