Open Journal of Anesthesiology, 2019, 9, 83-98

http://www.scirp.org/journal/ojanes
ISSN Online: 2164-5558
ISSN Print: 2164-5531

A Comparative Study of Intrathecal Injection of

Bupivacaine Alone or with Fentanyl, Clonidine,
and Neostigmine in Lower Abdominal Surgeries

Elsayed Mohamed Abdelzaam* , Ahmed Hamdy Abd Elrahman

Department of Anesiology, Faculty of Medicine, Benha University, Benha, Egypt

How to cite this paper: Abdelzaam, E.M. Abstract

and Elrahman, A.H.A. (2019) A Compara-
tive Study of Intrathecal Injection of Bupi- Background: Anesthesiologists are responsible for the development of pain
vacaine Alone or with Fentanyl, Clonidine, services in the current era. Hence ideal adjuvants that can be used with bupi-
and Neostigmine in Lower Abdominal
vacaine for stable intraoperative conditions and prolonging the postoperative
Surgeries. Open Journal of Anesthesiology,
9, 83-98. analgesia with fewer side effects are being investigated. Opioids, despite use-
https://doi.org/10.4236/ojanes.2019.94009 ful as adjuvants, are associated with undesirable side effects. Aim of the
work: The study was done to compare analgesic efficacy and hemodynamic
Received: March 19, 2019
of intrathecal injection of bupivacaine alone or with fentanyl, clonidine, and
Accepted: April 27, 2019
Published: April 30, 2019
neostigmine in lower abdominal surgeries, over the first 24 postoperative
hours, in a randomized, double-blind, and clinical trial. Methods: 100 Pa-
Copyright © 2019 by author(s) and tients were randomized into four equal groups, 25 patients in each group;
Scientific Research Publishing Inc.
Group B patients received 2.5 ml of 0.5% hyperbaric bupivacaine and 0.5 ml
This work is licensed under the Creative
Commons Attribution International
of normal saline. Group BF patients received 2.5 ml of 0.5% hyperbaric bupi-
License (CC BY 4.0). vacaine with (25 mics) of fentanyl. Group BC patients received 2.5 ml of 0.5%
http://creativecommons.org/licenses/by/4.0/ hyperbaric bupivacaine with 0.5 ml (75 mics) of clonidine. Group BN patients
Open Access received 2.5 ml of 0.5% hyperbaric bupivacaine with 0.1 ml of neostigmine
(50 mics) and 0.4 ml of normal saline. Intrathecal anesthesia was done with a
recording of parameters intraoperative and the post-operative period. Each
patient was assessed for hemodynamic parameters and effective analgesia in
operation, and presence of complications (nausea, vomiting, sedation and
pruritus) visual analogue pain score (VAS) postoperatively by a blinded in-
vestigator in the post-anesthesia care unit (PACU) and at 1, 2, 3, 4, 8 12, 18
and 24 h postoperatively. Results: The postoperative analgesia is more effec-
tive with group BC (the gold standard) than group B, group BF, and group
BN. As regard complications during the study in all groups, complications as
nausea, and vomiting were mainly with group BN; hypotension was primarily
in group BC. Conclusion: Bupivacaine clonidine, bupivacaine neostigmine,
and bupivacaine fentanyl intrathecal anesthesia produced a longer duration

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E. M. Abdelzaam, A. H. A. Elrahman

of postoperative analgesia after lower abdominal surgery in patients than bu-

pivacaine alone. Bupivacaine clonidine mixture had the most extended period
of analgesia, but with hypotension. So bupivacaine fentanyl mixture with
moderate duration of analgesia and minimal side effects is most safe for a pa-
tient.

