Review of Literature

This is an over view of previous studies of patients undergoing elective

cesarean section under spinal anesthesia and being administered either

phenylephrine orephedrine for maintenance of the mother's blood pressure. It also

includes the effect of these two vasopressors on the Apgar score of the baby and

the other negative effects on the mother.

In a randomized, double-blind study, conducted by Moran, etal.(1995) sixty

women planning for elective cesarean section in spinal anesthesia randomly received

either ephedrine(n=29)at a dose of10mg intravenous bolus, or phenylephrine (n=31)

at 80µg IV bolus doses to maintain systolic blood pressure of ≥100mmHg. Umbilical

arterial blood gases were measured and the neonatal Apgar score and early neonatal

neuro-behavioral scale points were evaluated. There were significant differences

between groups in the mean umbilical artery pH,PCO2, and base deficit in favor

of phenylephrine. There were no significant differences between the groups in

the neonatal Apgar score, early neonatal neur-obehavioral scale score, or the

presence of maternal nausea and vomiting. The authors concluded that

phenylephrine is as effective as ephedrine in the treatment of maternal hypotension

when used in small additive bolus injections (Moran,etal., 1991).

A study was conducted in the United States by Laporta, et al.(1995). In this

study, the authors compared the maternal and neonatal catecholamine

concentrations, followed by the use of either phenylephrine or ephedrine to treat a

drop in maternal blood pressure after spinal anesthesia for cesarean section. Forty

women were randomized into two groups: Group1(n=20) were treated with ephedrine

that was given as 5 mgi. v. bolus injections; Group II (n=20) were treated with

phenylephrine, which was given in 40µgi. v. bolus injections, both to keep the

mother's systolic blood pressure at or above 100 mmHg. Maternal vein (MV),

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umbilicalvein (UV), and umbilical artery (UA) blood samples were taken at the time

of delivery. Samples were assayed for catecholamine concentrations and blood

gas. When they compare the blood gas values between the two groups,

catecholamine concentrations in UA, UV and MV (upondelivery) samples were

significantly higher in the ephedrine group compared to the phenylephrine group. No

significant differences in maternal characteristics were noted, such as acid-base

values, nausea and vomiting, and Apgar scores between the groups. The authors

concluded that phenyl ephrine is as safe and effective as ephedrine in the treatment

of low blood pressure in healthy women undergoing cesarean delivery. The use of

phenylephrine was also accompanied by significantly lower nor epinephrine

concentrations in both the mother and the newborn.

An experiment was conducted in the USA, in which 38women undergoing

elective cesarean section under spinal anesthesia were randomized to receive either

phenyl ephrine boluses(100mcgdoses), or ephedrine(5mg doses)for the

maintenance of the mother's blood pressure. The purpose of the administration of

vasopressors was aslope of systolic pressure to ≤90% of baseline values. Maternal

blood pressure (BP) and heart rate (HR) were measured every minute. Cardiac

output (CO) was measured by cross-sectional and Doppler echocardiography before

and after giving1500ml of Ringer lactate fluids and after every 2min after

administration of bupivacaine. The umbilical artery pulsatility index(PI) was measured

using Doppler before and after spinal anesthesia. The results showed that the

median(range) number of boluses of phenylephrine and ephedrine was similar.

Maternal systolic blood pressure and CO results were the same in both groups, but the

mean [95% CI] maximum percentage change in the mother's HR was greater in the

phenylephrine group than in the ephedrine group. This study supports the use of

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phenylephrine for the maintenance of maternal arterial pressure in patients undergoing

cesarean section electively during spinal anesthesia (Thomaset al.,1996).

A quantitative systematic review was conducted in China, in which the authors

compared the efficacy and safety of ephedrine with phenylephrine for the prevention

and treatment of hypotension under spinal anesthesia for cesarean section delivery.

