Minimal alveolar concentration of sevoflurane for inductionof isoelectric electroencephalogram in middle-aged adultsB. Niu1†, Y. Fang1†, J. M. Miao1, Y. Yu2, F. Cao1,4, H. X. Chen1, Z. G. Zhang3, W. Mei1* 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, China4 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.)

Editor’s key points

† Induction of an isoelectricEEG by anaesthetics hasbeen implicated inneuroprotection, andmight be clinically usefulor detrimental in specificsituations.

† The potency ofsevoflurane in producingan isoelectric EEG wasdetermined in adulthuman subjects beforesurgical incision.

† The minimal alveolarconcentration (MAC) ofsevoflurane for isoelectricEEG was 3.5 vol%, which isabout 2.1 times the MACfor skin incision.

Background. We determined the minimal alveolar concentration (MAC) of sevoflurane inducingan isoelectric EEG in 50% of adult subjects (MACie).

Methods. We included 31 middle-aged subjects; 30 subjects finished the study protocol andreceived sevoflurane at preselected concentrations according to a modified Dixon ‘up-and-down’ design starting at 1.7 vol% with 0.2 vol% steps size. General anaesthesia was inducedand maintained with sevoflurane; tracheal intubation was facilitated with cisatracurium. Aftera period of 30 min before skin incision, the state of isoelectric EEG was considered assignificant when a burst suppression ratio of 100% lasted for .1 min. The haemodynamicresponses to skin incision and the vasopressor requirement to maintain stable haemo-dynamic status were also analysed according to the EEG state.

Results. MACie was 3.5% (95% confidence interval, 3.4–3.7%) in middle-aged subjects. Whencompared with subjects not in isoelectric EEG state, subjects in isoelectric EEG state receivedmore phenylephrine to maintain stable haemodynamics (10 of 10 compared with 7 of 20subjects, P¼0.001) and experienced less sympathetic responses to skin incision (1 of 10compared with 11 of 20 subjects, P¼0.024).

Conclusions. MACie for sevoflurane was �2.1 times MAC for immobilization in phenobarbitalpremedicated middle-aged adults. Sevoflurane-induced isoelectric EEG state is associatedwith significant cardiovascular depression but reduced haemodynamic responses to skinincision.

Keywords: anaesthetics volatile, sevoflurane; cardiovascular system, responses; monitoring,depth of anaesthesia; monitoring, electroencephalography

Accepted for publication: 7 June 2013

Minimal alveolar concentration (MAC) was introduced tocompare the potencies of inhalation anaesthetic agents.1 2

Sevoflurane is a commonly used inhalation anaesthesiaagent today. Its effects on motor response (MAC),3 adrenergicreflexes (MACBAR),4 5 reflex pupillary dilatation (MACpup)6 tonociceptive stimulation, and eye opening to verbal command(MACawake)7 in 50% of subjects have been widely investigated.However, the relation between concentration of sevofluraneand different EEG states is relatively unstudied.8

EEG burst suppression and isoelectric (or persistently sup-pressed) EEG, typically associated with states of profoundbrain inactivation, do not appear in normal sleep.9 They arefrequently observed in deep general anaesthesia, patho-logical conditions including hypothermia, hypoxic–ischaemictrauma, coma, and early infantile encephalopathy. Previous

studies have demonstratedthat burst suppressionor isoelectricEEG can be purposely induced by anaesthetic agents to protectthe brain during neurosurgery10 or cardiosurgery.11 Althoughstill a controversial issue, low EEG-derived indices might beassociated with adverse outcomes after cardiac and non-cardiac surgery.12 – 16 Understanding the relation between con-centrations of volatile anaesthetics and abnormal EEG statesincluding burst suppression or isoelectric EEG might help prac-titioners avoid excessively deep anaesthesia in vulnerablepatients, or achieve transient burst suppression or isoelectricEEG when desired. Hence, this study aimed to determine theMAC of sevoflurane inducing isoelectric EEG (MACie) and burstsuppression EEG (MACbs) in 50% of middle-aged adults. In add-ition, haemodynamic stability and responses to incision in astate of isoelectric EEG were also analysed.

† These authors contributed equally to this work.

