2. Comparison of Metaraminol, Phenylephrine and Ephedrine in Prophylaxis and Treatment of...

7/26/2019 2. Comparison of Metaraminol, Phenylephrine and Ephedrine in Prophylaxis and Treatment of Hypotension in Ces

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Rev Bras Anestesiol. 2014;64(5):299---306

REVISTA

BRASILEIRA DE

ANESTESIOLOGIA Official Publicationofthe BrazilianSociety ofAnesthesiologywww.sba.com.br

SCIENTIFIC ARTICLE

Comparison ofmetaraminol, phenylephrine and

ephedrine in prophylaxis and treatment ofhypotension

in cesarean section under spinal anesthesia

Fbio Farias de Aragoa,b,, Pedro Wanderley de Aragob,Carlos Alberto de Souza Martins a,b, Natalino Salgado Filhob,Elizabeth de Souza Barcelos Barroqueirob

a Sociedade Brasileira deAnestesiologia, Brazilb Universidade Federal do Maranho (UFMA), So Lus, MA, Brazil

Received 28 June 2013; accepted 25 July 2013

Available online 2 July 2014

KEYWORDSAnesthesia;Cesarean section;

Spinal anesthesia;Hypotension;Vasoconstrictoragents

Abstract Maternal hypotension is a common complication after spinal anesthesia for cesarean

section, with deleterious effects on the fetus and mother. Among the strategies aimed at min-

imizing the effects of hypotension, vasopressor administration is the most efficient. The aim

of this study was to compare the efficacy of phenylephrine, metaraminol, and ephedrine inthe prevention and treatment of hypotension after spinal anesthesia for cesarean section.

Ninety pregnant women, not in labor, undergoing cesarean section were randomized into three

groups to receive a bolus followed by continuous infusion of vasopressor as follows: phenyle-

phrine group (50g + 50g/min); metaraminol group (0.25mg+0.25mg/min); ephedrine group

(4mg+4mg/min). Infusion dose was doubled when systolic blood pressure decreased to 80% of

baseline and a bolus was given when systolic blood pressure decreased below 80%. The infusion

dose was divided in halfwhen systolic blood pressure increased to 120% and was stopped when

it became higher. The incidence ofhypotension, nausea and vomiting, reactive hypertension,

bradycardia, tachycardia, Apgar scores, and arterial cord blood gases were assessed at the 1st

and 5th minutes.

Therewas no difference in the incidence ofhypotension,bradycardia, reactive hypertension,

infusion discontinuation, atropine administration or Apgar scores. Rescue boluses were higher

only in the ephedrine group compared to metaraminol group. The incidence of nausea and

vomitingand fetal acidosis were greater in the ephedrine group. The three drugs were effectivein preventing hypotension; however, fetal effects were more frequent in the ephedrine group,

although transient.

2014 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda.

Corresponding author.E-mail: [email protected](F.F. de Arago).

http://dx.doi.org/10.1016/j.bjane.2013.07.0140104-0014/ 2014 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda.

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300 F.F. de Arago et al.

PALAVRAS-CHAVEAnestesia;Cesariana;Raquianestesia;Hipotenso;Agentesvasoconstritores

Avaliaco comparativa entre metaraminol, fenilefrina e efedrina na profilaxia e no

tratamento da hipotenso em cesarianas sob raquianestesia

Resumo Hipotenso materna uma complicaco comum aps raquianestesia em cirurgia

cesariana, trazendo efeitos deletrios para o feto e a me. Entre as estratgias com o objetivo

de minimizar os efeitos da hipotenso, a administraco de vasopressores a mais eficiente.

O objetivo deste estudo foi comparar a eficcia da fenilefrina, metaraminol e efedrina na

prevenco e tratamento de hipotenso aps raquianestesia em cirurgia cesariana. Noventagestantes que no estavam em trabalho de parto submetidas cesariana eletiva foram ran-

domizadas em trs grupos para receber um bolus, seguido de infuso contnua de vasopressor

da seguinte forma: Grupo Fenilefrina (50 g + 50 g/min); Grupo Metaraminol (0,25 mg + 0,25

mg/min); Grupo Efedrina (4 mg + 4 mg/min). A dose da infuso foi dobrada quando a presso

arterial sistlica (PAS) decresceu at 80% dos valores basais e um bolus foi dado quando a PAS

decresceu para valores abaixo de 80%. A dose da infuso foi dividida ao meio quando a PAS

aumentou at 120% e foi interrompida quando mais elevada. Foram analisadas as incidncias

de hipotenso, nuseas e vmitos, hipertenso reativa, bradicardia, taquicardia e escores de

Apgar no primeiro e quinto minutos e gases de sangue arterial do cordo umbilical.

No houve diferencas nas incidncias de hipotenso, bradicardia, hipertenso reativa,

interrupco da infuso, administraco de atropina ou escores de Apgar. A administraco de

bolus de resgate foram superiores apenas no Grupo Efedrina em comparaco com Metaraminol.

A incidncia de nuseas e vmitos e acidose fetal foram superiores no Grupo Efedrina. Os

trs frmacos foram eficazes na prevenco de hipotenso, mas repercusses fetais foram maisfrequentes no Grupo Efedrina, embora transitrias.

