REVISTA
BRASILEIRA
DE
ANESTESIOLOGIA
PublicaçãoOficialdaSociedadeBrasileiradeAnestesiologia www.sba.com.brREVIEW
ARTICLE
Oxytocin
in
cesarean-sections.
What’s
new?
Eduardo
Tsuyoshi
Yamaguchi
a,∗,
Mônica
Maria
Siaulys
b,
Marcelo
Luis
Abramides
Torres
caHospitalUniversitáriodaUniversidadedeSãoPaulo(HU-USP),SãoPaulo,SP,Brazil
bHospitaleMaternidadeSantaJoana,SãoPaulo,SP,Brazil
cDepartmentofSurgery,FaculdadedeMedicina,UniversidadedeSãoPaulo(USP),SãoPaulo,SP,Brazil
Received9October2014;accepted28November2014 Availableonline30April2016
KEYWORDS
Oxytocin; Cesareansection; Desensitization; Dose
Abstract Oxytocinistheuterotonicagentofchoiceinthepreventionandtreatmentof post-partumuterine atony.Nevertheless,thereisnoconsensusontheoptimaldoseandratefor useincesareansections.Theuseofhighbolusdoses(e.g.,10IUofoxytocin)candetermine deleteriouscardiovascularchangesforthepatient,especiallyinsituationsofhypovolemiaor lowcardiacreserve.Furthermore,highdosesofoxytocinforprolongedperiodsmay leadto desensitizationofoxytocinreceptorsinmyometrium,resultinginclinicalinefficiency. © 2016 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
PALAVRAS-CHAVE
Ocitocina; Cesariana; Dessensibilizac¸ão; Dose
Ocitocinaemcesarianas.Oquehádenovo?
Resumo Aocitocinaéouterotônicodeprimeiraescolhanaprevenc¸ãoenotratamentoda atoniauterinaapósoparto.Apesardisso,nãoexisteconsensosobrequaladoseevelocidade ideaisdeseuusoemcesarianas.Ousodealtasdoses(porexemplo,10UIdeocitocina)embolus podedeterminaralterac¸õescardiocirculatóriasdeletériasparaapaciente,especialmenteem situac¸õesdehipovolemiaoubaixareservacardíaca.Alémdisso, altasdosesdeocitocinapor períodosprolongadospodemlevaràdessensibilizac¸ãodosreceptoresdeocitocinalocalizados nomiométrioeresultaremineficáciaclínica.
© 2016 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. Este é um artigo Open Access sob a licença de CC BY-NC-ND (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
∗Correspondingauthor.
E-mail:[email protected](E.T.Yamaguchi).
Introduction
Oxytocin,thefirstpolypeptidehormonetobesynthesized
in 1953 by Vincent DuVigneau, is the drug of choice for
both prevention and treatment of uterine atony after
childbirth.1 Oxytocin bindsto itsreceptor on the surface
http://dx.doi.org/10.1016/j.bjane.2014.11.015
of the myometrium cell, interacts with phospholipase C,
and generates diacylglycerol and inositol triphosphate.
Diacylglycerol leads to the synthesis of prostaglandins,
important in the mechanism of contraction, while
inos-itol triphosphate increases calcium concentration in the
cell sarcoplasmic reticulum, thereby determining the
contractionofmyometrium.
Uterineatonyistheleadingcauseofpostpartum
bleed-ing,whichgivesoxytocinanimportantroleinreducingthe
severity of uterine bleeding and hence maternal
mortal-ity. According tothe websiteof the Ministry of Health, a
clear decrease(69.3%)in therisk ofmaternal deathfrom
hemorrhage occurred in Brazil between 1990 and 2010.2
The best training of professionals involved in the care of
thesewomen,aswellastherationaluseofavailabledrugs
to prevent or treat uterine atony (such as oxytocin, for
example) may be one of the factors responsible for this
reduction.
The aim of this review was to update the article on
theuseofoxytocinincesareansectionspublishedbythese
authors seven years ago.3 A literature search in PubMed
database was performed with the keywords ‘‘oxytocin’’
and ‘‘cesarean section’’ up to April 2013, with
prefer-encetoarticlespublishedfrom2007(yearoftheprevious
review publication). The authors selected the items
con-sideredmostrelevanttothepracticeofanesthesiologists,
besidesobtainingpossiblereferencesfromthearticles
ini-tiallyselected.
