Heesen et al-2015-anaesthesia

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 interestsNo external funding and no com-

peting interests declared.

M. BeachProfessor of Anesthesiology,Pediatrics, and CommunityMedicineDepartment of AnesthesiologyGeisel School of Medicine atDartmouthDartmouth-Hitchcock MedicalCenterLebanonNH, USAB. SitesAssociate Professor of Anesthesiologyand OrthopedicsDepartment of Anesthesiology andPain ManagementGeisel School of Medicine atDartmouthDartmouth-Hitchcock MedicalCenterLebanonNH, USAEmail: [email protected]

References1. Hanley JA, Lippman-Hand A. If nothing

goes wrong, is everything all right?Interpreting zero numerators. Journalof the American Medical Association1983; 249: 1743–5.

2. Beringer RM, Kelly F, Cook TM, et al. Acohort evaluation of the paediatrici-gelTM airway during anaesthesia in120 children. Anaesthesia 2011; 66:1121–6.

3. Fleiss J, Levin B, Paik M. Statisticalmethods for rates and proportions.New York: Wiley, 1981.

4. Brown L, Cai T, DasGupta A. Intervalestimation for a binomial proportion.Statistical Science 2001; 16: 101–17.

5. Agresti A, Coull B. Approximate is bet-ter than ‘‘exact’’ for interval estimationof binomial proportions. American Stat-istician 1998; 52: 119–26.

6. Newcombe RG. Two-sided confidenceintervals 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 itwork? On the ‘worst we can expect’from observational trial results, withreference to airway managementdevices. Anaesthesia 2012; 67: 578–83.

8. Newman TB. If almost nothing goeswrong, is almost everything all right?Interpreting small numerators. Journalof the American Medical Association1995; 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.ml�1, ephed-

rine 3 mg.ml�1, or phenylephrine

50 lg.ml�1 in combination with

ephedrine 3 mg.ml�1. 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.kg�1.min�1 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.min�1. In

one, phenylephrine was infused at

100 lg.min�1 for 3 min following

spinal anaesthesia, after which par-

turients were randomly allocated

into two groups. In one, phenyleph-

rine 100 lg.min�1 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.min�1 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.min�1. Studies by Stewart et al.

[19] and Allen et al. [20] both sug-

gested that compared with higher

doses, 25–50 lg.min�1 offers the



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.min�1, 50-

lg.min�1 and 100-lg.min�1 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.min�1 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



(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.min�1 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 interestsNo external funding and no

competing interests declared.

M. HeesenConsultant AnaesthetistKantonsspitalBaden, SwitzerlandA. StewartR. FernandoConsultant AnaesthetistsDepartment of AnaesthesiaUniversity College London Hospitals

NHS Foundation TrustLondon, UKEmail: [email protected]

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10. Veeser M, Hoffman T, Roth R, et al.Vasopressors for the management ofhypotension after spinal anaesthesia forelective caesarean section. Systematic



review and cumulative meta-analysis.Acta Anaesthesiologica Scandinavica2012; 56: 810–6.

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14. George RB, McKeen D, Columb MO, etal. Up-down determination of the 90%effective dose of phenylephrine forthe treatment of spinal anesthesia-induced hypotension in parturientsundergoing cesarean delivery. Anesthe-sia and Analgesia 2010; 110: 154–8.

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doi:10.1111/anae.13007



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