Randomised double-blinded comparison of phenylephrine

vs ephedrine for maintaining blood pressure during spinal

anaesthesia for non-elective Caesarean section
Anaesthesia
Volume 63 Issue 12, Pages 1319 - 1326
Published Online: 11 Nov 2008
2009 The Association of Anaesthetists of Great Britain and Ireland
W. D. Ngan Kee, K. S. Khaw, T. K. Lau, F.F.Ng , K. Chui, K.L.Ng
WHY THIS STUDY IS SIGNIFICANT?
Early animal studies: -adrenergic agonists during pregnancy:
potential to decrease uteroplacental perfusion
Recent clinical studies: agonists during spinal anaesthesia for
Caesarean section no evidence of detrimental effects
Supported the use of phenylephrine for maintaining maternal BP during
spinal anaesthesia for Caesarean section because compared to
ephedrine
greater efficacy
ease of titration
and less propensity to depress fetal pH and base excess

1. Most clinical studies: performed in healthy, low-risk, elective patients
2. Few data are available for non-elective cases, particularly those in whom
there is actual or potential fetal compromise.
This is important because in the latter group, possible adverse effects of vasopressors on
uteroplacental perfusion may be more likely to be detrimental to the fetus.
AIM OF THE STUDY
ETo compare the use of phenylephrine and ephedrine for
treating hypotension in women having spinal anaesthesia
for non-elective Caesarean section

E Primary outcome compared was fetal acid-base status

E Also compared umbilical cord blood oxygenation and
lactate concentration as well as the clinical outcome of
neonates
METHODS
Institutional approval: Joint Chinese University of Hong Kong-New Territories East
Cluster Clinical Research Ethics Committee, Shatin, Hong Kong, China
Registered in the Clinical Trials Registry: Centre of Clinical
Trials, The Chinese University of Hong Kong
204 ASA 1 and 2 women: term singleton pregnancies scheduled for non-
elective Caesarean section for which spinal anaesthesia was decided upon for clinical reasons
booked on the day of surgery as emergencies
patients who were admitted to the labour ward in labour but subsequently
proceeded to Caesarean section
Written informed consent
EXCLUSION CRITERIA
pre-existing or pregnancy-induced hypertension
cardiovascular or cerebrovascular disease
multiple gestation
known fetal abnormality
any medical contra-indication to spinal anaesthesia such as
thrombocytopenia or coagulopathy
..METHODS
Premedicated orally with 0.3 M sodium citrate 30 ml on arrival to the
operating theatre
Monitoring:
NIBP
ECG
Pulse Oximetry
Fetal heart rate: monitored by external cardiotocography until the time of
surgical preparation
No intravenous prehydration was given
Spinal anaesthesia was induced in the right lateral position
Skin infiltration with lidocaine: 25-gauge, pencil-point needle: L3-4 or
L4-5: 2.0-2.2 ml hyperbaric 0.5% bupivacaine (10-12 mg) and
fentanyl 15 g

..METHODS
Immediately returned to the left-tilted supine position.
Started rapid cohydration: up to 2L of RL.
Oxygen 6-8 L/min: by clear facemask until delivery.
BP: at 1-min intervals: beginning 1 min after spinal.
Hypotension: defined as systolic BP (SBP) < 100 mmHg.
..METHODS
Randomised to receive an i.v. bolus immediately
after each episode of hypotension:
phenylephrine 100 g (phenylephrine group) or
ephedrine 10 mg (ephedrine group) immediately
Randomisation: performed according to computer-generated codes
contained in opaque, sealed and sequentially-numbered envelopes
Doses of phenylephrine and ephedrine chosen
empirically: based on authors clinical experience of the drugs.
..METHODS
To maintain blinding: the vasopressor solutions were
prepared in identical syringes by an anaesthetist or investigator not involved
in subsequent patient care.
For the purposes of comparison between
groups: the upper sensory level of anaesthesia was measured by
assessing loss of pinprick discrimination 5 min after spinal injection.
Timing of the decision to allow surgery to
proceed: at the discretion of the attending anaesthetist.
..METHODS
Recorded using a stopwatch (time of):
of skin incision
uterine incision
delivery
Continued the vasopressor protocol until the time of
uterine incision.
After this, the study was terminated and further
management was at the discretion of the attending
anaesthetist.

