Attenuation of haemodynamic response to laryngoscopy and
tracheal intubation in adult patients with a single intravenous bolus
dose of 3μg/kg clonidine: A prospective, randomized, double blind
study
ABSTRACT: BACKGROUND: Laryngoscopy and endotracheal intubation is often associated
with hypertension and tachycardia because of sympatho-adrenal stimulation which is usually
transient and lasts for up to 5-10 minutes. Many methods have been tried to blunt this
haemodynamic response. Clonidine a centrally acting α – 2 agonist which has antihypertensive,
sedative, analgesic actions in addition to reducing the anaesthetic drug requirements. Till
recently clonidine was available in India as oral preparation only and as such oral preparation
was only being used to attenuate the intubation response. Now clonidine has been introduced in
parenteral form and can be used through intravenous route for attenuation of sympathetic
response to laryngoscopy and intubation. AIMS: The present study was undertaken to study the
efficacy of 3µg/kg clonidine IV, given 15 minutes before laryngoscopy and intubation in
obtunding the haemodynamic response compared to the control. In addition, to evaluate the
effect of clonidine on the dose requirement of thiopentone sodium, vecuronium and also to study
the sedation and side effects. METHODS AND MATERIAL: STUDY DESIGN AND
SETTING. One hundred normotensive patients aged between 18 to 60 years, scheduled for
various elective surgical procedures belonging to ASA class I and II were assigned randomly
into two groups. Group I (n=50) - received 10 ml of normal saline over 120seconds, Group II
(n=50) - received injection Clonidine 3µg/kg diluted to 10 ml normal saline over 120seconds,
both given15 minutes prior to laryngoscopy and intubation. Haemodynamic changes associated
with intubation were noted in both the groups at different time points. RESULTS: The reduction
in the heart rate and blood pressure by clonidine in the post-intubation period was statistically
1
highly significant (p<0.001). In addition Clonidine reduced the requirement of thiopentone and
vecuronium and produced arousable sedation after extubation without any side effects like
bradycardia and hypotension. CONCLUSION: Clonidine in the dose of 3µg /kg body weight
given 15 minutes before laryngoscopy and intubation was seen to effectively attenuate the
haemodynamic response to laryngoscopy and intubation without any side effects.
KEY WORDS: Clonidine, Laryngoscopy, Tracheal intubation, Haemodynamic response,
INTRODUCTION: Laryngoscopy and tracheal intubation are commonly accompanied by
1
increases in arterial blood pressure and heart rate . The principle mechanism in hypertension and
tachycardia is the sympathetic response 2, 3 which may be the result of increase in catecholamine
activity 4. Transitory hypertension and tachycardia are probably of no consequence in healthy
individuals. But either or both may be hazardous to those with hypertension, myocardial
4
insufficiency or cerebrovascular diseases . This laryngoscopic reaction in such individuals may
predispose to development of pulmonary edema, dysrrythmias, myocardial insufficiency and
cerebrovascular accident
5, 6.
Pressor response is exaggerated in hypertensive patients even
though rendered normotensive pre-operatively by antihypertensive medication7.
Intravenous anaesthetic induction agents do not adequately or predictably suppress the
circulatory responses evolved by endotracheal intubation8. So prior to initiating laryngoscopy,
additional pharmacological measures like use of volatile anaesthetics9, topical and intravenous
lidocaine10, 11, 12, opioids 13, 14, 15, vasodilators – SNP 16, NTG 17, Calcium channel blockers 18 ,19 ,
20
and β-blockers 21, 22, 23, have been tried by various authors.
Besides minimizing the cardiovascular response, anaesthesia induction for patients at risk
must also satisfy the following requirements: it must be applicable regardless of patient group,
2
prevent impairment of cerebral blood flow and avoid awareness of the patient; it should neither
be time consuming nor affect the duration or modality of the ensuing anaesthesia and also should
not have any effect on the recovery characteristics. Among the recommended procedures,
24
intravenous clonidine appears to fulfill the criteria .
Intravenous Clonidine, a central α–2 agonist has become a popular agent for obtunding
haemodynamic responses to laryngoscopy and intubation. Further clonidine has sedative,
analgesic, antihypertensive actions in addition to reducing the anesthetic drugs requirement 24.
