Anaesthesia, 2009, 64, pages 719–726 doi:10.1111/j.1365-2044.2009.05916.

x
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Optimal remifentanil dosage for providing excellent

intubating conditions when co-administered with a single
standard dose of propofol
L. Bouvet,1,2 A. Stoian,1,2 T. Rimmelé,1,2 B. Allaouchiche,1,2 D. Chassard1,2 and
E. Boselli1,2
1 Claude Bernard University, University of Lyon, Lyon, France
2 Department of Anaesthesia and Intensive Care, Édouard Herriot Hospital, 5 place d’Arsonval, Lyon, France

Summary
This dose–response study aimed to determine the dose of remifentanil combined with propofol
2.5 mg.kg)1 which provided excellent intubation conditions in 95% of patients. Ninety pre-
medicated female ASA 1 and 2 patients were randomly allocated to five remifentanil dose groups
(1, 2, 3, 4 or 5 lg.kg)1). Induction of anaesthesia was performed with a blinded dose of remi-
fentanil infused over 60 s simultaneously co-administered with propofol 2.5 mg.kg)1 infused over
45 s. Tracheal intubation was attempted 150 s after the beginning of induction. Intubating con-
ditions were assessed with the Copenhagen score. A probit analysis was performed to calculate the
intubating efficient doses (IED) of remifentanil in 95% of patients (IED95). Our data revealed that
the IED95 of remifentanil was 4.0 (95% CI: 3.4–5.6) lg.kg)1, which was associated with a max-
imum decrease in heart rate and mean arterial pressure of < 30%, a finding which also applied to
the other groups.
. ......................................................................................................
Correspondence to: Dr Lionel Bouvet
E-mail: lionel.bouvet@chu-lyon.fr
Accepted: 22 January 2009

Excellent intubating conditions are important to minimise the speed of infusion of remifentanil and propofol, and the
the occurrence of damage to the airway, the fourth timing and assessment of tracheal intubation.
highest cause of claims related to injuries associated with Using an optimised sequence of induction of anaes-
general anaesthesia [1, 2]. The use of neuromuscular thesia and a standardised scale for the assessment of the
blocking drugs at induction of anaesthesia provides quality of tracheal intubation we therefore conducted a
significantly better intubating conditions and less vocal dose–response study to determine the intubating efficient
cord sequelae than relaxant-free anaesthesia, and has dosage (IED) of remifentanil co-administered with pro-
therefore been advocated prior to tracheal intubation for pofol 2.5 mg.kg)1 which would provide excellent intu-
elective surgery [2, 3]. bating conditions in 95% (IED95) of patients undergoing
However, patient factors may contraindicate the use elective surgery.
of neuromuscular blocking drugs, and administration
of these drugs is associated with several complications,
Methods
including anaphylactic reactions, residual curarisation, and
awareness during general anaesthesia [4–6]. Patients
Significant improvements in the quality of tracheal After approval of the study by our institution’s Ethics
intubation without paralysis were reported when remifen- Committee and obtaining patients’ written consent,
tanil was co-administered with propofol 2 or 2.5 mg.kg)1 female patients scheduled for elective gynaecological
[7–13]. However, the optimal dose of remifentanil surgery requiring tracheal intubation were enrolled.
required for providing excellent intubating conditions Inclusion criteria were: ASA 1 and 2 physical status, age
when co-administered with propofol remains unknown from 18 to 65 years and body mass index from 20 to
since published results are inconsistent [7–14]. This may be 24 kg.m)2. Patients with a history or evidence of a
related to different protocols with respect to the timing and difficult airway (combination of the Mallampati score 3 or

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Journal compilation  2009 The Association of Anaesthetists of Great Britain and Ireland 719
L. Bouvet et al. Æ Optimal remifentanil dosage for providing excellent intubating conditions Anaesthesia, 2009, 64, pages 719–726
. ....................................................................................................................................................................................................................