..METHODS
Recorded:
the total dose of vasopressor given up to the time of uterine incision
the total volume of intravenous fluid given
any incidences of nausea (reported spontaneously by patients) or
vomiting (observed by investigators)
number of episodes of hypotension.
Bradycardia was defined as HR < 50/min and, if
associated with hypotension, was treated with
intravenous atropine 0.6 mg.
..METHODS
Attending paediatrician:
Apgar scores at 1 and 5 min after delivery.
Recorded:
Number of neonates admitted to the special care baby unit and
neonatal intensive care unit and the respective durations of stay.

Umbilical arterial (UA) and umbilical venous (UV) blood
samples:
From double-clamped segments of umbilical cord into heparinised syringes
Measured blood gases using a Rapid Point 400 analyser [Bayer Diagnostics Mfg (Sudbury) Ltd, Sudbury].
Measured oxygen content using an IL 682 CO-oximeter (Instrumentation Laboratory,
Lexington, MA, USA) with correction for 70% fetal haemoglobin.
Centrifuged samples of UA and UV blood and measured plasma lactate:
using the Vitros DT60 II Chemistry System (Ortho-Clinical Diagnostics, Raritan, NJ, USA).

STATISTICS
Prospective power analysis: based on historical audit data of emergency
CS performed in 2001.

Primary outcome was defined as the umbilical arterial (UA) pH and an
effect size of 0.03 units was chosen based on differences observed in
elective cases.

Sample size of 85 patients per group would be required:
90% power at the 0.05 significance level to detect a difference between
groups.

Final sample size of 102 patients per group:
To compensate for anticipated dropouts and difficulties with data collection
given the emergency nature of the cases, it was decided to increase the sample
size by 20%.
STATISTICS
Univariate intergroup comparisons were made using the unpaired
Students t-test or the Mann-Whitney U-test as appropriate.

Nominal data were compared using the Chi-Square test or Fishers
exact test.

Analyses were made using SPSS version 10.1.4 (SPSS Inc., Chicago, IL,
USA) and Confidence Interval Analysis 2.0.0 (T. Bryant, University of
Southampton).

Values of p < 0.05 were considered statistically significant.
RESULTS: distribution of patients who consented to participate
RESULTS: Patient characteristics and surgical times
Phenylephrine group (n =
102)
Ephedrine group (n =
102)
Age; years 31 (4.9) 30 (4.3)
Weight; kg 66.7 (9.7) 65.6 (8.6)
Height; cm 156 (5.3) 157 (5.4)
Block height at 5 min;
dermatome
T4 [T3-T5] T4 [T3-T5]
Uterine incision-to-delivery
time; s
67 [50-120] 73 [47-122]
Induction-to-delivery time;
min
21.0 [17.6-25.3] 20.9 [16.5-25.9]
Patient characteristics and surgical times. Values are mean (SD) or median [IQR]. No significant differences between groups
RESULTS: number of episodes of hypotension and the total
volume of intravenous fluid given in each group was similar
Phenylephrine group (n =
102)
Ephedrine group (n =
102)
p
value
Episodes of hypotension; n 1.0 [0-3.3] 2.0 [0.3-3.0] 0.52
Total intravenous fluid given; ml 1100 [738-1700] 1350 [838-1763] 0.26
Minimum recorded systolic blood
pressure; mmHg
96 [89-101] 95 [88-102] 0.98
Maximum recorded systolic blood
pressure; mmHg
127 [120-135] 127 [120-138] 0.74
Minimum recorded heart rate;
beats.min
1

