British Journal of Anaesthesia 82 (4): 561–5 (1999)

Sevoflurane requirements for tracheal intubation with and

without fentanyl
T. Katoh*, Y. Nakajima, G. Moriwaki, S. Kobayashi, A. Suzuki, T. Iwamoto, H. Bito
and K. Ikeda

Department of Anaesthesiology and Intensive Care Medicine, Hamamatsu University School of Medicine,
3600 Handa-cho, Hamamatsu, 431–31 Japan
*To whom correspondence should be addressed

We studied 80 healthy ASA I patients (aged 20–52 yr) to determine if fentanyl affects
sevoflurane requirements for achieving 50% probability of no movement in response to
laryngoscopy and tracheal intubation (MAC-TI). Patients were allocated randomly to one of
four fentanyl dose groups (0, 1, 2 and 4 µg kg–1). Patients in each group received sevoflurane
at a pre-selected end-tidal concentration according to an ‘up–down’ technique. After steady
state sevoflurane concentration had been maintained for at least 10 min, fentanyl was
administered i.v. Tracheal intubation was performed 4 min after administration of fentanyl, and
patients were assessed as moving or not moving. Heart rate (HR) and mean arterial pressure
(MAP) were recorded before induction of anaesthesia, just before administration of fentanyl,
just before laryngoscopy for intubation, and after intubation. The MAC-TI of sevoflurane was
3.55% (95% confidence intervals 3.32–3.78%), and this was reduced markedly to 2.07%, 1.45%
and 1.37% by addition of fentanyl 1, 2 and 4 µg kg–1, with no significant difference in the
reduction between 2 and 4 µg kg–1, showing a ceiling effect. Fentanyl attenuated haemodynamic
responses (HR and MAP) to tracheal intubation in a dose-dependent manner, even with
decreasing concomitant sevoflurane concentration. Fentanyl 4 µg kg–1 suppressed the changes
in HR and MAP more effectively than fentanyl 1 or 2 µg kg–1 at sevoflurane concentrations
close to MAC-TI.
Br J Anaesth 1999; 82: 561–5
Keywords: anaesthetics volatile, sevoflurane; analgesics opioid, fentanyl; intubation tracheal;
potency, anaesthetic, MAC; interactions (drug)
Accepted for publication: November 13, 1998

Sevoflurane is pleasant smelling and relatively non-irritating
to the airways, and its blood-gas partition coefficient is
similar to that of desflurane or nitrous oxide. Hence induc-
tion of anaesthesia using sevoflurane is rapid and acceptable
to many patients. The minimum alveolar concentration
(MAC) which prevents movement in response to surgical
incision in 50% of patients for halothane and enflurane is
less than that which prevents movement in response to
laryngoscopy and tracheal intubation (MAC-TI).1 2 Sevoflu-
rane may differ from older anaesthetics in its capacity to
prevent movement in response to laryngoscopy and tracheal
intubation. The capacity of opioids to decrease MAC-TI
has not been studied for any potent inhaled anaesthetic.
Haemodynamic responses to laryngoscopy and tracheal
intubation is another concern to clinicians, and its pharmaco-
logical modifications have not been well documented.
The purpose of this study was to determine MAC-TI of
sevoflurane and the effect of fentanyl administered 4 min
before tracheal intubation on MAC-TI. In addition, the
effect of four different combinations of sevoflurane and
fentanyl on haemodynamic responses (mean arterial pres-
sure and heart rate) was investigated.
Patients and methods
With approval of the Departmental Ethics Committee and
informed consent, we studied 80 patients (45 males), aged
20–52 yr, ASA I, undergoing elective surgery. Exclusion
criteria were a history of cardiac, pulmonary or renal
disease; history of oesophageal reflux or hiatal hernia; drug
or alcohol abuse; significant obesity (body mass index
.30 kg m–2); any vasoactive medications (chronic anti-
hypertesive agents, vasoconstrictors or vasodilators); and
contraindications to inhalation induction. Patients were
fasted for at least 8 h before surgery and received no
premedication. Patients were allocated randomly (except
for five patients to replace unusable data of five previous
patients) to one of four different fentanyl dose groups

