Hindawi Publishing Corporation

Journal of Anesthesiology
Volume 2016, Article ID 6148782, 6 pages
http://dx.doi.org/10.1155/2016/6148782

Clinical Study
Comparing the Analgesic Efficacy of Intrathecal
Bupivacaine Alone with Intrathecal Bupivacaine Midazolam or
Magnesium Sulphate Combination in Patients Undergoing
Elective Infraumbilical Surgery
Josef Attia, Amany Abo Elhussien, and Mostafa Zaki
Departments of Anesthesiology and ICU, Faculty of Medicine, Minia University, Minia 61111, Egypt
Correspondence should be addressed to Josef Attia; [email protected]
Received 14 October 2015; Accepted 28 January 2016
Academic Editor: Bilge Karsli
Copyright 2016 Josef Attia et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background. Spinal anaesthesia, which is one of the techniques for infraumbilical surgeries, is most commonly criticized for limited
duration of postoperative analgesia. Aim of the Work. The aim of this study was to decrease bupivacaine dose used in spinal
anesthesia in patients undergoing orthopedic lower limb surgery and reduce its possible side effects. Patient and Methods. Sixty
adult patients of both sexes, divided into three. Group C received 2.5 mL bupivacaine and 0.5 mL saline 0.9%. Group A received
2.5 mL bupivacaine and 0.5 mL midazolam. Group B received 2.5 mL bupivacaine and 0.5 mL magnesium sulphate. Results. As
regards onset of both motor and sensory blockade, there are a significant decrease in group A and a significant increase in group B
as compared to group C, with a significant decrease in duration of motor blockade and significant increase in duration of sensory
blockade in both group A and group B, respectively, as compared to group C, with a significant decrease in the duration of sensory
blockade in group B as compared to group C. Conclusions. These results suggested that intrathecal midazolam as an adjuvant for
bupivacaine increases the duration of both sensory and motor blockade more than that of magnesium sulphate.

1. Introduction
Spinal anesthesia achieved a widespread popularity as a simple and effective method of producing conduction block for
surgery in the presence of some ready available drugs, complete aseptic technique, and careful practice; subarachnoid
block provides adequate anesthesia for patients undergoing
infraumbilical surgery [1].
Among the local anesthetics, 0.5% hyperbaric bupivacaine is the most commonly used drug for spinal anesthesia;
however, the most important disadvantage of the single
injection is its limited duration [2]. Bupivacaine is a local
anesthetic of the amide type, chemically related to mepivacaine; bupivacaine, like other local anesthetics, causes a
reversible blockade of impulse propagation along nerve fibers
by preventing the inward movement of sodium ions through
the nerve membrane. Bupivacaine has a rapid onset and a
medium to long duration. The duration is dose-dependent
[3].

Midazolam exerts its effect by occupying benzodiazepine

receptor that modulates -amino butyric acid (GABA),
the major inhibitory neurotransmitter in the brain [4, 5].
The hypnotic effects of benzodiazepine are mediated by
alterations in the potential dependent calcium ion flux [4].
Midazolam also possesses anticonvulsant action which is
attributed to enhanced activity of GABA on motor circuit of
brain. It exhibits a muscle relaxant effect via its action as the
glycine receptors in the spinal cord [6]. Magnesium has analgesic properties, primarily related to the regulation of calcium
influx into cells [7] and antagonism of N-methyl-D-aspartate
receptors in the central nervous system [8]. Consequently, it
has been suggested that an intrathecal injection would allow
more effective magnesium activity at spinal cord NMDA
receptors. Indeed, rat models revealed that direct intrathecal
administration of magnesium enhances the antinociceptive
effect of opioids used in acute incisional pain [9]. The earliest
clinical trials investigating intrathecal and epidural magnesium reported an increase in the median duration of analgesia

2
[10]. The aim of the study is to decrease bupivacaine dose
used in spinal anesthesia in patients undergoing orthopedic
lower limb surgery and in turn reduce its possible side effects.
On the other hand, increase of the time is needed to the
first analgesic request; this is achieved by using adjuvant
to intrathecal bupivacaine in the form of midazolam or
magnesium sulphate.

