Chinese Medical Journal 2009;122(8):935-940 935

Original article
Relationship between depth of anesthesia and effect-site
concentration of propofol during induction with the
target-controlled infusion technique in elderly patients
LIU Shao-hua, WEI Wei, DING Guan-nan, KE Jing-dong, HONG Fang-xiao and TIAN Ming

Keywords: propofol; target-controlled infusion; depth of anesthesia; effect-site concentration; elderly patients

Background There are few studies to assess whether the effect-site concentration of propofol can predict anesthetic
depth during the target-controlled infusion (TCI) induction in elderly patients. This study aimed to evaluate the
relationship between effect-site concentration of propofol and depth of anesthesia during the TCI induction in elderly
patients.
Methods Ninety patients (60–80 years) with an American Society of Anesthesiologists (ASA) physical status of 1–3,
undergoing scheduled abdominal and thoracic surgery under general anesthesia were randomly allocated into one of
three groups, Group S1, S2 and S3 (30 patients in each group). The patients in Group S1 received propofol with a target
plasma concentration of 4.0 µg/ml; patients in Group S2 received propofol with an initial target plasma concentrations of
2.0 µg/ml that was raised to 4.0 µg/ml 3 minutes later; patients in Group S3 received an infused scheme of 3 steps;
starting from a target plasma concentration of 2.0 µg/ml that was increased stepwised by 1 µg/ml until a target plasma
concentration of 4.0 µg/ml was achieved, the interval between the two steps was 3 minutes. When an Observer′s
Assessment of Alertness/Sedation (OAA/S) score of 1 was achieved, remifentanil (effect-site concentration (Ce) of 4.0
ng/ml) and rocuronium 0.9 mg/kg were administered. Tracheal intubation was started 2 minutes after rocuronium
injection. Changes of propofol Ce, blood pressure (BP), heart rate (HR), and bispectral index (BIS) were recorded.
Results When an OAA/S score of 1 was achieved, Ce of propofol were (1.7±0.4) µg/ml, (1.9±0.3) µg/ml, (1.9±0.4)
µg/ml and the BIS values were 64±5, 65±8, and 62±8 in Groups S1, S2 and S3. Before intubation, Ce of propofol was
(2.8±0.2) µg/ml, (2.8±0.3) µg/ml, (2.7±0.3) µg/ml, and the BIS values were 48±7, 51±7, and 47±5 in Groups S1, S2 and
S3. By linear regression analysis, a significant correlation between Ce of propofol and BIS values was found (r=–0.580, P
<0.01). Systolic blood pressure (SBP) before intubation was significantly lower in Group S1 than in Groups S2 and S3.
SBP and HR after intubation in the three groups were significantly increased when compared with pre-intubation values,
but they did not exceed baseline values
Conclusions During the TCI induction, Ce of propofol with (1.9±0.3) µg/ml may make the elderly patients unconscious.
When remifentanil with a Ce of 4.0 ng/ml is added a Ce of propofol with (2.8±0.3) µg/ml is suitable for intubation. The Ce
of propofol has a close correlation with the BIS values. Also, a two-step TCI technique seems to be a more suitable
method of anesthesia induction in elderly patients compared with the no-stepwise TCI technique and three-step TCI
technique.
Chin Med J 2009;122(8):935-940

I ntravenous anesthesia with propofol infusion has been

used widely in clinical practice. It has been
demonstrated that the use of a target controlled infusion
(TCI) system can accurately predict plasma
concentrations of propofol.1 Also previous work showed
that in healthy young patients there is a good correlation
between the predicted effect-site concentration (Ce) of
propofol and the depth of anesthesia as recorded by
various monitoring variables, such as bispectral index
(BIS), auditory evoked potential (AEP), and entropy.2,3
The concept of a minimum alveolar concentration (MAC)
for volatile anesthetics is well known and widely used to
ensure that in the clinic patients receive sufficient
anesthesia to prevent awareness during surgery.4 A similar
concept exists for intravenous anesthetics agents. It is
referred to as the effective concentration 50 (EC50), which
is defined as the concentration of an intravenous
anesthetic at which 50% of patients will not respond to
skin incision.5 A previous study6 showed the EC50 and
EC95 of propofol at which adult Chinese patients loss of
consciousness. However, there are few published data to
assess whether the Ce of propofol may predict anesthetic
depth in elderly patients. Therefore, we designed this
prospective clinical study to evaluate the relationship
between the Ce of propofol and the depth of anesthesia
during anesthesia induction using the TCI technique in
elderly patients. Our study was to determine the Ce of
DOI: 10.3760/cma.j.issn.0366-6999.2009.08.011
Department of Anesthesiology, Beijing Friendship Hospital,
Capital Medical University, Beijing 100050, China (Liu SH, Wei
W, Ding GN, Ke JD, Hong FX and Tian M)
Correspondence to: Prof. TIAN Ming, Department of
Anesthesiology, Beijing Friendship Hospital, Capital Medical
University, Beijing 100050, China (Fax: 86-10-63023261. Email:
tianm@china.com)
936 Chin Med J 2009;122(8):935-940

