A Review of the Impact of Phenylephrine Administration on...
Transcript of A Review of the Impact of Phenylephrine Administration on...
Society for Obstetric Anesthesia and Perinatology
Section Editor: Cynthia A. Wong
REVIEW ARTICLE
A Review of the Impact of PhenylephrineAdministration on Maternal Hemodynamicsand Maternal and Neonatal Outcomes in WomenUndergoing Cesarean Delivery UnderSpinal AnesthesiaAshraf S. Habib, MBBCh, MSc, MHS, FRCA
Phenylephrine is effective for the management of spinal anesthesia-induced hypotension inparturients undergoing cesarean delivery under spinal anesthesia. While ephedrine waspreviously considered the vasopressor of choice in obstetric patients, phenylephrine isincreasingly being used. This is largely due to studies suggesting improved fetal acid-basestatus with the use of phenylephrine as well as the low incidence of hypotension and itsrelated side effects with prophylactic phenylephrine regimens. This review highlights theeffects of phenylephrine compared with ephedrine on maternal hemodynamics (arterial bloodpressure, heart rate, and cardiac output), and occurrence of intraoperative nausea andvomiting. The impact of the administration of phenylephrine as a bolus for the treatment ofestablished hypotension compared with its administration as a prophylactic infusion isdiscussed. This article also reviews the impact of phenylephrine compared with ephedrine onuteroplacental perfusion, and fetal outcomes such as neonatal acid-base status and Apgarscores. The optimum dosing regimen for phenylephrine administration is also discussed.(Anesth Analg 2012;114:377–90)
Spinal anesthesia is commonly used for cesarean de-livery because it avoids the risks of general anesthesiarelated to difficult intubation and aspiration of gastric
contents. It is frequently associated with hypotension,which can have detrimental effects on the mother andneonate, including nausea, vomiting, and dizziness in themother, as well as decreased uteroplacental bloodflowresulting in impaired fetal oxygenation and fetal acidosis.Whether the mode of anesthesia affects neonatal outcomesis controversial. A meta-analysis reported that umbilicalartery pH may be lower with spinal anesthesia than withgeneral or epidural anesthesia.1 A large retrospective studyalso suggested an association between type of anesthesia andneonatal mortality of very preterm infants, with spinal anes-thesia being associated with an increased risk of neonatalmortality compared with general or epidural anesthesia.2
On the basis of better preservation of uteroplacentalcirculation in animal models, ephedrine was historically
considered the “gold standard” vasopressor for the man-agement of spinal anesthesia-induced hypotension.3,4
However, studies over the last 2 decades have suggestedthat fetal acid-base status might be improved if phenyleph-rine or other �-adrenergic agonists are used during cesar-ean delivery instead of ephedrine.5 Consequently, the useof phenylephrine for arterial blood pressure managementduring cesarean delivery under spinal anesthesia has in-creased. In 2001, a United Kingdom survey of the ObstetricAnesthetists Association consultant members found that95% of respondents used ephedrine as the first-choicevasopressor,6 whereas in 2006, 51% indicated that phenyl-ephrine is their first-line vasopressor.a In 2007 a survey ofthe members of the Society of Obstetric Anesthesia andPerinatology reported that 32% used ephedrine for treatingspinal-induced hypotension, 23% used phenylephrine, and41% used either drug on the basis of heart rate.7 However,there is still significant variation in practice regarding thechoice, dosing, and method of administration of vasopres-sors during cesarean delivery.7 This article will review theimpact of phenylephrine administration on maternal hemo-dynamics, intraoperative nausea and vomiting (IONV),and neonatal outcomes including Apgar scores and acid-base status. The optimum dose and method of administra-tion of phenylephrine will also be discussed.
From the Department of Anesthesiology, Duke University Medical Center,Durham, North Carolina.
Accepted for publication September 7, 2011.
Funding: Departmental.
The author declares no conflict of interest.
Reprints will not be available from the author.
Address correspondence to Ashraf S. Habib, MBBCh, MSc, MHS, FRCA,Department of Anesthesiology, Duke University Medical Center, Box 3094,Durham, NC 27710. Address e-mail to [email protected].
Copyright © 2012 International Anesthesia Research SocietyDOI: 10.1213/ANE.0b013e3182373a3e
aMcGlennan A, Patel N, Sujith B, Bell R. A survey of pre-loading andvasopressor use during regional anaesthesia for caesarean section. Int JObstet Anesth 2007;16:S27.
February 2012 • Volume 114 • Number 2 www.anesthesia-analgesia.org 377
INTRAOPERATIVE BLOOD PRESSURE, NAUSEA,AND VOMITINGHypotension is one of the most important causes of IONV,8
particularly in the initial period after initiation of spinalanesthesia. Hypotension may lead to cerebral hypoperfu-sion and brainstem ischemia, which is thought to activatethe vomiting center.9 It has also been suggested thathypotension results in gut hypoperfusion with the subse-quent release of emetogenic substances such as serotonin.10
Prevention of hypotension significantly reduces the inci-dence of IONV. Optimum use of vasopressors has thereforea significant impact on the incidence of IONV, with somestudies suggesting that IONV might be affected by thechoice and method of administration of the vasopressor.
