HH

CLINICAL RESEARCH
e-ISSN 1643-3750
© Med Sci Monit, 2019; 25: 1093-1101
DOI: 10.12659/MSM.914143
Received: 2018.11.15
Accepted: 2019.01.16 A Comparative Study of Bolus Norepinephrine,
Published: 2019.02.09
Phenylephrine, and Ephedrine for the Treatment
of Maternal Hypotension in Parturients with
Preeclampsia During Cesarean Delivery Under
Spinal Anesthesia
Authors’ Contribution: E 1 Xian Wang* 1 Department of Anesthesiology, Obstetrics and Gynecology Hospital Affiliated to
Study Design A BC 1 Mao Mao* Nanjing Medical University, Nanjing, Jiangsu, P.R. China
Data Collection B 2 Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical
Analysis C
Statistical F 2 Shijiang Liu University, Nanjing, Jiangsu, P.R. China

Data Interpretation D AG 1 Shiqin Xu 3 Department of Anesthesiology, The First Affiliated Hospital of Zhengzhou
Manuscript Preparation E D 3,4 Jianjun Yang University, Zhengzhou, Henan, P.R. China
Literature Search F 4 Department of Anesthesiology, Jinling Hospital Affiliated to Nanjing Medical
Funds Collection G University, Nanjing, Jiangsu, P.R. China
* Xian Wang and Mao Mao contributed equally to this study

Corresponding Author: Shiqin Xu, e-mail: [email protected], Jianjun Yang, e-mail: [email protected]
Source of support: This study was supported by the Young Talents Project of Maternal and Child Health Care in Jiangsu Province (FRC201787)
Background: This study aimed to compare the efficacy and safety of bolus norepinephrine, phenylephrine, and ephedrine in
parturient with preeclampsia who had hypotension during cesarean delivery under spinal anesthesia.
Material/Methods: One hundred and sixty-six parturient women with preeclampsia who had a baseline systolic blood pressure
(SBP) <80% during spinal anesthesia for cesarean section were divided into three treatment groups; bolus nor-
epinephrine 4 μg (group N) (n=56), phenylephrine 50 μg (group P) (n=55), and ephedrine 4 mg (group E) (n=55).
Primary outcomes included overall SBP and heart rate (HR) until delivery. Secondary outcomes included the in-
cidence of tachycardia (HR >120 bpm), bradycardia (HR <60 bpm), hypertension (SBP >120% baseline), number
of boluses of vasopressor required and episodes of hypotension, maternal side effects, and neonatal outcome.
Results: Overall HR in group N was significantly increased compared with group P (80.5±12 vs. 76.6±6.9 bpm; P=0.04),
and significantly lower compared with group E (80.5±12 vs. 84.9±7.1 bpm; P=0.02). Parturients in group N had
fewer episodes of bradycardia compared with group P (3.6% vs. 21.8%; RR=0.26l; 95% CI, 0.07–0.73; P=0.004)
and fewer episodes of tachycardia compared with group E (16.1% vs. 36.4%; RR 0.54; 95% CI, 0.29–0.90; P=0.02).
Conclusions: A bolus dose of norepinephrine showed similar efficacy to phenylephrine but improved maternal and neona-
tal safety in parturients with preeclampsia with hypotension during cesarean section under spinal anesthesia.
MeSH Keywords: Ephedrine • Norepinephrine • Pre-Eclampsia • Treatment Outcome • Phenylephrine
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Wang X. et al.:
CLINICAL RESEARCH Maternal hypotension in preeclampsia
© Med Sci Monit, 2019; 25: 1093-1101
Background In low-risk normotensive parturients, several studies have now

