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1]

Original Article

Efficacy of Magnesium Sulphate and/or Fentanyl as Adjuvants to

Intrathecal Low‑Dose Bupivacaine in Parturients Undergoing Elective
Caesarean Section

Abstract Shelly Rana,

Background and Aim: Recent developments in the field of intrathecal adjuvants have led to Dheeraj Singha,
accelerated functional recovery with adequate postoperative analgesia following caesarean section. Sudarshan Kumar,
Encouraging results have been obtained with the use of intrathecal magnesium with or without
fentanyl in parturients. This study was conceived to evaluate the effects of adding magnesium Yuvraj Singh,
sulphate and/or fentanyl to low‑dose intrathecal bupivacaine in parturients undergoing caesarean Jai Singh,
section under subarachnoid block  (SAB). Materials and Methods: Ninety, American Society R K Verma
of Anesthesiologists I or II, parturients for the elective caesarean section were enrolled in this Department of Anaesthesia,
prospective randomized, double‑blind study. The parturients were randomly assigned to three groups. DRPGMC, Kangra,
In Group M, parturients received 8.5 mg (1.7 mL) hyperbaric bupivacaine 0.5% with 50 mg (0.1 mL) Himachal Pradesh, India
magnesium sulphate and 0.4  mL normal saline. Group  F received 8.5  mg hyperbaric bupivacaine
0.5% with 20 µg (0.4 mL) fentanyl and 0.1 mL of normal saline and Group MF parturients received
8.5  mg hyperbaric bupivacaine 0.5% with 20  µg fentanyl added to 50  mg magnesium sulphate.
Results: Parturients in the group  MF were pain free for longest period  (273.70  ±  49.30  min) as
compared to group  M  (252.67  ±  40.76  min) and group  F  (239.80  ±  38.45  mins)  [gp MF vs F and,
gp M vs F  (P  =  0.00)]. The total doses of rescue analgesics were least in group  MF  (2.43  ±  0.56)
and maximum in group  F  (3.30  ±  0.63), with comparable neonatal outcomes in three groups.
Conclusion: Our data supports synergistic action of intrathecal magnesium sulphate to fentanyl,
and it is concluded that on addition of intrathecal magnesium sulphate and fentanyl to low‑dose
bupivacaine as adjuvant in subarachnoid block, results in prolonged duration of postoperative
analgesia with lesser pain scores and lesser dose of rescue analgesia with better haemodynamic
stability.

Keywords: Adjuvants, anaesthesia, analgesia, pain, postoperative, magnesium sulphate

Introduction benefit of an awake mother at delivery and

Changing patterns of obstetric management
and an increase in maternal requests
have contributed to the increasing rate
of caesarean delivery,[1] the incidence
ranging between 20–40%. Post‑caesarean
delivery pain relief is important as adequate
analgesia tends to enhance the mother’s
ability to optimally care for her infant in
the immediate postpartum period. Pain
relief must be safe, effective and should not
interfere with the mother’s ability to care
for her infant, with no adverse neonatal
effects[2] in breast‑feeding women.
Neuraxial anaesthesia for caesarean
delivery[3] is preferred to general
anaesthesia, because it minimizes the
risk of failed intubation, ventilation and
aspiration. Neuraxial anaesthesia has the
no anaesthetic exposure to the neonate.
Addition of opioids to intrathecally and/or
epidurally administered local anaesthetic
provides an easy and effective means to
maintain prolonged postoperative analgesia.
The combination allows for a reduction
in doses of both classes of drugs, thus
reducing the likelihood of side effects
Address for correspondence:
attributable to each.[4] Dr. Dheeraj Singha,
Recent studies suggested[5,6] that magnesium Department of Anaesthesia,
DRPGMC, Kangra,
sulphate can also play a beneficial role in Himachal Pradesh, India.
spinal anaesthesia when administered via E‑mail: dheerajsinghaa@
intrathecal route. Intrathecal magnesium gmail.com
sulphate has been shown to increase the
potency of lipophilic opioids with or without
Access this article online
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D-aspartate (NMDA)‑receptor antagonist. DOI: 10.4103/joacc.JOACC_24_16
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How to cite this article: Rana S, Singha D, Kumar S,
Singh Y, Singh J, Verma RK. Efficacy of magnesium
sulphate and/or fentanyl as adjuvants to intrathecal
low-dose bupivacaine in parturients undergoing
elective caesarean section. J Obstet Anaesth Crit
Care 2017;7:20-5.

