British Journal of Anaesthesia 112 (1): 728 (2014) Advance Access publication 23 August 2013 . doi:10.

1093/bja/aet280

Minimal alveolar concentration of sevourane for induction of isoelectric electroencephalogram in middle-aged adults
B. Niu 1, Y. Fang1, J. M. Miao 1, Y. Yu2, F. Cao 1,4, H. X. Chen1, Z. G. Zhang3, W. Mei 1* and Y. K. Tian1*
1

Department of Anaesthesiology and Pain Medicine, Tongji Hospital, 2 Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, and 3 School of Medicine and Health Management, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China 4 Department of Neuroscience, Baylor College of Medicine, Houston, TX 77054, USA * Corresponding author. E-mail: wmei@tjh.tjmu.edu.cn (W.M.); yktian@tjh.tjmu.edu.cn (Y.K.T.)

Editors key points

Induction of an isoelectric EEG by anaesthetics has been implicated in neuroprotection, and might be clinically useful or detrimental in specic situations. The potency of sevourane in producing an isoelectric EEG was determined in adult human subjects before surgical incision. The minimal alveolar concentration (MAC) of sevourane for isoelectric EEG was 3.5 vol%, which is about 2.1 times the MAC for skin incision.

Background. We determined the minimal alveolar concentration (MAC) of sevourane inducing an isoelectric EEG in 50% of adult subjects (MACie). Methods. We included 31 middle-aged subjects; 30 subjects nished the study protocol and received sevourane at preselected concentrations according to a modied Dixon up-anddown design starting at 1.7 vol% with 0.2 vol% steps size. General anaesthesia was induced and maintained with sevourane; tracheal intubation was facilitated with cisatracurium. After a period of 30 min before skin incision, the state of isoelectric EEG was considered as signicant when a burst suppression ratio of 100% lasted for . 1 min. The haemodynamic responses to skin incision and the vasopressor requirement to maintain stable haemodynamic status were also analysed according to the EEG state. Results. MACie was 3.5% (95% condence interval, 3.43.7%) in middle-aged subjects. When compared with subjects not in isoelectric EEG state, subjects in isoelectric EEG state received more phenylephrine to maintain stable haemodynamics (10 of 10 compared with 7 of 20 subjects, P 0.001) and experienced less sympathetic responses to skin incision (1 of 10 compared with 11 of 20 subjects, P 0.024). Conclusions. MACie for sevourane was 2.1 times MAC for immobilization in phenobarbital premedicated middle-aged adults. Sevourane-induced isoelectric EEG state is associated with signicant cardiovascular depression but reduced haemodynamic responses to skin incision. Keywords: anaesthetics volatile, sevourane; cardiovascular system, responses; monitoring, depth of anaesthesia; monitoring, electroencephalography Accepted for publication: 7 June 2013

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Minimal alveolar concentration (MAC) was introduced to compare the potencies of inhalation anaesthetic agents.1 2 Sevourane is a commonly used inhalation anaesthesia agent today. Its effects on motor response (MAC),3 adrenergic reexes (MACBAR),4 5 reex pupillary dilatation (MACpup)6 to nociceptive stimulation, and eye opening to verbal command (MACawake)7 in 50% of subjects have been widely investigated. However, the relation between concentration of sevourane and different EEG states is relatively unstudied.8 EEG burst suppression and isoelectric (or persistently suppressed) EEG, typically associated with states of profound brain inactivation, do not appear in normal sleep.9 They are frequently observed in deep general anaesthesia, pathological conditions including hypothermia, hypoxicischaemic trauma, coma, and early infantile encephalopathy. Previous

studies have demonstrated that burst suppression or isoelectric EEG can be purposely induced by anaesthetic agents to protect the brain during neurosurgery10 or cardiosurgery.11 Although still a controversial issue, low EEG-derived indices might be associated with adverse outcomes after cardiac and noncardiac surgery.12 16 Understanding the relation between concentrations of volatile anaesthetics and abnormal EEG states including burst suppression or isoelectric EEG might help practitioners avoid excessively deep anaesthesia in vulnerable patients, or achieve transient burst suppression or isoelectric EEG when desired. Hence, this study aimed to determine the MAC of sevourane inducing isoelectric EEG (MACie) and burst suppression EEG (MACbs) in 50% of middle-aged adults. In addition, haemodynamic stability and responses to incision in a state of isoelectric EEG were also analysed.