supported the efficacy and safety of norepinephrine in the
Preeclampsia in parturients, or women before giving birth, is management of maternal hypotension using different dosing
associated with significant morbidity in between 5–7% of cases. regimens and schedules [9–13]. However, there is limited in-
Preeclampsia is characterized by the abnormal development of formation available for the use of norepinephrine in parturi-
maternoplacental blood vessels, resulting in increased vascu- ents with preeclampsia and hypotension.
lar vasomotor responsiveness and the potential for placental
hypoperfusion [1]. Currently, spinal anesthesia and cesarean Therefore, this study aimed to compare the efficacy and safety
section are a standard treatment for women with preeclampsia of bolus norepinephrine, phenylephrine, and ephedrine in par-
in the absence of an indwelling epidural catheter or contrain- turient women with preeclampsia who had hypotension during
dications to neuraxial anesthesia [2]. Although hypotension is cesarean delivery with spinal anesthesia. The comparative clini-
less frequent and easier to treat in patients with preeclampsia cal study included the measurement of maternal hemodynamics,
when compared with normotensive parturients, hypotension vasopressor requirements, and maternal side-effects, neonatal
during spinal anesthesia is undesirable in the presence of fe- Apgar scores, and umbilical artery pH and blood gases.
toplacental hypoperfusion. Therefore appropriate interven-
tion for spinal hypotension is necessary and may include fluid
loading, lateral positioning, and the use of vasopressors [3]. Material and Methods
Phenylephrine and ephedrine are two of the most com- Subjects and ethics
monly used vasopressors for the treatment of hypotension.
Phenylephrine is a pure a-adrenergic receptor agonist with This study was approved by the Clinical Research Ethics
no b agonism properties, can restore the spinal anesthesia- Committee of Nanjing Medical University, Nanjing, China
induced decrease of systemic vascular resistance, and is cur- (No 2018-79) and was registered in the Chinese Clinical Trial
rently recommended as first-line vasopressor treatment during Registry (ChiCTR1800019408). The study was conducted be-
cesarean section with spinal anesthesia [4]. However, phenyl- tween January to June 2018 at a maternal and child health-
ephrine is associated with a dose-dependent decrease in heart care hospital in Nanjing, China.
rate (HR) and cardiac output. Ephedrine is also a commonly
used vasopressor, with a sympathomimetic activity that ex- Inclusion criteria
erts positive inotropic and chronotropic effects on the heart
via stimulation of a-adrenergic and b-adrenergic receptors and Parturient women were recruited according to the following
is favorable for maintaining uterine blood flow. However, the inclusion criteria: American Society of Anesthesiologists (ASA)
use of ephedrine has potential adverse outcomes including su- status I or II, singleton, non-laboring, scheduled for spinal an-
praventricular tachycardia, tachyphylaxis, reactive hyperten- esthesia and diagnosed with pre-eclampsia. The cut-off blood
sion, and fetal acidemia [5]. Severe fetal acidemia, or fetal ac- pressure (BP) value for pre-eclampsia is ³140/90 mmHg at least
idosis, typically defined as a pH <7.20 in the umbilical artery, twice with an interval of 4 h, comorbid with 24 h proteinuria
can lead to poor neonatal outcomes [6]. ³300 mg or ³1+ with a dipstick. The blood pressure (BP) value
for severe pre-eclampsia is ³160/110 mmHg, comorbid with
Recently, the vasopressor, norepinephrine, has attracted in- one or more of the following abnormalities: thrombocytopenia,
creasing attention in obstetric anesthesia. Norepinephrine has cerebral or visual disturbance; pulmonary edema; liver func-
a weak b-receptor agonist activity and no properties of a-re- tion impairment; and impairment of renal function [14]. Eligible
ceptor agonism. Therefore, norepinephrine might have less parturients were invited to participate in the study immedi-
tendency to decrease HR, resulting in improved maintenance ately after entering the operating room.
of cardiac output when compared with phenylephrine. Also,
norepinephrine has been shown to be likely to increase HR Exclusion criteria
compared with ephedrine, reducing the risk of tachycardia-
related maternal arrhythmia. Current literature indicates that Exclusion criteria included the following: a diagnosis of
the time of onset for the activity of for norepinephrine is less chronic hypertension or comorbid chronic hypertension with
than 60 seconds [7], which is more rapid than for ephedrine, preeclampsia; comorbidity with diabetes mellitus or cardiovas-
which takes 2 or 3 minutes. Also, as a catecholamine, norepi- cular disease; twin gestation; suspected fetal compromise. For
nephrine does not readily cross the placenta, and maternofe- those not willing to participate in the study, standard obstetric
tal transfer has been shown to be 11.6±0.6% in a in vitro per- procedures were used, and their data were not collected.
fused human placental [8].
Wang X. et al.:
Maternal hypotension in preeclampsia
© Med Sci Monit, 2019; 25: 1093-1101
CLINICAL RESEARCH
Allocation to the treatment groups baseline); number of vasopressor boluses required; number of
hypotension episodes (from the emergence of hypotension un-
Allocation to the treatment groups was determined using com- til its recovery to the defined threshold); maternal side effects,
puter-generated random numbers, sealed in an opaque envelope, including nausea, vomiting, dizziness and shivering; and neo-
and held by one of the researchers. Just before spinal anesthesia, natal outcome, including Apgar scores at one minute and five
an allocation number was used to determine which vasopres- minutes; umbilical artery blood gas and pH. Nausea was a self-
sor would be given. In cases of spinal anesthesia failure or when reported sensation to vomit, while vomiting was recorded in
no spinal hypotension was administered, the assigned number case of rhythmic abdominal muscle contraction whether gas-
was automatically allocated to the next subject. Both patient tric contents were expulsed or not, both collectively defined
and anesthesiologist were unaware of the study drug allocation. as intraoperative nausea and vomiting (IONV). An indepen-
dent researcher recorded all hemodynamic variables, as well
Intraoperative monitoring and patient management as maternal and neonatal outcome in this study. Sensory der-
matome block during anesthesia was determined by pinprick
After obtaining written informed consent, the parturient was testing, and if adequate, it reached the T5 distribution, and
positioned in a supine position having a wedge under their surgery commenced. During anesthesia and surgery, all par-
right hip to achieve left uterine displacement (LUD). The an- turients breathed air spontaneously, and additional oxygen
