International Journal of Obstetric Anesthesia (2016) 25, 1722

0959-289X/$ - see front matter 2015 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijoa.2015.08.009

ORIGINAL ARTICLE

www.obstetanesthesia.com

The effects of prophylactic bolus phenylephrine on hypotension

during low-dose spinal anesthesia for cesarean section
H.-M. Lee,a,b S.-H. Kim,a B.-Y. Hwang,a B.-W. Yoo,b W.-U. Koh,a D.-M. Jang,a
W.-J. Choia
a

Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine,
Seoul, Republic of Korea
b
Department of Anesthesiology and Pain Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine,
Gangneung, Republic of Korea
ABSTRACT
Background: Continuously infused phenylephrine is frequently used to reduce the incidence of hypotension in women undergoing
cesarean section under spinal anesthesia, but less is known about the prophylactic bolus method. We evaluated three prophylactic
bolus doses of phenylephrine during low-dose spinal anesthesia for cesarean section.
Methods: One-hundred-and-eighty-four patients were randomized to receive 0.9% saline 2 mL (Control Group) or phenylephrine
1.0 lg/kg (PHE1 Group), 1.5 lg/kg (PHE1.5 Group), or 2.0 lg/kg (PHE2 Group) immediately after induction of combined spinalepidural anesthesia. Maternal blood pressure and heart rate were recorded at 1-min intervals until delivery. Hypotension, defined
as systolic blood pressure <80% of baseline, was treated with rescue doses of phenylephrine 100 lg at 1-min intervals until
hypotension resolved. The incidence of nausea, vomiting, bradycardia, and hypertension, as well as Apgar scores and umbilical
blood gases, were recorded.
Results: The incidence of hypotension was 71.7% (33/46) in the Control Group, 68.9% (31/45) in the PHE1 Group, 37.0% (17/46)
in the PHE1.5 Group and 45.7% (21/46) in the PHE2 Group (P=0.001). The total rescue dose of phenylephrine was greater in the
Control Group than those in the PHE1.5 Group (P <0.05) and PHE2 Group (P <0.05). The incidence of hypertension increased as
the dose of prophylactic phenylephrine increased (P <0.001) and was highest in the PHE2 group (37%). Other variables did not
differ among the four groups.
Conclusions: Under the conditions of this study, prophylactic bolus injection of phenylephrine 1.5 lg/kg was a suitable alternative
method for reducing the incidence of hypotension during low-dose spinal anesthesia for cesarean section.
2015 Elsevier Ltd. All rights reserved.
Keywords: Cesarean section; Phenylephrine; Spinal hypotension

Introduction
Spinal anesthesia for cesarean section can avoid the serious maternal complications associated with general
anesthesia.1 However, hypotension after spinal anesthesia is frequent and may have deleterious effects on
maternal and fetal outcomes.2 Phenylephrine may be
used to prevent hypotension:3,4 it improves fetal acidbase balance, increasing fetal pH and reducing PCO2
when compared with ephedrine.58
The optimal administration method of phenylephrine, which has a short duration of action, has not
been established. Continuous infusions are commonly
Accepted August 2015
Correspondence to: Woo-Jong Choi, MD, PhD, Associate Professor,
Department of Anesthesiology and Pain Medicine, Asan Medical
Center, University of Ulsan College of Medicine, Seoul, Republic of
Korea.
E-mail address: woojongchoi@amc.seoul.kr

used and are associated with a very low incidence of

hypotension and a reduction in the incidence of nausea
and vomiting, even when high-dose spinal anesthetics
are used.911 Prophylactic infusion with rescue phenylephrine boluses is effective in maintaining maternal
hemodynamic stability, and can also reduce physician
interventions compared with rescue boluses alone.12
However, although continuous infusion is effective and
convenient, it requires an infusion pump and appropriately trained personnel. Doherty et al.13 compared bolus
and infusion phenylephrine regimens, and reported that
blood pressure was better maintained with boluses, especially in the initial 6 min after spinal anesthesia. Thus,
bolus regimens may be effective for early hypotension
after spinal anesthesia.
Recently, das Neves et al.14 reported that the incidence of hypotension after spinal anesthesia was 32.5%
in patients who received a prophylactic bolus of

18
phenylephrine 50 lg compared with 85% in a group that
received phenylephrine as a therapeutic dose only after
hypotension occurred. However, a prophylactic bolus
of phenylephrine 50 lg is less than the ED95 of 122 lg
reported by Tanaka et al.15
We hypothesized that an appropriate prophylactic
bolus of phenylephrine may reduce the incidence of
hypotension during spinal anesthesia for cesarean section. We evaluated the effects of three prophylactic
doses of phenylephrine on hypotension, and also
assessed hemodynamic adverse effects and neonatal
status.

