Randomised double-blinded comparison of phenylephrine
vs ephedrine for maintaining blood pressure during spinal
anaesthesia for non-elective Caesarean section Anaesthesia Volume 63 Issue 12, Pages 1319 - 1326 Published Online: 11 Nov 2008 2009 The Association of Anaesthetists of Great Britain and Ireland W. D. Ngan Kee, K. S. Khaw, T. K. Lau, F.F.Ng , K. Chui, K.L.Ng WHY THIS STUDY IS SIGNIFICANT? Early animal studies: -adrenergic agonists during pregnancy: potential to decrease uteroplacental perfusion Recent clinical studies: agonists during spinal anaesthesia for Caesarean section no evidence of detrimental effects Supported the use of phenylephrine for maintaining maternal BP during spinal anaesthesia for Caesarean section because compared to ephedrine greater efficacy ease of titration and less propensity to depress fetal pH and base excess
1. Most clinical studies: performed in healthy, low-risk, elective patients 2. Few data are available for non-elective cases, particularly those in whom there is actual or potential fetal compromise. This is important because in the latter group, possible adverse effects of vasopressors on uteroplacental perfusion may be more likely to be detrimental to the fetus. AIM OF THE STUDY ETo compare the use of phenylephrine and ephedrine for treating hypotension in women having spinal anaesthesia for non-elective Caesarean section
E Primary outcome compared was fetal acid-base status
E Also compared umbilical cord blood oxygenation and lactate concentration as well as the clinical outcome of neonates METHODS Institutional approval: Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee, Shatin, Hong Kong, China Registered in the Clinical Trials Registry: Centre of Clinical Trials, The Chinese University of Hong Kong 204 ASA 1 and 2 women: term singleton pregnancies scheduled for non- elective Caesarean section for which spinal anaesthesia was decided upon for clinical reasons booked on the day of surgery as emergencies patients who were admitted to the labour ward in labour but subsequently proceeded to Caesarean section Written informed consent EXCLUSION CRITERIA pre-existing or pregnancy-induced hypertension cardiovascular or cerebrovascular disease multiple gestation known fetal abnormality any medical contra-indication to spinal anaesthesia such as thrombocytopenia or coagulopathy ..METHODS Premedicated orally with 0.3 M sodium citrate 30 ml on arrival to the operating theatre Monitoring: NIBP ECG Pulse Oximetry Fetal heart rate: monitored by external cardiotocography until the time of surgical preparation No intravenous prehydration was given Spinal anaesthesia was induced in the right lateral position Skin infiltration with lidocaine: 25-gauge, pencil-point needle: L3-4 or L4-5: 2.0-2.2 ml hyperbaric 0.5% bupivacaine (10-12 mg) and fentanyl 15 g
..METHODS Immediately returned to the left-tilted supine position. Started rapid cohydration: up to 2L of RL. Oxygen 6-8 L/min: by clear facemask until delivery. BP: at 1-min intervals: beginning 1 min after spinal. Hypotension: defined as systolic BP (SBP) < 100 mmHg. ..METHODS Randomised to receive an i.v. bolus immediately after each episode of hypotension: phenylephrine 100 g (phenylephrine group) or ephedrine 10 mg (ephedrine group) immediately Randomisation: performed according to computer-generated codes contained in opaque, sealed and sequentially-numbered envelopes Doses of phenylephrine and ephedrine chosen empirically: based on authors clinical experience of the drugs. ..METHODS To maintain blinding: the vasopressor solutions were prepared in identical syringes by an anaesthetist or investigator not involved in subsequent patient care. For the purposes of comparison between groups: the upper sensory level of anaesthesia was measured by assessing loss of pinprick discrimination 5 min after spinal injection. Timing of the decision to allow surgery to proceed: at the discretion of the attending anaesthetist. ..METHODS Recorded using a stopwatch (time of): of skin incision uterine incision delivery Continued the vasopressor protocol until the time of uterine incision. After this, the study was terminated and further management was at the discretion of the attending anaesthetist.
..METHODS Recorded: the total dose of vasopressor given up to the time of uterine incision the total volume of intravenous fluid given any incidences of nausea (reported spontaneously by patients) or vomiting (observed by investigators) number of episodes of hypotension. Bradycardia was defined as HR < 50/min and, if associated with hypotension, was treated with intravenous atropine 0.6 mg. ..METHODS Attending paediatrician: Apgar scores at 1 and 5 min after delivery. Recorded: Number of neonates admitted to the special care baby unit and neonatal intensive care unit and the respective durations of stay.