2014 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda.

Introduction

Maternal hypotension after spinal anesthesia for cesareansections is a common complication and may occur in up to80% ofcases.1 If not treated promptly, it can cause unde-

sired effects on the mother and fetus.

2

The effects that mostcommonly affectmothers are nausea and vomiting, althoughmore serious complications such as circulatory collapse andcardiac arrestmay occur iftreatment is not prompt and effi-cient. In the fetus, placental hypoperfusion may cause fetaldistress, resulting in fetal acidosis, increased base excessand low Apgar values.3

Several strategies have been used to prevent or minimizehypotension, such as infusion of intravenous fluids, uter-ine displacement to the left and elastic compression ofthelower limbs. However, these measures alone are generallynot effective. The use ofvasopressors is required.4

The optimal vasopressor should offset the progressiveeffects ofascending sympathetic blockade, which is diffi-

cult to achieve because the - and -adrenergic activitiescan vary independently during blockade installation. Still,changes in sympathetic activity may be organ-specific (inhi-bition of cardiac fibers), region-specific (inhibition in thelower body and increased activity in the upper body) orsystemic (inhibition of catecholamine release from theadrenal medulla). The most commonly used vasopressors(phenylephrine, metaraminol, and ephedrine) have primar-ily systemic effects and may have undesirable effects onorgans, vascular beds or fetus.5

Ephedrine is a non-catecholamine sympathomimeticagent that stimulates the - and -adrenergic receptorsby direct and indirect action. It became the vasopressor of

choice for treatment and prophylaxis ofhypotension after astudywith sheep in the 70Ys, which showedminimal changesin uterine blood flow after administration, while drugs withpredominant -agonist effect caused a significant reductionin the flow.6

However, the supremacy of ephedrine as a vasopres-sor of choice in cesarean sections began to be questionedafter its association with fetal acidosis and lower values ofbase excess compared to vasopressors with predominant -agonist effect. This fact is explicable because ephedrinecrosses the uteroplacental barrier, acts directly on thefetus, and increases its metabolism through 2-adrenergicreceptors.7 The administration of ephedrine for cesareansections, besides causing fetal acidosis, also became asso-ciated with the highest incidence of maternal nausea andvomiting.8

The aim of this study was to compare the efficacyof phenylephrine, metaraminol and ephedrine for theprevention and treatment of maternal hypotension dur-

ing cesarean section, evaluate vasopressor therapy-relatedadverse effects, and study fetal changes through Apgar scoreand umbilical cord arterial and venous blood gases.

Methodology

This study was approved by the Research Ethics Committeeof the Hospital Universitrio Presidente Dutra, under Opin-ion No 174/11. Pregnant women were included in the studyonly after signing the informed consent form. A randomized,controlled, double-blind clinical trial was performed involv-ing pregnant women with gestational age between 39 weeks

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Comparison ofmetaraminol, phenylephrine and ephedrine 301

and one day and 40 weeks and six days, undergoing electivecesarean delivery in a private maternity hospital ofSo Lus(MA).

Sample

The primary outcome was the umbilical artery pH, which

served as the basis for sample calculation. With data fromprevious studies, it was calculated that a sample of 26pregnant women per group would have 90% power with asignificance level of5% to detect a difference of0.05 unitsin the umbilical artery pH between groups. However, in orderto minimize possible losses, the inclusion was scheduled for30 pregnant women in each group.

Inclusion, non-inclusion and exclusion criteria

Pregnant women between 39 weeks and one day and 40weeks and six days of gestational age, undergoing electivecesarean delivery, physical status ASA I (American Society

of Anesthesiologists classification), with a single gestationand between 20 and 34 years old were included in thestudy, as this age group is indifferent to maternal and fetalcomplications.9

It is well documented that pregnant women over 35years of age are more likely to have premature rup-ture ofmembranes, placenta praevia, gestational diabetesand preeclampsia, in addition to a higher chance of hav-ing chronic diseases, such as systemic hypertension10; andpregnant women under 20 years ofage have a higher risk offetal death.11

Non-inclusion criteria were pregnant women refusal,comorbidities, fetal abnormalities, contraindication for

spinal anesthesia and a history of hypersensitivity to drugsused in the study.Exclusion criteria were volume of collected umbilical

cord blood insufficient to determine blood gases and anes-thetic block failure.

Treatment groups

Pregnant women were randomly divided into three groups:metaraminol (GroupM); phenylephrine (Group P); ephedrine(Group E). The method used was the drawing ofsequentialsealed envelopes containing numbers previously generatedby computer. Both pregnant women and anesthesiologists

who participated in the surgeries were blinded to groupallocation.

Preparation ofvasopressors

A second anesthetist, who did not attend the surgery, pre-pared the vasopressor agents. The solutions were preparedin a syringe of20mL as follows:

Group P: phenylephrine 100g/mL; Group M: metaraminol 0.5mg/mL; Group E: ephedrine 8mg/mL.

Anesthetic technique

Patients were monitored with continuous electrocardiogra-phy, noninvasive blood pressure and pulse oximetry, withInfinity Delta monitor (Drgerwerk AG & Co. KGaA, 2009).