A description of studies included in this review isshown in Table 1. Studies of IV phenylephrine administra-tion reporting on IONV are summarized in Table 2. A fewdetails are important to consider when interpreting thereported incidence of IONV in these studies. First, theduration of data collection was different among studies,with some studies stopping at uterine incision or delivery,and therefore not including postdelivery IONV episodes(likely induced by uterine exteriorization and visceral ma-nipulation). Second, many studies relied on self-reportingof nausea by patients, and so might have missed someepisodes of nausea.11,12 Third, studies might not havecompared equipotent doses of phenylephrine and ephed-rine. There has been some controversy regarding the vaso-pressor potency ratio, with some published studies usingratios varying from 20:1 to 250:1. A dose–response study ofprophylactic infusions using an up–down sequential allo-cation technique found a potency ratio of 83:1.13 Finally,most of the studies did not have IONV as a primaryendpoint and were therefore not powered to report statis-tically significant differences in this outcome despite re-porting clinically relevant differences.
Ephedrine Versus Phenylephrine BolusesThe use of phenylephrine boluses of 100 �g for the treat-ment of hypotension was associated with a lower incidenceof IONV than was ephedrine 6 to 10 mg despite a similarincidence and frequency of hypotension.14,15 The lowerincidence of IONV with the use of phenylephrine might berelated to the faster onset of pressor effect compared withephedrine (mean onset 61 seconds vs 89 seconds),16 leadingto more rapid correction of hypotension. The use of lowerdoses of phenylephrine of 40 to 80 �g, however, failed toreduce the incidence of IONV compared with ephedrine 5to 10 mg,17,18 with the 40-�g dose being associated with ahigher incidence of hypotension than ephedrine 5 mg.18
Similarly, the addition of 20 �g of phenylephrine to a 5-mgephedrine bolus for the treatment of hypotension was noteffective in reducing the incidence of hypotension or IONVcompared to ephedrine alone.19
Ephedrine Versus Phenylephrine InfusionsIn contrast to treating established hypotension, the use of aprophylactic vasopressor infusion might be more effectivein reducing the incidence of hypotension and IONV. Theuse of prophylactic phenylephrine infusions ranging from33 to 100 �g/min has been more effective in reducing the
incidence of hypotension and IONV than prophylacticephedrine infusions 1 to 8 mg/min.12,20,21 However, theuse of a lower infusion rate of phenylephrine at 10 �g/minwas not better than ephedrine 1 to 2 mg/min in reducingthe incidence of hypotension or IONV.22 Reactive hyper-tension has been reported with the use of prophylacticvasopressor infusions11,12,20,23–26; however, this is usuallytransient and responds quickly to stopping the infusion.
Combined Ephedrine andPhenylephrine InfusionsThe addition of phenylephrine 10 �g/min to an ephedrineinfusion at 2 mg/min resulted in a significantly lowerincidence of hypotension and IONV than did ephedrinealone.25 In contrast, the addition of ephedrine to a phenyl-ephrine infusion did not result in any extra benefit overphenylephrine alone in terms of lower incidence of hypo-tension or IONV,12,21 with 1 study reporting the incidenceof IONV increasing from 17% with phenylephrine alone to55% when ephedrine was added to phenylephrine, despitesimilar arterial blood pressure control.21 Cooper et al.suggested that this might be secondary to phenylephrine-induced venoconstriction, reducing preload and avoidingexcessive �-adrenergic stimulation.21 This in turn decreasesthe risk of increased vagal tone that might lead to IONVwith spinal anesthesia. Furthermore, another study comparingvarious combinations of phenylephrine and ephedrine infusionsreported that as the proportion of phenylephrine decreased andthe proportion of ephedrine increased, hemodynamic con-trol worsened and the incidence of IONV increased.12 Inthis study, the groups contained the proportional potencyequivalent of 100%, 75%, 50%, 25%, or 0% of phenylephrineand 0%, 25%, 50%, 75%, or 100%, respectively, of ephed-rine, assuming 100 �g phenylephrine to be equipotent to 8mg ephedrine.
Phenylephrine Bolus VersusPhenylephrine infusionAdministration of phenylephrine as a prophylactic infusionwas associated with an incidence of hypotension of13%–23% compared to an incidence of 85%–88% whenphenylephrine boluses of 100 �g were used to treat a 20%decrease in arterial blood pressure.11,27 Infusions comparedto bolus administration were also associated with a lowerincidence of IONV.11 Allen et al.,26 however, did not find areduction in the incidence of IONV with the use of prophy-lactic phenylephrine infusions at 25, 50, 75, and 100 �g/mincompared to treatment of hypotension with 100 �g phen-ylephrine boluses, despite a significantly lower incidence ofhypotension with the infusion regimens. Data collection inthis latter study continued for 10 minutes after delivery,and therefore exteriorization of the uterus, visceral ma-nipulation, and administration of oxytocin might havecontributed to a higher overall incidence of nausea in allgroups. In another study, the administration of a singleprophylactic phenylephrine bolus of 50 �g was less effec-tive than a prophylactic infusion in reducing the incidenceof hypotension and IONV.27
REVIEW ARTICLE
378 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA
Tabl
e1.Stu
dies
Com
paring
Ephe
drin
eto
Phe
nyle
phrine
:A
nest
heti
cTe
chni
que
and
Hem
odyn
amic
Man
agem
ent
Gro
ups
NSpi
naldr
ugs
Flui
dm
anag
emen
tB
Pgo
alB
Pm
anag
emen
tre
gim
enB
rady
card
iade
finit
ion
Ant
icho
liner
gic
indi
cati
onEn
dof
stud
y(i
fsp
ecifi
ed)
Nga
nK
ee1
4PE
bolu
s100
�g
102
Bup
10–1
2m
g�
Fent
15
�g
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prel
oad,
colo
adw
ithup
to2
LLR
SB
P�
100
mm
Hg
Bol
usfo
rS
BP
�100
mm
Hg
�50
bpm
HR
�50
bpm
and2
BP
Ute
rine
Inci
sion
Ebo
lus
10
mg
102
Prak
ash1
5PE
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s100
�g
30
Bup
10
mg
10
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kgLR
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oad
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15–2
0m
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SB
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80%
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for
SB
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31
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min
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(Con
tinue
d)
Impact of Phenylephrine on Maternal and Neonatal Outcomes
February 2012 • Volume 114 • Number 2 www.anesthesia-analgesia.org 379
Tabl
e1.