Keywords
Intrathecal, Bupivacaine, Fentanyl, Neostigmine, Clonidine

1. Introduction
Transmission of pain from peripheral tissues to higher centers in the brain is
adjusted in the dorsal horn of the spinal cord. Incoming messages can be in-
creased or decreased by different transmitters derived from either primary affe-
rent A delta and C fibers, interneurons or descending bulbospinal fibers. After
noxious stimulation, excitatory neurotransmitters are released from afferent fi-
bers. Compensatory inhibitory neurotransmitters include (norepinephrine and
acetylcholine). Therefore, an interplay between excitatory and inhibitory spinal
neuronal systems will detect the message conveyed to higher levels of the central
nervous system. Increased understanding in spinal processing of pain has to lead
to the development of specific drugs that inhibit pain transmission without mo-
tor blockade [1].
Intrathecal opioid and local anesthetic combination are popular for analgesia
because of rapid, effective pain relief, but the duration of analgesia is limited.
This study will be done to detect whether the addition of, fentanyl and neostig-
mine to intrathecal bupivacaine will increase the length of analgesia without in-
creasing complications for patient [2].
Bupivacaine is the most commonly employed local anesthetic for a subarach-
noid block but has a limited duration of action. Perioperative hemodynamic
status is also a concern. Opioids, in spite of useful as adjuvants, are associated
with undesirable complications. Therefore, ideal adjuvants that can be used with
bupivacaine for stable intraoperative conditions and prolonging the postopera-
tive analgesia with fewer complications are being investigated [3].
Intrathecal local anesthetic acts by inhibiting voltage-gated sodium channels
in the spinal cord, which interferes with afferent and efferent sensory and motor
impulses. The degree of sensory and motor block depends on technique, agent,
and dose administered. Opioids act in the intrathecal space by activating opioid
receptors in the dorsal gray matter of the spinal cord, which adjusts the function
of afferent pain fibers [4].
Clonidine, a selective alpha two agonist agent, routinely used as a premedica-
tion for general anesthesia decreases the requirement of analgesics and anesthet-
ic drugs intraoperative. Intrathecal clonidine produces analgesia by indirectly
inhibiting the activity of wide dynamic range (WDR) neurons [5].

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 E. M. Abdelzaam, A. H. A. Elrahman

Clonidine produces spinal cholinergic activation. Cholinergic interaction in spinal

alpha two adrenergic receptors which are located on descending nor-adrenergic
pathways produces noradrenaline release that causes analgesia directly, and also
it releases acetylcholine to provide analgesia. Clonidine also has an intrinsic
block of A delta and C-fibers at lamina, utilizing that, generating analgesia [6].
Clonidine has been used by oral, epidural, spinal, perneural and parenteral
routes to achieve postoperative analgesia [7].
Neostigmine is an anticholinesterase agent which increases the acetylcholine
concentrations at cholinergic synapses. Spinal neostigmine activates descending
pain inhibitory systems that rely on a spinal cholinergic interneuron, probably
exacerbating cholinergic tonus that is already activated during the postoperative
period, and seems to be extremely efficient for soothing somatic pain [8].
But intrathecal administration of neostigmine causes well-known complica-
tions of nausea and vomiting postoperatively due to a rostral spread of neostig-
mine to brainstem site [9].

2. Subjects and Methods

2.1. Ethics Committee
After achieving approval by the Benha University Hospital Ethics Committee,
and written informed consent from the patient, this study was conducted on 100
patients their ages ranged between 18 and 65 years old, ASA grade I and ІІ of
both sexes, from February 2018 to February 2019, randomization was done into
four equal groups by lottery method. These patients were scheduled for elective
lower abdominal surgeries. All cases were done in Benha University Hospitals
after agreed consent of the patients.

2.2. Type of Study

A prospective, comparative, double-blind, randomized clinical study.

2.3. Inclusion Criteria

1) ASA physical status classes I, II.
2) Age range between 18 - 65years.
3) Type of operation lower abdominal surgeries.
4) Patients were giving valid informed consent.

