Intrathecal Administration of Fentanyl with Hyperbaric Bupivacaine either a Mixture or Sequentially in Elective Cesarean Section: A Randomised Single Blind Study

Abstract

Introduction: Effect of adjuvant drug’s density on local anaesthetic agent’s movement in CSF has not been studied extensively which may affect the onset, level and quality of spinal anaesthesia.
Aim: To compare intrathecal fentanyl with hyperbaric bupivacaine as either a mixture or sequentially in elective caesarean section under spinal anaesthesia.
Materials and Methods: A randomised, controlled, comparative study was done on 160 parturients scheduled for elective caesarean section from December 2018 to March 2019. Parturients were randomly allocated into two groups M and S, each having 80 parturients. Group M parturients received 7.5 mg bupivacaine heavy (0.5%) premixed with 25 μg fentanyl in the same syringe as spinal anaesthetic agents. Group S parturient received 25 μg fentanyl in the first syringe and 7.5 mg bupivacaine 0.5% in the second syringe without barbotage. Both groups were compared for block characteristics, haemodynamic changes, duration of analgesia (primary outcome) and fetal outcome, side effects (secondary outcome). Statistical analysis was done using unpaired t-test, chi square test, Fisher-exact test. The level of significance was taken as p-value

Full text

Journal of Clinical and Diagnostic Research. 2020 Jun, Vol-14(6): UC06-UC10
66
DOI: 10.7860/JCDR/2020/43916.13753
Original Article
Anaesthesia Section
Intrathecal Administration of Fentanyl with
Hyperbaric Bupivacaine either a Mixture or
Sequentially in Elective Caesarean Section:
A Randomised Single Blind Study
INTRODUCTION
Bupivacaine is the most common Local Anaesthetic Agent (LA)
used intrathecally for caesarean section [1]. Adjuvants are added,
to decrease the dose of LA, improve the quality of anaesthesia and
to prolong the duration of postoperative analgesia [2-5].
The onset, level and quality of Subarachnoid Block (SAB) depends
upon factor affecting intrathecal spread of LA [6]. Density of LA
influences its spread [7,8]. In an in-vitro study, the mean densities
of fentanyl and morphine were found to be 0.9957 and 1.0013
respectively, whereas the density of hyperbaric bupivacaine was
1.0262 [9]. The mean density of Cerebrospinal Fluid (CSF) in term
pregnant females is 1.00030 [10].
Alterations in the baricity of a solution to the extent of 0.0006 g/mL
can alter the spread of local anaesthetic solution in CSF [11]. Mixing
adjuvant during spinal anaesthesia in a single syringe before injecting
the drugs intrathecally is an usual practice, which may affect the
density of both the drugs, hence affecting their spread in CSF as well
as action [6,12,13].
Use of LA and adjuvants separately in spinal anaesthesia may have
different effects than using them as mixture. Using two separate
syringes for hyperbaric Bupivacaine & Fentanyl can minimise the
effect on density of both the drugs.
The aim of the study was to compare Intrathecal Fentanyl with
hyperbaric Bupivacaine as either a mixture or sequentially in elective
caesarean section under spinal anaesthesia in the terms of primary
objectives as block characteristics (both sensory and motor block),
haemodynamic changes {Blood Pressure (BP) and Heart Rate (HR)},
Duration of analgesia and secondary objectives as Fetal outcome
(in terms of APGAR score) side effects if any.
MATERIALS AND METHODS
With due approval from Ethical Committee (F.1/Acad/MC/
JU/18/5155, 27.03.2018) Dr SN Medical College and associated
groups of hospitals, Jodhpur (Raj) and Clinical Trials Registry India
(CTRI), a prospective, hospital based, single-blinded, randomised,
controlled, comparative study was carried out in the Department
of Anaesthesiology on patients undergoing elective LSCS. Study
period was from December 2018 to March 2019 and study carried
out in Janana wing of MDM hospital and Umaid hospital, Jodhpur.
