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Sri Lankan Journal of Anaesthesiology
CLINICAL INVESTIGATIONS
A RANDOMIZED, DOUBLE BLIND, CONTROLLED STUDY ON THE
EFFECTS OF ADDITION OF CLONIDINE TO BUPIVACAINE USED
FOR PATIENTS UNDERGOING SPINAL ANAESTHESIA
*Bhavini Shah
1
, Ramchandra Shidhaye
1
, Devdas Divekar
1
, Mrudul Panditrao
2
; Minnu Panditrao
2
;
Chhaya Suryawanshi
2
Assistant Lecturer, Professor, Department of Anesthesiology and Critical Care, Pravara Institute of
Medical Sciences, Loni 413736 India
1
; Professor Department of Anesthesiology and Critical Care, Dr.
D.Y. Patil Medical College Pimpri, Pune 411018 India
2
*Corresponding author: rvshidhaye@yahoo.com
Key words: Intrathecal; Clonidine; Bupivacaine; Postoperative pain; Spinal anaesthesia
Background:
Spinal anaesthesia provided by bupivacaine alone may be too short for the planned surgery. The
addition of clonidine 1 µg/kg to bupivacaine provides a prolonged anaesthetic action. The aim of
this randomized double-blinded controlled study was to investigate the effects of addition of low
dose clonidine to hyperbaric bupivacaine 0.5%, for spinal anaesthesia in patients undergoing lower
abdominal and lower limb surgeries, on analgesic efficacy, quality of block, duration of analgesia
and adverse effects.
Methods:
Forty adult ASA Grade I and II patients of either sex posted for lower abdominal and lower
extremity surgeries were randomly divided equally in to clonidine or control group.
Control group received intrathecal 3.5ml of 0.5% hyperbaric bupivacaine with 0.5 ml of normal
saline and Clonidine group received identical volume of intrathecal clonidine 1 µg/kg with 0.5%
hyperbaric bupivacaine.
Results:
Average two level regression time (129.55 min) was significantly prolonged in clonidine group
than in the control group (74.5 min). (p-value < 0.01) Mean time for post operative analgesia was
significantly longer in clonidine group (8.8 hours) than in the control group (4.1 hours). (p-value <
0.01). Heart rate at 15 minute intervals compared to 2 minute intervals was significantly less in
clonidine group. ( p-value < 0.05). Bradycardia, hypotension, urinary retention and headache did
not require any therapeutic intervention
Conclusion:
Adding clonidine 1 µg/kg to intrathecal bupivacaine prolongs the duration of spinal anaesthesia
and analgesia. It is safe and is likely to be as effective as higher doses of bupivacaine without
severe adverse effects.
Spinal anaesthesia has increasingly become the
technique of choice for lower abdominal and
lower extremity surgeries due to quick onset and
effective sensory and motor blockade and ease of
administration. To overcome its disadvantage of
limited duration of anaesthesia and analgesia,
various adjuvant drugs (opioids, benzodiazepines,
ketamine, or neostigmine) have been used which
have their own side effects. In our study the α
2
-
adrenergic agonist clonidine which has the ability
17
to potentiate the effects of local anaesthetics
1-3
has
been used as an adjuvant . Unlike spinal opioids,
clonidine does not produce pruritus or respiratory
depression but prolongs the sensory blockade
2, 4
and reduces the amount or concentration of local
anaesthetic required to produce postoperative
analgesia
5, 6
. The aim of this randomized double-
blinded controlled study was to investigate the
effect of addition of clonidine to hyperbaric
bupivacaine 0.5%, for spinal anaesthesia in
patients undergoing lower abdominal and lower
limb surgeries on analgesic efficacy, quality of
block, duration of analgesia and adverse effects.
Materials and Methods
After approval from the hospital ethical
committee, this study was carried out in 40 adult
ASA Grade I and II patients of either sex posted
for lower abdominal and lower extremity
surgeries. Excluding criteria were: systemic
disorders like diabetes mellitus, hypertension,
heart disease, allergy to bupivacaine or clonidine
and all known contraindications for spinal
anaesthesia, such as spine deformity, increased
intracranial pressure, neurological disorders,
haemorrhagic diathesis, or infection at the
puncture site. A double-blind, randomized,
placebo-controlled study design with two parallel
groups was used. After valid informed written
consent selected patients were randomly allocated
to two groups by lottery method.
