A Quantitative, Systematic Review of Randomized Controlled
Trials of Ephedrine Versus Phenylephrine for the
Management of Hypotension During Spinal Anesthesia for
Cesarean Delivery
Anna Lee, MPH, PhD, Warwick D. Ngan Kee,
Tony Gin, MBChB, MD, FANZCA, FRCA
Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Prince of Wales Hospital, China
This quantitative systematic review compared the effi-
cacy and safety of ephedrine with phenylephrine for the
prevention and treatment of hypotension during spinal
anesthesia for cesarean delivery. Seven randomized con-
trolled trials (n ⫽ 292) were identified after a systematic
search of electronic databases (MEDLINE, EMBASE, The
Cochrane Controlled Trials Registry), published articles,
and contact with authors. Outcomes assessed were mater-
nal hypotension, hypertension and bradycardia, and neo-
natal umbilical cord blood pH values and Apgar scores.
For the management (prevention and treatment) of ma-
ternal hypotension, there was no difference between
phenylephrine and ephedrine (relative risk [RR] of
1.00; 95% confidence interval [CI], 0.96 –1.06). Maternal
H
ypotension during spinal anesthesia for cesarean
delivery can have detrimental effects on both
mother and neonate; these effects include de-
creased uteroplacental blood flow, impaired fetal oxy-
genation with asphyxial stress and fetal acidosis, and
maternal symptoms of low cardiac output, such as nau-
sea, vomiting, dizziness, and decreased consciousness
(1). Therefore, there has been much attention in the lit-
erature to methods of preventing and treating hypoten-
sion in obstetric anesthesia. Uterine displacement is rou-
tine, whereas the use of IV fluid preload is controversial
(2). Despite these conservative measures, a vasopressor
drug is often required. The drug usually recommended
Presented, in part, at the combined scientific meeting of The
Australian and New Zealand College of Anaesthetists and The
Hong Kong College of Anaesthesiologists, Hong Kong, China, May
5–9, 2001.
Accepted for publication November 27, 2001.
Address correspondence to Anna Lee, PhD, Department of An-
aesthesia and Intensive Care, The Chinese University of Hong
Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China.
Address e-mail to annalee@cuhk.edu.hk.
920 Anesth Analg 2002;94:920–6
MBChB, MD, FANZCA, and
bradycardia was more likely to occur with phenylephrine
than with ephedrine (RR of 4.79; 95% CI, 1.47–15.60).
Women given phenylephrine had neonates with higher
umbilical arterial pH values than those given ephedrine
(weighted mean difference of 0.03; 95% CI, 0.02– 0.04).
There was no difference between the two vasopressors in
the incidence of true fetal acidosis (umbilical arterial pH
value of ⬍7.2; RR of 0.78; 95% CI, 0.16 –3.92) or Apgar
score of ⬍7 at 1 and 5 min. This systematic review does not
support the traditional idea that ephedrine is the pre-
ferred choice for the management of maternal hypoten-
sion during spinal anesthesia for elective cesarean deliv-
ery in healthy, nonlaboring women.
(Anesth Analg 2002;94:920 –6)
in this context is ephedrine, which is effective in restor-
ing maternal arterial pressure after hypotension (1).
Despite the wide acceptance of ephedrine as the va-
sopressor of choice for obstetric anesthesia (1,3), its su-
periority over other vasopressors has not been clearly
defined. Historically, ephedrine was recommended on
the basis of observations in pregnant sheep that showed
it was more effective for increasing arterial pressure with
better preservation of uteroplacental blood flow com-
pared with other vasopressors (4,5). This was explained
by ephedrine’s predominant ␤-effect that caused an in-
crease in arterial pressure by increasing cardiac output
rather than by vasoconstriction. Accordingly, the use of
pure ␣-agonists such as phenylephrine has generally
been avoided because of concerns about their potential
adverse effect on uterine blood flow (4,5).
