Original Article. Summary. Introduction. M. Mohta, 1 S. Duggal 2 and G. T. Chilkoti 3

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1 Original Article doi: /anae Randomised double-blind comparison of bolus phenylephrine or ephedrine for treatment of hypotension in women with preeclampsia undergoing caesarean section* M. Mohta, 1 S. Duggal 2 and G. T. Chilkoti 3 1 Professor, 2 Senior Resident, 3 Associate Professor, Department of Anaesthesiology and Critical Care, University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi, India Summary Treatment of post-spinal hypotension during caesarean section assumes special concern in pre-eclamptic patients due to a compromised fetoplacental circulation and increased risk of placental hypoperfusion. Phenylephrine and ephedrine are the most commonly used vasopressors, although the best choice is still not clear. We studied 80 preeclamptic women with a singleton pregnancy who underwent caesarean section with spinal anaesthesia, and who developed hypotension defined as a decrease in systolic arterial pressure 20% from baseline or absolute value < 100 mmhg. Women were randomly allocated to receive phenylephrine 50 lg or ephedrine 4 mg boluses for treatment of hypotension. Blood pressure changes following vasopressor administration were similar in both groups, but heart rate remained higher after ephedrine at all time-points. The primary outcome measure of umbilical artery ph was 7.26 (0.11) in the phenylephrine group and 7.25 (0.09) in the ephedrine group (p = 0.86). The incidence of neonatal acidosis (umbilical artery ph < 7.20) was 9 (22.5%) in the phenylephrine group and 11 (27.5%) in the ephedrine group (p = 0.80). Other secondary outcome measures were comparable. In conclusion, phenylephrine 50 lg and ephedrine 4 mg, administered as intravenous boluses to treat post-spinal hypotension during caesarean section in pre-eclamptic patients, resulted in similar fetal acid-base values, were equally effective in treating hypotension and were associated with good maternal and neonatal outcome.... Correspondence to: M. Mohta medhamohta@gmail.com Accepted: 2 February 2018 Keywords: caesarean section: morbidity; ephedrine; phenylephrine; pre-eclampsia; spinal hypotension: treatment *Presented in part at the Annual National Conference of the Indian Society of Anaesthesiologists, Ludhiana, India, November 2016 Introduction Pre-eclampsia is a common disorder of pregnancy, characterised by abnormal maternal-placental angiogenesis leading to increased vasomotor responsiveness and persistent placental hypoperfusion [1]. Spinal anaesthesia has, in the past, been considered unsafe for pre-eclamptic patients undergoing caesarean section due to the risk of severe hypotension and uteroplacental hypoperfusion; however, more recent studies have demonstrated that spinal anaesthesia is a safe technique as post-spinal hypotension is less common, less severe and easier to treat in women with pre-eclampsia 2018 The Association of Anaesthetists of Great Britain and Ireland 839

2 Mohta et al. Phenylephrine vs. ephedrine in women with pre-eclampsia compared with healthy women [2, 3]. However, effective treatment of post-spinal hypotension is important, as hypotension may prove deleterious in these patients who already have a compromised fetoplacental circulation. Ephedrine was traditionally preferred as the firstline vasopressor in women with uncomplicated pregnancies at caesarean section due to its favourable effects on the uteroplacental circulation [4], whereas phenylephrine, an a-agonist, was believed to cause uterine vasoconstriction. However, an increased risk of fetal acidosis from ephedrine, and the proven safety of a-agonists in humans, has led to the emergence of phenylephrine as the treatment of choice for postspinal hypotension in healthy, low-risk parturients with normal baseline blood pressure [5 8]. The best vasopressor in pre-eclamptic patients is still not clear. Until recently, there was little evidence in this field, with the few animal and human trials providing inconclusive results [2, 3, 9 12], although further studies have just been published [13, 14]. We conducted the present study to compare the effect of phenylephrine and ephedrine, used for treatment of hypotension in pre-eclamptic patients undergoing caesarean section under spinal anaesthesia, on umbilical artery ph. Methods We performed this randomised, double-blind study at our University teaching hospital after approval from the Institutional Ethics Committee for Human Research. The study was carried out between January 2015 and February We obtained written informed consent from women with pre-eclampsia who had a singleton pregnancy and were going to have a caesarean section under spinal anaesthesia. Pre-eclampsia was diagnosed if the blood pressure was 140/90 mmhg on two or more occasions at least 4 h apart, and proteinuria 300 mg in 24 h or 1 + on a dipstick test [15]. Women were not included if they had chronic hypertension or other cardiovascular disease, cerebrovascular disease, known fetal abnormality or severe fetal distress. Severe pre-eclampsia was diagnosed if blood pressure was 160/110 mmhg on two or more occasions at least 4 h apart, or there was thrombocytopaenia (platelet count < l 1 ); pulmonary oedema; newonset cerebral or visual disturbances; impaired liver function; or a serum creatinine concentration > 1.1 mg.dl 1 or more than twice the baseline serum creatinine concentration [15]. We used a parallel design with a 1:1 allocation ratio. Slips with the name of the study drug were sealed and kept in a container. At the time of randomisation, one of these slips was selected by an investigator who was not otherwise involved in the study, who prepared the study drug accordingly. A volume of 7 ml of the study drug was prepared in a 10-ml syringe. For the phenylephrine group, an ampoule containing 10 mg was diluted to the final concentration of 50 lg.ml 1, and the required volume drawn up into the syringe. To prepare ephedrine 4 mg.ml 1, one ampoule containing 30 mg in 1 ml volume was diluted to a total volume of 7.5 ml, and then 0.5 ml was discarded. Both the patient and the anaesthetist were blinded to the group allocation. In case of failure to achieve adequate spinal block, or in the event that the patient did not develop post-spinal hypotension, the study drug was discarded and this patient was excluded. A similarly labelled slip was returned to the container. In the operating room, standard monitoring of ECG, heart rate, non-invasive blood pressure and pulse oximetry was applied. Baseline systolic and diastolic arterial pressure and heart rate were taken as the average of three consecutive readings. Spinal anaesthesia was performed in the sitting position with a 25-G spinal needle using a midline approach at L3 4, or L2 3 in case of failure at L3 4. Hyperbaric bupivacaine 0.5% was used, in a volume of 2.2 ml if the patient s height was 150 cm, or 2.0 ml if she was < 150 cm. The patient was then immediately turned supine, and a wedge was placed under the right buttock. Intravenous (i.v.) coload with 10 ml.kg 1 Ringer lactate solution was administered, and the patient received 40% oxygen by facemask. A minimum sensory block level of T6 to pain was ensured using a sterile 26-G needle. Systolic and diastolic arterial pressures and heart rate were measured every minute from the spinal injection until delivery of the baby. Hypotension after spinal anaesthesia was defined as a decrease in systolic arterial pressure < 80% baseline, or an absolute value < 100 mmhg. Whenever this was recorded, a bolus of The Association of Anaesthetists of Great Britain and Ireland

