The Efficacy and Safety of Norepinephrine and Its Feasibility as a...

Review ArticleThe Efficacy and Safety of Norepinephrine and ItsFeasibility as a Replacement for Phenylephrine to ManageMaternal Hypotension during Elective Cesarean Deliveryunder Spinal Anesthesia

XianWang ,1 Xiaofeng Shen,1 Shijiang Liu ,2 Jianjun Yang,3 and Shiqin Xu 1

1Department of Anesthesiology, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, China2Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China3Nanjing Medical University, Nanjing, China

Correspondence should be addressed to Shiqin Xu; [email protected]

Received 19 September 2018; Revised 17 November 2018; Accepted 4 December 2018; Published 31 December 2018

Academic Editor: Kazunori Uemura

Copyright © 2018 Xian Wang et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Maternal hypotension commonly occurs during spinal anesthesia for cesarean delivery, with a decrease of systemic vascularresistance recognized as a significant contributor. Accordingly, counteracting this effect with a vasopressor that constricts arterialvessels is appropriate, and the pure 𝛼-adrenergic receptor agonist phenylephrine is the current gold standard for treatment.However, phenylephrine is associated with dose-dependent reflex bradycardia and decreased cardiac output, which can endangerthe mother and fetus in certain circumstances. In recent years, the older, traditional vasopressor norepinephrine has attractedincreasing attention owing to its mild 𝛽-adrenergic effects in addition to its 𝛼-adrenergic effects. We search available literaturefor papers directly related to norepinephrine application in spinal anesthesia for elective cesarean delivery. Nine reports werefound for norepinephrine use either alone or compared to phenylephrine. Results show that norepinephrine efficacy in rescuingmaternal hypotension is similar to that of phenylephrine without obviousmaternal or neonatal adverse outcomes, and with a lowerincidence of bradycardia and greater cardiac output. In addition, either computer-controlled closed loop feedback infusion ormanually-controlled variable-rate infusion of norepinephrine provides more precise blood pressure management than equipotentphenylephrine infusion or norepinephrine bolus. Thus, based on the limited available literature, norepinephrine appears to bea promising alternative to phenylephrine; however, before routine application begins, more favorable high-quality studies arewarranted.

1. Introduction

Maternal hypotension is a physiological response duringcesarean delivery with spinal anesthesia that significantlycontributes to adverse maternal outcomes such as nausea,vomiting, dizziness, and even cardiovascular collapse. Inaddition, compromised placental perfusion raises concernsof fetal acidosis, hypoxia, and even postnatal neurologicalinjury. Thus, effective prevention and treatment of maternalspinal hypotension is of great clinical significance.

At present, phenylephrine is the first-line vasopressorused in obstetric anesthesia to manage maternal spinal

hypotension. However, in recent years, another vasopres-sor norepinephrine has attracted increasing attention, as afeasible substitute for phenylephrine in obstetric anesthesia.Use of norepinephrine to prevent or treat maternal spinalhypotension during obstetric anesthesia is a recent advanceand thus available data are limited. Further, concerns existregarding the use of such potent vasopressor in a noninten-sive setting, such as the operating room [1]. In this paper, wesearch for recently published studies using post-spinal nore-pinephrine application. We then summarize norepinephrineefficacy and safety inmanaging maternal hypotension duringcesarean section with spinal anesthesia. Finally, we discuss

HindawiBioMed Research InternationalVolume 2018, Article ID 1869189, 14 pageshttps://doi.org/10.1155/2018/1869189

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https://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1155/2018/1869189

2 BioMed Research International

its feasibility as a substitute for the current gold standardphenylephrine that is used in this context.

2. Materials and Methods

2.1. Information Retrieval. We performed a systematic liter-ature search in the database websites of Pubmed, Embase,and GeenMedical to find reports directly related to post-spinal norepinephrine application using the keyword phrase‘norepinephrine ANDobstetric anesthesia’ and set the searchend point at Oct 31, 2018. Reference lists of these retrievedpapers and reviews related to vasopressor use during spinalanesthesia were also screened to minimize possible omis-sions. Eliminating editorial, review, and nonscience indexcited reports, we found nine suitable reports (details shown inTable 1). A detailed flowchart of literature retrieval is shownin Figure 1.

2.2. Assessment of Articles. All nine included reports werepublished from2015 to 2018.Three are randomized controlledtrials (RCTs) for norepinephrine (NE) alone [2–4], oneis a sequential allocation dose-finding study for NE [5],one is a random-allocation dose-response study for bothNE and phenylephrine (PE) [6], and the remaining fourpapers are RCTs that compare these two vasopressors [7–10]. All enrolled subjects were healthy parturients withoutcomorbidities that had an intrathecal injection of bupivacaineor ropivacaine in combination with opioid fentanyl and/ormorphine. Similarly, fluid loading and the left tilt supineposition were used for all parturients in all reports. Nonin-vasive hemodynamics were monitored in four reports usingUSCOM [3, 9], LIDCO [4] or Nexfin [7]. Of note, results inNgan Kee et al. 2017 [8] are a reanalysis of data from theirstudy in 2015 [9]; the first paper focuses on hemodynamicstability and the second on cardiac output (CO). As a result,there are actually three groups of RCT trials available thatcompare NE and PE. This small sample size, along withthe heterogeneity in primary observational outcomes andadministration regimens, does not provide enough statisticalpower to performameta-analysis.Thus, we only descriptivelypresent the results of the nine reports and discuss potentialadvantages of NE compared to PE.