These authors contributed equally to this work.

& The Author [2013]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com

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necessary to maintain 36.5 to 37.58C. Surgery started at least 30 min after inhalation induction, so that the determined sevourane concentration was stable for at least 15 min and the difference of inspired and end-tidal concentrations was , 10%.4 A cuff-based continuous arterial pressure monitor was used; an audible alarm was set to indicate mean arterial pressure (MAP) reduction of . 20% of baseline values. Phenylephrine 0.1 mg was administered i.v. if necessary to maintain MAP. Neither Entropy nor Narcotrend alarms were set. MAC was determined using the Dixon up-and-down method. To avoid awareness, the rst subject received end-tidal sevourane concentration of 1.7% (1 MAC). As shown in Figure 1, the presence or absence of isoelectric EEG of the previous subject determined the end-tidal sevourane concentration of the following subject. End-tidal concentration of sevourane for the next subject was decreased by 0.2% (isoelectric EEG) or increased by 0.2% (non-isoelectric EEG). A crossover response was dened as the consecutive inclusion of a subject who presented isoelectric EEG, followed by another who did not. The value of a pair was the average of the end-tidal concentration used for the two subjects of this pair. The MACie was determined by averaging the values of six consecutive pairs. For each subject, a 30 min interval was given to allow equilibration between arterial and brain tensions.2 The isoelectric EEG was considered as signicant when the isoelectric state lasted . 1 min.19 The maximal BSR was recorded if isoelectric EEG was not reached. Then, the endtidal concentration of sevourane was maintained until 3 min after incision. Heart rate (HR) and MAP were recorded at 2 and 1 min before skin incision, and then at 3 min after surgical incision. The pre-incision value was dened as the mean value of the 2 and 1 min before skin incision. Adrenergic reexes (an increase in either HR or MAP . 15% above the pre-incision values)5 cases were counted.

Methods
The study was approved by the local Institutes Ethical Committee (Huazhong University of Science and Technology) and registered with ClinicalTrials.gov (ref: NCT01662622). After written informed consent, we enrolled 31 subjects aged 4565 yr, undergoing upper abdominal surgery using general anaesthesia from March to May 2012 at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. All participants had an ASA physical status classication of I or II. Patients were excluded from the study if they had one of the following criteria: any neurological disease or having received central nervous system active drugs; a cardiac ejection fraction , 40%; previous history of difcult intubation or anticipated difcult intubation; daily alcohol consumption; and obesity (dened as a body mass index . 30 kg m 2). Those without informed consent were also excluded. As premedication, 0.1 g of phenobarbital and 0.5 mg of atropine were administered by i.m. injection. After arrival in the operating theatre, standard monitoring, including electrocardiography, non-invasive arterial pressure, and pulse oximetry, was established. The i.v. infusion rate of lactated Ringers injection was 15 ml kg21 h21 via an 18 G venous catheter. A neuromuscular monitor (TOF-watch SX; Organon, Dublin, Ireland) was placed over the ulnar nerve at the wrist. Electrical activity of the brain was measured and recorded with a Narcotrend Monitor (unprocessed EEG) and S/5 Compact Anaesthesia Monitor [burst suppression ratio (BSR)]. Sensors of the Narcotrend Monitor (MonitorTechnik, Bad Bramstedt, Germany, version 4.0) and Entropy Module (S/5 Compact Anaesthesia Monitor, Datex-Ohmeda, Helsinki, Finland) were attached to the forehead of each subject according to the manufacturers recommendation. Impedances were measured for each set of electrodes to ensure adequate electrode contact dened as 6 kV for the Narcotrend Monitor and 7.5 kV for the Entropy Module. To calculate BSR, suppression is dened as periods . 0.5 s during which EEG voltage is , 5 mV. Time in a suppressed state is measured and BSR is reported as the fraction of the epoch during which the EEG is suppressed. BSR is averaged over at least 15 epochs (60 s). The presence of burst suppression was dened as BSR . 0.17 A BSR of 100% implies isoelectric EEG. General anaesthesia was induced by tidal volume breathing of 8% sevourane in 100% oxygen at 6 litre min21 with a semi-closed face mask. Cisatracurium 0.15 mg kg21 was administered after loss of the lash reex,18 with manual ventilation until the amplitude of T1 decreased to zero. Tracheal intubation was performed and switched to mechanical ventilation with a fresh gas ow of 2 litre min21. Oxygen, carbon dioxide, and sevourane were sampled with a 19 G tube connected to the distal end of the tracheal catheter. Gas concentration and partial pressure were analysed by a gas analyser (S/5 Compact Anaesthesia Monitor) with a sample ow rate of 200 ml min21. The end-tidal partial pressure of carbon dioxide was maintained at 4.7 kPa. An oesophageal temperature probe was inserted and a warming unit was used if

