Pre-eclamptic parturients present a challenge to the anaesthetist because of the problems that preeclampsia poses to the foetus and the mother 1. Although general anaesthesia can be used in pre-eclamptic women, it is accompanied by greater maternal morbidity and mortality. Currently, the safety of regional anaesthesia techniques is well established and they can provide better obstetric and foetal outcomes when chosen properly 2.
Hypotension during spinal anaesthesia during a caesarean delivery can have detrimental effects on both the mother and the neonate; these effects include decreased uteroplacental blood flow, impaired foetal oxygenation with foetal acidosis and asphyxia, and maternal symptoms of low cardiac output, such as nausea, vomiting, dizziness and disturbed consciousness 3. Therefore, considerable attention has been paid in the literature on methods to prevent and treat hypotension in obstetric anaesthesia.
Prophylactic measures used during spinal anaesthesia include left uterine displacement, volume preloading and vasopressor boluses or infusions 1. Fluid preloading and maternal tilt alone only reduce the incidence of hypotension to 50% 4.
Despite the wide acceptance of ephedrine as a vasopressor of choice for obstetric anaesthesia, its superiority over the other vasopressor in pre-eclamptic patients has not been clearly defined 3.
Several studies in the last few years have shown that phenylephrine is superior to ephedrine in the prevention of spinal-induced hypotension 5.
Patients and methods
After approval of the ethical and scientific committee and obtaining informed consent from the patients, the study was carried out on 60 parturient women, presenting with mild preeclampsia with gestational age (37–40) weeks, defined as BP of at least 140/90 mmHg and below 160/100 mmHg after 20 weeks’ gestation, proteinuria more than or equal to 300 mg/24 h.
Exclusion criteria included patients with severe preeclampsia, diabetes, cardiovascular diseases, cerebrovascular disease, autonomic neuropathy, spinal deformities, other neurological diseases, infection in the lumbar area, coagulation abnormalities, chronic renal disease, chronic hypertension, patients with placental complications (placenta previa or placental abruption), cord prolapse, foetal distress or foetal malformations and those with a neonatal birth weight of less than 2.5 kg.
Two doses of oral ranitidine (150 mg) were administered on the evening before and morning of surgery. Thirty millilitre of 0.3 mol/l sodium citrate was administered orally 30 min before the operation.
A peripheral vein was cannulated using an 18-G intravenous catheter for the administration of intravenous fluids and oxygen 3 l/min was administered through a nasal cannula. Monitoring comprised a three-lead ECG and pulse oximetry, and invasive arterial blood pressure was measured using a 20-G arterial cannula inserted under local anaesthesia into the independent radial artery. Baseline maternal heart rate, foetal heart rate and invasive systolic blood pressure (SBP) were recorded, and a uterine blood flow through uterine artery was measured by colour Doppler. In all patients, the bladder was catheterized to measure urine output during caesarean section.
The maternal uterine artery (the main branch on the placental side of the uterus) was identified by colour Doppler by GE Logic 5 (Wave Imaging, Willoughby, Ohio, USA) near the cervix before its divisions and the pulsatility index (PI)=(systolic peak velocity end-diastolic velocity) was measured from the blood velocity waveform profile. Three consecutive correctly imaged blood velocity waveforms were analysed and the mean value was used in further analysis. Maternal heart rate, SBP, oxygen saturation and foetal heart rate were recorded every 2 min during the study.
After the first Doppler measurement (baseline value), patients received lactated Ringer solution at 5 ml/min. Patients were placed in the supine position with a left lateral tilt 15°.
Patients were left undisturbed for several minutes, during which SBP and heart rate were taken as a baseline reading.
Spinal anaesthesia was induced in the sitting position as follows: after skin infiltration with lidocaine 2%, a 25–27-G Whitacre spinal needle was inserted at the L2–3 or the L3–4 vertebral interspace and hyperbaric 0.5% bupivacaine 1.5–2 ml and fentanyl 12.5 µg were injected intrathecally.
Patients were immediately turned supine with left uterine displacement. SBP was measured continuously using invasive radial arterial cannulation. Maternal hypotension is defined as a decrease in SBP of at least 80% baseline value or SBP of less than 100 mmHg.