This study is registered under the number CTRI/2018/12/016698.
Inclusion criteria: Parturients with singleton pregnancy, American
Society of Anaesthesiologist (ASA) I and II physical status, weighing
50-80 kg, height 150-170 cm were included in the study.
Exclusion criteria: Parturient with multiple pregnancies, PIH, major
systemic disease, any contraindication of SAB and having history of
hypersensitivity to LA and fentanyl were excluded from study.
A written informed consent was taken from all patients participating
in the study after complete explanation about the study protocol,
anaesthetic technique, merits and demerits of the procedure and
perioperative course of anaesthesia.
During pre-operative visits, patients detailed history, general
physical examination and systemic examination was carried out.
Basic demographic data like age, height, weight and all routine
investigations were recorded.
ANITA KANWARIYA1, CHANDA KHATRI2, SARITA JANWEJA3
Keywords: Block characteristics, Hypotension, Local anaesthetic agent, Two syringe technique
ABSTRACT
Introduction: Effect of adjuvant drug’s density on local
anaesthetic agent’s movement in CSF has not been studied
extensively which may affect the onset, level and quality of
spinal anaesthesia.
Aim: To compare intrathecal fentanyl with hyperbaric
bupivacaine as either a mixture or sequentially in elective
caesarean section under spinal anaesthesia.
Materials and Methods: A randomised, controlled, comparative
study was done on 160 parturients scheduled for elective
caesarean section from December 2018 to March 2019.
Parturients were randomly allocated into two groups M and S,
each having 80 parturients. Group M parturients received 7.5
mg bupivacaine heavy (0.5%) premixed with 25 µg fentanyl
in the same syringe as spinal anaesthetic agents. Group S
parturient received 25 µg fentanyl in the first syringe and 7.5 mg
bupivacaine 0.5% in the second syringe without barbotage. Both
groups were compared for block characteristics, haemodynamic
changes, duration of analgesia (primary outcome) and fetal
outcome, side effects (secondary outcome). Statistical analysis
was done using unpaired t-test, chi square test, Fisher-exact
test. The level of significance was taken as p-value <0.05.
Results: Hypotension was recorded in 30 patients (37.50%) in
group M and 18 patients (22.5%) in group S without significant
difference. However, early hypotension at 3 minutes and
6 minutes was significantly higher in group M than group S.
No significant difference of onset time of sensory, motor block
was found between the groups. Time to reach the highest level
of sensory and motor block was higher in group M (p<0.05).
Duration of motor block and time of 1st dose of analgesic
required (p<0.0001) were significantly higher in group S.
Conclusion: Two syringe techniques of fentanyl and hyperbaric
bupivacaine provide better quality of sensory block without
incidence of hypotension and provide prolonged post-operative
analgesia as compared to one syringe technique.

www.jcdr.net Anita Kanwariya et al., Intrathecal Administration of Fentanyl with Hyperbaric Bupivacaine
Journal of Clinical and Diagnostic Research. 2020 Jun, Vol-14(6): UC06-UC10 77
Evaluation of Block
1. Block start time (needle insertion) was recorded
2. Onset of sensory and motor block
3. Peak level of sensory block
4. Time to achieve maximum motor blockade, sensory blockade
and duration of surgical procedure was also recorded
5. Two segment regression of sensory block from peak level
6. Duration of motor block
All times were recorded after intrathecal injection of the spinal
anaesthetic drugs. Time of first analgesic requirement for post-
operative pain relief was recorded.
Spinal anaesthesia-related side-effects; nausea, vomiting,
respiratory depression, or shivering were recorded and managed.
Itching was graded and managed as: Mild, Moderate and Severe
[15]. Mild itching need no treatment, Moderate was treated with IV
Chlorpheniramine Maleate, 10 mg, if not responding or in the case
of severe itching IV Naloxone was given in a dose titrated according
to the effect. Neonatal outcome was recorded in the form of APGAR
score at 1 and 5 min.