British Journal of Anaesthesia 112 (1): 72–8 (2014)Advance Access publication 23 August 2013 . doi:10.1093/bja/aet280

& 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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MethodsThe study was approved by the local Institute’s Ethical Com-mittee (Huazhong University of Science and Technology) andregistered with ClinicalTrials.gov (ref: NCT01662622). Afterwritten informed consent, we enrolled 31 subjects aged45–65 yr, undergoing upper abdominal surgery using generalanaesthesia from March to May 2012 at Tongji Hospital,Tongji Medical College, Huazhong University of Science andTechnology, Wuhan, China. All participants had an ASA physic-al status classification of I or II. Patients were excluded fromthe study if they had one of the following criteria: any neuro-logical disease or having received central nervous system–active drugs; a cardiac ejection fraction ,40%; previoushistory of difficult intubation or anticipated difficult intubation;daily alcohol consumption; and obesity (defined as a bodymass index .30 kg m– 2). Those without informed consentwere also excluded.

As premedication, 0.1 g of phenobarbital and 0.5 mg of at-ropine were administered by i.m. injection. After arrival in theoperating theatre, standard monitoring, including electrocar-diography, non-invasive arterial pressure, and pulse oximetry,was established. The i.v. infusion rate of lactated Ringer’s injec-tion was 15 ml kg21 h21 via an 18 G venous catheter. A neuro-muscular monitor (TOF-watch SX; Organon, Dublin, Ireland)was placed over the ulnar nerve at the wrist.

Electrical activity of the brain was measured and recordedwith a Narcotrend Monitor (unprocessed EEG) and S/5 Com-pact Anaesthesia Monitor [burst suppression ratio (BSR)].Sensors of the Narcotrend Monitor (MonitorTechnik, Bad Bram-stedt, Germany, version 4.0) and Entropy Module (S/5 CompactAnaesthesia Monitor, Datex-Ohmeda, Helsinki, Finland) wereattachedto the forehead of each subject according to the man-ufacturer’s recommendation. Impedances were measured foreach set of electrodes to ensure adequate electrode contactdefined as 6 kV for the Narcotrend Monitor and 7.5 kV for theEntropy Module. To calculate BSR, suppression is defined asperiods .0.5 s during which EEG voltage is ,5 mV. Time in asuppressed state is measured and BSR is reported as the frac-tion of the epoch during which the EEG is suppressed. BSR isaveraged over at least 15 epochs (60 s). The presence of burstsuppression was defined as BSR .0.17 A BSR of 100% impliesisoelectric EEG.

General anaesthesia was induced by tidal volume breath-ing of 8% sevoflurane in 100% oxygen at 6 litre min21 witha semi-closed face mask. Cisatracurium 0.15 mg kg21 wasadministered after loss of the lash reflex,18 with manual ven-tilation until the amplitude of T1 decreased to zero. Trachealintubation was performed and switched to mechanical venti-lation with a fresh gas flow of 2 litre min21. Oxygen, carbondioxide, and sevoflurane were sampled with a 19 G tube con-nected to the distal end of the tracheal catheter. Gas concen-tration and partial pressure were analysed by a gas analyser(S/5 Compact Anaesthesia Monitor) with a sample flow rateof 200 ml min21. The end-tidal partial pressure of carbondioxide was maintained at 4.7 kPa. An oesophageal tempera-ture probe was inserted and a warming unit was used if

necessary to maintain 36.5 to 37.58C. Surgery started atleast 30 min after inhalation induction, so that the deter-mined sevoflurane concentration was stable for at least15 min and the difference of inspired and end-tidal concentra-tions was ,10%.4 A cuff-based continuous arterial pressuremonitor was used; an audible alarm was set to indicatemean arterial pressure (MAP) reduction of .20% of baselinevalues. Phenylephrine 0.1 mg was administered i.v. if neces-sary to maintain MAP. Neither Entropy nor Narcotrendalarms were set.

MAC was determined using the Dixon up-and-down me-thod. To avoid awareness, the first subject received end-tidalsevoflurane concentration of 1.7% (1 MAC). As shown inFigure 1, the presence or absence of isoelectric EEG of the pre-vious subject determined the end-tidal sevoflurane concentra-tion of the following subject. End-tidal concentration ofsevoflurane for the next subject was decreased by 0.2% (iso-electric EEG) or increased by 0.2% (non-isoelectric EEG). Acrossover response was defined as the consecutive inclusionof a subject who presented isoelectric EEG, followed byanother who did not. The value of a pair was the average ofthe end-tidal concentration used for the two subjects of thispair. The MACie was determined by averaging the values ofsix consecutive pairs. For each subject, a 30 min interval wasgiven to allow equilibration between arterial and brain ten-sions.2 The isoelectric EEG was considered as significantwhen the isoelectric state lasted .1 min.19 The maximal BSRwas recorded if isoelectric EEG was not reached. Then, the end-tidal concentration of sevoflurane was maintained until 3 minafter incision. Heart rate (HR) and MAP were recorded at 2 and 1min before skin incision, and then at 3 min after surgical inci-sion. The pre-incision value was defined as the mean value ofthe 2 and 1 min before skin incision. Adrenergic reflexes (an in-crease in either HR or MAP .15% above the pre-incisionvalues)5 cases were counted.

