|Year : 2014 | Volume
| Issue : 2 | Page : 215-220
Ephedrine versus phenylephrine effects on fetal outcome and hemodynamics of pre-eclamptic mothers undergoing cesarean section under spinal anesthesia
Esam E.M. Abdalla, Ola M. Wahba, Mahmoud A. Mohammed, Mohammed G. Almaz
Anesthesia and Intensive Care Department, Assiut University, Assiut, Egypt
|Date of Submission||18-Jun-2013|
|Date of Acceptance||30-Nov-2013|
|Date of Web Publication||31-May-2014|
Esam E.M. Abdalla
Anesthesia and Intensive Care Department, Faculty of Medicine, Assiut University, Assiut 7111
Source of Support: None, Conflict of Interest: None
This randomized double-blind study was started with an objective of comparing two commonly used vasopressors (phenylephrine and ephedrine) as intravenous bolus injection to reduce hypotension in elective cesarean section in mothers with pre-eclampsia and estimating their impact on fetal outcome.
Place of the study
The study was conducted in Woman Health Hospital, Assiut University, Egypt.
Patients and methods
We studied 40 pre-eclamptic patients undergoing elective cesarean section under spinal anesthesia who developed hypotension after subarachnoid block. They were randomly allocated to one of the two groups to receive an intravenous bolus of the following drugs: group P, phenylephrine (75 μg, n = 20) or group E, ephedrine (6 mg, n = 20). Hypotension was defined as a decrease in systolic pressure to more than 25% of baseline values or systolic blood pressure of less than 90 mmHg.
There were significant differences in systolic and diastolic blood pressure and pulse rate for the two studied drugs, which were less affected in the ephedrine group as compared with the phenylephrine group. Neonatal Apgar scores were within normal range in both groups. With respect to arterial and venous blood gases, there was significant difference in base excess and nonsignificant difference in pH and PO 2 between the two groups.
Both vasopressors phenylephrine (75 μg) and ephedrine (6 mg) were given as a bolus dose to pre-eclamptic candidates receiving spinal anesthesia, causing hemodynamic stability to mothers. However, the usage of phenylephrine was safer for fetal outcome than epinephrine in high-risk cesarean sections (pre-eclampsia) under spinal anesthesia.
Keywords: Cesarean section; ephedrine; phenylephrine; pre-eclampsia; spinal anesthesia
|How to cite this article:|
Abdalla EE, Wahba OM, Mohammed MA, Almaz MG. Ephedrine versus phenylephrine effects on fetal outcome and hemodynamics of pre-eclamptic mothers undergoing cesarean section under spinal anesthesia. Ain-Shams J Anaesthesiol 2014;7:215-20
|How to cite this URL:|
Abdalla EE, Wahba OM, Mohammed MA, Almaz MG. Ephedrine versus phenylephrine effects on fetal outcome and hemodynamics of pre-eclamptic mothers undergoing cesarean section under spinal anesthesia. Ain-Shams J Anaesthesiol [serial online] 2014 [cited 2019 Jul 16];7:215-20. Available from: http://www.asja.eg.net/text.asp?2014/7/2/215/133444
| Introduction|| |
Pre-eclampsia, a human-pregnancy-specific disease defined as the occurrence of hypertension and significant proteinuria in a previously healthy woman on or after the 20th week of gestation, occurs in about 2-8% of pregnancies .
Pre-eclampsia/eclampsia, being a complex disease, offers a great challenge for most experienced anesthetist, who has to focus on blood pressure stabilization, optimization of fluid status, and prevention of seizures .
The most common side effect during spinal anesthesia for cesarean delivery is hypotension (80%). This can have detrimental effects on both mother and neonate; these detrimental effects include decreased uteroplacental blood flow, impaired fetal oxygenation with asphyxial stress and fetal acidosis, and maternal symptoms of low cardiac output, such as nausea, vomiting, dizziness, and decreased consciousness ,. To avoid these effects, the lowest possible effective dose of local anesthetic together with adequate hydration should be used .
A number of strategies for preventing hypotension have been investigated, because it decreased maternal and neonatal undesirable effects, which include the use of lateral uterine displacement, intravenous fluid preload, gravity (Trendelenburg or leg rising), compression devices on the legs, and prophylactic usage of vasopressors such as phenylephrine and ephedrine ,. Phenylephrine and ephedrine are the most commonly used and effective drugs among the vasopressors . Intravenous ephedrine given immediately after the induction of spinal anesthesia has been described to manage hypotension during cesarean section ,. Different doses of ephedrine (10-20-30 mg or 0.25 mg/kg) were not effective in eliminating hypotension completely ,,,. Meta-analysis of trials comparing phenylephrine and ephedrine were discussed for management of hypotension during spinal anesthesia for cesarean section and their impact on fetal outcome .