The intraoperative quality of surgical anaesthesia was estimated
using Ochsner Health System which measures patient satisfaction
in four grades: Excellent- The patient felt comfortable during
operation, no complaints; Good- A little discomfort but no need for
additive medication; Fair- Discomfort, but controlled by nitrous oxide
mask with or without fentanyl; and Poor- Unable to be controlled
even with additive medication and shift to general anaesthesia was
mandatory [16].
STATISTICAL ANALYSIS
Based on a previous study [15] using a SPSS software version 22.0
(SPSS Inc, Chicago, II, USA), the sample size in this study was 80
in each group assuming α error=0.05 and β error=0.2 or power
(1-β)=0.8(80% power and 95% confidence level) and 5% drop out.
Data were analysed using IBM SPSS. Statistics Windows, Version
20.0 (Trial version). The statistical significant difference among
groups was determined by the unpaired t-test, chi-square test
and fisher-exact test. The level of significance was set at p<0.05.
Descriptive data were presented as mean±SD. Continuous data
were analysed by student unpaired t-tests and chi-square test to
assess the statistical difference between groups.
RESULTS
One hundred and eighty parturients were assessed for eligibility,
16 did not fulfill inclusion criteria and were excluded. Four
parturients refused participation in research study. Thus, finally 160
parturients were randomised in two groups (80 in each group). All the
parturients in each group were analysed [Table/Fig-1]. Demographic
parameters such as age, height, weight and American Society of
Anaesthesiologists (ASA) status were comparable between groups
[Table/Fig-2]. All patients passed smooth intraoperative course
without complications within a mean duration range 40-55 minutes
with no significant difference between the groups [Table/Fig-2].
In this study, there was no significant difference in incidence of
bradycardia [Table/Fig-3,4]. In group M, 8 (10%) patients developed
bradycardia and in group S, 7 (8.75%) patients developed
bradycardia. All patients responded to Inj. Atropine 0.6 mg IV bolus.
Overall, hypotension was recorded in 30 patients (37.50%) in
Group M and 18 patients (22.50%) in Group S without significant
difference. Early hypotension occurred in 25 patients (31.25%) in
Group M at 3 minute and 6 minutes which was significantly higher
than those in 8 patients of Group S (10.0%) [Table/Fig-4,5].
There was no significant difference between onset time and peak
level (T4-T6) of sensory block in both the groups. Time to reach
the peak level of sensory block was significantly higher in group
On the day of surgery, in the operating room, patient was received
with fasting of at least 8 hour, monitor for HR, non-invasive BP,
electrocardiography and oxygen saturation (SpO2) was connected
and baseline parameters were recorded.
After establishing 18 gauge venous cannula, Inj. Ranitidine 50 mg
and Inj. Metoclopramide 10 mg I.V. was given. By computer
generated data, patients were randomly allocated into one of the
two groups- group M and group S.
Group M parturients received spinal anaesthesia using 7.5 mg
bupivacaine heavy 0.5% premixed with 25 µg fentanyl in the
same syringe. Group S parturients received the same medications
sequentially without premixing using two different syringes; in
the first syringe 25 µg fentanyl and in the second syringe 7.5 mg
bupivacaine 0.5% without barbotage.
Preparation of drugs and SAB was given by the same
anaesthesiologist. The vitals were recorded by another
anaesthesiologist who was unaware to the technique and the drug
used for spinal anaesthesia.
In sitting position, using all aseptic precautions, Quincke spinal
needle, 25-gauge, was inserted in the L3-4 inter-vertebral space
after checking free flow of CSF and negative aspiration of blood,
drug was injected. Timing between the first and second syringes
was kept as low as possible to prevent CSF loss with part of the
fentanyl dose. Then the parturient was asked to lie down immediately
after bupivacaine injection, 15°-20° left displacement of uterus was
done until birth of baby by keeping a wedge under the right buttock.