Venipuncture with an 18G Jelco was performed and thenpatients were placed supine, with uterine displacement tothe left for a few minutes. Then, blood pressure was mea-

sured three times at 3-min intervals and the arithmeticaverage of the values was calculated, which was consid-ered the basal pressure ofpregnant women and recorded onthe data collection form. Then, with the patient in sittingposition, spinal anesthesia was performed with 27G needle(Whitacre) between the third and fourth lumbar vertebrae.Patients received 10mg of0.5% hyperbaric bupivacaine com-bined with 100g ofmorphine, at a rate of1mL every 15 s.12

Immediately after the blockade, concomitant hydration ofRingers lactate (10mL kg---1) was started.13

After blockade, the measurement of pregnant womensystolic blood pressure (SBP) was recorded every minuteon data collection form up to fetus extraction. The levelof sensory block was assessed with the pinprick test everyminute after the puncture, until it reached the dermatomelevel ofthe fifth thoracic nerve root (T5). The beginningof surgery was then authorized. The time from blockade toskin incision, uterine incision, and extraction of fetus wererecorded.12

Protocol for administration ofvasopressors

Immediately after blockade, the patients received a bolusof 0.5mL of the solution, which corresponded to 50gof phenylephrine, 250g of metaraminol, and 4mg ofephedrine, followed by subsequent doses of continuous

intravenous infusion with a syringe pump (Samtronic SadeTechnologia, model 670), programmed for an infusion rateof30mL/h, so that all patients received the doses previouslyestablished:

Group P: phenylephrine 50g/min---1;14

Group M: Metaraminol 250g/min---1;15

Group E: ephedrine 4mg g/min---1.16

Although infusion with fixed rates is easier to perform,varying infusion rates were used according to the SBP values,in order to enable greater effectiveness in controlling bloodpressure.17 Thus, the rate of infusion of vasopressors wasadjusted according to the protocol as shown in Table 1.

Table 1 Vasopressor infusion rates.

SBP values (%) Approach

Above 120% Infusion discontinuation until SBP return

to


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Reactive hypertension after the use of vasopressor wasdefined as SBP 20% greater than the baseline value and, ifitoccurred, it was treated with infusion discontinuation untilblood pressure reached values lower than 120% ofbaseline,and the infusion was restarted. When patient had more thantwo episodes ofreactive hypertension, infusion was perma-nently discontinued (which was recorded), and subsequentepisodes ofhypotension were treated with bolus infusion of

the solution (1mL). Bradycardia was considered when heartrate values were lower than 50 beats per minute and, whenaccompanied by hypotension, it was treated with atropine(0.5mg). Tachycardia was considered at a heart rate greaterthan 100 beats per minute.12 Values less than 100% ofbase-line SBP were considered hypotension.

Evaluation ofpregnant woman

Maternal SBP were recorded every minute on data collectionform. Episodes of hypotension, hypertension, tachycardiaand bradycardia, need for rescue doses of vasopressor,infusion discontinuation, and atropine administration until

birth were recorded. Episodes ofnausea and vomiting werealso recorded until the end of cesarean section and, if itoccurred, it was treated with 4mg intravenous ondansetron.

Newborn evaluation

Arterial blood samples were collected from the fetal umbil-ical cord immediately after birth, and during the clamp, thesurgeon was requested to withdraw a fragment of about10cm long for arterial puncture. At the operating room,analysis ofblood gas, lactate, and glucose was performedusing a portable gas analysis device (Epoc, Epocal Inc.,Ottawa, Canada). An umbilical pH less than 7.2 was con-

sidered fetal acidosis.18

Newborns were evaluated by an assistant pediatricianwho assessed the Apgar score at the 1st and 5th minutesof birth, and a low Apgar was considered when the valuesassigned were less than 7.

The newborn destination was also evaluated, if he wastaken to the neonatal intensive care unit, if he was underobservation in the neonatal resuscitation room or taken tothe apartment.

Statistical analysis

The results were statistically analyzed with the softwareBioEstat 5.3.Numerical variables were compared among thethree groups using the Kruskal---Wallis test followed by theMann---Whitney test. Categorical variables were comparedamong the three groups using the chi-square test followedby Fishers exact test. Results were considered statisticallysignificant when p < 0.05.

Results

Among the three groups, all pregnant women were over 20andunder 35 years ofage, gestational age between 39 weeksand one day and 40 weeks and six days and, until birth, they

received the same amount offluids.One ofthe pregnant women who received ephedrine was

excluded due to insufficient volume ofblood collected fromthe umbilical cord.

Pregnant women evaluation showed no significant differ-ence regarding the incidence of hypotension in the threegroups, as well as incidence ofreactive hypertension, needfor infusion discontinuation, and bradycardia. Regarding res-cue dose administration, there was no statistical differencebetween groups M and E, although higher in Group E, whichwas not observed in Group P. The incidence oftachycardia,nausea and vomiting was higher in Group E (Table 2).

Clinical evaluation of newborns showed no differencein Apgar scores at the 1st or 5th minute between groups

(Table 3). Only one newborn in Group E had Apgar score lessthan seven at the 1st minute, associated with fetal acid-osis. However, he showed clinical improvement and Apgarscore=9 at the 5th minute. No infant received resuscitationmaneuvers or required care in the intensive care unit.