3 Mohta et al. Phenylephrine vs. ephedrine in women with pre-eclampsia 1 ml of the study drug was given. If 4 ml of the study drug had been used with the delivery of the baby not expected during next 3 min, the investigator was requested to prepare a further syringe. Intravenous glycopyrronium 0.2 mg was administered for bradycardia (heart rate < 50 beats.min 1 ) associated with hypotension, or for heart rate < 45 beats.min 1 irrespective of the systolic arterial pressure value. The study period continued until delivery of the baby. Umbilical artery and vein blood samples were collected from a cord segment double-clamped before the baby s first breath, and blood gas analysis was performed immediately. Apgar scores were recorded at 1 and 5 min after delivery. Our primary outcome measure was umbilical artery ph. The secondary outcome measures included: Apgar scores at 1 and 5 min; incidence of fetal acidosis, defined as umbilical artery ph < 7.20; number of vasopressor boluses given; number of episodes of hypotension (from the first hypotensive systolic arterial pressure reading until restoration above the defined threshold); incidence of tachycardia (heart rate > 130 beats.min 1 ), bradycardia, arrhythmia and hypertension (systolic arterial pressure > 120% baseline). Considering a SD of 0.03 for umbilical artery ph in women with pre-eclampsia undergoing caesarean section under spinal anaesthesia [3], we calculated that a sample size of 22 patients in each group was required to detect a difference of 0.03 units in umbilical artery ph, with a power of 90% at a 5% significance level. However, an initial pilot study revealed an SD of 0.04 for umbilical artery ph in our pre-eclamptic population. A recalculation of sample size based on this SD required 39 patients per group, hence we decided to study 40 patients in each group. Statistical analysis was performed using SPSS Version 20.0 (SPSS Inc., Chicago, IL, USA). Analysis with unpaired t-test, Pearson s Chi-squared, Fisher s exact test or Mann Whitney U-test were used as appropriate. Since the interval till delivery varied, intergroup trends of systolic and diastolic arterial pressure and heart rate for 12 min following vasopressor administration were analysed using mixed-model analysis, taking the best covariance structure based on Akaike s information criterion (AIC) instead of repeated measures ANOVA, with smaller values of AIC representing a better model. In the mixed model, group and time (in minutes) of equal intervals from 0 to 12 min were included, and the interaction between group and time was studied. A value of p < 0.05 was considered statistically significant. Results A total of 201 patients were assessed for eligibility, and 150 were randomly allocated to the two groups (Fig. 1). The characteristics of the patients in the groups were similar (Table 1). Thirty-four patients in the phenylephrine group, and 29 in the ephedrine group, were receiving antihypertensive treatment with oral and/or i.v. labetalol. Seventeen women in the phenylephrine group had severe preeclampsia vs. 15 in the ephedrine group (p = 0.82), of whom 10 and 9 patients, respectively, received seizure prophylaxis with magnesium sulphate. Baseline systolic and diastolic arterial pressures were comparable. Baseline heart rate was higher in the ephedrine group than in the phenylephrine group (Table 2). The median number of hypotensive episodes, vasopressor boluses to treat the first hypotensive episode and the total number of boluses given throughout the study period were similar between groups (Table 2). Systolic arterial pressure values after the first vasopressor administration remained similar between the two groups (p = 0.053; Fig. 2). Heart rate values were significantly higher in the ephedrine group than the phenylephrine group at all time-points (p < ; Fig. 3). No patients had tachycardia, bradycardia or arrhythmias. One patient in the phenylephrine group had an episode of hypertension after administration of three boluses. Umbilical artery and vein po 2 could not be determined in one patient in each group. Fetal acid-base status, and neonatal Apgar scores at 1 and 5 min, were similar between the two groups (Table 3). The incidence of neonatal acidosis, defined as umbilical artery ph < 7.20, was 9 (22.5%) in the phenylephrine group and 11 (27.5%) in the ephedrine group (p = 0.80). Two neonates in the phenylephrine group had 1- min Apgar score < 7 as well as fetal acidosis (umbilical artery ph 7.08 and 6.75). The mothers of these neonates had severe pre-eclampsia. One had meconium The Association of Anaesthetists of Great Britain and Ireland 841