3. Results

3.1. Efficacy Evaluation of NE for Obstetric Parturients. Effi-cacy to rescue maternal hypotension is of main concern withregard to vasopressor choice and NE efficacy evaluated inthese reports is detailed in Table 2. In 2015, Ngan Kee etal. [9] compared parturients undergoing elective cesareandelivery with spinal anesthesia receiving a variable ratecontinuous infusion of NE 0-5 𝜇g/min to those receiving PE0-100 𝜇g/min, with a computer-assisted closed loop feedbackalgorithm for maintaining systolic blood pressure (SBP) nearbaseline. Both groups had similar incidences of hypotension,hypertension, maternal side effects, and neonatal outcomes.However, NE group had a lower incidence of bradycardiaand a greater CO. The authors suggested the observed CO

with NE is primarily related to a greater heart rate (HR)that possibly comes from its weak 𝛽-adrenergic agonistproperty, which is absent in PE. A reanalysis of these datafurther showed that NE infusion was associated with amore precise control of SBP compared to PE infusion, asdemonstrated by a decreased MDPE (themedian of all valuesof performance error for each patient), MDAPE (the medianof the absolute values of performance error for each patient),and Wobble (the median value of the differences betweeneach value of performance error and MDPE) [8]. Such supe-riority of NE is plausibly attributable to its pharmacologicalproperties including a fast onset and short duration [11]that make accurate titration possible. However, computer-assisted infusion technology is currently not recommendedfor clinical practice [1]. Thus, Ngan Kee et al. explored theefficacy of a simpler algorithm, using manually controlledvariable rate infusion of NE 0-5 𝜇g/min tomaintain SBP nearbaseline, compared to using a rescue bolus of 5 𝜇g wheneverhypotension occurred [3]. Compared to the rescue bolus, themanually controlled infusion regimen was associated with alower incidence of hypotension, a similar CO, and a bettercontrol for SBP stability. Although a relatively larger dose ofNE was applied, no maternal or neonatal adverse outcomeswere observed. Considering intravenous bolus is still thefavored medication paradigm for most anesthesiologists [12],a final RCT trial compared the efficacy of equipotent bolusNE and PE for maternal hypotension with the incidence ofbradycardia as primary outcome. Compared to PE, an NEintermittent bolus resulted in a nearly 71% reduction in theoccurrence of bradycardia, which indicates its potential forbetter maintenance of CO [10].

A lower MDPE indicates a lower level of SBP for NE,suggesting 0-5 𝜇g/min of NE might be less potent (notequivalent, as expected) than PE 0-100 𝜇g/min [8]. A sub-sequent dose-response study for rescuing the first episodeof maternal hypotension calculated an ED90 of 18 𝜇g versus239 𝜇g for NE and PE, respectively in obstetric anesthesia, apotency ratio of approximately 13:1 [6]. Another dose-findingstudy found an ED90 of NE for SBP maintenance to higherthan baseline value was approximately 6 𝜇g [5]; the majorityof those receiving a dose lower than 6 𝜇g still presentedwith hypotension (5 of 6 cases). Difference in the timing ofintervention, at SBP < 80% baseline in Ngan Kee et al. [6]and at SBP < baseline in Onwochei et al. [5], might accountfor the dosing differences observed in these two studies.

Three RCT trials explored NE efficacy for SBP mainte-nance using a fixed rate infusion regimen [4, 7]. In ChenD et al. [4], NE 5 or 10 𝜇g/kg/h, a dose equal to 5 or 10𝜇g/min for a parturient with a weight of 60 kg, provideda better BP maintenance without increased incidence ofhypertension compared to a dose of 15 𝜇g/kg/h. Vallejo et al.[7] compared NE 0.05 𝜇g/kg/min and PE 0.1 𝜇g/kg/min, adose that equivalent to NE 3 𝜇g/min and PE 6 𝜇g/min for a60 kg parturient, and found the former had a less need forephedrine. However, a similar high incidence of need for res-cue bolus of both vasopressors (PE and ephedrine), 65.8% vs48.8%, suggested suchdosingmight not be adequate to rescuematernal hypotension. Further, in a recently published trial[2], two doses, 0.05 or 0.075 𝜇g/kg/min dose of NE infusion,

BioMed Research International 3

Table1:Ch

aracteris

ticso

fenrolledstu

dies.

Reference

Stud

ydesig

nParticipants

Anesth

esia

Dosingregimen

Interventio

nObservatio

nal-e

ndpo

int

Prim

aryou

tcom

evaria

bles

Hasanin

etal.,2

018[2]

Dou

ble-blind

RCT

284healthywo

men

Spinalanesthesiawith

bupivacaine10mg+

fentanyl20𝜇g,rapid

crystallo

idcoloadingto

1500

mlstartingat

subarachno

idblock,left

tiltsup

inep

osition

Fixedrateinfusio

n

NEinfusio

n0.025,0.05,or0

.075

𝜇g/kg/m

inforS

BPmaintenance

after

aninitialbo

luso

fNE5𝜇g

givenpo

stspinalanesthesia,

ephedrine9

mgisgivenwhen

SBP<80%baselin

eorS

BP<

80%baselin

e+bradycardia

(HR<

55bp

m),ephedrine15mg

isgivenforsevereh

ypotensio

n(SBP<60

%baselin

e),atro

pine

0.5m

gforb

radycardiapersisted

after

thep

reviou

smeasure

Immediatelypo

stspinalanesthesiaun

til5min

postdelivery

Frequencyo

fpo

st-spinal

hypo

tension(SBP<

80%baselin

e)

Sharkeye

tal.,

2018

[10]

Dou

ble-blind

RCT

112healthywo

men


bupivacaine13.5mg+

fentanyl10𝜇g+

morph

ine100𝜇g,rapid

hydrationfor10m

l/kg

immediatelypreceding

intrathecalinjectio

n,left

tiltsup

inep

osition

Interm

ittentb

olus

NEbo

lus6𝜇gvs.P

E100𝜇g

wheneverS

BPlowe

rthan

baselin

e,ephedrine10mgis

givenwhenSB

P<80%baselin

e+HR<60

bpm

orSB

P<80%

baselin

efor

2consecutive

readings

Immediatelypo


tildelivery

Incidenceo

fbradycardia(H

R<50

bpm)inthe

predeliveryperio

d

NganKe

eet

al.,2

018[3]

