International Journal of Obstetric Anesthesia (2017) 29, 1825

0959-289X/$ - see front matter 2016 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijoa.2016.08.005

ORIGINAL ARTICLE
www.obstetanesthesia.com

An open-label randomized controlled clinical trial for

comparison of continuous phenylephrine versus norepinephrine
infusion in prevention of spinal hypotension during cesarean
delivery
M.C. Vallejo,a A.F. Attaallah,a O.M. Elzamzamy,a D.T. Cifarelli,a A.L. Phelps,b
G.R. Hobbs,a R.E. Shapiro,a P. Ranganathana
a
West Virginia University School of Medicine, Morgantown, WV, USA
b
Duquesne University School of Business, Pittsburgh, PA, USA

ABSTRACT
Background: During spinal anesthesia for cesarean delivery phenylephrine is the vasopressor of choice but can cause bradycardia.
Norepinephrine has both b- and a-adrenergic activity suitable for maintaining blood pressure with less bradycardia. We hypoth-
esized that norepinephrine would be superior to phenylephrine, requiring fewer rescue bolus interventions to maintain blood pres-
sure.
Methods: Eighty-five parturients having spinal anesthesia for elective cesarean delivery were randomized to Group P (phenyle-
phrine 0.1 lg/kg/min) or Group N (norepinephrine 0.05 lg/kg/min) fixed-rate infusions. Rescue bolus interventions of phenyle-
phrine 100 lg for hypotension, or ephedrine 5 mg for bradycardia with hypotension, were given as required to maintain
systolic blood pressure. Maternal hemodynamic variables were measured non-invasively.
Results: There was no difference between groups in the proportion of patients who required rescue vasopressor boluses (Group P:
65.8% [n=25] vs. Group N: 48.8% [n=21], P=0.12). The proportion of patients who received P1 bolus of phenylephrine was sim-
ilar between groups (Group P: 52.6% [n=20] vs. Group N: 46.5% [n=20], P=0.58). However, more patients received P1 bolus of
ephedrine in the phenylephrine group (Group P: 23.7% [n=9] vs. Group N: 2.3% [n=1], P <0.01). The incidence of emesis was
greater in the phenylephrine group (Group P: 26.3% vs. Group P: 16.3%, P <0.001). Hemodynamic parameters including heart
rate, the incidence of bradycardia, blood pressure, cardiac output, cardiac index, stroke volume, and systemic vascular resistance
and neonatal outcome were similar between groups (all P <0.05).
Conclusion: Norepinephrine fixed-rate infusion has efficacy for preventing hypotension and can be considered as an alternative to
phenylephrine.
2016 Elsevier Ltd. All rights reserved.