4 Mohta et al. Phenylephrine vs. ephedrine in women with pre-eclampsia Enrollment Assessed for eligibility (n = 201) Excluded (n = 51) Not meeting inclusion criteria (n = 17) Declined to participate (n = 4) Received general anaesthesia (n = 30) Randomised (n = 150) Allocation Allocated to phenylephrine group (n = 78) Received allocated intervention (n = 40) Did not develop post-spinal hypotension (n = 33) Failed spinal (n = 5) Allocated to ephedrine group (n = 72) Received allocated intervention (n = 40) Did not develop post-spinal hypotension (n = 29) Failed spinal (n = 3) Follow up Completed study protocol (n = 40) Completed study protocol (n = 40) Analysis Analysed (n = 40) Analysed with incomplete data (n = 1) Umbilical artery PaO 2 not assessed (n = 1) Umbilical venous PaO 2 not assessed (n = 1) Analysed (n = 40) Analysed with incomplete data (n = 1) Umbilical artery PaO 2 not assessed (n = 1) Umbilical venous PaO 2 not assessed (n = 1) Figure 1 CONSORT flow diagram. stained amniotic fluid, and the other had fetal growth retardation with oligohydramnios. All other neonates had 1-min and 5-min Apgar scores of 7. The mean (SD) neonatal weight was 2.41 (0.33) kg and 2.58 (0.36) kg in the phenylephrine and ephedrine groups, respectively (p = 0.031). The incidence of nausea, vomiting and dizziness was comparable between the two groups (p = 0.51, 1.0 and 1.0, respectively). Four patients developed nausea in the phenylephrine group, one of whom vomited, and one developed dizziness. In the ephedrine group, seven patients developed nausea, but none had any episode of vomiting or dizziness. Nausea and vomiting were observed primarily during hypotensive episodes, and resolved with the treatment of hypotension. Discussion We did not find any difference in our primary outcome measure of umbilical artery ph when comparing Table 1 Physical characteristics of 80 patients receiving phenylephrine or ephedrine for treatment of postspinal hypotension. Values are mean (SD) or median (IQR [range]). Phenylephrine Ephedrine n = 40 n = 40 Age; years 26.1 (4.4) 26.1 (4.8) Weight; kg 61.5 (5.8) 61.6 (4.3) Height; cm (4.7) (4.5) Gestation; 38 (36 40 [24 41]) 37 (36 38 [32 42]) weeks Parity 1 (0 1 [0 6]) 0 (0 1 [0 3]) Spinal 13.3 (3.2) 13.7 (3.2) delivery interval; min Uterine incision delivery interval; s 65.1 (20.5) 69.7 (23.3) phenylephrine and ephedrine. We also did not find any statistically significant between-group differences in our secondary outcome measures The Association of Anaesthetists of Great Britain and Ireland

5 Mohta et al. Phenylephrine vs. ephedrine in women with pre-eclampsia Phenylephrine is considered the vasopressor of choice in normotensive low-risk pregnancies as there is higher umbilical artery ph [16, 17] and reduced maternal nausea and vomiting [6, 18] when compared with ephedrine. Prophylactic administration by infusion has improved the overall quality of perioperative management of obstetric patients [19]. However, the choice of vasopressor remains controversial in the presence of acute or chronic uteroplacental insufficiency. Erkinaro et al. compared the effects of ephedrine and phenylephrine for treatment of maternal hypotension in a sheep model with Table 2 Haemodynamic variables in patients receiving phenylephrine or ephedrine for treatment of post-spinal hypotension. Values are mean (SD) or median (IQR [range]). Phenylephrine Ephedrine n = 40 n = 40 p value Baseline heart rate; beats.min (7.8) 89.1 (9.1) Baseline systolic arterial pressure; mmhg (11.2) (11.2) 0.96 Baseline diastolic arterial pressure; mmhg 90.2 (16.2) 92.7 (6.4) 0.37 Number of hypotensive episodes 1.5 (1 2 [1 5]) 2 (1 2 [1 4]) 0.49 Number of vasopressor boluses to treat first hypotensive episode 1 (1 2 [1 8]) 1 (1 2 [1 9]) 0.84 Total number of vasopressor boluses used 2 (1 3 [1 8]) 2 (2 3 [1 14]) 0.57 mmhg Time (min) Figure 2 Systolic arterial pressure changes after administration of phenylephrine (circles) or ephedrine (squares). Error bars are SD. Beats.min 1 Time (min) Figure 3 Heart rate changes after administration of phenylephrine (circles) or ephedrine (squares). Error bars are SD The Association of Anaesthetists of Great Britain and Ireland 843