Dou

ble-blind

RCT

107healthywo

men


bupivacaine11m

g+


hydrationfor2

Lpo

stspinalanesthesia,left

tilt

supine

position,

suprasternalDop

pler

(USC

OM)for

hemod

ynam

icmon

itor

Manually

controlled

varia

bler

ateinfusion

vs.intermittentb

olus

NEinfusio

n0-5𝜇

g/min

forS

BPnear

baselin

evs.NEbo

lus5𝜇g

wheneverS

BP<80%baselin

e

Immediatelypo


tildelivery

Incidenceo

fhypo

tension(SBP<

80%baselin

e),and

overallstabilityof

SBP

controlcom

pared

with

perfo

rmance

error(MDAPE

,MDPE

,Wob

ble)

Chen

Detal.,

2018

[4]

Dou

ble-blind

RCT

117healthywo

men


ropivacaine11-12.5mg+

morph

ine0

.1mg,

preloading

with

LR10

ml/k

g,lefttiltsup

ine

position,

noninvasive

mon

itorin

g(LID

CO)for

COandSV

R

Fixedrateinfusio

n

NEinfusio

n5,10,or15𝜇g/kg/h

vs.salinefor

SBPmaintenance,

NErescue

bolus10𝜇gforS

BP<

80%baselin

eor<

90mmHg

Immediatelypo


tilthee

ndof

surgery

Prop

ortio

nof

hypo

tension

participants(SBP<

80%baselin

eor<

90mmHg)


Table1:Con

tinued.

Reference

Stud

ydesig

nParticipants

Anesth

esia

Dosingregimen

Interventio

nObservatio

nal-e

ndpo

int

Prim

aryou

tcom

evaria

bles

VallejoM

etal.,2

017[7]

Openlabel

RCT

81healthywo

men


bupivacaine12-15

mg+

fentanyl20𝜇g+

morph

ine0

.2mg,

preloading

with

LR500

ml,lefttiltsup

ine

position,

noninvasive

mon

itorin

g(N

exfin

)for

CO,C

I,SV

,SVR

Fixedrateinfusio

n

NE0.05

vs.P

E0.1𝜇

g/kg/m

infor

SBPwith

100-120%

ofbaselin

e,rescue

bolusP

E100𝜇gfor

hypo

tension(SBP<baselin

e)or

rescue

ephedrine5

mgfor

hypo

tension+bradycardia(H

R<60

bpm)

Immediatelypo


tilthep

atient

care

transfe

rred

tothe

labo

rand

delivery

nursep

ostoperativ

ely

Num

bera

ndtype

ofrescue

bolus

interventio

nneeded

tomaintainSB

P

Onw

ocheiet

al.,2

017[5]

Dou

ble-blind

up-dow

nsequ

entia

lallocatio

ndo

se-find

ing

study

40pregnant

women


bupivacaine13.5mg+

fentanyl10𝜇g+

morph

ine0

.1mg,rapid

hydrationfor10m

l/kg

immediatelypreceding

intrathecalinjectio

n,left

tiltsup

inep

osition

Interm

ittentb

olus

NEbo

lus3

,4,5,6,7,or8𝜇g

wheneverS

BP<100%

baselin

e

Immediatelypo


tildelivery

Successo

fNE

regimen

tomaintain

SBPator

above8

0%of

baselin

e

NganKe

eet

al.,2

017[6]

Rand

omallocatio

n-graded

dose-

respon

sestu

dy

180healthywo

men


bupivacaine11m

g+


cohydrationwith

Plasma-Lyte-A

2L,left

tiltsup

inep

osition

Interm

ittentb

olus

NEbo

lus4

,5,6,8,10,12𝜇gvs.

PE60

,80,100,120,160,200𝜇g

forfi

rstepisode

ofhypo

tension

(SBP<80%baselin

e)

Postspinalanesthesia

until

completionof

each

respon

semeasurement

Doser

espo

nsec

urve

NganKe

eet

al.,2

017[8]

Two-arm

parallel,

doub

le-blin

dRC

T

101h

ealth

ywo

men


bupivacaine11m

g+


cohydrationwith

LRto

maxim

al2L

justaft

erintrathecalinjectio

n,left

tiltsup

inep

osition

Closed-lo

opfeedback

compu

ter-controlled

infusio

n

NE0-5𝜇g/min

vs.P

E0-100

𝜇g/min

forS

BPnear

baselin

ewith

compu

terd

esigned

algorithm

Immediatelypo


tildelivery

MDAPE

)


Table1:Con

tinued.

Reference

Stud

ydesig

nParticipants

Anesth

esia

Dosingregimen

Interventio

nObservatio

nal-e

ndpo

int

Prim

aryou

tcom

evaria

bles

NganKe

eet

al.,2

015[9]

Two-arm

parallel,

doub

le-blin

dRC

T

101h

ealth

ywo

men


bupivacaine11m

g+


cohydrationwith

LRto

maxim

al2Ljustaft

erintrathecalinjectio

n,left

tiltsup

inep

osition

,suprasternalDop

pler

(USC

OM)for

CO

mon

itor

Closed-lo

opfeedback

compu

ter-controlled

infusio

n

NE0-5𝜇

g/min

vs.P

E0-100

𝜇g/min

forS

BPnear

baselin

ewith

compu

terd

esigned

algorithm

Immediatelypo


tildelivery

CO

RCT:

rand

omized

controlledtrial;NE:no

repineph

rine;PE

:phenyleph

rine;SB

P:systo

licbloo

dpressure;H

R:heartrate;LR

:lactatedrin

gers’solution;CO

:cardiac

output;C

I:cardiacind

ex;SV:

strokev

olum

e;SV

R:syste

micvascular

resistance;MDAPE

:medianabsoluteperfo

rmance

error;MDPE

:medianperfo

rmance

error;Wob

ble:am

easure

ofthev

ariabilityof

perfo

rmance

errora

roun

dMDPE

fore

achpatient.