tecubital vein was cannulated with an 18G indwelling needle was given only when the pulse oximeter reading was <95%.
to establish vascular access. A BSM 2351K monitor (Nihon
Kohden, Tomioka, Japan) was attached to detect blood pres- Calculation of sample size
sure (BP), heart rate (HR), and pulse oximetry, with the average
of three consecutive readings was taken as the baseline value. An undesired difference between women receiving norepi-
nephrine and ephedrine is the frequency of tachycardia. In a
Spinal anesthesia was performed with patients in a left lateral pilot study with a sample size of 20, tachycardia occurred at a
position. Hyperbaric bupivacaine 0.5% was injected through rate of 15% and 40% for norepinephrine and ephedrine treat-
a 25-G spinal needle, in a volume of 2.0–2.2 ml, based on the ments, respectively, in parturients with preeclampsia. Using an
patient’s height, at the L2–3 or L3–4 intervertebral space. The a set at 0.05, a b set at 0.20, and the power of the test (1-b) at
parturient was then returned to the LUD position. Immediately 0.80, a minimum of 49 cases per group were needed to detect
preceding intrathecal injection, Ringer’s lactate solution was a statistically significant difference in tachycardia. Considering
infused at a maximum rate of 10 ml/kg. potential dropouts or missing data, the sample size was in-
creased to approximately 55 in each group. Also, the sample
BP and HR were recorded every minute from intrathecal in- size of the phenylephrine group was set to 55, a number that
jection until delivery. Women were randomly allocated to re- was adequate to detect differences in bradycardia between
ceive bolus norepinephrine 4 μg (Group N), phenylephrine the norepinephrine and phenylephrine groups, based on the
50 μg (Group P), or ephedrine 4 mg (Group E) to rescue ma- pilot study data. Bradycardia occurred at a rate of 5% and 30%
ternal hypotension, defined as systolic blood pressure (SBP) after norepinephrine and phenylephrine treatments, resulting
<80% of baseline. One researcher for all patients prepared ei- in a minimum of 36 cases per group required for the statis-
ther norepinephrine, phenylephrine or ephedrine and diluted tically significant difference in the between-group analysis.
by normal saline to 4 μg/ml, 50 μg/ml, or 4 mg/ml, respectively.
Intravenous atropine 0.5 mg was injected for bradycardia (HR Statistical analysis
<60 bpm) comorbid with hypotension, or for HR <50 bpm irre-
spective of blood pressure. The study endpoint was set at de- Data were expressed as the mean ± standard deviation (SD),
livery. An umbilical artery blood sample was collected from a the median, and the interquartile range (IQR), or percentage (%).
double-clamped cord, and blood gas was immediately analyzed Intergroup univariate data were assessed for normality using
using a GEM Premier 3000 system (Synergy Medical Systems the D’Agostino-Pearson omnibus normality test, and one-
LLP, Mumbai, India). One pediatrician evaluated the neonatal way analysis of variance (ANOVA) followed by a two-sample
Apgar score at one minute and at five minutes. t-test or Mann-Whitney test. Nominal data between groups
were analyzed using a chi-squared (c2) test or Fisher’s ex-
Primary and secondary outcomes act test. Standardized SBP and the heart rate (HR) between
groups were also analyzed using a two-step summary mea-
The primary outcome was the overall maternal SBP and HR sure described by Matthews et al. [15]. Standardized SBP and
throughout the observational period. Secondary outcomes mea- HR were first obtained via calculation of the average area un-
sured included the incidence of tachycardia (HR >120 bpm), der the curve (AUC). Then, derived data were compared using
bradycardia (HR <60 bpm), and hypertension (SBP >120% of standard intergroup analysis with a t-test or Mann-Whitney
Wang X. et al.:
© Med Sci Monit, 2019; 25: 1093-1101
test. Statistical analysis was conducted with GraphPad Prism detected and overall SBP over time was also similar among
version 7.0 (GraphPad Inc., San Diego, CA) or Microsoft Excel groups (Figure 2A). The standardized HR over time was higher
2010 (Microsoft Corporation, USA). A P-value <0.05 was con- in group N compared with group P (80.5±12 vs. 76.6±6.9 bpm,
sidered to be statistically significant. P=0.04), with a difference of –4.0±1.9 mmHg (95% confidence
interval [CI], –7.7 to –0.2). The standardized HR was lower in
group N compared with group E (80.5±12 vs. 84.9±7.1 bpm;
Results P=0.02), with a difference of 4.4±1.9 mmHg (95% CI, 0.62–
8.19) (Figure 2B). The incidence of tachycardia, defined as HR
Figure 1 shows the flowchart of parturient enrollment, allo- >120 bpm was consistently lower in group N compared with
cation, follow-up, and analysis. A total of 368 parturients ini- group E (16.1% vs. 36.4%; relative risk [RR]=0.54; 95% CI, 0.29–
tially enrolled. Of these, 56, 55 and 55 parturients in groups 0.90; P=0.02). The incidence of bradycardia, defined as HR <60
N, P, and E, respectively, were analyzed after a strict exclusion bpm, was lower in group N compared with group P (3.6% vs.
and follow-up. Forty-two patients in group N, 40 in group P, 21.8%; RR=0.26; 95% CI, 0.07–0.73; P=0.004). No other he-
and 40 in group E were receiving antihypertensive treatment. modynamic variables tested had statistically significant dif-
There were ten patients in group N, 12 patients in group P, ferences, including the incidence of hypertension, the number
and eight patients in group E who were diagnosed with severe of vasopressor boluses, the number of hypotensive episodes,
preeclampsia, of whom six, five, and five patients, respectively, and the time to first bolus post-intrathecal injection. SBP and
were receiving magnesium sulfate as prophylaxis against sei- HR changes are shown in Figure 2A, 2B for the first 12 min-
zures. Table 1 presents the demographic characteristics of the utes post-spinal anesthesia, a time point with data available
study participants, which showed that all variables were simi- for most parturients.
lar among three study groups.
For maternal side effects (Table 3), fewer reports of intraoper-
In groups N, P, and E, the baseline SBPs were 149±5.7, 150±4.8, ative nausea and vomiting (IONV) were observed for parturi-
and 148±5.5 mmHg and the baseline HRs were 84.4±6.9, ents in group N compared with group E (5.4% vs. 20%; RR=0.39;
84.3±5.1, and 85.4±7.5 bpm, respectively. No intergroup dif- 95% CI, 0.14–0.90; P=0.02). No differences in dizziness or shiv-
ferences were observed (Table 2). Although the SBP was lower ering were observed between groups N and E. The observed in-
in group E compared with groups N and P at the 5 or 6 min- cidence of maternal side effects was similar between groups N
utes after spinal anesthesia, no statistical difference was and P. Neonatal outcome, including birth weight, Apgar scores,
Figure 1. Flowchart of the enrolment of

