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The relationship between calculated effect-site sevoflurane levels and awakening from anaesthesia.


We have previously described a system that displays real-time estimates of effect-site sevoflurane concentrations. Estimates of effect-site levels should be similar to minimum alveolar concentration (MAC) values, which are determined after allowing time for equilibrium. This study aimed to determine estimated effect-site sevoflurane concentrations at awakening from routine anaesthesia and to compare this with published estimates of MAC-awake. If these values were similar, this would validate our approach to the calculation of effect-site concentration. Sixty-five patients undergoing a variety of surgical procedures were observed. Prior to disconnection from the breathing circuit, forward estimates of effect-site sevoflurane were recorded. Patients were observed in the post-anaesthesia care unit and the time at which they responded to command was recorded. Age-adjusted effect-site sevoflurane at the time of awakening was determined. Correlation with patient, surgical and anaesthetic factors including age, gender, ASA status and intraoperative opioid usage were explored. Mean age-adjusted calculated effect-site concentration at awakening was 0.59 (SD 0.27) vol%. This value is within the range of values determined for MAC-awake of sevoflurane. There was no correlation with any of the demographic or anaesthetic factors, but patients undergoing major surgery woke at a significantly lower mean sevoflurane level. These results support the use of effect-site sevoflurane concentration to guide administration of anaesthesia.

Key Words: anaesthesia, inhalation, pharmacokinetics, anaesthesia recovery period, sevoflurane effect-site


We have previously described a system which provides real-time estimates and forward predictions of effect-site concentrations of inhalational anaesthetics (1). The effect-site would intuitively appear to be a logical 'target' for control of any drug. However to demonstrate the clinical utility of real-time estimates of effect-sites it would be useful to relate these effect-site values to known clinical measures of anaesthetic effect. Various measures of anaesthetic potency based on the concept of minimum alveolar concentration (MAC) (2) have been described. The MAC for any response is the alveolar concentration at which 50% of subjects show that response. Since MAC is determined after maintaining a given alveolar concentration for 10 to 20 minutes to allow equilibrium between the alveolar and brain (or effect-site) concentrations, the 'MAC' for a given response should be similar to the effect-site concentration required to produce that response in 50% of subjects. If the calculation of effect-site concentration is valid then these effect-site concentrations should be similar to those determined for the MAC for that response but without the need to wait for equilibrium to occur.

MAC-awake for sevoflurane has been determined in a number of studies at 0.58 to 0.67 vol% (3-5). The primary aim of this study was to determine the calculated sevoflurane effect-site concentration at wake-up in patients undergoing a wide range of surgery and to compare this value to published estimates of MAC-awake. We also wished to explore the relationship between the sevoflurane effect-site concentration at wake-up and other patient, anaesthetic and surgical parameters.


This study was approved by the Canterbury Regional Ethics Committee. As the study collected and collated data routinely collected in the perioperative period, and did not involve intervention or additional data collection, individual patient consent was not required by the Committee.

The prediction system

Our model-based predictive display for volatile anaesthesia takes values of fresh gas flow (FGF) and vaporizer setting from the anaesthetic machine (Datex ADU) and monitor (Datex A/S3) every ten seconds and uses this to model the progress of the anaesthetic in a nine compartment model. We have previously shown that, despite a number of potential limitations, this model predicts end-tidal (ET) sevoflurane and isoflurane levels at least as well as many propofol TCI systems predict effect-site propofol leves (6). Calculation of effect-site concentration (Ceff) is dependent only on blood (or central compartment) concentration, estimated by ET values, and on the value chosen for the rate of flux between the central and effect-site compartments (ke0). We use a value for t1/2 ke0 of 3.2 minutes (7-9) to provide an estimate of Ceff which is also updated every ten seconds. The predicted concentrations in the lung and brain compartments of the model are then aligned to the current ET and Ceff respectively and displayed numerically and graphically (Figure 1). By changing FGF and vaporizer dial setting the user can rapidly see the effect of different input patterns and choose that which best suits the clinical needs. We have previously demonstrated that this display allows anaesthetists to make step changes in ET sevoflurane levels at least twice as fast as when the display is unavailable (10).


Over an eight-week period (November 2004 to January 2005) 65 patients in whom surgery was expected to last more than 30 minutes were observed. Selection was based on the availability of the observer (MS) and of suitable subjects in one of the four operating theatres in which our predictive/display system is installed. Subjects were selected on the basis of an anaesthetic plan based on sevoflurane without the use of nitrous oxide, and were divided into three groups based on the invasiveness of the surgical procedure. Group 1-minor, body surface procedures; Group 2-intermediate procedures such as peripheral orthopaedic or laparoscopic procedures; and Group 3-major or open body cavity procedures. Approximately equal numbers of patients were observed in each group to ensure a wide distribution of patient types. The actual conduct of the anaesthetic was entirely at the discretion of the anaesthetist in charge of the case.