2. Patients and Methods

After approval of the Local Ethics Committee of Minia
University Hospital, informed written consent was obtained
from patients. Our study includes 60 patients undergoing
orthopedic lower limb surgery in Minia University Hospital.
2.1. Preoperative Assessment. Full medical history and physical examination (chest, heart, abdomen, and other systems)
were carried out. Preoperative investigation was done in the
form of complete blood count, renal function tests, liver
function tests, bleeding time, clotting time, blood sugar, and
chest X-ray and ECG if needed. The patient was excluded
from the study if the patient is under 18 years old or older than
60, refused to participate, had known hypersensitivity to the
drugs and skin infection related to the site of the spinal needle
entrance, ASA III or IIIV, had vertebral column deformity,
and was pregnant.
2.2. Patients. 60 patients of both sexes are divided into three
groups (each group contains 20 patients). Group C received
2.5 mL bupivacaine and 0.5 mL saline 0.9%. Group A received
2.5 mL bupivacaine and 0.5 mL midazolam (2.5 mg) [11].
Group B received 2.5 mL bupivacaine and 0.5 mL magnesium
sulphate (50 mg) [11].
2.3. Drug Used. Bupivacaine ampule 4 mL (5 mg in each mL)
was purchased from Mylan Company, magnesium sulfate
ampule 25 mL (100 mg in each mL) was purchased from
Egypt Otsuka Pharmaceutical Co., midazolam ampule 1 mL
(5 mg in each mL) was purchased from Roche Company, and
saline 0.9% was purchased from Egypt Otsuka Pharmaceutical Co.
2.4. Anesthetic Technique. Patients were taken to the operating room where an intravenous access was assured by
inserting an intravenous cannula and all patients received
500 cc lactated Ringers solution before operation.
After that, patient was prepared to receive spinal anesthesia. An assistant helped maintaining the patient in a
comfortable curled position.
Sterilization was done by scrubbing with an antiseptic
solution and gloves up carefully and then cleaning the
patients back with the swabs and antiseptic to ensure that
gloves do not touch unsterile skin. Swab radially from the
proposed injection site and repeat several times making sure
that a sufficiently large area was cleaned.
Spinal anesthesia was given at L3/4 interspace using
standard spinal anesthesia needle 25 G 90 mm; the rate
of injection was kept 0.2 mL/second. After receiving spinal

Journal of Anesthesiology
Table 1: Bromage score.
Score
0
1
2
3

Definition
Able to raise straightened legs against resistance, no
detectable motor block.
Unable to raise straightened legs, but able to flex
knees.
Unable to flex knees, but able to flex ankle.
Unable to move hip, knee, or ankle.

anesthesia, the patient was put in supine position with head

up (30 degrees) and the level of sensory blockade was assessed
by pinprick test using visual analogue scale (VAS) and motor
blockade was assessed by Bromage scale [11]. Supplemental
oxygen was delivered via a nasal cannula just after intrathecal
injection.
2.5. Parameters Assessed: The Following
Parameters Were Assessed
2.5.1. Level of Sensory Block. Level of sensory block was
assessed by VAS using pinpricks test every minute till sensory
block occurs at the level of T10 and VAS at this level is
zero, and during the postoperative period the test was done
every 30 mins till rescue analgesia was needed. VAS score
is a tool for assessment of analgesia in the intraoperative
and postoperative period. VAS pain score is a linear pain
scoring tool ranging from 0 to 100 mm where patients marked
a circle around a point (0, 1, 2, 3, etc.) on a 10 cm scale.
Duration of analgesia was defined from the administration of
subarachnoid block till patient demand for rescue analgesia
or VAS value is greater than 40 mm, with one of them earlier
than the other [12].
2.5.2. Motor Block. Motor block was assessed by using 4point Bromage scale. Intraoperative Bromage score was performed every minute after intrathecal injection until achieving Bromage score 3 and then every 30 minutes postoperatively until achieving Bromage score 0 [13] (Table 1).
2.5.3. Hemodynamic Changes. Heart rate, blood pressure,
and oxygen saturation were assessed every 10-minute interval
till the end of surgery and postoperatively at the following
interval (every 30 minutes and then every hour until achieving VAS greater than 4 or Bromage score 3). Only hemodynamic changes that require treatment were considered significant.
2.5.4. Adverse Effects as Sedation. Sedation was assessed
according to Ramsay sedation scale [14].

