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26]

Original Article

Effect of sevoflurane with morphine or fentanyl on

haemodynamic response to laryngoscopy and tracheal
intubation: a prospective, randomised, double‑blind study
S. R. A. N. Bhushanam Padala, Muralidhar Anakapalli1, Hanumantha Rao Mangu1, Madhusudan Mukkara1,
Aloka Samantaray
Departments of Anaesthesiology and Critical Care Medicine and 1Anaesthesiology and Critical Care, Sri Venkateswara Institute of Medical
Sciences, Tirupati, Andhra Pradesh, India

Abstract Background: Multimodal therapy can be used for obtundation of the haemodynamic response to
laryngoscopy and tracheal intubation. The current study was undertaken to compare the haemodynamic
response to laryngoscopy and tracheal intubation after administration of 0.2 mg/kg morphine or 2 μg/kg
fentanyl with 2% end tidal sevoflurane during induction of anaesthesia.
Methods: Sixty patients were randomised into two equal groups to receive either 2% end tidal
sevoflurane + fentanyl 2 μg/kg (Group SF) or 2% end tidal sevoflurane + morphine 0.2 mg/kg (Group SM).
General anaesthesia technique was standardised for both the groups. Haemodynamic parameters heart
rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP)
were recorded for 15 min.
Results: The maximum increase in HR compared to baseline was statistically significant in Group SM
(16.5%, P = 0.0002) which occurred at one min after tracheal intubation. The maximum increases in SBP,
DBP and MAP compared to baseline occurred at one min after tracheal intubation in both the groups,
Group SF (7.04%, 6.5% and 7.9% respectively) and Group SM (6.2%, 8.2% and 8.1% respectively) which was
not statistically significant. The attenuation of haemodynamic response between the two groups was not
statistically significant (for HR P = 0.1428, for SBP P = 0.8558, for DBP P = 0.1958 and for MAP P = 0.5303).
Conclusions: With 2% end tidal sevoflurane during induction of anaesthesia, both 0.2 mg/kg morphine and
2 μg/kg fentanyl were equally effective in attenuating haemodynamic response to laryngoscopy and tracheal
intubation. However morphine appeared to be less effective in attenuating the chronotropic response
resulting in a greater increase in heart rate from baseline.

Keywords: Fentanyl, Haemodynamic response, Intubation, Laryngoscopy, Morphine

Address for correspondence: Dr. Madhusudan Mukkara, Associate Professor, Department of Anaesthesiology and Critical Care, Sri Venkateswara Institute
of Medical Sciences, Tirupati, Andhra Pradesh, India.
E‑mail: drmadhu37@gmail.com

INTRODUCTION airway during surgery under general anaesthesia. King et al.

in 1951 described the circulatory response to laryngeal and
Laryngoscopy, endotracheal intubation and airway
management are essential for anaesthesiologists in maintaining This is an open access journal, and articles are distributed under the terms of the Creative
Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to
Access this article online remix, tweak, and build upon the work non‑commercially, as long as appropriate credit
is given and the new creations are licensed under the identical terms.
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How to cite this article: Bhushanam Padala SR, Anakapalli M,
Mangu HR, Mukkara M, Samantaray A. Effect of sevoflurane with
DOI: morphine or fentanyl on haemodynamic response to laryngoscopy and
10.4103/JCSR.JCSR_31_18 tracheal intubation: a prospective, randomised, double-blind study. J
Clin Sci Res 2018;7:58-63.