propofol required for loss of consciousness and tracheal

intubation during TCI induction, and the suitable TCI
technique in elderly patients.

METHODS

Patients′ selection and preparation

Ninety patients, aged 60 to 80 years, with an American
Society of Anesthesiologists (ASA) physical status of 1–3
who were undergoing scheduled abdominal and thoracic
surgery under general anesthesia were included in this
study. Exclusion criteria were body mass index ≤18 or ≥
30, a history of mental disorders and hepatic or renal
diseases, recent administration of sedative or opioid drugs
and drug addiction.

The patients were fasted for 8 hours before surgery and

received no premedication. After patients entered the
operating room routine monitoring was applied. A
20-gauge plastic cannula was inserted into the radial
artery for continuous arterial blood pressure (BP)
monitoring and a 18-gauge intravenous (IV) catheter was
inserted into an upper limb vein for IV administration of
drugs and fluid. After a stabilization period of 10 minutes,
baseline values of BP and heart rate (HR) were obtained
from the average of three measurements obtained 2
minutes apart. Then the skin of the forehead was prepared
with 75% alcohol and a BIS variable was taken with a
A-2000 BIS Monitor (Aspect Medical Systems, Natick,
MA, USA; Xp Version). Before drug administration 5
ml/kg of Lactated Ringer′s solution was given by IV and
then maintained at an infusion rate of 7 ml·kg-1·min-1.
Study design
Patients were randomly allocated into one of three groups
(Groups S1, S2 and S3, 30 patients in each group).
Randomization was performed using computer generated
random numbers in sealed envelopes. The patients in
Group S1 received propofol with a target plasma
concentration of 4.0 µg/ml; patients in Group S2 initially
received with a target plasma concentration of 2.0 µg/ml
that was raised to 4.0 µg/ml 3 minutes later; patients in
Group S3 received an infusion scheme of 3 steps, starting
from a target plasma concentration of 2.0 µg/ml that was
increased stepwise by 1 µg/ml until a target plasma
concentration of 4.0 µg/ml was achieved, the interval
between the two steps was 3 minutes (Figure 1).
Target-controlled infusion of propofol was performed
using a motor-driven syringe pump (Graseby 3500,
Smiths Medical International, Watford, UK) with an
Astra-Zeneca Diprifusor TCI system, which contains a
Marsh′s pharmacokinetic model. This system can display
the predicted Ce of propofol.
A modified Observer′s Assessment of Alertness/Sedation
(OAA/S) scale (Table 1) was used to assess the depth of
both sedation and anesthesia.7 It was tested one time
every 15 seconds. If the patient was not responsive to
shaking and calling his or her name loudly, it was
Figure 1. TCI schemes of propofol in the three groups. LOC:
loss of consciousness.
Table 1. Responsiveness scores of the Modified Observer′s
Assessment of Alertness/Sedation Scale
Score Responsiveness
5 Responds readily to name spoken in normal tone
4 Lethargic response to name spoken in normal tone
3 Responds only after name is called loudly and/or repeatedly
2 Responds only after mild prodding or shaking
1 Responds only after painful trapezius squeeze
0 No response after painful trapezius squeeze
considered that an OAA/S score of 1 had been achieved.
When an OAA/S score of 1 was achieved, remifentanil,
with a Ce of 4.0 ng/ml and rocuronium at 0.9 mg/kg,
were administered by IV. The patient was ventilated via a
facemask with 100% oxygen. If any difficulty was
encountered in performing facemask ventilation, the
patient was withdrawn from the study, and his/her card
was resealed in an envelope and randomly placed among
the remaining envelopes to be used later. Tracheal
intubation was started 2 minutes after IV injection of
rocuronium. The patients requiring more than one attempt
to achieve successful intubation were excluded from
statistical analysis of the data.
Observable variables
Ce, BP, HR and BIS were recorded at four points:
baseline values before induction (T0), OAA/S score of 1
(T1), immediately before intubation (T2), and
immediately after intubation (T3). BIS was recorded 5
seconds after each time point. To minimize the bias,
assessments of sedation levels during the tracheal
intubations were performed by one anesthesiologist. Also
investigators involved in recording data were blinded to
Chinese Medical Journal 2009;122(8):935-940 937