3. Statistical Analysis of the Data

Data were checked, coded, entered, and analyzed by using
SPSS (the Statistical Package for Social Sciences) version 17.0
software [8]. Recorded values were presented as means
standard deviation. Statistical analysis included parametric
and nonparametric methods by one-way or two-way analysis

Journal of Anesthesiology

Group C
Group A
Group B

5 1.1
3.7 1.13a
6.6 2.7ab

112 15
253 53a
157 36ab

Data represented as mean SD, value < 0.05. a Significant changes from
group C and b significant changes from group A.

4.3. Onset and Duration of Sensory Blockade. As regards the

onset of sensory blockade, there was a significant decrease
in onset of sensory blockade in group A (3.7 1.13 min) as
compared to group C (5 1.1 min). However, a significant
increase was detected in group B (6.6 2.7 min) as compared
to group C (5 1.1 min) and group A (3.7 1.13 min).
On the other hand, there was a significant increase in
duration of sensory blockade in both group A and group
B, respectively (253 53 and 157 36 min), as compared
to group C (112 15 min) with a significant decrease in the
duration of sensory blockade group B (157 36 min) as
compared to group C (112 15 min) (Table 3).
4.4. Hemodynamic Changes. There were no significant
changes in mean arterial blood pressure (mmHg) at any time
during the study periods (preoperatively, intraoperatively,
and postoperatively) inside each group or between the three
groups (Figure 1).
4.5. Adverse Effects as Sedation. We did not detect any degree
of sedation in the three groups of our study.
4.5.1. Heart Rate. There were no significant changes in
heart rate (beat/min) at any time during the study periods

2 h postoperatively

l h postoperatively

30 min postoperatively

4.2. Onset and Duration of Motor Blockade. As regards the

onset of motor blockade, there was a significant decrease
in onset of motor blockade in group A (3.1 1.3 min) as
compared to group C (4.7 0.44 min). However, a significant
increase was detected in group B (6 2.8 min) as compared
to group C (4.7 0.44 min) and group A (3.1 1.3 min).
On the other hand, there was a significant decrease in
duration of motor blockade in both group A and group
B, respectively (162 27.3 and 126 33 min), as compared
to group C (263 48 min) with a significant decrease in
the duration of motor blockade group B (126 33 min) as
compared to group C (263 48 min) (Table 1).

80 min

4.1. Demographic Data (Patient Characteristics). There were

no statistically significant differences ( < 0.05) between
three groups as regards age, mean body mass index (Table 2).

90
80
70
60
50
40
30
20
10
0
Preoperatively

4. Results

(mmHg)

of variance (ANOVA) among the 3 different groups. Categorical data were compared using the Fisher exact test. A value
of < 0.05 was considered statistically significant.

70 min

Data represented as mean SD, value < 0.05. a Significant changes from
group C and b significant changes from group A.

Duration of
sensory blockade
(min)

60 min

263 48
162 27.3a
126 33ab

Onset of sensory blockade

(min)

50 min

4.7 0.44
3.1 1.3a
6 2.8ab

Groups

40 min

Group C
Group A
Group B

Duration of motor
blockade (min)

30 min

Onset of motor blockade

(min)

20 min

Groups

Table 3: Onset of sensory blockade and duration of sensory

blockade.