Clonidine group: 3.5ml Bupivacaine (0.5%) + Inj
Clonidine 1mcg/kg (Preservative free) + normal
saline to make the volume 4ml intrathecally
Control group: 3.5 ml Bupivacaine (0.5%) + 0.5
ml Normal Saline intrathecally
Both the patient and anesthesiologist were blinded
to the study solutions. Syringes were prepared
immediately before the spinal injection ensuring
the volumes at 4ml by a third person other than the
anaesthesiologist who administered the drugs
intrathecally and later on did the parameter
assessment. This third person only did the random
allocation and he knew the status of
experiment/control of the patient to unblind the
status in case of an emergency. Sedatives and
hypnotics were avoided during the pre operative
and intra operative period. Intravenous line was
secured with a 20 G cannula and all patients were
preloaded with Ringer Lactate solution at 10ml/kg.
Lumbar puncture was done in the sitting position
under aseptic conditions in the L3-L4 space with a
26G Quincke needle. Intrathecal study drug was
injected and patient was placed in the supine
position. The time at which the intrathecal
injection was completed was considered as zero.
Noninvasive arterial blood pressure, heart rate, and
oxygen saturation assessed at zero time and every
2 minutes for the first 10 minutes after spinal
injection, and thereafter, every 5 minutes during
the surgery.
The level of sensory blockade was tested by
pinprick method in midline and the motor
blockade was tested with the modified Bromage
scale used by Breen et al
7
. The time of onset and
time of peak sensory and motor block, time to
regression of sensory block by two dermatomes,
time to full recovery of motor block, level of intra
operative sedation and time to first rescue
analgesic were recorded. Hypotension, defined as
a decrease of systolic blood pressure of more than
20% from baseline, was treated with metaraminol
and bradycardia, defined as a heart rate decrease
of more than 20% from baseline was treated with
atropine. For rescue analgesia Inj tramadol 100mg
or Inj diclofenac sodium 75 mg was given.
The various data obtained, which included
different parameters measured at different time
intervals, were calculated and compared with
baseline values within each group as well as with
corresponding times among groups using
independent t test. For comparison of
complications in the two groups chi
2
test was
used. A ‘p’ value <0.05 was taken as significant.
The sample size was not calculated before the start
of the study and number of patients to be studied
in the trial was based on previous literature.
4, 8
Post-hoc power analysis was carried out for “two
segment regression time in minutes” and “time for
first rescue analgesia in hours.” Estimated power
for two-sample comparison of means was 1.00.
Results
The patients’ characteristics are shown in Table I.
There is no significant difference in the two
groups. (p-value > 0.05)
18
Table I: Demographic characteristics
Parameter Clonidine group
(n=20)
Mean ± SD
Control
group (n=20)
Mean ± SD
Age (yrs) 38.15 ± 12.89 38.2 ± 11.00 *
Weight (kg) 54.3 ± 8.81 56.85 ± 7.12 *
Sex (M:F) 10 : 10 7 :13
ASA I : II 17 :3 17:3
* p-value > 0.05 ** p-value significant at
0.05; *** p-value significant at 0.01
Table II compares the time for onset and peak of
sensory and motor blockade in both groups. Time
required for onset of sensory and motor blockade
was similar in both groups. Peak sensory blockade
was delayed in clonidine group than control group,
but the time required for peak motor blockade was
similar in both groups. Average two level
regression time (129.55 min) was significantly
prolonged in clonidine group than control group
(74.5 min). (p-value < 0.01)
Mean time for post operative analgesia was
significantly longer in clonidine group (8.8 hours)
than control group (4.1hour)(p-value < 0.01)
Table II: Analysis of Sensory, Motor blockade
and Duration of analgesia
Parameter Clonidine
group (n=20)
Mean ± SD
Control group
(n=20)
Mean ± SD
Time in seconds for
onset of sensory
blockade
70.35 ± 16.56 71.05 ± 16.85 *
Time in seconds for
onset of motor
blockade
113.7 ± 28.16 118.1 ± 22.06 *
Time in minutes for
peak of sensory
blockade
5.015 ± 0.81 4.3 ± 0.78 ***
Time in minutes for
peak of motor
blockade
7.27 ± 1.63 8.25 ± 1.91 *
Two segment
regression time in
minutes
129.55 ± 14.55 74.5 ± 7.16 ***
Time for first rescue
analgesia in hours
8.8 ± 1.9 4.1 ± 0.6 ***
* p-value > 0.05 ** p-value
significant at 0.05; *** p-value significant at
0.01
Table III compares heart rates, systolic and
diastolic blood pressure in both groups at different
time intervals. Both groups are comparable
regarding systolic and diastolic blood pressure at
all time except at sixty minutes. Heart rate at 15
minutes compared to 2 minutes is significantly
less in clonidine group (p-value < 0.05). Mean
heart rate was significantly higher at the end of
surgery in control group, than in clonidine group.