(Con
tinu
ed)
Gro
ups
NSpi
naldr
ugs
Flui
dm
anag
emen
tB
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card
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onEn
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fsp
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ed)
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min
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kgLR
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fusi
onst
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%,
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.In
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ven
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cm)
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oad
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BP
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27
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sion
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ently
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min
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min
20
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min
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(Con
tinue
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REVIEW ARTICLE
380 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA
Tabl
e1.
(Con
tinu
ed)
Gro
ups
NSpi
naldr
ugs
Flui
dm
anag
emen
tB
Pgo
alB
Pm
anag
emen
tre
gim
enB
rady
card
iade
finit
ion
Ant
icho
liner
gic
indi
cati
onEn
dof
stud
y(i
fsp
ecifi
ed)
Nga
nK
ee2
4PE
100
�g/
min
tom
aint
ain
SB
Pat
100%
base
line
24
Bup
10
mg
�Fe
nt15
�g
No
prel
oad,
LRat
min
imal
rate
Afte
r2
min
utes
,S
BP
at100%
,90%
,an
d80%
ofba
selin
ein
100%
,90%
,an
d80%
grou
ps,
resp
ectiv
ely
Infu
sion
for
2m
inut
es,
then
cont
inue
dif
SB
P�
100%
,90%
or80%
,an
dtu
rned
off
ifS
BP
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,or
80%
.PE
100
�g
give
nif
SB
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100%
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,or
80%
for
3m
inut
es.
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bpm
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and
SB
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Ute
rine
inci
sion
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min
tom
aint
ain
SB
Pat
90%
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25
PE100
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min
tom
aint
ain
SB
Pat
80%
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Ste
war
t28
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PE25
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min
25
Bup
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nt15
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oad
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een
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e
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sion
stop
ped
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BP
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100
�g
ifS
BP
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for
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es,
E6
mg
ifS
BP
still
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afte
r2
mor
em
inut
es
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bpm
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and
SB
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Del
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Impact of Phenylephrine on Maternal and Neonatal Outcomes
February 2012 • Volume 114 • Number 2 www.anesthesia-analgesia.org 381
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REVIEW ARTICLE
382 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA
Comparison of Different PhenylephrineInfusion RegimensA phenylephrine infusion at 100 �g/min combined with a2-L crystalloid coload was associated with a lower inci-dence of hypotension, compared to a similar regimen withfluid administered at a minimal rate (1.9% vs 23.8%).23 Theincidence of IONV was low and not different between thegroups. In another study by the same group of investiga-tors, a similar phenylephrine infusion regimen initiated at100 �g/min was titrated to maintain systolic blood pres-sure at 80%, 90%, or 100% of baseline.24 The incidence ofIONV was lowest in the group with the blood pressure goalof 100% of baseline. Stewart et al. reported a dose-relatedreduction in the incidence of IONV as the infusion rateincreased from phenylephrine 25 �g/min (25% incidence)to 50 �g/min (4%) and 100 �g/min (0%). There was also asignificant dose-related increase in systolic blood pressurein this study.28 These studies stopped data collection atdelivery or uterine incision.23,24,28 Allen et al. howevercollected data up to 10 minutes after delivery and reporteda higher incidence of IONV, ranging from 32% to 40%, withphenylephrine infusions of 25, 50, 75, and 100 �g/min;there was no significant difference among groups.26 Al-though the incidence of hypotension was higher in thelower-infusion-rate groups, the differences were not statis-tically significant, and the study was not powered for thisendpoint.
INTRAOPERATIVE HEART RATE ANDCARDIAC OUTPUTHeart Rate ChangesPhenylephrine has both direct and indirect sympathomi-metic effects; it primarily functions as an �-adrenergicreceptor agonist. The indirect effect results from norepi-nephrine release from nerve terminals’ storage sites.29
Unlike ephedrine, it lacks direct inotropic or chronotropiceffects. Phenylephrine administration is associated withreflex bradycardia. Studies have consistently reported aslower heart rate with phenylephrine than with ephed-rine.12,14–17,20,21,30 Use of prophylactic phenylephrineinfusions is associated with an overall slower heart ratecompared to treatment of hypotension with phenylephrineboluses.11,31 Comparison of different phenylephrine infu-sion rates demonstrate dose-related reductions in heartrate.24,28 Bradycardia occurring during administration of aprophylactic phenylephrine infusion should be managedby reducing the rate or stopping the infusion, unlessaccompanied by hypotension. Administration of an anti-cholinergic to treat bradycardia in the absence of hypoten-sion results in significant hypertension.26,32
Cardiac Output ChangesInitiation of spinal anesthesia is associated with changes incardiac output. Robson et al. used intermittent suprasternalDoppler flow measurements at 5, 10, and 15 minutes afterspinal anesthesia with 10 to 12.5 mg hyperbaric bupiva-caine in 16 women receiving a prophylactic ephedrineinfusion.33 Stroke volume was significantly decreased in 16patients, and cardiac output was reduced in 12; the de-crease in cardiac output exceeded 1 L/min in 9 subjects.More recently, Langesaeter et al. measured cardiac outputTa
ble
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Impact of Phenylephrine on Maternal and Neonatal Outcomes
February 2012 • Volume 114 • Number 2 www.anesthesia-analgesia.org 383
continuously using pulse waveform analysis after spinalanesthesia using bupivacaine 7 to 10 mg with or without aphenylephrine infusion at 0.25 �g/kg/min, and reportedan initial decrease in systemic vascular resistance togetherwith a concomitant increase in cardiac output after theinitiation of spinal anesthesia31; such an increase may bemissed in studies using intermittent measurements startingseveral minutes after initiation of the spinal anesthetic.