2.4. Exclusion Criteria

Patient refusal:
1) Age < 18 or >65 years;
2) Infection at the site of the injection;
3) Any preexisting neurological disease;
4) The patients with a known history of allergy to local anesthetics drugs;
5) Failed spinal anesthesia;
6) Obese Patients BMI > 30;

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E. M. Abdelzaam, A. H. A. Elrahman

7) Known to be a cardiac patient;

8) Known to be a Diabetic patient;
9) Known to be Hypertensive patient;
10) Patients were receiving any anticoagulant.

2.5. Group Allocation

Patients were randomly divided into four-study groups of 25 patients each as per
computer-generated random number list. The name of the drug to be given was
sealed in envelopes numbered 1 - 100, which was opened by an anesthesiologist
not included in the intraoperative and postoperative care of the patient and pre-
pared in an unlabeled 3 ml syringe. This was then handed over to the attending
anesthesiologist in a coded form who was blind to the nature of drug given.
100 patients will be randomly divided into four equal groups:
Group I: intrathecal bupivacaine (control group) (B), Group B (n = 25) pa-
tients will receive 2.5 ml of 0.5% hyperbaric bupivacaine with 0.5 ml of normal
saline.
Group II: intrathecal bupivacaine and fentanyl (BF).
Group BF (n = 25) patients will receive 2.5 ml of 0.5% hyperbaric bupivacaine
with (25 mics) of fentanyl.
Group III: intrathecal bupivacaine and clonidine (BC).
Group BC (n = 25) patients will receive 2.5 ml of 0.5% hyperbaric bupivacaine
with 0.5 ml (75 mic) of clonidine.
Group IV: intrathecal bupivacaine and neostigmine (BN).
Group BN (n = 25) patients will receive 2.5 ml of 0.5% hyperbaric bupivacaine
along with 0.1 ml of neostigmine (50 mics) and 0.4 ml of normal saline.
They will be compared with regards to sensory characteristics, motor charac-
teristics, hemodynamic stability, and any complications.

2.6. Methodology
Anesthetic management:
All patients were evaluated one day before surgery initially by medical history
and a complete physical examination; routine preoperative investigations were
done (e.g. CBC, PT, PTT, INR, liver function tests, kidney function tests, and
ECG). Patients were instructed about the use of a visual analogue scale (VAS)
preoperatively as a tool for measuring postoperative pain.
Preoperatively adequate fasting was confirmed, and baseline heart rate and
blood pressure were noted. These patients were premedicated with tablet raniti-
dine 150 mg and after shifting the patient to the operation theater, before inser-
tion of intravenous (IV) cannula, baseline parameters such as heart rate (HR),
systolic blood pressure (SBP), diastolic blood pressure (DBP), respiratory rate
(RR), peripheral oxygen saturation (SpO2), and ECG were recorded. After
achieving an IV access, preloading was done with 10 ml/kg of lactated Ringer’s
solution over 15 - 20 min, under aseptic precautions, and the patient in setting