Table 2 Hemodynamic changes related to maternal sympathetic block and side effects secondary to vasopressor therapy in

pregnant women undergoing elective cesarean section under spinal anesthesia.

Metaraminol

n =30

Phenylephrine

n= 30

Ephedrine

n= 29

p

Hypotension 5 (16.7%) 6 (20%) 10 (34.5%) 0.23

Hypertension 11 (36.7%) 7 (23.3%) 8 (27.6%) 0.51Bradycardia 3 (10%) 3 (10%) 0 (0%) 0.24

Tachycardia 1 (3.3%) 0 (0%) 12 (41.4%)a


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Table 3 Clinical evaluation ofthe newborn through the Apgar test at the 1st and 5th minutes after birth in elective cesarean

sections under spinal anesthesia.

Apgar Metaraminol Phenylephrine Ephedrine p

1st minute 9 (7---9) 9 (8---9) 9 (6---9) 0.7413

5th minute 10 (9---10) 10 (9---10) 10 (9---10) 0.7542

Values are expressed as median and interquartile range (Kruskal---Wallis).

Regarding laboratory evaluation of newborns, the aver-age pH was 7.310.03 in Group M, 7.300.03 in GroupP and 7.260.07 in Group E. In group E, three newborns(10.3%) had pH less than 7.20. However, the p-value wassignificant (p = 0.0035).

Considering the mean value of excess base, there wasa significant difference between groups M and P in rela-tion to E, but not between groups M and P. Lactate valuesalso showed significant difference between groups and werehigher in Group E compared to groups M and P. Parameterssuch as pO2, pCO2, HCO3, and glucose showed no statisticaldifferences (Table 4).

There was no statistical difference between groupsregarding the time elapsed between blockade and skin inci-sion, blockade and uterine incision, and blockade and birth(Table 5).

Discussion

The vasopressor doses administered in this study wereappropriate for the prevention and treatment ofmaternalhypotension. Currently, it is known that the three vaso-pressors are considered equally effective for preventinghypotension during elective cesarean sections.3,15,19

When phenylephrine is administered by continuous infu-

sion, the incidence ofhypotension varies between 13% and23%.17 Allen et al.14 compared fixed infusions of 25, 50, 75and 100g/min ofphenylephrine and reported better hemo-dynamic stability when doses of 25 and 50g/min wereused. The incidence of hypotension in this study was 20%and satisfactoryhemodynamic control was obtained with thevariable infusion started with 50g/min.

In a study by Ngan Kee et al.,15 in which metaraminolwas administered as a bolus of 0.5mg followed by contin-uous infusion of0.25mg/min, the incidence ofhypotension

was 35%, which is higher than that obtained in this study(16.7%). Although the initial infusion doses in both stud-ies were similar, the difference observed probably occurredbecause the doses administered in this study varied accord-ing to blood pressure measurements, which promotes betterhemodynamic control.17

Regarding ephedrine, this study observed hypotension in34.5% ofcases, whereas in the study by Carvalho et al.,20

the incidence was 45%. Note that both the work by NganKee et al.15 and Carvalho et al. used prior administrationof crystalloid, an approach proven ineffective. Because inthis study fluids were concomitantly administered with the

blockade, this may explain the difference in results.On the other hand, Bhardwaj et al.21 in a study comparing

the three vasopressors used in the present study, adminis-tered bolus followed by continuous infusion and reportedincidence of hypotension in Group M (14.8%) and GroupP (12.5%), results closest to this study. As for ephedrine,hypotension occurred in 23% ofthe cases.

To avoid distortions in the results, all patients received avolume of10mL/kg ofRingers solution until child delivery,as concomitant hydration (cohydration). Banerjee et al.22

considered rational to start the rapid infusion ofcrystalloid,such as Ringers solution, concurrently with the anestheticblock, as crystalloids improve systolic volume and cardiacoutput only transiently, and it is considered a cheaper option

than colloids, with less risk of complications (anaphylaxis,coagulation disorders).23

In cases ofreactive hypertension and vasopressor infusiondiscontinuation, the results match those ofthe literature,19

i.e., there were no significant differences among the threegroups. Regarding the incidence ofbradycardia, although itwas similar in the three groups, the results are opposite tothe studies by Veeser et al., which reported lower risk ofbradycardia in pregnant women receiving ephedrine.

Table 4 Laboratory evaluation ofthe newborn performed with sample collection ofumbilical cord arterial blood for measure-

ment ofglucose, lactate, and blood gases during elective cesarean section under spinal anesthesia.