Keywords: Cesarean delivery; Spinal anesthesia; Phenylephrine; Norepinephrine

Introduction cardiovascular instability, decreased uteroplacental

Spinal anesthesia is the anesthetic technique of choice
for elective cesarean delivery (CD); however, it results
in maternal hypotension in most women if not actively
prevented.13 The incidence without prophylactic man-
agement during CD under spinal anesthesia can be in
excess of 80%.2 If left untreated, maternal hypotension
can lead to serious sequelae including nausea, emesis,
Accepted August 2016
Correspondence to: Manuel C. Vallejo, MD, DMD, Professor,
Department of Medical Education, PO Box 9001A, Robert C. Byrd
Health Sciences Center, Morgantown, WV 26506, USA.
E-mail address: vallejom@wvumedicine.org
blood flow and fetal acidosis.3
To avoid maternal hypotension and blood pressure
variability, the current standard is to administer a con-
tinuous phenylephrine infusion to limit the change from
baseline.46 Prophylactic continuous infusion with res-
cue bolus dosing is more effective for hemodynamic sta-
bility than relying on rescue dosing alone, with the
advantage of limiting clinician workload and increasing
maternal comfort.7 Compared with ephedrine, phenyle-
phrine is associated with less neonatal acidosis while
maintaining uteroplacental blood flow.8 However, it
has also been shown that phenylephrine can have
M.C. Vallejo et al.
clinically significant side effects such as a baroreceptor-
mediated bradycardia with a consequent decrease in
cardiac output (CO).911 A recent study showed that
norepinephrine was also effective for maintaining blood
pressure in obstetric patients;12 its use was associated
with greater heart rate (HR) and CO compared with
phenylephrine, but further studies confirming its safety
and efficacy in this setting were recommended.12
The aim of this study was to compare prophylactic
intravenous infusions of phenylephrine and nore-
pinephrine during CD under spinal anesthesia. We
tested the hypothesis that a fixed-rate norepinephrine
infusion would be superior to a fixed-rate phenylephrine
infusion. The primary endpoint was reduction in the
number and total dose of intraoperative provider-
administered rescue bolus interventions needed to main-
tain systolic blood pressure (SBP).
Methods
The local West Virginia University Institutional Review
Board (IRB) approved this study and informed verbal
and written consents were obtained from all study
patients. The study was registered with the U.S.
National Institutes of Health National Clinical Trials
(trial registry number: NCT02354833). We conducted
a prospective, observational, randomized, open-labeled
trial on parturients scheduled for elective CD under
spinal anesthesia.
Inclusion criteria were: American Society of Anesthe-
siologists physical status class <3, singleton gestation
>36 weeks, scheduled elective CD under spinal anesthe-
sia, fasting >6 h. Exclusion criteria were: cardiovascular
disease, pregnancy-related hypertensive disease,
preeclampsia, eclampsia, the use of cardiac medication
or medication for blood pressure control, multiple gesta-
tion, gestational diabetes requiring insulin, documented
history of postoperative nausea and vomiting, previous
gastric bypass surgery, history of chronic opioid use
(chronic pain syndrome), body mass index (BMI)
>40 kg/m2, emergency CD for maternal and/or fetal
distress, suspicion of abnormal placentation, history of
seizures and progressive neurologic disease.
Patients were randomized using a computer-generated
table to one of two treatment groups (Group P: phenyle-
phrine 100 lg/mL infused at 0.1 lg/kg/min or Group N:
norepinephrine infused at 0.05 lg/kg/min) to maintain
SBP within 100120% of baseline during standardized
spinal anesthesia. Baseline SBP and HR were recorded
as the mean of three consecutive preoperative measure-
ments taken 5 min apart one hour before arrival in the
operating room. All patients had a peripheral
intravenous catheter placed in the upper extremity and
received lactated Ringers solution 500 mL over 15 min
in their hospital room by the labor and delivery nurse
as per our hospital protocol. Study group assignments
19
were concealed in opaque envelopes and were revealed
to the anesthesia providers upon entering the operating
room. The study infusion medication was started at the
same time cerebrospinal fluid was obtained, immediately
before injection of spinal medications. Vasopressor
infusions were administered through small-bore tubing
connected directly to the peripheral intravenous catheter.
A standardized spinal anesthetic consisting of hyperbaric
bupivacaine 1215 mg, preservative-free morphine
0.2 mg and fentanyl 20 lg was administered in the sitting
position at the L34 or L45 vertebral interspace. After
intrathecal injection, patients were placed in the supine
position and the table tilted 15 to provide left uterine
displacement. The spinal sensory level was tested
bilaterally by pinprick to ensure a T4 dermatomal level
before surgical incision.
A rescue bolus of phenylephrine 100 lg was adminis-
tered by the anesthesia care provider whenever SBP
decreased below 100% of baseline. Hypotension was
defined as the requirement for a rescue bolus interven-
tion. Hypertensive episodes (SBP >120% of baseline)
were treated with infusion cessation, and the infusion
was restarted when SBP decreased below the upper limit
of the target range (120% of baseline SBP value). Brady-
cardia (HR <60 beats/min) was treated by stopping the
infusion and if accompanied by hypotension, a rescue
bolus of ephedrine 5 mg was given.
Study variables included SBP, diastolic blood pres-
sure (DBP), HR, CO, cardiac index (CI), stroke volume
(SV), systemic vascular resistance (SVR), number and
type of provider interventions for maintaining blood
pressure, Apgar scores <7 at 1 and 5 min, umbilical cord
blood gases if clinically indicated as part of routine care,
and intraoperative maternal nausea and emesis. Nausea
was defined as a subjectively unpleasant sensation asso-
ciated with awareness of the urge to vomit and emesis
was defined as rhythmic contractions of the abdominal
muscles with or without expulsion of gastric contents
from the mouth (i.e. including retching). Intravenous
ondansetron 4 mg was administered after delivery of
the baby to all patients.