Identification

Screening

Eligibility

Included

Excluded (n=7)- Editorial (n=5)- Review (n=1)- Compared to ephedrine and not science

citation index cited (n=1)

A number of 10 articles assessed for eligibility

Excluded (n=1)- Case series without data available for

extraction (n=1)

9 full-text articles included in final analysis- RCTs for norepinephrine alone (n=3)- Sequential allocation dose-finding study for

norepinephrine (n=1)- Random-allocation dose-response study for both

norepinephrine and phenylephrine (n=1)- RCTs for comparison between norepinephrine

and phenylephrine (n=4)

A total of 17 records identified throughdatabase searching

Figure 1: Flowchart of studies included. Footnote: The excluded two articles that neither editorial nor review are as follows: Selim MF.Norepinephrine versus ephedrine to maintain arterial blood pressure during spinal anesthesia for cesarean delivery: a prospective double-blinded trial. Anesthesia, essays, and researches 2018; 12: 92-97. Ngan KeeWD. Norepinephrine for maintaining blood pressure during spinalanaesthesia for caesarean section: a 12-month review of individual use. Int J Obstet Anesth 2017; 30: 73-74.

were both effective in reducing postspinal hypotension andNE 0.075 𝜇g/kg/min did not provide an additional advantagecompared to 0.05 𝜇g/kg/min other than a slighter higherSBP (nearly 5 mmHg). Thus, the authors suggested that 0.05𝜇g/kg/min, a dose equal to 3𝜇g/min for a 60 kg parturient, isthe best infusion dose for NE during spinal anesthesia withcesarean delivery.

The ultimate goal of hemodynamic management is tomaintain adequate maternal CO and uteroplacental perfu-sion. Four reports measured CO [3, 4, 7, 9] with variousdevices (USCOM, LIDCO, Nexfin), and only Ngan Kee et al.[9] reported a greater CO in the NE vs. PE group. However,it should be noted that, except for the first five minuteswhen CO in the PE group was at 94% baseline, CO wasabove preanesthetic baseline in both groups at all measuredtimepoints in the study. In addition, the subtly greater COobserved did not translate into clinical advantages, as nodifferences in maternal or neonatal outcomes were observedfor NE compared to PE. This may be because all the enrolledparturients were healthy ones and without comorbidity. COadvantage should be further clarified in high risk situationssuch as maternal cardiac disease, placental insufficiency, orcompromised fetal status.

3.2. Safety Evaluation of NE for Obstetric Parturients. Com-monly used variables to evaluate vasopressor safety includematernal side effects such as nausea, vomiting, dizziness,

shivering, and local tissue ischemia and neonatal outcomesincluding Apgar score and umbilical blood gas analysis.Although not used as primary observational outcomes, amajority of included reports measured these parameters(Table 3). For maternal outcomes, most studies found nodifferences in nausea or vomiting between NE and PE [2–5, 8–10]. A high incidence of emesis in Vallejo M et al. [7] wasobserved for PE compared to NE (26.3% vs 16.3%); however,a chi-square test easily showed that this difference was notstatistically significant with a P = 0.29 rather than a value <0.001, as provided by the authors. Thus, available literatureconsistently shows a maternal safety in terms of nausea orvomiting.

NE-induced vasoconstriction and skin necrosis isanother concern for NE application in obstetric anesthesia,where a peripheral rather than central vein is commonlyused [13]. Chen D et al. [4] observed skin color, an indicatorof peripheral vascular constriction, and they found theincidence of pale skin was relatively low and similar amonggroups. In addition, Ngan Kee et al. [3, 6] and Onwocheiet al. [5] suggested that NE is safe for local tissue perfusionsince NE is diluted before use and administered in a runningfluid for a relatively short duration, thus reducing the risk oftissue ischemia. Further, an equal potency of NE infusionor bolus has a theoretically similar vasoconstrictive potencyas the currently used PE, so that risk should be no differentto that posed by PE. Furthermore, a previous study showed


Table2:Effi

cacy

evaluatio

nof

norepineph

rine.

Reference

Participantsanddo

sing

regimen

BPHR

Non

-invasiv

ehemod

ynam

icDrugconsum

ption

Perfo

rmance

error

Hasanin

etal.,2

018[2]

Group

NE1

(n=9

5),0.025

𝜇g/kg/m

in;N

E2(n=9

3),

0.05𝜇g/kg/m

in;N

E3(n=9

6),0.75𝜇

g/kg/m

in;

follo

wedwith

aninitial

boluso

fNE5𝜇ggivenpo

stspinalanesthesia

SBPwas

high

erwith

NE2

/NE3

comparedto

NE1∗

Frequencyo

fpost-s

pinal

hypo

tension:

NE1>

NE2

/NE3

,42.1%

,24.7%

,and26.0%,respectively∗

Frequencyo

fsevere

hypo

tension,

intraoperativ

ehypertensio

n,and

postd

eliveryhypo

tension:

ns

HRwas

lowe

rinNE2

/NE3

comparedto

NE1∗

Frequencyo

fbradycardia

requ

iring

atropine,ns

N/A

Ephedrine

requ

irements:

NE1>

NE2

/NE3

,7±10,5±

9,and5±

9mg,

respectiv

ely∗

N/A

Sharkeye

tal.,

2018

[10]