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Statistical analysis
Patient characteristic data were collected and presented as mean (SD) or as number (%) where appropriate. The MACie was calculated as the mean of six independent crossovers of end-tidal sevourane concentration as shown in Figure 3. Up-and-down sequences were analysed by the probit test (SPSS for Windows 12.0; SPSS, Inc., Chicago, IL, USA), which enabled MACie and MACbs with 95% condence limits of the mean to be derived.20 Data were also analysed with logistic regression for the probability of isoelectric EEG and burst suppression vs end-tidal concentration, the maximum-likelihood estimation, and goodness-of-t. Subjects were divided into an isoelectric EEG (ie + ) group and a non-isoelectric EEG (ie 2 ) group. The frequency of phenylephrine injection and incidence of positive adrenergic reexes were compared between groups by two-tailed Fishers exact test. Numerical data were analysed by Students t-test or the Mann Whitney U-tests where appropriate. P-values of , 0.05 were considered statistically signicant.

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Assessed for eligibility (n=31)

Ineligible (n=0) Eligible but not recruited (n=0)

Recruited (n=31)

Allocated to end-tidal concentration of 1.7%

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End-tidal concentration of the next patient was decreased by 0.2%

Yes

Isoelectric EEG

No

End-tidal concentration of the next patient was increased by 0.2%

No

6 crossovers of responses

Yes

Analysed (n=30) Excluded for severe hypotension (n=1)

Fig 1 Flow chart for the Dixon up-and-down method.

Results
As shown in Figure 1, of 40 patients assessed for eligibility, 31 were screened and subsequently enrolled. One subject was excluded because of severe hypotension during the equilibration period. Data analysis was performed on 30 ASA I II subjects who nished the study. Grouped patient characteristic data are presented in Table 1. There were more subjects in the ie 2 group than in the ie + group (20 compared with 10) because of the experimental design. However, the groups were similar with respect to other characteristics. In addition, the three surgeons who were involved in the study were equally distributed between the two groups, and the surgical incisions were of similar type and length.

Figure 2 shows the Narcotrend index change over the course of anaesthesia from Subject 15, who received end-tidal sevourane concentration of 3.7% and showed a representative curve of the ie + group.