Methods
This prospective, randomized, clinical study included
women who were American Society of Anesthesiologists
physical status I and II with term singleton pregnancies
scheduled for elective cesarean section under combined
spinal-epidural anesthesia from September 2012 to
January 2013 at the Asan Medical Center. The trial
was registered with the Clinical Research Information
Service (code number KCT 0001087) and received ethics
approval by the Asan Medical Center Institutional
Review Board. All patients provided written informed
consent. Women were excluded if they had pre-existing
or pregnancy-induced hypertension, cardiac or respiratory disease, cerebrovascular disease, fetal anomalies
or contraindications to spinal anesthesia.
Patients were randomized to one of four groups by
computer-generated random allocation (http://www.
randomization.com/). An anesthesiologist not involved
in patient care prepared 2 mL solutions in identical syringes, with the contents based on the random allocation.
Patients in the Control Group received 0.9% saline
2 mL, whereas patients in the PHE1, PHE1.5, and
PHE2 groups received phenylephrine 1.0, 1.5, and
2.0 lg/kg, respectively, diluted to 2 mL with saline.
Premedication of sodium citrate 30 mL and ranitidine
150 mg was given orally on the morning of surgery.
Before the induction of anesthesia, an 18-gauge intravenous cannula was inserted without local anesthesia.
Standard monitoring (Intellivue MP70; Philips Medizin
Systeme, Boeblingen, Germany) was attached, including
non-invasive blood pressure, electrocardiogram, and
pulse oximetry. With patients in the supine position with
left lateral tilt, blood pressure and heart rate were measured three times at 1-min intervals with the average of
these three measurements recorded as baseline. Lactated
Ringers solution was infused with a fully opened clamp
to a maximum of 2 L from induction to delivery.
Patients were placed in the left lateral decubitus position for the combined spinal-epidural procedure. After
skin decontamination and injection of cutaneous local
anesthetic, an 18-gauge Tuohy needle was inserted at
the L34 or L45 interspace using a loss-of-resistance

Prophylactic phenylephrine for cesarean section

technique. The dura mater was punctured with a
27-gauge Whitacre spinal needle using a needlethrough-needle technique (Portex, Smiths Medical
International Ltd, Hythe, Kent, UK). After verifying
free flow of cerebrospinal fluid, a mixture of 0.5% hyperbaric bupivacaine 7 mg and fentanyl 15 lg was administered over 10 s. After withdrawal of the spinal needle, a
20-gauge multi-orifice epidural catheter was inserted
45 cm into the epidural space and the Tuohy needle
was removed. The epidural catheter was firmly fixed
and patients were immediately positioned supine. If
the epidural catheter insertion was considered difficult,
without further delay, patients were positioned supine.
At the end of intrathecal injection (time 0 min) an anesthesiologist blinded to group allocation administered the
intravenous study dose.
Block height was assessed bilaterally using loss of
cold sensitivity to alcohol at 5-min intervals for
15 min. If the block height did not reach the T6 dermatome, spinal anesthesia was considered to have failed
and epidural top-ups of 2% lidocaine 5 mL were administered to a maximum of 20 mL as required.
Blood pressure and heart rate were recorded at 1-min
intervals until delivery. The primary outcome was the
incidence of hypotension, defined as systolic blood pressure (SBP) <80% of baseline. Hypotension was treated
with rescue doses of phenylephrine 100 lg every 1 min
until hypotension resolved. The total rescue dose of
phenylephrine administered to each patient was
recorded.
Before induction of anesthesia, patients were asked to
report any symptoms of nausea or vomiting. To evaluate
adverse effects of prophylactic boluses of phenylephrine,
the incidence of nausea, vomiting, bradycardia (heart
rate <50 beats/min), and hypertension (SBP >120% of
baseline) were recorded. Patients who experienced
bradycardia concomitant with hypotension were given
atropine 0.5 mg. Apgar scores at 1 and 5 min, estimated
blood loss, and fluid administration until delivery were
recorded. Umbilical cord blood gas analysis was
performed to evaluate the possible effects of phenylephrine on the newborn.