Doppler measurements from the same uterine artery were obtained at 2-min intervals during the first 10 min after an intrathecal injection of bupivacaine. During these measurements, sensory block was assessed by loss of sensation to ice cold or pin-prick sensation. After completion of ultrasound measurement and establishment of adequate block at the sensory level (T4), the patients were divided randomly using closed envelops methods into four groups (each of which included 15 patients); each patient was administered the study drug immediately following the deposition of local anaesthetic into the subarachnoid space.
Group A was administered 5 mg ephedrine intravenously and 5 mg boluses whenever there was maternal hypotension.
Group B was administered 25 µg phenylephrine intravenous bolus and 25 µg boluses whenever there was maternal hypotension.
Group C was administered a phenylephrine infusion at 25 µg/min; subsequently, the rate of infusion was adjusted according to SBP.
Group D was administered 15 ml/kg lactated ringer solution before spinal anaesthesia; subsequently, the rate of infusion was adjusted according to SBP.
The Apgar score of the newborn was assessed at 1 and 5 min after delivery. Blood samples from double-clamped umbilical arteries were obtained immediately after delivery for determination of newborn pH.
Data were statistically described in terms of mean±SD, median and range, or frequencies (number of cases) and percentages when appropriate. Comparison of numerical variables between the study groups was carried out using the Mann–Whitney U-test for independent samples. For comparison of categorical data, the χ2-test was performed. The exact test was used when the expected frequency was less than 5. P values less than 0.05 were considered statistically significant. All statistical calculations were carried out using computer programs statistical package for the social science (SPSS Inc., Chicago, Illinois, USA) version 15 for Microsoft Windows.
Table 1 shows the demographic data of the patients and the weight of the newborns.
Maternal heart changes in each group
Maternal heart rate changes were recorded every 2 min in each group as shown in Fig. 1.
There were differences in basal values of the maternal heart rate in group 1, group 2, group 3 and group 4, but these differences were not significant (P=0.675). Figure 1 also shows that the heart rate increased with ephedrine and decreased with phenylephrine, but bradycardia did not occur and there was no need for atropine injection.
Changes in maternal systolic blood pressure in each group
Changes in SBP occurred with the induction of spinal anaesthesia; hypotension developed in the four groups, as shown in Fig. 2.
Changes in the basal values of SBP in all the four groups were nonsignificant (P=0.340). Continuous monitoring of SBP every 2 min was performed in each of the four groups.
At 2 min, there were differences in SBP and these differences were not significant (P=0.514).
With continuous monitoring of SBP in each group, hypotension remained in each group and was managed according to each group with ephedrine or phenylephrine (bolus or infusion) or increasing fluid flow of crystalloid, and SBP was measured in each group every 2 min, showing no statistically significant differences (P=0.689).
By the end of the 20-min observation period, there were differences in SBP, but these differences remained insignificant (P=0.666).
Doppler measurements from the same uterine artery were performed at 2-min intervals during the first 10 min after an intrathecal injection of bupivacaine; the PI was recorded and statistical analysis of the results was carried out.
As shown in Fig. 3, there were no statistically significant differences in PI in the four groups during the first 10 min after the initiation of spinal anaesthesia (differences in PI in the first 2 min showed a P value of 0.768; at 4 min, the P value was 0.713; at 6 min, the P value was 0.964 and at 8 min, the P value was 0.871. The P value showed no significant differences in PI throughout the 8-min observation period).
Neonatal arterial blood pH
Neonatal arterial blood gases (from double-clamped umbilical arteries) were obtained. In group 1, pH changes were 7.22–7.30; in group 2, pH changes were 7.22–7.32; in group 3, pH changes were 7.22–7.32 and in group 4, pH changes were 7.21–7.30; these differences were not significant. The P value was 0.899 as shown in Fig. 4.
Apgar scores at 1 and 5 min were recorded and analysed as follows: at 1 min, the Apgar score range in group 1 was 7–8 (mean=7.6); in group 2, the Apgar score range was 7–8 (mean=7.6); in group 3, the Apgar score range was 7–8 (mean=7.6) and in group 4, the Apgar score range was 7–8 (mean=7.47). These differences were not significant (P=0.856) as shown in Fig. 5.