Statistical analysis

Patient characteristic data were collected and presented asmean (SD) or as number (%) where appropriate. The MACiewas calculated as the mean of six independent crossovers ofend-tidal sevoflurane 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), whichenabled MACie and MACbs with 95% confidence limits of themean to be derived.20 Data were also analysed with logisticregression for the probability of isoelectric EEG and burst sup-pression vs end-tidal concentration, the maximum-likelihoodestimation, and goodness-of-fit.

Subjects were divided into an isoelectric EEG (ie+) groupand a non-isoelectric EEG (ie2) group. The frequency ofphenylephrine injection and incidence of positive adrenergicreflexes were compared between groups by two-tailedFisher’s exact test. Numerical data were analysed by Student’st-test or the Mann–Whitney U-tests where appropriate.P-values of ,0.05 were considered statistically significant.

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ResultsAs shown in Figure 1, of 40 patients assessed for eligibility, 31were screened and subsequently enrolled. One subject wasexcluded because of severe hypotension during the equilibra-tion period. Data analysis was performed on 30 ASA I–II sub-jects who finished the study.

Grouped patient characteristic data are presented in Table 1.There were more subjects in the ie2 group than in the ie+group (20 compared with 10) because of the experimentaldesign. However, the groups were similar with respect toother characteristics. In addition, the three surgeons whowere involved in the study were equally distributed betweenthe two groups, and the surgical incisions were of similartype and length.

Figure 2 shows the Narcotrend index change over the courseof anaesthesia from Subject 15, who received end-tidal sevo-flurane concentration of 3.7% and showed a representativecurve of the ie+ group.

MAC calculation

Figure 3 shows the up-and-down progression. MACie deter-mined by the Dixon method was 3.5 (0.1)%. As the concentra-tion of sevoflurane increased, suppression of the EEG was notall or none. Figure 4 shows the maximal BSR of each subjectobtained in the period before skin incision. Twenty-one of 30subjects displayed burst suppression EEG.

Figure 5 showsthe dose–response curve of the probabilityofisoelectric EEG (Fig. 5A) and burst suppression (Fig. 5B). The 50%

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%

End-tidal concentrationof the next patient wasdecreased by 0.2%

End-tidal concentrationof the next patient wasincreased by 0.2%

Yes No

No

Isoelectric EEG

6 crossoversof responses

Yes

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

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

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effective dose for isoelectric EEG was 3.5% sevoflurane [95%confidence interval (CI), 3.4–3.7%] and 95% effective dosewas 3.7% (3.6–4.9%). The calculated probabilities of the occur-rence of isoelectric EEG for other quantiles are detailed inTable 2. Maximum-likelihood estimation showed a P¼1 andgoodness-of-fit x2¼0.533.

The 50% effective dose for burst suppression EEG was3.0% (2.1–3.3%). Maximum-likelihood estimation showeda P¼0.922 and goodness-of-fit x2¼3.841.

Vasopressor requirement

MAP was maintained by repeated administration of phenyl-ephrine. When compared with the ie2 group (7 of 20), all sub-jects in the ie+ group (10 of 10) needed phenylephrine(Table 3); the difference was significant (P¼0.001).

Adrenergic response to incision

Only 1 of 10 ie+ subjects showed an increase of .15% in HRor MAP, whereas 11 of 20 ie2 subjects showed an increase(Table 3). Compared with ie2 subjects, ie+ subjects experi-enced less adrenergic responses to incision (P¼0.024).

DiscussionThe MACie of sevoflurane in 100% oxygen was 3.5% (2.1 timesMAC) in middle-aged adults premedicated with phenobarbital.The crossover responses observed were markedly stablebetween 3.3% (all five subjects ie2) and 3.7% (all six subjectsie+), suggesting high reliability of the target sevofluraneconcentration.