Studies investigating cardiac output changes associatedwith phenylephrine suggest that heart rate changes parallelchanges in cardiac output. An earlier study using intermit-tent suprasternal Doppler for 15 minutes after intrathecalinjection reported no overall changes in cardiac output withephedrine 5 mg compared to phenylephrine 100 �g for thetreatment of hypotension.30 This study, however, did notspecifically report cardiac output changes immediatelyafter vasopressor administration. Furthermore, atropinewas used in 58% of patients who received phenylephrine.More recently, Dyer et al. measured cardiac output con-tinuously using pulse waveform analysis and thoracicbioimpedance. In patients who required a vasopressor totreat a 20% decrease in mean arterial blood pressure, therewas a 35% decrease in systemic vascular resistance com-pared to baseline, accompanied by a 12% increase in heartrate, 9% increase in stroke volume, and 23% increase incardiac output before vasopressor administration. Cardiacoutput and heart rate were significantly lower during the150 seconds after administration of a phenylephrine bolusof 80 �g compared to ephedrine 10 mg for the treatment ofhypotension, but cardiac output values after phenylephrineadministration [mean � sd (5.2 � 1.5 L/min)] were stillnumerically higher than baseline values (4.6 � 0.9L/min).16 In comparison with prevasopressor values, car-diac output increased by 5% with ephedrine and decreasedby 14% with phenylephrine. Stroke volume was not differ-ent between the groups. Heart rate was slower in patientsreceiving phenylephrine and strongly correlated with car-diac output. The authors suggested that maintaining heartrate at baseline might therefore be a surrogate for main-taining baseline cardiac output.
In women receiving phenylephrine infusions at 25, 50,and 100 �g/min after spinal anesthesia with 11 mg hyper-baric bupivacaine, there were significant dose-related andtime-related reductions in heart rate and cardiac outputmeasured using suprasternal Doppler for 20 minutes afterintrathecal injection.28 Stroke volume remained stable withno significant differences among the groups, suggestingthat cardiac output changes were mainly due to heart ratereduction. In another study using lower doses of intrathecalbupivacaine (7 and 10 mg), Langesaeter et al. randomizedpatients to receive a prophylactic low-dose phenylephrineinfusion (0.25 �g/kg/min, equivalent to about 20 �g/min)or placebo. Hypotension was treated with phenylephrineboluses of 30 �g. The investigators reported that heart rateand cardiac output were also significantly lower in patientsreceiving the phenylephrine infusion.31 The initial increasein cardiac output seen after initiation of spinal anesthesiawas obtunded with phenylephrine. Similar to other studies,stroke volume was not different between groups.
Cardiac Output Changes in Womenwith Pre-EclampsiaTihtonen et al. measured cardiac output using bioimped-ance in 10 pre-eclamptic women undergoing cesareandelivery under spinal anesthesia and compared hemody-namic variables with those of healthy parturients.34 Atbaseline, mean arterial blood pressure and systemic vascu-lar resistance index were higher, while stroke index andcardiac index were lower in pre-eclamptic women. Sys-temic vascular resistance index and mean arterial bloodpressure decreased in both groups after spinal anesthesia,while cardiac index and stroke index were not changed.Hypotension, defined as a decrease in systolic arterialblood pressure to 80% of baseline or �100 mm Hg, oc-curred in 3 patients with pre-eclampsia and was treatedwith ephedrine, which increased both mean arterial bloodpressure and systemic vascular resistance index. In anotherobservational study involving 15 women with severe pre-eclampsia undergoing cesarean delivery under spinal an-esthesia,35 Dyer et al. reported that cardiac output washigher than baseline when women were placed supinebefore lateral tilt immediately after spinal placement, andthen was not different from baseline until it increased afterdelivery and oxytocin administration. In this study, 10patients received phenylephrine 50 �g boluses for thetreatment of a 20% decrease in mean arterial blood pres-sure. Phenylephrine administration was associated with asignificant decrease in heart rate, a trend toward a reduc-tion in cardiac output, and no change in stroke volume.