Not many studies have been done in India using clonidine in the parenteral form for suppression
of intubation response. Hence, we studied the effects of intravenous clonidine for attenuation of
haemodynamic responses to laryngoscopy and intubation.
OBJECTIVE: Primary objective of the study was to evaluate the efficacy of intravenous
clonidine in the dose of 3µg/kg body weight in attenuating the haemodynamic responses to
laryngoscopy and endotracheal intubation.
Secondary objective was to study the effect of clonidine on the dose requirement of thiopentone
for induction of anaesthesia and vecuronium for muscle relaxation and to study any adverse
effects associated with clonidine administration such as increased sedation, prolonged recovery,
hypotension and bradycardia.
METHODOLOGY: Study population: One hundred patients, scheduled for various elective
surgical procedures. Inclusion criteria: Patients belonging to ASA class I and II were included
in the study after obtaining ethical committee clearance as well as informed consent from all
patients. The patients were normotensive with age varying from 18 to 60 years. Exclusion
criteria: Patients with hypertension, with heart rate less than 60bpm, systolic blood pressure less
3
than 100mm of Hg, presence of 1st, 2nd or 3rd degree heart block, patients with difficult airway
(Mallampatti class 3 or 4; thyromental distance < 6cm) and hyperthyroid patients. Data
collection: Patients were randomized into two groups. Group I - Control group (n=50) - received
10 ml of normal saline intravenously over 120 seconds and Group II - Clonidine group (n=50) received injection Clonidine 3µg/kg, diluted to 10 ml normal saline intravenously over 120
seconds both given 15 minutes prior to laryngoscopy and intubation. The allocation sequence
was generated by random number tables. On arrival of the patient in the operating room, an 18gauge intravenous cannula was inserted under local anaesthetic infiltration and an infusion of
normal saline was started. The patients were connected to multichannel monitor which records
Heart rate (HR), non-invasive measurements of systolic, diastolic and mean arterial pressure(
SBP, DBP, MAP), EtCO2 and continuous ECG monitoring and oxygen saturation. The baseline
SBP, DBP, MAP and HR were recorded. After recording the baseline reading, study drugs was
given, both given 15min before intubation. The study drug was prepared by the senior
anaesthesiologist who was not involved with the study and observer as well as patient were
blinded for the study. All the patients were premedicated with inj.glycopyrrolate 0.2mg,
inj.midazolam 1mg and inj.pentazocine 15mg IV before preoxygenation. After preoxygenation
for 3 minutes anaesthesia was induced with inj.thiopentone as a 2.5% solution till loss of eye lash
reflex occurred and dose of thiopentone required for loss of eye lash reflex recorded. This is
followed by inj.lidocaine 1.5mg/kg. Endotracheal intubation was facilitated with 0.1mg/kg
vecuronium three minute prior to laryngoscopy and intubation. 15 minutes after giving study
drug, gentle laryngoscopy and intubation was performed using Macintosh no.3 blade, trachea
intubated. After confirmation of bilateral equal air entry, the endotracheal tube was fixed.
4
The heart rate, arterial blood pressure (systolic, diastolic and mean), SPO2 were recorded at eight
specified intervals, namely, Basal - before giving study drug, Pre induction - before giving
premedication, At Induction, At Intubation, One, three, five and ten minutes after intubation.
EtC02 was maintained within 35±5 mmHg to avoid effects of hypercarbia or hyperventilation on
the haemodynamic variables. The ECG was monitored continuously for arrhythmias and
ischemia. No other medications were administered or procedures performed during the 10-min
data collection period after tracheal intubation. Anaesthesia was maintained using 66% nitrous
oxide and 33% of oxygen with 1% isoflurane. Neuromuscular blockade was maintained with
vecuronium 0.05 mg/kg and the total dose of vecuronium required for the surgery was recorded.
Incidence of side effects like hypotension, bradycardia, dysrrhythmia, delayed recovery were
recorded in both the groups.