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Rana, et al.: Intrathecal adjuvants: MgSo4 and/or fentanyl in LSCS
The present study compared the synergistic effect of
magnesium sulphate and/or fentanyl added to low‑dose
intrathecal bupivicaine 0.5%  (hyperbaric), in parturients
undergoing caesarean section under subarachnoid
block (SAB).
Material and Methods
After approval by Hospital Institutional Ethics
Committee, this prospective, randomized, double‑blind,
controlled clinical trial was conducted from May 2014
to December 2015. This study was carried out on
90American Society of Anesthesiologists  (ASA) I‑II
parturients, undergoing elective caesarean section under
SAB. Parturients refusal for block, presence of bleeding
disorders, thrombocytopenia, local infection at the site
of intrathecal injection, any history of allergy to study
drugs, parturients having pregnancy‑induced hypertension
were excluded from study. Parturient in whom the block
effect was partial and required supplementary anaesthesia,
parturients on magnesium therapy and foetal distress were
also excluded from the study.
All parturients were explained about the procedure,
advantages and risks of the procedure during the
preoperative assessment done one day prior to surgery and
then informed consent was obtained from the patient. Pain
was assessed using a verbal numeric scale  (VNS) from
0 to 10  (0  =  no pain; 10  =  maximum imaginable pain).
The parturients were randomized into three groups using
computer generated random number table.
In Group  M, parturients received 8.5  mg  (1.7  mL)
hyperbaric bupivacaine 0.5% with 50  mg  (0.1  mL)
magnesium sulphate and 0.4  mL normal saline. Group  F
received 8.5  mg hyperbaric bupivacaine 0.5% with
20  µg  (0.4  mL) fentanyl and 0.1  mL of normal saline
and Group  MF parturients received 8.5  mg hyperbaric
bupivacaine 0.5% with 20  µg fentanyl added to 50  mg
magnesium sulphate.
Random group assigned was enclosed in a sealed opaque
envelope to ensure concealment of allocation sequence.
After shifting the patient inside operation theatre, sealed
envelope was opened by anaesthesiologist not involved
in the study to prepare the drug solution according
to randomization. The observer who collected the
peri‑operative data as well as the parturients were blinded
to the drug solution administered.
All patients were kept nil orally for eight hours for solid
food and clear fluid was allowed, till two hour before the
procedure. They were given premedication in the form of
injection ranitidine 50  mg and injection metoclopramide
10  mg intravenously half an hour prior to surgery.
On arrival to operation theatre, standard monitoring
including pulse oximeter, automated blood pressure
and five lead electro‑cardiogram was commenced and
baseline parameters, i.e.,  heart rate  (HR), systolic blood
Journal of Obstetric Anaesthesia and Critical Care | Volume 7 | Issue 1 | January-June 2017
pressure  (SBP), diastolic blood pressure  (DBP), mean
blood pressure (MBP), peripheral oxygen saturation (Spo2)
were recorded. Parturients were given intravenous preload
of 10 ml/kg Ringer’s lactate solution before surgery.
Lumbar puncture was performed in the left lateral position
using a 26‑gauge quincke needle at L3‑4 interspace using
a midline approach. After free flow of cerebrospinal
fluid, the premixed solution  (2.2  mL) was injected
over  10  seconds with the needle orifice directed cephalad.
The parturients were immediately placed in supine position.
Oxygen was supplemented at the rate of 4 liters/min to the
parturients with oxygen mask.
HR, SBP, DBP and mean arterial pressure were noted at
baseline, immediately after block insertion and then every
2 min for the first 30 min and every 5 min until the end of
the surgery. Hypotension was defined as a fall in systolic
pressure  >20% below baseline and injection phenylephrine
25 µg bolus was given. Bradycardia  (heart rate  <50/min)
was treated with intravenous atropine sulphate 0.02 mg/kg.
Sensory block was assessed every minute by pinprick in
the dermatomes T‑10, T‑8 and T‑6, until a stable level of
block was achieved and surgery was permitted after T6
sensory block.
The duration of sensory block was defined as the time
from intrathecal injection to regression of the sensory
block to L1. Motor block was assessed using a modified
bromage score [0 = no motor loss; 1 = inability to flex hip;
2 = inability to flex hip and knee; 3 = inability to flex hip,
knee and ankle] with motor recovery assumed, when the
score was zero.
The duration of analgesia was defined as the period from
spinal injection to the time of administration of first
rescue analgesic for pain in the postoperative period. Pain
was assessed using a VNS from 0 to 10  (0  =  no pain;
10  =  maximum imaginable pain) every 15  min after the
block until the end of the surgery and 2, 4, 8, 12, 24  h
postoperatively. Postoperatively, intramuscular diclofenac
75  mg was given for rescue analgesia, whenever the pain
score was  >3 and second rescue analgesic in the form of
tramadol  (1  mg/kg), slow intravenously, if no relief was
achieved within 30 min of the diclofenac injection.
The incidence of side effects such as sedation, pruritus,
nausea and vomiting was noted every 15 min during surgery
and 2, 4, 8, 12 and 24 h postoperatively. Neonatal outcome
was assessed by Apgar score at 1 and 5  min and the need
for neonatal mask ventilation and tracheal intubation by a
paediatrician, unaware of the study medication.
The primary outcome included block characteristics and
duration of analgesia. The secondary outcomes were VNS
score over a period of 24  h, number of rescue analgesics,
haemodynamic stability and neonatal outcomes.
Data was collected and entered in MS Excel 2010.
Statistical analysis was performed using SPSS
21
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Rana, et al.: Intrathecal adjuvants: MgSo4 and/or fentanyl in LSCS