NEONATAL OUTCOMESAssessments of Uteroplacental PerfusionA few studies compared the effects of ephedrine tophenylephrine and other �-agonists on uteroplacental circu-lation using ultrasound measurements. These studies re-ported on the pulsatility index in maternal and fetal vessels,which is calculated as the difference between the peak systolicand end-diastolic flow velocity divided by the average flowvelocity.36 Alahuhta et al. administered a bolus of ephedrine 5mg or phenylephrine 100 �g followed by an infusion ofephedrine 50 mg/h or phenylephrine 1000 �g/h when thelevel of spinal block reached T5.36 The investigators reportedthat compared to baseline, mean maternal uterine and placen-tal arcuate arteries pulsatility index values were increased inpatients receiving phenylephrine but not those receivingephedrine, suggesting an increase in vascular resistance withphenylephrine. In contrast, the pulsatility index in fetal renalarteries decreased with phenylephrine. There was no changein fetal umbilical artery pulsatility in either group. In anotherstudy in which hypotension was treated with boluses ofephedrine 5 mg or phenylephrine 100 �g,30 there was also nodifference in umbilical artery pulsatility index measured atbaseline and 15 minutes after initiation of spinal anesthesia.Similarly, Ngan Kee et al. reported no difference in uterineartery pulsatility index in parturients who received a prophy-lactic ephedrine or metaraminol infusion initiated immedi-ately after induction of spinal anesthesia.37
Apgar Scores and Umbilical Cord Blood GasesNeonatal assessments were performed in most studiesusing Apgar scores and umbilical cord blood gas and pH
REVIEW ARTICLE
384 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA
analysis, with the latter commonly being the primaryoutcome of the study. While Apgar scoring is widely usedin clinical practice, and provides a useful assessment of thecondition of the infant in the first minutes after birth, itsusefulness as a predictor of neonatal outcome continues tobe debated. For instance, low Apgar scores alone are notsufficient evidence of hypoxia that might cause neurologi-cal damage.38 Poor correlation between Apgar scores andumbilical cord pH has been observed.39 On the other hand,umbilical cord blood gas and pH provide an indication ofthe fetal condition immediately before delivery, and mighttherefore be more useful than Apgar scores when assessingperfusion and the impact of vasopressors on the fetus.While pH is most commonly quoted, the scale is logarith-mic. Therefore, the base excess, which is also adjusted forPco2, provides a more linear measure of metabolic acidaccumulation. Low arterial cord pH may be associated withclinically significant neonatal outcomes.40 While umbilicalartery pH of 7.2 was historically considered the lower limitof normal,41 the use of this threshold value has beenchallenged. It has been suggested that pH values of 7.02 to7.18 represent the lower limit of normal umbilical arterypH.42 In fact, a pH�7.0 seems to be a better threshold valuesince significant adverse outcomes in the neonate are rarewith umbilical artery pH �7.0 or base excess ��12mmol/L.43
Studies examining Apgar scores and fetal acid-basestatus have consistently reported no difference in Apgarscores, but a higher umbilical artery pH and base excesswith IV phenylephrine compared with ephedrine in low-risk parturients undergoing elective cesarean delivery(Table 3). This result has been reported whether the vaso-pressors were administered as a bolus for the treatment ofestablished hypotension or as a prophylactic infusion. Thehigher fetal pH has been attributed to a greater placentaltransfer of ephedrine compared to phenylephrine (medianumbilical vein/maternal artery concentration ratio of 1.13compared with 0.17) and less early metabolism or redistri-bution in the fetus of the more lipid soluble ephedrine.20 Inturn, fetal ephedrine stimulates fetal �-adrenergic recep-tors, therefore increasing metabolic activity,20,21,44 and re-sulting in higher umbilical artery and vein Pco2, lower fetalpH, and increased fetal concentrations of lactate, glucose,epinephrine, and norepinephrine.20,21,45 The difference inpH is usually in the range of 0.01 to 0.08 pH units. It isunclear whether this difference is clinically relevant inlow-risk pregnancies.
Some studies have reported a lower umbilical artery andumbilical vein Po2 with phenylephrine compared withephedrine, possibly related to greater vasoconstriction ofthe uteroplacental circulation with resultant reducedflow and increased oxygen extraction.12,14,20 This doesnot appear to have a detrimental effect on the neonate.Sheep studies suggest that this lack of adverse effect isdue to greater uterine blood flow relative to what isrequired to meet fetal oxygen demand under normalphysiologic conditions.46
All the above studies were conducted in women withlow-risk pregnancies undergoing elective cesarean deliv-ery. In women undergoing nonelective cesarean delivery,
there was no difference in acid-base status when hypoten-sion was treated with ephedrine or phenylephrine boluses,but fetal lactate concentrations were higher with ephed-rine.14 Similarly, in a retrospective study, Cooper et al.reported no difference in umbilical artery pH with the useof ephedrine or phenylephrine for arterial blood pressurecontrol in high-risk cesarean deliveries.47
When comparing different regimens of phenylephrineadministration, there was no difference in neonatal acid-base status when phenylephrine was administered as abolus for the treatment of hypotension or as a prophylacticinfusion, despite a lower incidence of maternal hypoten-sion with the infusion.11,26 This is probably due to prompttreatment and short duration of hypotension. However,infusions titrated to maintain maternal systolic blood pres-sure at baseline were associated with a small (0.02 pH unitdifference) but statistically significantly higher umbilicalartery pH compared to infusion rates titrated to maintainblood pressure at 80% or 90% of baseline.24
Optimum Dosing and Administration Regimenof PhenylephrineThe optimal administration regimen for phenylephrine isunknown. Treatment of established hypotension by bolusadministration is simple but associated with more hypo-tension and more IONV than prophylactic infusions.11,26
Conversely, prophylactic administration is associated witha higher incidence of reactive hypertension and bradycar-dia. Studies have generally used phenylephrine bolus dosesranging from 40 to 100 �g. Doses of 40 to 80 �g wereassociated with a higher incidence of hypotension andfailed to reduce the incidence of IONV compared withephedrine in some studies.17,18 Furthermore, 2 recent dose-finding studies using an up–down sequential allocationmethodology suggested that a dose of phenylephrinehigher than what is routinely used in practice and inprevious studies may be needed for bolus administration.Tanaka et al. reported that the ED95 of a prophylactic bolusdose of phenylephrine to prevent hypotension or nausea,when given immediately after intrathecal injection of 12 mghyperbaric bupivacaine, was 159 �g (95% confidence inter-val: 122 to 371 �g).48 For the treatment of establishedhypotension after intrathecal administration of a similardose of bupivacaine, George et al. estimated that the ED90of a bolus dose of phenylephrine was 147 �g (95% confi-dence interval: 98 to 222 �g).49 It is important to note thatboth studies estimated the dose needed early after intrathe-cal injection when the sympathectomy was evolving; thismight differ from the dose required to treat hypotensionlater, once the block has stabilized.