parturients, group allocation,
Enrollment
Evaluated for eligibility (n=368) follow-up, and data analysis.
Excluded (53)
• Not meeting inclusion criteria (n=42)
• Reluctant to participate (n=11)
Allocation
Randomized (n=315)
Allocated to group N (n=105) Allocated to group P (n=102) Allocated to group E (n=108)

• Failure in spinal anesthesia • Failure in spinal anesthesia • Failure in spinal anesthesia
(n=2) (n=2) (n=3)
• Did not develop post-spinal • Did not develop post-spinal • Did not develop post-spinal
hypotension (n=47) hypotension (n=45) hypotention (n=50)
Follow-up
Final enrolled (n=56) Final enrolled (n=55) Final enrolled (n=55)

• Lost to follow-up (n=0) • Lost to follow-up (n=0) • Lost to follow-up (n=0)
• Intervention discontinued • Intervention discontinued • Intervention discontinued
(n=0) (n=0) (n=0)
Analysis
Final analyzed (n=56) Final analyzed (n=55) Final analyzed (n=55)

• Excluded from analysis (n=0) • Excluded from analysis (n=0) • Excluded from analysis (n=0)
Wang X. et al.:
© Med Sci Monit, 2019; 25: 1093-1101
CLINICAL RESEARCH
Table 1. Demographic characteristics and surgical times.
Demographic characteristics Group N (n=56) Group P (n=55) Group E (n=55)