Statistical analysis
In a pilot study, the incidence of hypotension during
spinal anesthesia in women undergoing cesarean section
was approximately 70%. Assuming that prophylactic
administration of phenylephrine could reduce the incidence by 50%, power analysis indicated that a minimum
of 42 subjects per group would be adequate to detect a
difference in the incidence of hypotension, with power
of 0.8 and an a error of 0.0083 (0.05/6). The final sample
size was increased to 184 patients to accommodate an
attrition rate of 10%. Intergroup comparisons of patient
characteristics, obstetric data, and additional phenylephrine dose were analyzed using one-way ANOVA or

H.-M. Lee et al.

19

Kruskal-Wallis one-way ANOVA on ranks with the

Bonferroni test for post hoc multiple comparisons.
The incidence of hypotension, nausea, bradycardia,
and hypertension were compared using Pearsons chisquared test to detect differences among the groups
and linear by linear association test to detect trends
among the groups. We applied Bonferroni corrections
for multiple comparisons as appropriate. Systolic blood
pressure in the four groups was compared using twoway repeated measures ANOVA with the Bonferroni
test for multiple comparisons. All statistical analyses
were performed using IBM SPSS Statistics version
20.0 (IBM, Armonk, NY, USA), with a P value <0.05
considered statistically significant.

Results
Of the 184 patients initially enrolled in the study, one
patient in the PHE1 Group was excluded because spinal
anesthesia failed. The characteristics of patients in the
four groups were similar (Table 1). Combined spinalepidural anesthesia was successful in 183 patients and
the block height was similar among groups. No patient
required an additional epidural top-up dose before

Table 1

delivery. Baseline blood pressure and heart rate were

similar in the four groups.
The incidence of hypotension was significantly different among the groups (P=0.001) and was lowest in the
PHE1.5 Group (37%) (Table 2). Fig. 1 shows SBP after
spinal anesthesia in the four groups. There was a significant interaction between group and time for the mean
changes of SBP (P <0.001). In the Control Group,
SBP decreased rapidly and reached its nadir at 4 min.
Systolic blood pressure was significantly lower in the
Control Group than that in the other three groups during the first 2 min (P <0.05). Between 2 and 5 min, SBP
was significantly lower in the Control than that in the
PHE1.5 (P <0.001) and PHE2 Groups (P <0.001). In
the PHE1.5 and PHE2 Groups, SBP slowly decreased,
reaching a nadir between 7 and 9 min. Thereafter, there
were no significant differences in SBP among the four
groups, with SBP remaining stable in all groups.
Patients in both the Control and PHE1 Groups
required greater amounts of additional phenylephrine
than patients in the PHE1.5 (P <0.05) and PHE2
Groups (P <0.05) (Table 2). Fig. 2 shows the numbers
of rescue phenylephrine injections at different time intervals. Patients in the Control Group required the most

Patient characteristics

Age (years)
Height (cm)
Weight (kg)
BMI (kg/m2)
Systolic BP (mmHg)
Heart rate (beats/min)
Block height
Estimated blood loss (mL)
Fluid until delivery (mL)

Control Group
(n=46)

PHE1 Group
(n=45)

PHE1.5 Group
(n=46)

PHE2 Group
(n=46)

P value

32 [3035]
161.7 5.0
67.9 [61.173.8]
25.8 [23.827.1]
117 [109125]
82.4 15.5
T4 [T6T4]
500 [400725]
900 [7751125]

34 [3137]
160.4 6.3
65.0 [61.373.1]
25.9 [24.729.4]
118 [109125]
81.2 14.3
T4 [T6T4]
700 [475800]
800 [7001000]

33 [3136]
162.0 4.9
66.9 [60.072.6]
25.2 [23.827.7]
116 [107125]
79.0 10.5
T4 [T6T4]
700 [500800]
800 [700900]

34 [3138]
162.3 4.4
69.0 [62.574.5]
25.7 [24.127.7]
114 [107121]
80.5 12.7
T4 [T6T4]
700 [400800]
800 [700900]

0.53
0.32
0.87
0.43
0.62
0.69
0.76
0.28
0.18

Data are mean SD or median [IQR].