The changes in the Apgar score at 5 min in group 1 were 9–10 (mean=9.6); in group 2, the Apgar score range was 9–10 (mean=9.47); in group 3, the Apgar score range was 9–10 (mean=9.47) and in group 4, the Apgar score range was 9–10 (mean=9.33). These differences were not significant (P=0.561) as shown in Fig. 6.
Preeclampsia is a common complication of pregnancy associated with high maternal morbidity and mortality and intrauterine foetal growth restriction. There is extensive evidence that the reduction in uteroplacental blood flow in this syndrome results from the toxic combination of hypoxia, imbalance of angiogenic and antiangiogenic factors, inflammation and deranged immunity 6. Many pre-eclamptic patients require caesarean delivery of their infant 7. Given the potential for significant hypotension after spinal anaesthesia and its effect on already compromised foetus, prevention of hypotension in pre-eclamptic patients is crucial.
Hypotension remains a common clinical problem after induction of spinal anaesthesia during caesarean delivery. Maternal hypotension has been associated with considerable morbidity (maternal nausea and vomiting and foetal/neonatal acidaemia).
Traditionally, ephedrine has been the vasopressor of choice because of the concerns of the potential adverse effects of phenylephrine on uterine blood flow, but several recent studies have shown that phenylephrine has an efficacy similar to that of ephedrine in preventing and treating hypotension and may be associated with a lower incidence of foetal acidosis 8.
Thus, the purpose of our study is to assess the impact of using phenylephrine and ephedrine for the prevention and treatment of maternal hypotension resulting from spinal anaesthesia during caesarean delivery, and also assess its effect on the foetal outcome.
Some studies have reported that pre-eclamptic patients may experience less hypotension after spinal anaesthesia than their healthy counterparts 5.
In a prospective study carried out by Valami et al.9, it was reported that the incidence and severity of hypotension following spinal anaesthesia is less in preeclampsia compared with healthy parturients, and spinal anaesthesia, when administered and monitored properly, is a safe alternative to epidural anaesthesia in pre-eclamptic patients including those with severe preeclampsia 10.
In a study carried out by Valami et al.9, it was reported that development of hypotension and dosage of ephedrine injection in pre-eclamptic patients were less than those in healthy pregnant women during a caesarean section under spinal anaesthesia. As such, spinal anaesthesia is a safe method for caesarean section in pre-eclamptic patients 9.
Antoine et al. and Valami et al. 10 showed that hypotension that occurred in pre-eclamptic patients undergoing caesarian delivery under spinal anaesthesia was less severe than that in normal parturients 10. Pressor agents lead to an increase in blood pressure, usually by vasoconstriction, but also by increasing cardiac output. Vasoconstriction may be the direct action on the smooth muscle of the arterioles or venules, or by stimulation of the adrenergic receptors 11.
In practice, the most commonly used drugs are the sympathomimetic agents, which exert their effects through the adrenergic receptors. These may act directly on the receptor or indirectly by inducing the release of noradrenaline, which then acts on the receptors. Because of their mode of action, the indirectly acting drugs may show tachyphylaxis (decreasing effect with repeated doses) on repeated administration 11.
Phenylephrine is a direct-acting, potent α-1 agonist with no β activity. It, therefore, causes a rapid increase in systemic vascular resistance and blood pressure 12.
Ephedrine is a potent α and β agonist but it also increases cardiac output, thereby acting both directly and also indirectly. Its effects on vascular resistance are less pronounced than the other α agonists but it also increases cardiac output, thereby maintaining blood pressure 3.
Our study is in agreement with that of Lee et al. 3 and Ngan Kee et al.5; no significant differences were found in the efficacy of phenylephrine over ephedrine in the management of hypotension or in clinical outcome.
It is suggested that the phenylephrine infusion rate should be titrated to maintain SBP as close as possible to the parturient’s normal baseline value, avoiding hypertension and bradycardia 13.
Studies carried out by Ngan Kee et al.14 showed that the use of prophylactic phenylephrine infusions is associated with an overall slower heart rate compared with the treatment of hypotension with phenylephrine boluses. Comparison of different phenylephrine infusion rates indicated dose-related reductions in heart rate 15. Our study showed that initially, there was no difference in the effects of phenylephrine infusion or boluses on maternal heart rate but within 20 min, the phenylephrine infusion was associated with a slower heart rate compared with the phenylephrine boluses.