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Padala, et al.: Morphine versus fentanyl on haemodynamic response
tracheal stimulation following laryngoscopy and tracheal
intubation as reflex sympathoadrenal stimulation.[1] This
results in increase in heart rate (HR) and blood pressure which
are short‑acting and may have detrimental effects in high‑risk
patients, especially those with cardiovascular diseases.[2]
Different classes of drugs and techniques have been
used to prevent this haemodynamic response.[3] Opioids
administered in moderate‑to‑high dose, have been suggested
as a means of blunting this response. Availability of
literature on the effect of currently used inhalational agents
on the pressor response to laryngoscopy and tracheal
intubation is limited. Multimodal therapy rather than a single
agent has been recommended to obtund the sympathetic
discharge associated with tracheal intubation. The advantage
of combining drugs is that side effects of individual agents
will be less because of lower doses used.[4] Not many studies
have examined the combination of opioids and inhalational
anaesthetics for attenuation of the haemodynamic response
to laryngoscopy and tracheal intubation. Hence, the
current study is undertaken to compare the haemodynamic
responses to laryngoscopy and tracheal intubation after
administration of 0.2 mg/kg morphine or 2 μg/kg fentanyl
with 2% end‑tidal  (ET) sevoflurane during induction of
anaesthesia. The main objective of this study is to know
which opioid in combination with 2% ET sevoflurane is
better in attenuating intubation response (11 min, i.e.,1 min
after intubation).
MATERIAL AND METHODS
After obtaining approval from the Institutional Research
and Ethics Committee, a prospective, randomised,
double‑blind study was conducted at our superspeciality
university teaching hospital. The study population
comprised 60 patients belonging to the American Society
of Anaesthesiologists physical status[5] Grade 1 and
Grade 2 (except hypertensives) in the age group of 18–
50 years of either sex weighing between 40 and 70 kg posted
for elective surgical procedures under general anaesthesia.
Patients who were not willing to participate in the study,
obese patients with body mass index (BMI) >30 kg/m2,
hypertensive patients, pregnant and lactating women were
excluded from the study. Patients with known allergic
reaction to study drugs, raised intracranial pressure,
expected difficult intubation and in whom intubation took
more than one attempt were also excluded from the study.
After detailed pre‑anaesthetic evaluation, each patient was
explained about the study and the anaesthesia technique.
Written informed consent was obtained from each patient.
All patients were pre‑medicated with tablet ranitidine
150 mg orally and tablet alprazolam 0.25 mg orally the
Journal of Clinical and Scientific Research | Volume 7 | Issue 2 | April-June 2018 59
night before surgery and were kept nil per oral 6 h for
solids, 2 h for clear liquids[6] Randomisation and sequence
were generated before initiating the study. Patients were
randomised into one of the two groups each containing
30 patients by a computer‑generated random number table
and sealed opaque envelope technique. The double‑blind
nature of the study was ensured by having an independent
anaesthesiologist, not participating in the study, preparing
fentanyl or morphine in ready to inject form for a total
volume of 10 ml using 0.9% normal saline.
On arrival in the operating room, the patients were
monitored by electrocardiogram, pulse oximeter and
non‑invasive blood pressure (IBP). Baseline values
of haemodynamic parameters such as HR, systolic
blood pressure (SBP), diastolic blood pressure (DBP)
and mean arterial pressure (MAP) were noted. Under
local anaesthesia, a good intravenous (IV) line with
18G cannula was secured to allow administration of
fluids (lactated Ringer’s solution at the rate of 300 ml/h)
and medication. General anaesthesia technique was
standardised for both the groups. Patients were induced
by an anaesthesiologist not a part of this study and the
observations were recorded by the investigator himself
who was blinded to the study drugs. The study drug (either
fentanyl or morphine) diluted to 10 ml was administered
by slow IV route over 2 min after securing the IV line
and starting of administration of the study drug was
considered as ‘0’ min. The closed circuit was primed
with 2% ET sevoflurane with 50% oxygen (O2) + 50%
nitrous oxide (N2O) for the first 5 min. Between 5 and
7 min, patients were induced with thiopentone 4 mg/kg
and paralysed by vecuronium 0.1 mg/kg and ventilated
with closed circuit which was already primed with 2% ET
sevoflurane and fresh gas flows O2 and N2O in a ratio of
50:50. Patients were intubated, 3 min after induction with
appropriate size endotracheal tube [Table 1].
Haemodynamic parameters recorded in this study were HR,
SBP, DBP and MAP at 2, 5, 8, 9 and 10 min and for 5 min
Table 1: Study procedure
Time Group SF Group SM
0–2 min Injection fentanyl Injection morphine
2 μg/kg IV 0.2 mg/kg IV
0–5 min Circuit priming Circuit priming
5–7 min Injection thiopentone Injection thiopentone
4 mg/kg IV 4 mg/kg IV
Injection vecuronium Injection vecuronium
0.1 mg/kg IV + 2% end tidal 0.1 mg/kg IV + 2% end tidal
sevoflurane O2:N2O ‑ 50:50 sevoflurane
O2:N2O ‑ 50:50
10 min Intubation Intubation
Group SF= Sevoflurane‑fentanyl group; Group SM= Sevoflurane‑morphine
group; IV= Intravenous; O2= Oxygen; N2O= Nitrous oxide
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Padala, et al.: Morphine versus fentanyl on haemodynamic response