Age (year) 32±4.1 32±4.4 32±4.4
Height (cm) 162±5.1 162±4.7 163±4.3
Weight (kg) 76.5±8.1 78.5±9.2 76.7±8.4
Gestational age (day) 274±9 273±12 273±3
Repeated cesarean delivery 32 (57%) 36 (65.5%) 37 (67%)
Severe pre-eclampsia 10 (17.8%) 12 (21.8%) 8 (14.5%)
Block dermatome (at 5 min) T5 (T5–T6) T5 (T5–T6) T5 (T5–T6)
Block dermatome (at 15 min) T4 (T3–T5) T4 (T4–T4) T4 (T4–T4)
Fasting time (hour) 11±4 11±3 11±3
Volume of cohydration (ml) 759±92 767±93 740±79
Estimated blood loss (ml) 485±161 485±152 479±149
Time interval
Induction to delivery (s) 650±115 634±80 679±162
Incision to delivery (s) 246±77 250±81 281±107
Uterine incision to delivery (s) 57±36 58±42 58±33
Values are expressed as mean ±SD, number (%), or median (IQR).
Table 2. Maternal hemodynamic variables and drug consumption.
Hemodynamic variables Group N (n=56) Group P (n=55) Group E (n=55)

Baseline SBP (mmHg) 149±5.7 150±4.8 148±5.5
Baseline HR (bpm) 84.4±6.9 84.3±5.1 85.4±7.5
Standardized SBP over time (mmHg) 125.1±8.5 124.2±6.6 123.1±6.8
Standardized HR over time (bpm) 80.5±12*# 76.6±6.9# 84.9±7.1
Tachycardia 9 (16.1%)#
8 (14.6%) #
20 (36.4%)
Bradycardia 2 (3.6%)* 12 (21.8%) #
1 (1.8%)
Hypertension 0 0 0
Number of vasopressor boluses 3 (2–3) 3 (2–3) 3 (2–3)
Number of hypotensive episodes 2 (1.25–3) 2 (2–3) 2 (2–3)
Time to first bolus (min) 5.1±2.0 5.7±1.7 5.6±2.0
Values are expressed as mean ±SD, number (%), or median (IQR). SBP – systolic blood pressure; HR – heart rate. * P<0.05 compared to
group P. # P<0.05 compared to group E.
and umbilical artery blood gas and pH, are shown in Table 4. in group E remained within the normal range. Also, no neonate
Due to insufficient blood samples, inadequate anticoagula- had fetal acidosis, defined as umbilical artery pH <7.20. Group N
tion, or equipment failure, umbilical artery blood gas was not also had a higher base excess (BE) (0.2±1.9 vs. –0.2±1.6; dif-
performed in eight, eight, and 10 subjects in groups N, P, and ference 1.5±0.50; 95% CI, 0.54–2.5; P=0.003), a lower HCO3–
E, respectively. Apgar scores of <7 at 1 min were observed for (22.2±1.5 vs. 24.1±5.8; difference –1.8±0.87; 95% CI, –3.6 to
four, five, and five neonates, in groups N, P, and E, respectively. –0.12; P=0.037), and lactate (1.3±0.3 vs. 1.8±0.5; difference
No neonate had an Apgar score of <9 at 5 min. Although pH- –0.54±0.08; 95% CI, –0.70 to –0.37; P <0.001) compared with
value of umbilical cord blood was higher in group N compared group E, respectively. However, no differences in PO2, PCO2, or
with group E (7.32±0.02 vs. 7.31±0.03l difference –0.02±0.005; glucose were detected between groups N and E. There was no
95% CI, –0.03 to –0.005; P=0.006), the entire range of values difference in uterine arterial blood gas between groups N and P.
Wang X. et al.:
© Med Sci Monit, 2019; 25: 1093-1101
A Figure 2. Serial changes in systolic blood

160 pressure (A) and heart rate (B). Serial
Systolic blood pressure (mmHg)
values for the first 12 measurements

140 when data were available for most
parturients. Data are shown as the
mean ± standard deviation (SD).
120
100
Baseline 1 2 3 4 5 6 7 8 9 10 11 12
(min) Norepinephrine
B Phenylephrine
120
Ephedrine
Heart rate (beats/min)
100
80
60
Baseline 1 2 3 4 5 6 7 8 9 10 11 12
(min)
Table 3. Maternal side effects.
Group N (n=56) Group P (n=55) Group E (n=55)

