Minimal alveolar concentration of sevoflurane for induction of ... - BJA

British Journal of Anaesthesia Page 1 of 7
doi:10.1093/bja/aet280
BJA Advance Access published September 24, 2013
Minimal alveolar concentration of sevoflurane for induction
of isoelectric electroencephalogram in middle-aged adults
B. Niu 1† ,Y.Fang 1† , J. M. Miao 1 ,Y.Yu 2 ,F.Cao 1,4 , H. X. Chen 1 , Z.G. Zhang 3 ,W.Mei 1 * and Y. K. Tian 1 *
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.)
Editor’s key points
† Induction of an isoelectric
EEG by anaesthetics has
been implicated in
neuroprotection, and
might be clinically useful
or detrimental in specific
situations.
† The potency of
sevoflurane in producing
an isoelectric EEG was
determined in adult
human subjects before
surgical incision.
† The minimal alveolar
concentration (MAC) of
sevoflurane 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 sevoflurane inducing
an isoelectric EEG in 50% of adult subjects (MACie).
Methods. We included 31 middle-aged subjects; 30 subjects finished the study protocol and
received sevoflurane at preselected concentrations according to a modified Dixon ‘up-anddown’
design starting at 1.7 vol% with 0.2 vol% steps size. General anaesthesia was induced
and maintained with sevoflurane; tracheal intubation was facilitated with cisatracurium. After
a period of 30 min before skin incision, the state of isoelectric EEG was considered as
significant 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% confidence interval, 3.4–3.7%) 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, P¼0.001) and experienced less sympathetic responses to skin incision (1 of 10
compared with 11 of 20 subjects, P¼0.024).
Conclusions. MACie for sevoflurane was ≏2.1 times MAC for immobilization in phenobarbital
premedicated middle-aged adults. Sevoflurane-induced isoelectric EEG state is associated
with significant cardiovascular depression but reduced haemodynamic responses to skin
incision.
Keywords: anaesthetics volatile, sevoflurane; 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
Sevoflurane is a commonly used inhalation anaesthesia
agent today. Its effects on motor response (MAC), 3 adrenergic
reflexes (MACBAR), 45 reflex 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 sevoflurane
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, hypoxic–ischaemic
trauma, coma, and early infantile encephalopathy. Previous
studies have demonstratedthat burst suppressionorisoelectric
EEG can be purposely induced by anaesthetic agents to protect
the brain during neurosurgery 10 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 sevoflurane 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.
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Methods
The study was approved by the local Institute’s Ethical Committee
(Huazhong University of Science and Technology) and
registered with ClinicalTrials.gov (ref: NCT01662622). After
written informed consent, we enrolled 31 subjects aged
45–65 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 classification 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 difficult intubation or anticipated difficult intubation;
daily alcohol consumption; and obesity (defined 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 Ringer’s injection
was 15 ml kg 21 h 21 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
attachedto the forehead of each subject according to the manufacturer’s
recommendation. Impedances were measured for
each set of electrodes to ensure adequate electrode contact
defined as 6 kV for the Narcotrend Monitor and 7.5 kV for the
Entropy Module. To calculate BSR, suppression is defined 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 defined as BSR .0. 17 A BSR of 100% implies
isoelectric EEG.
General anaesthesia was induced by tidal volume breathing
of 8% sevoflurane in 100% oxygen at 6 litre min 21 with
a semi-closed face mask. Cisatracurium 0.15 mg kg 21 was
administered after loss of the lash reflex, 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 flow of 2 litre min 21 . Oxygen, carbon
dioxide, and sevoflurane 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 flow rate
of 200 ml min 21 . 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
Niu et al.
necessary to maintain 36.5 to 37.58C. Surgery started at
least 30 min after inhalation induction, so that the determined
sevoflurane 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 first subject received end-tidal
sevoflurane 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 sevoflurane concentration
of the following subject. End-tidal concentration of
sevoflurane for the next subject was decreased by 0.2% (isoelectric
EEG) or increased by 0.2% (non-isoelectric EEG). A
crossover response was defined 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 significant
when the isoelectric state lasted .1 min. 19 The maximal BSR
was recorded if isoelectric EEG was not reached. Then, the endtidal
concentration of sevoflurane 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 defined as the mean value of
the 2 and 1 min before skin incision. Adrenergic reflexes (an increase
in either HR or MAP .15% above the pre-incision
values) 5 cases were counted.
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 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), which
enabled MACie and MACbs with 95% confidence 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-fit.
Subjects were divided into an isoelectric EEG (ie+) group
and a non-isoelectric EEG (ie2) group. The frequency of
phenylephrine injection and incidence of positive adrenergic
reflexes were compared between groups by two-tailed
Fisher’s exact test. Numerical data were analysed by Student’s
t-test or the Mann–Whitney U-tests where appropriate.