patient group assignment. BIS were not significantly different among the three
groups (Table 3).
Study hypothesis
The hypothesis of this study was that there would be Table 3. Ce of propofol, BIS values and total dosages of propofol
significant differences in the cardiovascular intubation at OAA/S of 1 and intubation in the three groups (n=30)
Characteristics Group S1 Group S2 Group S3
responses among the three groups. From a clinical point
OAA/S of 1
of view, we considered that a 20% difference in systolic Ce (µg/ml) 1.7±0.4 1.9±0.3* 1.9±0.4*
blood pressure (SBP) and HR changes during the BIS 64±5 65±8 62±8
observation would be a clinically important difference. Total dosages (mg) 96.1±14.7 96.8±19.7 95.3±20.2
Power calculations8 indicated that at least 28 patients in Intubation
Ce (µg/ml) 2.8±0.2 2.8±0.3 2.7±0.3
each group would be required to detect this difference
BIS 48±7 51±7 47±5
between groups with a power of 80% and a P value of Total dosages (mg) 130.8±21.9 128.6±19.9 128.9±19.5
0.05. Allowing for possible exclusions due to difficulties Values are expressed as mean ± SD, *P <0.05 compared with Group S1.
in facemask ventilation and intubation, we chose to
examine a minimum of 30 patients in each group. Relationship between Ce of propofol and BIS values
By the linear regression analysis, a close correlation
Statistical analysis between Ce of propofol and BIS values was found. The
Statistical analysis of data was performed with SPSS regression equation was: BIS=76.2–8.7Ce (µg/ml)
(version 11.5; SPSS Inc., USA). All continuous data were (r=–0.580, P <0.01) (Figure 2).
tested for normality using the Kolmogorov-Smirnov
method. The comparisons among the three groups were
performed using one way analysis of variance (ANOVA).
For multiple comparisons of inter-individual data,
Friedman repeated-measures analysis of variance on
ranks with subsequent all pairwise multiple comparison
procedures (Tukey test) was applied. The correlation
between the Ce and BIS was analyzed by linear
regression and the Spearman correlation coefficients were
calculated. A P value <0.05 was considered statistically
significant.