Group

NE(n=5

6)and

grou

pPE

(n=5

6),N

Ebo

lus

6𝜇gvs.P

E100𝜇g

wheneverS

BPlowe

rthan

baselin

e,ephedrine10mgis

givenwhenSB

P<80%

baselin

e+HR<60

bpm

orSB

P<80%baselin

efor

2consecutiver

eading

s

Incidenceo

fhypotensio

n,hypertensio

n,and

tachycardia:ns

NeedforN

EandPE

bolus:

nsNeedforrescuee

phedrin

ebo

lus:7.2

%vs.21.4

%∗

Incidenceo

fbradycardia:

grou

pNE<grou

pPE

,6(10.9%

)vs2

1(37.5%)∗

Incidenceo

f>2episo

deso

fbradycardia:grou

pNE<

grou

pPE

,2(3.6%)v

s11(

19.6%)∗

N/A

Prop

ortio

nof

need

fore

phedrin

e:grou

pNE<grou

pPE

,7.2%

vs.21.4

%∗

Vasopressorb

olus

requ

ired:9[6-14]

for

NEvs.8[5.5-10.5]

for

PE,ns

N/A

NganKe

eet

al.,2

018[3]

Group

NE1

(n=5

3),

manually

controlled

varia

bler

ateinfusion,

0-5

𝜇g/min

forS

BPnear

baselin

eGroup

NE2

(n=5

4),bolus

5𝜇gwheneverS

BP<80%

baselin

e

Incidenceo

fhypotensio

n:grou

pNE1<NE2

,9(17%

)vs

35(66%

)∗AU

Cof

SBPover

time:

grou

pNE1>NE2

,110.9±

8.3vs

101.9±9.4

mmHg∗

Incidenceo

fbradycardia:4

(7.5%

)vs4

(7.4%

),ns

AUCof

HRover

time:

grou

pNE1<NE2

,82.2±

10.4vs

88.2±12.1mmHg∗

CO:6.85±1.3

7for

grou

pNE1

vs6.42±

1.31L

/min

forg

roup

NE2

,ns

Totald

ose:grou

pNE1

>NE2

,61.0

(47.0

-72.5)

vs5.0

(0-18.1)𝜇g

Medianrate:group

NE1>NE2

,2.22

(1.87-2.57)v

s0.28

(1.87-2.57)𝜇

g/min

MDPE

:group

NE1<NE2

,-2.99(-6.36

to0.29)v

s-11.15(-14.77to

-7.65)∗

MDAPE

:group

NE1<NE2

,4.97

(3.81to6.74)v

s11.3

3(7.86

to14.99)∗

Wob

ble,3.13

(2.51to3.76)

vs3.32

(2.45to5.00

),ns

Chen

Detal.,

2018

[4]

Group

NE1

(n=2

9),5

𝜇g/kg/h;N

E2(n=3

0),10

𝜇g/kg/h;N

E3(n=2

8),15

𝜇g/kg/h;con

trolgroup

(n=3

0),salineinfusion;

rescue

bolus10𝜇gforS

BP<80

%baselin

eor<

90mmHg

Incidenceo

fhypotensio

n:controlgroup>NE1,N

E2,

NE3

,86.7,37.9,

20,25%

,respectiv

ely∗

Incidenceo

fhypertension:

controlgroup<NE1/N

E2<

NE3

,10,41.4,36.6,and

75%,respectively∗

Incidenceo

fbradycardia:0,

3.4,3.3,10.7%,ns

HR:

nsam

onggrou

psCO,SVR:

ns

Totald

ose:control

grou

p<NE1<NE2

,NE3

,23±

20,186.9±

79.6,375.8±137.3

,479.1±243.8𝜇

g,respectiv

ely∗

N/A


Table2:Con

tinued.

Reference

Participantsanddo

sing

regimen

BPHR

Non

-invasiv

ehemod

ynam

icDrugconsum

ption

Perfo

rmance

error

VallejoM

etal.,2

017[7]

Group

NE(n=4

3),0.05

𝜇g/kg/m

in;group

PE(n=3

8),0.1𝜇g/kg/m

in;for

SBPwith

100-120%

ofbaselin

e,rescue

bolusP

E100𝜇gforh

ypotensio

n(SBP<baselin

e)or

rescue

ephedrine5

mgfor

hypo

tension+bradycardia

(HR<60

bpm)

Prop

ortio

nof

vasopressor

requ

irement:21

(48.8%

)for

grou

pNEand25

(65.8%

)forg

roup

PE,ns

Requ

irementfor

PErescue

bolus:20

(46.5%

)for

grou

pNEand20

(52.6%

)for

grou

pPE

,ns

Requ

irementfor

ephedrine

rescue

bolus:grou

pNE<

PE,1

(2.3%),9(23.7%

)∗Incidenceo

fhypertension:

1(2.6%

)vs2

(4.7%),ns

Incidenceo

fbradycardia:8

(18.6%

)for

grou

pNEand9

(23.7%

)for

grou

pPE

,ns

CO,C

I,SV

,SVR:

ns

Mediantotalrescue

PEdo

se:100[0-700]

forg

roup

NEand50

[0-100

0]𝜇gfor

grou

pPE

,ns

Mediantotalrescue

ephedrined

ose:0

[0-30]

forg

roup

NE

and0[0-85]

mgfor

grou

pPE

,ns

N/A

Onw

ocheiet

al.,2

017[5]

BolusN

E3(

n=6),4

(n=2

),5(n=9

),6(n=2

0),7𝜇g

(n=3

)torescue

firstepiso

deof

hypo

tension

ED90

ofNE5.49𝜇g

(95%

CI5.15-5.83)

using

trun

catedDixon

andMoo

dmetho

d;5.80𝜇g(95%

CI5.01-6.59)

usingtheisotonic

regressio

nmetho

dHypotensio

nincidence:6

(15%

),of

which

5(83.3%

)with

NE<6𝜇

g;Incidence

ofhypertensio

n:4(10%

)