at one min interval after intubation (i.e., 11,12,13,14 and
15 min). During the study period, no other stimulations
were given such as bladder catheterisation, nasogastric
tube insertion, change in position or surgical incision.
Any hypertension (rise in SBP >25% of baseline value)
during the study was treated with injection esmolol 5 mg
IV, whereas hypotension (fall in SBP >25% of baseline
value) was treated with injection ephedrine 3 mg IV or
injection phenylephrine 50 μg IV depending on HR.
The incidence of tachycardia (HR >120 beats/min)
and bradycardia (HR <50 beats/min) were treated with
injection esmolol 5 mg IV and injection atropine 0.4 mg
IV, respectively. The study period ended in 15 min after
starting of administration of study drugs.
Statistical analysis
We used Microsoft Excel 2007 (Microsoft Crop, Redmond
USA), GNU PSPP for GNU/Linux (Version 0.8.5, Boston
MA) and MedCalc version 11.3.0 for windows 2000/
XP/ Vistal 7 (MedCalc Software Bvba, Belgium) software
for statistical analysis. Quantitative variables such as age,
weight, HR, SBP, DBP and MAP were expressed as mean
and standard deviation. Intergroup data were analysed
by using unpaired Studentʼs t‑test. Intra‑group data were
analysed using repeated‑measures analysis of variance
and appropriate post hoc testing. Qualitative data were
analysed by using the Chi‑square test. P < 0.05 was taken
as statistically significant.
and there was no statistically significant difference between
the two groups [Table 2].
We observed statistically significant difference in HR
between the two groups, Group SF and Group SM, only
at 12 and 13 min [Figure 1] whereas for DBP and MAP
only at 12.13 and 14 min (P = 0.0141,0.0328 and 0.0120,
respectively, for DBP; 0.0171,0.0126 and 0.0103 for MAP).
There was no statistically significant difference in SBP at
any time intervals.
In our study, the maximum increase in HR compared
to baseline value occurred at 11 min (i.e.,1 min after
tracheal intubation) in both the groups, Group SF
(8.4%, P = 0.2031) and Group SM [16.5%, P = 0.0002;
Figure 1]. It was statistically significant only in
Group SM.
The maximum increases in SBP, DBP and MAP compared
to baseline values occurred at 11 min (i.e.,1 min after tracheal
intubation) in both the groups, Group SF (7.04%, 6.5%
and 7.9%, respectively) and Group SM (6.2%, 8.2% and
8.1%, respectively). They were not statistically significant
in both the groups.
Table 2: Comparison of demographic variables between the
study groups
Demographic variable Group SF Group SM P - value

