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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
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
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
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
(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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Journal of Obstetric Anesthesia 2014;
23 (Suppl 1): S10.
29. Lirk P, Haller I, Wong CA. Management
of spinal anaesthesia-induced spinal
hypotension for caesarean delivery: a
European survey. European Journal of
Anaesthesiology 2012; 29: 452–3.
doi:10.1111/anae.13007
Editorial Anaesthesia 2015, 70, 241–257
© 2015 The Association of Anaesthetists of Great Britain and Ireland 257

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Heesen et al-2015-anaesthesia

  • 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 References 1. Van de Velde M. Spinal anesthesia in the obstetric patient: prevention and treatment of hypotension. Acta Anaes- thesiologica Belgica 2006; 57: 383–6. 2. Reynolds F, Seed PT. Anaesthesia for caesarean section and neonatal acid- base status: a meta-analysis. Anaes- thesia 2005; 60: 636–53. 3. Ralston DH, Shnider SM, DeLorimier AA. Effects of equipotent ephedrine, metaraminol, mephentermine and me- thoxamine on uterine blood flow in the pregnant ewe. Anesthesiology 1974; 40: 354–70. 4. Ngan Kee WD, Khaw KS, Lee BB, et al. A dose-response study of prophylactic intravenous ephedrine for the pre- vention of hypotension during spinal anaesthesia for cesarean delivery. Anesthesia and Analgesia 2000; 90: 1390–5. 5. Cooper DW, Carpenter M, Mowbray , et al. Fetal and maternal effects of phenylephrine and ephedrine during spinal anesthesia for cesarean delivery. Anesthesiology 2002; 97: 1582–90. 6. Ngan Kee WD, Lau TK, Khaw KS, et al. Comparison of metaraminol, ephedrine infusions for maintaining arterial pres- sure during spinal anesthesia for elec- tive cesarean section. Anesthesiology 2001; 95: 307–13. 7. Khaw KS, Ngan Kee WD, Shara WL. Hypotension during spinal anaesthesia for caesarean section: implications, detection, prevention and treatment. Fetal and Maternal Medicine Review 2006; 17: 1–27. 8. Ngan Kee WD, Lee A. Multivariate analysis of factors associated with umbilical arterial pH and standard base excess after caesarean section under spinal anaesthesia. Anaesthesia 2003; 58: 125–30. 9. Ngan Kee WD, Lee A, Khaw KS, et al. A randomized double-blinded comparison of phenylephrine and ephedrine infu- sion combinations to maintain blood pressure during spinal anesthesia for cesarean delivery: the effects on fetal acid-base status and hemodynamic control. Anesthesia and Analgesia 2008; 107: 1295–302. 10. Veeser M, Hoffman T, Roth R, et al. Vasopressors for the management of hypotension after spinal anaesthesia for elective caesarean section. Systematic Anaesthesia 2015, 70, 241–257 Editorial 256 © 2015 The Association of Anaesthetists of Great Britain and Ireland
  • 6. review and cumulative meta-analysis. Acta Anaesthesiologica Scandinavica 2012; 56: 810–6. 11. Heesen M, Kl€ohr S, Rossaint R, et al. Prophylactic phenylephrine for caesar- ean section under spinal anaesthesia: systematic review and meta-analysis. Anaesthesia 2014; 69: 143–65. 12. Beilin Y. The treatment should not be worse than the disease. Anesthesiol- ogy 2006; 104: 1348–49. 13. Das Neves JF, Monteiro GA, de Almeida JR, et al. Phenylephrine for blood pres- sure control in elective cesarean sec- tion: therapeutic versus prophylactic doses. Revista Brasileira de Anestesio- logia 2010; 60: 391–8. 14. George RB, McKeen D, Columb MO, et al. Up-down determination of the 90% effective dose of phenylephrine for the treatment of spinal anesthesia- induced hypotension in parturients undergoing cesarean delivery. Anesthe- sia and Analgesia 2010; 110: 154–8. 