Vitals recorded just after the anaesthesia was considered to be at
0 time. Co-loading was done with Ringer’s lactate solution in a dose
of 15 ml/kg started as fast drip during and continued after spinal
anaesthesia. Surgery was allowed after achieving adequate level
of block (T5). In cases with failure of SAB, general anaesthesia was
given and such patients were excluded from the study.
Haemodynamic parameters such as HR, Systolic Blood Pressure
(SBP), Diastolic Blood Pressure (DBP) were monitored at every
3 minutes for initial 15 minutes, than at every 5 minute for
30 minutes, and at every 10 minutes for next 30 minutes, and at
every 15 minutes for next one hour. Every 30 minutes for next one
hour, than at 1 hour interval for next 3 hour in post-operative room.
Any episode of hypotension and bradycardia during the procedure
was noted. Hypotension (Fall in BP by >20% of baseline values) was
treated with a rapid infusion of crystalloids (200 mL) and a bolus of
Ephedrine 6 mg intravenous (IV) was administered if hypotension
persisted. Bradycardia (Fall in HR>20% of baseline values) was
treated with injection atropine 0.6 mg IV. Electrocardiogram and
oxygen saturation were monitored continuously.
Onset of Sensory block and peak level was assessed by pin prick
method using a 20 gauge hypodermic needle, after 1 minute of
SAB and every 1 minute until the level was established for four
consecutive tests, after that assessment continued until 2 segment
regression occur.
Onset of Motor block was assessed by Modified Bromage scale
[14] Time to reach Modified Bromage scale 3 is taken as motor
block onset time and assessed after 1 minute of spinal anaesthesia
and after every minute till Modified Bromage 1 block was
achieved. Duration of motor block was considered as time from
motor block onset to reach Modified Bromage scale 6. Modified
Bromage Score- Grade 1: Complete block (unable to move
feet or knee); Grade 2: Almost complete block (able to move
feet only); Grade 3: Partial block (Just able to move knees);
Grade 4: Detectable weakness of hip flexion while supine (full flexion
of knees); Grade 5: No detectable weakness of hip flexion while
supine; Grade 6: Able to perform partial knee bend.

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In the present study, there was no significant difference between onset
time of motor block in both the groups. Time to achieve complete
motor block was earlier in group S (5.33±0.98 min) than group M
(5.76±1.02 min). The p-value was 0.008, which was statistically
significant. Duration of motor block was significantly higher in group S
(182±12.42 min) than group M (156.7±12.39 min), p-value <0.0001
[Table/Fig-6]. Time to 1st dose of analgesia required was higher in
group S (304.62±25.89 min) as compare to group M (283.37±28.37
min). It was statistically significant, p-value <0.0001 [Table/Fig-6].
There was no significant difference in the incidence of itching and
nausea /vomiting [Table/Fig-4]. In this study, 37.50% patients in
group S labeled the effect as excellent and they would prefer this
technique in future, whereas 12.50% patients in group M labeled
it excellent. The difference in both the groups was found to be
statistically significant (p<0.001) [Table/Fig-7].
There was no significant difference in the APGAR Score at 1 minute
and 5 minute in both the groups [Table/Fig-8].
[Table/Fig-1]: Consort fiow diagram.
Parameter Group M Group S p-value
Age (years)
(Mean±SD†)24.66±3.39 25.13±3.87 0.410
Weight (kg)
(Mean±SD†)65.45±3.95 64.27±4.28 0.073
Height (cm)
(Mean±SD†)157.16±4.05 157.29±4.21 0.844
Duration of surgery (minutes)
(Mean±SD†)45.31±5.75 45.26±5.86 0.956
ASA* grading
ASA I (%) 85.00 88.75 >0.05
ASA II (%) 15.00 11.25 >0.05
[Table/Fig-2]: Demographic parameters in both groups.
†SD: Standard Deviation; *ASA: American society of anaesthesiologist
[Table/Fig-3]: Comparison of Heart Rate (HR) in both groups.