4 and thyromental distance of less than 60 mm [15, 16], Assessment of intubating conditions
mouth opening of less than 35 mm) were excluded. The quality of tracheal intubation was assessed using the
qualitative scoring system proposed by the consensus
Anaesthetic protocol conference on good clinical research practice (GCRP) in
All patients were premedicated with alprazolam 0.5 mg Pharmacodynamic Studies of Neuromuscular Blocking
and hydroxyzine 1 mg.kg)1 orally given 1 h before Agents [17]. Six variables were recorded: jaw relaxation,
induction of anaesthesia. Patients were randomised by a resistance to laryngoscope, vocal cord position, vocal cord
computer-generated list to receive one of five doses movement, and patient response to intubation or cuff
of remifentanil (1, 2, 3, 4 or 5 lg.kg)1). Allocation inflation (cough or movement). Each of these variables
concealment was ensured by the use of coded, sealed was rated as excellent, good or poor. The criteria for
opaques envelopes. Remifentanil was diluted with 0.9% assigning values to each variable are set out in Table 1.
saline (50 lg.ml)1) into a 50-ml syringe. In the operating Intubating conditions were excellent if all criteria were
room, patients were pre-oxygenated until their end-tidal scored as excellent, good if all criteria were either
oxygen percentage was > 90%, after which anaesthesia excellent or good, and poor if a single criteria was poor.
was induced. At time T0, the chosen dose of remifentanil
was infused over 60 s using a programmable device Statistical analysis
(Pilote Anesthésie 2, Fresenius Vial, Brezins, France) In a Cochran–Armitage test for trend in proportions, a
hidden behind a sheet, followed by a continuous sample size of 17 patients per group is required from five
infusion of 0.15 lg.kg)1.min)1. Propofol 2.5 mg.kg)1 groups with remifentanil dosage values equal to 1, 2, 3, 4,
was simultaneously administered over 45 s. Once loss of and 5 lg.kg)1 and proportions of excellent intubating
eyelash reflex occurred, ventilation via facemask was conditions equal to 0.50, 0.60, 0.70, 0.80, and 0.90,
initiated. respectively. The total sample of 85 subjects achieves an
The same experienced senior physician, blinded to the 81% power to detect a linear trend using a two-sided Z
anaesthetic procedure, performed all intubations using a test with continuity correction and a significance level of
Macintosh 3 laryngoscope metal blade and inserted an 0.05 (PASS 8.0.05; NCSS, LCC, Kaysville, Utah) [18].
endotracheal tube of 6.5 or 7 mm at his discretion. At The STATISTICA version 6.0 computer software pack-
time T0 + 150 s the physician attempted to intubate the age (Statsoft, Tulsa, OK, USA) was used for analysis of the
trachea, with the aim of completing the tracheal intuba- patients characteristics and haemodynamic data. As
tion within 15 s. The quality of tracheal intubation was appropriate, patients’ characteristics and median doses of
assessed as described below. If intubating conditions were ephedrine were analysed using Kruskal–Wallis H test.
judged uncomfortable, supplemental boluses of remifen- Repeated measures of haemodynamic values were anal-
tanil 1 lg.kg)1 and ⁄ or propofol 0.5 mg.kg)1 were ysed by a two-way analysis of variance. Incidence data
administered at the discretion of the intubating anaesthe-
tist. No topical anaesthesia of the larynx was given. The Table 1 Scoring conditions for tracheal intubation [17]. Intu-
tracheal tube cuff was inflated with 5–10 ml of air, while bation conditions: excellent, all responses are excellent; good, all
ensuring that intracuff pressure was < 25 cmH2O, con- responses are excellent or good; poor, the presence of one or
tinuously monitored throughout anaesthesia. more poor response. Excellent and good intubation conditions
are taken to be clinically acceptable intubation conditions.
Anaesthesia was maintained with 1.5–2% end-tidal
sevoflurane in 50% oxygen started once tracheal intuba-
Intubation conditions
tion was completed, with a continuous infusion of
remifentanil 0.15 lg.kg)1.min)1. The lungs were venti- Clinically not
Clinically acceptable acceptable
lated to normocapnia. No further stimulation was applied
to the patient during the study period. Monitoring Variable Excellent Good Poor
included non-invasive blood pressure, electrocardiogram,
pulse oximeter and capnography. Control values of blood Laryngoscopy
Jaw relaxation Relaxed Not fully Poor
pressure and heart rate (HR) were recorded before Resistance to None Slight Active
induction of anaesthesia (pre-induction values), 1 min laryngoscope
after the end of the propofol infusion, and 1, 3 and 5 min Vocal cords
Position Abducted Intermediate Closed
following tracheal intubation. If mean arterial pressure Movements None Moving Closing
(MAP) or HR fell more than 30% in comparison to Reaction to tube insertion or cuff inflation
corresponding pre-induction values, ephedrine 3 mg or Movement of limbs None Slight Vigorous
Coughing None Diaphragm Sustained
atropine 0.5 mg were administered intravenously in order (>10 s)
to reach at least 70% of the pre-induction value.