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position. The skin of the back of the patient was prepared with an iodine-containing
sterilizing solution, then the L3-4, L4-5 interspace was detected by palpation, as
the highest point of iliac crest is corresponding to the level with the spinous
process of the fourth lumbar vertebrae. The midline skin is anesthetized with 1%
percent lidocaine 1 ml by 25 g needle at a midpoint between the adjacent two
vertebrae. The needle was inserted and introduced under the skin until the in-
terspinous ligament was reached which was confirmed by firm resistance then
further introduced needle until passing the ligament flavum (that was detected
by sudden loss of strength) and the flow of CSF was observed, Following further
aspiration, application of the recommended intrathecal drug was made in the
selected interspace; the drug is injected slowly over 10 to 15 sec. Then the patient
was allowed to lye down in supine position with the head slightly elevated.
After the block and during the surgery, including heart rate (HR), noninvasive
arterial blood pressure, electrocardiogram (3 leads), and peripheral oxygen satu-
ration (SpaO2), a nasal cannula was applied and supplemental oxygen given
during the procedure at 3 L/min.
Sensory block was assessed bilaterally using 25 gauge hypodermic needle. The
onset of sensory block was considered as the time taken from intrathecal injec-
tion to the highest level of the sensory block. The duration of sensory block was
made from the time of intrathecal injection to regression of the level of sensory
block to L1 dermatome (level assessed by re-appearance of sensation on heel and
sole of the foot). The onset of motor block was defined as when a modified Bro-
mage score was three or lesser10. Duration of motor block was noted from onset
time to time when the patient can afford to lift the extended leg. Sensory charac-
teristics, were evaluated by using pin prick method, and motor characteristics,
were evaluated by modified Bromage scale.
The duration of complete analgesia was taken from the time of intrathecal
drug administration to the first report of pain. The duration of effective analge-
sia is from the time of intrathecal drug administration to the time of the early
supplementation with rescue analgesic. Injection diclofenac sodium 1.0 mg/kg
intravenous was the rescue analgesic given.
Surgery was allowed to commence on achieving adequate sensory block height
(T6-4). Sensory block was recorded 5, 10, and 15 min after intrathecal injection
and then, every 15 min. In the postoperative period, motor block recovery, and
sensory block regression were assessed during surgery.
Systolic blood pressure, DBP, HR, and SpO2 were recorded 5 min before in-
trathecal injection, 5, 10, 15, 20, and 25 min after intrathecal injection and then,
at 30, 60 and90 min for the duration of surgery
At the end of the operation, patients were transferred to the post-anesthesia
care unit (PACU) where monitoring was continued. Postoperatively, monitoring
of vital signs, VAS scores, and sedation scores was continued until the time of
regression of sensory block to L1 dermatome. The incidence of hypotension (ar-
terial blood pressure < 20% of baseline), bradycardia (heart rate < 50 beats/min),

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E. M. Abdelzaam, A. H. A. Elrahman

pruritus, nausea, vomiting, and urinary retention were monitored in the recov-
ery room and then transferred to the ward.
The anesthesiologist who performed subarachnoid block was not included in
the assessment of patients and observers were blinded. The Statistical software
namely SPSS 17.0, Stata 8.0, were used for the analysis of the data and Microsoft
Word and Excel have been used to produce graphs, tables, etc.
Pain scores using VAS were assessed in the PACU at 0, 1, 2, 3, 4, 8, 12, 18, and
24 h. Patients had been informed before surgery that they could request an
analgesic when they felt pain in the postoperative period. Any patient reporting
VAS ≥ 5 was administered a supplemental dose of analgesic Injection diclofenac
sodium 1.0 mg/kg IV. The total number of patients who were managed analgesic
was noted in each group. Any patient with failed spinal anesthetic or patient
complaining of pain in the intraoperative period, which required administration
of general anesthesia, was excluded from the study.
All data were analyzed using SPSS 20.0 for windows (SPSS Inc., Chicago, IL,
USA). Continuous variables were expressed as the mean ± SD & median (range),
and the categorical variables were expressed as a number (percentage). Conti-
nuous variables were checked for normality by using Shapiro-Wilk test. One way
ANOVA was used to compare normally distributed variables between four
groups while Kraskall Wallis H test was used for non-normally distributed va-
riables. Independent samples Student's t-test was used to compare two groups of
normally distributed data while Mann Whitney U test was used for non-normally
distributed data. All tests were two tailed. P-value < 0.05 was considered statisti-
cally significant (S), P-value < 0.01 was considered highly statistically significant
(HS), and P-value > 0.05 was considered statistically insignificant (NS).