Metaraminol Phenylephrine Ephedrine p

Ph 7.31 0.03 7.30 0.03 7.26 0.07a 0.0035

pO2 (mm Hg) 17.32 11.67 12.82 3.76 14.21 6.18 0.1139

pCO2 (mmHg) 49.25 7.97 53.09 7.19 53.98 11.96 0.1681

HCO3 (mm Hg) 24.77 2.99 25.78 2.37 23.80 3.46 0.0745

Base excess (mEq L---1) 1.71 2.63 1.22 1.98 3.44 2.39b 0.0005

Glicemia 51.53 9.72 50.60 9.84 49.76 11.32 0.6545

Lactate 1.46 0.31 1.58 0.53 2.11 0.69c 0.0004

Values are expressed as mean and standard deviation (Kruskal---Wallis, Mann---Whitney).a p= 0.0024 versus metaraminol;p = 0.0177 versus phenylephrine.b p= 0.0018 versus metaraminol;p = 0.0003 versus phenylephrine.c p= 0.0002 versus metaraminol;p = 0.0017 versus phenylephrine.


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Table 5 Intraoperative variables.

Metaraminol (min) Phenylephrine (min) Ephedrine (min) p

Blockade-skin incision 7.53 2.10 6.67 2.55 6.97 1.97 0.37

Blockade-uterine incision 13.03 3.90 11.17 3.79 12.52 3.52 0.27

Blockade-birth 14.17 3.96 12.47 3.81 13.69 3.53 0.34

Skin incision-birth 6.73 2.49 5.73 2.39 6.62 2.32 0.21

Uterine incision-birth 1.17 0.46 1.30 0.53 1.17 0.38 0.41

Values are expressed as mean and standard deviation (Kruskal---Wallis).

An interesting observation was that pregnant womentreated with metaraminol had less need for rescue dosesthan those who received ephedrine. The same was notobserved with phenylephrine. This probably occurredbecause metaraminol increases the systemic vascular resis-tance (afterload), recruits splanchnic blood, and increasesthe venous return (preload), besides presenting positiveinotropic activity, unlike phenylephrine, which acts basicallyonly in the afterload.24

The incidence of tachycardia was higher in Group E

than in other groups, which was expected because whenephedrine is used to prevent hypotension during surgeryunder spinal anesthesia, it causes an increase ofcardiac out-put at the expense of increased heart rate. On the otherhand, it is known that -agonist drugs, such as phenyle-phrine and metaraminol, may cause reflex bradycardia tothe increased peripheral vascular resistance.25 However,there were no differences between groups in the incidenceof bradycardia, which may be due to the administration ofadequate doses ofmetaraminol and phenylephrine.

In this study, despite effective blood pressure control,there was a relationship between the use ofephedrine andthe incidence ofnausea and vomiting. Lee et al.,2 in a sys-

tematic review on the use of ephedrine, found that evenunderbloodpressure control in cesarean sections there weredifferences between the ephedrine group and the controlgroup (without vasopressor) regarding the occurrence ofnausea and vomiting.

Ngan Kee et al.,26 in a study comparing infusions withvarying combinations of ephedrine and phenylephrine formaintenance ofblood pressure during elective cesarean sec-tion, found that the higher the proportion ofephedrine andthe lower the proportion of phenylephrine, the hemody-namic control was more difficult, fetal acid-base profile lessfavorable, and incidence ofnausea and vomiting higher.

It is known that intraoperative nausea and vomiting incesarean sections may be prevented through hypotension

control and improving the use ofneuraxial and intravenousopioids, which improves the anesthetic block quality, mini-mizes surgical stimulation, and reduces the use ofuterotonicdrugs. Whereas all pregnant women in this study receivedthe same dose of opioids and uterotonic drugs, as wellas adequate levels of anesthetic blockade, the increasedincidence of nausea and vomiting caused by ephedrineis probably due to an effect of the drug itself, besidesindicating that the etiology of nausea and vomiting ismultifactorial.27

Some studies have reported a lower incidence of nau-sea, vomiting, and maternal hypotension when vasopressorsare administered by continuous infusion. Therefore, in this

study, the administration of bolus followed by continuousinfusion waschosen.6,17,28 However, it is known that continu-ous infusion ofvasopressors is associatedwith higher doses inorder to maintain blood pressure close to baseline values.29

The vasopressor of choice with better profile for hemo-dynamic control of pregnant women in cesarean sectionsis still largely debatable, by the observation that duringthe anesthetic block installation there is a reduction in sys-temic vascular resistance, associated with increased cardiacoutput, which is mediated by increased heart rate. Thus,

bradycardia caused by the administration of -agonistsresults in decreased maternal cardiac output, leading someanesthesiologists to base their choice on the mothers heartrate.30

Dyer et al., in a study evaluating pregnant women under-going cesarean section under spinal anesthesia throughminimally invasive cardiac output monitors (LiDDCO andBioZ) who received ephedrine or phenylephrine, showedthat, after spinal anesthesia, the pregnant women had amarked decrease in systemic vascular resistance, with acompensatory increase in cardiac output, and concludedthat low doses of phenylephrine are able to restore thesystemic vascular resistance and cardiac output to baseline

values.31

Auler et al.32 who also assessed maternal hemodynamicchanges through minimally invasive monitoring ofpregnantwomen undergoing cesarean section under spinal anesthe-sia and who received metaraminol to control blood pressure,reported a decrease in systolic volume, offset by increasedheart rate, but did not observe significant changes in meanarterial pressureand systemic vascular resistance, and spec-ulated that these results occurred because of more rapidand effective correction of mean arterial pressure by theadministration ofmetaraminol.