In a study carried out by Saravanan et al.16, a clinical method was established to determine the equivalent minimum vasopressor dose of ephedrine and phenylephrine in the prevention of hypotension after spinal anaesthesia for caesarean delivery. They found that phenylephrine was more potent than ephedrine by a factor of 80 for equivalent maternal blood pressure control 16. Many studies have reported that ephedrine is no longer the ‘gold standard’ for prophylaxis and treatment of hypotension after spinal anaesthesia for caesarean delivery 17.
In the present study, we found that maternal heart rate increased in the ephedrine group and in the group that was preloaded with crystalloids and decreased in both phenylephrine groups, either by a bolus or by an intravenous infusion.
Uterine blood flow is directly dependent on maternal blood pressure and maternal hypotension may have deleterious effects on the foetus. If sustained, it may lead to foetal compromise and possibly death. Milder, less prolonged hypotension may result in foetal/neonatal acidosis 18.
A few studies compared the effects of ephedrine with phenylephrine and other α agonists on uteroplacental circulation using ultrasound measurements. These studies reported on the PI in maternal and foetal vessels, which is calculated as the difference between the peak systolic and end-diastolic flow velocity divided by the average flow velocity 19.
Alahuhta et al. 20 reported that baseline, mean maternal uterine and placental arcuate arteries PI values were increased in patients receiving phenylephrine but not those receiving ephedrine, suggesting an increase in vascular resistance with phenylephrine. However, another study carried out by Thomas et al. 21 showed that there was no difference in the uterine artery PI measured at baseline and 15 min after the initiation of spinal anaesthesia and the hypotension was treated by boluses of ephedrine compared with boluses of phenylephrine.
In contrast to Alahuhta et al.20, and in agreement with Thomas et al.21, our study showed no significant changes in PI in patients receiving phenylephrine and those receiving ephedrine. Our study also showed that there was an inverse relationship between PI and maternal blood pressure.
Similarly, Ngan Kee et al.22 reported no difference in the uterine artery PI in parturients who received a prophylactic ephedrine or metaraminol infusion initiated immediately after induction of spinal anaesthesia.
Pre-eclamptic parturients have been shown to develop relative hypovolaemia throughout their pregnancy compared with normal parturients 23, and rapid volume expansion with crystalloid 24 or colloid solution 25 has therefore resulted in beneficial effects in pre-eclamptic patients as it decreases the systemic vascular resistance and increases the cardiac output.
In agreement with the result of our study, Grunewald et al.24 and Joupilla et al.26 reported no change in uterine artery PI after rapid volume expansion. Hence, volume expansion in pre-eclamptic patients with either a crystalloid or a colloid solution appears to be reasonable to restore central blood volume and to stabilize maternal haemodynamic state, especially before induction of a central neural block.
The good condition of the neonates was a further indication of undisturbed uterine haemodynamic state during the study.
Neonatal assessments were performed in most studies using Apgar scores and umbilical cord blood gases and pH analysis, with the latter commonly being the primary outcome of the study. Although Apgar scoring is used widely in clinical practice, and provides a useful assessment of the condition of the infant in the first minutes after birth, its usefulness as a predictor of neonatal outcome continues to be debated. For instance, low Apgar scores alone are not sufficient evidence of hypoxia that might cause neurological damage 19. A poor correlation has been observed between Apgar scores and umbilical cord pH 27.
However, umbilical cord blood gases and pH provide an indication of the foetal condition immediately before delivery, and might therefore be more useful than Apgar scores when assessing perfusion and the impact of vasopressors on the foetus 28.
Low arterial cord pH may be associated with clinically significant neonatal outcomes 28. Although umbilical artery pH of 7.2 was historically considered the lower limit of normal 29, the use of this threshold value has been challenged. It has been suggested that pH values of 7.02–7.18 represent the lower limit of normal umbilical artery pH 30.
In a study carried out by Cooper et al. 17, it was found that administration of phenylephrine alone by infusion at caesarean delivery was associated with a lower incidence of foetal acidosis and maternal nausea and vomiting than administration of ephedrine alone.
In studies carried out by Ngan Kee et al.14 examination of Apgar scores and foetal acid–base status consistently indicated no difference in Apgar scores, but higher umbilical artery pH with intravenous phenylephrine compared with ephedrine in parturients undergoing elective caesarean delivery.