Nausea 2 (3.6%) 3 (5.5%) 5 (9.1%)
Vomiting 1 (1.8%) 1 (1.8%) 6 (11%)
IONV (nausea + vomiting) 3 (5.4%)
#
4 (7.3%) 11 (20%)
Dizziness 0 1 (1.8%) 2 (3.6%)
Shivering 4 (7.1%) 2 (3.6%) 3 (5.5%)
Values are expressed as number (%). IONV – intraoperative nausea and vomiting. # P<0.05 compared to group E.
Discussion The results from available clinical trials that have studied the
use of vasopressors to rescue spinal hypotension in parturients
The aims of this study were to compare the efficacy and safety with preeclampsia used bolus phenylephrine or ephedrine and
of bolus norepinephrine, phenylephrine, and ephedrine in par- have shown that phenylephrine administration restored mean
turient women with preeclampsia who had hypotension during arterial pressure, but not did not significantly increase mater-
cesarean delivery with spinal anesthesia. The study included 166 nal cardiac output [16]. Small doses of ephedrine can also be
parturient women with preeclampsia who had a baseline sys- used [17], which may restore spinal anesthesia-induced de-
tolic blood pressure (SBP) <80% during spinal anesthesia for ce- crease of peripheral vascular resistance [18] and provide a fa-
sarean section and were allocated into three treatment groups, vorable effect on uteroplacental circulation [19]. Comparative
the bolus norepinephrine (4 μg) group (N), the phenylephrine studies have shown that phenylephrine and ephedrine were
(50 μg) group (P), and the ephedrine (4 mg) group (E). The re- similarly effective in rescuing spinal hypotension, with no dif-
sults showed that treatment with bolus norepinephrine (4 μg), ferences observed in neonate Apgar scores and umbilical artery
phenylephrine (50 μg), and ephedrine (4 mg) were all effective pH in the presence of uteroplacental insufficiency [20]. However,
for managing spinal hypotension in women with preeclampsia. phenylephrine might present more favorable BE and umbilical
Norepinephrine may be associated with fewer cases of bradycar- artery oxygen saturation compared with ephedrine. Despite
dia compared with phenylephrine; simultaneously, fewer cases extensive research, it remains unclear which drug is the bet-
of tachycardia and maternal intraoperative nausea and vom- ter choice for the management of women with preeclampsia.
iting (IONV), and increased pH, base excess (BE), and reduced Many obstetricians prefer both phenylephrine and ephedrine
HCO3–, lactate in umbilical artery blood compared with ephedrine. due to their safety, efficacy, and ease of use.
Wang X. et al.:
© Med Sci Monit, 2019; 25: 1093-1101
CLINICAL RESEARCH
Table 4. Neonatal outcomes.
Group N (n=56) Group P (n=55) Group E (n=55)
Birth weight (g) 3402±428 3446±485 3492±453
Apgar score (0–10)
1-minute 9 (7.25–9) 9 (7–9) 9 (7–9)
5-minute 10 (9–10) 10 (9–10)
1-minute Apgar <7 4 (7.1%) 5 (9.1%) 5 (9.1%)
5-minute Apgar <9 0 0 0
UA blood gas analysis n=48 n=47 n=45
pH 7.32±0.02# 7.32±0.02# 7.31±0.03
pH <7.2 0 0 0
PO2, mmHg 14.5±5.8 13.5±4.4# 15.2±5.2
PCO2, mmHg 50.9±4.1 50.8±4.4 50.4±6.7
HCO3 (mEq/L)
–
22.2±1.5# 21.8±1.1# 24.1±5.8
BE 0.2±1.9# –0.2±1.6# –1.3±2.9
Glucose (mmol/L) 3.5±0.7 3.3±0.8 3.4±0.8
Lactate (mmol/L) 1.3±0.3# 1.2±0.2# 1.8±0.5
Values are expressed as mean ±SD, number (%), or median (IQR). UA – umbilical artery; BE – base excess. # P<0.05 compared to
group E.
Recently, norepinephrine has been proposed as a promising hypertension. Also, patients with preeclampsia have a lower
vasopressor for treatment of maternal spinal hypotension in incidence of spinal hypotension that requires fewer vasopres-
low-risk normotensive pregnancies without obvious maternal sors [3]. Therefore, a prophylactic infusion paradigm may not
or neonatal adverse outcome. Compared with phenylephrine, be reasonable.
norepinephrine is associated with fewer cases of bradycardia
and a greater cardiac output [10]. Also, either computer con- The relative potency of norepinephrine and phenylephrine when
trolled closed loop feedback [9] or manually controlled variable used to rescue the first episode of spinal hypotension in nor-
rate infusion of norepinephrine [21] provided a more accurate motensive women is estimated to be nearly 13: 1 [24], while
blood pressure control compared with an equivalent dose of phenylephrine versus ephedrine is estimated 80: 1 [25]; thus
phenylephrine infusion or norepinephrine bolus without in- a potency ratio of approximately 1000: 1 is indirectly obtained
creasing maternal or neonatal adverse outcome. for norepinephrine and ephedrine. As the commonly used clin-
ical dose for phenylephrine is 100 μg to rescue maternal hypo-
However, before this study, the feasibility of norepinephrine had tension in normotensive women, smaller dosing was selected
not been explored for women with preeclampsia with utero- of norepinephrine 4 μg or ephedrine 4 mg for hypotensive pa-
placental insufficiency. Na et al. [22] compared maternal nor- tients who had preeclampsia, both being equivalent to phenyl-
epinephrine in pregnant women with preeclampsia and nor- ephrine 50 μg. The number of top-up doses required was the
motensive pregnant women and found that parturients with same for groups N, P, and E (median=3, IQR: 2–3), indicating
preeclampsia had prominently increased levels of norepineph- a similar efficacy in all three vasopressors to rescue maternal
rine, raising the concern regarding whether women with pre- hypotension. Equivalent dosing is important to ensure that
eclampsia would remain sensitive to exogenous norepineph- dosing bias does not influence the comparison of clinical effi-
rine. In this study, intermittent boluses were applied rather cacy. In one recently published study, Ali et al. [26] compared
than the continuous infusion of norepinephrine or ephedrine a 5 μg bolus dose of norepinephrine with a 10 mg bolus dose
to rescue spinal hypotension. Although prophylactic infusion of ephedrine to maintain arterial blood pressure during cesar-
is a recommended paradigm for rescuing spinal hypotension ean section with spinal anesthesia. Because this dose of nor-
to minimize hemodynamic fluctuation and maternal side ef- epinephrine halved the potency of ephedrine, it was not un-
fects [23], it may be related to a higher incidence of reactive expected that more norepinephrine boluses were required.
Wang X. et al.:
© Med Sci Monit, 2019; 25: 1093-1101
A recent study compared a 10 μg dose of norepinephrine normal [32]. Also, in a recently published clinical trial that com-