Based on the MAC for middle-aged subjects of 1.7%,21 theMACie was �2.1 MAC, which was close to MACBAR (2.2MAC).22 The EEG recorded by the Entropy Module demonstratescortical activity,23 while the autonomic cardiovascular centresare located in the medulla. So MACBAR and MACie representthe sensitivity of different brain structures to sevoflurane. Pre-vious studies showed that burst suppression induced by

Table 1 Subject characteristics. Data are presented as mean (SD),mean (range), or number (%). Temperature and PE′CO2

wererecorded 2 min before incision. Time interval, time from inductionto incision; fluids administered was calculated from entering theroom to incision

ie1 (n510) ie2 (n520)

Age (yr) 56 (46–65) 55 (45–64)

Male gender [n (%)] 5 (50) 12 (60)

Height (cm) 164 (8) 162 (8)

Weight (kg) 57 (11) 61 (11)

Temperature (8C) 36.6 (0.5) 36.4 (0.3)

Time interval (min) 33 (3) 32 (2)

Fluids administered (ml) 745 (26) 757 (30)

PE′CO2(kPa) 4.8 (0.2) 5.0 (0.2)

1 2A

B

C

D

E

F

3 4 5 6 1 Induction2 Intubation3 EEG burst suppression4 Isoelectric EEG5 Incision6 End

09:00 10:00 11:00

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

3.9

ie–

ie+

Crossover

MACie

3.73.53.33.12.92.72.52.32.11.91.7

1 2 3 4 5 6 7 8 9 101112131415161718192021222324252627282930Patients

End

-tid

al s

evof

lura

ne %

Fig 3 Response of each subject to predetermined end-tidal sevoflurane concentrations. The points of ie+ and ie2 responses plus the broken lineshow six crossovers of responses. The horizontal line represents the MACie value.

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sevoflurane was synchronous over the whole cortex, but wasnot synchronous in phylogenetically different brain areas:phylogenetically older areas were more resistant to EEG sup-pression than the neocortex.24 25 In our study, the value ofMACie was close to the MACBAR, which could be explained bythe approximate requirement of sevoflurane to suppress elec-tric activity in the cortex and medulla. Accordingly, our resultsdemonstrate that the state of isoelectric EEG allows less adren-ergic responses to nociceptive stimulation compared with thestate of non-isoelectric EEG. Subjects in the state of isoelectricEEG needed more vasopressor to maintain haemodynamicstability in the absence of surgical stimulation. The synchron-ous inhibition of HR and cortical electrical activity had beendemonstrated in humans receiving isoflurane and enfluraneanaesthesia.26 27 Provided MACie is equal (or close) toMACBAR, we may intentionally produce isoelectric EEG tar-geted to blunt autonomic reflexes in indicated patients.However, medications such as opioid and benzodiazepine

100

Bur

st s

uppr

essi

on r

atio

(%

)80

60

40

20

01

61Age (yr)FEsevo (%)

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 57 571.7 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

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

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 ageand end-tidal concentration of sevoflurane are indicated.

100A

B

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

3.43.3 3.5 3.6End-tidal sevoflurane concentration (%)

End-tidal sevoflurane concentration (%)

Pro

babi

lity

of is

oele

ctric

EE

G (

%)

100

90

80

70

60

50

40

30

20

10

0

Pro

babi

lity

of b

urst

sup

pres

sion

(%

)

3.7 3.8

Fig 5 (A) The dose–response curve from the probit analyses of end-tidal sevoflurane concentrations and the probability of isoelectricEEG (MACie). MACie is 3.5 vol% (3.4–3.7 vol%). (B) The dose–response curve from the probit analyses of end-tidal sevofluraneconcentrations and the probability of the presence of burstsuppression (MACbs). MACbs is 3.0 vol% (2.1–3.3 vol%).

Table 2 Calculated probabilities of isoelectric EEG

Probability End-tidal sevofluraneconcentration (vol%)

95% CI

0.01 3.28 2.24, 3.40

0.05 3.35 2.56, 3.44

0.10 3.39 2.75, 3.47

0.20 3.43 2.98, 3.50

0.30 3.47 3.16, 3.54

0.40 3.49 3.30, 3.59

0.50 3.52 3.40, 3.67

0.60 3.55 3.46, 3.81

0.70 3.58 3.50, 3.99

0.80 3.61 3.54, 4.22

0.90 3.66 3.57, 4.59

0.95 3.70 3.60, 4.93

0.99 3.78 3.64, 5.62

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might differentially affect MACBAR and MACie, an interestingdirection for further studies.