Umbilical arterial (UA) and umbilical venous (UV) blood samples: From double-clamped segments of umbilical cord into heparinised syringes Measured blood gases using a Rapid Point 400 analyser [Bayer Diagnostics Mfg (Sudbury) Ltd, Sudbury]. Measured oxygen content using an IL 682 CO-oximeter (Instrumentation Laboratory, Lexington, MA, USA) with correction for 70% fetal haemoglobin. Centrifuged samples of UA and UV blood and measured plasma lactate: using the Vitros DT60 II Chemistry System (Ortho-Clinical Diagnostics, Raritan, NJ, USA).
STATISTICS Prospective power analysis: based on historical audit data of emergency CS performed in 2001.
Primary outcome was defined as the umbilical arterial (UA) pH and an effect size of 0.03 units was chosen based on differences observed in elective cases.
Sample size of 85 patients per group would be required: 90% power at the 0.05 significance level to detect a difference between groups.
Final sample size of 102 patients per group: To compensate for anticipated dropouts and difficulties with data collection given the emergency nature of the cases, it was decided to increase the sample size by 20%. STATISTICS Univariate intergroup comparisons were made using the unpaired Students t-test or the Mann-Whitney U-test as appropriate.
Nominal data were compared using the Chi-Square test or Fishers exact test.
Analyses were made using SPSS version 10.1.4 (SPSS Inc., Chicago, IL, USA) and Confidence Interval Analysis 2.0.0 (T. Bryant, University of Southampton).
Values of p < 0.05 were considered statistically significant. RESULTS: distribution of patients who consented to participate RESULTS: Patient characteristics and surgical times Phenylephrine group (n = 102) Ephedrine group (n = 102) Age; years 31 (4.9) 30 (4.3) Weight; kg 66.7 (9.7) 65.6 (8.6) Height; cm 156 (5.3) 157 (5.4) Block height at 5 min; dermatome T4 [T3-T5] T4 [T3-T5] Uterine incision-to-delivery time; s 67 [50-120] 73 [47-122] Induction-to-delivery time; min 21.0 [17.6-25.3] 20.9 [16.5-25.9] Patient characteristics and surgical times. Values are mean (SD) or median [IQR]. No significant differences between groups RESULTS: number of episodes of hypotension and the total volume of intravenous fluid given in each group was similar Phenylephrine group (n = 102) Ephedrine group (n = 102) p value Episodes of hypotension; n 1.0 [0-3.3] 2.0 [0.3-3.0] 0.52 Total intravenous fluid given; ml 1100 [738-1700] 1350 [838-1763] 0.26 Minimum recorded systolic blood pressure; mmHg 96 [89-101] 95 [88-102] 0.98 Maximum recorded systolic blood pressure; mmHg 127 [120-135] 127 [120-138] 0.74 Minimum recorded heart rate; beats.min 1
63 [58-74] 69 [63-79] 0.003 Maximum recorded heart rate; beats.min 1
104 [96-118] 114 [97-125] 0.086 Episodes of hypotension, total intravenous fluid and minimum and maximum values for systolic blood pressure and heart rate. Values are median [IQR]. RESULTS E The minimum recorded HR was in the phenylephrine group vs the ephedrine group but there was no difference in maximum recorded HR or minimum and maximum recorded SBP. E No patient required atropine. E The number of doses of vasopressor required was similar. E More patients had nausea or vomiting in the ephedrine group vs the phenylephrine group (13/102 (12.7%) vs 4/102 (3.9%), p = 0.02). Phenylephrine group (n = 102) Ephedrine group (n = 102) 0 28 28 1 24 21 2 13 23 3 12 16 4 10 6 5 5 5 >5 10 2 Number of doses of vasopressor required. No significant differences between groups RESULTS of umbilical cord blood analysis Umbilical cord blood analysis (intention-to-treat basis). Values are median [IQR]. Phenylephrine group (n = 102) Ephedrine group (n = 102) p value Umbilical arterial pH 7.28 [7.26 to 7.31] 7.28 [7.25 to 7.31] 0.70 PCO 2 ; kPa 7.2 [6.5 to 7.7] 7.1 [6.4 to 7.8] 0.98 PO 2 ; kPa 2.2 [1.8 to 2.6] 2.4 [1.9 to 2.8] 0.09 Base excess; mmol.l 1 2.5 [4.1 to 1.7] 2.9 [4.3 to 1.6] 0.31 Haemoglobin concentration; g.dl 1 15.3 [14.5 to 16.2] 14.7 [13.8 to 15.8] 0.13 Oxygen content; ml.dl 1 6.9 [4.6 to 8.8] 6.6 [5.0 to 8.8] 0.54 Lactate concentration; mmol.l 1 2.4 [1.9 to 3.0] 2.6 [2.3 to 3.3] 0.002 Umbilical venous pH 7.33 [7.31 to 7.35] 7.33 [7.30 to 7.35] 0.94 PCO 2 ; kPa 6.0 [5.6 to 6.5] 5.9 [5.5 to 6.5] 0.60 PO 2 ; kPa 3.9 [3.2 to 4.5] 4.0 [3.4 to 4.6] 0.13 Base excess; mmol.l 1 2.9 [4.2 to 1.7] 3.1 [4.1 to 2.0] 0.44 Haemoglobin concentration; g.dl 1 15.4 [14.5 to 16.4] 14.9 [14.1 to 16.0] 0.11 Oxygen content; ml.dl 1 13.6 [11.1 to 15.6] 13.7 [11.1 to 15.5] 0.59 Lactate concentration; mmol.l 1 2.3 [1.9 to 2.8] 2.5 [2.2 to 3.2] 0.016 There was no difference between groups in the primary outcome, UA pH. In the ephedrine group, two cases had UA pH < 7.0 compared with no case in the phenylephrine group (p = 0.50); the former two cases were the only cases in which UA base excess was < 12 mmol.l1. Lactate concentration was higher in the ephedrine vs the phenylephrine group for both UA blood [median difference 0.3 (95% CI of difference 0.1-0.6) mmol.l1, p = 0.002] and UV blood [median difference 0.3 (95% CI of difference 0-0.4) mmol.l1, p = 0.016]. RESULTS of umbilical cord blood analysis Results were similar to those found in the intention-to-treat analysis. However, an additional finding was that UA PO2 was lower in the phenylephrine group vs the ephedrine group [median difference 0.23 (95% CI of difference 0.02-0.45) kPa, p = 0.032] and UV PO2 was lower in the phenylephrine group vs the ephedrine group [median difference 0.39 (95% CI of difference 0.08-0.70) kPa, p = 0.012]. However, there were no differences between groups in UA or UV oxygen content. Umbilical cord blood analysis (per protocol basis). Values are median [IQR]. Phenylephrine group (n = 74) Ephedrine group (n = 74) p value Umbilical arterial pH 7.29 [7.26 to 7.31] 7.28 [7.24 to 7.31] 0.34 PCO 2 ; kPa 7.1 [6.4 to 7.8] 7.2 [6.5 to 7.8] 0.82 PO 2 ; kPa 2.2 [1.8 to 2.7] 2.4 [2.0 to 2.8] 0.032 Base excess; mmol.l 1 2.5 [4.1 to 1.5] 3.2 [4.5 to 1.7] 0.17 Haemoglobin concentration; g.dl 1
15.4 [14.5 to 16.3] 14.7 [13.7 to 15.8] 0.15 Oxygen content; ml.dl 1 6.9 [4.4 to 9.2] 6.8 [5.2 to 9.2] 0.39 Lactate concentration; mmol.l 1 2.3 [1.9 to 2.8] 2.7 [2.3 to 3.5] <0.001 Umbilical venous pH 7.32 [7.31 to 7.36] 7.33 [7.30 to 7.35] 0.71 PCO 2 ; kPa 6.0 [5.7 to 6.6] 5.9 [5.4 to 6.6] 0.30 PO 2 ; kPa 3.8 [3.0 to 4.2] 4.1 [3.6 to 4.9] 0.012 Base excess; mmol.l 1 2.8 [4.0 to 1.9] 3.1 [4.1 to 2.1] 0.31 Haemoglobin concentration; g.dl 1
15.4 [14.5 to 16.4] 15.0 [14.1 to 16.2] 0.11 Oxygen content; ml.dl 1 13.2 [10.1 to 15.4] 14.3 [11.8 to 15.8] 0.14 Lactate concentration; mmol.l 1 2.2 [1.8 to 2.8] 2.6 [2.2 to 3.3] 0.002 RESULTS Fetal compromise was considered potentially to have been present in a total of 48 patients; there was a similar proportion of these patients in the two groups (phenylephrine group 22% vs ephedrine group 26%, p = 0.5). Subanalysis of these patients showed that UA PO2 was lower in the phenylephrine group compared with the ephedrine group but all other blood gas parameters and lactate concentrations were similar. Umbilical cord blood analysis for patients with factors suggesting potential fetal compromise. Values are median [IQR]. Phenylephrine group (n = 22) Ephedrine group (n = 26) p value Umbilical arterial pH 7.26 [7.22 to 