63 [58-74] 69 [63-79] 0.003
Maximum recorded heart rate;
beats.min
1

104 [96-118] 114 [97-125] 0.086
Episodes of hypotension, total intravenous fluid and minimum and maximum values for systolic blood pressure and
heart rate. Values are median [IQR].
RESULTS
E The minimum recorded HR was in the phenylephrine group vs the ephedrine group
but there was no difference in maximum recorded HR or minimum and maximum
recorded SBP.
E No patient required atropine.
E The number of doses of vasopressor required was similar.
E More patients had nausea or vomiting in the ephedrine group vs the phenylephrine
group (13/102 (12.7%) vs 4/102 (3.9%), p = 0.02).
Phenylephrine group (n = 102) Ephedrine group (n = 102)
0 28 28
1 24 21
2 13 23
3 12 16
4 10 6
5 5 5
>5 10 2
Number of doses of vasopressor
required. No significant differences
between groups
RESULTS of umbilical cord blood analysis
Umbilical cord blood analysis (intention-to-treat
basis). Values are median [IQR].
Phenylephrine group (n = 102) Ephedrine group (n = 102) p value
Umbilical arterial
pH 7.28 [7.26 to 7.31] 7.28 [7.25 to 7.31] 0.70
PCO
2
; kPa 7.2 [6.5 to 7.7] 7.1 [6.4 to 7.8] 0.98
PO
2
; kPa 2.2 [1.8 to 2.6] 2.4 [1.9 to 2.8] 0.09
Base excess; mmol.l
1
2.5 [4.1 to 1.7] 2.9 [4.3 to 1.6] 0.31
Haemoglobin concentration; g.dl
1
15.3 [14.5 to 16.2] 14.7 [13.8 to 15.8] 0.13
Oxygen content; ml.dl
1
6.9 [4.6 to 8.8] 6.6 [5.0 to 8.8] 0.54
Lactate concentration; mmol.l
1
2.4 [1.9 to 3.0] 2.6 [2.3 to 3.3] 0.002
Umbilical venous
pH 7.33 [7.31 to 7.35] 7.33 [7.30 to 7.35] 0.94
PCO
2
; kPa 6.0 [5.6 to 6.5] 5.9 [5.5 to 6.5] 0.60
PO
2
; kPa 3.9 [3.2 to 4.5] 4.0 [3.4 to 4.6] 0.13
Base excess; mmol.l
1
2.9 [4.2 to 1.7] 3.1 [4.1 to 2.0] 0.44
Haemoglobin concentration; g.dl
1
15.4 [14.5 to 16.4] 14.9 [14.1 to 16.0] 0.11
Oxygen content; ml.dl
1
13.6 [11.1 to 15.6] 13.7 [11.1 to 15.5] 0.59
Lactate concentration; mmol.l
1
2.3 [1.9 to 2.8] 2.5 [2.2 to 3.2] 0.016
There was no difference between groups in the primary outcome, UA pH. In the ephedrine group, two cases had UA pH < 7.0 compared
with no case in the phenylephrine group (p = 0.50); the former two cases were the only cases in which UA base excess was < 12
mmol.l1. Lactate concentration was higher in the ephedrine vs the phenylephrine group for both UA blood [median difference 0.3 (95%
CI of difference 0.1-0.6) mmol.l1, p = 0.002] and UV blood [median difference 0.3 (95% CI of difference 0-0.4) mmol.l1, p = 0.016].
RESULTS of umbilical cord blood analysis
Results were similar to those found in the intention-to-treat analysis. However, an additional finding was that UA PO2 was
lower in the phenylephrine group vs the ephedrine group [median difference 0.23 (95% CI of difference 0.02-0.45) kPa, p =
0.032] and UV PO2 was lower in the phenylephrine group vs the ephedrine group [median difference 0.39 (95% CI of
difference 0.08-0.70) kPa, p = 0.012]. However, there were no differences between groups in UA or UV oxygen content.
Umbilical cord blood analysis (per
protocol basis). Values are median
[IQR].
Phenylephrine group (n = 74) Ephedrine group (n = 74) p value
Umbilical arterial
pH 7.29 [7.26 to 7.31] 7.28 [7.24 to 7.31] 0.34
PCO
2
; kPa 7.1 [6.4 to 7.8] 7.2 [6.5 to 7.8] 0.82
PO
2
; kPa 2.2 [1.8 to 2.7] 2.4 [2.0 to 2.8] 0.032
Base excess; mmol.l
1
2.5 [4.1 to 1.5] 3.2 [4.5 to 1.7] 0.17
Haemoglobin concentration;
g.dl
1