Seven randomized controlled trials (n=292)were recognized. Variables that were

assessed were maternal hypotension, hypertension and bradycardia, as well as

neonatal umbilical cord blood pH values and Apgar scores. The study found that there

was no difference between phenylephrine and ephedrine for the management

(prevention and treatment) of maternal hypotension, but, they showed that maternal

bradycardia was more likely to happen with phenylephrine than with ephedrine. Also,

the results showed that women who were given phenylephrine had neonates with

higher umbilical arterial pH values than those women given ephedrine. In fact, there

was no difference between the two vasopressors in the incidence of true fetal

acidosis or Apgar scores of 7 at 1 and 5min. The authors concluded that the present

systematic review does not support that ephedrine is the preferred drug for the

management of maternal hypotension during spinal anesthesia for elective

cesarean delivery in healthy, non-laboring women (Lee etal.,2002).

A study conducted in India by Sahuetal.(2003) included sixty women

undergoing elective and emergency caesarean section in spinal anesthesia who

developed hypotension after subarachnoid block. Women were randomly assigned

to three groups, Group P (receiving a phenylephrine dose of 100µg,I.V (n = 20)),

group E(receiving an ephedrinedose of 6mg,I.V (n= 20)) and group M (receivinga

mephentermine dose of 6mg IV (n= 20)). Hypotension was defined as a decrease in

systolic arterial pressure of >20% of baseline values. The authors concluded that

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elevation of systolic arterial pressure in the phenylephrine group was significantly

higher for the first six minutes out of the bolus dose when compared with the

ephedrine and mephentermine groups. There was a significant reduction in heart

rate in the phenylephrine group. Neonatal Apgar scores were >7 in all three groups.

A systematic literature study was conducted in China to compare the effect of

ephedrine and phenylephrine for the treatment of spinal anesthesia-induced

hypotension during cesarean section. A total of 15 trials and 742 mothers undergoing

elective C-sections were analyzed. When used to prevent hypotension, patients who

received ephedrine and phenylephrine did not change significantly in the presence of

hypotension, umbilical artery pH or venous pH values. In the treatment of

hypotension, patients who received ephedrine and phenylephrine had a comparable

incidence of intraoperative hypotension, whereas mothers who received

phenylephrine had newborns with higher umbilical arterial pH and venous pH values

than those who had received ephedrine. The authors conclude that the use of

prophylactic ephedrine and phenylephrine were both effective in preventing

maternal hypotension during C-section under spinal anesthesia. Phenylephrine was

superior to ephedrine to treat hypotension, evidenced by higher cord blood pH

(Linetal., 2012).

Gunda, et al.,(2010) conducted a study of 100 ASA I and II patients scheduled

for elective cesarean section with spinal anesthesia. Each patient was randomized to

one of the two double-blind study groups. Group E received an ephedrine dose of

one ml (5mg/ml) with normal saline for hypotension if present (n=50). Group C

received one ml of phenylephrine (100ug /ml) with normal saline for hypotension if

present(n= 50).Heart rate, systolic blood pressure, diastolic blood pressure, and

mean arterial blood pressure were compared between and within groups to the basal

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values at 0,2,4,6,8,10,15,20,25,30,45, and 60 minutes from the start of the operation.

The occurrence of side effects and neonatal results were studied between the

groups. This study showed that all patients had treatment for hypotension.

Provision of phenylephrine was with considerable slope in HR. Variance in SBP,

DBP, and MAP was analogous in both groups for the most common times. The

incidence of nausea, vomiting and tachycardia were significantly higher in the

ephedrine group. The authors concluded that phenylephrine and ephedrine are

allowable options to counter maternal hypotension associated with spinal anesthesia

in elective cesarean section. They also found that complications of intra- operative

nausea and vomiting, tachycardia and bradycardia should be considered when

making a choice of vasopressors, which suggests that phenylephrine may be more

relevant in promoting maternal well-being.

A study was conducted in Iran by Moslemi & Rasooli (2015). The aim of the

study was to compare the effect of prophylactic infusion of phenylephrine compared

to ephedrine in the prevention of hypotension women undergoing spinal anesthesia

in elective cesarean section. Eighty- three patients were included in the study and

were divided randomly into three groups. Group Ph got phenylephrine infusion;

Group Egotephedrine infusion while Group P was delivered as placebo. Any

decrease in BP around 20% from the baseline was treated with 50-100µg of

phenylephrine in the Ph group, or 5-10mg of ephedrine in the E and P groups. This

was repeated as necessary. These drugs were prepared in numerical marked

syringes and given to nurses (blind to medication) who were asked to monitor

patients. They were instructed to administer one ml of this drug solution if

hypotension was higher than 20% from baseline(each1mlof phenylephrine was

prepared as 50 micrograms and each one cc of ephedrine was 5mg).Vital

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signs(blood pressure, heart rate and arterial oxygen saturation) were registered in

time. Mother and newborn perioperative complications were monitored and

recorded. Systolic and diastolic blood pressures were higher in the phenylephrine

group of recipients than the control group, but no higher than in the ephedrine group.

