Effect-site concentration of remifentanil for smooth inhalational induction with desflurane
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Effect-site concentration of remifentanil for smooth inhalational induction with desflurane
Ji Young Yoo 0
Sook Young Lee 0
Hae Won Jeong 0
Hyung Bae Park 0
Yun Jeong Chae 0
0 Department of Anaesthesiology and Pain Medicine, School of Medicine, Ajou University , Suwon , Republic of Korea
Objective: To determine the effect-site concentration (Ce) of remifentanil target-controlled infusion required for a smooth inhalational induction without airway irritation using desflurane in a stepwise incremental manner for 50% of patients (EC50) and 95% of patients (EC95). Methods: Patients with an American Society of Anesthesiologists physical status I and II, aged 1960 years undergoing elective surgery were enrolled in this study. When target Ce of remifentanil was reached, desflurane was inhaled at 4 vol% initially and then it was increased to 8 and 12 vol% at intervals of 30 s. Smooth induction was regarded as an absence of airway irritation signs and excitatory movements. The EC50 and EC95 values for remifentanil were determined using a modified Dixon's up-and-down method as well as an isotonic regression method with a bootstrapping approach. Results: The EC50 and EC95 of remifentanil for smooth induction during inhalation of desflurane were 3.40 ng/ml (95% confidence interval [CI] 2.42, 4.38 ng/ml) and 4.31 ng/ml (95% CI 2.15, 5.98 ng/ml), respectively. Conclusion: Prior administration of remifentanil could provide smooth inhalational induction with desflurane in a stepwise increment.
Anaesthetic techniques; induction; desflurane; remifentanil; target-controlled infusion
Desflurane has the lowest blood–gas
partition coefficient among all inhalation
anaesthetics.1 Therefore, it has been predicted that
desflurane is suitable for rapid induction
and recovery from general anaesthesia.2,3
However, the pungent nature of desflurane
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limits its use in inhalation induction because
it can cause a high incidence of airway
irritation, including breath holding,
coughing, excessive secretion, laryngospasm, and
Opioids are effective in reducing the
airway irritation caused by desflurane.4–7
Preadministration of an opioid before
desflurane has been reported to be able to make
the transition from being awake to loss
of consciousness (LOC) smooth and feasible
without causing airway irritation.4,5,8,9
Remifentanil is an ultrashort-acting opioid;
the onset time is very rapid and the context
sensitive half-life is 3–5 min.10,11 Therefore,
it is easy to titrate and adjust remifentanil to
obtain its optimal dose without the concern
of delayed recovery. Two studies have
reported airway irritation-free results
following the administration of remifentanil
prior to desflurane being used for inhalation
induction.8,9 The desflurane used in these
previous studies was limited to 1 minimum
alveolar concentration (MAC) of the dial of
the vapourizer,8,9 implying that the
expiratory concentration was lower than 1 MAC,
which means the actual concentration of
desflurane was lower than 1.0–1.5 MAC,
the threshold for airway irritation.12,13
Therefore, the previous airway
irritationfree results could be due to the low MAC of
desflurane used in these studies,8,9 regardless
of the prior administration of remifentanil. In
addition, the use of a low MAC of desflurane
cannot guarantee the loss of consciousness
under the potent stimuli of intubation.
Therefore, we hypothesized that the effect
of remifentanil on airway irritation could
work on desflurane induction in a stepwise
incremental manner using a higher
concentration of desflurane, which is more common
for inhaled induction to ensure that LOC is
achieved in patients. The objective of this
study was to determine the effect-site
concentration of remifentanil target-controlled
infusion required for a smooth inhalational
induction without airway irritation using
desflurane in a stepwise incremental manner
for 50% of patients (EC50) and 95% of
Patients and methods
Patient population and study design
This prospective observational study enrolled
consecutive patients who met the following
criteria at the Department of Anaesthesiology
and Pain Medicine, Ajou University
Hospital, Suwon, Republic of Korea between
January 2015 and August 2015. The inclusion
criteria were as follows: (i) American Society
of Anesthesiologists physical status I and II;14
(ii) aged 19–60 years; (iii) patients who were
undergoing elective surgery under general
anaesthesia. The exclusion criteria were as
follows: (i) suspected difficult airway; (ii)
known history of reactive airway disease.
The study protocol was approved by the
Institutional Review Board (no.
AJIRBMED-CT4-14-327) of Ajou University
Hospital, Suwon, Republic of Korea. It
was registered at ClinicalTrials.gov (NCT
02379715) and written informed consent was
obtained from all patients.