15.4 [14.5 to 16.3] 14.7 [13.7 to 15.8] 0.15
Oxygen content; ml.dl
1
6.9 [4.4 to 9.2] 6.8 [5.2 to 9.2] 0.39
Lactate concentration; mmol.l
1
2.3 [1.9 to 2.8] 2.7 [2.3 to 3.5] <0.001
Umbilical venous
pH 7.32 [7.31 to 7.36] 7.33 [7.30 to 7.35] 0.71
PCO
2
; kPa 6.0 [5.7 to 6.6] 5.9 [5.4 to 6.6] 0.30
PO
2
; kPa 3.8 [3.0 to 4.2] 4.1 [3.6 to 4.9] 0.012
Base excess; mmol.l
1
2.8 [4.0 to 1.9] 3.1 [4.1 to 2.1] 0.31
Haemoglobin concentration;
g.dl
1

15.4 [14.5 to 16.4] 15.0 [14.1 to 16.2] 0.11
Oxygen content; ml.dl
1
13.2 [10.1 to 15.4] 14.3 [11.8 to 15.8] 0.14
Lactate concentration; mmol.l
1
2.2 [1.8 to 2.8] 2.6 [2.2 to 3.3] 0.002
RESULTS
Fetal compromise was considered potentially to have been present in a total of 48 patients; there was a similar
proportion of these patients in the two groups (phenylephrine group 22% vs ephedrine group 26%, p = 0.5).
Subanalysis of these patients showed that UA PO2 was lower in the phenylephrine group compared with the
ephedrine group but all other blood gas parameters and lactate concentrations were similar.
Umbilical cord blood analysis for
patients with factors suggesting
potential fetal compromise. Values are
median [IQR].
Phenylephrine group (n = 22) Ephedrine group (n = 26) p value
Umbilical arterial
pH 7.26 [7.22 to 7.29] 7.27 [7.23 to 7.31] 0.43
PCO
2
; kPa 7.2 [6.7 to 8.3] 7.0 [6.4 to 7.5] 0.54
PO
2
; kPa 2.0 [1.6 to 2.2] 2.4 [1.7 to 2.7] 0.045
Base excess; mmol.l
1
4.1 [5.0 to 1.8] 4.1 [5.4 to 2.8] 0.62
Haemoglobin concentration; g.dl
1
15.7 [15.0 to 16.5] 14.3 [13.5 to 15.8] 0.31
Oxygen content; ml.dl
1
5.4 [3.5 to 7.5] 6.5 [3.7 to 8.6] 0.34
Lactate concentration; mmol.l
1
3.4 [2.5 to 4.3] 3.3 [2.6 to 5.0] 0.85
Umbilical venous
pH 7.32 [7.28 to 7.34] 7.32 [7.28 to 7.35] 0.68
PCO
2
; kPa 6.1 [5.6 to 6.6] 5.9 [5.4 to 6.5] 0.82
PO
2
; kPa 3.4 [2.9 to 3.9] 3.6 [3.2 to 4.1] 0.34
Base excess; mmol.l
1
4.2 [5.5 to 2.0] 4.1 [6.1 to 2.7] 0.88
Haemoglobin concentration; g.dl
1
15.6 [14.7 to 16.3] 14.6 [13.5 to 16.0] 0.08
Oxygen content; ml.dl
1
12.6 [10.1 to 14.2] 11.7 [9.5 to 15.3] 0.82
Lactate concentration; mmol.l
1
3.3 [2.4 to 3.9] 3.2 [2.3 to 4.5] 0.71
RESULTS
There was no difference between groups in the
clinical outcome of the neonates.
One neonate in the ephedrine group had an Apgar score < 7 at 1 min and 5
min and one neonate in the phenylephrine group had an Apgar score < 7 at 1
min; all other Apgar scores were 7.
Seventeen (17%) neonates in the phenylephrine group (17%) and 21 (21%)
neonates in the ephedrine group were admitted to the special care baby unit (p
= 0.45).
There was no difference in the duration of stay
between groups.
One neonate in the ephedrine group was admitted to the neonatal intensive
care unit because of feto-maternal transfusion syndrome; total duration of
stay was 22 days and treatment included blood transfusion and treatment of
convulsions.
DISCUSSION
This study showed that neonatal outcome
was similar between groups when
phenylephrine or ephedrine was used to treat
hypotension in patients having non-elective
Caesarean section under spinal anaesthesia.
Although there were differences between groups in UA and
UV lactate concentration and PO2, the magnitudes of these
differences were small and there were no differences in pH or
base excess.
DISCUSSION