RESULTS Mean age (years) 38.70±9.77 40.03±8.44 0.5740

Mean weight (kg) 56.16±9.67 58.13±7.07 0.3724
Mean height (cm) 160.36±8.83 161.70±8.28 0.5488
The elective spine surgeries requiring general endotracheal BMI (kg/m2) 21.87±3.70 22.28±2.80 0.6318
anaesthesia such as discectomies, decompressive Male/female 11/19 13/17 0.7920
MPG (1/2) 4/26 3/27 >0.99
laminectomies and fusions performed in our institute were Age, weight, height, BMI are depicted as “mean±SD”.
included in our study. Three patients were observed to have BMI= Body mass index; MPG= Mallampati grading; Group
persistent hypertension and one patient was observed to have SF= Sevoflurane‑Fentanyl group; Group SM= Sevoflurane‑Morphine
group; SD= Standard deviation
persistent tachycardia on the operating table before inducing
anaesthesia. One patient desaturated after giving study drug
and we immediately intervened with 100% O2 and in one
patient, there was an unanticipated difficult intubation in
which intubation took two attempts. All the above six cases
were excluded from the study. During the conduct of the
study, three patients developed hypertension (two patients
in Group sevoflurane‑fentanyl [SF] and one patient in
Group sevoflurane‑morphine [SM]), 18 patients developed
hypotension (13 patients in Group SF and 5 patient in
Group SM), four patients developed tachycardia (two patients
each in Group SF and Group SM). They were treated
accordingly. None of the patients developed bradycardia.
Figure 1: Comparison of heart rate between the study groups
*Intubation; †P < 0.05
Demographic variables such as age, weight, height, BMI, BL= Base line; Group SF= Sevoflurane‑fentanyl group;
gender distribution and Mallampati grade were comparable, Group SM; Sevoflurane‑morphine group