When given as a prophylactic infusion, phenylephrinedoses ranging from 10 to 100 �g/min have been used;however, the 10 �g/min dose was ineffective with a 90%incidence of hypotension.22 Two recent dose–responsestudies investigated fixed phenylephrine infusion dosesranging from 25 to 100 �g/min.26,28 Both groups of inves-tigators recommended the use of lower infusion rates of 25to 50 �g/min because these were associated with lessreactive hypertension,26 bradycardia,28 and reduction incardiac output28 compared to higher-dose infusions. The 50�g/min rate was also associated with the fewest number of
Impact of Phenylephrine on Maternal and Neonatal Outcomes
February 2012 • Volume 114 • Number 2 www.anesthesia-analgesia.org 385
Tabl
e3.
Um
bilic
alC
ord
Gas
Dat
aan
dA
pgar
Sco
res
Stu
dyG
roup
spH (A
)pH (V
)
PC
O2
(A),
mm
Hg
PC
O2
(V),
mm
Hg
PO
2
(A),
mm
Hg
PO
2
(V),
mm
Hg
Bas
eex
cess
(A),
mm
ol/L
Bas
eex
cess
(V),
mm
ol/L
pH<
7.2
Lact
ate
(A),
mm
ol/L
Lact
ate
(V),
mm
ol/L
Apg
ar<
7A
pgar
<7
1m
inut
e5
min
utes
Nga
nK
ee1
4PE
bolu
s100
�g
7.2
97.3
253.4
45.1
16.5
28.6
�2.5
�2.8
0/1
02
(0)(p
H�
7re
port
ed)
2.3
2.2
1/1
02
(0)
0/1
02
(0)
Ebo
lus
10
mg
7.2
87.3
354.1
44.4
18*
30.8
*�
3.2
�3.1
2/1
02
(2)
2.7
*2.6
*1/1
02
(0)
1/1
02
(0)
Prak
ash1
5PE
bolu
s100
�g
7.3
27.3
843.5
36.0
18.1
28.1
�1.6
�1.1
0/3
0(0
)0/3
0(0
)0/3
0(0
)E
bolu
s6
mg
7.2
9*
7.3
4*
44.0
35.9
17.5
26.5
�2.8
3*
�1.9
*0/3
0(0
)0/3
0(0
)0/3
0(0
)
Pier
ce5
2PE
40
�g
bolu
s7.3
17.3
654.0
44.8
16.9
29.6
E5
mg
bolu
s7.2
97.3
554.1
43.7
21.2
31.2
Dye
r16
PE80
�g
bolu
s7.3
152.5
12
�1.3
4E
10
mg
bolu
s7.2
848.7
15.2
*�
4.7
5*
Thom
as3
0PE
100
�g
bolu
s7.2
950.4
18.8
�2.0
0/1
9(0
)0/1
9(0
)0/1
9(0
)E
5m
gbo
lus
7.2
7*
53.4
18.8
�2.9
1/1
9(5
)0/1
9(0
)0/1
9(0
)
LaPo
rta4
5PE
40
�g
bolu
s7.3
27.3
750.2
41.9
19.9
29.2
0.9
0.7
0/2
0(0
)0/2
0(0
)E
5m
gbo
lus
7.2
8*
7.3
555*
42.2
19
28.6
2.2
*2.0
*0/2
0(0
)0/2
0(0
)
Mor
an1
7PE
bolu
s80
�g
for
initi
al2
SB
Pof
�5
mm
Hg
follo
wed
by40–8
0�
gto
keep
SB
P�
100
mm
Hg
7.3
27.3
652.1
43.7
21.0
29.6
�0.3
8�
0.3
30/3
1(0
)0/3
1(0
)
Ebo
lus
10
mg
follo
wed
by5–1
0m
gas
inPE
grou
p7.2
8*
7.3
556.6
*43.2
19.6
30.7
�2.2
*�
1.5
4*
1/2
9(3
)0/2
9(0
)
Mag
alha
es1
8PE
80
�g
prop
hyla
ctic
bolu
sfo
llow
edby
40
�g
for2
BP
7.2
77.2
838.9
35.2
18.0
24.3
�9.2
�7.9
0/3
0(0
)0/3
0(0
)
E10
mg
prop
hyla
ctic
bolu
sfo
llow
edby
5m
gfo
r2
BP
7.2
2*
7.2
740.0
34.7
19.5
25.6
�10.5
�7.2
0/3
0(0
)0/3
0(0
)
Loug
hrey
19
E10
mg
�PE
40
�g
prop
hyla
ctic
bolu
sfo
llow
edby
E5m
g�
PE20
�g
for2
BP
7.2
47.3
30/2
0(0
)0/2
0(0
)
E10
mg
prop
hyla
ctic
bolu
sfo
llow
edby
E5m
gfo
r2
BP
7.2
47.3
30/2
0(0
)0/2
0(0
)
Nga
nK
ee2
0PE
100
�g/
min
7.3
37.3
449
46
20
28
�1.9
�1.6
2.2
2.2
1/5
2(2
)0/5
2(0
)E
8m
g/m
in7.2
5*
7.3
1*
56*
47
20
30*
�4.8
*�
4.3
*4.2
*3.4
*0/5
2(0
)0/5
2(0
)
Nga
nK
ee1
2PE
100
�g/
min
7.2
97.3
453
45
16
27
�2.3
�2.7
0/2
4(0
)0/2
4(0
)0/2
4(0
)PE
75
�g/
min
�E
2m
g/m
in7.2
87.3
455
45
18
30
�2.8
�2.2
3/2
4(1
3)
0/2
4(0
)0/2
4(0
)
PE50
�g/
min
�E
4m
g/m
in7.2
67.3
257
45
14
28
�3.1
�3.2
6/2
5(2
4)
0/2
5(0
)0/2
5(0
)
PE25
�g/
min
�E
6m
g/m
in7.2
47.3
262
47
15
29
�4.0
�3.6
7/2
4(2
9)
0/2
4(0
)0/2
4(0
)
E8
mg/
min
7.2
1#
7.3
0#
62#
45
14#
32#
�5.1
#�
4.9
#12/2
5(4
8)#
0/2
5(0
)0/2
5(0
)(C
ontin
ued)
REVIEW ARTICLE
386 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA
Tabl
e3.