software 17 (SPSS, Inc., Chicago, IL). Normal 2.39  ±  0.51, 5.28  ±  1.76 and 3.46  ±  0.64  min in groups  F,
distribution of the collected data was first verified with MF and M, respectively  (P  =  0.001)  [Figure  1]. Total
the Kolmogorov‑Smirnov test. Continuous variables were duration of sensory block  (regression to T10) was
analyzed with analysis of variance or the Kruskal‑Wallis maximum in group MF (211 ± 59.67 min) and minimum in
test on the basis of data distribution. Post hoc comparisons group F (177.13 ± 62.42 min) and in group M, the duration
were performed with the unpaired Student’s t‑test or the was 192 ± 50.67 min. (P = 0.102) [Figure 2].
Mann–Whitney U‑test with Bonferroni’s correction, as
Mean duration of motor block (time taken to achieve bromage
indicated. Categorical variables were analyzed with the
0) was minimum in group  MF  (108.33  ±  29.12  min) and
contingency table analysis and the Fisher’s exact test.
maximum in group  M  (155.10  ±  59.79  min). In group  F,
P  ≤ 0.05 was considered significant. Continuous variables
this time was 148.37  ±  60.12  min  (P  <  0.001; gp M and
are presented as mean  ±  SD or median  (range) according
MF, F and MF: P =0.000, 0.002)  [Figure  2]. First rescue
to data distribution, whereas categorical variables are
analgesia was provided when the VNS score of the patient
presented as number (percentage).
was  >3 at any time in the postoperative period. Mean
Duration of analgesia was taken as the outcome measure time till requirement of first post‑operative analgesic
for the purpose of sample size calculation. It was estimated dose was minimum in group  F  (239.80  ±  38.45  min) and
that 24 subjects would be required per group in order to maximum in group  MF  (273.70  ±  49.30  min). Mean time
detect a difference of 45  min in this parameter between till requirement of first post‑operative analgesic dose was
the groups, with 80% power and 5% probability of Type  1 252.67 ± 40.76 min in group M (gp MF vs F; gp M and gp
error. This calculation assumed a pooled standard deviation F: P =0.001) [Figure 2].
of 45  min for the duration of analgesia. To account
for probable drop outs and block failure we included No parturient in any group complained of pain during
30 patients in each group. intraoperative period. In the postoperative period, pain
scores were significantly lower at 4  h in the magnesium
Results plus fentanyl group as compared to magnesium and
fentanyl group  (mean  ±  SD) 0.5  ±  0.33; 2.50  ±  1.33 and
Ninety‑eight parturients with singleton pregnancy, 3.50  ±  1.70  vs. 0.5  ±  0.33, respectively  (gp MF and F:
scheduled for elective caesarean section under SAB P  =  0.003 and MF and M: P =  0.023). Though the pain
enrolled in the study; of these eight parturients were scores at 8, 12 and 24  h were not significant, cumulative
excluded for not meeting the inclusion criteria. Thereby,
remaining 90 parturients were randomly divided into three
groups. All patients had successful spinal anaesthesia, so
no patient was excluded from the study and thirty in each
group completed the study successfully. All the parturients
were comparable to each other with respect to maternal
age, gestational age, gravida status and body mass index,
duration of surgery and ASA status [Table 1].
The median value for peak level of sensory block
was T4(T4‑T6), T4(T4‑T6) and T4(T3‑T6) in groups  M, MF
and F, respectively (P  >  0.05). Sensory block at
T10 level was achieved in minutes  (mean  ±  SD:
1.51  ±  0.39, 2.15  ±  0.74 and 1.61  ±  0.46; gp M and F,
gp F and MF: P =  0.000), respectively, in groups  F,
Figure 1: Block characteristics in three groups. Values expressed as mean
MF and M. Mean time taken to achieve adequate ± SD. *: gp M and F (P < 0.05), †: gp F and MF (P < 0.05), ‡: gp M and MF
motor block  (bromage score 3) was  (mean  ±  SD) (P < 0.05)