Preliminary studies of neuroprotection suggested thatanaesthetic-associated protection might be mediated by areduced metabolic demand,28 such that complete suppressionof cortical electric activity would lead to maximal neuroprotec-tion. But, most of the evidence was based on animal experi-ments29 since it was hard to do similar experiments withhuman subjects. Doyle and Matta10 showed that isoelectricEEG gave more metabolic suppression than 0% and 50% BSRin 11 patients undergoing general anaesthesia. Although stillcontroversial,15 a growing body of preliminary evidence associ-ates low BIS values and intermediate-term mortality in bothcardiac and non-cardiac surgical patients.12 – 14 16 It is notclear whether the deep anaesthesia-associated adverse out-comes are different between cardiac and non-cardiac surgicalpatients, or whether the correlation is causal. Our study wasnot to analyse the cerebral protective or impairing effects ofa certain anaesthesia depth, but to find a basis on which afurther study can be carried out.

This trial has some important limitations. All subjects werehospitalized middle-aged adults, not healthy volunteers,which might lead to Berkson’s bias. Elderly and critically illpatients, who are more likely to have serious complicationsunder excessively deep anaesthesia, were excluded for safetyreasons. Such a cohort needs to be included in further studiesto 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 sevofluranevaporizer output covers a small range from 0% to 8%, alinear rather than logarithmic scale was used.5 6 When usingthe modified Dixon up-and-down method, sample size deter-mination is relatively speculative. In order to balance the inter-est of accurate MACie estimation and variability estimation,we terminated our experiment after six crossovers wereobserved to minimize the potential bias.20 The primary focusof the present study was to determine the concentration ofsevoflurane inducing isoelectric EEG in 50% of subjects(MACie); values for other quantiles can be estimated withthe probit model, but these estimates might not be reliableat both tails of the tolerance distribution.30 Cerebral bloodflow and cerebral oxygen metabolism rate might have

influenced the state of isoelectric EEG, but we were unable tocollect these data. Volatile anaesthetic induction and main-tenance with sevoflurane avoided potential interactions withother anaesthetics that might confound MACie estimation.Patients with known factors that might confound MAC wereexcluded, and the experiment was strictly controlled to avoidpossible confounds such as hypotension, hypothermia, andhyperthermia. Several factors, including age and i.v. anaes-thetics, might change the value of MACie of sevoflurane,which should be studied in the next step. All subjects receiveda single dose of phenobarbital as premedication according tolocal standards, which could affect the MACie determination;further work is needed to clarify this issue, and to determinethe MACie for other currently used volatile agents.

In summary, the MACie of sevoflurane in middle-agedadults premedicated with phenobarbital was 3.5 vol%. Thesevoflurane-induced isoelectric EEG state is associated withsignificant cardiovascular depression but reduced haemo-dynamic responses to skin incision. These data might beuseful in avoiding excessive depth of anaesthesia in vulnerablepatients, or achieving transient burst suppression or isoelectricEEG when desired.

Authors’ contributionsB.N., W.M., and Y.K.T. had full access to all data in the studyand take responsibility for data integrity and the accuracy ofthe data analysis. B.N., W.M., and Y.K.T.: study concept anddesign. 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. andY.F.: draft of the manuscript. F.C., W.M., and Y.K.T.: critical revi-sion 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.

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

Declaration of interestNone declared.

Table 3 Haemodynamic parameters. Data are presented as mean (SD) or number (%). HR, heart rate; MAP, mean arterial pressure. HR and MAPwere recorded on entering the room, 2 min before, and 3 min after skin incision, respectively. NS, not significant

ie1 (n510) ie2 (n520) P-value

Preoperative MAP (mm Hg) 92 (7) 95 (6) NS

Pre-incision MAP (mm Hg) 94 (7) 89 (7) NS

Post-incision MAP (mm Hg) 99 (14) 100 (11)

Preoperative HR (beats min21) 72 (9) 69 (7) NS

Pre-incision HR (beats min21) 82 (9) 80 (5) NS

Post-incision HR (beats min21) 90 (10) 90 (9)

Phenylephrine injection [n (%)] 10 (100) 7 (35) 0.001

MAP or HR increase .15% [n (%)] 1 (10) 11 (55) 0.024

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FundingThis work was supported by grants from the National NaturalScience Foundation of P.R. China (no. 31000417 to W.M. andno. 81070890 and no. 30872441 to Y.K.T.) and 2010 ClinicalKey Disciplines grant from the Ministry of Health of PR China.

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