Hemodynamic variables were continuously recorded
using the Nexfin non-invasive hemodynamic monitor
(Edwards Lifesciences Corp, Irvine, CA, USA). This
was used according to guidelines provide by the manu-
facturer. A finger cuff was applied to the mid-phalanx
of the middle finger and an appropriate arterial wave-
form was obtained. An acceptable waveform was char-
acterized by a high-quality shape, amplitude, and a
visible dicrotic notch. Hemodynamic variables were
analyzed at nine defined intervals throughout the proce-
dure (baseline, infusion start, spinal insertion, left uter-
ine displacement, surgical incision, delivery, oxytocin
start, fascial closure, procedure end). The study ended
when patient care was transferred to the labor and deliv-
ery nurse postoperatively.
20
Statistical analysis
Ohpasanon et al. reported a 65% incidence of hypoten-
sion after spinal anesthesia in cesarean delivery without
a phenylephrine infusion.13 A local pilot study was con-
ducted on 20 parturients who were given a continuous
infusion of phenylephrine for elective CD under spinal
anesthesia where 35% of the patients experienced mater-
nal hypotension treated by at least one bolus interven-
tion. Based on this information, power analysis
indicated that 35 patients were required per group to
detect a reduction to 10% in the incidence of hypoten-
sion (patients requiring one or more rescue boluses) at
the 0.05 significance level with 80% power. To allow
for parturients who may not complete the study, we
planned to enroll a total of 85 patients.
The primary endpoint was the number and total dose
of rescue bolus interventions needed to maintain SBP. A
two-sample Z-test was used to determine a significant
difference in the proportion of patients in each group
requiring at least one bolus dose intervention. Demo-
graphic data and duration of infusion were compared
using a two-sided t-test between groups. Gravidity and
parity were compared using the Mann-Whitney U test.
Ephedrine total dose and phenylephrine total dose were
also compared between groups using the Mann-Whitney
U test because the skewed distributions did not meet the
required assumptions for the t-test. Differences in the
incidence of nausea, emesis, bradycardia, number of res-
cue bolus interventions of ephedrine and phenylephrine,
and Apgar scores <7 at 1 and 5 min were compared
between groups using the chi-square test. Multivariate
analysis of variance (MANOVA) was used to detect sig-
nificant differences in the repeated hemodynamic
parameters to measure trends over time for each mea-
sured variable. MANOVA accommodates for the multi-
variate, dependent responses by combining each
numerical variable as a single vector of responses.
P<0.05 was considered statistically significant. Data
analysis was performed using Excel 2013 (Microsoft
Corporation, Redmond, WA, USA) and JMP software
from SAS (SAS Institute Inc., Cary, NC, USA).
Results
Patient recruitment and flow are shown in Fig. 1. The
study enrolled 85 patients from August 2014 through
August 2015. Thirty-eight women were enrolled in the
phenylephrine group and none were excluded. Forty-
three women were enrolled in the norepinephrine group;
however, four patients were excluded (two because of
monitoring equipment failure, and two who had emer-
gency CD). The enrollment difference between groups
was due to each patient being randomly assigned to
one of two groups without restriction to an equal sample
size. All patients had successful spinal anesthesia with an
adequate bilateral sensory level to T4; no patient
Vasopressors for spinal hypotension during cesarean delivery
required supplemental intravenous opioids for intraop-
erative pain. No differences were noted between groups
with respect to demographic data (age, BMI, gravidity,
parity and gestation).
There were no differences between the two groups in
infusion duration, incidence of bradycardia, or inci-
dence of nausea but the incidence of emesis was greater
in the phenylephrine group (Group P=26.3% vs. Group
N=16.3%, P <0.001), (Table 1).
The proportion of patients who required rescue
boluses of phenylephrine (given for SBP <baseline)
and/or ephedrine (given for bradycardia and hypoten-
sion) is shown in Fig. 2. Overall, the proportion of
patients who received P1 vasopressor bolus was similar
between groups (Group P: 65.8% [n=25] vs. Group N:
48.8% [n=21], P=0.12). The proportion of patients
who received P1 bolus of phenylephrine was similar
between groups (Group P: 52.6% [n=20] vs. Group N:
46.5% [n=20], P=0.58). However, the proportion of
patients who received P1 bolus of ephedrine was
greater in the phenylephrine group (Group P: 23.7%
[n=9] vs. Group N: 2.3% [n=1], P <0.01). There was
no difference in the total amount of rescue phenyle-
phrine and ephedrine given during the time interval
from infusion start to delivery and from infusion start
to procedure end (Table 1).
There were no differences between groups in the pro-
portion of Apgar scores <7 at 1 min and 5 min, or in
umbilical venous cord blood gases (Table 2). One
patient in Group P and two in Group N required infu-
sion cessation because of hypertension; only one of
whom in group P became bradycardic.
Regarding the measured non-invasive hemodynamic
parameters, there were no differences in MANOVA
modeling, treating the repeated outcome measures as
multivariate sample of means or when followed by sep-
arate testing at each of recorded separate intervals (HR:
P=0.17, CO: P=0.5, CI: P=0.84, SV P=0.5, SBP:
P=0.25, DBP: P=0.15, and SVR: P=0.54), (Fig. 3).
Discussion
Our results confirm our clinical impression that a fixed-
rate infusion of norepinephrine is effective for maintain-
ing maternal blood pressure in elective CD under spinal
anesthesia. When a norepinephrine infusion was used,
the number of required rescue boluses of ephedrine
was decreased and fewer patients had emesis compared
with a phenylephrine infusion.
A recent study by Ngan Kee et al. compared both
drugs for cesarean delivery.12 Our study was different
in that whereas the previous investigators used a
computer-controlled closed-loop feedback system to
administer and titrate the vasopressors with CO as the
primary outcome, we used a fixed-rate infusion with
the number of rescue boluses required as the primary
M.C. Vallejo et al. 21