Extrapolation from animal studies to humans may
not be appropriate because there are species differ-
ences and differences in dose, titration, and duration
of the administration and use of IV prehydration to
consider. Results of several trials suggest that phenyl-
ephrine (6 –9) may have similar efficacy to ephedrine
©2002 by the International Anesthesia Research Society
0003-2999/02
ANESTH ANALG
2002;94:920 –6
for preventing and treating hypotension during spinal
anesthesia. However, the relative effects of these va-
sopressors on neonatal outcome are unclear.
Therefore, we undertook a quantitative, systematic
review of randomized controlled trials (RCTs) of
ephedrine versus phenylephrine in women having
spinal anesthesia for cesarean delivery. Our objectives
were to examine whether ephedrine and phenyleph-
rine were different in their efficacy for managing ma-
ternal hypotension and their risk of adverse neonatal
outcome. In the absence of a large RCT, which would
require considerable time and resources to answer
these questions, we chose to evaluate the current
available evidence using a quantitative, systematic
review.
Methods
Information Retrieval
We performed a systematic search on electronic data-
bases (MEDLINE 1966 –June 2001, EMBASE 1988 –
June 2001, Cochrane Controlled Trials Register). The
electronic search strategy included the optimal sensi-
tive search strategy (10) for identifying RCTs with the
following medical subject heading terms and text
words: “spinal anesthesia,” “hypotension,” “cesarean
section,” “pregnancy complications,” “pregnancy out-
come,” “fetal outcome,” “neonatal outcome,” “umbilical
cord blood gases,” “vasopressors,” “phenylephrine,”
and “ephedrine.” Additional reports were identified
from reference lists of retrieved reports, review articles of
hypotension during spinal anesthesia, and review arti-
cles of vasopressors. We contacted authors of the RCTs
included in this systematic review (6–9,11–13) for further
published and unpublished trials that had not been iden-
tified in our original search. Although there was no
language restriction, all RCTs included in this systematic
review were published in English.
Eligibility of Articles
Full reports of RCTs that examined the effect of ephed-
rine compared with phenylephrine for managing ma-
ternal hypotension during spinal anesthesia or com-
bined spinal-epidural anesthesia for cesarean delivery
were included in this systematic review. We consid-
ered any trials of ephedrine and phenylephrine ad-
ministered before, during, or immediately after the
induction of spinal anesthesia regardless of dose or
mode of the administration.
Outcome Measures
The outcomes collected were maternal hypotension,
hypertension and bradycardia, uterine and umbilical
blood circulation, Apgar scores at 1 and 5 min, and
OBSTETRIC ANESTHESIA LEE ET AL. 921
VASOPRESSORS AND SPINAL HYPOTENSION
umbilical arterial and venous pH values and standard
base excess. We did not attempt to standardize the
definitions of the above outcomes but rather used the
authors’ primary definition for the meta-analysis. In
the paper by Alahuhta et al. (6), there were several
definitions of hypotension; we used their primary def-
inition of hypotension (decrease in systolic arterial
pressure of ⬎10 mm Hg from baseline) rather than
their alternative definition of systolic arterial pressure
of ⬍90 mm Hg.
Data Extraction
The selection of trials for inclusion in the systematic
review was performed independently by the review-
ers (Lee and Ngan Kee) after using the search strategy
described above. Trials were examined for duplicate
data. Data were abstracted independently by Lee and
Ngan Kee using a standardized data collection form.
There was no attempt to blind the reviewers to the
authors or results of the relevant trials. Details of
anesthetic technique, study population, prehydration,
uterine displacement, and definition of maternal hy-
potension were collected. Where appropriate, the pri-
mary author of a RCT was contacted for clarification
of data. Discrepancies were resolved by discussion, or
advice was sought from a third party (Gin).
Quality Assessment
The quality of the eligible trials was assessed indepen-
dently. The level of allocation concealment, defined as
the process used to prevent the foreknowledge of
group assignment in a RCT, was graded as A (ade-
quate), B (unclear), or C (inadequate), as previously
described (14). Blinding, losses to follow-up, and
whether the authors did a sample size calculation
before trial commencement were recorded.