Table 1: Demograhic data of parturients in three groups

M (n=30) F (n=30) MF (n=30) P
Maternal Age (Yrs)* 27.17±3.51 25.33±3.70 27.33±3.85 0.072
Gestational Age (Wks)* 38.68±2.39 38.27±1.43 38.55±1.88 0.388
Gravida Status† 0.169
Primigravida 14 16 13
Multigravida 16 14 17
BMI (kg/m2)* 22.12±1.54 22.34±1.68 21.76±1.42 0.352
Duration of Surgery (mins)* 35.00±11.43 31.17±10.70 36.32±12.44 0.630
Group M=Magnesium group, Group F=Fentanyl group, Group MF=Magnesium and fentanyl group. Values expressed as mean±SD and number
as appropriate.*ANOVA (analysis of variance) ,†=Chi‑square, BMI=Basal metabolic Index

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Rana, et al.: Intrathecal adjuvants: MgSo4 and/or fentanyl in LSCS

VNS scores in the first 24  h were lower in magnesium
plus fentanyl groups than in magnesium and fentanyl
groups [Figure 3]. Mean dose of rescue analgesics required
was minimum in group  MF  (2.0  ±  0.56) and maximum
in group  F  (2.80  ±  0.63), while mean rescue analgesic
requirement was 2.50  ±  0.79 in group  M  (gp F vs MF:
P = 0.04).
Parturients were haemodynamically stable in the
perioperative period; however, the requirement of
phenylephrine was maximum in group  F  (43.3%) and
minimum in group  M  (13.3%). Total phenylephrine
requirement in group MF was (30%: gp F vs M: P = 0.02)
[Figure 4].
Neonatal outcome was comparable in the three groups,
and no baby required mask ventilation or tracheal
intubation at birth. Apgar score of newborn’s at birth,
1 min and 5 min after birth was >7 in all the study groups
(P = 0.43) [Figure 5].
Discussion
Addition of opioids to intrathecally and/or epidurally
administered local anaesthetic solutions increases the
duration of postoperative pain relief. However, the
beneficial effect of opioids is dose dependent and increased
does are associated with significant side effects.[7]
The use of intrathecal magnesium sulphate in studies,[8]
have proved its synergistic effect on lipophilic opioids
at lower doses especially in prolonging the duration of
analgesia in the postoperative period, by virtue of NMDA
receptor antagonist properties.
The present study intended to compare the synergistic effect
of magnesium sulphate, and/or fentanyl added to low‑dose
intrathecal bupivicaine  (8.5  mg) 0.5% in parturients
undergoing caesarean section under SAB.
Caesarean delivery requires traction of peritoneum
and handling of intra‑peritoneal organs, resulting in
intra‑operative visceral pain as observed by Pedersen
et al.[9] Thirty‑six parturients undergoing elective caesarean
section were given intrathecal 7.5 mg–10 mg bupivacaine in
group A and 10–12.5 mg of bupivacaine in group B on the
basis of height. The moderate to severe pain, in association
with peritoneal traction, occurred in 12  patients in
group A (70.5%), but only in 6 patients in group B (31.6%).
With higher doses of hyperbaric bupivacaine, incidence of
intra‑operative visceral pain associated is reduced, but with
adverse effects like hypotension, bradycardia and nausea.

Figure 2: Block characteristics in three groups, values expressed

as mean ± SD. *: gp M and F (P  < 0.05), †: gp F and MF (P  < 0.05),
‡: gp M and MF (P < 0.05)

Figure 3: Graphical presentation of verbal numeric score (VNS) over

a period of 24 h postoperatively. Data expressed as mean ± SD.
*: gp M and F (P < 0.05), †: gp F and MF (P < 0.05), ‡: gp M and MF (P < 0.05)

Figure 4: Phenylephrine requirement in three groups expressed

as numbers. *: gp M and F (P  < 0.05), †: gp F and MF (P  < 0.05), Figure 5: Neonatal Apgar score at 1 and 5 minute expressed as median.
‡: gp M and MF (P < 0.05) P > 0.05 in all three groups