BMI: body mass index; BP: blood pressure.

Table 2

Adverse eects of prophylactic bolus of phenylephrine

Hypotension
Rescue phenylephrine (lg)
Lowest SBP (mmHg)
Highest SBP (mmHg)
Early highest SBP (mmHg)
Mean SBP (mmHg)
Nausea
Bradycardia
Hypertension

Control Group
(n=46)

PHE1 Group
(n=45)

PHE1.5 Group
(n=46)

PHE2 Group
(n=46)

P value

33 (71.7%)
200 [0300]
84 13
119 11
114 11
102 7
6 (13.0%)
3 (6.5%)
2 (4.3%)

31 (68.9%)
150 [0200]
87 13
125 15
124 16*
105 10
9 (20%)
3 (6.7%)
3 (6.7%)

17 (37.0%)
y
0 [0100]*
*
91 13
y
129 15*
*
127 15
108 10
9 (19.6%)
2 (4.3%)
5 (10.9%)

21 (45.7%)
0 [0200]*
90 16
y
133 16*
*
131 18
109 11*
5 (10.9%)
4 (8.7%)
17 (37.0%)

0.001
0.002
0.038
<0.001
<0.001
0.005
0.54
0.87
<0.001

Data are number (%), mean SD or median [IQR].

SBP: systolic blood pressure; Early highest SBP: the highest SBP after prophylactic bolus of phenylephrine until additional bolus of phenylephrine
y
or delivery of the baby; *P <0.05 vs. Control; P <0.05 vs. PHE1.

20

Prophylactic phenylephrine for cesarean section

scores at 1 and 5 min and umbilical cord blood gas
results were similar among groups (Table 3).

Discussion

Fig. 1 Serial changes in systolic blood pressure. In the

Control Group, blood pressure decreased rapidly and reached
its nadir 4 min after regional anesthesia. Data are mean SD.
*
P <0.05 compared with the PHE1 Group. yP <0.05 compared
with the PHE1.5 Group. P <0.05 compared with the PHE2
Group

Fig. 2 Number of rescue phenylephrine injections over time

following spinal anesthesia

rescue phenylephrine injections between 4 and 6 min,

whereas patients in the PHE1.5 and PHE2 Groups
required the most rescue phenylephrine injections
between 7 and 9 min.
The incidence of hypertension increased as the dose
of prophylactic phenylephrine increased (P <0.001)
and was highest in the PHE2 Group (37%) (Table 2).
The incidences of bradycardia and nausea were not
related to the dose of prophylactic phenylephrine and
no patient vomited. Three patients had bradycardia
concomitant with hypotension and required treatment
with atropine and there was no case of bradycardia with
hypertension following atropine administration. Apgar