Therefore, we designed a randomized, double-blinded study to determine the efficacy and safety of ephedrine (6 mg) versus phenylephrine (75 μg) on maternal hemodynamics and fetal outcome of pre-eclamptic mothers undergoing cesarean section under spinal anesthesia.
| Patients and methods|| |
This study was an interventional randomized, double-blinded study that was performed in Woman Health Hospital, Assiut University, Egypt. The study was approved by the Ethical Committee of the Faculty of Medicine, Assiut University. Written informed consents were obtained from all patients who were scheduled to undergo elective cesarean section. We discussed our aim of the study and its safety and legality with all patients. This study was conducted during 1 year period from June 2012 to June 2013.
Forty pre-eclamptic full-term parturients undergoing elective cesarean section were included in this study. They were of 20-40 years of age. They had lower limb edema, proteinuria, and blood pressure not less than 140/90. We excluded patients with classic contraindications to spinal block, pre-existing systemic disease (such as cardiovascular, respiratory, or renal diseases), known fetal abnormalities, and patients taking any medications that could influence the hemodynamic response.
Patients were randomized into two equal groups (ephedrine and phenylephrine) using computer-generated random numbers, which were contained in a sealed envelope. All patients in the two groups received unlabeled syringes at induction time. The ephedrine group (group E) patients received 6 mg ephedrine as an intravenous bolus when there was 25% or more decrease in the maternal blood pressure from baseline or systolic blood pressure of less than 90 mmHg . The phenylephrine group (group P) patients received 75 μg phenylephrine as an intravenous bolus when there was 25% or more decrease in the maternal blood pressure from baseline or systolic blood pressure of less than 90 mmHg . Atropine was given if the heart rate was 60 beats/min or less.
All operations were carried out by one team of obstetric surgeons and anesthetists; premedication and anesthesia were standardized in all patients.
Each patient received 10 ml/kg of Ringer's lactate solution, which was infused rapidly as preload. The patients were connected to noninvasive sphygmomanometer, pulse oximetry, and five-lead ECG. An 18-G cannula was introduced in a peripheral vein for fluid preload. With careful antiseptic preparation and patients in the sitting position, subarachnoid block was performed by 25-G spinal needle with 2 ml of hyperbaric bupivacaine 0.5% and 0.5 mg morphine through a lumbar puncture at L4-L5 interspaces for both groups. The patient was turned to supine position and after 5 min wedge was placed under the right flank. Oxygen was administered at a rate of 3 l/min by a face mask to all patients until the umbilical cord was clamped. Injection of ergometrine (0.25 mg slow intravenously) and injection of oxytocin (10 U in 5% dextrose) were given after clamping the cord.
Assessment of the patients
Patients' routine data were recorded, such as age, weight, height, kidney functions, liver functions, and presence of lower limb edema. After preloading, change in maternal blood pressure was recorded before spinal block and every 3-min interval after it until delivery of the baby. Heart rate was also recorded before and every 3-min interval after spinal block. Fetal blood gases were obtained from both umbilical artery and umbilical vein for determination of pH, PO 2 , PCO 2 , base excess, and SaO 2 %.
Whenever hypotension (decrease in systolic pressure >25% from the baseline value or systolic blood pressure <90 mmHg) occurred, the studied drug was given as intravenous bolus injection. A second dose of ephedrine or phenylephrine was given to the mother whenever another attack of hypotension occurred during the time of the study.
The highest level of sensory block was assessed by pinprick method 5 min after the subarachnoid block. The induction delivery and incision delivery interval were recorded. Pediatricians assessed the Apgar score for every neonate at 1 and 5 min after delivery.
Study sample size was calculated according to the following formula:
where n is the required sample size, t the confidence level at 95% (standard value of 1.96), P the percentage picking a choice, and m the margin of error at 5% (standard value of 0.05).
Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS 16.0 software; SPSS Inc., Chicago, Illinois, USA). Data were collected and tabulated in excel files. Then, comparison between the groups was performed using the Mann-Whitney U-test for comparison of patients between the two groups. For comparison within the same group, two related samples tests (Wilcoxon tests) were performed. Data are presented as mean±SD as frequency distributions, median (IQR), and sample percentage according to need. A statistical significance was regarded to any difference when P-value was less than 0.05.
| Results|| |
All patients completed the study, 20 in each group. There were no significant differences between the two groups with respect to age, sex, weight, height, BMI, and Apgar scores of babies of the two groups. The clinical and laboratory data of both groups showed nonsignificant difference [Table 1].
|Table 1: Patients' demographics, clinical characteristics, and relevant data|
Click here to view
The vasopressors (epinephrine or phenylephrine) were given to all patients in the two groups as hypotension occurred.
The systolic and diastolic blood pressure decreased significantly (P < 0.001) at the onset of hypotension and increased after bolus dose of studied drug in both groups. On intergroup comparison, the increase in systolic blood pressure at 6, 9, 12, 15, and 18 min for the two studied drugs was less in the ephedrine group compared with the phenylephrine group. No significant differences were observed between changes in diastolic blood pressure in the ephedrine and phenylephrine groups after 3, 6, 9, and 12 min (P > 0.05). However, there were significant differences in diastolic blood pressure on intergroup comparison at 6, 9, and 12 min [Table 2].
|Table 2: Maternal changes in blood pressure (systolic and diastolic) monitoring in both groups|
Click here to view
[Table 3] shows maternal heart rate monitoring in both groups; there was significant difference after 6, 9, 12, and 18 min on intergroup comparison and between two groups (P < 0.000). At 6 min (after injection of phenylephrine), there was significant reduction in the pulse rate when compared with basal reading in the phenylephrine group.
Umbilical cord blood gases (fetal acid-base status): In arterial and venous blood gases, there was significant difference with respect to base excess and nonsignificant difference with respect to pH and PO 2 between the two groups. However, there was a significant difference in PCO 2 (venous sample) and SaO 2 (arterial) between the two groups [Table 4].
| Discussion|| |
Regional anesthesia, in particular spinal anesthesia, has become the first choice for operative delivery in elective cesarean section, largely because of the recognition of the dangers of failed intubation, which occurs approximately eight times more frequently in the obstetric population than in the general surgical population .
After subarachnoid block for cesarean section, hypotension can be minimized by the use of intravenous fluid preload, avoidance of aortocaval compression, and judicious use of vasopressor agent. It has been shown that the percentage decrease in placental perfusion is related to the percentage reduction in maternal arterial pressure and not to the absolute reduction in pressure . The current study addressed the issue of neonatal outcome and compared hemodynamic data of mothers in the two groups. For the purpose of this study, hypotension was defined as a decrease in systolic blood pressure to more than 25% from baseline systolic blood pressure or alternative definition of systolic blood pressure of less than 90 mmHg .
In this study, we found that there was no difference between ephedrine and phenylephrine in their efficacy for managing hypotension in the range of doses that have been studied. This is in agreement with the study by Thomas et al.  who reported that bolus phenylephrine 100 μg is as effective as ephedrine 5 mg in restoring maternal arterial pressure above 100 mmHg. In addition, Moran et al.  gave ephedrine 10 mg or phenylephrine 80 μg as intravenous bolus to maintain systolic arterial pressure above 100 mmHg. They concluded that phenylephrine is as effective as ephedrine and when used in small incremental bolus injections it appears to have no adverse neonatal effects.
Of concern was that maternal bradycardia occurred more frequently with phenylephrine than with ephedrine . In our study, phenylephrine caused reduction in heart rate after the bolus dose, which is in agreement with other studies, reporting the same results in phenylephrine-treated women ,,,. This is to be expected because an increase in blood pressure with an α-agonist may lead to reactive bradycardia. However, this was responsive to atropine treatment without adverse consequences . In addition, ephedrine has mixed α-adrenoreceptor and β-adrenoreceptor activity; it maintains arterial pressure mainly by increases in cardiac output and heart rate as a result of its predominant activity on β1-adrenoreceptors . However, phenylephrine is an α1-adrenergic agonist and lacks action on β1-adrenoreceptors, whose action would be expected to counteract the decrease in systemic vascular resistance induced by spinal anesthesia .
After delivery, the most common method used to detect neonatal condition is the first- and fifth-minute Apgar scores and the most accurate and predictive measurement is neonatal umbilical arterial acid-base values. The primary outcome measures are the mean neonatal umbilical arterial and venous base deficit, and this is a more specific index of the metabolic component of acid-base balance ,,.