Incidenceo

fbradycardia:3

(7.3%

)N/A

CumulativeN

Edo

se:

6to

78𝜇g

N/A

NganKe

eet

al.,2

017[6]

NEbo

lus4

,5,6,8,10,12𝜇g

vs.P

E60

,80,100,120,160,

200𝜇g(n=15fore

achdo

segrou

p)forfi

rstepisode

ofhypo

tension

ED50

forN

EandPE

is10

𝜇g(95%

CI,6-17𝜇

g),137𝜇g

(95%

CI,79-236𝜇g)

ED90

forN

EandPE

is18

𝜇g(95%

CI,5-63𝜇

g),239𝜇g

(95%

CI,66-869𝜇

g)Po

tencyr

atioof

NE

comparedto

PE:13.1(95%

CI,10.4-

15.8)

HRdecrease:N

E<PE∗

N/A

N/A

N/A

NganKe

eet

al.,2

017[8]

NE0-5𝜇

g/min

(n=4

9)vs.

PE0-100𝜇

g/min

(n=5

2)for

SBPnear

baselin

ewith

compu

terd

esigned

algorithm

Incidenceo

fhypotensio

n:4(8.2%

)for

grou

pNE,

4(7.7

%)for

grou

pPE

,ns

Incidenceo

fhypertension:

4(8.2%)for

grou

pNE,

9(17.3

%)for

grou

pPE

,ns

Incidenceo

fbradycardia:9

(18.4%

)for

grou

pNE,

29(55.8%

)for

grou

pPE∗

N/A

Totalvasop

ressor

volume:10.4

[9.5-14.1],14.3

[9.9-16.9]

ml,ns

MDPE

(%):grou

pNE<

PE,0.75[-1.5

6to

2.52]v

s.2.61

[0.83to

4.57]∗

MDAPE

(%):grou

pNE<

PE,3.79[2.82to

5.17]v

s.4.70

[3.23to6.57]∗

Wob

ble(%):2.85

[2.07to

3.92]v

s.3.39

[2.62to

4.90]∗

Divergence(

%/m

in):ns


Table2:Con

tinued.

Reference

Participantsanddo

sing

regimen

BPHR

Non

-invasiv

ehemod

ynam

icDrugconsum

ption

Perfo

rmance

error

NganKe

eet

al.,2

015[9]

NE0-5𝜇

g/min

(n=4

9)vs.

PE0-100𝜇

g/min

(n=5

2)for

SBPnear

baselin

ewith

compu

terd

esigned

algorithm

AUCof

SBPover

time:ns

AUCof

HRover

time:

grou

pNE>PE∗

AUCof

CO:group

NE>PE∗

AUCof

SV:ns

AUCof

SVR:

grou

pNE<PE∗

N/A

N/A

NE:

norepineph

rine;PE

:phenyleph

rine;MDPE

:medianperfo

rmance

error;MDAPE

:medianabsoluteperfo

rmance

error;SB

P:systo

licbloo

dpressure;H

R:heartrate;CO

:cardiac

output;C

I:cardiacindex;SV

:str

okevolume;SV

R:syste

micvascular

resistance;AU

C:area

underthe

curve;Va

lues

aremean(stand

arddeviation),m

edian[in

terquartile

range],orn

umber(%);∗

P<0.05;ns:no

statisticalsig

nificance

between

grou

ps;N

/A:n

otavailable.


Table3:Safety

evaluatio

nof

norepineph

rine.

Reference

Maternalsidee

ffects

Anticho

linergicd

rug

Apgarscorin

gBloo

dgasa

nalysis

Umbilicalbloo

dcatecholam

ines

Hasanin

etal.,2018

[2]

Nauseao

rvom

iting

:ns

Four

inNE1,3

inNE2

,and

7in

NE3

:ns

Apgara

t1and10

min:ns

pH,P

CO2,P

O2,H

COin

UA:ns

N/A

Sharkeye

tal.,2018

[10]

Nauseao

rvom

iting

:ns

N/A

Apgara

t1and5min:ns

pH,P

CO2,P

O2,H

CO3,B

Ein

UAand

UV:

nsN/A

NganKe

eetal.,2018

[3]

Nauseao

rvom

iting

:ns

Nopatie

ntNoAp

gar<

7at1m

inor<8

at5m

inin

either

grou

ppH

,PCO2,P

O2,B

Ein

UAandUV:

nsN/A

Chen

Detal.,2018,

[4]

Shivering,nausea,and

paleskin:ns

One

inNE3

:ns

Apgara

t1and5min:ns

Glucose:N

E2,N

E3>NE1,con

trolgroup

ineither

maternalorn

eonatalU

A;pH,

PCO2,P

O2,H

CO3,L

ac,B

E:ns

amon

ggrou

psin

maternaland

neon

atalUA

N/A

VallejoM

etal.,2

017

[7]

Nausea:51.2%forg

roup

NEand63.2%

forg

roup

PE,n

s;em

esis:

16.3%forg

roup

NEvs.26.3%

forg

roup

PE,ns

N/A

Apgar<

7at1m

inor

5min:

nspH

,PCO2,P

O2,H

CO3,B

Ein

UV:

nsN/A

Onw

ocheietal.,2017

[5]

Nausea:11(27.5

%),of

which

4(36.4%

)and7(63.6%

)with

NE<6𝜇gandat6𝜇g,

respectiv

ely;n

ovomiting

observed

N/A

AllAp

gar>

8at1m

inor

5min

Incidenceo

fUApH<7.2

:6(15%

),1w

ithNE<6𝜇

g,5with

NE6𝜇g

BEishigh

erin

thosew

ithNE<6𝜇

gcomparedto

thosew

ith6𝜇g:-2.56vs

-4.94∗

N/A

NganKe

eetal.,2017

[6]

