Anesthesia March 2015

1. important. In an editorial in this
journal, Pandit [7] extended the
‘rule of threes’ to the case of one
failure and highlighted how small
studies with few failures can be
misleading. Newman [8] presents a
useful rule to estimate the two-
tailed upper 95% confidence limit
for 0–4 failures, which is slightly
larger than the estimates presented
here. We believe that easy-to-
remember rules, while not exact, are
important tools that clinicians can
and should use either when reading
the literature or when discussing
new techniques with colleagues. The
utility of the ‘rule of three-and-
three-halves’ is not so much in its
accuracy as in its easy application. It
keeps the reader alert and skeptical
as to the potential benefit of new
technique (intubation, in our exam-
ple). We believe that the addition of
this rule can assist in this goal. It is
easy to calculate, and in a limited
setting, outperforms other estimates
that are more difficult to calculate.
This allows us to ask, with reference
to Hanley and Lippman-Hand [1]:
if only a little bit is wrong, how
much is alright?
Competing interests
No external funding and no com-
peting interests declared.
M. Beach
Professor of Anesthesiology,
Pediatrics, and Community
Medicine
Department of Anesthesiology
Geisel School of Medicine at
Dartmouth
Dartmouth-Hitchcock Medical
Center
Lebanon
NH, USA
B. Sites
Associate Professor of Anesthesiology
and Orthopedics
Department of Anesthesiology and
Pain Management
Geisel School of Medicine at
Dartmouth
Dartmouth-Hitchcock Medical
Center
Lebanon
NH, USA
Email: brian.d.sites@hitchcock.org
References
1. Hanley JA, Lippman-Hand A. If nothing
goes wrong, is everything all right?
Interpreting zero numerators. Journal
of the American Medical Association
1983; 249: 1743–5.
2. Beringer RM, Kelly F, Cook TM, et al. A
cohort evaluation of the paediatric
i-gelTM
airway during anaesthesia in
120 children. Anaesthesia 2011; 66:
1121–6.
3. Fleiss J, Levin B, Paik M. Statistical
methods for rates and proportions.
New York: Wiley, 1981.
4. Brown L, Cai T, DasGupta A. Interval
estimation for a binomial proportion.
Statistical Science 2001; 16: 101–17.
5. Agresti A, Coull B. Approximate is bet-
ter than ‘‘exact’’ for interval estimation
of binomial proportions. American Stat-
istician 1998; 52: 119–26.
6. Newcombe RG. Two-sided confidence
intervals for the single proportion:
comparison of seven methods. Statis-
tics in Medicine 1998; 17: 857–72.
7. Pandit JJ. If it hasn’t failed, does it
work? On the ‘worst we can expect’
from observational trial results, with
reference to airway management
devices. Anaesthesia 2012; 67: 578–
83.
8. Newman TB. If almost nothing goes
wrong, is almost everything all right?
Interpreting small numerators. Journal
of the American Medical Association
1995; 274: 1013.
doi:10.1111/anae.12980
Editorial
Vasopressors for the treatment of maternal hypotension following
spinal anaesthesia for elective caesarean section: past, present
and future
Spinal anaesthesia is the standard
technique in many countries when
providing anaesthesia for elective
caesarean section, as it provides
excellent operating conditions and is
well tolerated [1]. Hypotension
remains a common side-effect, and
can result in unpleasant symptoms
in the mother and harm to the
fetus [2].
Until fairly recently, ephedrine
was the main vasopressor used for
Anaesthesia 2015, 70, 241–257 Editorial
252 © 2015 The Association of Anaesthetists of Great Britain and Ireland

2. the treatment of spinal hypotension.
It became the first-line vasopressor
following findings from early stud-
ies on pregnant ewes that recom-
mended it over metaraminol and
other a-adrenoreceptor agonists, as
it was associated with less reduction
in uterine blood flow [3].