(Con
tinu
ed)
Stu
dyG
roup
spH (A
)pH (V
)
PC
O2
(A),
mm
Hg
PC
O2
(V),
mm
Hg
PO
2
(A),
mm
Hg
PO
2
(V),
mm
Hg
Bas
eex
cess
(A),
mm
ol/L
Bas
eex
cess
(V),
mm
ol/L
pH<
7.2
Lact
ate
(A),
mm
ol/L
Lact
ate
(V),
mm
ol/L
Apg
ar<
7A
pgar
<7
1m
inut
e5
min
utes
Coo
per2
1PE
33
�g/
min
7.3
17.3
752
40
14
28
�1.8
�2.6
1/4
8(2
)0/4
8(0
)0/4
8(0
)E
1m
g/m
in7.2
97.3
657
42
12
24
�2.2
�2.8
11/4
8(2
1)
0/5
0(0
)0/5
0(0
)PE
16.5
�g/
min
�E
0.5
mg/
min
7.3
1#
7.3
7#
54#
41
11
25
�1.4
�2.2
1/4
7(2
)#0/4
9(0
)0/4
9(0
)
Hal
l22
PE20
�g
bolu
sfo
llow
edby
10
�g/
min
7.3
47.3
717.9
26.6
1.6
0.6
0/1
0(0
)0/1
0(0
)
E6
mg
bolu
sfo
llow
edby
2m
g/m
in7.3
17.3
819.9
32.6
�0.7
0.7
0/9
(0)
0/9
(0)
E6
mg
bolu
sfo
llow
edby
1m
g/m
in7.2
97.3
519
30.6
�1.5
0.1
0/1
0(0
)0/1
0(0
)
Mer
cier
25
E2
mg/
min
�PE
10
�g/
min
7.2
47.3
36/1
9(3
1)
0/1
9(0
)0/1
9(0
)
E2
mg/
min
7.1
9*
7.2
8*
13/2
0(6
3)
0/2
0(0
)0/2
0(0
)
Nga
nK
ee1
1PE
100
�g/
min
7.3
17.3
752
44
15
25
�2.7
�1.9
1/2
6(4
)2/2
6(8
)0/2
6(0
)PE
100
�g
bolu
s7.3
17.3
654
44
16
23
�2.7
�2.1
1/2
4(4
)0/2
4(0
)0/2
4(0
)
Alle
n26
PEbo
lus
100
�g
7.2
97.3
456.6
48.9
19.7
26.9
�2.5
�2.0
2/1
9(1
1)
2.8
2.2
PE25
�g/
min
7.3
17.3
552.3
44.5
19.9
27.1
�1.8
�1.6
0/1
8(0
)2.2
1.9
PE50
�g/
min
7.2
77.3
356.7
45.7
16.7
24.9
�2.0
�1.8
0/1
8(0
)2.7
2.0
PE75
�g/
min
7.2
87.3
359.3
48.4
16.5
25.1
�2.5
�2.6
2/1
8(1
1)
2.9
2.4
PE100
�g/
min
7.2
67.3
356.7
47.1
16.9
24.9
�2.8
�2.2
0/1
7(0
)2.6
2.0
Nga
nK
ee2
3PE
100
�g/
min
�2
LLR
colo
ad7.2
87.3
454
45
15
27
�2.4
�2.5
1/5
3(2
)0/5
3(0
)
PE100
�g/
min
�LR
atm
inim
alra
te7.2
97.3
456
46
15
25
�1.9
�1.8
1/5
3(2
)0/5
3(0
)
Nga
nK
ee2
4PE
100
�g/
min
tom
aint
ain
SB
Pat
100%
base
line
7.3
27.3
752.6
42.9
15.8
27.8
�1.9
�1.6
0/2
4(0
)1/2
4(4
)0/2
4(0
)
PE100
�g/
min
tom
aint
ain
SB
Pat
90%
base
line
7.3
07.3
655.6
44.4
14.3
25.6
�1.8
�1.8
0/2
5(0
)0/2
5(0
)0/2
5(0
)
PE100
�g/
min
tom
aint
ain
SB
Pat
80%
base
line
7.3
0#
7.3
655.6
44.4
12.8
25.6
�2.3
�1.9
0/2
5(0
)0/2
5(0
)0/2
5(0
)
Ste
war
t28
PE25
�g/
min
7.3
17.3
6�
0.9
�1.2
PE50
�g/
min
7.3
17.3
5�
1.2
�1.7
PE100
�g/
min
7.3
07.3
5�
1.2
�1.5
Coo
per4
7PE
(ret
rosp
ectiv
e)7.2
87.3
451.9
42.8
12
20.3
�2.8
�2.3
22/1
48
(15)
6/1
48
(4)
E(r
etro
spec
tive)
7.2
77.3
353.4
43.6
11.3
22.6
�2.4
�2.7
24/1
22
(20)
0/1
22
(0)
No
vaso
pres
sor
7.2
67.3
251.1
42.9
11.3
20.3
#�
2.3
�2.7
26/1
15
(23)
3/1
15
(3)
Coo
per5
3PE
33
�g/
min
7.3
27.3
550
45
17
28
�0.2
�1.5
2/2
3(9
)E
1.5
mg/
min
7.2
0*
7.2
8*
62*
47*
14
26
�2.9
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Impact of Phenylephrine on Maternal and Neonatal Outcomes
February 2012 • Volume 114 • Number 2 www.anesthesia-analgesia.org 387
physician interventions needed to maintain arterialblood pressure within the target range and had thelowest degree of inaccuracy of systolic blood pressurecontrol compared to the 25, 75, and 100 �g/min rates; thedifferences were, however, only statistically significantwhen compared to the 100 �g/min group.26 The choiceof a starting infusion rate balances the risk of hypoten-sion versus reactive hypertension. For instance, the 25�g/min rate has been associated with an incidence ofhypotension of 30%–40%, compared to 15%–20% with 50�g/min.26,28 However, the incidence of reactive hyperten-sion was 40% and 25% with the 50 and 25 �g/min doses,respectively.26,50
With the exception of the study by Cooper at al,21 mostof the published studies to date have investigated a fixed-rate infusion regimen that is switched on and off based onblood pressure response.11,12,20,22–24,26,28 While this tech-nique is simple, a variable rate infusion titrated to bloodpressure changes may allow more accurate blood pressurecontrol. Recently, Ngan Kee et al. reported that a closed-loop variable rate algorithm provided tighter and moreaccurate blood pressure control compared to the manualon/off technique, but with no difference in other maternalor neonatal outcomes.51 More studies investigating variablerate phenylephrine infusions are needed.