More patients had nausea or vomiting in the
ephedrine group but there were no other
differences in clinical outcome.

Previous studies have supported the use of
phenylephrine in low-risk elective patients.

The current data provide evidence to suggest that
phenylephrine is also an appropriate vasopressor to
use in non-elective cases.
DISCUSSION

The results of this study are important
E because animal studies have shown that phenylephrine
and other alpha adrenergic agonists have a greater
propensity to reduce uteroplacental perfusion
compared with ephedrine.
not clinically relevant in healthy, low-risk
elective cases
E it has not been known whether the same would apply in
the presence of potential or actual fetal compromise

DISCUSSION
The results of recent studies in sheep do provide
some basis for concern about the use of
phenylephrine in the presence of uteroplacental
insufficiency.
Erkinaro et al. compared phenylephrine and ephedrine for correcting
epidural-induced hypotension after a period of maternal hypoxaemia in a
chronically-instrumented sheep model.
In an earlier study, they found that, although ephedrine was associated
with more favorable effects on uterine and placental circulations, there
was no difference in fetal acid-base status or lactate concentration.

DISCUSSION
In the latter study, haemodynamic effects of the
vasopressors were similar to those in the earlier
study, but in addition, they found that
phenylephrine was associated with higher values
for fetal lactate.
DISCUSSION
This is relevant because there is evidence that
fetal lactate may be a better predictor of severe
neonatal morbidity than pH.