RESULTS

Patients′ characteristic and clinical data

A total of 90 patients (47 females and 43 males) were
studied. No patient was excluded from the study because
Figure 2. A linear regression analysis showed significant
of difficult facemask ventilation or failed intubation at the correlation between Ce of propofol and BIS values.
first attempt. The three groups were comparable with BIS=76.2–8.7Ce (µg/ml) (r=–0.580, P <0.01).
respect to the patients′ characteristic data (Table 2).
Changes in SBP
Table 2. Characteristic data of patients in the three groups (n=30) As compared to baseline values before induction, SBP
Characteristics Group S1 Group S2 Group S3
and HR decreased significantly when the OAA/S score
Age (years) 69±5 70±5 68±4
Weight (kg) 69±11 63±10 66±12
was 1. Before intubation, SBP and HR further decreased
Gender (F/M) 14/16 17/13 16/14 due to administration of remifentanil. Also SBP before
SBP (mmHg) 153±18 146±13 146±14 intubation was significant lower in Group S1 than in
HR (beats/min) 75±9 77±10 76±10 Groups S2 and S3. SBP and HR after intubation in the
BIS 95±2 95±2 96±1 three groups was significantly increased compared with
Hypertension I/II stage 11/5 12/5 10/6
those values before intubation, but they did not exceed
Values are expressed as mean ± SD except for gender data and hypertension I/II
stage (n). There were no statistically significant differences in all variables
baseline values (Table 4).
among the three groups.
DISCUSSION
Clinical response, BIS values and Ce of propofol
When OAA/S was 1, BIS values and total dosages of The aim of this study was to evaluate whether there was
propofol in the three groups were similar (P >0.05 significant correlation between the Ce of propofol and the
between groups). The Ce value of propofol was depth of anesthesia during induction using the TCI
significantly lower in Group S1 than in Groups S2 and S3 technique in elderly Chinese patients. In addition to the
(P=0.044 and 0.024, respectively), but it did not differ use of the OAA/S score as a clinical endpoint, BIS was
significantly between Groups S2 and S3 (P=0.802). also employed to assess the depth of anesthesia. In this
Immediately before intubation, Ce values of propofol and study we also wished to determine whether the Ce of
938
Table 4. Changes of SBP and HR during anesthesia induction and
intubation in the three groups (n=30)
Variables Groups T0 T1 T2
SBP S1 153±18 128±18* 109±15*
S2 146±13 121±14* 118±13*‡
S3 146±14 121±14* 115±14*‡
HR S1 75±9 75±8 68±8 *
S2 77±10 74±9 68±10*
S3 76±10 75±9 70±11*
Values are expressed as mean±SD. *P<0.01, compared to T0; †P <0.05,
compared to T2; ‡P <0.05, compared to Group S1. T0: baseline before induction;
T1: OAA/S=1; T2: immediately before intubation; T3: immediately after
intubation.
propofol and BIS are useful variables for predicting loss
of consciousness and the suitable anesthetic depth
required to perform tracheal intubation.
In our study, the patients were randomly divided into
three groups and the stepwise infusion techniques were
used in Groups S2 and S3 for the following reasons. First,
previous researches suggest that a longer infusion time
can result in a higher C50.9-11 Second, a prolonged
infusion time helps to stabilize hemodynamic variables
during anesthesia induction in elderly patients. Also
anesthesia induction using a step-by-step TCI technique
with propofol can result in stable hemodynamics,
especially for the elderly patients, or in those with the
cardiovascular diseases.12
Our results clearly show that at the OAA/S score of 1 and
at intubation, total dosages of propofol did not differ
among the three groups, but the Ce of propofol was lower
in Group S1 than in Groups S2 and S3. SBP before
intubation was significantly higher in Groups S2 and S3
than in Group S1. Also SBP increase by intubation was
numerically smaller in Groups S2 (7.5%) and S3 (7.0%)
than in Group S1 (13.2%), although no statistical
differences among the three groups were achieved. These
results suggest that compared with a non-stepwise TCI
technique with propofol (Group S1), the stepwise TCI
techniques of propofol (Groups S2 and S3) can achieve a
more stable anesthesia induction and a more effective
attenuation of cardiovascular intubation response in
elderly patients. This is in agreement with the results of
previous studies.9-12 Additionally, our study demonstrated
that when the OAA/S score was 1, the Ce value of
propofol did not significantly differ between Groups S2
and S3. Also, SBP and HR at all measuring points did not
differ between Groups S2 and S3. It suggests that
compared with a two-step TCI technique of propofol, a
three-step TCI technique of propofol does not further
improve features of anesthesia induction and control of
cardiovascular intubation response while it required a
longer infusion time. According to these results, we
consider that compared with the non-stepwise TCI
technique and three-step TCI technique, a two-step TCI
technique may be a more reasonable method of anesthesia
induction with propofol in elderly patients.
Two previous studies have evaluated the relationship of
the predicted Ce of propofol with clinical endpoints.13,14
Chin Med J 2009;122(8):935-940
Because of the different propofol infusion rates, there is a
large difference in the predicted plasma concentrations
T3
between the two studies. However, the predicted Ce of
126±18*†
127±23*†
propofol was similar in the two studies. The existence of
123±21*† considerable discrepancy between the predicted plasma
78±11† concentration and Ce of propofol suggests that during
76±13† induction and recovery, the predicted Ce of propofol may
75±10†
be a more useful clinical correlate than the predicted
plasma concentration.11
The effect-site EC50 and EC95 of propofol at loss of
consciousness have been shown to be 2.8 and 4.1 µg/ml
in Caucasian populations13 and 2.7 and 3.8 µg/ml in
Chinese populations.14 This indicates no difference in the