6 Mohta et al. Phenylephrine vs. ephedrine in women with pre-eclampsia Table 3 Neonatal outcome data. Values are mean (SD) or median (IQR [range]). Phenylephrine Ephedrine n = 40 n = 40 p value Umbilical artery ph 7.26 (0.11) 7.25 (0.09) 0.86 PO 2 ; mmhg* 18.1 (5.9) 19.1 (14.2) 0.71 PCO 2 ; mmhg 47.9 (13.6) 48.9 (11.4) 0.70 HCO 3 ; meq.l (8.0) 21.1 (4.8) 0.68 BE; meq.l (9.3) 6.8 (6.1) 0.12 Umbilical vein ph 7.32 (0.08) 7.31 (0.08) 0.50 po 2 ; mmhg* 23.8 (7.2) 23.4 (9.5) 0.84 pco 2 ; mmhg 43.5 (12.4) 42.7 (10.1) 0.74 HCO 3 ; meq.l (4.5) 20.8 (3.5) 0.27 BE; meq.l (5.0) 5.2 (4.5) 0.22 Apgar score at 1 min 9 (8 9 [6 10]) 9 (9 9 [7 10]) 0.56 Apgar score at 5 min 10 ( [8 10]) 10 (9 10 [9 10]) 0.31 *n = 39 in each group. increased placental vascular resistance [9]. Although there was no difference in fetal acid-base values, they demonstrated potential advantages of ephedrine over phenylephrine in terms of effects on the uteroplacental circulation. Most of the initial studies exploring the role of spinal anaesthesia in pre-eclamptic patients used ephedrine to treat hypotension [2, 3, 20, 21]. Aya et al. suggested that small incremental doses of ephedrine should be used in pre-eclamptic patients, and raised concerns about the possibility of hypertensive responses with pressor drugs such as phenylephrine, due to increased sensitivity [3]. Dyer et al. observed that phenylephrine administration restored arterial pressure, but did not increase maternal cardiac output, in women with severe pre-eclampsia [10]. Comparative studies have not supported the hypothesis that phenylephrine is inferior to ephedrine. One non-randomised study showed no difference in neonatal outcomes. Using a conversion ratio of phenylephrine 100 lg: ephedrine 8 mg, the median vasopressor dose requirements were significantly higher in the phenylephrine group than in the ephedrine group; however, the mean gestational age was earlier in the ephedrine group [12]. Abdalla et al. found 75 lg phenylephrine or 6 mg ephedrine to be equally efficacious in treating hypotension, with no significant differences in umbilical artery and vein ph and Apgar scores between groups [11]. However, phenylephrine showed more favourable base excess and umbilical artery oxygen saturation than ephedrine. Recently, a study by Dyer et al. demonstrated that phenylephrine more effectively reversed spinal anaesthesia-induced haemodynamic changes in patients with severe pre-eclampsia than ephedrine, including increases in maternal heart rate [13]. We also found higher heart rate when using ephedrine. Based on these observations, it was suggested that phenylephrine should be considered the vasopressor of first choice in women with early onset severe pre-eclampsia and preserved systolic function [13]. Another study by the same group of workers compared lg phenylephrine and mg ephedrine boluses for treatment of post-spinal hypotension in patients with severe pre-eclampsia and fetal compromise [14]. There were no significant differences in umbilical artery base excess, umbilical arterial and venous ph and lactate concentrations, incidence of fetal acidosis and Apgar scores. We decided to use intermittent boluses of vasopressors to treat hypotension. Even though prophylactic phenylephrine infusion has been recommended for prevention of post-spinal hypotension [8], it may be associated with a higher incidence of reactive hypertension and bradycardia [22]. As patients with preeclampsia have a lower incidence of post-spinal hypotension and vasopressor requirements, a prophylactic infusion may not be required [8]. Furthermore, administration as an infusion requires availability of a syringe infusion pump, which may not be always The Association of Anaesthetists of Great Britain and Ireland