Therefore, a possible implication of these results
for clinical practice is that some caution with the
use of phenylephrine in emergency cases may be
warranted.
DISCUSSION
However, the results of this clinical
study contradict those of the animal
studies described above.
4 Rather than finding increased fetal lactate concentrations when
phenylephrine was used, this study found that umbilical arterial and
venous lactate concentrations were lower in the phenylephrine group
compared with the ephedrine group.
DISCUSSION
There may be several reasons for the
differences in results among these studies.
4 Substantial differences in study design may be
important.
4 For example, Erkinaro et al. performed their studies in
anaesthetised sheep that were ventilated in the supine
position; this may not be a valid representation of spinal
anaesthesia in pregnant humans.
4 Species differences may also be important.
DISCUSSION
Previously, it has been suggested that the
decreases in pH and base excess in umbilical cord
blood observed when ephedrine is used in humans
may be associated with metabolic stimulation in
the fetus secondary to the effects of placental
transfer of ephedrine.
4 This may account for the higher values for lactate
concentration found in the ephedrine group in our
current study.
DISCUSSION
In sheep, however, placental morphology differs
from that of humans.
4 The thicker synepitheliochorial placenta of the sheep may present
a greater diffusion barrier to ephedrine compared with the
haemomonochorial placenta of humans and thus it is possible that
placental transfer of ephedrine and its metabolic effects in sheep
may be less.
However, in the absence of comparative studies of
placental transfer of vasopressors, this explanation
remains speculative.
DISCUSSION
Nonetheless, these results emphasize the
importance of caution when extrapolating
the results of animal studies to clinical
practice in humans.
DISCUSSION
An interesting finding:
4for the phenylephrine group vs the ephedrine group,
there were lower values for UA and UV PO2 in the
per-protocol analysis and lower values for UA PO2
in patients with potential fetal compromise.
DISCUSSION
The reasons and clinical significance
uncertain.
4It is possible that they may reflect a
vasoconstrictive effect of phenylephrine on the
uteroplacental circulation that resulted in reduced
flow and increased oxygen extraction.
DISCUSSION
Consistent with studies in sheep which show that
although uterine blood flow varies over a wide
range, fetal oxygen uptake remains relatively
constant.
4 suggesting that the efficiency of oxygen extraction is
increased when perfusion decreases.
E Animal studies demonstrated margin of safety for uteroplacental perfusion :protects the
fetus from fluctuations in uterine blood flow.
E May explain why human clinical studies, including the present one, have failed to
demonstrate a decrease in fetal pH when phenylephrine and other alpha agonists have
been used to maintain BP in obstetric patients despite strong animal evidence that these
drugs have the propensity to cause vasoconstriction of the uteroplacental circulation.
DISCUSSION
Clinical outcome of the neonates :generally favourable
E as evidenced by Apgar scores and the requirement for only one neonate to be
admitted to the neonatal intensive care unit.

For cases where there was evidence of severe fetal or
maternal compromise: general anaesthesia.
It may not be valid to extrapolate our findings to cases of
severe fetal compromise when the relative clinical importance
of stimulation of fetal metabolism or uteroplacental
vasoconstriction may differ.
LIMITATIONS OF THE STUDY
Inclusion criteria for this study were very
broad
heterogeneous mix of patients with a range of
degrees of clinical urgency
Small proportion of patients (24%) in whom fetal compromise
was considered potentially to have been present.
LIMITATIONS OF THE STUDY
Arbitrary absolute value of 100 mmHg as our
threshold for the definition of hypotension.

The doses of phenylephrine (100 g) and ephedrine
(10 mg) used in the study were determined
empirically
Saravanan et al. published data from which they estimated that the potency
ratio of phenylephrine: ephedrine was approximately 80 : 1 (phenylephrine
100 g = ephedrine 8 mg) when the drugs were given by infusion.

LIMITATIONS OF THE STUDY
Arbitrary absolute value of 100 mmHg as our
threshold for the definition of hypotension.

The doses of phenylephrine (100 g) and ephedrine
(10 mg) used in the study were determined
empirically
Saravanan et al. published data from which they estimated that the potency
ratio of phenylephrine: ephedrine was approximately 80 : 1 (phenylephrine
100 g = ephedrine 8 mg) when the drugs were given by infusion.

LIMITATIONS OF THE STUDY
Not all patients developed hypotension and required a
vasopressor and the total dose requirement for
vasopressors was small compared with previous studies
in elective cases.

Consistent with previous observations: patients in labour are less
prone to hypotension during spinal anaesthesia compared with non-
labouring patients.

Small doses of vasopressors used in this study may explain that UA
and UV pH and base excess were not lower in the ephedrine group
compared with the phenylephrine group as has been shown in studies
of elective cases.
SUMMARY
Phenylephrine is at least as suitable as ephedrine for
maintaining maternal BP during spinal anaesthesia for
non-elective Caesarean section.

Phenylephrine had the clinical advantage of being
associated with a lower incidence of nausea and vomiting
compared with ephedrine.