An early dose-response study
performed by Ngan Kee et al.
investigated its use in 80 patients
undergoing spinal anaesthesia for
elective caesarean section. Patients
received either a saline control or
10, 20 or 30 mg of prophylactic
intravenous ephedrine. Systolic
blood pressure (SBP) after spinal
anaesthesia was significantly higher
for the 30-mg group compared with
other groups. More importantly,
however, the proportion of patients
found to have an umbilical arterial
pH < 7.2 was 11%, 25%, 42%
and 22%, in the control, 10-mg,
20-mg, and 30-mg groups, respec-
tively. These findings suggested that
although blood pressure control was
better with ephedrine than without,
there was no improvement in neo-
natal outcome [4].
These concerns prompted the
search for a safer vasopressor for use
during spinal anaesthesia for caesar-
ean section. Vasopressors with more
a-agonist activity had traditionally
been considered to be for second-
line use only, because of concerns
raised from animal studies. Work
with human parturients, however,
has since shown that both phenyl-
ephrine [5] and metaraminol [6]
infusions result in improved fetal
acid-base status compared with
ephedrine. Subsequently, phenyleph-
rine emerged as the vasopressor of
choice on the labour ward, as it was
more easily available to early investi-
gators and as a result used more
widely than metaraminol [7].
A randomised, double-blind
study performed by Cooper et al.
compared three groups of pati-
ents undergoing elective caesarean
section, receiving infusions of
phenylephrine 100 lg.mlÀ1
, ephed-
rine 3 mg.mlÀ1
, or phenylephrine
50 lg.mlÀ1
in combination with
ephedrine 3 mg.mlÀ1
. They found a
lower incidence of fetal acidosis in
the groups receiving phenylephrine
alone or in combination with
ephedrine [5]. Subsequently, Ngan
Kee and Lee performed a multiple
linear regression analysis on 337
consecutive caesarean sections
under spinal anaesthesia, investigat-
ing different factors that may pre-
dict uterine arterial pH and base
excess. The use of ephedrine was a
significant factor predicting adverse
changes in both pH and base
excess, and the authors concluded
that in order to minimise the risk
of fetal acidosis, ephedrine should
not be used before delivery, and
that a-agonists should be used to
minimise spinal hypotension [8].
The same group went on to
perform a complex study investigat-
ing the effect of varying different
proportions of vasopressors when
used in combination. One hundred
and twenty-five parturients under-
going spinal anaesthesia for caesar-
ean section were randomly assigned
to receive 100%, 75%, 50%, 25% or
0% phenylephrine with 0%, 25%,
50%, 75% or 100% ephedrine,
respectively. Infusions were adjusted
to maintain SBP close to baseline.
They found that as the proportion
of phenylephrine decreased and
the proportion of ephedrine incre-
ased, haemodynamic control was
reduced, and fetal acid-base status
was less favourable [9]. A recent
meta-analysis of vasopressor use
during elective caesarean section, by
Veeser et al, collated data from 20
trials (n = 1069), finding the rela-
tive risk for true fetal acidosis to be
5.29 for ephedrine versus phenyl-
ephrine [10].
Following such compelling evi-
dence, the use of ephedrine has all
but disappeared and phenylephrine
has become firmly established as
the vasopressor of choice, for both
prophylaxis and treatment of spinal
hypotension in obstetrics. However,
research continues in order to opti-
mise and refine its administration.
Areas studied have included: how
phenylephrine could best be admin-
istered; whether it should be
used proactively (prophylactically)
or reactively (only when spinal
hypotension has occurred); whether
continuous infusions are superior
to bolus administration; and the
appropriate dose or doses required
to avoid unwanted side-effects such
as reactive hypertension and brady-
cardia.
A meta-analysis looking at the
use of prophylactic phenylephrine
for caesarean section under spinal
anaesthesia [11] concluded that a
continuous infusion (proactive
treatment) started immediately after
initiation of spinal anaesthesia sig-
nificantly reduced the incidence of
spinal hypotension compared with
bolus doses given only in response
to a fall in SBP (reactive treatment).