N/A

N/A

Apgar<

7at1m

inor<8at

5min:ns

Incidenceo

fUApH<7.2

:4(4.4%)v

s5(5.6%

),ns

N/A

NganKe

eetal.,2015

[9]

Nauseao

rvom

iting

:3(6.1%

)for

grou

pNEand2(3.8%)for

grou

pPE

,ns

N/A

AllAp

gar>

7at1m

inand5

min

Nopatie

nthadUA

pH<7.2

pHandoxygen

content:grou

pNE>PE

inUV∗;P

CO2,P

O2,B

E:ns

inUV;

pH,

PCO2,P

O2,B

E,oxygen

content,ns

inUA

Glucose

content:grou

pNE>PE

inUA

andUV∗

Epinephrinec

ontent:

grou

pNE<PE

inUA∗;

NEcontent:grou

pNE

<PE

inUA

andUV∗

BE:basee

xcess;NE:

norepineph

rine;PE

:phenyleph

rine;UA

:umbilicalartery;U

V:um

bilicalvein;ns:no

significantd

ifference

betweenor

amon

ggrou

ps;valuesa

renu

mber(%);N/A

:not

available.


spinal anesthesia increases skin perfusion and that this effectis not counteracted by NE application [14]. Collectively,results suggest NE likely has no adverse effect on local tissueperfusion in patients with spinal anesthesia for commonlyused infusion or bolus doses. Commercially available NE(Levophed) does not specify that NE needs to be givencentrally, indicating only that it should be via a large vein,preferably antecubital [15].

The safety profile of NE for the fetus and neonate isanother consideration. Apgar scoring was performed in allreports and no obvious detrimental effects observed for NE.Similarly, UA or UV blood gas analysis showed no adverseeffects for NEwith regard to pH, PCO

2, PO2, HCO

3, and base

excess (BE) values. Onwochei et al. [5] observed a 6 𝜇g doseof NE was related to a more negative BE compared to smallerdoses, thus raising the concern for fetal acidosis of NE.However, such lower BE was still within a normal range andthis study was not powered enough to detect a true differencein NE safety with different doses. NE infusion may increasematernal and neonatal glucose, partially resulting from anincrease in catecholamine stimulated glucose metabolismincrease and a 𝛽-receptor-mediated insulin decrease [4, 9].NE is not expected to readily cross the placenta, which hasthe ability to break down catecholamines. In fact, as suggestedby Ngan Kee et al. [9], the use of NE may actually reducefetal catecholamine level compared to PE, eliminating thepotential stimulation of fetal metabolism and acidemia oftenseen with ephedrine.

4. Discussion

Understanding of maternal hypotension postneuraxial anes-thesia is improving as new evidence accumulates. As earlyas the 1940s, studies suggested that aortocaval compressionimpedes venous return and sympathetic block exacerbatesvenous blood pooling in the lower extremity to synergisticallyreduce venous return, decreasing CO and causing maternalhypotension [16, 17].Thus, therapeutics such as fluid loading,left uterine displacement, left table tilt, or mechanical lowerextremity compression have long been favored to expandintravascular volume based on such understanding [18, 19].However, these strategies did not consistently show theexpected efficacy in alleviating maternal hypotension.

Then, nearly a decade ago, studies suggested, the pri-mary effect postspinal anesthesia is a decrease of system-atic vascular resistance (SVR) secondary to small arteryvasodilation[20], along with a modest degree of venousvasodilation [21, 22]. Since then, prevailing opinion suggestsloss of arteriolar tone and a significant decrease of SVRis likely the main mechanism involved in maternal spinalhypotension. In this context, use of vasopressors, given theirarterial vessels constriction property, is rational and recom-mended to rescue spinal anesthesia-induced hypotension.

At present, ephedrine, PE, and NE are three commonlyused vasopressors during elective cesarean delivery withspinal anesthesia. Other alternatives exist, including methox-amine, mephentermine, and metaraminol, but these are notfirst choices for most clinicians due to removal from the

market (for metaraminol) [23] or other concerns, includingcompromised uterine blood flow, adverse effect on fetalacid-base status, or inconvenient preparation requirements[24]. Ephedrine’s properties, including slow onset, reactivehypertension, tachyphylaxis, high placental transfer, andstimulation of fetal metabolism and potential fetal acidemia,collectively render it an inferior choice compared to PE [25].

Thus, PE is at present the first line vasopressor in obstetricspinal anesthesia [25], and its superiority in this context hasbeen comprehensively explored with regard to different dos-ing regimens and maintenance mode, with reviews available[26, 27]. As a kind of sympathomimetic amine, PE is a pure𝛼-adrenergic receptor agonist with no 𝛽-adrenergic receptoractivity. It induces arteriolar vasoconstriction to increase SVRand mean arterial pressure (MAP), reflexively leading to adose-dependent decrease of HR and, in turn, a decrease ofCO [28]. In venous capacitance vessels, such vasoconstrictionmay increase venous return; however, venous resistance alsoincreases, thus limiting venous return to the heart [29]. Incomparison, NE has weak 𝛽-receptor agonist activity as wellas 𝛼-adrenergic receptor agonism. Theoretically, NE is lesslikely to decrease HR and CO, rendering it a promisingalternative to PE in obstetric anesthesia. Pharmacology ofboth drugs is summarized in Table 4 using data frommultiple sources [30, 31], but these data still need to beconfirmed in obstetric spinal parturients. Of note, the peakpressor time of bolus PE is 61.8 s [22] while for NE, mostliterature suggests an onset time of < 60 s [30–32]. BothNE and PE are catecholamines that do not readily cross theplacenta. In Ngan Kee et al.’ [33], a median umbilical venousto maternal arterial plasma concentration ratio is 17% for PE.ForNE, clinical data are not available, but in vitro, the transferfrom the maternal to the fetal side is 11.6 ± 0.6% in a perfusedhuman placental lobe [34].