with 5 mg of ephedrine to treat anesthesia-induced hypoten- pared treatment with bolus phenylephrine and ephedrine for
sion in hypertensive patients undergoing spinal surgery, and spinal hypotension in women with severe preeclampsia, fetal
showed that this dose of norepinephrine had twice the po- acid-base status was found to be independent of the use of
tency of ephedrine, resulting in fewer hypotensive events, the vasopressor [33]. Therefore, the observed lower pH value for
need for fewer vasopressor doses to rescue the first episode women receiving ephedrine is unlikely to have clinical signif-
of hypotension, and fewer doses in total [27]. In the present icance. Also, in women receiving norepinephrine and phenyl-
study, despite a similar efficacy for the maintenance of SBP, ephrine, there was a higher BE, and lower HCO3–, lactate, which
there was a significant difference in maternal HR after treat- are measures of fetal acid-base status and metabolic markers.
ment of the three vasopressors used. The overall HR was the It might be assumed that such differences mainly resulted from
highest in parturients receiving ephedrine, followed by nor- a greater placental transfer of ephedrine due to its higher lipid
epinephrine, and was lowest with phenylephrine, which was solubility when compared with catecholamines such as nor-
consistent with their respective pharmacological properties. epinephrine or phenylephrine, and the followed stimulation of
All hemodynamic variables, as well as maternal and neonatal fetal b-adrenergic receptors to increase fetal metabolism [34].
outcome in this study were recorded by an independent re-
searcher, to minimize possible investigator bias. For maternal An significant concern when using a vasopressor with an
outcome, norepinephrine treatment was observed to result in a-agonist is the reduction in uteroplacental blood flow. Previous
fewer cases of IONV when compared with ephedrine. The eti- studies have shown phenylephrine is associated with a lower
ology of IONV is recognized to be multifactorial and reactive umbilical artery or umbilical venous PO2 when compared with
treatment of established hypotension, as used in the present ephedrine, possibly attributable to its greater vasoconstriction
study, has previously been reported to be related to an in- property, resulting in a reduction of uteroplacental perfusion
creased incidence of IONV when compared with prophylactic and an increase in oxygen extraction [35]. However, norepineph-
vasopressor infusion before the onset of hypotension [28]. In rine restored the decreased peripheral vascular resistance less
2004, Ngan Kee et al. compared phenylephrine infusion regi- than phenylephrine [9]. In 2010, Minzter et al. [36] reported that
mens based on three different BP thresholds and showed that norepinephrine had no effect on fetal arterial perfusion pres-
for optimal management, phenylephrine should be adjusted to sure and fetoplacental microcirculation was not compromised.
maintain maternal BP at near-baseline values [29]. Importantly, In the present study, no difference in fetal umbilical artery PO2
ephedrine has been shown to have a duration of onset of be- was detected, suggesting that norepinephrine might not com-
tween two and three minutes, resulting in slower correction promise fetal oxygen supply when compared with ephedrine in
of hypotension when compared with norepinephrine or phen- a bolus regimen. A bolus of norepinephrine (4 μg) has a similar
ylephrine, which act within 60 seconds after injection [30]. efficacy for rescuing maternal hypotension but was associated
with fewer cases of bradycardia compared with phenylephrine
There may have been several factors that contributed to the (50 μg), as well as more infrequent maternal tachycardia, IONV,
development of IONV, including maternal demographics and a a greater neonatal acid-base status, and umbilical artery pH
previous history of IONV or motion sickness, operative proce- compared with ephedrine (4 mg).
dures, use of perioperative opioids, or peritoneal traction [31].
However, these details were not collected in the present study, This study had several limitations. Uterine arterial blood flow
and their possible involvement in the IONV difference found be- was not measured to directly observe the effect of vasopres-
tween the groups was not explored, which should be regarded sors on uteroplacental perfusion, which is an important con-
as a limitation that requires further study. In this study, the neo- sideration for women with preeclampsia. Secondly, other than
natal Apgar scores were measured as an indicator of neonatal BP, the other contributors to an increased incidence of IONV
well-being in the first minutes after birth, as well as umbilical observed in women receiving ephedrine were not fully verified.
artery blood gas and pH, which is useful to assess fetal condi- Finally, the study endpoint was set at delivery, and whether
tion immediately before delivery. There were no observed dif- or not norepinephrine has similar efficacy and safety for he-
ferences in Apgar score at one minute or five minutes among modynamic management throughout surgery required fur-
the three study groups, and no differences in umbilical artery ther investigation.
pH between groups N and P. However, a higher umbilical ar-
tery pH value was observed in women receiving norepineph-
rine and phenylephrine when compared with those treated Conclusions
with ephedrine (7.32±0.02 and 7.32±0.02 versus 7.31±0.03).
However, the entire range of pH-values in group E was still A bolus dose of norepinephrine (4 μg) showed similar efficacy
within the normal range, and no neonate experienced fetal for the maintenance of systolic blood pressure (SBP) when
acidosis, defined as pH value <7.2, which is the lower limit of compared with bolus doses of phenylephrine (50 μg) and
Wang X. et al.:
© Med Sci Monit, 2019; 25: 1093-1101
CLINICAL RESEARCH
ephedrine (4 mg) in parturient women with preeclampsia with rescue maternal hypotension in parturients with preeclampsia
hypotension during spinal anesthesia and cesarean section. during spinal anesthesia and cesarean section.
However, there was improved maternal safety for norepineph-
rine (4 μg) when compared with phenylephrine (50 μg) and Conflict of interest
improved maternal and neonatal safety when compared with
ephedrine (4 mg). Therefore, bolus norepinephrine may act None.
as a promising alternative to phenylephrine or ephedrine to
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CLINICAL RESEARCH