Maternal rhythm disorders were more common in the ephedrine and phenylephrine

groups than the control group. Vomiting was more common in the ephedrine group

(P<0.05). Further, five minute Apgar scores were higher in newborns in the

phenylephrine and ephedrine groups than in the placebo group (P<0.05).The

newborn phenylephrine group had less acidosis than the other groups. They

concluded that prophylactic infusion of phenylephrine can effectively reduce spinal

anesthesia-related hypotension without any significant complication for the mother or

her fetus (Moslemi& Rasooli, 2015).

In a randomized double-blind study in India, women received either doses of

ephedrine bolus of 6mg (group 1, n=30) or 100µg of phenylephrine (group 2, n=30)

when the mother's systolic pressure was 80% of baseline. The study showed that

differences in systolic pressure were comparable in thetwo groups. There were no

differences in the incidence of bradycardia, nausea and vomiting. Umbilical artery pH

and venous pH was significantly greater in the phenylephrine group than in the group

of ephedrine. The base excess of the umbilical artery was significantly less in

group E than in group P. Apgar score sat 1,5 and 10 minutes and neuro behavioral

score of 2-4 hours, 24 hours and 48 hours were similar in the two groups. They

concluded that 100 µgof phenylephrine and 6 mg of ephedrine have similar efficacy

in the treatment of maternal hypotension during spinal anesthesia for elective

cesarean section. Newborns in group Ph ad significantly higher umbilical artery pH

and base excess values than those in group E (Prakashetal. 2010).

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A study was conducted in India by Nazir, et al.(2012). A total of 100 patients

undergoing elective cesarean section under spinal anesthesia with a normal

pregnancy were randomly allocated in to two groups of 50 each. Group I received a

prophylactic bolus dose of ephedrine 10mgi.v.at the time of intrathecal block with

rescue boluses of 5mg. Group II received a prophylactic bolus dose of phenylephrine

100 gat the time of intrathecal block with rescue boluses of 50g. Hemodynamic

variables such as blood pressure and heart rate were recorded every two minutes

upto the delivery of the baby and then every 5 minutes. Neonatal outcome was

assessed using Apgar score at 1 and 5 minutes and neonatal umbilical cord blood pH

values. The authors found that there was no difference in managing hypotension

between the two groups. Incidence of bradycardia was high Incidence of bradycardia

was higher in the phenylephrine group. The differences in umbilical cord pH, Apgar

score, and birth weight between the two groups were found to be statistically

insignificant. The author concluded that phenylephrine and ephedrine are equally

efficient in managing hypotension during spinal anesthesia for elective cesarean

delivery. There was no difference between the two vasopressors in the incidence of

true fetal acidosis. Neonatal outcome remained equally good in both groups.

A study from Finland conducted by Alahuhta, et al. (1992) researched the

effects of i.v. vasopressors on 19 healthy parturient women undergoing elective

cesarean section. Doppler velocimetry of maternal uterine, placental arcuate arteries

and fetal umbilical cords, and kidney and middlecerebralarterieswere studiedduring

spinalanesthesia. Fetalcardiac muscle function was investigated simultaneously by

M-mode echocardiography. Patients were randomized into two groups given either

ephedrine or phenylephrine asa prophylactic infusion supplemented with smaller

bolus doses if systolic arterial pressure decreased by more than10 mmHg from the

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control value. Both the vasopressors restored maternal arterial pressure effectively.

Ephedrine group showed no significant differences in any of the Doppler velocimetry

recordings in relation to the fundamental values, but during phenylephrine infusion,

indices of blood flow velocity wave form of uterine and placental arcuate arteries

increased significantly and vascular resistance decreased significantly in the fetal

renal arteries. Healthy fetuses seemed to tolerate these changes in uteroplacental

circulation well. However, the Apgar score for newborns and acid-base values in the

umbilical cord was within the normal range in both groups. The results suggest that

caution is required when selecting the specific vasoconstrictor drug, dosage and

route of administration for treatment of maternal hypotension resulting from spinal

anesthesia for cesarean section.