10 min

Table 2: Onset of motor blockade and duration of motor blockade.

Group A
Group B
Group C

Figure 1: Mean arterial blood pressure changes in the study group.

(preoperatively, intraoperatively, and postoperatively) inside

each group or between the three groups (Figure 2).

5. Discussion
The onset and duration of spinal anesthesia have greater concern in anesthetic practices, so many studies used midazolam
as an adjuvant to bupivacaine in spinal anesthesia [1517].
Also many studies used magnesium sulphate as an adjuvant
[1820].
As regards the duration of sensory blockade there was
a significant prolongation of sensory blockade (the duration
from the sensory block after spinal procedure determined
by VAS reaching zero value till patient demand for rescue
analgesia or VAS value is greater than 40 mm, with one of
them earlier than the other); it was significantly higher in
patients receiving midazolam as an adjuvant more than the
other two groups. This is due to the benzodiazepine receptors
which present in the spinal cord and in turn trigger the use of
intrathecal midazolam for prolongation of spinal anesthesia
[21]. In vitro autoradiography has shown that there is a high
density of benzodiazepine receptors in Lamina II of the dorsal
horn in the human spinal cord suggesting a possible role in
pain modulation [11].

Journal of Anesthesiology
88

(beat/min)

86
84
82
80
78
76

2 h postoperatively

l h postoperatively

30 min postoperatively

80 min

70 min

60 min

50 min

40 min

30 min

20 min

10 min

Preoperatively

74

Group A
Group B
Group C

Figure 2: Mean of heart rate changes in the study group.

Batra et al. [22] reported a similar finding in which

intrathecal administration of midazolam along with bupivacaine produces better postoperative analgesia and a prolonged sensory blockade. Furthermore, Kim and Lee [15]
reported that, in a meta-analysis, addition of 1 or 2 mg of
intrathecal midazolam prolonged the postoperative analgesic
effect of bupivacaine by approximately 2 h and 4.5 h, respectively, as compared to control group after hemorrhoidectomy, and this finding suggested a dose-dependent action of
intrathecal midazolam. It was reported that hemorrhoidectomy pain can be alleviated only by sacral sensory nerves.
Our patients were undergoing lower limb surgeries, and,
for effective analgesia, these patients require blockade of
lower lumber dermatomes as well. Furthermore, we found
that intrathecal midazolam at a dose of 2.5 mg significantly
prolonged the duration of motor block and in turn must be
put into consideration when early ambulation is desirable.
Bharti et al. [23] reported a prolonged sensory and motor
block following midazolam administration as adjuvant with
bupivacaine in lower abdominal surgery occurred.
Our study showed prolongation of motor and sensory
blockade in magnesium sulphate-treated group as compared
with control group although it is less than that in intrathecal
group. These midazolam-treated results are consistent with
a previous study conducted by Arcioni et al. [18]. In studies
done by Lee et al. [19] in which 50 mg magnesium sulfate
was given intrathecally to patients undergoing total knee
replacement, knee arthroscopy, and thoracic surgery they
observed that the VRS scores at first analgesic requirement
and 36 h morphine requirement were significantly lower after
intrathecal injection of magnesium sulfate, respectively, as
compared with the control group. Nath et al. [24] reported a
delay in sensory recovery and motor blockade after intrathecal magnesium sulphate and this result is in contrast to our
result with different dose.

Our result was in contrast to that of Unlugenc and

colleagues [25] who reported that in a study done on ninety
patients undergoing cesarean section there was a decrease
in the duration of analgesia with the addition of intrathecal
magnesium sulphate and this may be due to the small dose
of intrathecal bupivacaine (10 mg) used and different surgical
procedure (caesarean section) as compared with our study,
where we used 12.5 mg of heavy bupivacaine for lower limb
surgery, although their results showed a delay in the onset of
sensory and motor blockade as what we had found in our
study results. Dayioglu et al. [26] also did not report any
increase in the duration of the motor blockade in a study done
on 60 patients.
As regards the motor and sensory onset, our study results
showed a significant delay in the onset of both sensory and
motor blockade with the intrathecal magnesium sulphate.