3. Results
In the current study; One hundred patients were randomly divided into four
equal groups each group were 25 patients
There were no significant differences between the four groups regard to age,
height, and body mass index, sex (male or female) and ASA grade (I or II)
(Table 1).
There were significant differences detected between the four groups regard to
Onset of sensory blocks mean and stander deviation in group B 150.40 ± 28.35,
BF 137.20 ± 29.65, BC 134.40 ± 29.73, BN 120.00 ± 30.00 as a P value < 0.05 as
shown in Table 2 and Figure 1.
There were no significant differences between the four groups regard to Onset
of motor blocks means and stander deviation in group B 241.20 ± 56.52, 232.80
± 61.07, BC 234.40 ± 51.57, BN 230.40 ± 47.74 as P value > 0.05 as shown in Ta-
ble 2.
On comparing the four studied groups as regards the duration of analgesia,
There was a highly significant difference between four groups sees to duration of
analgesia being the bupivacaine clonidine the longest duration 0f analgesia as

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 E. M. Abdelzaam, A. H. A. Elrahman

Table 1. Comparison between the studied groups regarding socio-demographic data.

Total studied group n = 100

B BF BC BN F test P Value
n = 25 n = 25 n = 25 n = 25
Age
Mean ± SD 45.52 ± 8.96 43.20 ± 9.39 45.36 ± 9.15 44.12 ± 9.91 0.343 0.794NS
Height (cm)
Mean ± SD 164.36 ± 8.33 163.36 ± 8.37 163.72 ± 8.29 163.12 ± 8.00 0.066 0.978NS
BMI
Mean ± SD 28.48 ± 2.04 28.68 ± 2.59 28.56 ± 2.34 28.36 ± 3.34 0.107 0.956NS
Sex
male 16 (64%) 14 (56%) 13 (52%) 13 (52%) 0.974 0.808
female 9 (36%) 11 (44%) 12 (48%) 12 (48%) NS
ASA
I 13 (52%) 15 (60%) 18 (72%) 18 (72%) 3.886 0.692
II 12 (48%) 10 (40%) 7 (28%) 7 (28%) NS

F = ANOVA test (analysis of variance); NS = non-significant.

Table 2. Comparison between the studied groups regarding the onset of motor and sensory block.

total studied group n = 100

B BF BC BN Test F P value
n = 25 n = 25 n = 25 n = 25
Onset of sensory block/sec.
Mean ± SD 150.40 ± 28.35 137.20 ± 29.65 134.40 ± 29.73 120.00 ± 30.00 4.48 0.005NS
Onset of motor block/sec.
Mean ± SD 241.20 ± 56.52 232.80 ± 61.07 234.40 ± 51.57 230.40 ± 47.74 0.181 0.909NS

Figure 1. Comparison between the studied groups regarding a sensory level.

mean and stander deviation 238.00 ± 125.79 (Table 3).

On comparing the four studied groups as regards the conscious level at 5, 10,
and 15 minutes after block there was no significant difference among the four
groups, as P value > 0.05 (Figure 2).

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E. M. Abdelzaam, A. H. A. Elrahman

Figure 2. Comparison between the studied groups regarding analgesic requirements.

Table 3. Comparison between the studied groups regarding the duration of analgesia.

Total studied group n = 100

Test P
B BF BC BN K Value
n = 25 n = 25 n = 25 n = 25

Duration of
analgesia
(min)

Mean ± SD 60.00 ± 11.70 72.60 ± 13.93 238.00 ± 125.79 67.40 ± 15.42 53.42 <0.001HS

K = Kruskal Wallis test.