Consistent with its pharmacological properties, NE pro-vides amaternal HR advantage compared to PE inmost trials.Further, as recommended by a recent consensus statement,monitoring of maternal HR can be used as a surrogate forCO if the latter is not monitored [35]. Better maintenance ofHR and a potentially greater CO is considered a significantbenefit of NE. NE is considered an appropriate vasopressorin women with low baseline HR or compromised cardiacfunction [2]. As current evidence still suggest PE infusion isa default ‘good’ approach, whether the slight HR or possibleCO advantage of NE is sufficient to induce practitioners toswitch to the more ‘perfect’ NE is unclear [13]. More evidencemight be needed to prove the benefits of NE compared overPE to motivate practitioners to make a change.

Although efficacy and safety of NE are suggested by thesereports, the optimal dosing and administration paradigm isstill debated. Either computer-controlled closed loop feed-back infusion or manually controlled variable rate infusionof NE provides a more precise blood pressure managementcompared to equipotent PE infusion or NE bolus. However,such infusion regimens require smart pumps or more physi-cian intervention that is not feasible at all institutions. Inaddition, a recent consensus statement notes that hypoten-sion is frequent and, therefore, vasopressors should be usedroutinely and preferably prophylactically [35]. Prophylactic


Table 4: Pharmacology of phenylephrine and norepinephrine.

Phenylephrine NorepinephrinePharmacology 𝛼1, 𝛼2 𝛼1, 𝛼2, 𝛽1>> 𝛽2Onset time 60 s < 60sHalf time 5 min 1-2 min

Molecular structureCH

OH

NH

HO ＃（3

＃（2 CH

OHHO

HO ＃（2 N（2

Molecular weight 167 g/mol 169 g/molMetabolism Deamination, glucuronidation, sulfation COMT+MAO to VMARelative potency 1× 13×Placental transfer Minimal Likely minimal tooFetal metabolismstimulation Lower than ephedrine Lower than phenylephrine

MAP ↑ ↑

HR Dose dependently ↓ ± or ↓SV ± ± or ↑CO Dose dependently ↓ ± or ↑SVR ↑ ↑

Venous resistance ↑ ±

Venous return ± ±

Myocardial contractility ± or ↓ ↑

COMT: catechol-O-methyltransferase; MAO: monoamine oxidase; VMA: vanillylmandelic acid; MAP: mean arterial pressure; HR: heart rate; SV: strokevolume; CO: cardiac output; SVR: systemic vascular resistance; ± indicates neutral effect.

fixed-rate infusion is associated with less hemodynamicfluctuation and fewer maternal side effects compared to areactive bolus. Different groups have explored the optimalfixed infusion rate for NE alone [2, 4, 7] or in comparisonwith PE [9], with doses ranging from 1.5 to 15 𝜇g/min (fora 60 kg parturient). Results showed that a dose 3-5 𝜇g/minis sufficient in most cases, with a higher dose (10-15 𝜇g/min)exposing parturients to hypertension.

In summary, NE is similarly effective to PE in managingmaternal spinal hypotension. However, this conclusion isobtained using < 10 reports, and thus our confidence inresults must remain moderate compared to the hundreds ofreports available on PE efficacy and safety. Further, not allthe reports in our study are high-quality ones. For example,the study of Vallejo et al.’ [13] is highly questioned bya subsequent editorial. Firstly, the study design was notblinded, a serious limitation in a clinical trial. Second, afixed infusion of PE at a dose of 6 𝜇g/min is significantlylower than the commonly used dosing range of 25-100𝜇g/min for parturients with elective cesarean delivery andalmost certainly less potent than NE 3 𝜇g/min. Such dosingbias inevitably made it difficult to detect true differencesin drug efficacy or adverse outcomes. Third, continuousBP monitoring with Nexfin finger cuff made the observermore likely to intervene with hemodynamic management,potentially leading to an investigator bias. These limitations,combined with the lack of fetal umbilical artery blood gas

analysis, reduce our confidence in the results of the study.Thus, based on the limited available literature, NE is likely apromising alternative to PE, but before routine application,more favorable high-quality studies are warranted.

5. Conclusion

Although this minireview suggests NE is effective and safein obstetric spinal anesthesia, several uncertainties requireexploration. First, CO superiority is demonstrated by theavailable literature for NE compared to PE, but it does notmanifest any clinical advantages because no differences inmaternal side effects, neonatal Apgar scoring, or blood gasanalysis are observed. This may be because all enrolled par-turientswere healthy andwithout comorbidity. COadvantageshould be further clarified in high risk situations, such asmaternal cardiac disease, placental insufficiency, or poorfetal status. Second, certain details regarding NE applicationneed to be worked out, including target blood pressure,infusion administration or bolus regimen, and, importantly,the optimumdose [35]. Finally, data regarding the applicationof NE in special circumstances is lacking, such as in womenwith pre-eclampsia, in women who are morbidly obese, or ininstitutions where resources are constrained.

The available literature suggests NE is likely a promisingalternative for rescuing maternal hypotension in obstetricanesthesia. However, due to the relatively small number of


available studies, it is too early to draw a definite conclusion.For assurance of routine use in obstetric anesthesia, acquisi-tion of more high-quality supporting data of NE is warranted.

Conflicts of Interest

This study is supported by Young Talents Project of Maternaland Child Health Care in Jiangsu Province (FRC201787).Theauthors declare there are no conflicts of interest regarding thepublication of this paper.

Acknowledgments

The authors would like to thank Editage (www.editage.com)for English language editing.

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