The higher foetal pH has been attributed to a greater placental transfer of ephedrine compared with phenylephrine (median umbilical vein/maternal artery concentration ratio of 1.13 compared with 0.17) and less early metabolism or redistribution in the foetus of the more lipid-soluble ephedrine. In turn, foetal ephedrine stimulates foetal α adrenergic receptors, therefore increasing metabolic activity, and resulting in higher umbilical artery and vein PCO2, lower foetal pH and increased foetal concentrations of lactate, glucose, epinephrine and norepinephrine 31.
In the present study, there were differences in foetal pH between the ephedrine and the phenylephrine group; foetal pH increased in the phenylephrine group than the ephedrine group, but these differences were not statistically significant and did not affect neonatal outcome and there were no significant differences in Apgar scores between the ephedrine and the phenylephrine group.
Conclusion and recommendations
Both ephedrine and phenylephrine are effective in the management of spinal anaesthesia-induced hypotension. Phenylephrine may be associated with higher umbilical artery pH and base excess compared with ephedrine. However, the difference in pH is small, statistically nonsignificant and unlikely to be clinically relevant in mild pre-eclamptic parturients. More studies on uteroplacental blood flow using PI in pre-eclamptic patients during caesarian delivery and more regimens for phenylephrine in pre-eclamptic patients are recommended to confirm or refute our results.
Conflicts of interest
There are no conflicts of interest.
1. Karinen J, Alahuhta S, Jouppila R, Räsänen J, Jouppila P.Maternal and uteroplacental haemodynamic state in pre-eclamptic patients during spinal anaesthesia
for caesarean section.Br J Anaesth1996;76:616–620.
2. Mandal NG, Surapaneni S.Regional anaesthesia in preeclampsia
: advantages and disadvantages.Drugs2004;64:223–236.
3. Lee A, Ngan Kee WD, Gin T.A quantitative, systematic review of randomized controlled trials of ephedrine
for the management of hypotension during spinal anesthesia for cesarean delivery.Anesth Analg2002;94:920–926.
4. Erkinaro T, Kavasmaa T, Päkkilä M, Acharya G, Mäkikallio K, Alahuhta S, Räsänen J.Ephedrine
for the treatment of maternal hypotension in a chronic sheep model of increased placental vascular resistance.Br J Anaesth2006;96:231–237.
5. Ngan Kee WD, Khaw KS, Ng FF.Prevention of hypotension during spinal anesthesia for cesarean delivery: an effective technique using combination phenylephrine
infusion and crystalloid cohydration.Anesthesiology2005;103:744–750.
6. Eiland E, Nzerue C, Faulkner M.Preeclampsia
7. Amorium MMR, Souza ASR, Katz L, Noronha Weto C.Planned cesarean section versus planned vaginal delivery for severe preeclampsia
.Cochrane Online Librar2011;CD 009430
8. Erkinaro T, Alahuhta S, Räsänen J.Ephedrine
for treatment of maternal hypotension.Br J Anaesth2006;96:804–805.
9. Valami SMH, Jahromi SAH, Shirazi J, Mohammadi N.Comparison of the effects of spinal anesthesia between pre-eclamptic patients and normal pregnant women during cesarean section.Pak J Med Sci2010;26:809–813.
10. Aya AGM, Mangin R, Vialles N, Ferrer J-M, Robert C, Ripart J, De La Coussaye J-E.Patients with severe preeclampsia
experience less hypotension during spinal anesthesia for elective cesarean delivery than healthy parturients: a prospective cohort comparison.Anesth Analg2003;97:867–872.
11. McKinlay J, Lyons G.Obstetric neuraxial anaesthesia: which pressoragents should we be using for caesarean section?Acta Anaesthesiol Scand1988;32:559–565.
12. Lee A, Ngan Kee WD, Gin T.Prophylactic ephedrine
prevents hypotension during spinal anesthesia for cesarean delivery but does not improve neonatal outcome: a quantitative systematic review.Can J Anaesth2002;49:588–599.
13. Ngan Kee WD.Prevention of maternal hypotension after regional anaesthesia for caesarean section.Curr Opin Anaesthesiol2010;23:304–309.