In this study, there were no significant differences in the Apgar scores at 1 and 5 min between the two groups. In our study on high-risk cesarean sections, the main reason that we did not find a significant difference in umbilical artery or venous pH between ephedrine and phenylephrine was probably that the majority of the ephedrine group received a relatively low dose of ephedrine (6 mg), thereby reducing its fetal metabolic effects. This is in agreement with the study by Cooper et al.  who compared the effect of ephedrine and phenylephrine on high-risk cesarean section, and they found that umbilical artery and venous pH were similar whether ephedrine or phenylephrine was used to maintain maternal arterial pressure. In addition, Cooper et al.  reported that infusion of phenylephrine at cesarean delivery was associated with low incidence of fetal acidosis.
Pre-eclampsia and labor may have contributed to the lack of difference between the vasopressor groups in this high-risk study by reducing hypotension, and therefore vasopressor requirements. Both of these variables have been associated with reduced hypotension during spinal anesthesia ,. The urgent nature of the surgery for many of the high-risk patients may also have reduced the difference between the groups by reducing the spinal-delivery interval, and therefore the total dose of ephedrine given before delivery and the duration of fetal exposure.
We observed umbilical venous PO 2 to be greater with ephedrine than with phenylephrine and significant differences (P < 0.05) in SaO 2 (arterial) and PCO 2 (venous) among ephedrine and phenylephrine groups, but we cannot draw any conclusion from these observations because the differences were small, within normal range, and we did not have an accurate record of maternal oxygen administration, which can affect these variables.
This is in agreement with the study by Cooper et al.  and others ,; they found that prophylactic ephedrine had a detrimental effect on fetal acid-base when used during cesarean section to avoid spinal hypotension ,,. In addition, the usage of ephedrine to prevent or treat hypotension associated with spinal and epidural anesthesia for cesarean delivery may not correct fetal acidosis and may even increase it, especially if hypotension still occurs . This could be attributed to β-adrenoreceptor activity of ephedrine .
| Conclusion|| |
The clinical implications of our findings are arguable. Although we have shown that ephedrine was associated with nonsignificant lower umbilical cord blood pH values when compared with phenylephrine, both drugs had similar efficacy for preventing or treating hypotension. There was no difference in clinical neonatal outcome as measured by the Apgar scores. Hence, the usage of phenylephrine was safer for fetal outcome than ephedrine in high-risk cesarean sections (pre-eclampsia) under spinal anesthesia.
| Acknowledgements|| |
Conflicts of interest
| References|| |
|1.||Smith GC, Fretts RC. Stillbirth. Lancet 2007; 370:1715-1725. |
|2.|| Rout CC, Rocke DA. Prevention of hypotension following spinal anesthesia for cesarean section. Int Anesthesiol Clin 1994; 32:117-135. |
|3.|| Rout CC, Rocke DA, Levin J, Gouws E, Reddy D. A reevaluation of the role of crystalloid preload in the prevention of hypotension associated with spinal anesthesia for elective cesarean section. Anesthesiology 1993; 79:262-269. |
|4.|| Wilkening RB, Meschia G. Current topic: comparative physiology of placental oxygen transport. Placenta 1992; 13:1-15. |
|5.|| Park GE, Hauch MA, Curlin F, Datta S, Bader AM. The effects of varying volumes of crystalloid administration before cesarean delivery on maternal hemodynamics and colloid osmotic pressure. Anesth Analg 1996; 83:299-303. |
|6.|| Clark SL, Cotton DB, Pivarnik JM, Lee W, Hankins GD, Benedetti TJ, et al. Position change and central hemodynamic profile during normal third-trimester pregnancy and post partum. Am J Obstet Gynecol 1991; 164:883-887. |
|7.|| Kol IO, Kaygusuz K, Gursoy S, Cetin A, Kahramanoglu Z, Ozkan F, et al. The effects of intravenous ephedrine during spinal anesthesia for cesarean delivery: a randomized controlled trial. J Korean Med Sci 2009; 24:883-888. |