© British Journal of Anaesthesia

 Katoh et al.
(n5 20 each): group 1 received no fentanyl, while groups
2, 3 and 4 received fentanyl 1.0, 2.0 and 4.0 µg kg–1 i.v.
over a 30-s period, 4 min before tracheal intubation.
All patients breathed through a face mask connected
to a semi-closed anaesthetic circuit. To prevent contamina-
tion of end-tidal samples with inspired gas, the deadspace
was augmented at the sampling port. Gas was drawn
continuously from the sampling port, located between the
face mask and deadspace, at the rate of 200 ml min–1.
Concentrations of carbon dioxide, sevoflurane and oxygen
were measured continuously using an infrared anaesthetic
gas analyser (Capnomac Ultima, Helsinki, Finland), which
was calibrated before anaesthesia for each patient using
a standard gas mixture. Anaesthesia was induced with
sevoflurane and oxygen, first during spontaneous ventila-
tion, and ventilation was assisted if tidal volume was
too small to provide adequate end-tidal sampling for
measurement of anaesthetic concentrations. The inspired
concentration of sevoflurane was adjusted to maintain the
measured end-tidal concentration at a constant value
according to a pre-selected concentration. A steady state
end-tidal sevoflurane concentration was maintained for at
least 10 min. Thereafter, fentanyl was administered i.v.
using the pre-selected dose. Laryngoscopy was started
4 min after administration of fentanyl and a tracheal tube
with a high volume low pressure cuff (Eschmann Health
Care, UK) was inserted. The cuff of the tracheal tube
was inflated to an intra-cuff pressure of 20 cm H2O
using a cuff control inflator (Portex VBM, Japan Medico
Co., Nagoya, Japan). Laryngoscopy never lasted for more
than 20 s and all intubations were performed by one
investigator (T. K.).
The initial concentrations of anaesthetic were 2.4, 2,
1.2 and 1.0% for groups 1, 2, 3 and 4, respectively. The
outcome of each patient’s response to tracheal intubation
determined the anaesthetic concentration for the subsequent
patient. The patient’s response to laryngoscopy and
tracheal intubation was described as positive or negative.
We considered it to be ‘negative’ only when bucking
did not occur after cuff inflation in the trachea, and
when we observed gross purposeful muscular movements
or vocal cord movements during laryngoscopy, or bucking
after cuff inflation, it was considered to be positive. When
the response was negative, the anaesthetic concentration for
the next patient in the same group was decreased by a
step of 0.4, 0.3, 0.2 or 0.2% for groups 1, 2, 3 or 4,
respectively. Conversely, when the response was positive,
the anaesthetic concentration for the next patient was
increased by the same amount.
Heart rate (HR) and mean arterial pressure (MAP), as
determined by automated oscillometry (CBM 7000, Colin
Co., Tokyo, Japan), were recorded before induction of
anaesthesia, just before administration of fentanyl, just
before laryngoscopy for intubation, at incision and at
1-min intervals for 5 min after incision. The means of
the peak increases in HR and MAP in response to
562
tracheal intubation were calculated from the patients
studied after the first pair of consecutive patients with
positive–negative responses to tracheal intubation in
each group.
Statistical analysis
We estimated MAC-TI as the anaesthetic concentration
required to prevent any movement in response to tracheal
intubation in 50% of patients using a logistic regression
analysis, and MAC-TI values between groups were com-
pared using Waud’s technique.3 MAC-TI95 was calculated
directly from the best-fitting logistic curve. Data between
groups were analysed by analysis of variance, followed
by Fisher’s PLSD test, when appropriate (StatView 4.02;
Abacus Concepts, Berkeley, CA, USA). Probability values
,0.05 were considered statistically significant.
Results
In two patient in group 1, the trachea could not be intubated
because of massive movement at laryngoscopy. Five patients
were excluded from data analysis for haemodynamic
responses because more than 20 s was required for tracheal
intubation. The trachea was intubated successfully in the
other patients within 20 s. Severe muscle rigidity was not
observed in any patient.
The groups did not differ significantly in age, pre-
anaesthetic HR or MAP (Table 1). Individual responses are
shown in Figure 1. The MAC-TI for sevoflurane in the
absence of fentanyl was 3.55% (95% confidence intervals
(CI) 3.32–3.78%) or 1.92 MAC (CI 1.80–2.04 MAC).
Fentanyl 1 µg mg–1 i.v., given 4 min before laryngoscopy
and tracheal intubation, reduced significantly MAC-TI to
2.07% (95% CI 1.87–2.27%) (Fig. 2). Similarly, fentanyl
2 µg kg–1 and 4 µg kg–1 decreased significantly MAC-TI
to 1.45% (95% CI 1.23–1.67%) and 1.37% (95% CI 1.18–
1.56%), respectively (Fig. 2). There was no difference
in the reduction in MAC-TI between the fentanyl 2 and
4 µg kg–1 groups.
Mean sevoflurane concentration in patients studied after
the first pair of consecutive patients with positive–negative
responses to tracheal intubation was 3.52% (SD 0.34%),
2.12% (0.27%), 1.48% (0.23%) and 1.40% (0.22%) for
groups 1, 2, 3 and 4, respectively. These values were similar
to the MAC-TI for each group.
MAP decreased after induction of anaesthesia with sevo-
flurane, but HR did not change. The reduction in MAP was
concentration-dependent. Fentanyl decreased significantly
HR and MAP (Table 1). Fentanyl attenuated haemodynamic
responses (HR and MAP) to tracheal intubation in a dose-
dependent manner. Fentanyl 4 µg kg–1 suppressed the
changes in HR and MAP more effectively than fentanyl
1 or 2 µg kg–1 at sevoflurane concentrations near MAC-TI
(Figs 3, 4).
 Fentanyl and intubation responses