Use
in
cesarean
sections
Despite being a fairly common practice, oxytocin is used
incesareansectionsempirically.Surprisingly,todatethere
is no consensusabout the idealregime of its
administra-tion,evenafter60yearsofitssynthesisandroutineusein
obstetric centers.An example is thestudy by Wedisinghe
etal.,4inwhichtheyreportedtheexistenceofatleast38
differentregimensofoxytocininfusionintheUK.Although
thereisnosuchdocumentation,thisfactdoesnotseemto
bevery differentfrom whathappensin Brazilian medical
institutions.
The variability of doses and infusion rates of
oxy-tocin complicates a meta-analysis that contribute to the
establishment of a consensus on the best use of
oxy-tocin to prevent postpartum bleeding.5 Anyway, it must
be remembered that oxytocin is used prophylactically in
mostobstetricpatientsassupplementationofendogenous
oxytocin. Thus, the use of high doses (either by bolus or
continuousinfusion)wouldbeunnecessaryandeven
detri-mental to patients due to the possibility of side-effects
(particularlycardiovascular).
Butwicketal.6attemptedtofindtheminimumeffective
dose (ED)of oxytocinthatwoulddetermine asatisfactory
uterine contractility during elective cesarean section. To
thisend,75pregnantwomenprimigravidaeandwithoutrisk
factors for developing uterine atonywere evaluatedwith
logisticregressionmethod.Theauthorsconcludedthat
sat-isfactoryuterinecontractilitycouldbeobtainedwiththeuse
oflow-doseoxytocinbolus(0.5---3IU).ThecalculationofED
topromoteuterinecontractionin50%(ED50)and90%(ED90)
of patients was possible because, curiously, the uterine
tonewasevaluatedassatisfactory in 73%of cases bythe
obstetricteaminplacebogroup(withoutoxytocin).Itis
pos-siblethatthisfacthasoccurredduetotheuterinemassage
performed by the obstetrician for the uterus
externaliza-tion.However,theisolateduterinemassagedoesnotspare
the use of oxytocin because the placebo group required
rescueoxytocin.This confirmsthattheoptimumapproach
is the combination of prophylactic oxytocin and uterine
massage.
Oxytocin administration by continuous infusion in
cesareansectionreducestheneedforusingotheruterotonic
agents.Sheehanetal.7 performedaprospective,
random-ized, multicenter study in Ireland with 2069 women who
underwentelectivecesareansection.Allpatientsreceived
oxytocin 5IU in one minute, followed by oxytocin 40IU
diluted in 500mL saline for four hours or saline alone
(placebo group). Although the infusion of oxytocin have
notaffected the generaloccurrence of obstetrical
bleed-ing,therewasasignificantreductionintheneedforother
uterotonicagentswiththeuseofbolusfollowedbyinfusion
ofoxytocincomparedwiththeuseofoxytocinbolusalone
(12.2%vs.18.4%;p<0.001).
Thus,theuseoflow-doseoxytocinbolusdoesnotspare
theuseofcontinuousinfusionofoxytocin.Although there
isnorecord onthatprobablytheuseofoxytocin
continu-ousinfusionalone(dilutedinsalineandcontrolledbydrip),
thatis,withoutinitialbolus,istheapproachmostcommonly
usedbyBraziliananesthesiologists.Georgeetal.8studied50
patientsundergoingelective cesareansectionwithout risk
factorsforuterineatony.Theauthorsshowedthatoxytocin
ED90inthesepatientswas0.29IUmin−1,whichisequivalent
todiluting15IUofoxytocinin1Lsalineandinfusethis
solu-tionin 1h. These resultscorrespond to50% lessthan the
previouslyusedinfusionattheinstitutionwherethestudy
wasconducted.However,duetothelargevariationofthe
confidenceinterval (95%CI, 0.15---0.43IUmin−1),this ED
90
estimatemaybeinaccurate.Thus,otherstudiesareneeded
toconfirmtheseresults.
King et al.9 unlike the previously mentioned authors,
evaluatedpatientswhohadatleastoneriskfactorforthe
developmentofuterineatony(uterinedistention,prolonged
exposuretooxytocinpriortocesarean section,
chorioam-nionitis, and others). The use of initial bolus of oxytocin
(5IU),followedbyoxytocininfusion(40IUin500mLsaline
infusedover 30min, followed by20IU in 1Lover 8h) did
notalter the need for other uterotonic agentin the first
24h aftercesarean section,when comparedwithinfusion
alone.