This study found that prophylactic boluses of phenylephrine 1.5 and 2 lg/kg reduced the incidence of
hypotension during spinal anesthesia for cesarean
section. The total additional dose of phenylephrine
required to treat hypotension was also small in these
groups. The largest dose of 2 lg/kg was associated with
a higher rate of hypertension. These results suggest that,
under the conditions of this study, a prophylactic bolus
of phenylephrine 1.5 lg/kg was the most suitable for
reducing the incidence of hypotension.
Most studies assessing phenylephrine regimens in
obstetric anesthesia have investigated continuous infusions;12,16,17 fewer studies have investigated prophylactic
bolus regimens. Recently, das Neves et al.14 compared
three different regimens: continuous infusion (0.15 lg/
kg/min) vs. prophylactic bolus (50 lg) vs. therapeutic
bolus (50 lg). The incidences of hypotension were
17.5%, 32.5% and 85%, respectively. Although the best
results were seen in the continuous infusion group, a
50 lg prophylactic dose was also effective in preventing
hypotension. A previous study of prophylactic boluses
of phenylephrine reported that the ED95 was 122 lg.15
In our study, the prophylactic bolus dose of phenylephrine 1.5 lg/kg was equivalent to doses ranging from
90120 lg. However, the dose of phenylephrine 1.0 lg/
kg, equivalent to doses ranging from 6080 lg, was
not effective in preventing hypotension, in contrast to
the results from das Neves et al.14 Further studies are
needed to determine the optimal prophylactic regimen
under different conditions. Although the intermittent
bolus technique may be more labor intensive and less
convenient than continuous infusion,18 nevertheless,
appropriate prophylactic boluses of phenylephrine may
be an alternative method to reduce early hypotension
after spinal anesthesia.
Although the optimal dose of bolus phenylephrine
has yet not been determined, large doses can cause
maternal hypertension or bradycardia. Maternal cardiac
output correlates with heart rate changes.19 A study
of maternal cardiac output and heart rate in women
receiving three different continuous infusions of
phenylephrine (25, 50, and 100 lg/min) found significant dose-dependent reductions in both cardiac output
and heart rate when SBP was maintained above 80%
of baseline.20 However, it is contentious whether the
uteroplacental flow depends on maternal cardiac output
or blood pressure, because the uterine arteries are maximally dilated in pregnancy. It has been shown that,
even when phenylephrine was used in high doses
(>2000 lg), deleterious fetal effects were not observed.17
In our study, neonatal outcomes were not different in

H.-M. Lee et al.

Table 3

21

Neonatal outcome

Apgar score 1 min

Apgar score 5 min
UV pH
UV PCO2 (mmHg)
UA pH
UA PCO2 (mmHg)

Control Group
(n=46)

PHE1 Group
(n=45)

PHE1.5 Group
(n=46)

PHE2 Group
(n=46)

P value

8 [88]
9 [99]
7.36 0.02
44.6 2.7
7.31 0.01
52.3 2.3

8 [88]
9 [99]
7.35 0.05
45.1 5.2
7.33 0.03
48.9 3.2

8 [88]
9 [99]
7.35 0.02
43.8 3.3
7.32 0.03
49.8 3.9

8 [88]
9 [99]
7.37 0.02
44.0 2.9
7.33 0.01
47.3 3.0

0.59
0.92
0.23
0.57
0.61
0.27

Data are median [IQR] or mean SD.

UV: umbilical vein; UA: umbilical artery.

the four groups. We found that the incidence of hypertension increased as the dose of prophylactic phenylephrine increased, but the rates of bradycardia were not
related to the dose of prophylactic phenylephrine. The
clinical significance of these findings is unclear and
demands further investigation.
In our study, we found that blood pressure in the
Control Group decreased, particularly 36 min after
induction of spinal anesthesia. A prophylactic bolus of
phenylephrine may prevent hypotension in this period.
However, blood pressure in the PHE1, PHE1.5 and
PHE2 Groups decreased more gradually, reaching a
nadir 79 min after administration of the prophylactic
bolus and requiring administration of additional rescue
boluses of phenylephrine. Thus, a single prophylactic
bolus alone could not completely prevent hypotension.
Our study had several limitations. First, we used lowdose local anesthetic (bupivacaine 7 mg and fentanyl
15 lg) for spinal anesthesia which may limit the generalizability of our findings. The incidence (71.7%) of
hypotension in the Control Group was high, whereas
in other studies low-dose spinal bupivacaine (68 mg)
resulted in a lower risk of hypotension,21,22 which may
be may be related to a dose-sparing effect of spinal
opioids. A study from Korea reported that the anesthetic effects of bupivacaine 8 mg and fentanyl 10 lg
were similar to those of bupivacaine at 12 mg.23 A
second limitation was that we only measured blood
pressure and heart rate and not cardiac output. Further
work is needed, including comparisons of changes in
cardiac output in response to different doses of bolus
phenylephrine.
In conclusion, our findings suggest that a prophylactic bolus of phenylephrine 1.5 lg/kg followed by additional boluses as required may be an alternative
method to reduce the incidence of hypotension during
low-dose spinal anesthesia for cesarean section.

Disclosure
This study was supported by departmental funds and
none of the authors have any conflicts of interest to
declare.

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