Anaesthesia induction methods
Venous access was obtained from all
patients using a 20 G intravenous catheter
inserted into the forearm whilst the patient
was on the ward. Patients received no
premedication. Pulse oximetry,
electrocardiography, and noninvasive blood pressure
were performed for patients after they
arrived at the operating room. Remifentanil
(40 mg/ml solution) was loaded into a
targetcontrolled infusion device (Orchestra Base
Primea; Fresenius Vial, Bre´ zins, France)
using the pharmacokinetic model of Minto
et al.15 Inspiratory and expiratory
concentrations of desflurane were measured using a
gas analyser within an anaesthesia ventilator
(Dra¨ ger Primus ; Dr a¨gerwerk, Lu¨ beck,
After patients were preoxygenated with
100% oxygen at 4 l/min using a face mask
for 3 min, infusion of remifentanil was
commenced. If the respiratory rate was <8
breaths/min, the patient was encouraged to
breath. Their chest wall rigidity (chest
tightness and difficulty in breathing)
accompanied by desaturation (< 95%) was assessed
for active management. When the target
effect-site concentration of remifentanil was
reached, the vapourizer of desflurane was
dialled at 4 vol% initially. The
concentration of desflurane was then increased to 8
and 12 vol% at intervals of 30 s. The
concentration of desflurane was also calculated
as a MAC value. The MAC value was the
age-corrected MAC value of each patient
calculated by Mapleson’s method.16 Each
patient was asked to open his or her eyes
every 10 s during inhalation of desflurane.
The time when the patient did not respond
to this command was regarded as being
when the patient had achieved LOC. After
LOC was achieved, 0.6 mg/kg rocuronium
was administered via intravenous (i.v.)
injection. Tracheal intubation was then performed
90 s after the administration of 0.6 mg/kg
rocuronium i.v. If airway irritation signs,
such as breath holding, coughing,
laryngospasm and excitatory movements (head
movement, limb movement, verbal/forceful removal
of the mask by the patient), developed during
the induction period, the dial of the vapourizer
of desflurane was then set to zero. In addition,
4 mg/kg thiopental i.v. and 0.6 mg/kg
rocuronium i.v. were administered immediately.
After that, intubation and routine anaesthesia
were continued. Breath holding was
considered no breathing movements for > 30 s.
Laryngospasm was defined as complete airway
obstruction associated with decrease in oxygen
saturation for > 20 s. Regardless of the severity
of the airway irritation sign, the presence of
irritability was considered as a failed state and
the onset time of airway irritation signs,
inspiratory and end-tidal concentrations of
desflurane were recorded.
The LOC time was defined as the time
from the start of desflurane inhalation via a
face mask to the point that the patient did
not respond to the verbal command. The
LOC time, inspiratory and end-tidal
concentrations of desflurane at the LOC point
were recorded. Haemodynamic data were
recorded at baseline (T0), when the target
effect-site concentration of remifentanil was
reached (T1), 1 min after desflurane
inhalation (T2), and at LOC (T3). In the case of
bradycardia (heart rate < 45 beats/minute
[bpm]) or tachycardia (heart rate > 130
bpm), 0.5 mg atropine i.v. or 0.2 mg/kg
esmolol i.v. were administered, respectively.
Hypertension and hypotension were treated
at the discretion of the attending
anaesthesiologists (J.Y.Y., Y.J.C., and S.Y.L.). The
investigators (H.W.J. and H.B.P.) who
conducted the inhaled induction of desflurane
and assessed the complications and airway
irritation were blinded to the effect-site
concentration of remifentanil.
The effect-site concentration of
remifentanil for preventing airway reactivity was
determined using a modified Dixon’s
upand-down method.17,18 The initial effect-site
concentration of remifentanil was 4 ng/ml.
The next target effect-site concentration of
remifentanil was determined based on the
response of the previous patient. A
successful response was regarded as the absence of
breath holding, coughing, laryngospasm, or
excitatory movements. If any of these
symptoms occurred, it was regarded as a failure
and the next target effect-site concentration
of remifentanil was increased by 0.5 ng/ml.