MAC calculation
Figure 3 shows the up-and-down progression. MACie determined by the Dixon method was 3.5 (0.1)%. As the concentration of sevourane increased, suppression of the EEG was not all or none. Figure 4 shows the maximal BSR of each subject obtained in the period before skin incision. Twenty-one of 30 subjects displayed burst suppression EEG. Figure 5 shows the dose response curve of the probability of isoelectric EEG (Fig. 5A) and burst suppression (Fig. 5B). The 50%

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effective dose for isoelectric EEG was 3.5% sevourane [95% condence interval (CI), 3.4 3.7%] and 95% effective dose was 3.7% (3.6 4.9%). The calculated probabilities of the occurrence of isoelectric EEG for other quantiles are detailed in Table 2. Maximum-likelihood estimation showed a P 1 and goodness-of-t x 2 0.533. The 50% effective dose for burst suppression EEG was 3.0% (2.1 3.3%). Maximum-likelihood estimation showed a P 0.922 and goodness-of-t x 2 3.841.

Table 1 Subject characteristics. Data are presented as mean (SD), mean (range), or number (%). Temperature and PE CO2 were recorded 2 min before incision. Time interval, time from induction to incision; fluids administered was calculated from entering the room to incision
ie 1 (n 5 10) Age (yr) Male gender [n (%)] Height (cm) Weight (kg) Temperature (8C) Time interval (min) Fluids administered (ml) PE CO2 (kPa) 56 (46 65) 5 (50) 164 (8) 57 (11) 36.6 (0.5) 33 (3) 745 (26) 4.8 (0.2) ie 2 (n 5 20) 55 (45 64) 12 (60) 162 (8) 61 (11) 36.4 (0.3) 32 (2) 757 (30) 5.0 (0.2)

Vasopressor requirement
MAP was maintained by repeated administration of phenylephrine. When compared with the ie 2 group (7 of 20), all subjects in the ie + group (10 of 10) needed phenylephrine (Table 3); the difference was signicant (P 0.001).

Adrenergic response to incision

Only 1 of 10 ie + subjects showed an increase of . 15% in HR or MAP, whereas 11 of 20 ie 2 subjects showed an increase (Table 3). Compared with ie 2 subjects, ie + subjects experienced less adrenergic responses to incision (P 0.024).
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A B C D

1 2

45 6

1 2 3 4 5 6

Induction Intubation EEG burst suppression Isoelectric EEG Incision End

Discussion
The MACie of sevourane in 100% oxygen was 3.5% (2.1 times MAC) in middle-aged adults premedicated with phenobarbital. The crossover responses observed were markedly stable between 3.3% (all ve subjects ie 2 ) and 3.7% (all six subjects ie + ), suggesting high reliability of the target sevourane concentration. Based on the MAC for middle-aged subjects of 1.7%,21 the MACie was 2.1 MAC, which was close to MACBAR (2.2 MAC).22 The EEG recorded by the Entropy Module demonstrates cortical activity,23 while the autonomic cardiovascular centres are located in the medulla. So MACBAR and MACie represent the sensitivity of different brain structures to sevourane. Previous studies showed that burst suppression induced by

E F 09:00 10:00 11:00

Fig 2 Narcotrend index change over the course of anaesthesia for Subject 15.

3.9 3.7 3.5 3.3 3.1 2.9 2.7 2.5 2.3 2.1 1.9 1.7

End-tidal sevoflurane %

ie ie+ Crossover MACie

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Patients
Fig 3 Response of each subject to predetermined end-tidal sevourane concentrations. The points of ie + and ie 2 responses plus the broken line show six crossovers of responses. The horizontal line represents the MACie value.

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Burst suppression ratio (%) 100 80 60 40 20 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Age (yr) 61 57 56 60 64 56 54 48 58 48 55 48 54 46 63 55 45 58 61 65 56 56 51 59 57 52 46 51 57 57 FEsevo (%) 1.7 1.9 2.1 2.3 2.5 2.7 2.9 3.1 3.3 3.5 3.7 3.5 3.3 3.5 3.7 3.5 3.3 3.5 3.7 3.5 3.3 3.5 3.7 3.5 3.3 3.5 3.7 3.5 3.7 3.5

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Fig 4 Maximal BSR of each subject in per cent. BSR between 0% and 100% shown by bars, 0, no burst suppression EEG; 100, isoelectric EEG. The age and end-tidal concentration of sevourane are indicated.