P-values of ,0.05 were considered statistically significant.
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MAC of sevoflurane for isoelectric EEG
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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%
End-tidal concentration
of the next patient was
decreased by 0.2%
Yes
Isoelectric EEG
No
6 crossovers
of responses
Yes
No
Analysed (n=30)
Excluded for severe hypotension (n=1)
End-tidal concentration
of the next patient was
increased by 0.2%
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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 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 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 sevoflurane
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 sevoflurane 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 showsthe dose–response curve of the probabilityof
isoelectric EEG (Fig. 5A) and burst suppression (Fig. 5B). The 50%
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Niu et al.
Table 1 Subject characteristics. Data are presented as mean (SD),
mean (range), or number (%). Temperature and PE ′ CO 2
were
recorded 2 min before incision. Time interval, time from induction
to incision; fluids administered was calculated from entering the
room 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 ′ CO 2
(kPa) 4.8 (0.2) 5.0 (0.2)
A
B
C
D
E
F
1 2
3 4 5 6 1 Induction
2 Intubation
3 EEG burst suppression
4 Isoelectric EEG
5 Incision
6 End
09:00 10:00 11:00
Fig 2 Narcotrend index change over the course of anaesthesia for
Subject 15.
effective dose for isoelectric EEG was 3.5% sevoflurane [95%
confidence 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 P¼1 and
goodness-of-fit x 2 ¼0.533.
The 50% effective dose for burst suppression EEG was
3.0% (2.1–3.3%). Maximum-likelihood estimation showed
a P¼0.922 and goodness-of-fit x 2 ¼3.841.
Vasopressor requirement
MAP was maintained by repeated administration of phenylephrine.
When compared with the ie2 group (7 of 20), all subjects
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 HR
or MAP, whereas 11 of 20 ie2 subjects showed an increase
(Table 3). Compared with ie2 subjects, ie+ subjects experienced
less adrenergic responses to incision (P¼0.024).
Discussion
The MACie of sevoflurane 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 five subjects ie2) and 3.7% (all six subjects
ie+), suggesting high reliability of the target sevoflurane
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 sevoflurane. Previous
studies showed that burst suppression induced by
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End-tidal sevoflurane %
3.9
3.7
3.5
3.3
3.1
2.9
2.7
2.5
2.3
2.1
1.9
1.7
ie–
ie+
Crossover
MACie
1 2 3 4 5 6 7 8 9 101112131415161718192021222324252627282930
Patients
Fig 3 Response of each subject to predetermined end-tidal sevoflurane concentrations. The points of ie+ and ie2 responses plus the broken line
show six crossovers of responses. The horizontal line represents the MACie value.
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MAC of sevoflurane for isoelectric EEG
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100
80
60
40
20
0
1 2 3 4 5 6 7 8 9 101112131415161718192021222324252627282930
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
FE sevo (%) 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
Burst suppression ratio (%)
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 sevoflurane are indicated.
A 100
90
80
70
60
50
40
30
20
10
0
3.3 3.4 3.5 3.6 3.7 3.8
End-tidal sevoflurane concentration (%)
B 100
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 (%)
Probability of isoelectric EEG (%)
Probability of burst suppression (%)
Fig 5 (A) The dose–response curve from the probit analyses of endtidal
sevoflurane 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 sevoflurane
concentrations and the probability of the presence of burst
suppression (MACbs). MACbs is 3.0 vol% (2.1–3.3 vol%).
Table 2 Calculated probabilities of isoelectric EEG
Probability
End-tidal sevoflurane
concentration (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
sevoflurane 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 sevoflurane 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 isoflurane and enflurane
anaesthesia. 26 27 Provided MACie is equal (or close) to
MACBAR, we may intentionally produce isoelectric EEG targeted
to blunt autonomic reflexes in indicated patients.
However, medications such as opioid and benzodiazepine
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Niu et al.
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 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 min 21 ) 72 (9) 69 (7) NS
Pre-incision HR (beats min 21 ) 82 (9) 80 (5) NS
Post-incision HR (beats min 21 ) 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
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 experiments
29 since it was hard to do similar experiments with
human subjects. Doyle and Matta 10 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 find 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 Berkson’s 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 sevoflurane
vaporizer output covers a small range from 0% to 8%, a
linear rather than logarithmic scale was used. 56 When using
the modified 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
sevoflurane 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
flow and cerebral oxygen metabolism rate might have
Page 6 of 7
influenced the state of isoelectric EEG, but we were unable to
collect these data. Volatile anaesthetic induction and maintenance
with sevoflurane 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 sevoflurane,
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 sevoflurane in middle-aged
adults premedicated with phenobarbital was 3.5 vol%. The
sevoflurane-induced isoelectric EEG state is associated with
significant 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.
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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MAC of sevoflurane for isoelectric EEG
BJA
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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