Table 1 Age, heart rate (HR) and mean arterial pressure (MAP) before anaesthesia, before administration of fentanyl and before intubation (mean (SD or range)).
No significant difference between groups before anaesthesia. *P,0.05 compared with fentanyl 0 µg kg–1; †P,0.05 compared with pre-anaesthetic value;
‡P,0.05 compared with value before fentanyl administration; ¶P,0.05 compared with values before intubation, because fentanyl was not administered in this group

Preanaesthetic Before fentanyl administration Before intubation

Fentanyl
dose (µg kg) n Age (yr) HR (beat min–1) MAP (mm Hg) HR (beat min–1) MAP (mm Hg) HR (beat min–1) MAP (mm Hg)

0 20 38 (20–52) 72 (10) 88 (8) 67 (9)†¶ 61 (4)†¶ 68 (9)† 60 (4)†

1 20 42 (23–49) 75 (9) 91 (8) 66 (9)† 72 (5)*† 62 (10)*†‡ 68 (7)†‡
2 20 40 (21–50) 71 (10) 88 (9) 68 (11)† 77 (6)*† 60 (10)*†‡ 68 (6)*†‡
4 20 43 (22–51) 72 (8) 87 (9) 67 (10)† 80 (5)*† 59 (9)*†‡ 70 (5)*†‡

Fig 1 Consecutive target sevoflurane concentrations in each fentanyl group

(fentanyl 0, 1, 2 and 4 µg kg–1). When a patient moved in response to
tracheal intubation, the anaesthetic concentration for the next patient in
each group was decreased by a step of 0.4, 0.3, 0.2 or 0.2% for groups 1,
2, 3 and 4, respectively. Conversely, when a patient did not move, the
anaesthetic concentration for the next patient was increased by the same
step. Closed and open symbols indicate non-movement and movement,
respectively.
Fig 3 Effect of fentanyl on mean arterial pressure (MAP) responses to
tracheal intubation (mean (SD)). Fentanyl attenuated MAP responses in a
dose-dependent manner. There were significant differences between the
doses (P,0.05) except between the effects of fentanyl 1 and 2 µg kg–1.
Fentanyl 4 µg kg–1 suppressed the changes in MAP more effectively than
1 or 2 µg kg–1 (P,0.05).

Fig 4 Effect of fentanyl on heart rate (HR) responses to tracheal intubation

Fig 2 Sevoflurane concentration required to prevent movement in response
to tracheal intubation in 50% or 95% of patients (MAC-TI or MAC-TI95,
respectively), without and with fentanyl. The different doses of fentanyl
(1, 2 and 4 µg kg–1) reduced significantly the MAC-TI of sevoflurane
(*P,0.05) but there was no significant difference between the effects of
the two larger fentanyl doses. Data are mean (95% confidence intervals).
†Compare with fentamyl 1 µg kg–1.
Discussion
We found that the MAC-TI for sevoflurane was lower than
that suggested by Kimura and colleagues.4 They used
similar methods to ours and found that MAC-TI was 4.52%
(95% CI 3.91–5.21%) in patients aged 39613 yr. They did
not specify the tracheal tube used, type of cuff or intracuff
(mean (SD)). Fentanyl attenuated HR responses in a dose-dependent
manner. There were significant differences between the doses
(P,0.05) except between the effects of fentanyl 1 and 2 µg kg–1. Fentanyl
4 µg kg–1 suppressed the changes in HR more effectively than 1 and
2 µg kg–1 (P,0.05).
pressure applied to inflate the cuff. In our patients, we
found that most positive responses to laryngoscopy and
intubation were a result of bucking after cuff inflation. This
suggests that the stimulus created by the cuff of the tracheal
tube is one of the most important factors which may affect
MAC-TI. We used a tracheal tube with a high volume low
pressure cuff, and inflated the cuff to an intracuff pressure
of 20 cm H2O. We believe that this technique provides a