(p-value < 0.01) It was more or less stable at lower
levels throughout in the clonidine group.
Table III: Analysis of heart rate, systolic and
diastolic blood pressure
2
Min
15
Min
30
Min
45
Min
60
Min
90
Min
120
Min
Measured at
time interval
from the start
of intrathecal
block
Mea
n ±
S.D.
Mea
n ±
S.D.
Mea
n ±
S.D.
Mea
n ±
S.D.
Mean
±
S.D.
Mea
n ±
S.D.
Mea
n ±
S.D.
Clon
idine
grou
p
82.8
±
12.4
4
76.1
5 ±
12.1
3**
75.8
5 ±
15.9
3
72.6
±
12.4
8
74.32
±12.7
6
75.1
8 ±
12.1
8
71.8
±
5.31
Heart
Rate
per
min.
Cont
rol
grou
p
86.5
5 ±
10.0
1*
82.8
5 ±
15.9
3*
76.6
±
13.1
9*
71.4
5 ±
12.3
6**
78.17
***
±
12.94
77.0
5 ±
8.92
**
78 ±
6.78
***
Clon
idine
grou
p
122.
65 ±
13.7
109.
5 ±
13.5
1
106.
95 ±
13.4
6
100.
35 ±
13.2
100.6
3
±13.8
3
107
.82
±
12.1
6
101.
94
±14.
00
Sys.
Blood
Pres.
mm
of Hg
Cont
rol
grou
p
117.
9
±
16.3
9*
105.
65 ±
13.4
1*
105.
05 ±
14.2
0*
107
±
14.0
3*
109.7
8
±
12.94
***
115.
87 ±
10.9
9*
115.
5
±
18.2
8*
Clon
idine
grou
p
73.2
5 ±
8.6
65.2
8 ±
7.99
64.5
5 ±
12.3
3
61.3
±
11.7
63.12
±13.0
2
65.8
8 ±
12.4
4
58.4
±
7.7
Diast.
Blood
Pres.
mm
of Hg
Cont
rol
grou
p
70.0
5
±
14.8
*
60.9
5
±
11.1
4*
62.5
±
12.4
2*
65.1
±
9.46*
67.33
±
7.45*
71.4
7 ±
9.07
*
72.5
±
9.57
*
* p-value > 0.05 ** p-value
significant at 0.05; *** p-value significant at
0.01
Table IV shows the incidence of complications in
both groups which were not serious enough to
warrant any intervention. There was no morbidity.
19
Table IV: Complications
Complications
Clonidine Group
(n = 20)
Control Group
(n = 20)
Bradycardia
#
5 (25%)
3 (15%)
Hypotension 4 (20%) 2 (10%)
Urinary Retention 2 (10%) 0 (0%)
Position-dependent
headache
0 0
# data are number of cases and percentage of
total.
There was no significant difference between the
groups. (p-value > 0.05)
Patients from clonidine group were found to be
more sedated but respiratory depression was not
observed.
Respiratory rate and oxygen saturation(SpO
2
)
were similar in both groups.
Discussion
Clonidine is now an acceptable adjuvant to local
anaesthetics for epidural route
1
; nevertheless
clinical trials provide evidence that less clonidine
is needed intrathecally than epidurally to produce
the same analgesic effect with fewer side effects
2
.
Hypotension was less pronounced after intrathecal
than oral clonidine
3
. Intrathecal clonidine has been
used to enhance postoperative analgesia in
cesarean deliveries, repair of femoral fractures,
and ambulatory knee arthroscopy
2-6
. According to
Niemi L
7
marked haemodynamic changes and
sedation, limits the usefulness of intrathecal
clonidine. He used very high doses (3µg/kg) of
clonidine. van Tuijl I et al
8
used very low doses of
intrathecal Clonidine (15 µg) with satisfactory
outcome. Their patients were for inguinal
herniorrhaphy and knee arthroscopy. We included
lower abdominal surgeries in our study and so we
decided to use low dose(1µg /kg) similar to
Kaabachi O et al
9
. Time required for onset of
sensory and motor blockade and peak motor
blockade was found to be similar in both groups in
our study. Though peak sensory blockade was
found to be delayed in clonidine group it has very
little clinical significance. Similar to many other
studies
9, 10
We also found that addition of 1 µg/kg
of clonidine to 0.5% bupivacaine significantly
prolongs the block (average two level regression
time, clonidine : control =129.55 : 74.5 min ) and
postoperative analgesia (8 to 10 hrs) and thus
reduces the postoperative analgesic requirement.