Although the hemodynamic control was satisfactory withthe three vasopressors, a limitation of the study was thatthe doses administered were extracted from other stud-

ies without equipotent ratio, as there are no studies inliterature comparing equipotent doses ofvasopressors stud-ied. Still, measurement of maternal pressure was used atintervals ofone minute, which besides being uncomfortablefor the mother may hinder blood pressure measurement,as sometimes it takes more than a minute to measureblood pressure. Cooper et al.33 in a study evaluating thecontrol ofsystolic blood pressure with continuous infusionof phenylephrine for elective cesarean sections, showedthat infusion rate adjustments with measurement ofmater-nal blood pressure at 2-min intervals are effective forcontrolling hypotension and nausea and vomiting inci-dence.


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Regarding fetal prognosis, although the chosen vasopres-sor doses were suitable for maternal hypotension control inthe three groups, the newborns of mothers who receivedephedrine showedpH values and base excess lower than theother groups.

Fetal acidosis, assessed through umbilical cord bloodpH and base excess, is considered a marker of neona-tal prognosis. Although some studies report that only

severely acidotic fetuses (pH< 7), after an acute intra-partum event, have a higher risk ofmortality and morbidity(hypoxic-ischemic encephalopathy, intraventricular hem-orrhage, cerebral palsy), a recent meta-analysis showedthat when acidosis was defined as pH 8 at the 5th minute and did notrequire resuscitationmaneuvers or transfer to the intensivecare unit.

Base excess comparison showed no differences betweenthe M and P groups compared to Group E. The values werelower in the latter. However, despite the differences, thesevalues are within normal limits.35

From fetal standpoint, no doubt that phenylephrineand metaraminol are associated with higher values of pHand base excess in umbilical cord blood that were higherthan those ofephedrine,2,15,36 which were confirmed in thepresent study, reason for which the use of ephedrine for

hypotension management in obstetric anesthesia is beingquestioned as a first-choice vasopressor. Thus, one can pre-dict that the administration of high doses of ephedrine,especially in situations of fetal compromise, should beavoided.15,37

Fetal changes caused by ephedrine are related to the factthat it rapidly crosses the uteroplacental barrier, stimulatesfetal -adrenergic receptors, and increases fetal metabolicdemand. This can be seen by the increase in lactate, glu-cose, and catecholamines in umbilical cord blood. In thepresent study,when the mother received phenylephrine, thelactate values in umbilical cord bloodwere higher than whenthe mother received ephedrine and metaraminol. However,regarding glycemia, there were no differences between the

three groups, in contrast to the results ofNgan Kee et al.38

Fetal metabolic response to vasopressor administeredin the mother may depend on the fetal 2-adrenoceptorgenotype and further complicate the understanding ofthe relationship between ephedrine administration andlower pH values. Fetal homozygosity for the ADRB2 genep.Arg16 seems to be more resistant to ephedrine-inducedacidemia.39

On the other hand, a recent study by Bhardwaj et al.21

showed no differences between the M, E, and P groupsregarding pH of umbilical cord blood and base excess val-ues. This difference probably occurred due to the use ofsmaller doses ofephedrine.

None of the infants in this study had low Apgar score(less than 7) at the 5th minute. It is known that episodesof hypotension during elective cesarean sections are not acause ofclinically significant fetal changes when treatedpromptly. In a systematic review by Veeser et al.19, whichincluded 20 studies with a total of 1069 newborns, it wasdemonstrated that only one newborn had Apgar score lessthan 7 in the 5th minute.

In order to minimize the occurrence of fetal acidosis,in addition to the approaches already described here, it isknown that the time elapsed between the skin incision andbirth, and between uterine incision and birth, is directlyrelated to fetal acidosis. This has encouraged surgeons toreduce the duration ofsurgeries.40

In this study, the duration of surgery in all study groupswas lower than that reported in the literature, which maybe a reasonable explanation for the favorable outcome ofnewborns, even in cases where fetal acidosis occurred. Astudy by Maayan-Metzger et al. showed that infants bornto women who had an interval of more than two minutesbetween uterotomia and birth had a higher incidence offeeding problems and prolonged hospitalization.41

Currently, vasopressorswith predominantly alpha-agonisteffects are considered drugs of choice for preventingmaternal hypotension, nausea and vomiting during spinalanesthesia for elective cesarean sections. Although its useis associated with reduced heart rate and cardiac output, itis clinically insignificant in low-risk pregnancies and electivecesarean sections.

Our results show that in elective cesarean sections underspinal anesthesia hypotension can be controlled with anyof the vasopressors studied, as there were no clinically sig-nificant maternal or fetal changes, which shows that strictcontrol of blood pressure is an important condition formaternal and fetal well-being. However, metaraminol and

phenylephrine had advantages over ephedrine, especially inthe incidence ofnausea and vomiting. Repercussionsofvaso-pressor therapy in emergency cesarean sections and high riskpregnancies are still a matter ofmuch discussion.

Conflicts of interest

The authors declare no conflicts of interest.

References

1. Macarthur A, Riley ET. Obstetric anesthesia controversies:vasopressor choice for postspinal hypotension during cesareandelivery. Int Anesthesiol Clin. 2007;45:115---32.