Withtherisksandbenefitsof usingoxytocinasabase,
TsenandBalki10 proposedamanagementregimebasedon
evidence and called ‘‘rule of threes’’. The authors
sug-gesttheuseof 3IU of intravenousoxytocin(administered
athigherspeedthan15s)asthestartingdose,whichmay
berepeatedtwomoretimes(inthreeminuteintervals)if
uterinetoneisnotsatisfactory.The oxytocinmaintenance
doseis3IUL−1at100mLh−1.
Extrauterine
actions
Muchmorecomplexthanpreviouslythought,theextrauterin
Forexample,oxytocinmayincreasematernaltemperature
withdeleteriousconsequencesforbothmotherandfetusby
theincreasedsecretionstimulationofinflammatory
medi-ators(PGEandPGF2␣). However,in aretrospective study
ofpregnantwomenwithintrauterinefetaldeathinthe
sec-ondtrimesterof pregnancy,theuse ofhigh-doseoxytocin
(0.267---1.667IUmin−1)did notdetermine rise in maternal
temperature.11
Hemodynamicchanges thatoccur during cesarean
sec-tionhavemultifactorialcauses,suchassympatheticnervous
systemblockadesecondarytothespinalanesthesia,
aorto-caval decompression and maternal autotransfusion after
placental delivery, bleeding, use of vasopressor,etc. The
useof oxytocinis justoneof thesecauses andis directly
dependentonthewayitisadministered(doseandinfusion
rate).
Human vascular endothelial cell has oxytocin
recep-tors that are structurally identical to receptors present
in myometrium and mammary gland.12 The interactionof
oxytocinwithitsendothelialreceptordetermines
calcium-dependent response via nitric oxide, resulting in smooth
muscle relaxation of resistance and capacitance vessels.
Thus, vasodilation is the primary cardiocirculatory event
after the use of oxytocin. Tachycardia, increased stroke
volume and cardiac output (CO) occur as compensatory
mechanisms tovasodilation. These effects are more
pro-nounced when oxytocin is administrated as bolus and
can be harmful to patients with impaired cardiovascular
reserve.
The use of high-dose bolus (e.g., 5---10IU of oxytocin)
hasfrequentlybeendiscouraged,particularlyafterreports
of maternal death after bolus administration of oxytocin
(10UI)tohypovolemicpatientduetouterineatony,
accord-ingto the triennial surveyof maternal deathoccurred in
theUK.13
In elective cesarean sections, standard non-invasive
monitoring (ECG, noninvasive blood pressure, and pulse
oximetry)isused,whichmaynotdetectthepossible
hemo-dynamic changes determined after the use of oxytocin,
especially because they are most pronounced about the
firstminuteafteroxytocinadministration.Whilenotroutine
duringcesareansection,invasivemonitoringmethodshave
allowedabetterunderstandingofthehemodynamicprofile
ofthesepatientsafteroxytocinadministration.Langesaeter
et al.14 with invasive monitoring (LiDCOPlus® monitor) in
healthypregnantwomen, observedan increase incardiac
index (CI), decreased systemic vascular resistance (SVR)
andsystolicbloodpressure(BP)(rangeof36---62mmHg)45s
afteroxytocininjection.This samegroupof authors
stud-ied18patientswithpreeclampsiawhounderwentcesarean
section.15 Withthesamemonitoring astheprevious study
(LiDCOPlus®)connectedtotheradialarteryofpatients,the
authorsfoundincreasedheartrate(HR)anddecreasedSVR
andBPinallpatientsreceivingoxytocin(5IU)afterdelivery.
Thehemodynamicinstabilitythatcanoccurduring
postpar-tumhemorrhagemaynotbesolelyduetohypovolemia,but
the association of both hypovolemia and use of oxytocin
bolus.16
Hemodynamic changes determined by oxytocin are
directly dependent ondose and rate of infusion. Thomas
et al.17 found that bolus administrationof oxytocin (5IU
over5s)promotesgreaterdecreaseinmeanBPandgreater
increase inheart ratethanthe administrationof oxytocin
(5IU over 5min) in patients undergoingelective cesarean
section. The authors recommend that oxytocin should be
administeredslowlytominimizecardiovasculareffectsthat
may notbe well tolerated by the hypovolemic patientor
withlowcardiacreserve.