Prophylactic administration of
phenylephrine has been regarded by
some as being too aggressive, due
Editorial Anaesthesia 2015, 70, 241–257
© 2015 The Association of Anaesthetists of Great Britain and Ireland 253

3. to its ability to cause reactive hyper-
tension and associated bradycardia
[12]. In the meta-analysis described
above [11], the risk of reactive
hypertension did not differ between
prophylactic and reactive regimens,
but this result was based on only
three studies with a total of 241
patients. The risk of bradycardia
was also similar between groups,
but again this was based on only
small numbers. These results might
suggest that there is a paucity of
evidence in this area, rather than an
absence of an association between
phenylephrine and hypertension.
However, in the absence of such
evidence, prophylactic (proactive)
treatment would appear to be pref-
erable, as delaying the start of a
prophylactic phenylephrine infusion
could limit its efficacy in reducing
the incidence of hypotension.
Most studies have compared
prophylactic phenylephrine infu-
sions with reactive phenylephrine
boluses. There are only limited data
comparing prophylactic phenyleph-
rine infusions with prophylactic
bolus doses. Das Neves et al. com-
pared a prophylactic phenyleph-
rine infusion running at 0.15
lg.kgÀ1
.minÀ1
with a prophylactic
bolus dose of 50 lg phenylephrine
given immediately after spinal injec-
tion; a third group received the
vasopressor only when SBP had
dropped. The continuous infusion
group had the least incidence of
hypotension (18%), nausea (10%),
and vomiting (0%) compared with
the prophylactic bolus (respectively
33%, 15% and 8%) and therapeutic
bolus (respectively 85%, 40% and
13%) groups [13]. The higher inci-
dence of hypotension, nausea and
vomiting in the prophylactic bolus
group may have been because the
bolus dose used in the study was
small. A study by George et al. [14]
found the ED90 of phenylephrine
required for the treatment of spinal
anaesthesia-induced hypotension to
be 150 lg. The ED95 of phenyleph-
rine, found by Tanaka et al. [15],
was 159 lg, and the dose to prevent
pre-delivery spinal-induced hypo-
tension and nausea at elective
caesarean section was 120 lg. Addi-
tionally, in the study by das Neves
et al., spinal anaesthesia was
achieved with only 10 mg bupiva-
caine [13]. These findings support
the view that a continuous infusion
is superior to bolus administration.
A further area to consider is
whether phenylephrine, when given
by infusion compared with manual
bolus administration, can reduce
the workload of the attending an-
aesthetist. Manual bolus doses of a
vasopressor to treat hypotension or
symptoms of nausea and vomiting
certainly can occupy the anaesthe-
tist’s attention. A recent study
achieved a reduction in anaesthe-
tists’ workload by adhering to an
algorithm adjusting the infusion
rate of a prophylactic phenylephrine
infusion according to changes in
blood pressure and heart rate [16].
Another yet unresolved issue is
the ideal infusion regimen that will
control the maternal blood pressure,
with minimal maternal side-effects,
while avoiding maternal hyperten-
sion. Ngan Kee and colleagues con-
ducted their studies infusing
phenylephrine at 100 lg.minÀ1
. In
one, phenylephrine was infused at
100 lg.minÀ1
for 3 min following
spinal anaesthesia, after which par-
turients were randomly allocated
into two groups. In one, phenyleph-
rine 100 lg.minÀ1
was infused
when the SBP fell below baseline,
and this was stopped only if SBP
exceeded 120% of baseline. A con-
trol group received 100-lg intrave-
nous boluses of phenylephrine after
each episode of SBP < 80% of base-
line. The infusion group had a
reduced incidence of hypotension
(23%) compared with the control
group (88%). However, hyperten-
sion (SBP > 120% of baseline)
occurred in 38% of patients in the
infusion group compared with only
8% in the control group [17]. In
the second study by the same
group, an infusion of phenylephrine
100 lg.minÀ1
was started immedi-
ately after completion of the intra-
thecal injection, and was continued
for the first 2 min unless SBP
exceeded 120% of baseline, in which
case it was stopped. After this, the
infusion was continued if SBP was
less than or equal to baseline, and
stopped once it went above base-
line. Patients were randomly
assigned to two groups depending
on the crystalloid infusion received,
either a rapid infusion (co-hydra-
tion or co-load) group or a minimal
maintenance group. Total phenyl-
ephrine consumption was lower in
the group receiving co-hydration,
and hypertension (SBP > 120% of
baseline) occurred in almost 50% of
patients in both groups [18].