2. Lee A, NganKee WD, GinT. A quantitative, systematic review ofrandomized controlled trials of ephedrine versus phenylephrinefor themanagement of hypotension during spinal anesthesia forcesarean delivery. Anesth Analg. 2002;94:920---6.

3. Cyna AM, Andrew M, Emmett RS, et al. Techniques for pre-venting hypotension during spinal anaesthesia for caesareansection; 2010 (Review). Available from: http://onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/CD002251/pdf fs.html[accessed 7.11.10].

4. Jackson R, Reid JA, Thorburn J. Volume preloading is not essen-tial to prevent spinal-induced hypotension at cesarean section.Br J Anaesth. 1995;75:262---5.
http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/CD002251/pdf_fs.htmlhttp://onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/CD002251/pdf_fs.htmlhttp://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0020http://onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/CD002251/pdf_fs.htmlhttp://onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/CD002251/pdf_fs.htmlhttp://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0010http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0005


8/8


5. Cooper DW. Cesarean delivery vasopressor management. CurrOpin Anesthesiol. 2012;25:300---8.

6. Ralston DH, Shnider SM, Delorimier AA. Effects of equipotentephedrine, metaraminol, mephentermine, and methoxamineon uterine blood flow in the pregnant ewe. Anesthesiology.1974;40:354---70.

7. Clyburn P. Spinal anaesthesia for caesarean section: time forre-appraisal? Anaesthesia. 2005;60:633---5.

8. Cooper DW, Carpenter M, Mowbray P, et al. Fetal and maternal

effects of phenylephrine andephedrineduring spinal anesthesiaform cesarean delivery. Anesthesiology. 2002;97:1589---90.

9. Montan S. Increased risk in the elderly parturient. Curr OpinObstet Gynecol. 2007;19:110---2.

10. Ezra Y, McParland P, Farine D. High delivery intervention ratesin nulliparous women over age 35. Eur J Obstet Gynecol ReprodBiol. 1995;62:203---7.

11. Vienne CM, Creveuil C, Dreyfus M. Does young maternal ageincrease the risk of adverse obstetric, fetal and neonatal out-comes: a cohort study. Eur J Obstet Gynecol Reprod Biol.2009;147:151---6.

12. Neves JFNP, Monteiro GA, Almeida JR, et al. Utilizaco dafenilefrina para controle da presso arterial em cesarianas ele-tivas: dose teraputica versus profiltica. Rev Bras Anestesiol.2010;60:391---8.

13. Cardoso MSC, Santos MM, Yamaguchi ET, et al. Expansovolmica em raquianestesia para cesariana: como realiz-la?Rev Bras Anestesiol. 2004;54:13---9.

14. Allen TK, George RB, White WD, et al. A double-blind,placebo-controlled trial of four fixed rate infusion regimens ofphenylephrine for hemodynamic support during spinal anesthe-sia for cesarean delivery. Anesth Analg. 2010;111:1221---9.

15. Ngan Kee WD, Lau TK, Khaw KS. Comparison of metaraminoland ephedrine infusions formaintainingarterial pressure duringspinal anesthesia for elective cesarean section. Anesthesiology.2001;95:307---13.

16. Saravanan S, Kocarev M, Wilson RC, et al. Equivalent dose ofephedrine and phenylephrine in the prevention of post-spinalhypotension in caesarean section. Br J Anaesth. 2006;96:95---9.

17. Habbib AS. A review of the impact of phenylephrine adminis-

tration on maternal hemodynamics and maternal and neonataloutcomes in women undergoing cesarean delivery under spinalanesthesia. Anesth Analg. 2012;114:337---90.

18. Magalhes E, Govia CS, Ladeira LCA, et al. Efedrina versusfenilefrina: prevenco de hipotenso arterial durante aneste-sia raqudea para cesariana e efeitos sobre o feto. Rev BrasAnestesiol. 2009;59:11---20.

19. Veeser M, Hofmann T, Roth R, et al. Vasopressors for the man-agement of hypotension after spinal anesthesia for electivecaesarean section. Systematic review and cumulative meta-analysis. Acta Anaesthesiol Scand. 2012;56:810---6.

20. Carvalho JCA, Cardoso MMSC, Capelli EL, et al. Efedrinaprofiltica durante raquianestesia para cesariana: estudo dose-resposta da administraco em blus e em infuso contnua. RevBras Anestesiol. 1999;49:309---14.

21. Bhardwaj N, Kajal J, Arora S, et al. A comparison of threevasopressor for tight control of maternal blood pressureduring cesarean section under spinal anesthesia: effect onmaternal and fetal outcome. J Anaesthesiol Clin Pharmacol.2013;29:26---31.

22. Banerjee MD, Stocche RM, Angle P, et al. Preload or coloadfor spinal anesthesia for elective cesarean delivery: a meta-analysis. Can J Anaesth. 2010;57:24---31.

23. Mercier FJ. Cesarean delivery fluid management. Curr OpinAnesthesiol. 2012;25:286---91.

24. Siaulys M, Yamagushi ET. Anestesiapara cesariana. In: Siaulys M,editor. Condutasemanestesiaobsttrica. 1sted.Riode Janeiro:Elsevier; 2012. p. 41---74.