There was a highly significant difference between four groups regards to re-
quirements of analgesia, being the bupivacaine clonidine the lowest elements of
analgesia as mean and stander deviation 74.0 ± 34.4, and the most requirements
of analgesia as in group B 191.6 ± 51.3 (Figure 3).
On comparing the four studied groups as regards the visual analogue scale
(Figure 4) it showed no statistically significant difference at baseline, 1 h, and, 2
h, between 4 groups. There were significantly different at three h, and four h,
between B & BC, BF & BC, BC & BN. There was a highly significant difference at
eight h, 12 h, 18 h and 24 hours between B & BC. There was a significant differ-
ence at eight h, 12 h, 18 h and 24 hours between BF & BC, and BC & BN. There
was no statistically significant difference at 8 h, 12 h, 18 h, and 24 hours between
B & BF, B & BN, BF & BN.
On comparing the four studied groups as regards the mean arterial pressure
(Figure 5), there was no statistically significant difference at baseline, 5 min, 60
min, 90 min and 120 min postoperative.
But it showed significantly difference at:
10 min: between B & BC;
15 min: between B & BC, BF & BC, BC & BN;
20 min: between B & BC, BF & BC, BC & BN;
25 min: between B & BC, BF & BC, BC & BN;
30 min: between BF & BC, BC & BN.
But it showed a highly significant difference at:

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 E. M. Abdelzaam, A. H. A. Elrahman

Figure 3. Comparison between the studied groups regarding visual analogue scale.

Figure 4. Comparison between the studied groups regarding visual analogue scale (VAS).

Figure 5. Comparison between the studied groups regarding mean arterial blood pres-
sure (MAP).

10 min: between BF & BC;

30 min: between B & BC.
On comparing the four studied groups as regards the heart rate (Figure 6):

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E. M. Abdelzaam, A. H. A. Elrahman

Figure 6. Comparison between the studied groups regarding heart rate (HR).

There was no statistically significant difference at baseline, basal line, 5 min,

10 min, 60 min and 90 min postoperative.
But it showed a significant difference at:
15 min: between BF & BN and BC & BN;
20 min: between BF& BN, BF & BC, B & BN and B & BC;
25 min: between BF & BN, BC & BN and B & BC;
30 min: between BC & BN, and B & BC;
120 min: between B & BN;
But it showed a highly significant difference at:
15 min: between B & BN;
25 min: between B & BN;
30 min: between B & BN and BF & BN.
On comparing the four studied groups as regards to hypotension (Figure 7),
there was significant difference as P value < 0.05, group B: 4 patients, group BF:
3 patients, group BC: 6 patients, group 18 patients. High incidence occurred
with clonidine.
On comparing the four studied groups as regards vomiting (Figure 8), there
was a significant difference among the four groups as a P value < 0.05, group B: 1
patient, group BF: 2 patients, group BC: 5 patients, group 12 patients, high inci-
dence occurred with neostigmine.
On comparing the four studied groups as regards nausea (Figure 9), there was
a significant difference among the four groups as a P value < 0.05, group B3 pa-
tients, group BF: 2 patients, group BC: 6 patients, group 10 patients, high inci-
dence occurred with neostigmine.

4. Discussion
This study was held in Benha University Hospital; to compare between intra-
thecal injection of bupivacaine alone or with fentanyl, clonidine, and neostig-
mine in lower abdominal surgeries. Spinal anesthesia is a favorite anesthesia tech-
nique for lower abdominal surgeries. Even though it provides effective analgesia

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 E. M. Abdelzaam, A. H. A. Elrahman

Figure 7. Comparison between the studied groups regarding adverse effects (hypoten-
sion).

Figure 8. Comparison between the studied groups regarding adverse effects (vomiting).

Figure 9. Comparison between the studied groups regarding adverse effects (nausea).

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E. M. Abdelzaam, A. H. A. Elrahman