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A 100
Probability of isoelectric EEG (%) 90 80 70 60 50 40 30 20 10 0 3.3 3.7 3.8 3.4 3.5 3.6 End-tidal sevoflurane concentration (%)

Table 2 Calculated probabilities of isoelectric EEG

Probability 0.01 0.05 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 0.95 0.99 End-tidal sevourane concentration (vol%) 3.28 3.35 3.39 3.43 3.47 3.49 3.52 3.55 3.58 3.61 3.66 3.70 3.78 95% CI 2.24, 3.40 2.56, 3.44 2.75, 3.47 2.98, 3.50 3.16, 3.54 3.30, 3.59 3.40, 3.67 3.46, 3.81 3.50, 3.99 3.54, 4.22 3.57, 4.59 3.60, 4.93 3.64, 5.62

B 100
Probability of burst suppression (%) 90 80 70 60 50 40 30 20 10 0 2.2 2.4 2.6 2.8 3.0 3.2 3.4 3.6 3.8 4.0 End-tidal sevoflurane concentration (%)
Fig 5 (A) The dose response curve from the probit analyses of endtidal sevourane concentrations and the probability of isoelectric EEG (MACie). MACie is 3.5 vol% (3.4 3.7 vol%). (B) The dose response curve from the probit analyses of end-tidal sevourane concentrations and the probability of the presence of burst suppression (MACbs). MACbs is 3.0 vol% (2.1 3.3 vol%).

sevourane was synchronous over the whole cortex, but was not synchronous in phylogenetically different brain areas: phylogenetically older areas were more resistant to EEG suppression than the neocortex.24 25 In our study, the value of MACie was close to the MACBAR, which could be explained by the approximate requirement of sevourane to suppress electric activity in the cortex and medulla. Accordingly, our results demonstrate that the state of isoelectric EEG allows less adrenergic responses to nociceptive stimulation compared with the state of non-isoelectric EEG. Subjects in the state of isoelectric EEG needed more vasopressor to maintain haemodynamic stability in the absence of surgical stimulation. The synchronous inhibition of HR and cortical electrical activity had been demonstrated in humans receiving isourane and enurane anaesthesia.26 27 Provided MACie is equal (or close) to MACBAR, we may intentionally produce isoelectric EEG targeted to blunt autonomic reexes in indicated patients. However, medications such as opioid and benzodiazepine

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Table 3 Haemodynamic parameters. Data are presented as mean (SD) or number (%). HR, heart rate; MAP, mean arterial pressure. HR and MAP were recorded on entering the room, 2 min before, and 3 min after skin incision, respectively. NS, not signicant
ie 1 (n 5 10) Preoperative MAP (mm Hg) Pre-incision MAP (mm Hg) Post-incision MAP (mm Hg) Preoperative HR (beats min21) Pre-incision HR (beats min21) Post-incision HR (beats min21) Phenylephrine injection [n (%)] MAP or HR increase . 15% [n (%)] 92 (7) 94 (7) 99 (14) 72 (9) 82 (9) 90 (10) 10 (100) 1 (10) ie 2 (n 5 20) 95 (6) 89 (7) 100 (11) 69 (7) 80 (5) 90 (9) 7 (35) 11 (55) 0.001 0.024 NS NS P-value NS NS