De Negri P et al
11
observed minimal influence on
haemodynamic parameters with 105 micrograms
of intrathecal Clonidine. We also found both
groups comparable with regard to systolic and
diastolic blood pressure at almost all time
intervals. Though heart rates started dropping in
Clonidine group after 15 minutes, maximum being
after 45 minutes, bradycardia was never severe to
be a cause for concern. In conclusion, the present
study indicates that adding clonidine 1 µg/kg to
intrathecal bupivacaine prolongs spinal
anaesthesia and the duration of analgesia. It is safe
and is as effective as bupivacaine in higher dosage
without severe adverse effects.
References
1. Persec, J., Z. Persec, and I. Husedzinovic,
Postoperative pain and systemic inflammatory
stress response after preoperative analgesia with
clonidine or levobupivacaine: a randomized
controlled trial. Wien Klin Wochenschr, 2009.
121(17-18):558-63.
2. Filos KS, G.L., Patroni O, Polyzou V., Intrathecal
clonidine as a sole analgesic for pain relief after
cesarean section. Anesthesiology. 1992 ;77(2):267-
74.
3. Dobrydnjov I, A.K., Samarütel J, Holmström B.,
Postoperative pain relief following intrathecal
bupivacaine combined with intrathecal or oral
clonidine. Acta Anaesthesiol Scand. 2002
;46(7):806-14.
4. De Kock, M., et al., Intrathecal ropivacaine and
clonidine for ambulatory knee arthroscopy: a dose-
response study. Anesthesiology, 2001. 94(4):574-8.
5. Elia N, C.X., Mazza C, Schiffer E, Tramèr MR.,
Clonidine as an adjuvant to intrathecal local
anesthetics for surgery: systematic review of
randomized trials.
Reg Anesth Pain Med. 2008;33(2):159-67.
6. van Tuijl I, van der Werff DB, Kalkman CJ., The
effect of addition of intrathecal clonidine to
hyperbaric bupivacaine on postoperative pain and
morphine requirements after Caesarean section: a
randomized controlled trial. Br J Anaesth. 2006;
97(3):365-70.
7. Niemi L, Effects of intrathecal clonidine on
duration of bupivacaine spinal anaesthesia,
haemodynamics, and postoperative analgesia in
patients undergoing knee arthroscopy.
Acta Anaesthesiol Scand. 1994 ;38(7):724-8.
8. van Tuijl, I., et al., Intrathecal low-dose hyperbaric
bupivacaine-clonidine combination in outpatient
knee arthroscopy: a randomized controlled trial.
Acta Anaesthesiol Scand, 2008. 52(3):343-9.
20
9. Kaabachi O, Z.A., Ouezini R, Abdelaziz AB,
Chattaoui O, Kokki H., Clonidine
1 microg/kg is a safe and effective adjuvant to
plain bupivacaine in spinal anaesthesia in
adolescents. Anesth Analg. 2007;105(2):516-9.
10. Santiveri, X.A., A.; Plaja, I.; Metje, M. T.;
Martínez, B.; Villalonga, A.; López, M.,
Anaesthetic and postoperative analgesic effects of
spinal clonidine as an additive to prilocaine in the
transurethral resection of urinary bladder tumours.
European Journal of Anaesthesiology: 2002 ;19:
589-593.
11. De Negri P, B.F., Salvatore R, Visconti C, De Vivo
P, Mastronardi P, Spinal anaesthesia with clonidine
and bupivacaine in young humans: interactions and
effects on the cardiovascular system. Minerva
Anestesiol. 1997;63(4):119-25.
************************************************************
THE COLLEGE OF ANAESTHESIOLOGISTS OF SRI LANKA
LECTURE DEMONSTRATION & CERTIFICATION
ON
Cardio Pulmonary Resuscitation
Venue - Trauma Lecture Hall
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Date - on Tuesdays
Time - 9.00 am
Conducted by
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Consultant Anaesthetist, NSU
Contact
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