25. Critchley LA, Stuart JC, Conway F, et al. Hypotension duringsubarachnoid anaesthesia: haemodynamic effects of ephedrine.Br J Anaesth. 1995;74:373---8.

26. Ngan Kee WD, Lee A, Khaw KS, et al. A randomized double-blinded comparison of phenylephrine and ephedrine infusioncombinations to maintain blood pressure during spinal anesthe-sia for cesarean delivery: the effects on fetal acid-base statusand hemodynamic control. Anesth Analg. 2008;107:1295---302.

27. Balki M, Carvalho JCA. Intraoperative nausea and vomiting dur-

ing cesarean section under regional anaesthesia. Int J ObstetAnaesthe. 2005;14:230---41.

28. Sia ATH, Tan HS, Sng BL. Closed-loop double-vasopressorautomated system to treat hypotension during spinal anaes-thesia for caesarean section: a preliminary study. Anaesthesia.2012;67:1348---55.

29. Doherty A, Ohashi Y, Downey K, et al. Phenylephrine infusionversus bolus regimens during cesarean delivery under spinalanesthesia: a double-blind randomized clinical trial to assesshemodynamic changes. Anesth Analg. 2012;115:1343---50.

30. Gupta S. Vasopressors and tight control of maternal blood pres-sure during cesarean delivery: a rocky alliance. J AnaesthesiolClin Pharmacol. 2013;29:1---3.

31. Dyer RA, Reed AR, Van Dyk D, et al. Hemodynamiceffects of ephedrine, phenylephrine, and the coadministra-

tion of phenylephrine with oxytocin during spinal anesthesiafor elective cesarean delivery. Anesthesiology. 2009;111:753---65.

32. Auler Jnior JOC, Torres MLA, Cardoso MM, et al. Clini-cal evaluation of the flotrac/vigileoTM system for continuouscardiac outputmonitoring in patients undergoing regional anes-thesia for elective cesarean section: a pilot study. Clinics.2010;65:793---8.

33. CooperDW, Schofield L, Hynd R, et al. Prospective evaluation ofsystolic arterial pressure control with a phenylephrine infusionregimen during spinal anaesthesia for caesarean section. Int JObstet Anaesth. 2012;21:245---52.

34. Malin GL, Morris RK, Khan KS. Strength of association betweenumbilical cord pH and perinatal and long term outcomes: sys-tematic review and meta-analysis. BMJ. 2010;340:c1471.

35. Reynolds F, Seed T. Anaesthesia for caesarean section andneonatal acid---base status: a meta-analysis. Anaesthesia.2005;60:636---53.

36. Lin F, Qiu M, Ding X, et al. Ephedrine versus phenylephrine forthe management of hypotension during spinal anesthesia forcesarean section: an updatedmeta-analysis.CNSNeurosci Ther.2012;18:591---7.

37. Dyer RA, Biccard BM. Ephedrine for spinal hypotension duringelective caesarean section: the final nail in the coffin? ActaAnaesthesiol Scand. 2012;56:807---9.

38. Ngan Kee DW, Khaw KS, Tan PE, et al. Placental transfer andfetal metabolic effects of phenylephrine and ephedrine dur-ing spinal anesthesia for cesarean delivery. Anesthesiology.2009;111:506---12.

39. Landau R, Liu S, Blouin J, et al. The effect of maternaland fetal 2-adrenoceptor and nitric oxide synthase geno-type on vasopressor requirement and fetal acid---base statusduring spinal anesthesia for cesarean delivery. Anesth Analg.2011;112:1432---40.

40. Ngan Kee DW, Lee A. Multivariate analysis of factors asso-ciated with umbilical arterial pH and standard base excessafter caesarean section under spinal anaesthesia. Anaesthesia.2003;58:125---30.

41. Maayn-Metzger A, Schuhan-Eisen I, Tordis L, et al. The effect oftime intervals on neonatal outcome in elective cesarean deliv-ery at term under regional anaesthesia. Int J Gynaecol Obstet.2010;111:224---8.
http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0025http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0025http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0025http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0030http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0030http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0030http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0030http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0030http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0030http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0035http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0035http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0035http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0040http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0040http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0040http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0040http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0045http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0045http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0045http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0050http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0050http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0050http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0050http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0055http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0055http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0055http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0055http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0055http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0060http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0060http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0060http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0060http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0060http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0060http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0060http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0065http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0065http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0065http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0065http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0065http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0065http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0070http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0070http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0070http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0070http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0070http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0075http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0075http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0075http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0075http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0075http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0075http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0080http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0080http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0080http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0080http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0080http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0085http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0085http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0085http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0085http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0085http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0090http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0090http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0090http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0090http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0090http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0090http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0090http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0095http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0095http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0095http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0095http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0095http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0100http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0100http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0100http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0100http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0100http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0100http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0100http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0100http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0105http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0105http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0105http://refhub.elsevier.com/S0104-0014(14)00068-2/sbref0105http://refhu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2. Comparison of Metaraminol, Phenylephrine and Ephedrine in Prophylaxis and Treatment of...

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