might differentially affect MACBAR and MACie, an interesting direction for further studies. Preliminary studies of neuroprotection suggested that anaesthetic-associated protection might be mediated by a reduced metabolic demand,28 such that complete suppression of cortical electric activity would lead to maximal neuroprotection. But, most of the evidence was based on animal experiments29 since it was hard to do similar experiments with human subjects. Doyle and Matta10 showed that isoelectric EEG gave more metabolic suppression than 0% and 50% BSR in 11 patients undergoing general anaesthesia. Although still controversial,15 a growing body of preliminary evidence associates low BIS values and intermediate-term mortality in both cardiac and non-cardiac surgical patients.12 14 16 It is not clear whether the deep anaesthesia-associated adverse outcomes are different between cardiac and non-cardiac surgical patients, or whether the correlation is causal. Our study was not to analyse the cerebral protective or impairing effects of a certain anaesthesia depth, but to nd a basis on which a further study can be carried out. This trial has some important limitations. All subjects were hospitalized middle-aged adults, not healthy volunteers, which might lead to Berksons bias. Elderly and critically ill patients, who are more likely to have serious complications under excessively deep anaesthesia, were excluded for safety reasons. Such a cohort needs to be included in further studies to generalize the estimation of MACie to a broader population. We arbitrarily started at 1.7% (1 MAC) with a step size of 0.2% (0.1 MAC) according to previous studies.6 As the sevourane vaporizer output covers a small range from 0% to 8%, a linear rather than logarithmic scale was used.5 6 When using the modied Dixon up-and-down method, sample size determination is relatively speculative. In order to balance the interest of accurate MACie estimation and variability estimation, we terminated our experiment after six crossovers were observed to minimize the potential bias.20 The primary focus of the present study was to determine the concentration of sevourane inducing isoelectric EEG in 50% of subjects (MACie); values for other quantiles can be estimated with the probit model, but these estimates might not be reliable at both tails of the tolerance distribution.30 Cerebral blood ow and cerebral oxygen metabolism rate might have

inuenced the state of isoelectric EEG, but we were unable to collect these data. Volatile anaesthetic induction and maintenance with sevourane avoided potential interactions with other anaesthetics that might confound MACie estimation. Patients with known factors that might confound MAC were excluded, and the experiment was strictly controlled to avoid possible confounds such as hypotension, hypothermia, and hyperthermia. Several factors, including age and i.v. anaesthetics, might change the value of MACie of sevourane, which should be studied in the next step. All subjects received a single dose of phenobarbital as premedication according to local standards, which could affect the MACie determination; further work is needed to clarify this issue, and to determine the MACie for other currently used volatile agents. In summary, the MACie of sevourane in middle-aged adults premedicated with phenobarbital was 3.5 vol%. The sevourane-induced isoelectric EEG state is associated with signicant cardiovascular depression but reduced haemodynamic responses to skin incision. These data might be useful in avoiding excessive depth of anaesthesia in vulnerable patients, or achieving transient burst suppression or isoelectric EEG when desired.

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Authors contributions
B.N., W.M., and Y.K.T. had full access to all data in the study and take responsibility for data integrity and the accuracy of the data analysis. B.N., W.M., and Y.K.T.: study concept and design. B.N., Y.F., J.M.M., H.X.C., and Y.Y.: acquisition of data. W.M. and Y.K.T.: analysis and interpretation of data. B.N. and Y.F.: draft of the manuscript. F.C., W.M., and Y.K.T.: critical revision of the manuscript for important intellectual content. Z.G.Z.: statistical analysis. W.M. and Y.K.T.: obtain funding. W.M. and Y.K.T.: study supervision.

Acknowledgement
We gratefully acknowledge the expertise of Ms Amber Chen (Project Intern, Department of Neuroscience, Baylor College of Medicine) in the preparation of the manuscript.

Declaration of interest
None declared.

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Funding
This work was supported by grants from the National Natural Science Foundation of P.R. China (no. 31000417 to W.M. and no. 81070890 and no. 30872441 to Y.K.T.) and 2010 Clinical Key Disciplines grant from the Ministry of Health of PR China.

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Handling editor: H. C. Hemmings

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