Other groups have studied differ-
ent infusion regimens of phenyleph-
rine ranging from 25 to 100
lg.minÀ1
. Studies by Stewart et al.
[19] and Allen et al. [20] both sug-
gested that compared with higher
doses, 25–50 lg.minÀ1
offers the
Anaesthesia 2015, 70, 241–257 Editorial
254 © 2015 The Association of Anaesthetists of Great Britain and Ireland

4. most favourable risk/benefit profile,
i.e. the lowest rates of both hypoten-
sion and hypertension. Nevertheless,
there were two problems with these
regimens. First, the need for interven-
tions by the anaesthetist remained
high and additional boluses of vaso-
pressor were still necessary in a high
proportion of the patients (40%, 20%
and 12% in the 25-lg.minÀ1
, 50-
lg.minÀ1
and 100-lg.minÀ1
groups,
respectively) [19]. Second, the effect
of such rigid haemodynamic control
had little beneficial effect on maternal
or fetal outcome.
The concept of crystalloid co-
hydration/co-load and vasopressor
use during elective caesarean section
under spinal anaesthesia has been a
subject of recent interest. Dyer et al.
compared crystalloid preload with
rapid crystalloid administration after
induction of spinal anaesthesia (co-
load), finding that coload provided
better maternal blood pressure con-
trol before delivery [21]. A recent
review by Ngan Kee further sup-
ported its use in the prevention of
maternal hypotension after regional
anaesthesia [22].
Ngan Kee and colleagues further
investigated phenylephrine infusions
and the optimal blood pressure to
which it should be titrated. They
randomly allocated parturients to
three groups, infusing phenylephrine
at 100 lg.minÀ1
to maintain SBP at
100%, 90% or 80% of baseline.
Although patients maintained at
100% of baseline had fewer episodes
of hypotension, total doses were
higher (1520 lg compared with
1070 lg and 790 lg, respectively).
Although higher in the 100%
group, umbilical artery pH was
always > 7.2. The authors concluded
that for optimal management, phen-
ylephrine should be titrated to main-
tain SBP at near-normal levels. In
contrast to their earlier work, high
doses of phenylephrine, titrated to
100% baseline, were not associated
with maternal hypertension (SBP
120% of baseline) [23].
Recent studies have incorpo-
rated non-invasive and minimally-
invasive cardiac output monitoring
during spinal anaesthesia for caesar-
ean section, providing additional
insight into the pathophysiology of
spinal hypotension in healthy par-
turients. Both Langesaeter et al. [24]
and Dyer et al. [25] used the Lid-
COplus, the latter group also using
transthoracic bioimpedence. Lang-
esaeter et al. used cardiac output
monitoring to assess maternal hae-
modynamic stability in patients
receiving high- or low-dose spinal
anaesthesia, with or without a con-
comitant phenylephrine infusion.
There was greater haemodynamic
stability in patients receiving low-
dose spinal anaesthesia combined
with a phenylephrine infusion. Dyer
et al. compared the effects of phen-
ylephrine and ephedrine boluses on
maternal cardiac output. They found
that phenylephrine reduced mater-
nal cardiac output compared with
ephedrine, and that the fall in car-
diac output correlated well with
maternal heart rate changes. Stewart
et al., using a suprasternal Doppler
measurement of cardiac output,
found that phenylephrine infusions
were associated with a dose-depen-
dent reduction of both heart rate
and cardiac output, although no
adverse effects on the fetus were
seen [21]. It would seem therefore
that the ideal infusion dose would
be one that maintained maternal
haemodynamic stability to near
baseline, without compromising
maternal cardiac output, and current
evidence suggests a dose of between
25 and 50 lg.min1
.
So what else is on the horizon?