Ozalevli
et al. [27] observed a similar delay in onset of
spinal anesthesia when they added intrathecal magnesium
sulphate to fentanyl and isobaric bupivacaine. In addition,
Malleeswaran et al. [28] reported a delay in sensory and
motor onset in a study conducted on sixty women with mild
preeclampsia undergoing caesarean section.
As regards the complications and adverse effects, we
found that both of magnesium sulphate and midazolam did
not cause any obvious side effect as hypotension, bradycardia.
In previous studies midazolam has been administered in the
dose of 1 mg, 2 mg, and 2.5 mg intrathecally [16, 29].
The safety of intrathecal magnesium administration has
been evaluated in animal and human studies. Lee et al. [19]
evaluated the safety profile of magnesium sulphate in several
experimental settings, including histopathological analysis;
thus intrathecal magnesium seems to have a good safety
profile. This is comparable to our study where there were no
side effects related to the drug.
Hemodynamic changes were assessed by frequent monitoring and recording of heart rate and blood pressure
preoperatively, intraoperatively, and postoperatively and we
found that there were no significant differences between the
study groups. The results of our study were comparable with
those of Agrawal et al. [29] and Kim and Lee [15]. Aikta et
al. [16] reported that there were no significant hemodynamic
changes in studies that used magnesium sulfate as an adjuvant
to bupivacaine in spinal anesthesia.
As regards the sedation we did not detect any degree of
sedation in the three groups of our study, and this result
was consistent with that of Chattopadhyay et al. [17] who
reported a prolongation of the sensory blockade without any
side effects when using intrathecal midazolam 2 mg with 0.5
bupivacaine.
However, it is in contrast to Yegin et al. [30] who reported
a prolonged analgesia with mild sedation in perianal cases on
using a higher dose midazolam (5 mg) and that is maybe the
cause of the sedation in their study.
As far as we could know sedation with the use of
magnesium sulphate intrathecally was not detectable in any
study done on intrathecal magnesium administration [28].
This result is the same as what we had found in our study, as
we did not detect any level of sedation with the magnesium
sulphate group.

Journal of Anesthesiology

6. Conclusion
Both of midazolam and magnesium sulphate increase the
duration of both sensory and motor blockade of spinal anesthesia when being used as an adjuvant for bupivacaine, with
less side effects. Intrathecal midazolam 2.5 mg as an adjuvant
for bupivacaine increases the duration of both sensory and
motor blockade more than that of magnesium sulphate.

7. Recommendations
Our study was limited to lower limb surgeries, so we recommend further studies on different types of operations as
caesarian sections, hysterectomy, and abdominal surgeries;
another recommendation is to compare midazolam and the
other adjuvants as opioids with the use of the different
approved doses of intrathecal midazolam.

Competing Interests
The authors declare that there are no competing interests
regarding the publication of this paper.

Authors Contributions
All authors contributed equally to the paper.

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http://www.hindawi.com

Volume 2014

Journal of

Oncology
Hindawi Publishing Corporation
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Volume 2014

Hindawi Publishing Corporation

http://www.hindawi.com

Volume 2014

Parkinsons
Disease

Computational and
Mathematical Methods
in Medicine
Hindawi Publishing Corporation
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Volume 2014

AIDS

Behavioural
Neurology
Hindawi Publishing Corporation
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Research and Treatment

Volume 2014

Hindawi Publishing Corporation

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Volume 2014

Hindawi Publishing Corporation

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Volume 2014

Oxidative Medicine and

Cellular Longevity
Hindawi Publishing Corporation
http://www.hindawi.com

Volume 2014