Sedation scoring as per Ramsay scale
Score
Response
1
Anxious or restless or both
2
Cooperative, orientated and tranquil
3
Responding to commands
4
Brisk response to stimulus
5
Sluggish response to stimulus
6
No response to stimulus
5
Statistical methods employed
-
Descriptive statistics ( to measure mean, standard deviation)
-
Independent sample ‘t’ test ( to measure difference between two groups i.e. intergroup
comparison)
-
Paired sample ‘t’ test ( to measure difference within the group i.e. intragroup comparison)
-
Contingency table analysis (for association between the rows and columns) p < 0.05 was
considered as significant and p < 0.001 was considered as highly significant.
RESULTS: The demographic data (age, sex, weight and surgical procedures and duration of
surgical procedures) were similar in both the groups (p>0.05).
Table 1: Changes in mean heart rate at various time intervals
Group I
Group II
p value
Basal
84.48  9.86
86.10  13.44
0.494
Pre-Induction
89.10  10.56
85.74  12.93
0.158
Induction
93.16  12.09
84.68  12.21
0.102
Intubation*
119.20  11.16
90.60  11.86
<0.001
1 min*
125.08  9.31
95.56  12.66
<0.001
3 min*
116.14  8.69
90.60  11.06
<0.001
5 min*
109.88  8.97
87.82  10.76
<0.001
10 min*
97.48  9.49
85.96  10.01
<0.001
*
p <0.001
6
Figure 1: Graph showing changes in mean Heart rate at various time intervals
130
Group 1
Mean HR
120
Group 2
110
100
90
80
Session
Table 2: Changes in mean systolic blood pressure (mmHg) at various time intervals
Group I
Group II
Basal
127.90  5.62
122.74  9.25
0.328
Pre-Induction
130.84  5.86
122.12  7.29
0.188
Induction
127.26  5.72
120.48  7.28
0.128
Intubation*
145.34  4.58
127.30  8.60
< 0.001
1 min*
158.02  4.50
132.46  10.24
<0.001
3 min*
149.16  8.27
126.56  9.06
<0.001
5 min*
139.24  8.02
124.54  8.42
<0.001
10 min
128.58  5.91
122.80  7.94
0.232
*
p <0.001
7
p value
Figure 2: Graph showing changes in mean systolic blood pressure (mmHg) at various time
intervals
160
Group 1
Mean SBP
150
Group 2
140
130
120
110
Session
Table 3: Changes in mean diastolic blood pressure (mmHg) at various time intervals
Group I
*
Group II
p value
Basal
77.00  6.10
77.70  7.58
0.612
Pre-Induction
80.80  6.49
78.68  7.75
0.142
Induction
78.30  6.88
76.22  8.09
0.170
Intubation*
94.04  3.46
82.66  7.81
0.001
1 min*
98.78  3.45
85.20  8.00
0.001
3 min*
92.12  7.24
82.32  6.99
0.001
5 min*
86.10  8.04
80.10  8.29
0.001
10 min
80.00  8.07
79.00  7.77
0.539
p < 0.001
8
Figure 3: Graph showing changes in mean diastolic blood pressure (mmHg) at various time
Intervals
100
Group 1
Mean DBP
Group 2
90
80
70
Session
Table 4: Changes in mean arterial pressure (mmHg) at various time intervals
Group I
Group II
Basal
93.62  5.05
91.84  6.59
0.544
Pre-Induction
97.28  5.33
93.00  6.87
0.652
Induction
93.66  5.35
90.68  6.75
0.133
Intubation*
110.86  2.82
97.58  7.17
0.001
1 min*
118.12  3.32
100.54  7.55
0.001
3 min*
110.28  7.01
96.96  6.97
0.001
5 min*
102.96  7.05
94.60  7.61
0.001
10 min
96.12  6.41
93.42  6.70
0.062
9
p value
*
p<0.001
Figure 4: Graph showing changes in mean arterial pressure (mmHg) at various intervals
120
Group 1
Group 2
Mean MAP
110
100
90
80
Session
Table 5: Changes in rate pressure product at various time intervals
Group I
*
Group II
p value
Basal
10842.80  1512
10608.00  2083
0.521
Pre-Induction
11679.84  1665
10504.22  1851
0.118
Induction*
11865.48  1713
10220.96  1577
0.001
Intubation*
17342.90  1893
11554.24  1795
0.001
1 min*
19787.86  1818
12678.22  2104
0.001
3 min*
17345.08  1816
11462.88  1724
0.001
5 min*
15318.78  1711
10943.38  1595
0.001
10 min*
12555.84  1567
10556.96  1388
0.001
p<0.001
10
Figure 5: Graph showing changes in Mean Rate Pressure Product(RPP)
21000
Group 1
Mean RPP
19000
Group 2
17000
15000
13000
11000