effect-site EC50 and EC95 of propofol at loss of
consciousness between Caucasian and Chinese
populations. In a study by Xu et al,15 however, effect-site
EC50 and EC95 of propofol at loss of consciousness were
2.2 and 3.2 µg/ml in the Chinese populations, which were
lower than the results of a previous study in Caucasians
populations.13 Zhong et al16 found that the effect-site
EC50 and EC95 of propofol at loss of consciousness were
2.5 and 3.4 µg/ml during TCI with propofol in Chinese
patients. This was similar with the results of Xu et al.15
Because the plasma concentration of propofol was not
measured in all studies above, it is impossible to know
whether these inconsistent results were due to
pharmacokinetic or pharmacodynamic differences among
the populations of different races. Therefore, further
studies are required to confirm it.
When the OAA/S decreased to 1, the Ce of propofol was
4.5 µg/ml in the study of Iannuzzi et al17 which is higher
than we found in our study. Barakat et al18 calculated the
predicted Ce from the two pharmacokinetic models
(Marsh/Schnider). The results showed that changes of
both the sedation score and BIS index correlated better
with the predicted Ce in using the Marsh model than in
using the Schnider model. Also the Schnider model
predicted much faster effect site equilibration in the blood
than the Marsh model. This may explain the discrepancy
in the Ce of propofol between Iannuzzi′s study with a
Schnider model and our study with a Marsh model.
However, the Ce of propofol from other previous studies
with a Marsh model were higher than our result.13-15 This
may indicate significant differences in the
pharmacokinetics and pharmacodynamics of propofol
between patients of different ages.6 Elderly patients are
reported to be more sensitive to propofol than are young
patients.19 In the study of Milne et al,13 Caucasian
patients aged 18–65 years were included. In the studies of
Irwin et al14 and Xu et al,15 Chinese patients aged <65
years were included. In contrast, Chinese patients aged
60–80 years were selected in this study. According to the
results from our work and from previous studies, we
consider that when the TCI technique of propofol is used
for anesthesia induction in the elderly patients, a lower
plasma concentration should be best selected with the
plasma-controlled TCI technique.
Chinese Medical Journal 2009;122(8):935-940
In the study of Iannuzzi et al,17 a good Spearman
correlation between the Ce of propofol and BIS values
was found (r=0.92). In their study, however, sample
points included the baseline point at which the Ce of
propofol was 0 µg/ml in all patients. This can result in a
deviation in that the correlation coefficient (r value) is
higher than the realistic state. In contrast, the baseline
point (T0) was excluded in our study and only three
points (T1, T2 and T3) were included to assess the
relationship between the Ce of propofol and BIS values.
If the baseline point is also included in our study, the
calculated value of the correlation coefficient would
exceed –0.9, being similar to the result of Iannuzzi et al.17
Previous studies have shown the existence of a significant
correlation between the Ce of propofol and BIS
values.20-22 It implies that, like MAC with inhaled
anesthesia,23 during the TCI intravenous anesthesia with
propofol, the Ce could indicate the depth of anesthesia.
However, a further clinical trial with large samples is
required to verify this point of view.
The OAA/S scores have been shown to have a good
correlation with levels of sedation.21 Struys et al24 found
that the BIS also correlated well with the levels of
sedation observed by OAA/S. Otherwise, Iannuzzi et al17
confirm that neither BIS nor the A-Line ARX index (AAI)
have the high level of discriminative power needed to be
definitive methods for identifying depth of anesthesia
endpoints. When using BIS and AAI to monitor depth of
anesthesia, therefore, they must be considered with
clinical judgment. Except for the use of Ce and BIS as
endpoints in our study, clinical signs including OAA/S
scores and cardiovascular changes are used to assess the
depth of anesthesia and adequacy of anesthesia induction
with the different TCI techniques.
A previous work suggests that SBP changes after
anesthesia induction are more sensitive than BIS in
prediction of movement response to laryngoscopy and
intubation.25 Also BP and HR changes during a procedure
may give an indirect indication of the distress. For this
reason,26 we observed the cardiovascular intubation
response by comparing the changes of SBP and HR
before and after intubation. Based on the results of this
study, we consider that cardiovascular changes by
intubation may be suitable indicators for identifying the
depth of anesthesia.
A limitation of our study was that the predicted plasma
concentrations of propofol did not follow a geometric
progression. This makes it impossible for us to calculate
effect-site EC50 and EC95 of propofol at loss of
consciousness and intubation. Therefore, further trials are
required in elderly Chinese patients to determine the
effect-site EC50 and EC95 of propofol at the different
clinical endpoints.
In conclusion, this study has demonstrated that when the
TCI technique with propofol and a Marsh model is used
939
for anesthesia induction in elderly Chinese patients, the
Ce of propofol at loss of consciousness is (1.9±0.3) µg/ml.
In combination with remifentanil a Ce of 4.0 ng/ml and
with rocuronium at 0.9 mg/kg, the Ce of propofol
required for intubation is (2.8±0.3) µg/ml. The Ce of
propofol has a close correlation with the BIS values. Also
a two-step TCI technique seems to be a more suitable
method of anesthesia induction in elderly patients
compared with the non-stepwise TCI technique or the
three-step TCI technique.
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(Received September 9, 2008)
Edited by CHEN Li-min