Conversely, if the desflurane induction was
successful, the next target effect-site
concentration of remifentanil was decreased by
The patients were enrolled in this study until
eight crossover pairs were obtained according
to Dixon’s sequential allocation method.18
The sample size was decided based on prior
literature that demonstrated that the
modified Dixon’s up-and-down method required
more than the minimum six crossover points
to minimize the inaccuracy of the individual
study.19 Thus, data from eight independent
crossovers of patients were collected for this
study. The EC50 of remifentanil was defined
as the mean value of independent crossover
pairs (i.e. failure to success of smooth
induction). The R statistical software package
version 3.3.3 (R Foundation for Statistical
Computing, Vienna, Austria) was used for
calculations using the isotonic regression
method to estimate EC50 and EC95 along
with 95% confidence interval (CI). The CI
was estimated using the bootstrapping
approach.20 Other statistical analyses were
performed using the SPSS statistical
package, version 11.0 (SPSS Inc., Chicago, IL,
USA) for Windows . Comparisons between
the success and failure groups were analysed
using independent t-test, 2-test, Fisher’s
exact test, or Mann–Whitney U-test where
appropriate. Haemodynamic data were
analysed with repeated measures of analysis of
variance, followed by paired t-test for
comparisons across successive time-points. Data
were reported as mean SD or the n of
patients. A P-value < 0.05 was considered
This study enrolled 26 patients (12 males,
14 females) and the demographic
characteristics of the success (n ¼ 14) and failure
(n ¼ 12) groups are summarized in Table 1.
There were no significant differences
between the two groups. The anaesthesia
induction characteristics for the two groups
are shown in Table 2. A respiratory rate < 8
breaths/min was observed in four patients in
each group and they responded to verbal
commands to breath. Chest wall rigidity
accompanied by desaturation (< 95%) did
not occur. Airway irritation signs in the
Values are expressed as mean SD or n of patients.
ASA, American Society of Anesthesiologists.
No significant between-group differences (P 0.05);
independent t-test, 2-test, or Fisher’s exact test.
failure group included excitatory
movements in all patients (12/12; 100%). Cough
presented in five patients (42%), breath
holding presented in two patients (17%)
and laryngospasm did not occur in any
patient. The mean SD onset time of
airway irritation signs was recorded in the
failure group instead of LOC time (169.0
23.9 s). The mean SD inspiratory and
expiratory concentrations of desflurane at
the onset of airway irritation signs were
8.5 1.3 vol% (1.31 0.21 MAC) and 6.6
0.9 vol% (1.01 0.13 MAC), respectively.
The mean SD LOC time in the success
group was 167.6 61.0 s. The mean SD
inspiratory and expiratory concentrations of
desflurane were 8.2 1.7 vol% (1.33 0.27
MAC) and 5.8 1.0 vol% (0.95 0.19
Individual data of concentration-response
within the up-and-down sequences are shown
in Figure 1. The mean SD EC50 of
remifentanil for smooth induction without airway
irritations during inhalation of desflurane via
a modified Dixon’s up-and-down method
Table 2. Anaesthesia induction characteristics of patients undergoing elective surgery under
general anaesthesia who participated in this study to examine the effect-site concentration of
remifentanil target-controlled infusion required for a smooth inhalational induction without
airway irritation using desflurane.
Values are expressed as mean SD or n of patients (%).
Ce, concentration at effect-site; Des.in, inspiratory concentration of desflurane; Des.ex, expiratory
concentration of desflurane; LOC, loss of consciousness.
*P < 0.05 compared with the success group; independent t-test or Fisher’s exact test.
The mean SD effect-site concentration of
remifentanil (EC50) for smooth inhalational
induction with desflurane via a modified
Dixon’s up-and-down method was at 3.56
0.70 ng/ml. The EC50 and EC95 of
remifentanil estimated by the isotonic regression
method were 3.40 ng/ml (95% CI 2.42,
4.38 ng/ml) and 4.31 ng/ml (95% CI, 2.15–
5.98 ng/ml), respectively.
The high pungency of desflurane causes
sympathetic stimulation and airway
irritation during induction.21,22 Opioids are
expected to be an effective adjuvant during
inhaled induction of desflurane because they
can prevent the drawbacks of both
cardiovascular stimulation23,24 and airway
irritation.4–7 The current study mainly focused on
airway irritation-free smooth transition
from being awake to LOC during the
inhalation of desflurane without using other
intravenous anaesthetics. To date, two
studies have reported smooth induction by
using preadministration of remifentanil
and inhalation of desflurane.8,9 As described
earlier, the concentration of desflurane used
in these previous two studies was limited to
around 1 MAC of the dial of the
vapourizer.8,9 The exhaled concentration measured
in one report was around 0.7 MAC,9 which
is not enough to cause airway irritation
because the threshold of desflurane for
irritating the airway is known to be 1.0–1.5
MAC.12,13 Therefore, these previous airway
irritation-free results could be due to a low
concentration of desflurane regardless of the
use of remifentanil. The use of a low
concentration of desflurane may not ensure
LOC in all patients with the potent
stimuli of intubation, although the authors
reported successful induction of anaesthesia.9
In addition, the optimal dose of remifentanil
was chosen to blunt the haemodynamic
response to intubation, unlike the current
study.9 This present study chose a stepwise
incremental manner using a high
concentration of desflurane because it would ensure
LOC was achieved. Opioids can increase the
threshold of airway irritation.6 These present
results revealed that remifentanil made
smooth inhalation induction possible when
using a high concentration of desflurane. This
could make induction of anaesthesia using
inhaled desflurane a feasible option in the
clinical situation. With regard to
cardiovascular stimulation, no severe hypertension or
tachycardia was observed in the present study.