At the time of disconnection of the patient from the anaesthetic breathing system the predicted effect-site concentrations for the following 20 minutes were recorded. The observer then followed the patient into the post-anaesthesia care unit (PACU) and noted the time at which the subject awoke, defined as eye-opening and response to command. Additional information including patient demographics (age, gender, weight), ASA status, duration and timing of the surgery and fentanyl, morphine and midazolam dosing were obtained from the anaesthetic record. The effect-site sevoflurane concentration at the time of wake-up was taken as that predicted for the point in time at which the patient awoke. This value was then corrected for age using the relationship between MAC values and age described by Mapleson (11). Effect-site fentanyl levels at the time of awakening were calculated by entering fentanyl doses and times into an Excel spreadsheet utilizing Scott's parameters (12).


Data from all groups were pooled and tested for normal distribution using a Kohnogorov-Smirnov test. Mean and standard deviation or median and interquartile range (IQR) were determined as appropriate. Results from the three groups were compared using a one-way ANOVA with Tukey's HSD post test or a Kruskal-Wallis test with Dunn's Multiple Comparison Test as a post test. Correlation between effect-site sevoflurane levels and the various patient and anaesthetic factors was explored using Pearson or Spearman correlation coefficients as appropriate. In all cases a P value <0.05 was taken as significant. Statistical analysis was performed using GraphPad Prism v4.Oc (GraphPad Software, San Diego, California, U.S.A.).


Data was collected and analysed for 65 cases. The mean duration of the procedures was 101 minutes (SD 54 minutes). The average age of the patients was 54 (17). The median ASA score was 2.0 (IQR 1-3). The median total dose of fentanyl was 95 [micro]g (IQR 100-200 [micro]g) and of morphine 5 mg (0-10 mg). At wake-up the estimated effect-site sevoflurane concentration varied between 0.12 vol% and 1.2 vol% with a mean of 0.58 vol% (SD 0.27 vol%) while the median estimated fentanyl effect-site level was 0.29 ng/ml (IQR 0.22-0.53 ng/ml). The individual data points are illustrated in Figure 2.


Table 1 summarizes the data and the statistical analysis for the pooled data and for each of the surgical groups. Duration, effect-site sevoflurane levels and age were all normally distributed; other parameters were not. A significant correlation with the estimated effect-site sevoflurane levels was seen with ASA status (P=0.015) and duration of surgery (P=0.03). There were significant between group differences for ASA status (P=0.02), duration (P<0.0001), total fentanyl dose (P=0.019), fentanyl levels (P=0.0006) and for age-adjusted effect-site sevoflurane concentration (P=0.0018). There was no effect of gender on wake-up levels (P=0.7). Significant post-test differences between groups for each parameter are indicated on Table 1.


The first major finding of this study is that subjects woke at a mean age-adjusted estimated effect-site sevoflurane concentration of 0.59 (SD 0.27) vol% (95% CI 0.52-0.66 vol%). This is within the range (0.58-0.67 vol%) determined in several studies of MAC-awake of sevoflurane (3-5). This observation supports the hypothesis that real-time effect-site estimates are similar to MAC values and supports the use of effect-site estimates as a guide to the delivery of volatile anaesthetic agents although the variability in our results is much greater than seen in studies of MAC-awake. This variability may be due to inherent variability between patients or may be due to the multiple other factors affecting anaesthetic requirements during routine anaesthesia and surgery. Of interest all values were less than 1.2 vol% (0.6 MAC) with the 95th centile at 1.0 vol%.

The second observation is that subjects undergoing major surgery (Group 3) woke at significantly lower estimated sevoflurane levels (mean 0.41 vol%, 95% CI 0.31-0.50 vol%) than subjects in the other two groups, both of which fall within the reported range for MAC-awake (Group 1, minor surgery, 0.59 vol% 95% CI 0.51-0.75 vol%), Group 2, intermediate surgery 0.63 vol%, 95% CI 0.57-0.80 vol%). This difference has not been reported in studies of MAC-awake. However, studies into MAC-awake tend to involve subjects undergoing less invasive surgery to allow the effects of various drugs to be studied in isolation. One implication of this result is that care should be taken when extrapolating various MAC values into groups and clinical settings where the conditions of the particular studies are not identical.