9000
Session
Table 6: Showing (mean±SD) dose of thiopentone sodium, vecuronium bromide and sedation
scoring in Group1 and 2
Mean Dose of
thiopentone required
for induction(mg)
Dose of Vecuronium
bromide required for
muscle relaxation( mg)
Group ‫׀‬
284.00  26
8.48  1.91
2.0  0.4
Group I I
242.50  27
5.64  1.52
2.74 0.5
0.011
0.022
p value
0.015
11
Sedation score
DISCUSSION
Laryngoscopy and tracheal intubation are considered as the most critical events during
administration of general anaesthesia as they provoke transient but marked sympathoadrenal
response manifesting as hypertension and tachycardia5. Many methods have been tried by
various authors for blunting haemodynamic responses to laryngoscopy and intubation. But all
such maneuvers had their own limitations. For example, with opioids respiratory depression and
chest wall rigidity were potential problems, use of halothane was associated with dysrhythmias,
calcium channel blockers produced reflex tachycardia, direct acting vasodilators needed invasive
haemodynamic monitoring and lidocaine did not give consistent results. Beta blockers blunt the
heart rate response better than blood pressure response 21, 22.Clonidine, an α – 2 agonist, can
blunt both the heart rate and blood pressure response to laryngoscopy and intubation, without
having any adverse effects like respiratory depression and post operative nausea and vomiting.
Clonidine was used in the dose of 0.625, 1.25, 3 and 6 µg/kg to attenuate the intubation response.
Clonidine at 0.625 and 1.25 µg/kg was not or partially effective for blunting the haemodynamic
response to laryngoscopy and intubation25,26. Doses greater than 3 µg/kg caused an increase in
blood pressure and peripheral vascular resistance with reduction in cardiac output because of
clonidine action on peripheral α 2- receptors
27
. Hence we used 3 µg /kg of body weight as the
dose to obtund the haemodynamic response28,29,30,31.
In the present study clonidine was diluted in 10 ml of normal saline and given intravenously over
120 seconds 29,32.
From the pharmacokinetic profile, it is seen that the distribution half life of intravenous
clonidine is approximately 11 minutes 24, 33. It has also been found that the maximum effect of
12
intravenous clonidine occurs approximately 15 minutes after its administration 25,26,28,29,31,32,34,35.
In view of this clonidine was given 15 minutes before laryngoscopy and intubation.
The patients in all the groups did not show any statistically significant differences in their age or
sex distributions. We selected the optimal age range of 18 to 60 years. All the groups were
similarly premedicated regarding anxiolysis. The preinduction values of HR, SBP, DBP and
MAP did not show any statistically significant difference in both the groups.
At 1 minute i.e., immediately after the laryngoscopy and intubation, the rise in the heart rate was
maximum in both the groups. The mean heart rate rise was 40.6 bpm from the basal heart rate in
the control compared to of 9.46 bpm in clonidine group (p<0.001). Zalunardo MP. et al 28 noted
that the plasma catecholamine concentration increased to the maximum at 1 minute after the
laryngoscopy. The decrease in the pulse rate after the clonidine administration was due to the
reduction of the sympathetic outflow, the simultaneous increase of the parasympathetic tone of
central origin and the influence of clonidine on the neurons which receive the baroreceptor
afferents36.
At 5 minutes, there was still a rise from the preinduction values of the heart rate in all the groups.
But the values showed a decline from those at 1 minutes, the decline being more rapid in the
clonidine group. At 10 minutes, the haemodynamic response declined in all the groups.