The administration of oxytocin (5IU over 3min) as a
loading dose, followed by oxytocin infusion (30IU over
4h) did not determine significant hemodynamic changes
comparedtoadministrationofthesameloadingdose,
fol-lowed by placebo infusion (crystalloid solution).18 With
the thoracic bioimpedance method, the studied
parame-ters (CI, left ventricular work and SVR) were gradually
returning to preoperative values of these patients during
the 4h of oxytocin infusion, probablydue to spinal block
regression.
ECG changes suggestive of myocardial ischemia have
beenreportedafteradministrationofoxytocinbolus(10IU
over30s)afterclampingtheumbilicalcordduringelective
cesarean sections.19 These changes were accompanied by
hypotension,tachycardia,andbreastdiscomfort,butwere
reversibleandofshortduration.However,thecombination
ofhypotension,tachycardia,andcoronaryvasoconstriction
maycause an imbalancebetweenmyocardial oxygen
sup-plyanddemandandpossiblemyocardialischemia,evenin
patientswithoutcoronarydisease.
Withstandard monitoring, changesin the patient’s HR
correlatebetterwithchangesinCOcomparedtovariations
inpressurevalues.Sartainetal.20 demonstratedagreater
increaseinHRusingoxytocin5IUcomparedtooxytocin2IU
(32±17bpmvs24±13bpm,respectively,p=0.015).These
dosesweredilutedtoafinalvolumeof5mLandinfusedover
5---10s.Allpatientsreceivedoxytocininfusion(10IUh−1over
4h)afterloadingdose.
In this context of hemodynamic changes associated
with oxytocin, Dyer et al.21 performed an important
study comparingmaternal hemodynamic effectsafter the
use of phenylephrine or ephedrine for arterial
hypoten-sion management after spinal anesthesia in cesarean
sections. Twenty patients who received no
vasopres-sors (ephedrine) were randomized to receive oxytocin
2.5IU or oxytocin 2.5IU associated with phenylephrine
(80g) 30s after birth. The authors concluded that
phenylephrine alleviates maternal hemodynamic effects
of oxytocin. Thus, in clinical practice, we often end
up managing possible hemodynamic effects of
oxy-tocin when a direct action vasopressor (phenylephrine
or metaraminol) is used in the treatment of maternal
hypotension secondary to sympathetic blockade in spinal
anesthesia.
Ascanbeseen,thehemodynamicchangesthatcouldbe
caused or contributed by oxytocin have been one of the
majorconcerns for researcherstoday. The clinical
signifi-cance of thesefindings stillseemsunclear, asthe effects
weretransientandreversibleinmostcases.Oxytocin,
prob-ably determine more significant hemodynamic changes in
patientswhohadlowheartreserveorhypovolemia;
there-fore,the use ofoxytocin bolus in thisparticular group of
patientsshouldbeavoided.22
According to the National Health Surveillance Agency
(Anvisa),23currentlyoxytocincanbefoundinBrazilfor
Table1 WhatshouldIlearnfromthisreview.
Oxytocinistheuterotonicofchoiceforthepreventionandtreatmentofuterineatony Thereisnoconsensusontheoptimumdoseandrateofitsadministrationincesareansections
Dripinfusionofoxytocin(5---20IU)dilutedincrystalloidsolutionseemstobetheusualmodeofuseincesareansectionsin Brazil
Theuseofoxytocinbolus(e.g.,10IU)shouldbeavoided,particularlyinhypovolemicpatientsorthosewithlow cardiovascularreserve
Highdosesoforprolongedexposuretooxytocincanleadtodesensitizationofitsreceptorsandbetranslatedclinicallyas therapeuticinefficacy
Incaseofresponsefailureaftertheuseofoxytocin,considerotheruterotonicagents(ergotderivatives,prostaglandins) Carbetocinisasyntheticanalogofoxytocin,butwithahalf-lifefourtimeslonger,andnotherapeuticdoseestablishedyet
Naox®,Obstecina®,Ocitoc®;allwithchlorobutanol added
as a preservative in the composition. In vitro study with humanatrialmyocytesshowedthatchlorobutanolhas neg-ativeinotropicaction.24
Desensitization
of
oxytocin
receptors
In 2004, Carvalho et al.25 demonstrated that oxytocin
ED90----the effective to promote satisfactory uterine
con-tractionsin90%ofpatients----wouldbearound0.35IU.The
study wasperformed withpatientsscheduled for elective
cesarean section without risk factors for uterine atony,
withthelogisticregressionmethod.Basedonexperimental
worksoffemaleratmyometrium,thesamegroupconducted
a study with similar design, but now involving pregnant
women who underwent cesarean section due to dystocia
and whoreceived oxytocin during labor. In such cases,it
wasfoundan increase inoxytocinED90 of almostninefold
(2.9IU).26 Thelikelyexplanationfortheseresultswouldbe
theoccurrence ofdesensitizationof oxytocinreceptorsin
myometrium after prolonged exposure to oxytocin during
labor.