The subjects in Group 3 (major surgery) tended to be older, have a higher ASA score, receive more opioids and have a longer duration of anaesthesia than subjects in the other two groups. The only factors to show a statistically significant correlation with awakening levels of sevoflurane were ASA status and duration of surgery. Modest opioid doses have a profound effect on the MAC values for various stimuli, such as skin incision or intubation (13,14). The effect on MAC-awake is much less profound. Morphine in doses of 10 mg (15) or 0.1 mg/kg (16) has been shown to have no effect. Fentanyl levels of 4 ng/ml have been shown to reduce MAC-awake while 2 ng/ml has no effect (5). In the present study the maximum estimated fentanyl level at the time subjects woke was 1.1 ng/ml and the median value in Group 3 was 0.28 ng/ml. Although the effect of combinations of opioids on MAC-awake has not been determined, it is unlikely that the total opioid levels were above the equivalent of 2 ng/ml of fentanyl and, additionally, awakening effect-site fentanyl levels were highest in the minor surgery group.

A number of other factors may also contribute to the difference seen with Group 3 and to the variability amongst subjects. These include the use of adjunctive drugs, major nerve blocks, environmental factors such as temperature and the effects of major surgery itself. Although the study was not designed to investigate these effects, they do deserve some comment. Other drugs used included benzodiazepines both as premedication and preinduction. Intravenous midazolam was used in 19 of the 65 subjects. Overall and within each group there was no correlation between midazolam use or dose and wake-up levels, as shown in Table 1. One subject in each group received clonidine. Three subjects in Group 3 received an epidural and the age-adjusted sevoflurane levels at wake-up for these subjects were 0.42, 0.36 and 0.28 vol%. Although isoflurane requirement has been shown to be reduced by 20% in the presence of epidural blockade (17), these data points are not sufficient to explain the group difference. The effect of temperature on MAC is well known (18,19). Although there is limited human data available, the decrease in MAC for stimulation is around 5% per [degrees]C. This is again insufficient alone to explain the differences between the groups, but it may be that, in contrast to the effect of opioids, temperature has a greater effect on MAC-awake than on MAC stimulation.

Of interest is the observation that gender did not affect the wake-up levels. This supports previous work on MAC-awake (20,21), but contrasts with recent work suggesting that women wake faster than men following anaesthesia and are possibly less sensitive to the hypnotic effect of anaesthetic agents (22).

MAC-awake and the concept of effect-site concentration are, by definition, independent of the duration of surgery. In this study there was a statistically significant correlation between duration of the anaesthetic and sevoflurane levels at wakeup when all groups are combined. However Figure 3 explores the relationship between duration and effect-site sevoflurane levels for the subgroups. Within each group there is no correlation between duration and sevoflurane levels at wake-up and there is no difference between Groups 1 and 2. These results suggest that duration alone is not a factor in the delayed wakeup and that the correlation in the pooled data is because the major cases, which woke at lower levels, lasted longer rather than a direct effect of duration. This is one of a number of observations from this study requiring further investigation.


The effect of age on MAC-awake parallels the well-documented effects of age on MAC of around 6% per decade (11,20,23). Our data is adjusted for age using a standard approach. We did not demonstrate a correlation between age and awakening levels supporting the parallel effects of age on MAC and MAC-awake (20). We also explored other parameters in our data set, such as use of midazolam, but were unable to demonstrate an effect of these parameters.

As illustrated by the factors discussed above, a weakness of this study is that the conduct of anaesthesia was not standardized beyond the use of sevoflurane without nitrous oxide. This makes it difficult to draw firm conclusions about some of the results seen. However, we also see this lack of standardization as a potential strength of this study since, given the similarity between wake-up effect-site sevoflurane levels and MAC-awake in the minor and intermediate surgery groups, these results may be applicable over a wide range of patients, types of surgery and other anaesthetic factors.

Until the 1990s, control of delivery of inhalational anaesthetic agents was based on the rate of delivery (vaporizer and fresh gas settings) to the breathing system. The widespread availability of agent analysis has allowed the use of end-tidal (ET) concentrations as the target. In combination with less soluble agents, this has allowed improved titration and control of levels of anaesthesia. However there is still a considerable delay between changes in ET concentration and effect-site concentration since the effect-site equilibrium half times (t1/2 ke0) for these agents are around three minutes which is longer than commonly accepted values for propofol (time to peak effect 1.6 minutes (24)) or remifentanil (t1/2 ke0 of one minute) (25).