Statistical Analysis
For the purpose of this systematic review, ephedrine
was considered the control group for all meta-
analyses. In one RCT (8), we combined dichotomous
data (hypotension, hypertension, bradycardia, and
Apgar scores of ⬍7) from the two arms of ephedrine.
For continuous data (umbilical arterial and venous pH
values and standard base excess), the lowest ephed-
rine dose arm was chosen for comparison with phen-
ylephrine. In another RCT (13), we combined dichot-
omous data (hypotension, hypertension, bradycardia,
and Apgar scores of ⬍7) from the two arms of phen-
ylephrine. The highest phenylephrine dose arm was
chosen for comparison with ephedrine for umbilical
venous pH values.
The DerSimonian and Laird random-effects model
was used to combine data for both continuous and
dichotomous outcomes because the treatment and
922 OBSTETRIC ANESTHESIA LEE ET AL.
VASOPRESSORS AND SPINAL HYPOTENSION
conditions in these studies were expected to have
some heterogeneity. This model incorporates both
between-study (different treatment effects) and
within-study (sampling error) variability and is
more conservative than a fixed-effects model (15).
The random-effects model has been recommended
as the approach for meta-analysis and is more real-
istic than the fixed-effects model (15). The pooled
relative risk (RR) and 95% confidence intervals
(CI) were calculated for dichotomous data. The
weighted mean difference (WMD) method was used
to pool continuous data. Heterogeneity was ana-
lyzed using the Q-statistic with a threshold for the P
value of ⬍0.10. If there was significant heterogene-
ity, the data were not pooled, and reasons for het-
erogeneity were sought. Sensitivity analyses accord-
ing to the quality of RCTs were not performed
because there were too few trials. All meta-analyses
were done using Arcus Quickstat software (version
1.2; Addison Wesley Longman Ltd, Cambridge,
England).
Results
Trials Included
Eight trials were found (6 –9,11–13,16), but one (16)
was excluded because epidural anesthesia was used.
Table 1 shows the seven RCTs (n ⫽ 292) of ephedrine
versus phenylephrine (6 –9,11–13) included in this sys-
tematic review. No additional trials were identified
after contacting the authors of the RCTs included in
this systematic review. The mode of ephedrine and
phenylephrine administration varied between trials
and included IV bolus doses (7,9,11,12), IV bolus fol-
lowed by infusion (6,8), and IM (13). In all trials,
ephedrine and phenylephrine were administered im-
mediately after the induction of spinal anesthesia.
Ephedrine and phenylephrine were used for the pre-
vention (6,8,13) and treatment (7,9,11,12) of hypoten-
sion (Table 1).
Characteristics of Patients
In all RCTs, the women were described as healthy or
were graded as ASA physical status I. There were no
reports of trials recruiting women undergoing emer-
gency cesarean delivery, and therefore, we have as-
sumed that all trials included in this systematic review
involved nonlaboring women undergoing elective ce-
sarean delivery. Drugs used for spinal anesthesia in-
cluded bupivacaine (6,7,9,12) and hyperbaric bupiva-
caine (8,11,13). All trials specified the use of uterine
displacement. Lactated Ringer’s solution was the most
common prehydration given (7–9,11–13). Combined
spinal-epidural anesthesia was used in one trial (13).
ANESTH ANALG
2002;94:920 –6
Quality of Trials
There was adequate allocation concealment in two
trials (7,13). The other trials had unclear allocation
concealment (6,8,9,11,12). All were double-blinded tri-
als. In one trial (11), three women in the Ephedrine
group and one in the Phenylephrine group were with-
drawn because their umbilical arterial pH value was
⬍7.25 before data-analysis. Sample size was estimated
before trial commencement in two trials (7,13).
Maternal Outcome Measures
Hypotension. All trials gave specific definitions of
maternal hypotension (Table 1). For the management
of hypotension (prevention and treatment), there was
no difference between the Phenylephrine and Ephed-
rine groups (RR of 1.00; 95% CI, 0.96 –1.06) (6 –9,11–
13). After limiting the analysis to trials for treatment of
maternal hypotension, there was no difference be-
tween the Phenylephrine and Ephedrine groups (RR
of 1.00; 95% CI, 0.95–1.05) (7,9,11,12). There was no
difference in the risk of hypotension between women
given phenylephrine or ephedrine for the prevention
of maternal hypotension (RR of 1.09; 95%CI, 0.71–1.69)
(6,8,13).