Fig. 1 Study CONSORT diagram showing patient recruitment and flow

Table 1 Demographic, vasopressor, maternal and fetal outcome data

Phenylephrine Group Norepinephrine Group P value
(n=38) (n=43)
Age (years) 29.1 5.6 (27.3 to 30.8) 30.2 6.8 (28.1 to 32.2) 0.43
Body mass index (kg/m2) 33.6 6.6 (31.5 to 35.7) 35.0 7.0 (32.9 to 37.1) 0.34
Gravidity 3 [15] 2 [18] 0.14
Parity 1 [04] 1 [02] 0.08
Gestation (weeks) 37.6 2.0 (37.0 to 38.3) 38.1 1.6 (37.6 to 38.6) 0.27
Infusion duration (minutes) 69.2 18.6 (63.3 to 75.1) 66.7 21.6 (60.2 to 73.1) 0.57
Median total rescue bolus dose
Ephedrine total dose (mg) 0 [085] 0 [030] 0.10
Phenylephrine total dose (lg) 50 [01000] 100 [0700] 0.73
Incidence of bradycardia (%) 23.7% (10.2% to 37.2%) 18.6% (7.0% to 30.2%) 0.58
Nausea (%) 63.2% (47.9% to 78.5%) 51.2% (36.3% to 66.1%) 0.28
Emesis (%) 26.3% (12.3% to 40.3%) 16.3% (5.3% to 27.3%) <0.001
Data are mean SD with 95% CI, median [range] or percentage with 95% CI for proportions.; Rescue bolus interventions reflect number of
interventions divided by number of time periods.

outcome. Another difference was that we aimed to
maintain maternal blood pressure within 100120% of
baseline value and intervened whenever SBP decreased
below 100% of baseline, and as a result much larger
doses would be expected to be used. Previously Ngan
Kee et al.6 determined that when maternal blood pres-
sure was maintained within 80%, 90% or 100% of base-
line using a phenylephrine infusion, patients in the 100%
baseline group had better maternal and neonatal
outcomes.
Phenylephrine is effective at increasing SVR but a
high infusion dose can cause a significant reduction of
up to 20% in both maternal HR and CO.912 Nore-
pinephrine has weak b-adrenergic receptor agonist activ-
ity in addition to its a-adrenergic receptor activity and
therefore may be a more suitable option for maintaining
maternal blood pressure with less negative effects on HR
and CO compared with phenylephrine.12,14 However,
contrary to previous findings of greater HR and CO in
the norepinephrine group by Ngan Kee et al.12 we did
22 Vasopressors for spinal hypotension during cesarean delivery