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720 Journal compilation  2009 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2009, 64, pages 719–726 L. Bouvet et al. Æ Optimal remifentanil dosage for providing excellent intubating conditions
. ....................................................................................................................................................................................................................

were analysed by chi-squared test, with Bonferroni Overall intubating conditions

adjustment for multiple comparisons when appropriate *†
18
[19]. The level of significance was set at p < 0.05. 16
The event ‘success’ or ‘failure’ of excellent intubating

Number of patients
14
conditions for each patient was analysed using SPSS version 12 Poor
12.0 (SPSS, Chicago, IL, USA) for probit regression to 10 Good
calculate the effective dose of remifentanil required to 8 Excellent
provide excellent intubating conditions in 50% and 95% 6
of patients (IED50 and IED95). 4
2
Results 0
1 2 3 4 5
Ninety patients were enrolled in this study (18 patients Dose of remifentanil (µg.kg–1)
per group). One patient from group 3 lg.kg)1 was
Figure 1 Overall intubating conditions in the five groups of
excluded from analysis, because of a violation of the remifentanil dosages according to the Viby-Mogensen classifi-
anaesthetic protocol (inadequate dose of infused remif- cation [17]. p < 0.001 between groups. *p = 0.001 compared
entanil). Patient characteristics are shown in Table 2. All to group 4 lg.kg)1 and to group 5 lg.kg)1 as regards overall
subjects were female. intubating conditions, and  p < 0.001 compared to group
The overall and individual intubating scores are 4 lg.kg)1 and to group 5 lg.kg)1 as regards excellent vs non-
excellent conditions (Bonferroni adjustments for multiple
summarised in Figs 1 and 2. For six patients (two from comparisons).
group 1 lg.kg)1, three from group 2 lg.kg)1 and one
from group 3 lg.kg)1), intubating conditions were
judged poor, and four of these patients could not be fentanil and propofol (Table 3). From probit analysis,
intubated in less than 15 s. All other patients were the IED50 of remifentanil was 1.8 lg.kg)1 (95% CI:
intubated in less than 15 s. With Bonferroni adjustments 1.0–2.3), and the IED95 was 4.0 lg.kg)1 (95% CI: 3.4–
for multiple comparisons, overall intubating conditions 5.6) (Fig. 3).
were significantly different in group 1 lg.kg)1 from Two way analysis of variance of HR and MAP showed
group 4 lg.kg)1 and group 5 lg.kg)1, corresponding to a significant decrease in HR and MAP following
significantly worse intubating conditions in group induction for all five groups of patients, without any
1 lg.kg)1 (Fig. 1). As regards the rates of acceptable significant difference between groups (Fig. 4). The
intubating conditions, there was no statistical significant greatest decrease in mean values of HR and MAP was
difference between groups (p = 0.19). There was no recorded 3 min after intubation and ranged from 19% to
significant difference between groups as regards jaw 23% for HR, and from 27% to 29% for MAP, across the
relaxation, resistance to laryngoscope, movements of five groups (Fig. 4). No statistical difference was found
limbs and of vocal cords, and coughing (Fig. 2). between groups with respect to ephedrine requirements
Concerning vocal cords position, the statistically signif- (Table 3). No patient required atropine.
icant difference was for less abducted vocal cords in
group 1 lg.kg)1 compared to groups 4 lg.kg)1 and
Discussion
5 lg.kg)1 (Fig. 2a). Nevertheless, there was no statistical
significant difference between groups as regards the rates This dose–response study allowed us to determine the
of closed vocal cords (p = 0.45). No difference was IED95 of remifentanil in elective adult female patients co-
recorded between the groups with respect to the administered with propofol 2.5 mg.kg)1. The combina-
requirement for supplemental administration of remi- tion of remifentanil with propofol for tracheal intubation