Closed-loop systems have emerged
recently, integrating blood pressure
recordings with an infusion pump
that responds according to a pro-
grammed algorithm, by altering the
administration of vasopressor. Sia
et al. [26] developed a ‘smart’ system
that, when SBP fell below 90% of
baseline, administered a 50-lg bolus
of phenylephrine; when hypotension
occurred with bradycardia, ephed-
rine was infused. Blood pressure
cycling was set at 15 s using a con-
tinuous non-invasive technique. No
additional vasopressor had to
be given by the attending anaes-
thetist. Ngan Kee et al. compared
a computer-based system, infus-
ing 0-100 lg.min1
phenylephrine
depending on SBP, with a fixed infu-
sion of 100 lg.min1
phenylephrine
that was manually run when SBP fell
below baseline, and stopped once
SBP (measured at 1-min intervals)
exceeded baseline. There were no
differences in the incidence of hypo-
tension, hypertension, nausea or
vomiting. Only the number of
interventions – including starting,
stopping, adjusting the computer
program or syringe pump, and man-
ual boluses – was different between
the groups (median of two in the
computer-controlled group and 10
in the manual group) [27].
Other vasopressors are being
investigated for prophylaxis and
treatment of spinal hypotension.
In the recent RESPOND study
Editorial Anaesthesia 2015, 70, 241–257
© 2015 The Association of Anaesthetists of Great Britain and Ireland 255

5. (randomised evaluative study of
phenylephrine or noradrenaline for
maintenance of blood pressure),
104 healthy women undergoing
elective caesarean section under
spinal anaesthesia were randomly
allocated to receive an infusion of
phenylephrine 100 lg.min1
or nor-
adrenaline 5 lg.min1
to maintain
maternal blood pressure. The inci-
dence of hypo-/hypertension and
nausea/vomiting was low and simi-
lar between the groups. Heart rate
and cardiac output were greater
over time in the noradrenaline
group, as were umbilical venous pH
and oxygen content, attributed to
greater uteroplacental blood flow.
The authors raised the idea that
noradrenaline (because of its intrin-
sic b-agonist activity) may be a bet-
ter obstetric vasopressor than
phenylephrine, and recommended
further work in this area [28].
Use of vasopressors for the
treatment and prevention of spinal
hypotension has grown in popular-
ity in recent years [29]. Ephedrine
has largely been superseded by
phenylephrine, as the evidence sug-
gests that the former can cause
harm to the fetus. We have moved
away from a reactive approach
(bolus administration once spinal
hypotension has occurred) to a
more proactive approach, with the
advent of phenylephrine infusions.
Moreover, we are aiming to limit
the amount of vasopressor used to
avoid unwanted side-effects such as
bradycardia.
The ideal vasopressor regimen
should allow careful titration to each
individual parturient’s needs,
according to changes in haemo-
dynamic parameters, whilst avoiding
excessive demands on the anaesthe-
tist’s time. Integrated closed-loop
systems with carefully programmed
algorithms, as used by Sia et al.,
seem to come closest to achieving
such a goal [25]. In the absence of
such technology, phenylephrine
should be administered as a pro-
phylactic infusion at a dose that
prevents maternal hypotension but
avoids a significant reduction in
maternal heart rate and cardiac
output; the literature supports a rate
of 25-50 lg.minÀ1
phenylephrine,
titrated to maintain maternal SBP >
80% of baseline, while avoiding
maternal hypertension.
As for the future: it will be
some time before we see routine
cardiac output monitoring during
elective caesarean section, and it is
currently reserved for the manage-
ment of high-risk parturients, or for
research purposes. More work
needs to be done investigating the
use of noradrenaline infusions for
spinal hypotension, and any poten-
tial for it to cause maternal or fetal
harm, before its use becomes more
widespread. Finally, the concept of
computer-programmed algorithms
could be achievable, if it could be
shown to be cost-effective.
Competing interests
No external funding and no
competing interests declared.
M. Heesen
Consultant Anaesthetist
Kantonsspital
Baden, Switzerland
A. Stewart
R. Fernando
Consultant Anaesthetists
Department of Anaesthesia
University College London Hospitals
NHS Foundation Trust
London, UK
Email: roshanagfernando@gmail.com
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