Complications
Group M Group S p-
value*N % N %
Hypotension
Early (within 10 min) 25 31.25 8 10.0 <0.05
Overall 30 37.50 18 22.50 0.501
Bradycardia 8 10.00 7 8.75 1.000
Nausea/Vomiting 12 15.00 8 10.00 0.474
Itching 16 20.00 20 25.00 0.57
[Table/Fig-4]: Comparison of side effects, *By Fischer-exact test (level of significance
at p<0.05).
[Table/Fig-5]: Comparison of Mean Arterial Pressure in both groups.
M (4.95±1.10 min) as compared to group S (4.56±1.68 min), with
range of time between 3-8 minute. Time for 2 segment regression
from peak sensory block was higher in group S (143.75±11.4 min)
as compared to group M (107.6±7.55 min) that was statistically
significant (p<0.0001) [Table/Fig-6].
Parameter
Group M
(Mean±SD)
Group S
(Mean±SD) p-value
Onset time of sensory block (minutes) 1.02±0.09 1.00±0.10 0.083
Onset time of motor block (Min) 2.02±0.63 1.98±0.64 0.711
Time to reach peak level of sensory
block (Min) 4.95±1.10 4.56±1.68 0.032
Duration of motor block (Min) 156.7±12.39 182±12.42 <0.0001
Duration of sensory block (Min) 283.37±28.37 304.62±25.89 <0.0001
Two segment regression time for
sensory block (Min) 107.6±7.55 143.75±11.40 <0.0001
Peak level of sensory block
T4 (%) 31.25 32.50
0.911T5 (%) 51.25 52.50
T6 (%) 17.50 15.00
[Table/Fig-6]: Comparison of block characteristics in both groups.
†SD: Standard Deviation; *ASA: American society of anaesthesiologist; level of significance at p<0.05
Satisfaction score
Group M Group S
N % N %
Poor 0 0.0 0 0.0%
Fair 28 35.00 19 23.75
Good 42 52.50 31 38.75
Excellent 10 12.50 30 37.50
Total 80 100.00 80 100.00
[Table/Fig-7]: Comparison of patients satisfaction score.
Time
APGAR score
t-value p-valueGroup M (Mean±SD) Group S (Mean±SD)
1 min 8.87±0.46 8.78±0.60 1.024 0.307
5 min 9.37±0.48 9.27±0.52 1.246 0.214
[Table/Fig-8]: Comparison of APGAR score in both groups.

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Journal of Clinical and Diagnostic Research. 2020 Jun, Vol-14(6): UC06-UC10 99
DISCUSSION
The present study aimed to compare effects of fentanyl and hyperbaric
bupivacaines sequentially versus as a mixture in single syringe in
Caesarean section. Intrathecal injection of Fentanyl and hyperbaric
Bupivacaine sequentially provided better quality of sensory block and
less frequency of hypotension in comparison to when used as a mixture.
Time to reach the peak level of sensory, motor block was higher in
group M. Two segment regression of sensory block, time to first rescue
analgesia and duration of motor block was higher in group S.
As regards the outcome incidence of hypotension at 3 and
6 minutes after administration of drug was less in group S than
group M [Table/Fig-5]. The mixture of hypobaric fentanyl and
hyperbaric bupivacaine sinks down when patient is in sitting
posture, but when patients lies down, both the drugs creep up
together and act at same level; hence the early hypotension in
group M. When used sequentially, hyperbaric bupivacaine being
denser than fentanyl, sinks more to a lower level and takes a
longer time to reach the final level; hence the delayed onset of the
sympathetic block giving time for a compensatory mechanism to
prevent hypotension. This delaying of onset of sympathetic block
match the results of other studies [15,17-19] which concluded that
isobaric bupivacaine produced more rapid onset of hypotension
compared to hyperbaric bupivacaine.
In this study, mean time to onset of sensory and motor block was
lesser in group S than group M that was statistically not significant
[Table/Fig-6]. Keera AAI and Elnabtity AMA, found similar result
in their study [15]. Sachan P et al., did the same study but with
clonidine instead of fentanyl and concluded that onset of sensory
and motor block was faster with separate injection group than with
mix injection group, but was not statistically significant [13]. Joshi
P et al., Bansal N and Ladi SD have done similar study but found
significant difference [17,20].