Effect-site guided anaesthesia delivery should allow delivery of agents to be more closely matched to the changing needs of the patient at different stages of surgery. Studies with propofol have demonstrated that propofol effect-site concentrations are more closely related to clinical endpoints than plasma levels (24,26) and that providing the anaesthetist with effect-site information improves the stability of effect-site concentrations (27,29) When combined with forward prediction', the display of effect-site information allows the anaesthetist to adjust delivery based on both current and anticipated future demands (10,29).

Several studies have suggested that lower concentrations of an inhalational agent, usually in combination with increased opioid levels, are associated with improved short-term (30,31) and possibly long-term (32) recovery characteristics. The optimum combinations determined in these studies are end-tidal levels in the range 40-80% MAC. At these levels the decrement time to MAC-awake is short and small alterations in the balance between effect-site concentration and level of stimulation may produce unwanted clinical effects, such as movement. Effect-site guided delivery may make maintaining appropriate levels more straightforward (29) than the use of end-tidal levels alone. In addition, our predictive display gives a real-time illustration of inhalation decrement times (Figure 1). These tools may assist the anaesthetist to optimize levels of the various components of anaesthesia for various stages of a procedure rather than relying on end-tidal values.

This study has shown that, in a wide variety of procedures, patients woke from sevoflurane-based anaesthesia at age-adjusted estimated effect-site levels within the range previously reported for MAC-awake. This data supports the use of estimated effect-site concentrations as a guide to anaesthesia delivery. Subjects undergoing major surgery woke at significantly lower sevoflurane effect-site concentrations than those having minor or intermediate surgery. Although many reasons for this difference can be postulated, the reasons for this difference are not clear from this data and will be the subject of further study.


M. M. Sakowska was supported by a grant from the George Rolleston Trust. This work was presented in part at the National Scientific Congress of the Australian Society of Anaesthetists, September 2005.

Accepted for publication on August 14, 2006.


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R. R. KENNEDY*, M. M. SAKOWSKA ([dagger])

Department of Anaesthesia, Christchurch Hospital and Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand

* M.B., Ch.B., Ph.D., F.A.N.Z.CA, Specialist Anaesthetist and Clinical Senior Lecturer. ([dagger]) B.Sc., B.Sc.(Hons.), Medical Student.

Reprints will not be available from the authors.
Demographic data and results for all subjects and for each
surgical group

Variable All subjects Minor surgery Intermediate

n 65 21 24

Age (y) 54 (SD17) 50 51

ASA 2.0 (SD 0.8) # 2.00 1.80

Duration (min) 101 (SD54) # 69 88

Gender (F/M) 45/41 23/18 11/13

Fentanyl total 150 150 100
dose ([micro]g) (IQR 100-200) (100-225) (100-175)

Morphine total
dose (mg) 10 (IQR 6-10) 7.0 (3.8-10) 8.5(5-10)

Fentanyl level
(ng/ml) 0.29 0.47 0.26
 (IQR 0.22-0.51) (0.30-0.79) (0.19-0.36)

dose (mg) 2.0 (IQR 1.5-2.3) 2.0 (1.8 - 5.0) 1.5 (1.0-1.5)

(vol%) 0.59 (SD 0.27) 0.63 0.68

Variable Major surgery Between Significant
 group P value post-test
 (ANOVA or between group
 Kruskal-Wallis) differences

n 18

Age (y) 60 0.17

ASA 2.40 0.02 2v3 *

Duration (min) 149 -0.001 1v3[dagger],

Gender (F/M) 10/10 0.70

Fentanyl total 200 0.019 2v3 *
dose ([micro]g) (125-300)

Morphine total
dose (mg) 10 (10-14.5) 0.01 1v3 *, 2v3 *

Fentanyl level 0.28 0.0006 1v2[double dagger],
(ng/ml) (0.18-0.49) 1v3[dagger]

dose (mg) 2.0 (2.0-2.8) 0.18

Effect-site 0.41 0.0018 1v3 *, 2v3[dagger]

Drugs doses are totals for the entire case while fentanyl levels and
effect-site sevoflurane are the calculated levels at the time subjects
woke. A significant correlation between a variable and effect-site
sevoflurane levels is indicated by a # symbol, with the P values given
in the text. The final column indicates the pairs of surgical groups
for which there were significant differences on the post-test. Exact P
value are not available for these tests, P value bands are indicated as
* 0.05>P>0.01, [dagger] 0.01>P>0.001, [double dagger] P<0.001. In those
combinations not listed P>0.05.
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Title Annotation:Original Papers
Author:Kennedy, R.R.; Sakowska, M.M.
Publication:Anaesthesia and Intensive Care
Date:Dec 1, 2006
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