Hypertension. Three trials collected data on hyper-
tension (8,9,13). It was defined as ⬎20% of baseline
systolic arterial pressure for 3 min (8), systolic blood
pressure of ⬎140 mm Hg (9), and mean arterial blood
pressure of ⬎25% of baseline values (13). There was
no difference in the risk of hypertension between the
Phenylephrine and Ephedrine groups (RR of 0.65; 95%
CI, 0.08 –5.13; n ⫽ 170).
Bradycardia. Four trials (6 – 8,13) collected data on
maternal bradycardia. Definitions of bradycardia
varied: heart rate ⬍40 bpm (8), heart rate ⬍60 bpm
requiring atropine treatment (7), and heart rate
⬍60 bpm (13). We noted that one patient was with-
drawn from a trial (6) because of bradycardia (not
defined). Bradycardia did not occur in either the
Ephedrine or Phenylephrine groups in one trial (13).
Atropine was required in 11 of 19 women in the
Phenylephrine (median dose of 600 ␮g) group com-
pared with 2 of 19 in the Ephedrine (median dose of
20 mg) group (7). Patients in the Phenylephrine
group were more likely than the Ephedrine group to
develop bradycardia (RR of 4.79; 95% CI, 1.47–15.60)
(7,8,13).
Uteroplacental Circulation. Data from two studies of
uterine and umbilical Doppler velocimetry were not
pooled because of differences in data presentation.
In one trial, the mean maternal uterine and placental
arcuate pulsatility indices increased significantly in
the Phenylephrine group compared with the Ephed-
rine group (P ⬍ 0.01), suggesting that phenyleph-
rine was associated with increased vascular resis-
ANESTH ANALG OBSTETRIC ANESTHESIA LEE ET AL. 923
2002;94:920 –6 VASOPRESSORS AND SPINAL HYPOTENSION

Table 1. Characteristics of Included Trials

Study Participants Anesthesia Intervention Outcomes

Moran 1991 (9), USA 61 healthy Prehydration 2.0 L lactated
women Ringer’s solution 15–
20 min before induction.
Left uterine displacement
15 degree tilt. Bupivacaine
7.5–15 mg.
Alahuhta 1992 (6), Finland 17 healthy Prehydration 20 mL/kg
women, balanced electrolyte
mean age solution over 20 min
29–30 yr before induction. Left
lateral tilt. Bupivacaine
11.5–13 mg.
Hall 1994 (8), UK 29 healthy Prehydration lactated
women, Ringer’s solution 20 mL/
mean age kg IV. Left lateral tilt using
30–32 yr wedge. Hyperbaric
bupivacaine 13.75–15 mg.
Ephedrine 10 mg IV bolus for a decrease
⬎5 mm Hg from baseline SBP followed by
5–10 mg to maintain maternal SBP
⬎100 mm Hg.
Phenylephrine 80 ␮g IV bolus for a decrease
⬎5 mm Hg from baseline SBP followed by
40 to 80 ␮g to maintain maternal SBP
⬎100 mm Hg.
Ephedrine 5 mg IV bolus followed by
0.83 mg/min infusion. If hypotension
occurred, rescue 5 mg IV bolus given.
Phenylephrine 100 ␮g IV bolus followed by
16.7 ␮g/min infusion. If hypotension
occurred, rescue 100 ␮g IV bolus given.
Rescue: IV bolus of relevant vasopressor
given.
Ephedrine 6 mg IV bolus and 1 mg/min IV
infusion for 30 min.
Ephedrine 6 mg IV bolus and 2 mg/min IV
infusion for 30 min.
Phenylephrine 20 ␮g IV bolus and 10 ␮g/
min IV infusion for 30 min.