Table 2 Patient characteristics. Data are

median (interquartile range), or number 1 2 3 4 5
of patients (n). No statistical differences Remifentanil dose (lg.kg ) )1
(n = 18) (n = 18) (n = 17) (n = 18) (n = 18)
were found between groups of patients.
Age (year) 38 (31–41) 39 (29–46) 37 (30–45) 37 (31–47) 39 (28–48)
Body mass index (kg.m)2) 21 (20–23) 23 (21–24) 21 (20–23) 23 (20–24) 22 (20–23)
ASA class 1 ⁄ 2 (n) 14 ⁄4 13 ⁄5 11 ⁄6 12 ⁄6 10 ⁄8
Mallampati class 1 ⁄ 2 (n) 13 ⁄5 12 ⁄6 12 ⁄5 11 ⁄7 12 ⁄6

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Journal compilation  2009 The Association of Anaesthetists of Great Britain and Ireland 721
L. Bouvet et al. Æ
Optimal remifentanil dosage for providing excellent intubating conditions Anaesthesia, 2009, 64, pages 719–726
. ....................................................................................................................................................................................................................

(a) † ‡ Vocal cord position (d) Coughing

18
*
18
16 16
Number of patients

Number of patients
14 14
12 12
Closed Sustained
10 10
Intermediate Slight
8 8
Abducted None
6 6
4 4
2 2
0 0
1 2 3 4 5 1 2 3 4 5
Dose of remifentanil (µg.kg–1) Dose of remifentanil (µg.kg–1)

(b) Movement of vocal cords (e) Jaw relaxation

18 18
16 16

Number of patients
14
Number of patients

14
12 12
Poor
Moving 10
10
Closing Not fully
8
8
None Relaxed
6
6
4
4
2
2
0
0 1 2 3 4 5
1 2 3 4 5
Dose of remifentanil (µg.kg–1)
Dose of remifentanil (µg.kg–1)

(c) Movements of limbs (f) Resistance to laryngoscope

18 18
16 16
Number of patients

14
Number of patients

14
12 12
Vigorous
10 Active
Slight 10
8 Slight
None 8
6 None
6
4
4
2
2
0
1 2 3 4 5 0
Dose of remifentanil (µg.kg–1) 1 2 3 4 5
Dose of remifentanil (µg.kg–1)

Figure 2 Distribution of patients in the five groups of remifentanil dosages for the quality of the six intubations characteristics [17].
*p = 0.0007 between groups (Fig. 2a).  p = 0.0019 compared to group 4 lg.kg)1 and to group 5 lg.kg)1 as regards vocal cords
position, and àp = 0.0001 compared to group 4 lg.kg)1 and to group 5 lg.kg)1 as regards abducted vs non-abducted vocal cords
(Bonferroni adjustments for multiple comparisons).

without the use of muscle relaxant has been previously depression of laryngeal reflexes than other hypnotic agents
studied [7–13]. These agents have similar pharmaco- such as thiopental [20]. The dosages of remifentanil
kinetic properties with a short and predictable onset time ranged from 1 to 5 lg.kg)1, as the results from previous
and duration of action, and propofol induces a greater trials concerning the quality of tracheal intubation

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722 Journal compilation  2009 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2009, 64, pages 719–726 L. Bouvet et al. Æ Optimal remifentanil dosage for providing excellent intubating conditions
. ....................................................................................................................................................................................................................

Table 3 Anaesthetic characteristics.