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Rana, et al.: Intrathecal adjuvants: MgSo4 and/or fentanyl in LSCS
Bupivacaine sparing effect of intrathecal fentanyl was
studied by Choi and colleagues[10] in spinal anaesthesia
for caesarean section, and the authors concluded that the
optimal dose of hyperbaric bupivacaine to produce surgical
anaesthesia was 12  mg, which was accompanied by high
sensory block. With the addition of 10  µg of fentanyl, the
dose of bupivacaine could be reduced to 8  mg in spinal
anaesthesia for caesarean delivery.
Therefore, the addition of fentanyl in cesarean section
has become more popular, with the aim of providing
haemodynamic stability with lesser doses of bupivacaine,
and quality analgesia in the perioperative period. The
results of study by Sabin Gauchan[11] indicated that 20 μg of
intrathecal fentanyl added to hyperbaric bupivacaine (2 ml)
for spinal anaesthesia increases the duration of postoperative
analgesia, without any adverse effect on foetus and mother.
Therefore, a dose of 20 μg  (0.4  mL) fentanyl as adjuvant
to low‑dose 1.7  ml  (8.5  mg) intrathecal bupivacaine was
chosen for this study.
The dose of magnesium used in the present study was based
on data from Buvendraan et al.,[12] where 50  mg of spinal
magnesium sulphate potentiated fentanyl anti‑nociception.
In the present study, the onset of both sensory and
motor block was shorter  (mean  ±  SD: 1.51  ±  0.39;
2.39 ± 0.51 min, respectively,) in parturients, who received
fentanyl and bupivacaine, than those who received
bupivacaine and magnesium (1.61 ± 0.46; 3.46 ± 0.64 min)
and fentanyl  +  magnesium with bupivacaine  (2.15  ±  0.74;
5.28  ±  1.76  min). There was significant difference in
sensory onset time between  [gp F vs MF and gp F vs
M: P value  =  0.00] group and in motor onset time the
significant difference was observed within all three
groups (P value = 0.04).
The earlier onset with fentanyl can be attributed to its
lipophilic properties. The lipophilic opioids rapidly traverse
the dura mater, where they are sequestered in the epidural
fat and enter the systemic circulation; they also rapidly
penetrate the spinal cord where they binds opioid receptors
within the white matter as well as dorsal horn receptors and
eventually enter the systemic circulation as they are cleared
from the spinal cord.[10] It may also exert a supraspinal
action by intrathecal cephalic spread.
However, magnesium had delayed effect on the onset
of sensory and motor block with or without fentanyl
suggesting that MgSO4 acted only at the spinal level. The
combination of fentanyl and magnesium sulphate might
result in change of pH, baricity of the injectate solution
and contribute to delay in onset, when two drugs are given
intrathecally.[13,14]
The results of the present study shows that addition
of intrathecal magnesium to fentanyl and bupivacaine
decreases the duration of motor block as compared to
fentanyl group; however, the duration was increased when
24 Journal of Obstetric Anaesthesia and Critical Care | Volume 7 | Issue 1 | January-June 2017
magnesium was added to bupivacaine. The results can be
explained by the lipophilic nature of fentanyl, leading to