7.29] 7.27 [7.23 to 7.31] 0.43 PCO 2 ; kPa 7.2 [6.7 to 8.3] 7.0 [6.4 to 7.5] 0.54 PO 2 ; kPa 2.0 [1.6 to 2.2] 2.4 [1.7 to 2.7] 0.045 Base excess; mmol.l 1 4.1 [5.0 to 1.8] 4.1 [5.4 to 2.8] 0.62 Haemoglobin concentration; g.dl 1 15.7 [15.0 to 16.5] 14.3 [13.5 to 15.8] 0.31 Oxygen content; ml.dl 1 5.4 [3.5 to 7.5] 6.5 [3.7 to 8.6] 0.34 Lactate concentration; mmol.l 1 3.4 [2.5 to 4.3] 3.3 [2.6 to 5.0] 0.85 Umbilical venous pH 7.32 [7.28 to 7.34] 7.32 [7.28 to 7.35] 0.68 PCO 2 ; kPa 6.1 [5.6 to 6.6] 5.9 [5.4 to 6.5] 0.82 PO 2 ; kPa 3.4 [2.9 to 3.9] 3.6 [3.2 to 4.1] 0.34 Base excess; mmol.l 1 4.2 [5.5 to 2.0] 4.1 [6.1 to 2.7] 0.88 Haemoglobin concentration; g.dl 1 15.6 [14.7 to 16.3] 14.6 [13.5 to 16.0] 0.08 Oxygen content; ml.dl 1 12.6 [10.1 to 14.2] 11.7 [9.5 to 15.3] 0.82 Lactate concentration; mmol.l 1 3.3 [2.4 to 3.9] 3.2 [2.3 to 4.5] 0.71 RESULTS There was no difference between groups in the clinical outcome of the neonates. One neonate in the ephedrine group had an Apgar score < 7 at 1 min and 5 min and one neonate in the phenylephrine group had an Apgar score < 7 at 1 min; all other Apgar scores were 7. Seventeen (17%) neonates in the phenylephrine group (17%) and 21 (21%) neonates in the ephedrine group were admitted to the special care baby unit (p = 0.45). There was no difference in the duration of stay between groups. One neonate in the ephedrine group was admitted to the neonatal intensive care unit because of feto-maternal transfusion syndrome; total duration of stay was 22 days and treatment included blood transfusion and treatment of convulsions. DISCUSSION This study showed that neonatal outcome was similar between groups when phenylephrine or ephedrine was used to treat hypotension in patients having non-elective Caesarean section under spinal anaesthesia. Although there were differences between groups in UA and UV lactate concentration and PO2, the magnitudes of these differences were small and there were no differences in pH or base excess. DISCUSSION
More patients had nausea or vomiting in the ephedrine group but there were no other differences in clinical outcome.
Previous studies have supported the use of phenylephrine in low-risk elective patients.
The current data provide evidence to suggest that phenylephrine is also an appropriate vasopressor to use in non-elective cases. DISCUSSION
The results of this study are important E because animal studies have shown that phenylephrine and other alpha adrenergic agonists have a greater propensity to reduce uteroplacental perfusion compared with ephedrine. not clinically relevant in healthy, low-risk elective cases E it has not been known whether the same would apply in the presence of potential or actual fetal compromise
DISCUSSION The results of recent studies in sheep do provide some basis for concern about the use of phenylephrine in the presence of uteroplacental insufficiency. Erkinaro et al. compared phenylephrine and ephedrine for correcting epidural-induced hypotension after a period of maternal hypoxaemia in a chronically-instrumented sheep model. In an earlier study, they found that, although ephedrine was associated with more favorable effects on uterine and placental circulations, there was no difference in fetal acid-base status or lactate concentration.
DISCUSSION In the latter study, haemodynamic effects of the vasopressors were similar to those in the earlier study, but in addition, they found that phenylephrine was associated with higher values for fetal lactate. DISCUSSION This is relevant because there is evidence that fetal lactate may be a better predictor of severe neonatal morbidity than pH.