Data are either number of patients (n), 1 2 3 4 5
or mg for each patient having received Remifentanil dose (lg.kg ) )1
(n = 18) (n = 18) (n = 17) (n = 18) (n = 18)
ephedrine. No statistical differences
were found between groups of patients.
Supplemental bolus of remifentanil (n) 3 3 1 0 0
Supplemental bolus of propofol (n) 0 1 1 1 1
Ephedrine requirement (n) 1 4 2 4 3
Total dose of administered ephedrine 6 3, 6, 6, 6 3, 9 6, 6, 6, 6 6, 6, 9
for each patient (mg)

Intubating conditions were assessed using the standar-

dised qualitative scoring system proposed by the consen-
sus conference on Good Clinical Research Practice in
Pharmacodynamic Studies of Neuromuscular Blocking
Agents in 1996 [17]. This scoring system was updated in
2005 [23], however, we decided not to apply this more
recent scoring system, because of its lack of clarity and
detail in comparison with the original version. In fact,
compared to the score proposed in 1996, only three
variables have to be assessed in the updated scoring system
for the assessment of the intubating conditions (laryngo-
scopy, vocal cords position, and reaction to insertion of
the tracheal tube and cuff inflation). This is because
Figure 3 Probit regression of the probability of excellent intu- several criteria have been grouped together, potentially
bating conditions as a function of induction dose of remifentanil. leading to a more subjective interpretation of the quality
Horizontal bars denote 95% confidence interval for intubating of tracheal intubation. Furthermore, the new system does
efficient dose (IED) in 50% and 95% of patients (IED50 and
not allow detailed analysis of the quality of tracheal
IED95).
conditions as set out in Fig. 2. The scale described in
1996 was also chosen for the two following reasons:
firstly, the criteria used in this scoring system are
provided by propofol combined with remifentanil were independent of the anatomical characteristics of the
varied. Indeed remifentanil 2 lg.kg-1 and propofol patients, contrary to other scales including Cormack
2 mg.kg)1 provided satisfactory intubating conditions in grading, and secondly this standardised scale allows
80% of patients in the study by Grant et al. [7], but our results to be compared to those previously published
resulted in excellent intubating conditions in only 50% of [2, 3, 24].
patients in the study by Stevens et al. [8], while greater With this scale, the variability amongst conditions
dosages of remifentanil of 3 or 4 lg.kg)1 led to excellent described as good or poor can be quite important. Indeed,
intubating conditions in 80% of patients. In the study by conditions are judged good when all criteria are either
Klemola et al. [13], intubating conditions were signifi- excellent or good, which means that good conditions
cantly improved by increasing the induction dosage of actually correspond to heterogeneous clinical situations,
remifentanil from 3 to 4 lg.kg)1, nevertheless, excellent ranging from one criteria judged as good (and all the
conditions were reached in only 12 ⁄ 20 patients after others excellent), to all criteria judged as good. In the
remifentanil 4 lg.kg)1 with propofol 2.5 mg.kg)1. Other same way, the distinction between slight and vigor-
authors have reported ideal intubating conditions in 14 ⁄ 20 ous movement may be observer-dependent, making it
patients after induction with propofol 2.5 mg.kg)1 given harder to separate good from poor conditions. Excellent
alone [14]. This discrepancy between studies may result conditions are probably less subject to inter-observer
from differences in study designs and in criteria for the variability, since they only occur when there is no
assessment of intubating conditions. In our study, the movement at all, so that an excellent score is easily
induction sequence of anaesthesia took into account separated from the other grades. In our dose-response
the pharmacokinetics ⁄ pharmacodynamics parameters of study, the optimal dose of remifentanil providing excel-
propofol and remifentanil, so that laryngoscopy and lent intubating conditions was determined, even if
tracheal intubation occured at the effect-site peak con- some previous studies assumed that good or acceptable
centrations of both agents [21, 22]. intubating conditions would be sufficient for minimising

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Journal compilation  2009 The Association of Anaesthetists of Great Britain and Ireland 723
L. Bouvet et al. Æ
Optimal remifentanil dosage for providing excellent intubating conditions Anaesthesia, 2009, 64, pages 719–726
. ....................................................................................................................................................................................................................