An additional difficulty is that studies have used differ-ent goals for blood pressure control with a prophylacticphenylephrine infusion. For instance, while some studieshave switched the infusion off when the blood pressureexceeded baseline,28 others have used the same target butallowed a 20% blood pressure increase in the first 2 to 3minutes,11,12,20,23 or allowed a 20%–25% increase in bloodpressure from baseline throughout the duration of theinfusion.21,22,26 Allowing an increase in blood pressurefrom baseline increased the incidence of reactive hyperten-sion with higher infusion rates of 100 �g/min, but not withrates of 25 and 50 �g/min.26,50 It is not clear, however, ifdifferent targets have an impact on the occurrence ofhypotension, IONV, or need to make frequent adjustmentsto the infusion rate. Most studies have also allowed a 20%decrease in blood pressure. A study by Ngan Kee et al.,however, reported that the incidence of IONV is lowest andfetal pH highest when blood pressure is maintained at100% of baseline compared to allowing a 10%–20% de-crease in blood pressure.24
Fluid administration regimens also varied among thestudies. This should be considered when comparing theresults of different studies to determine the optimumadministration regimen for phenylephrine. For instance, inwomen receiving a prophylactic phenylephrine infusion,administering a 2 L crystalloid coload was associated witha lower incidence of hypotension and reduced phenyleph-rine requirements compared with administering fluids at aminimal rate.23
The optimum duration of phenylephrine infusion is alsonot known. Most studies have stopped the infusion atuterine incision,11,12,20,21,23,28 while Allen at al.26 continuedthe infusion for 10 minutes after delivery to counteractoxytocin induced hypotension.
CONCLUSIONBoth ephedrine and phenylephrine are effective in manag-ing spinal anesthesia-induced hypotension. Phenylephrinemay be associated with a lower incidence of IONV, andhigher umbilical artery pH and base excess compared withephedrine. However, the difference in pH is small andunlikely to be clinically relevant in low-risk deliveries.Administration of phenylephrine as a prophylactic infusionis more effective in reducing the incidence of hypotensionand IONV compared with bolus administration. However,phenylephrine use is associated with a decrease in maternalcardiac output. The clinical significance of this reduction inhealthy low-risk parturients is unclear. Studies suggest thatsuch changes do not appear to have any consequences inhealthy mothers. The optimum phenylephrine administra-tion regimen is unclear. Studies addressing the use ofphenylephrine in high-risk pregnancies, such as thosecomplicated by placental insufficiency, preeclampsia, andgrowth restriction, are needed.
DISCLOSURESName: Ashraf S. Habib, MBBCh, MSc, MHS, FRCA.Contribution: This author helped analyze the data and writethe manuscript.Attestation: Ashraf S. Habib approved the final manuscript.This manuscript was handled by: Cynthia A. Wong, MD.
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Residual Neuromuscular Block: Lessons Unlearned. Part II: Methods to Reduce the Risk ofResidual Weakness: Erratum
Figures 1A and 1B in a recent manuscript on residual weakness were graciously provided by Dr. DouglasEleveld, Department of Anesthesiology, University Medical Center Groningen, University of Groningen,Groningen, The Netherlands. We apologize that the appropriate credit was unintentionally omitted andextend our appreciation to Dr. Eleveld for providing the images.
Reference:
Residual neuromuscular block: lessons unlearned. Part II: Methods to reduce the risk of residualweakness. Anesth Analg 2010;111:129–40
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