Hypotension (SBP ⬍100 mm Hg),
hypertension (SBP ⬎140 mm
Hg), Apgar scores, umbilical
arterial and venous pH, and
standard base excess.
Hypotension (decrease in SAP
⬎10 mm Hg from baseline) or
number of patients requiring
extra boluses, moderate
hypotension defined as SAP
⬍90 mm Hg. Uterine artery PI,
Apgar scores, and umbilical
arterial and venous pH.
Hypotension (decrease in SAP
⬎20% of baseline), hypertension
(increase in SAP ⬎20% baseline
for 3 min), bradycardia (HR
⬍40), Apgar scores, umbilical
arterial and venous pH, and
standard base excess.

Rescue: IV bolus of relevant vasopressor

Pierce 1994 (11), USA 26 ASA I Prehydration 2.0 L lactated
women, Ringer’s solution about
mean age 32 30 min before induction.
yr Left uterine displacement.
Hyperbaric bupivacaine
7.5–15 mg with 10 ␮g
fentanyl.
LaPorta 1995 (12), USA 40 ASA I Prehydration 1.5–2.0 L
women, lactated Ringer’s solution.
mean age Left lateral tilt.
31–33 yr Bupivacaine 7.5–15 mg.
Thomas 1996 (7), UK 38 healthy Prehydration 1.5 L lactated
women, Ringer’s solution 10–
mean age 15 mL/min. Left modified
27–30 yr supine. Bupivacaine
12.5 mg.
Ayorinde 2001 (13), UK 81 women, Prehydration 500 mL
mean age lactated Ringer’s solution.
30–31 yr Left lateral 15 degree tilted
position. Hyperbaric
11 mg bupivacaine with
fentanyl 20 ␮g.
given.
Ephedrine 5–10 mg increments to maintain
SBP ⬎100 mm Hg and within 90% baseline
SBP.
Phenylephrine 40 to 80 ␮g increments to
maintain SBP ⬎100 mm Hg and within
90% baseline SBP.
Ephedrine 10 mg initial IV bolus for a
decrease SBP, followed by 5–10 mg to
maintain SBP ⬎100 mm Hg.
Phenylephrine 80 ␮g initial IV bolus for a
decrease SBP, followed by 40–80 ␮g to
maintain SBP ⬎100 mm Hg.
Ephedrine 5 mg IV bolus for maintenance
SAP.
Phenylephrine 100 ␮g IV bolus for
maintenance SAP.
Ephedrine 45 mg IM given immediately after
spinal anesthesia.
Phenylephrine 2 mg IM given immediately
after combined spinal-epidural anesthesia.
Phenylephrine 4 mg IM given immediately
after combined spinal-epidural anesthesia.
Hypotension (SBP ⬍100 mm Hg
and decrease ⬎10% of baseline).
Umbilical arterial and venous
pH.
Hypotension (SBP ⬍100 mm Hg),
Apgar scores, umbilical artery
and venous pH, and standard
base excess.
Hypotension (decrease in SAP
⬎10% of baseline), bradycardia
(HR ⬍60 requiring atropine),
umbilical artery PI, Apgar
scores, umbilical arterial pH,
and standard base excess.
Hypotension (⬎25% decrease in
MAP), hypertension (⬎25%
increase in MAP), bradycardia
(HR ⬍60), Apgar scores, and
umbilical venous pH.

Rescue: Ephedrine 6 mg IV bolus given.

ASA ⫽ American Society of Anesthesiologists physical status; HR ⫽ heart rate; IM ⫽ intramuscular; IV ⫽ intravenous; MAP ⫽ mean arterial blood pressure;
PI ⫽ pulsatility index; SAP ⫽ systolic arterial pressure; SBP ⫽ systolic blood pressure.