* Xian Wang and Mao Mao contributed equally to this study

MeSH Keywords: Ephedrine • Norepinephrine • Pre-Eclampsia • Treatment Outcome • Phenylephrine

Full-text PDF: https://www.medscimonit.com/abstract/index/idArt/914143

3916 4 2 36

Background In low-risk normotensive parturients, several studies have now

Figure 1. Flowchart of the enrolment of

Evaluated for eligibility (n=368) follow-up, and data analysis.

Allocated to group N (n=105) Allocated to group P (n=102) Allocated to group E (n=108)

Final enrolled (n=56) Final enrolled (n=55) Final enrolled (n=55)

Final analyzed (n=56) Final analyzed (n=55) Final analyzed (n=55)

Table 1. Demographic characteristics and surgical times.

Demographic characteristics Group N (n=56) Group P (n=55) Group E (n=55)

Values are expressed as mean ±SD, number (%), or median (IQR).

Table 2. Maternal hemodynamic variables and drug consumption.

Hemodynamic variables Group N (n=56) Group P (n=55) Group E (n=55)

A Figure 2. Serial changes in systolic blood

values for the first 12 measurements

Table 3. Maternal side effects.

Group N (n=56) Group P (n=55) Group E (n=55)

Table 4. Neonatal outcomes.

Group N (n=56) Group P (n=55) Group E (n=55)

Birth weight (g) 3402±428 3446±485 3492±453

Apgar score (0–10)

1-minute 9 (7.25–9) 9 (7–9) 9 (7–9)

5-minute 10 (9–10) 10 (9–10)

1-minute Apgar <7 4 (7.1%) 5 (9.1%) 5 (9.1%)

5-minute Apgar <9 0 0 0

UA blood gas analysis n=48 n=47 n=45

pH 7.32±0.02# 7.32±0.02# 7.31±0.03

PO2, mmHg 14.5±5.8 13.5±4.4# 15.2±5.2

PCO2, mmHg 50.9±4.1 50.8±4.4 50.4±6.7

BE 0.2±1.9# –0.2±1.6# –1.3±2.9

Glucose (mmol/L) 3.5±0.7 3.3±0.8 3.4±0.8

Lactate (mmol/L) 1.3±0.3# 1.2±0.2# 1.8±0.5

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Figure 1. Flowchart of the enrolment of

A Figure 2. Serial changes in systolic blood