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Padala, et al.: Morphine versus fentanyl on haemodynamic response
There was no statistically significant difference
between Group SF and Group SM in maintaining the
haemodynamics immediately after IV bolus (2 min) and
just before induction of anaesthesia (5 min). However,
fentanyl appeared to maintain better haemodynamics
than morphine as Group SM showed a statistically
significant increase in HR from baseline at 2 and
5 min [Figure  1] and statistically significant decrease
in DBP and MAP at 5 min (P = 0.0001 and 0.0160,
respectively).
There was no statistically significant difference between
Group SF and Group SM in maintaining the haemodynamics
after induction (8, 9 and 10 min). However, morphine
appeared to maintain better chronotropic response
than fentanyl after induction as Group SF showed
statistically significant decrease in HR from baseline at
10 min [Figure 1]. Both the groups showed statistically
significant decreases in SBP, DBP and MAP from baseline
after induction, at 8, 9 and 10 min.
The difference in HR between the two groups was
statistically significant only at 12  min and 13  min  [i.e.,
2 and 3 min after intubation; Figure 1], whereas the
difference in SBP between the two groups was not
statistically significant at any time intervals. DBP and
MAP showed a statistically significant difference only
at 12, 13 and 14 min. (2, 3 and 4 min after intubation,
respectively) [Figure 2].
Our results showed that with 2% ET sevoflurane
during induction of anaesthesia, both 2 μg/kg fentanyl
and 0.2  mg/kg morphine were equally effective in
Figure 2: Comparison of SBP, DBP and MAP between the study
groups.
*Intubation; †P < 0.05
BL= Base line, SBP= Systolic blood pressure; DBP= Diastolic blood
pressure; MAP= Mean arterial blood pressure;
Group SF= Sevoflurane‑fentanyl group;
Group SM = Sevoflurane‑morphine group
Journal of Clinical and Scientific Research | Volume 7 | Issue 2 | April-June 2018 61
attenuating haemodynamic response to laryngoscopy and
tracheal intubation. The attenuation of haemodynamic
response between the two groups was not statistically
significant (for HR P = 0.1428, for SBP P = 0.8558, for
DBP P = 0.1958 and for MAP P = 0.5303). However,
morphine appeared to be less effective than fentanyl in
attenuating the chronotropic response because it resulted
in a greater increase in HR from baseline (16.5%), which
was statistically significant (P = 0.0002). Adverse events
are listed in Table 3.
DISCUSSION
Laryngoscopy and tracheal intubation are considered to be
stressful and cause exaggerated cardiovascular response.
Although transient hypertension and tachycardia are usually
of little consequence, they may be hazardous, especially in
patients with persistent hypertension, limited coronary and
myocardial reserve or cerebrovascular diseases.[7,8] Reflex
changes in the cardiovascular system after laryngoscopy and
intubation lead to an average increase in blood pressure
by 40%–50% and 20% increase in HR.[9] The magnitude
of haemodynamic changes observed may be dependent
on various factors such as depth of anaesthesia, whether
any measure is taken before airway manipulation, the
anaesthetic agent used, the duration of laryngoscopy
and intubation. Another factor contributing to pressor
response is anxiety. To relieve anxiety we have used tablet
alprazolam in pre‑medication. Tablet alprazolam 0.25 mg
orally was administered at bedtime in the night before
surgery. Coughing and straining were avoided by adequate
muscle relaxation and deeper planes of anaesthesia
by maintaining 2% ET sevoflurane concentration ET
aneasthetic concentrations.[10]
Numerous phar macological methods have been
recommended to obtund the sympathoadrenal cardiovascular
response to laryngoscopy and tracheal intubation. They
may be classified as non‑specific means achieved by
deepening the plane of anaesthesia or by specific means
involving various pharmacological preparations. Opioids
administered in moderate‑to‑high dose, have been suggested
as a means of blunting this response. A linear relationship
Table 3: Adverse events
Event Group SF Group SM Total Intervention
Hypertension 2 (11 min) 1 (11 min) 3 Injection esmolol 5 mg IV
Hypotension 5 (14 min) 4 (14 min) 18 Injection ephedrine
8 (15 min) 1 (15 min) 3 mg IV
Tachycardia 1 (2 min) 1 (2 min) 4 Injection esmolol 5 mg IV
1 (11 min) 1 (10 min)
Bradycardia 0 0 0 Nil
Group SF= Sevoflurane‑fentanyl group; Group SM= Sevoflurane‑morphine
group; IV= Intravenous
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Padala, et al.: Morphine versus fentanyl on haemodynamic response
exists between increasing opioid dose and reduction in
cardiovascular response.[11‑14] Fentanyl is available in our
country since 1998 and has various advantages such as
no histamine release, no bronchospasm, cardiostability,
rapid onset and short duration of action. It produces
analgesia and stable haemodynamics by modulating
stress response through receptor‑mediated actions on
hypothalamic‑pituitary‑adrenal axis. Fentanyl has been
tried in various bolus doses for control of haemodynamic
changes of laryngoscopy. However, large dose can lead to
muscular rigidity, bradycardia, nausea and vomiting. Large
doses may also cause post‑operative respiratory depression,
especially in surgery with short duration (<1 h). Morphine,
a prototype opioid analgesic was also used in various studies
to obtund the haemodynamic response to laryngoscopy
and tracheal intubation. Morphine has been recognised
for its hypotensive effect. Previous studies suggest that
morphine decreases arterial blood pressure as a result of
multiple mechanisms, including decreases in cardiac and