Bolus Requirements
70% 65.8%

60%
48.8%
50%

40%
31.6%
30% 27.9%

20%
13.2%
9.3%
10%
2.6%
0.0%
0%
Rescue Bolus (%) > 1 Boluses > 2 Boluses > 3 Boluses

Group P Group N

Phenylephrine + Ephedrine Bolus Requirements

70% 65.8%

60%
52.6%
48.8%
50% 46.5%

40%

30%
*
23.7%
#
20%
10.5%
10%
2.3%
0.0%
0%
Rescue Bolus (%) Rescue P Bolus (%) Rescue E Bolus (%) Both P + E Bolus (%)

Group P Group N

Fig. 2 Proportion of patients who received rescue boluses of phenylephrine for hypotension and/or ephedrine for bradycardia
and hypotension. The upper panel shows the proportion of patients who received different numbers of boluses. The lower panel
shows the proportion of patients who received either or both vasopressors (fields are not mutually exclusive). Group
P = Phenylephrine, Group N = Norepinephrine. *P <0.01), #P=0.03

Table 2 Neonatal outcome

Phenylephrine Group Norepinephrine Group P value
(n=38) (n=43)
Apgar scores at 1 min <7 6 6 0.82
Apgar scores at 5 min <7 2 1 0.48
Umbilical venous blood gases (n=5) (n=7)
pH 7.30 [7.227.33] 7.27 [7.167.32] 0.42
PCO2 (mmHg) 54.0 [20.078.5) 24.0 [18.033.0] 0.32
PO2 (mmHg) 51.0 [43.058.0] 56.0 [46.073.0] 0.46
HCO3 (mEq/L) 23.0 [17.926.0] 20.3 [20.022.3] 0.56
Base excess (mEq/L) 4.3 [2.507.45] 4.3 [0.75.1] 0.74
Data are number or median [interquartile range].

not find significant differences in HR, CO, CI, SV, and
SVR between the two study groups. This may be related
to the doses used. Furthermore, these measurements
were not defined study outcomes and therefore a type
II statistical error is a possibility.
Also worth noting, Ngan Kee et al.12 compared nore-
pinephrine with phenylephrine according to an estimate
of a potency ratio of 20:1, which was the ratio used in
previous clinical comparisons.1517 The potency ratio
used in our study was 2:1. In the doses used in our study,
we did not find a difference in the incidence of bradycar-
dia between groups. The true potency ratio in this set-
ting remains uncertain; using variable titrated rate
infusions could decrease the issue of potency ratio,
M.C. Vallejo et al. 23

Heart Rate Cardiac Output

120 10
90 8
6
bpm 60 L/min
4
30 2
0 0
Infusion Spinal Supine with Delivery Infusion Spinal Supine with Delivery
Start Insert LUD Start Insert LUD

Group P Group N Group P Group N

Cardiac Index Stroke Volume

5 150
4
3 100
L/min/m 2 ml/beat
2 50
1
0 0
Infusion Spinal Supine with Delivery Infusion Spinal Supine Delivery
Start Insert LUD Start Insert with LUD

Group P Group N Group P Group N

Mean Systolic Blood Pressure Mean Diastolic Blood Pressure

150 120
140 90
mmHg 130 mmHg 60
120 30
110 0
Infusion Spinal Supine with Delivery Infusion Spinal Supine with Delivery
Start Insert LUD Start Insert LUD