|8.|| Chan WS, Irwin MG, Tong WN, Lam YH. Prevention of hypotension during spinal anaesthesia for caesarean section: ephedrine infusion versus fluid preload. Anaesthesia 1997; 52:908-913. |
|9.|| King SW, Rosen MA. Prophylactic ephedrine and hypotension associated with spinal anesthesia for cesarean delivery. Int J Obstet Anesth 1998; 7:18-22. |
|10.|| 1 Lee A, Ngan Kee WD, Gin T. A quantitative, systematic review of randomized controlled trials of ephedrine versus phenylephrine for the management of hypotension during spinal anesthesia for cesarean delivery. Anesth Analg 2002; 94:920-926. |
|11.|| 1 Lee A, Ngan Kee WD, Gin T. A dose-response meta-analysis of prophylactic intravenous ephedrine for the prevention of hypotension during spinal anesthesia for elective cesarean delivery. Anesth Analg 2004; 98:483-490. |
|12.|| 1 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 Anaesth 2002; 49:588-599. |
|13.|| 1 Hawthorne L, Wilson R, Lyons G, Dresner M. Failed intubation revisited: 17-yr experience in a teaching maternity unit. Br J Anaesth 1996; 76:680-684. |
|14.|| 1 Corke BC, Datta S, Ostheimer GW, Weiss JB, Alper MH. Spinal anaesthesia for Caesarean section. The influence of hypotension on neonatal outcome. Anaesthesia 1982; 37:658-662. |
|15.|| 1 Thomas DG, Robson SC, Redfern N, Hughes D, Boys RJ. Randomized trial of bolus phenylephrine or ephedrine for maintenance of arterial pressure during spinal anaesthesia for Caesarean section. Br J Anaesth 1996; 76:61-65. |
|16.|| 1 Moran DH, Perillo M, LaPorta RF, Bader AM, Datta S. Phenylephrine in the prevention of hypotension following spinal anesthesia for cesarean delivery. J Clin Anesth 1991; 3:301-305. |
|17.|| 1 Hall PA, Bennett A, Wilkes MP, Lewis M. Spinal anaesthesia for caesarean section: comparison of infusions of phenylephrine and ephedrine. Br J Anaesth 1994; 73:471-474. |
|18.|| 1 Critchley LA, Stuart JC, Conway F, Short TG. Hypotension during subarachnoid anaesthesia: haemodynamic effects of ephedrine. Br J Anaesth 1995; 74:373-378. |
|19.|| 1 Helbo-Hansen HS, Bang U, Lindholm P, Klitgaard NA. Neonatal effects of adding epidural fentanyl to 0.5% bupivacaine for caesarean section. Int J Obstet Anesth 1993; 2:27-33. |
|20.|| 2 Dyer RA, Els I, Farbas J, Torr GJ, Schoeman LK, James MF. Prospective, randomized trial comparing general with spinal anesthesia for cesarean delivery in preeclamptic patients with a nonreassuring fetal heart trace. Anesthesiology 2003; 99:561-569. |
|21.|| 2 Okafor UV, Okezie O. Maternal and fetal outcome of anaesthesia for caesarean delivery in preeclampsia/eclampsia in Enugu, Nigeria: a retrospective observational study. Int J Obstet Anesth 2005; 14:108-113. |
|22.|| 2 Cooper DW, Sharma S, Orakkan P, Gurung S. Retrospective study of association between choice of vasopressor given during spinal anaesthesia for high-risk caesarean delivery and fetal pH. Int J Obstet Anesth 2010; 19:44-49. |
|23.|| 2 Cooper DW, Carpenter M, Mowbray P, Desira WR, Ryall DM, Kokri MS. Fetal and maternal effects of phenylephrine and ephedrine during spinal anesthesia for cesarean delivery. Anesthesiology 2002; 97:1582-1590. |
|24.|| 2 James KS, McGrady E, Patrick A. Combined spinal-extradural anaesthesia for preterm and term caesarean section: is there a difference in local anaesthetic requirements? Br J Anaesth 1997; 78:498-501. |
|25.|| 2 Ayorinde BT, Buczkowski P, Brown J, Shah J, Buggy DJ. Evaluation of pre-emptive intramuscular phenylephrine and ephedrine for reduction of spinal anaesthesia-induced hypotension during Caesarean section. Br J Anaesth 2001; 86:372-376. |
|26.|| 2 Cooper DW, Gibb SC, Meek T, Owen S, Kokri MS, Malik AT, et al. Effect of intravenous vasopressor on spread of spinal anaesthesia and fetal acid-base equilibrium. Br J Anaesth 2007; 98:649-656. |
|27.||2 Shalev Y, Gal R, Tchou PJ, Anderson AJ, Avitall B, Akhtar M, et al. Echocardiographic demonstration of decreased left ventricular dimensions and vigorous myocardial contraction during syncope induced by head-up tilt. J Am Coll Cardiol 1991; 18:746-751. |
[Table 1], [Table 2], [Table 3], [Table 4]