Mean time to peak sensory block level and to complete motor
block was higher in group M than group S, which was statistically
significant in present study [Table/Fig-6]. This difference might be
due to the preferential cephalad spread of fentanyl because of its
hypobaric nature which is lost when the drugs are premixed. Desai S
et al., also observed that the time to reach highest level of block was
less when Morphine and Fentanyl were administered sequentially
with spinal anaesthesia than when given as a mixture [12]. Similar
results were found in some other studies too [13,21].
Mean time to segment regression of sensory block and total duration
of motor block observed were less in group M than group S, that
were statistically highly significant in the present study [Table/Fig-6].
Mean time to 1st rescue analgesia was required early in group M
(283.37±28.37 minute) than group S (304.62±25.89 minute), which
was statistically highly significant. (p<0.0001) This difference might be
due to the fact that injecting Fentanyl and Bupivacaine as a mixture
dilutes Fentanyl and receptor occupancy might decrease leading to
less pronounced effect. And if Fentanyl is administered separately
a greater spread and therefore formation of stronger bonds with
the receptor leading to a denser and prolonged block may occur.
This was supported by observations of Desai S et al., Gray JR et
al., as they also found that duration of analgesia is increased when
intrathecal morphine is administered with normal saline (hypobaric)
than with dextrose saline (hyperbaric) [12,22]. Deshpande JP et
al., and Thakur A et al., also reported that duration of analgesia is
longer when clonidine is used sequentially than when it was given in
mixture with hyperbaric Bupivacaine in other surgery like lower limb
surgery and inguinal herniorrhaphy [23,24]. Result of this study also
coincide with previous studies [17,20,21].
In this study, the incidence of itching, nausea/vomiting, respiratory
depression, bradycardia were not statistically significant between
the groups [Table/Fig-3,4]. The present results are in line with other
studies [15,17,21].
In this study, 37.50% patients in group S labeled the effect as
excellent and they would prefer this technique in future whereas
12.50% patients in group M labeled it as excellent. The difference
in both the groups was found to be statistically significant (p<0.001)
[Table/Fig-7]. In other studies VAS score was used [15,17,21].
The APGAR score in this study were statistically comparable in both
groups and similar to other studies [15,17,21].
Limitation(s)
The temperature and rate of the injected drug was not recorded as
it affects the spread of drugs.
CONCLUSION(S)
Two syringe techniques of fentanyl and hyperbaric bupivacaine
provide significant improvement in the quality of sensory block
without incidence of hypotension and provide prolonged post-
operative analgesia as compared to one syringe technique.
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Journal of Clinical and Diagnostic Research. 2020 Jun, Vol-14(6): UC06-UC10
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PARTICULARS OF CONTRIBUTORS:
1. Resident, Department of Anaesthesiology, Dr S N Medical College, Jodhpur, Rajasthan, India.
2. Associate Professor, Department of Anaesthesiology, Dr S N Medical College, Jodhpur, Rajasthan, India.
3. Senior Professor, Department of Anaesthesiology, Dr S N Medical College, Jodhpur, Rajasthan, India.
PLAGIARISM CHECKING METHODS: [Jain H et al.]
• Plagiarism X-checker: Feb 12, 2020
• Manual Googling: Apr 06, 2020
• iThenticate Software: May 14, 2020 (25%)
ETYMOLOGY: Author Origin
NAME, ADDRESS, E-MAIL ID OF THE CORRESPONDING AUTHOR:
Chanda Khatri,
B-40, IInd Floor, Parshwanath City, Sangariya, Jodhpur, Rajasthan, India.
E-mail: chandakhatri90@gmail.com
Date of Submission: Feb 11, 2020
Date of Peer Review: Mar 26, 2020
Date of Acceptance: May 02, 2020
Date of Publishing: Jun 01, 2020
AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? Yes
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. NA
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