renal sympathetic nerve activity, an increase in vagal tone
and histamine release.[15‑17]
Availability of literature on the effect of currently used
inhalational agents on presser response to laryngoscopy
and tracheal intubation is limited. In rabbits, after
administration of 1%–4% concentration sevoflurane
caused a 50% reduction in MAP without any change in
HR. This was due to the baroreflex compensation for the
effects of sevoflurane on sympathetic and cardiomotor
activity up to a concentration of 3%.[18] The same effect
has been observed in clinical studies in humans. Autonomic
nerve activity was attenuated by sevoflurane administered
with N2O.[19] It has also been postulated that sevoflurane
depresses the sympathetic activity without altering the
parasympathetic response.[20]
Multimodal therapy rather than a single agent has been
recommended to obtund the sympathetic discharge
associated with tracheal intubation. The advantage of
combining drugs is that side effects of individual agents
will be less because of lower doses used.
Hoda and Khan[21] compared the haemodynamic response
to laryngoscopy and tracheal intubation after administration
of 2 μg/kg fentanyl bolus with a placebo with 2% ET
sevoflurane at induction of anaesthesia. In our study, we
also used the same dose of fentanyl in Group SF and
found comparable results. The maximum rise in HR, SBP,
DBP and MAP were 8.4% (vs. 15%), 7.04% (vs. 6%), 6.5%
(vs. 11%) and 7.9% (vs. 8%), respectively, which occurred
at 11 min, i.e., 1 min after intubation.
62 Journal of Clinical and Scientific Research | Volume 7 | Issue 2 | April-June 2018
Other studies [11,13] also compared different doses of
fentanyl and concluded that fentanyl 2 μg/kg significantly
attenuated haemodynamic response during laryngoscopy
and intubation as in our study, although higher doses
completely abolished these responses.
The maximum rise in HR, SBP and DBP in Group SF in our
study were comparable to the fentanyl group in a study[22] in
which they compared fentanyl 2 μg/kg IV and nalbuphine
0.2 mg/kg IV for control of haemodynamic changes during
endotracheal intubation, i.e., 8.4% (vs. 12.5%), 7.04%
(vs. 4.8%) and 6.5%(vs. 4.5%), respectively.
Various authors[23‑25] studied morphine in doses ranging
from 0.1 to 0.5 mg/kg for attenuation of haemodynamic
response to laryngoscopy and endotracheal intubation. We
used morphine 0.2 mg/kg in Group SM in our study and
got comparable results to them.
Not many studies have examined the combination of
opioids and inhalational anaesthetics for attenuation of
the haemodynamic response to laryngoscopy and tracheal
intubation. We have studied the changes in haemodynamic
parameters in response to laryngoscopy and tracheal
intubation in relation to HR, SBP, DBP and MAP after
administration of equipotent analgesic doses of fentanyl (2
μg/kg) or morphine (0.2 mg/kg) with 2% ET sevoflurane
during induction of anaesthesia. Our rationale was to
compare and know which of these combinations better
attenuate the haemodynamic response. The combined
effect of fentanyl during inhalational induction was
observed in different previous studies along with the use of
muscle relaxant[21] or without the use of muscle relaxant.[4]
We chose fentanyl 2 μg/kg and 2% ET sevoflurane based
on one of the previous studies[21] where this combination
attenuated the haemodynamic responses to a maximum
of 15% above baseline values. The dose of morphine is
selected based on the equipotent analgesic dose of fentanyl.
Fentanyl is 100 times more potent than morphine.[26]
The rise in HR in Group SM at 1 min after intubation (11 min)
was statistically significant (16.5%, P = 0.0002), whereas
the rise in HR in Group SF and the rise in SBP, DBP
and MAP in both the groups, Group SF and Group SM
post‑intubation were not statistically significant, but this
might be due to the offset of the fall compared to the
baseline in the post‑induction period and 2 min following
intubation, which lasted until 5 min post‑intubation.
There were a few limitations in our study. IBP monitoring
was not used due to cost constraints, which would have
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Padala, et al.: Morphine versus fentanyl on haemodynamic response
allowed us for the beat‑to‑beat recording of the parameters.
The age distribution of our patients was between 18
and –50 years which might have affected our results
because of the influence of age on the minimum alveolar
concentration of inhalational agents.[27] According to the
reference based on which we designed our study, the time
for onset of action is 5 min. Moreover, the time taken for
peak effect to be seen is 10 min.[26] However, some textbooks
quote, the time for peak effect to be approximately 20 min
or more, which might have affected the attenuation
of chronotropic response in Group SM. The patient
population included in this study might have associated with
chronic pain and might be receiving analgesics. Hence, there
might be differences in analgesic requirements in the study
population which could have affected our results.
We recommend further studies to assess different
concentrations of sevoflurane in combination with
different doses of fentanyl and morphine for obtaining
an optimum attenuation of the haemodynamic response
to tracheal intubation.
From our study, we conclude that fentanyl and morphine
were equally effective in attenuating haemodynamic response
to laryngoscopy and tracheal intubation. However, morphine
appeared to be less effective in attenuating the chronotropic
response resulting in a greater increase in HR from baseline.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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