In a systematic review study that was conducted in Germany by Veeser et al.

(2012), the combined data available for defining the maternal and neonatal effects of

the two vasopressors phenylephrine and ephedrine was analyzed. Hypotension,

hypertension and bradycardia of the mothers; fetal acidosis defined as a pH<7.20;

continuous variables base excess (BE); and arterial pCO2 of newborns were

registered. The eligibility criteria were met by 20 trials including 1, 069 patients. Risk

ratio (RR) of true fetal acidosis was 5.29 (95%CI 1.62- 17.25)for ephedrine versus

phenylephrine (P=0.006). BE values for ephedrine use was significantly lower than

after phenylephrine. Umbilical ArterypCO2 did not differ. Mothers treated with

ephedrine had a lower risk of bradycardia (P= 0.004). No differences between

vasopressors were observed for hypotension and hypertension. The authors

conclude that there is a reduced risk of fetal acidosis associated with the use of

phenylephrine. In addition to the results of BE, this suggests a beneficial effect of

phenylephrine on fetal outcome parameters.

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A study was conducted in Brazil by Magalhães, et al. in (2009). The purpose of

this study was to compare the effect of ephedrine and phenylephrine in the

prevention and treatment of maternal hypotension during spinal anesthesia for

patients undergoing cesarean surgery and to assess their side effects and fetal

changes. Sixty patients undergoing spinal anesthesia with bupivacaine and sufentanil

were randomly divided into two groups to receive prophylactic ephedrine (group E,

n=30, dose=10mg) or phenylephrine (group P, n=30, dose=80g). Hypotension (blood

pressure equal to or lower than 80% of baseline) was treated with bolus

administration of the vasoconstrictor with 50% of the initial dose. The incidence of

hypotension, reactive hypertension, bradycardia, vomiting, and Apgar scores at the

1 stand 5th minutes, and blood gases inumbilical cord blood were evaluated. The

authors found that the mean dose of ephedrine used was 14.8±3.8mg and

phenylephrine was 186.7±52.9 micrograms. Demographic parameters and the

incidence of vomiting, bradycardia, and reactive hypertension were similar in both

groups. Hypotension had an incidence of 70% in group E and 93% in Group

P(p<0.05).The mean arterial pH of umbilical cord blood and Apgar score in the 1st

minute were lower in Group E (p<0.05). Differences in the Apgar score in the 5th

minute were not observed. The author concluded that ephedrine was more effective

than phenylephrine in the prevention of hypotension. Both drugs had a similar

incidence of side effects. Fetal repercussions were less frequent with phenylephrine

and were transitory with the use of ephedrine.

A study was conducted in Brazil to compare the efficacy of phenylephrine,

metaraminol, and ephedrine in the prevention and treatment of hypotension after

spinal anesthesia for cesarean section. Ninety pregnant women undergoing cesarean

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section were randomized into three groups to receive a bolus followed by continuous

infusion of vasopressors as follows: phenylephrine group (50μg+50μg/min);

metaraminol group (0.25 mg + 0.25mg/min); ephedrine group (4mg+4mg/min). The

infusion dose was doubled when the systolic blood pressure dropped to 80% of the

baseline and a bolus was given when the systolic blood pressure dropped to below

80%.The infusion dose was divided in half when the systolic blood pressure

increased to 120% and was stopped when it became higher. The incidence of

hypotension, nausea and vomiting, reactive hypertension, bradycardia, tachycardia,

Apgar scores and umbilical arterial blood gases were assessed at the 1st and 5th

minute. There was no difference in the incidence of hypotension, bradycardia,

reactive hypertension, infusion discontinuation, atropine or Apgar. Rescue boluses

were higher only in the ephedrine group compared with the metaraminol group. The

incidence of nausea and vomiting and fetal acidosis was greater in the ephedrine

group. The three drugs were effective to prevent hypotension, butfetale ffects were

more common in the ephedrine group (Aragãoa, et al., 2014).

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