563
 Katoh et al.
minimal constant stimulation to the trachea, and an adequate
seal for positive airway pressure ventilation. Tracheal stimu-
lation may have been greater in the study of Kimura and
colleagues.
MAC-TI/MAC ratios of sevoflurane, halothane and
enflurane in children were 1.3.1 2 5 Inomata and colleagues
demonstrated that the MAC-TI of sevoflurane in children
was 2.69% (95% CI 2.23–3.37%) and the MAC-TI/MAC
ratio was 1.33.5 The MAC-TI/MAC ratio obtained in our
study appeared to be higher and may be explained by
tracheal stimulation created by cuff inflation which was not
present in children.
Our finding that small doses of fentanyl decreased the
sevoflurane concentration required to suppress movement
at tracheal intubation is new but not surprising. We demon-
strated that a small dose of fentanyl markedly reduced the
MAC of sevoflurane, yet previous work has shown that
fentanyl alone, even at extremely high concentrations, could
not prevent movement at surgical incision.6 This finding is
consistent with a ‘ceiling’ effect (no significant difference
between the effects of fentanyl 2 and 4 µg kg–1) for the
reduction in sevoflurane MAC-TI. The effect-site fentanyl
concentration 4 min after i.v. administration of fentanyl 1,
2 and 4 µg kg–1, calculated by pharmacokinetic simulation
using the parameters of Shafer and colleagues, would be
1.25, 2.5 and 5.0 ng ml–1, respectively.7 In our study,
fentanyl decreased the MAC-TI of sevoflurane by 41%,
59% or 61% at effect-site fentanyl concentrations of 1.25,
2.5 and 5 ng ml–1, respectively, while fentanyl decreased
the MAC of sevoflurane by 42%, 55% and 67% at the
same effect-site fentanyl concentrations. This suggests that
fentanyl produces a similar magnitude in the reduction
in sevoflurane requirements for preventing movement in
response to skin incision and tracheal intubation, although
the type of interaction between the two drugs depends on
the end-point.8 Fentanyl may block afferent nerve impulses
resulting from stimulation of the pharynx, larynx and lungs
during intubation. High concentrations of opioid receptor
are present in the solitary nuclei and the nuclei of the ninth
and 10th cranial nerves, associated with the visceral afferent
fibres of these nerves originating in the pharynx, larynx
and lungs.9 These receptors provide a possible mechanism
for the antitussive effects of fentanyl. Fentanyl may prevent
bucking after tracheal intubation by its antitussive effects,
resulting in reduction of MAC-TI.
Laryngoscopy and tracheal intubation are frequently
associated with severe hypertension. Increases in MAP
from 20 to 40 mm Hg compared with awake control
values,10–12 and from 35 to 60 mm Hg compared with pre-
intubation values10–13 have been reported after insertion of
a tracheal tube. Fentanyl has been shown to attenuate the
haemodynamic response to intubation after induction of
anaesthesia with thiopental. However, none of these studies
examined the effect of fentanyl during inhalation induction
with a volatile anaesthetic. Zbinden, Petersen and Thomson
could not find a concentration of isoflurane that blocked an
564
increase in HR or MAP in responses to intubation, and they
concluded that HR and MAP responses were independent
of isoflurane concentration.14 We tested sevoflurane in
oxygen at concentrations of 2.4–4.0% in the absence of
fentanyl. In 17 of 18 patients, there were increases in both
MAP and HR of more than 15%. Increasing the dose of fentanyl
decreased the haemodynamic reaction to intubation, even with
decreasing sevoflurane concentration. In only two of 20
patients, there were increases in HR and MAP of more than
15% with fentanyl 4 µg kg–1. In terms of attenuating haemo-
dynamic responses, fentanyl 4 µg kg–1 was more effective than
2 µg kg–1, and there was no manifest ceiling effect. This is
contrast with the finding in relation to the decrease in MAC-
TI by fentanyl. Large amounts of opioid used for patients
undergoing coronary artery bypass graft surgery, including
fentanyl, to doses as high as 100 µg kg–1, did not reliably
prevent an increase in HR or MAP in response to tracheal
intubation or sternotomy.15 16 Daniel and colleagues demon-
strated that fentanyl 1.5 µg kg–1 decreased the isoflurane con-
centration required to prevent haemodynamic responses to
surgical incision in 50% of patients with no further decrease
produced by fentanyl 3 µg kg–1.16
Somatic responses (e.g. movement) and autonomic
responses (e.g. HR and MAP) may be used as clinical end-
points for assessing depth of anaesthesia. In our study,
depth of anaesthesia, in terms of preventing movement in
response to intubation, was similar in the four groups,
because 50% of patients moved and 50% did not move in
each group. However, haemodynamic responses to intuba-
tion were apparently different between the four groups.
In summary, sevoflurane prevented gross purposeful
movements in response to tracheal intubation in 50% of
patients at a concentration of 3.55%, and this was reduced
to 2.07%, 1.45% and 1.37% with the addition of fentanyl
1, 2 and 4 µg kg–1 i.v., given 4 min before intubation.
In the absence of fentanyl, haemodynamic responses to
intubation were not suppressed by sevoflurane administered
as the sole agent at concentrations of 1 MAC-TI. With
increasing fentanyl dose, haemodynamic responses
decreased in a dose-dependent manner without a manifest
ceiling effect.
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