Therefore, a possible implication of these results for clinical practice is that some caution with the use of phenylephrine in emergency cases may be warranted. DISCUSSION However, the results of this clinical study contradict those of the animal studies described above. 4 Rather than finding increased fetal lactate concentrations when phenylephrine was used, this study found that umbilical arterial and venous lactate concentrations were lower in the phenylephrine group compared with the ephedrine group. DISCUSSION There may be several reasons for the differences in results among these studies. 4 Substantial differences in study design may be important. 4 For example, Erkinaro et al. performed their studies in anaesthetised sheep that were ventilated in the supine position; this may not be a valid representation of spinal anaesthesia in pregnant humans. 4 Species differences may also be important. DISCUSSION Previously, it has been suggested that the decreases in pH and base excess in umbilical cord blood observed when ephedrine is used in humans may be associated with metabolic stimulation in the fetus secondary to the effects of placental transfer of ephedrine. 4 This may account for the higher values for lactate concentration found in the ephedrine group in our current study. DISCUSSION In sheep, however, placental morphology differs from that of humans. 4 The thicker synepitheliochorial placenta of the sheep may present a greater diffusion barrier to ephedrine compared with the haemomonochorial placenta of humans and thus it is possible that placental transfer of ephedrine and its metabolic effects in sheep may be less. However, in the absence of comparative studies of placental transfer of vasopressors, this explanation remains speculative. DISCUSSION Nonetheless, these results emphasize the importance of caution when extrapolating the results of animal studies to clinical practice in humans. DISCUSSION An interesting finding: 4for the phenylephrine group vs the ephedrine group, there were lower values for UA and UV PO2 in the per-protocol analysis and lower values for UA PO2 in patients with potential fetal compromise. DISCUSSION The reasons and clinical significance uncertain. 4It is possible that they may reflect a vasoconstrictive effect of phenylephrine on the uteroplacental circulation that resulted in reduced flow and increased oxygen extraction. DISCUSSION Consistent with studies in sheep which show that although uterine blood flow varies over a wide range, fetal oxygen uptake remains relatively constant. 4 suggesting that the efficiency of oxygen extraction is increased when perfusion decreases. E Animal studies demonstrated margin of safety for uteroplacental perfusion :protects the fetus from fluctuations in uterine blood flow. E May explain why human clinical studies, including the present one, have failed to demonstrate a decrease in fetal pH when phenylephrine and other alpha agonists have been used to maintain BP in obstetric patients despite strong animal evidence that these drugs have the propensity to cause vasoconstriction of the uteroplacental circulation. DISCUSSION Clinical outcome of the neonates :generally favourable E as evidenced by Apgar scores and the requirement for only one neonate to be admitted to the neonatal intensive care unit.
For cases where there was evidence of severe fetal or maternal compromise: general anaesthesia. It may not be valid to extrapolate our findings to cases of severe fetal compromise when the relative clinical importance of stimulation of fetal metabolism or uteroplacental vasoconstriction may differ. LIMITATIONS OF THE STUDY Inclusion criteria for this study were very broad heterogeneous mix of patients with a range of degrees of clinical urgency Small proportion of patients (24%) in whom fetal compromise was considered potentially to have been present. LIMITATIONS OF THE STUDY Arbitrary absolute value of 100 mmHg as our threshold for the definition of hypotension.
The doses of phenylephrine (100 g) and ephedrine (10 mg) used in the study were determined empirically Saravanan et al. published data from which they estimated that the potency ratio of phenylephrine: ephedrine was approximately 80 : 1 (phenylephrine 100 g = ephedrine 8 mg) when the drugs were given by infusion.
LIMITATIONS OF THE STUDY Arbitrary absolute value of 100 mmHg as our threshold for the definition of hypotension.
The doses of phenylephrine (100 g) and ephedrine (10 mg) used in the study were determined empirically Saravanan et al. published data from which they estimated that the potency ratio of phenylephrine: ephedrine was approximately 80 : 1 (phenylephrine 100 g = ephedrine 8 mg) when the drugs were given by infusion.
LIMITATIONS OF THE STUDY Not all patients developed hypotension and required a vasopressor and the total dose requirement for vasopressors was small compared with previous studies in elective cases.
Consistent with previous observations: patients in labour are less prone to hypotension during spinal anaesthesia compared with non- labouring patients.
Small doses of vasopressors used in this study may explain that UA and UV pH and base excess were not lower in the ephedrine group compared with the phenylephrine group as has been shown in studies of elective cases. SUMMARY Phenylephrine is at least as suitable as ephedrine for maintaining maternal BP during spinal anaesthesia for non-elective Caesarean section.
Phenylephrine had the clinical advantage of being associated with a lower incidence of nausea and vomiting compared with ephedrine.
Comparative Study Between Cardioprotective Effects of Intermitternt Antegrade Blood Cardioplegia With Terminal Warm Blood Reperfusion (Hot Shot) vs Intermittent Antegrade Blood Cardioplegia in Pediatric
An Open-Label Randomized Controlled Clinical Trial For Comparison of Continuous Phenylephrine Versus Norepinephrine Infusion in Prevention of Spinal Hypotension During Cesarean Delivery