tance in uterine and umbilical vessels (6). In con- Neonatal Outcome Measures
trast, there was no change in the uterine arterial
pulsatility index during spinal anesthesia in the Apgar Scores. Six trials (6 –9,12,13) measured Apgar
other trial (7). scores at 1 and 5 min. At 1 min, there was one neonate
924 OBSTETRIC ANESTHESIA LEE ET AL.
VASOPRESSORS AND SPINAL HYPOTENSION
Figure 1. Meta-analysis of trials. The effect of phenylephrine versus
ephedrine on umbilical cord arterial blood pH. Data are mean
difference with 95% confidence intervals.
with an Apgar score of ⬍7 in the Ephedrine group
compared with no neonate in the Phenylephrine group
(9). At 5 min, no neonate in the Ephedrine or Phenyl-
ephrine groups had an Apgar score of ⬍7 (6 –9,12,13).
There was no difference in the risk of low Apgar scores
(⬍7) between the Phenylephrine and Ephedrine groups
at 1 min (RR of 0.77; 95% CI, 0.17–3.51) (6 –9,12,13) or at
5 min (RR of 1.00; 95% CI, 0.21– 4.83) (6 –9,12,13).
Umbilical Cord Blood Gases. Pooling the six trials
(6 –9,11,12) (n ⫽ 200) showed that women given phen-
ylephrine had neonates with higher umbilical arterial
pH values than those given ephedrine (WMD ⫽ 0.03;
95% CI, 0.02– 0.04, mean ephedrine umbilical arterial
pH values ranging from 7.27 to 7.29; Figure 1). This
analysis would be expected to be conservative because
three patients in the Ephedrine group and one patient
in the Phenylephrine group were excluded in the trial
by Pierce et al. (11) because of an umbilical arterial pH
value of ⬍7.25. Women given phenylephrine had ne-
onates with greater venous pH values than those
given ephedrine (WMD ⫽ 0.02; 95% CI, 0.01– 0.03,
mean ephedrine venous pH values ranging from 7.29
to 7.35) (6,8,9,11–13).
Arterial standard base excess was greater in the
Phenylephrine group compared with the Ephedrine
group (WMD ⫽ 1.41; 95% CI, 0.81–2.02, mean ephed-
rine arterial standard base excess ranging from ⫺2.90
to ⫺1.51) (7–9,12). Three trials (8,9,12) showed that
venous standard base excess was greater in the Phen-
ylephrine group compared with the Ephedrine group
(WMD ⫽ 1.23; 95% CI, 0.77–1.69, mean ephedrine
venous standard base excess ranging from ⫺2.00 to
0.14).
Fetal Acidosis. The risk of true fetal acidosis, which
we defined as an umbilical arterial pH value of ⬍7.20
(17), was similar between the Phenylephrine and
ANESTH ANALG
2002;94:920 –6
Ephedrine groups (RR of 0.78; 95% CI, 0.16 –3.92)
(6,7,12).
Discussion
In this systematic review, we showed that there was
no difference between ephedrine and phenylephrine
in their efficacy for managing hypotension in the
range of doses that have been studied. However, our
review showed that women given phenylephrine had
neonates with higher umbilical cord blood pH values
than women given ephedrine, although the risk of
true fetal acidosis (umbilical arterial pH value of
⬍7.20) was similar. We found no clear evidence that
phenylephrine was associated with decreased uterine
blood flow because there were few RCTs examining
this issue. On the contrary, acidotic changes in umbil-
ical arterial pH are sensitive indicators of reduced
uteroplacental perfusion (18). Our finding is indirect
evidence that uterine blood flow may in fact be better
with phenylephrine compared with ephedrine.
The exact reasons why ephedrine is associated with
lower umbilical cord blood pH values compared with
phenylephrine are unclear. In many studies of ephed-
rine, relatively large total doses of ephedrine were re-
quired to maintain maternal arterial pressure (8,9,12).
This may be related to the fact that ephedrine exhibits
marked tachyphylaxis because its sympathomimetic ef-
fects are largely indirect, arising from the release of nor-
adrenaline from postganglionic sympathetic nerve end-
ings that may become depleted after repeated dosing
(19). Furthermore, ephedrine has a relatively slow onset
of action and long duration of action. These factors mean
that ephedrine may be difficult to titrate, especially when
given by IV infusion compared with direct-acting vaso-
pressors (20), which may contribute to suboptimal con-
trol of arterial pressure. Finally, ephedrine crosses the
placenta (21); therefore, it is possible that ephedrine may
have a direct effect on the fetus that contributes to
acidosis.