in the initial postoperative period, this effect is very short lasting. In the context
of “Augmentation strategies” for intrathecal analgesia, the discovery of opioid
receptors and the following development of the technique of epidural and intra-
thecal opioid administration is certainly one of the most significant advances in
pain management in the last three decades. A wide variety of non-opioids have
also been used in epidural or subarachnoid space to achieve pain relief without
the risk of respiratory depression [10] [11].
Opioid receptors were detected in the central nervous system in 1971 [12] lat-
er, in 1977; these receptors were precisely localized in the posterior horn of the
spinal cord [13]. The effectiveness of intrathecal opioids relies on their bioavai-
lability. Penetration into medullary tissue is affected by their molecular weight, a
degree of ionization, and lipophilicity. Fentanyl and pethidine are absorbed
more rapidly than morphine for these reasons. They bind more firmly to neural
tissue. Clearance depends on diffusion along the neuraxis, as well as vascular
absorption. The drug reaches the cerebellomedullary cistern via distribution
where it is absorbed by the arachnoid granulations. This is especially true in the
case of morphine.
The present study was conducted on 100 patients of both sexes 18 to 65 years
old, with ASA physical status I or II, who were scheduled for lower abdominal
procedures. All patients received intrathecal anesthesia. The patients were for-
tuitously divided into four groups:
Group I: intrathecal bupivacaine (control group) (B), group B (n = 25) pa-
tients will receive 2.5 ml of 0.5% hyperbaric bupivacaine with 0.5 ml of normal
saline.
Group II: intrathecal bupivacaine and fentanyl (BF).
Group BF (n = 25) patients will receive 2.5 ml of 0.5% hyperbaric bupivacaine
with (25 mics) of fentanyl.
Group III: intrathecal bupivacaine and clonidine (BC).
Group BC (n = 25) patients will received 2.5 ml of 0.5% hyperbaric bupiva-
caine with 0.5 ml (75 mic) of clonidine.
Group IV: intrathecal bupivacaine and neostigmine (BN).
Group BN (n = 25) patients will receive 2.5 ml of 0.5% hyperbaric bupivacaine
along with 0.1 ml of neostigmine (50 mics) and 0.4 ml of normal saline.
They were being compared with regards to sensory characteristics, motor
characteristics, hemodynamic stability, and drawbacks.
The patients and monitoring anesthesiologist were blinded to the study solu-
tions. As regards the demographic variables there was an insignificant statistical
difference among the studied groups. As sees the mean arterial blood pressure
among the four groups, there was an insignificant statistical difference at base-
line, 60, 90 and 120 minutes after the block and the statistically significant dif-
ference was found at 5, 10, 15, 20, 25 and 30 minutes after injection. The de-
crease in mean arterial blood pressure (MAP) was pronounced in group BC (bu-
pivacaine-clonidine) followed by BF (bupivacaine-fentanyl) group. It could be

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 E. M. Abdelzaam, A. H. A. Elrahman

explained as clonidine inhibits sympathetic preganglionic activity in the spinal

medulla, by means of that, producing a reduction in arterial blood pressure. The
severity of the arterial hypotension seems to be related to the level of the injection as
well as with the drug dose used. In addition, the activation of the alph2-postsynaptic
receptors in the brain stem along with the peripheral alph2-presynaptic recep-
tors contributes towards an even greater decrease in arterial blood pressure by
reducing sympathetic activity [14].
As regards the need for ephedrine, there was a statistical difference in the use
of ephedrine, among the four groups. The highest number of patients who re-
quired small titration (6 - 15 mg) of ephedrine was in (bupivacaine-clonidine)
group was 22 patients. The lowest number was in (bupivacaine-fentanyl) was
three patients
As regards the heart rate changes assessment among the studied groups, there
was an insignificant statistical decrease at baseline, 5, 10, 60 and 90 minutes after
injection. But their significant statistical reduction was noticed at 15, and 20
minutes after injection. There was highly substantial statistical decrease at 30
minutes difference was seen between BN group and the other three groups as the
heart rate decrease all over the study in Neostigmine group but, not below 70
beats/minutes and did not require any interference.
In addition, the study of heart rate inside each studied group though out the
study showed a significant decrease in the heart rate in relation to the baseline
which continued for more than 60 minutes after the block. This has appeared in
two groups BC & BN groups.
The occurrence of bradycardia was more in the neostigmine groups though
the difference was not statistically significant. All the patients responded to
intravenous atropine. Neostigmine 50 ug caused bradycardia at 60 - 70 min after
administration of spinal anesthesia and bradycardia was successfully treated with
atropine.
In view of the time for onset of sensory blockade (sec) and the duration of it
(min); in the present study, there was a statistically significant difference among the
studied groups. The more rapid onset was noticed in the (bupivacaine-neostigmine).
As neostigmine increases action of spinally administered local anesthesia, spinal
administration of neostigmine, an acetylcholinesterase inhibitor, inhibits the
breakdown of the endogenous neurotransmitter acetylcholine, thereby inducing
analgesia, hence it is another alternative nonopioid additive to local anesthetics
devoid of opioid-associated side effects. And the longest duration of sensory
blockade was noticed in the bupivacaine-clonidine) group which could be ex-
plained as clonidine produces local vasoconstriction by acting on vascular
smooth muscle (alpha receptors), which decreases absorption of local anesthetics
from subarachnoid space thereby prolongation the duration of action.
In view of the sedation scale assessment, it showed statistically insignificant
differences among the four groups. Only three patients in fentanyl group and
two patients clonidine group reached level 3, and two patients in neostigmine
group achieved level 2 sedation, and they were easily aroused. this could be ex-