Values are expressed in mean SD.
T0, baseline; T1, when the target effect-site concentration of remifentanil was reached; T2, 1 min
after desflurane inhalation; T3, at the loss of consciousness.
*P < 0.05 compared with baseline value T0; paired t-test.
No significant between-group differences (P 0.05); repeated measures analysis of variance.
One previous study reported that 4 ng/ml
remifentanil was able to minimize the
haemodynamic change caused by inhalation
induction using 1.7 MAC desflurane.25 Thus,
the effect-site concentrations of remifentanil
observed in the current study of 3.7 ng/ml and
3.2 ng/ml in the success and failure groups,
respectively, seemed to be able to prevent
cardiovascular stimulation. However, when
4.31 ng/ml (EC95) of remifentanil was used for
smooth induction, caution was needed for
The inspiratory and expiratory
concentrations of desflurane at LOC in the success
group of the current study were 8.2 vol%
(1.33 MAC) and 5.8 vol% (0.95 MAC),
respectively. It has been reported that the
inspiratory and expiratory concentrations
at LOC using desflurane alone or with
nitrous oxide were 14.1–14.9 vol% and
10.1–10.9 vol%, respectively.26,27 In a study
using pretreatment with fentanyl and
midazolam, the inspiratory and expiratory
concentrations at LOC were 8.9 vol% and
5.3 vol%, respectively.27 These results
suggest that an opioid can decrease the
anaesthetic requirement for LOC. The mean SD
time to LOC was 167.6 61.0 s in this
present study. However, the lack of control
group means that it is not possible to
determine if this time was reduced by the
use of an opioid. Whether or not pretreatment
with an opioid shortens the LOC time remains
controversial because one controlled study
found a reduction,5 whereas another study
found no difference.27 Considering that
remifentanil produces dose-dependent respiratory
depression, there is still a possibility that these
respiratory depression effects offset to some
extent the expected shortening effect of
induction time due to a decrease of MAC of
The main airway irritation sign was
excitatory movements in the current study,
which was in line with previous studies.27,28
Excitatory movements occurred in all
patients in the failure group. Cough was
concurrently found in five of 12 (42%)
patients and breath holding was found in
two of 12 (17%) patients. There was no
evidence of laryngospasm. Excitatory
movements included verbal or forceful removal of
the mask by the patient, plus head and limb
movements. These excitatory movements
could have been the result of the patient’s
response to the pungent stimuli or the
expression of an excitatory stage (stage 2)
of anaesthesia. Whatever the cause of the
excitatory movements, their presence limited
the anaesthesiologist’s ability to increase the
concentration of desflurane and they were
the most common obstacle to the patient
tolerating inhaled induction with desflurane.
The current study had several limitations.
First, the same concentration of desflurane
was used for patients of all ages, but the
isoMACs are somewhat different in patients
aged 19 to 60 years.28 Secondly, there was a
basic bias between real plasma
concentration and the calculated one for remifentanil
based on the pharmacokinetic model of
Minto et al.15,29 Thirdly, the feasibility of
inhaled induction of desflurane was based
on the objective signs during inhalation.
There might be dissatisfaction of patients
despite the fact that they seemed to be calm
during inhalation. This was not checked in
this present study. Fourth, Dixon’s
up-anddown method has potential limitations for
estimating EC95. To overcome this
limitation, this present study adopted the isotonic
regression method and the bootstrapping
approach as supplementary analyses for
reducing bias and getting greater precision
rather than using conventional methods.20,30
In conclusion, the EC50 and EC95 of
effect-site concentrations of remifentanil
required for smooth inhalational induction
without airway irritation when using
desflurane in a stepwise increment were 3.40 ng/ml
and 4.31 ng/ml, respectively. Therefore,
prior administration of remifentanil could
provide smooth inhalational induction with
Declaration of conflicting interests
This research received no specific grant from any
funding agency in the public, commercial, or
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