Group P Group N Group P Group N

Systemic Vascular Resistance

1500

1000
dynes/sec/
cm5 500

0
Infusion Spinal Supine Delivery
Start Insert with LUD

Group P Group N

Fig. 3 Hemodynamic parameters at the specific time periods of infusion start, spinal insert, supine with left uterine displacement
and at delivery. Multiple analyses of variance for heart rate P=0.17, cardiac output P=0.5, cardiac index P=0.84, stroke volume
P=0.5, systolic blood pressure P=0.25, diastolic blood pressure P=0.15, and systemic vascular resistance P=0.54. Group P:
phenylephrine group. Group N: norepinephrine group. LUD: left uterine displacement

although a potency ratio between two drugs that differ
in effect can be problematic to define. Stewart et al.11
conducted a randomized double-blind study on women
scheduled for elective CD with differing phenylephrine
infusions at 25 lg/min, 50 lg/min or 100 lg/min. They
demonstrated that all three infusion regimens main-
tained maternal blood pressure equally, and recom-
mended that infusion rates of phenylephrine
insufficient to cause bradycardia should be used.11 Most
studies show that phenylephrine doses in the range of
0.251.0 lg/kg/min are clinically sufficient. In our study,
a substantial portion of the vasopressor used was actu-
ally in phenylephrine bolus form, which may be an
explanation of why few differences between groups were
seen. We also chose the lowest phenylephrine infusion
rate clinically used (0.1 lg/kg/min) and demonstrated
a lower incidence of bradycardia while maintaining
comparable HR, BP, CO, CI, SV, and SVR between
the two study groups. We found a greater use of ephe-
drine bolus interventions in the phenylephrine group,
24 Vasopressors for spinal hypotension during cesarean delivery
but not in the ephedrine total dose, which resulted in a
lower incidence of bradycardia in the phenylephrine
group (13.2% vs. 18.6%, P=0.71). However, a large pro-
portion of our findings may be due to the difference in
potency between the two drug solutions tested, rather
than differences in the drugs themselves.
Our patients received intrathecal preservative-free
morphine 0.2 mg and fentanyl 20 lg for postoperative
analgesia. High rates of nausea and vomiting have been
reported with this technique.18 While the blood pressure
was maintained at 100120% of baseline, our reported
rates of nausea and emesis could perhaps be attributed
in part to the use of these medications and the defini-
tions used to report them in our study.
The external non-invasive hemodynamic monitoring
system (Nexfin) has been validated in pregnant
patients.19 It was shown that intraoperative CO mea-
surement using Nexfin has a strong correlation (94%
concordance) with CO measured by esophageal
Doppler.20 A number of recent articles have shown
inaccuracies in agreement in measured hemodynamic
variables with non-invasive devices compared with
invasive devices;21,22 however, the Nexfin can provide
a reasonable estimate of CO, blood pressure, pulse pres-
sure variation, SV variation, and be used to adequately
reflect hemodynamic alterations.2325
We used a fixed-rate infusion which is different from
other protocols that have utilized variable rate infusions
with additional boluses if needed. Another limitation is
that the fixed-rate infusion of phenylephrine was low
(about 8 lg/min in an 80 kg woman) which is lower than
most current regimens. We found a high incidence of
nausea and emesis in both groups, which presumably
could be due to the low study phenylephrine infusion
rate. Another limitation was that this study was
unblinded (open-label) which could have led to bias.
This, however, was minimized in that all data were
recorded independently by a research assistant minimiz-
ing the providers ability to influence results. In our
study, hypotension was defined as the requirement for
rescue bolus intervention and ephedrine was adminis-
tered when bradycardia was accompanied by hypoten-
sion, which can result in a discrepancy in rescue bolus
treatment. The open-label aspect was incorporated as
a local IRB requirement to ensure best patient safety
practices owing to research on a vulnerable patient pop-
ulation. The IRB considers pregnant patients, prisoners,
and the pediatric population to be vulnerable popula-
tions and incorporated this requirement to ensure the
attending anesthesiologists were aware of the drug used,
in order to safeguard the patients best interest and
potential effects especially on the fetus.
In summary, norepinephrine fixed-rate infusion has
efficacy for preventing hypotension and can be consid-
ered as an alternative to phenylephrine. Future research
is needed to assess the safety of norepinephrine, its
potency compared to phenylephrine, its use in the par-
turient with other comorbidities, and to determine the
optimal infusion rate and dosing strategy for maintain-
ing maternal hemodynamics under spinal anesthesia for
CD.
Disclosure
This study received no external funding and the authors
have no conflicts of interest to declare.
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