Continuing these investigations, Balki et al.27 studied
myometrium fragments of pregnant mice and found a
decreaseintheamplitudeofmyometrialcontractionswhen
thesefragmentswerepreviouslyexposedtooxytocin
com-paredtocontrolgroup(saline).Although thecontractility
causedbyoxytocinwashigherthanthecontractilitycaused
by ergonovine or PGF2, the uterotonic effect of these
drugswasnotaffectedbypriorexposuretooxytocin.This
studysupportstheconceptofdesensitizationofmyometrial
receptorsafterprolongedexposuretooxytocin.Clinically,
theseresults demonstrate that high doses of oxytocinfor
prolongedperiodscanleadtoalowerefficiencyof
utero-tonicactionorevenuterineatony.
Measurement
of
oxytocin
in
blood
Therearefew studies describingoxytocin levelsinblood.
Usuallythesepapersinvolvepregnantwomeninlabor,orare
experimentalanimalstudies,withradioimmunoassay(RIA)
foroxytocinmeasurement.
Serumlevelsofoxytocinbyenzymeimmunoassay
tech-nique (ELISA) have been studied in pregnant women
undergoingelectivecesareansection.28Althoughthisstudy
wasnotdesignedtocorrelateserumdosesofoxytocinwith
clinicalefficacy,theauthorsdemonstratedthattheuseof
Oxytocin80IU (2.67IUmin−1) determined serumlevels of
oxytocinlargerat5and30min,comparedwiththeuseof
10IU (0.33IUmin−1 or 2.67IUmin−1). The technique used
(ELISA)hadtheadvantageofhandlingnon-radioactive
mate-rial, comparedwith the RIAtechnique. Furthermore, the
managementof peptides,such as oxytocin, requires
spe-cialcare becausestorage of samples shouldbe at −70◦C
topreventoxytocin degradation by maternal
aminopepti-dases.
Additional studies should be developed in an attempt
tocorrelateoxytocinbloodmeasurementwithsatisfactory
uterinecontractility and lower incidence of side effects.
Apparently,theclinicalefficacyofoxytocinismore
depend-entonitsinteractionwithitsreceptorthanactuallywithits
bloodconcentration.
Carbetocin
Carbetocin, a synthetic analog of oxytocin,has the same
affinityasoxytocinformyometrialreceptors,butdiffersfor
havingamuchlongerplasmahalf-lifethanoxytocin(40min
vs.15min, respectively),which hasarousedspecial
inter-estasan optiontotheuse ofoxytocintopreventuterine
atony.29
Cordovanietal.30usedcarbetocinatdosesof80
gand
120ginpatientswithlowriskofpostpartumbleedingand
whounderwentelectivecesareansection.Inthesepatients,
the uterine tone was satisfactory in 87% of cases; there
wasnosignificantdifferencebetweenthedosesused.The
authorsreportedahighincidence(55%)ofhypotensionwith
these doses, since carbetocin has a hemodynamic profile
similar to that of oxytocin. Moertl et al.31 in a
prospec-tive randomized study of 56 women undergoing elective
cesarean section, compared bolus doses (10s) of
carbe-tocin(100g)withoxytocin(5IU). Therewasan increase
inHR(14.20±2.45bpmvs.17.98±2.53bpm,respectively)
anddecreaseinBPinbothgroups,especiallyafter30---40s
ofadministrationofeachoftheseuterotonicdrugs.These
resultsarecomparabletothosefoundbyRosselandetal.,32
who used the same doses (5IU of oxytocin and 100g
of carbetocin, in addition to a placebo group) in a
simi-largroupofpatients,butinvasivelymonitoredwithradial
withAnvisaunderthetradenameDuratocin® in1mLvials
(100gmL−1).23However,otherstudiesshouldbedeveloped
toestablishtheeffectivedose ofcarbetocinandifitsuse
reducesthepostpartumincidenceofbleedingortheneed
forbloodtransfusion.
Finally,theessentialpointsofthisreviewmaybeseenin
Table1.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest
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