rapid decline in cerebrospinal fluid levels of the drug as
compared to magnesium. These findings correlate well with
the study[15] wherein the duration of motor block was more
in magnesium group as compared to fentanyl group.
However, when magnesium is given along with fentanyl
and bupivacaine, the resulting change in baricity or pH
might have impact on duration of motor block. Other
factors that might contribute are obstetric or non‑obstetric
patients and premixing or sequential administration of the
drugs intrathecally.
Increased duration of sensory block was observed
in MF and M group and can be explained due to a
synergistic interaction between NMDA antagonists and
local anaesthetics. Intrathecal magnesium sulphate has
been shown to increase the potency of lipophilic opioids
with or without local anaesthetics. Potentiation of opioid
antinociception occurs by blocking the spinally mediated
facilitatory component evoked by repetitive C‑fibre
stimulation.[16]
The duration of analgesia was increased with addition
of magnesium to fentanyl and local anaesthetic and is in
accordance to study by Dayioglu et al.[17] In the present
study, VNS score at 4 h and cumulative score over a period
of 24‑h postoperative was significantly less in the MF
group. Sometimes, adnexal handling and peritoneal stretch
results in parturient discomfort undergoing caesarean
section under spinal anaesthesia, leading to pain and
nausea. Intrathecal magnesium might increase the threshold
of pain due to peritoneal handling and provide greater
patient comfort, more so in combination with lipophilic
opioid.
In the present study, requirement of phenylephrine was
maximum in group F 13 (43.3%) and minimum in group M
4  (13.3%). Total phenylephrine requirement in group  MF
was 9  (30%),  [gp F vs M: P =  0.02]. Similar results were
shown in the study done by Sarika K et al.,[18] the incidence
of hypotension was more in fentanyl group as compared to
magnesium group. This may be attributable to supraspinal
action[18] or by intrathecal cephalic spread.
Neonatal outcome as assessed by Apgar score at 1 and
5  minutes in three groups was comparable. Similarly,
no adverse foetal outcome of intrathecal fentanyl and
magnesium was observed by Malleeswaran et al.[5]
The incidence of nausea and vomiting was comparable
in three groups with 26.6% in fentanyl group, as
compared to 23.3% and 20% in groups  M and MF,
respectively  (P  =  0.102), throughout the study period and
this may be related to absence of significant hypotension
among groups. The 20  µg of intrathecal fentanyl was also
found to be free of significant side effects as observed by
Sabin G et al.[11]
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Rana, et al.: Intrathecal adjuvants: MgSo4 and/or fentanyl in LSCS
In conclusion, the addition of both intrathecal magnesium
and fentanyl to low‑dose bupivacaine for spinal anaesthesia,
in partureints undergoing caesarean section, results in
prolonged duration of analgesia with lower pain scores,
better haemodynamic Stability and satisfactory neonatal
outcomes.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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