15. Tanaka M, Balki M, Parkes RK, et al. ED95 of phenylephrine to prevent spinal-induced hypotension and/or nausea at elective cesarean delivery. International Journal of Obstetric Anes- thesia 2009; 18: 125–30. 16. Siddik-Sayyid SM, Taha SK, Kanazi GE, et al. A randomized controlled trial of variable rate phenylephrine infusion with rescue phenylephrine boluses ver- sus rescue boluses alone on physician interventions during spinal anesthesia for elective cesarean delivery. Anesthe- sia and Analgesia 2014; 118: 611–8. 17. Ngan Kee WD, Khaw KS, Ng FF, et al. Prophylactic phenylephrine infusion for preventing hypotension during spinal anesthesia for cesarean delivery. Anes- thesia and Analgesia 2004; 98: 815–21. 18. Ngan Kee WD, Khaw KS, Ng FF. Preven- tion of hypotension during spinal anesthesia for cesarean delivery: an effective technique using combination phenylephrine infusion and crystalloid cohydration. Anesthesiology 2005; 103: 744–50. 19. Stewart A, Fernando R, McDonald S, et al. The dose-dependent effects of phen- ylephrine for elective cesarean delivery under spinal anesthesia. Anesthesia and Analgesia 2010; 111: 1230–7. 20. Allen TK, George RB, White WD, et al. A double-blind, placebo-controlled trial of four fixed rate infusion regimens of phenylephrine for hemodynamic support during spinal anesthesia for cesarean delivery. Anesthesia and Analgesia 2010; 111: 1221–9. 21. Dyer RA, Farina Z, Joubert IA, et al. Crystalloid preload versus rapid crystal- loid administration after induction of spinal anaesthesia (coload) for elective caesarean section. Anaesthesia Inten- sive Care 2004; 32: 351–7. 22. Ngan Kee WD. Prevention of maternal hypotension after regional anaesthesia for caesarean section. Current Opinion in Anesthesiology 2010; 23: 304–9. 23. Ngan Kee WD, Khaw KS, Ng FF. Com- parison of phenylephrine infusion regi- mens for maintaining maternal blood pressure during spinal anaesthesia for Caesarean section. British Journal of Anaesthesia 2004; 92: 469–74. 24. Langesaeter E, Rosseland LA, Stubhaug A. Continuous invasive blood pressure and cardiac output monitoring during cesarean delivery: a randomized, dou- ble-blind comparison of low-dose versus high-dose spinal anesthesia with intra- venous phenylephrine or placebo infu- sion. Anesthesiology 2008; 109: 856–63. 25. Dyer RA, Reed AR, van Dyk D, et al. Hemodynamic effects of ephedrine, phenylephrine, and the coadministra- tion of phenylephrine with oxytocin during spinal anesthesia for elective cesarean delivery. Anesthesiology 2009; 111: 753–65. 26. Sia AT, Tan HS, Sng BL. Closed-loop double-vasopressor automated system to treat hypotension during spinal anaesthesia for caesarean section: a preliminary study. Anaesthesia 2012; 67: 1348–55. 27. Ngan Kee WD, Khaw KS, Ng FF, et al. Randomized comparison of closed-loop feedback computer-controlled with manual-controlled infusion of phenyl- ephrine for maintaining arterial pres- sure during spinal anaesthesia for caesarean delivery. British Journal of Anaesthesia 2013; 110: 59–65. 28. Ngan Kee WD, Lee SWY, Ng FF, et al. Randomized evaluative study of phen- ylephrine or norepinephrine for main- tenance of blood pressure during spinal anaesthesia for caesarean deliv- ery: the RESPOND study. International Journal of Obstetric Anesthesia 2014; 23 (Suppl 1): S10. 29. Lirk P, Haller I, Wong CA. Management of spinal anaesthesia-induced spinal hypotension for caesarean delivery: a European survey. European Journal of Anaesthesiology 2012; 29: 452–3. doi:10.1111/anae.13007 Editorial Anaesthesia 2015, 70, 241–257 © 2015 The Association of Anaesthetists of Great Britain and Ireland 257