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E. M. Abdelzaam, A. H. A. Elrahman

plained by the variability in length and drug response between the patients.
This was in agreement with the study of who studied the combination of in-
trathecal bupivacaine with fentanyl in different doses and found that dose of
fentanyl in a treatment of 25 ug did not produce significant sedation [15].
As regards the visual analogue score (VAS), There was a statistically signifi-
cant difference among the four groups. The most powerful analgesic agent is in-
trathecal clonidine combined with bupivacaine followed by bupivacaine-fentanyl.
There was also the time-related decrease in VAS in relation to the baseline in
each studied group (inside each group, in the four groups) started with the onset
of action of analgesia and continued throughout the time of the study.
As regards adverse effects hypotension most occurred in a group (bupiva-
caine-clonidine), nausea and vomiting most happened in a group (bupiva-
caine-neostigmine). That also is in the study done by [16]. There was significant
difference in nausea where group (bupivacaine-neostigmine) BN had the highest
incidence (10 patients) and the lowest incidence with (bupivacaine-fentanyl)
group (2 patients) the nausea was mild and responding well to the second dose
of metoclopramide 10 mg. However, in Gupta S study, hypotension in the group
receiving neostigmine 75 ug was more than the other group receiving 50 ug.
Intrathecal neostigmine causes nausea in a dose-dependent manner. This high
occurrence of nausea and vomiting could be due to cephalad migration of neos-
tigmine to the brain stem where it produces an accumulation of acetylcholine.
This increased acetylcholine leads to vomiting by stimulating the chemoreceptor
trigger zone. The injection of neostigmine in hyperbaric dextrose solution while
maintaining the patient in head up position reduces the incidence of vomiting
[17].
In another study show that the administration of intrathecal neostigmine 25
ug/kg with bupivacaine leads to increased the duration of sensory, motor block
and also time to the first rescue of analgesia compared to the control group after
lower limb surgeries [18].
This is a present study in agreement with a study done by Kothari et al., that
found 35% to 45% of patients drowsy by addition of 50ug of clonidine to bupi-
vacaine [19].
Also, this study in agreement with another research which studies the effect of
intrathecal fentanyl (12 - 25 ug) when added to different doses of bupivacaine (3
- 5 mg) in postoperative analgesia for knee arthroscopy, that found the addition
of fentanyl lead to decrease the failure rate and improve the visual analogue
score [20].

5. Conclusion
Bupivacaine-clonidine mixture had the longest duration of analgesia, but with
an increased incidence of hypotension. So bupivacaine-fentanyl mixture with
moderate duration of analgesia and fewer complications is the safest for the pa-
tients.

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 E. M. Abdelzaam, A. H. A. Elrahman

Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this pa-
per.

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