In the control group, the systolic blood pressure increased maximally after 1 minute (mean rise
of 30.12mmHg) and it gradually decreased over 10 minutes to basal value. With the
administration of clonidine, the maximum increase as compared to the preinduction value was
rise of 9.72 mmHg, with the blood pressure response being attenuated more effectively by
13
clonidine (P<.001). Michael Muzi et al. suggest that this may be due to an active baroreflex
response to the change in the pressures37. The maximum increase in the diastolic blood pressure
was 21.78 mmHg as compared to the preinduction value in the control group. It was 7.50 mmHg
in the clonidine group (P<.001).
Similarly, the mean arterial pressure increased by 24.50 mmHg from the preinduction value in
the control group at 1 minute and it gradually decreased over 10 minutes. Clonidine limited it to
only 8.70 mmHg (P<.001). Sung et al., (2000) have also shown that a premedication with
clonidine helped in providing a perioperative haemodynamic stability38. Moreover, Yokota et al.,
(1998) concluded that the clonidine premedication might contribute to a haemodynamic stability
during a sedated fiberoptic nasal intubation39. Similar results were obtained in other studies
(Costello and Cormack)40. Nand Kishore Kalra, in 2011 12, concluded that intravenous clonidine
showed the best control of the systolic BP and no significant episodes of hypotension.
Overall, the clonidine premedicated patients showed a lower magnitude of the rise in the heart
rate and the blood pressure. Both the blood pressure response and the heart rate were attenuated
more effectively in the clonidine group as compared to control group. This finding was in
accordance with the data which was available from other studies.
We studied the total dose of thiopentone required for induction in each group. In control group
dose of thiopentone required for induction was 284mg (5.06mg/kg) and in clonidine group dose
required was 242.50mg (4.37mg/kg) showing reduction of 13.63%. This is statistically and
clinically significant (p<0.05). Marinangeli F. et al. 29, Leslie K. et al. 32, also studied the dose
sparing effect of clonidine. The anaesthetic sparing effect of clonidine is due to decrease in
14
central noradrenergic transmission and also α-2 receptor itself may mediate an anaesthetic
response 32.
We also studied the total dose of vecuronium required in each group. We found in control group
dose of vecuronium bromide required for muscle relaxation was 8.48mg(duration of surgery:99
minutes) and in clonidine group dose required was 5.64mg(duration of surgery:100.5 minutes
min).There is a significant reduction in the dose of vecuronium required in the clonidine group
(p<0.05) compared to the control group. Since duration of action of vecuronium depends on the
dose given, we can expect a prolongation of action of vecuronium by clonidine if similar doses
were used in both the groups. Nakahara T et al 41, who studied the effect of clonidine on the
duration of vecuronium induced neuromuscular blockade keeping the total dose of vecuronium
constant in clonidine and control group found a significant prolongation of the action of
vecuronium by clonidine.
In control group mean sedation score immediately after extubation was 2.0  0.4 and in group II
mean sedation score was 2.74 0.5. Statistical evaluation between the groups showed that the
patients in clonidine group are more sedated than the patients in control group which is
statistically significant (p < 0.05). Clonidine is known to produce arousable sedation by its action
on locus coeruleus nucleus without producing any respiratory depression
42.
No patient in our
study in the clonidine group had any post operative respiratory depression as there was no
change in the SPO2 breathing room air.
The results of the present study should encourage the routine use of clonidine as a premedication
for the patients who undergo laryngoscopy and intubation. By providing improved
15
haemodynamics, clonidine proved to be beneficial as compared to other drugs in any clinical
setup.
CONCLUSION
From the present study it can be concluded that
In control group patients significant rise in the mean heart rate (HR), systolic blood pressure
(SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) and rate pressure product
(RPP) occurred one minute following laryngoscopy and intubation. This cardiovascular response
persisted upto 10 minutes after which they returned towards baseline values.
In clonidine group patients, clonidine in the dose of 3µg /kg IV, given 15 minutes before
intubation, effectively attenuated the heart rate response and also arterial pressure response to
laryngoscopy and intubation.
There was a significant reduction in thiopentone and vecuronium dose requirement in clonidine
group compared to control group.
Side effects like hypotension and bradycardia were not observed in any of the clonidine group
patients.
Hence it is concluded that clonidine in the dose of 3µg/kg IV, given 15 minutes before
laryngoscopy and intubation can be safely employed to attenuate the haemodynamic response to
laryngoscopy and intubation without any side effects.
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