14. Ngan Kee WD, Lee A, Khaw KS, Ng FF, Karmakar MK, Gin T.A randomized double-blinded comparison of phenylephrine
infusion combinations to maintain blood pressure during spinal anesthesia for cesarean delivery: the effects on fetal acid-base status and hemodynamic control.Anesth Analg2008;107:1295–1302.
15. Stewart A, Fernando R, McDonald S, Hignett R, Jones T, Columb M.The dose-dependent effects of phenylephrine
for elective cesarean delivery under spinal anesthesia.Anesth Analg2010;111:1230–1237.
16. Saravanan S, Kocarev M, Wilson RC, Watkins E, Columb MO, Lyons G.Equivalent dose of ephedrine
in the prevention of post-spinal hypotension in caesarean section.Br J Anaesth2006;96:95–99.
17. Cooper DW, Carpenter M, Mowbray P, Desira WR, Ryall DM, Kokri MS.Fetal and maternal effects of phenylephrine
during spinal anesthesia for cesarean delivery.Anesthesiology2002;97:1582–1590.
18. Roberts SW, Leveno KJ, Sidawi JE, Lucas MJ, Kelly MA.Fetal acidemia associated with regional anesthesia for elective cesarean delivery.Obstet Gynecol1995;85:79–83.
19. No author name available.ACOG committee opinion. Use and abuse of the Apgar score. Number 174-July 1996 (replaces No. 49, November 1986). Committee on Obstetric Practice and American Academy of Pediatrics: Committee on Fetus and Newborn. American College of Obstetricians and Gynecologists.Int J Gynaecol Obstet1996;54:303–305.
20. Alahuhta S, Räsänen J, Jouppila P, Jouppila R, Hollmén AI.Ephedrine
for avoiding maternal hypotension due to spinal anaesthesia
for caesarean section. Effects on uteroplacental and fetal haemodynamics.Int J Obstet Anesth1992;1:129–134.
21. Thomas DG, Robson SC, Redfern N, Hughes D, Boys RJ.Randomized trial of bolus phenylephrine
for maintenance of arterial pressure during spinal anaesthesia
for caesarean section.Br J Anaesth1996;76:61–65.
22. Ngan Kee WD, Lau TK, Khaw KS, Lee BB.Comparison of metaraminol and ephedrine
infusions for maintaining arterial pressure during spinal anesthesia for elective cesarean section.Anesthesiology2001;95:307–313.
23. Roberts JM, Cunningham G, Lindhamer MD.Hypertension in pregnancy.Am J Hypertens2008;2:484–494.
24. Grunewald C, Nisell H, Carlstrom K, Kublickas M, Randmaa I, Nylund L.Acute volume expansion m normal pregnancy and preeclampsia
: effects on plasma atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) concentrations and feto-maternal circulation.Acta Obstet Gynecol Scand1994;73:294–299.
25. Belfort M, Uys P, Dommisse J, Davey DA.Haemodynamic changes in gestational proteinuric hypertension: the effects of rapid volume expansion and vasodilator therapy.Br J Obstet Gynaecol1989;96:634–641.
26. Joupilla P, Joupilla R, Barinof T, Koivola A.Placental blood flow during caesarean section performed under subarachnoid blockage.Br J Anaesth1989;56:1379–1383.
27. Sykes GS, Molloy PM, Johnson P, Gu W, Ashworth F, Stirrat GM, Turnbull AC.Do Apgar scores indicate asphyxia?Lancet1982;1:494–496.
28. Malin GL, Morris RK, Khan KS.Strength of association between umbilical cord pH and perinatal and long term outcomes: systematic review and meta-analysis.BMJ (Online)2010;340:1121.
29. Miller JM Jr, Bernard M, Brown HL, St. Pierre JJ, Gabert HA.Umbilical cord blood gases for term healthy newborns.Am J Perinatol1990;7:157–159.
30. Thorp JA, Dildy GA, Yeomans ER, Meyer BA, Parisi VM.Umbilical cord blood gas analysis at delivery.Am J Obstet Gynecol1996;175I517–522.
31. LaPorta RF, Arthur GR, Datta S.Phenylephrine
in treating maternal hypotension due to spinal anaesthesia
for caesarean delivery: effects on neonatal catecholamine concentrations, acid base status and Apgar scores.Acta Anaesthesiol Scand1995;39:901–905.