Of concern was that maternal bradycardia oc-
curred more frequently with phenylephrine than
with ephedrine. This is to be expected because an
increase in blood pressure with an ␣-agonist may
lead to reactive bradycardia. However, this was re-
sponsive to atropine treatment without adverse con-
sequences (7,8). The incidence of isolated phenyle-
phrine-related maternal bradycardia (heart rate
⬍60 bpm) was highest (58%) in one trial when large
doses of phenylephrine were used (7). The authors
suggested that maternal bradycardia was contrib-
uted to by cardiac sympathetic denervation because
the sensory block was high (7). Therefore, an
ephedrine-phenylephrine combination may help
prevent maternal bradycardia, as the ␤-mimetic ef-
fect of ephedrine would counteract this mechanism.
ANESTH ANALG
2002;94:920 –6
This may explain why the incidence of phenyle-
phrine-related maternal bradycardia was lower
when phenylephrine was used as prophylaxis with
rescue ephedrine (8,13) than when phenylephrine
was used for treating maternal hypotension (7).
The clinical implications of our findings are argu-
able. Although we have shown that ephedrine was
associated with lower umbilical cord blood pH values
compared with phenylephrine, both groups had sim-
ilar efficacy for preventing or treating hypotension,
and there was no difference in clinical neonatal
outcome as measured by Apgar scores. Brief periods
of hypotension can alter maternal and neonatal
acid-base values, but this did not affect neurobehav-
ioral performances at 24 hours of age (22). Nonethe-
less, because an objective of obstetric care should be
to deliver the fetus in the best condition possible, we
believe that the role of ephedrine as the only vaso-
pressor of choice in obstetric patients should be
seriously questioned.
The applicability of the results of this quantitative
systematic review was limited to healthy women
with term fetuses. We found no trials evaluating the
effects of vasopressors in women who were in labor,
had a compromised or preterm fetus, or had hyper-
tension. Extrapolation of our findings to these cir-
cumstances may not be valid. The quality of the
trials included in this systematic review was fair.
Only two of seven trials in this review had adequate
allocation concealment. Compared with trials with
adequate allocation concealment, trials with unclear
allocation concealment have been shown to exagger-
ate the treatment effect by 30% (14). Therefore, it is
possible that the presence of publication bias and
the quality of trials included in this review may be
overestimating any beneficial effects of phenyleph-
rine over ephedrine.
Some caution is required in interpreting the re-
sults of this meta-analysis, which is based on results
of many small trials, as subsequent large trials have
disagreed with meta-analyses 10% to 23% of the
time (23). One of the roles of systematic reviews is to
highlight areas of further research. Systematic re-
views should be regarded as complementary to, not
a substitute for, a large RCT. A large RCT with a
priori defined clinically significant outcome (fetal
acidosis) should to be done to confirm our findings.
If the baseline risk of fetal acidosis (pH value of
⬍7.20) is 14% (24), a large RCT of 4638 women
would have 80% power with a 0.050 two-sided sig-
nificance level to detect a smaller risk of fetal aci-
dosis (odds ratio of 0.78) associated with phenyl-
ephrine. A trial of this size would require con-
siderable time and resources. In the absence of such
a large multicentered trial, the best current strategy
for appraising the available evidence is to examine
the results of this meta-analysis.
OBSTETRIC ANESTHESIA LEE ET AL. 925
VASOPRESSORS AND SPINAL HYPOTENSION
In summary, this systematic review does not sup-
port the traditional idea that ephedrine is the pre-
ferred choice over phenylephrine for the management
of maternal hypotension during spinal anesthesia for
elective cesarean delivery in healthy, nonlaboring
women. The use of phenylephrine was associated
with better fetal acid-base status, but the risk of ma-
ternal bradycardia (responsive to atropine) was larger
than in those women given ephedrine.
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crystalloid preload in the prevention of hypotension associated
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