7 Mohta et al. Phenylephrine vs. ephedrine in women with pre-eclampsia feasible, especially in developing countries. A 100 lg bolus of phenylephrine remains the most widely used dose in normotensive parturients. The potency ratio of phenylephrine and ephedrine when used by infusion in normotensive women has been estimated to be approximately 80:1, so that 100 lg phenylephrine is equivalent to 8 mg ephedrine [23]. Due to the increased sensitivity and reduced requirement of exogenous vasopressors in pre-eclamptic women, we decided to use a lower bolus dose of 50 lg phenylephrine, together with the corresponding dose of 4 mg ephedrine. Most studies in obstetric patients have taken a decrease in systolic arterial pressure 20% from baseline systolic arterial pressure as cut-off for treatment with vasopressors [8]. For pre-eclamptic patients, various definitions have been used to define post-spinal hypotension such as a decrease in systolic arterial pressure > 20% [20], 20% [10], > 25% [24] or > 30% [2, 3] from baseline systolic arterial pressure; systolic arterial pressure 120 mmhg [21] and systolic arterial pressure < 100 mmhg [24, 25]. We used a definition of hypotension requiring treatment as a decrease in systolic arterial pressure 20% from baseline, or an absolute value of systolic arterial pressure < 100 mmhg. This schedule did not result in significant hypertension. Only one patient in the phenylephrine group had a single systolic arterial pressure value of 161 mmhg that exceeded the defined value of 158 mmhg for hypertension; this was after administration of three doses of phenylephrine. The magnitude of uteroplacental insufficiency is expected to be greater in severely pre-eclamptic patients as compared with those without severe disease. We performed a sub-group analysis of patients with severe pre-eclampsia, including 17 women who received phenylephrine and 15 who received ephedrine. Both groups were comparable with respect to patient characteristics, haemodynamic variables, vasopressor requirements and neonatal outcomes. These results are not definitive, however, as there is insufficient power to detect a difference based on this number of cases. This study has certain limitations. Our primary outcome measure was umbilical artery ph. It has been suggested that the lactate concentration of human fetal scalp blood is more sensitive than ph in predicting neonatal neurological disability [26], and lactate levels in scalp blood are known to correlate well with neonatal artery and vein cord blood levels [27]. However, due to logistical problems, lactate levels cannot be assessed in our institution. In summary, 50 lg phenylephrine and 4 mg ephedrine, administered as i.v. bolus doses, resulted in similar fetal acid-base status and effectiveness in treating hypotension in pre-eclamptic patients undergoing caesarean section. Acknowledgements We thank Dr. R. Kumar, Department of Biostatistics and Medical Informatics, University College of Medical Sciences, for his assistance in conducting the statistical analysis. The trial was prospectively registered on 19 December 2014 at Clinical Trials Registry India ( CTRI/2014/12/005317). No external funding or competing interests declared. References 1. Gogarten W. Preeclampsia and anaesthesia. Current Opinion in Anesthesiology 2009; 22: Aya AG, Mangin R, Vialles N, et al. Patients with severe preeclampsia experience less hypotension during spinal anesthesia for elective cesarean delivery than healthy parturients: a prospective cohort comparison. Anesthesia and Analgesia 2003; 97: Aya AG, Vialles N, Tanoubi I, et al. Spinal anesthesia-induced hypotension: a risk comparison between patients with severe preeclampsia and healthy women undergoing preterm cesarean delivery. Anesthesia and Analgesia 2005; 101: Burns SM, Cowan CM, Wilkes RG. Prevention and management of hypotension during spinal anaesthesia for elective caesarean section: a survey of practice. Anaesthesia 2001; 56: 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. Anesthesia and Analgesia 2002; 94: 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: Ngan Kee WD. Prevention of maternal hypotension after regional anaesthesia for caesarean section. Current Opinion in Anesthesiology 2010; 23: Kinsella SM, Carvalho B, Dyer RA, et al. International consensus statement on the management of hypotension with vasopressors during caesarean section under spinal anaesthesia. Anaesthesia 2018; 73: The Association of Anaesthetists of Great Britain and Ireland 845

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