95 Remifentanil 1 µg.kg–1
Remifentanil 2 µg.kg–1
90 Remifentanil 3 µg.kg–1
Remifentanil 4 µg.kg–1
85 * Remifentanil 5 µg.kg–1

80
Heart rate (beats.min–1)

*
* *
75

70

65 p = 0.28

60

55

50

45
Baseline value 1 min after intubation 5 min after intubation
1 min after propofol 3 min after intubation
Time

110
Remifentanil 1 µg.kg–1
100 Remifentanil 2 µg.kg–1
Remifentanil 3 µg.kg–1
Remifentanil 4 µg.kg–1
Mean arterial pressure (mmHg)

90
Remifentanil 5 µg.kg–1
80
*
* * *
70

60
p = 0.53

50

40
Figure 4 Mean haemodynamic changes
in the five groups of the study. Error
30 bars represent 95% confidence interval.
Baseline value 1 min after intubation 5 min after intubation *p < 0.001 vs baseline values. No sig-
1 min after propofol 3 min after intubation nificant statistical difference between
Time groups.

the occurrence of laryngeal symptoms and damage 2 mg.kg)1 with either remifentanil 2 lg.kg)1, remif-
[24, 25]. entanil 4 lg.kg)1 or suxamethonium 1 mg.kg)1. They
Increasing doses of remifentanil significantly improved reported, however, significantly less movements of the
intubating conditions, mainly through increasing the rate limbs in patients receiving remifentanil 4 lg.kg)1 or
of abducted vocal cords. Unfortunately, the majority of suxamethonium. When increasing the amounts of rem-
studies assessing the quality of tracheal intubation did not ifentanil from 0.5 to 2 lg.kg)1 co-administered with
analyse individual intubating conditions. McNeil et al. propofol 2 mg.kg)1, Grant et al. [7] reported significant
[11] did not report a significant improvement in vocal improvement in individual assessment of jaw relaxation,
cord position after induction of anaesthesia using propofol vocal cord position, limb movement and coughing. In the

 2009 The Authors

724 Journal compilation  2009 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2009, 64, pages 719–726 L. Bouvet et al. Æ Optimal remifentanil dosage for providing excellent intubating conditions
. ....................................................................................................................................................................................................................

same way, Klemola et al. [13] reported increased rates of rapid-sequence induction of anaesthesia, as laryngoscopy
open vocal cords after an induction sequence of anaes- and tracheal intubation should occur at the effect-site
thesia using remifentanil 4 lg.kg)1 combined with peak concentrations of both agents, i.e. more than 60 s
propofol 2.5 mg.kg)1, in comparison with propofol after administration for the drugs we used.
2.5 mg.kg)1 and remifentanil 3 lg.kg)1 or alfentanil In conclusion, our study investigated the best dose of
30 lg.kg)1. The intermediate position of vocal cords remifentanil combined with propofol 2.5 mg.kg)1 to
during tracheal intubation may contribute to laryngeal provide excellent intubating conditions in 95% of healthy
injuries and should be avoided [2]. patients. In such patients, if the use of muscle relaxants is
No clinically significant muscle rigidity occurred in any contraindicated or not required for surgery, a relaxant-
of the groups. Muscle rigidity has been described after free protocol of induction of anaesthesia combining
rapid infusion of a large dose of opioids [26]. We propofol 2.5 mg.kg)1 and remifentanil 4 lg.kg)1 will
therefore administered remifentanil over 60 s. However achieve excellent intubating conditions, with acceptable
muscular rigidity was not observed in previous studies haemodynamic tolerance.
with doses of remifentanil ranging from 1 to 4 lg.kg)1
administered over 90 s, combined with propofol 2
Conflict of interest
mg.kg)1 or with thiopental 5 mg.kg)1 [8, 27]. Moreover,
alprazolam given 60 min prior to induction of anaesthesia The authors have no conflict of interest to declare.
may also have helped minimise the occurrence of muscle
rigidity, since premedication with benzodiazepine is
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 2009 The Authors
Journal compilation  2009 The Association of Anaesthetists of Great Britain and Ireland