BJA Advance Access originally published online on March 8, 2007
British Journal of Anaesthesia 2007 98(5):649-656; doi:10.1093/bja/aem056
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Effect of intravenous vasopressor on spread of spinal anaesthesia and fetal acid–base equilibrium
James Cook University Hospital, Middlesbrough, Cleveland, UK
* Corresponding author: James Cook University Hospital, Middlesbrough, Cleveland TS4 3BW, UK. E-mail: drdavidcooper{at}aol.com
Accepted for publication January 25, 2007.
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Abstract |
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Background: We previously found rostral spread of spinal plain levobupivacaine to be less with prophylactic i.v. phenylephrine than with ephedrine during Caesarean delivery. This study investigated whether rostral spread of spinal hyperbaric bupivacaine is also less with phenylephrine than with ephedrine.
Methods: The study was randomized and double blind. It compared phenylephrine 100 µg ml–1 (phenylephrine group, n = 27), and ephedrine 4.5 mg ml–1 (ephedrine group, n = 27), given by infusion during spinal anaesthesia for Caesarean delivery. Block height was assessed to cold and light touch sensation at 15, 30, 60, and 90-min after the spinal injection of 2.8 ml of hyperbaric 0.5% w/v bupivacaine, combined with 0.4 ml diamorphine (1 mg ml–1). Umbilical blood gas values were monitored during the study.
Results: Block height was similar for both groups at all of the assessment times. Umbilical artery pH was higher with phenylephrine [median 7.32 (IQR 7.28–7.34)] than with ephedrine [7.20 (7.10–7.28)] (P < 0.0001). There was a strong negative correlation between umbilical artery pH and spinal-delivery interval, but only with ephedrine: phenylephrine group, r2 = 0.09 (P = 0.17), and ephedrine group, r2 = 0.53 (P < 0.0001). Five-minute Apgar scores were higher with phenylephrine [10 (9–10)] than ephedrine [9 (9–9)] (P = 0.009).
Conclusions: In contrast to its effect on spinal plain levobupivacaine, we did not find rostral spread of spinal hyperbaric bupivacaine to be less with prophylactic phenylephrine than with ephedrine. We observed an unexpectedly high incidence of fetal acidosis with ephedrine and found evidence that longer spinal-delivery intervals increase the risk of fetal acidosis developing with ephedrine, but not phenylephrine.
Keywords: acid–base equilibrium, pH; anaesthetic techniques, subarachnoid; fetus; sympathetic nervous system, ephedrine; sympathetic nervous system, phenylephrine
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Introduction |
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We previously found rostral spread of spinal plain levobupivacaine to be less with prophylactic i.v. phenylephrine than with ephedrine during Caesarean delivery.1 It was not clear whether this was of clinical significance because patients were not studied beyond 20-min post-spinal.
Hyperbaric bupivacaine is used more frequently for spinal anaesthesia for Caesarean delivery than plain levobupivacaine. Prophylactic phenylephrine has been recommended during spinal anaesthesia.2 However, we do not know whether prophylactic phenylephrine has a similar effect on the spread of spinal hyperbaric bupivacaine and, if so, whether it is of clinical significance.
This randomized double-blind study tested the hypothesis that rostral spread of spinal hyperbaric bupivacaine is less during Caesarean delivery when prophylactic i.v. phenylephrine is used, compared with ephedrine. Height of neural blockade was studied for 90-min post-spinal and patients were assessed for adequacy of anaesthesia. We also monitored the overall incidence of fetal acidosis during the course of the study because the use of ephedrine has been associated with decreased fetal pH compared with phenylephrine3 and its prophylactic use has been associated with a relatively high incidence of fetal acidosis at delivery.4–6
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Methods |
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This single-centre study was randomized and double blind. It was registered with the European Clinical Trials Database (EudraCT number 2004-002734-19), Clinical Trials Authorization (CTA) was received from the UK Medicines and Healthcare products Regulatory Agency (MHRA) and it was approved by the Thames Valley Multi-centre Research Ethics Committee. After obtaining written informed consent, we studied patients with American Society of Anaesthesiologists physical status I and II, who were scheduled to undergo elective Caesarean delivery during spinal anaesthesia. Women with a singleton pregnancy of at least 36 weeks gestation, with no known fetal abnormality, no history of preeclampsia, or diabetes mellitus, were included.
Before coming to the anaesthetic room, three arterial pressure and heart rate readings were measured with an automated oscillometer, at 3-min intervals, while sitting in bed. The lowest of the three readings was recorded as the baseline value for the maternal systolic arterial pressure and heart rate. Patients were randomly allocated to group by a computer-generated code that was kept in a numbered envelope. The patients, anaesthetists, and nurses involved with patient care were blinded to the patient grouping. The phenylephrine group received 100 µg ml–1 phenylephrine and the ephedrine group received 4.5 mg ml–1 ephedrine. The ratio of phenylephrine to ephedrine concentrations was 1:45, which was close to the overall dose ratio that we had required in two previous studies to maintain maternal arterial pressure at baseline.1 6 A syringe containing 10 ml of rescue vasopressor solution, consisting of phenylephrine, 50 µg ml–1, combined with ephedrine, 2.25 mg ml–1, was also prepared. Immediately before spinal anaesthesia, 10 mg of i.v. metoclopramide and 0.2 mg of i.v. glycopyrrolate were given. Immediately after the spinal injection, a rapid infusion of 10 ml kg–1 Hartmann's solution was commenced. Spinal anaesthetic was performed at L3–L4, with the patient in the sitting position. We gave 2.8 ml of hyperbaric bupivacaine 0.5% w/v (14 mg) combined with 0.4 ml of diamorphine (1 mg ml–1) (400 µg) via a 24 g pencil point spinal needle, with the bevel rostral, over 10–15 s. The 14 mg dose of hyperbaric bupivacaine was chosen because it is close to the ED95 for blocking T5 to light touch,7 which has been considered to be important for effective anaesthesia,8 and it would be expected to have at least a 95% chance of providing effective anaesthesia when combined with 400 µg of diamorphine.9
Immediately after the spinal injection, the patient was placed in the supine position, with left lateral tilt. Systolic arterial pressure and heart rate were measured every minute after spinal anaesthesia, using the same automated oscillometer that was used for the baseline arterial pressure. Maternal heart rate was continuously monitored with a pulse oximeter and an electrocardiograph. Additional i.v. glycopyrrolate, 0.2 mg, was given if maternal heart rate was less than 60 beats min–1 and systolic arterial pressure was less than 0.80 times baseline (or 90 mm Hg, whichever higher), or if the heart rate was less than 45 beats min–1.
Immediately after the spinal injection, an i.v. infusion of trial solution was started, using an IVAC P2000 infusion pump (Alaris Medical Systems, Basingstoke, UK) and adjusted according to a standard protocol. The trial solution was started at 20 ml h–1 (equating to 33 µg min–1 phenylephrine for the phenylephrine group and 1.5 mg min–1 ephedrine for the ephedrine group). The rate was doubled or halved, as necessary, to maintain systolic arterial pressure at baseline. The maximum infusion rate allowed in the protocol was 40 ml h–1, and the minimum rate was 2.5 ml h–1 (if less was required, the infusion was discontinued and recommenced as necessary). If the systolic arterial pressure increased above 1.20 times baseline the infusion was stopped and recommenced at half the rate when the systolic arterial pressure had decreased below that level.
Additional boluses of trial solution were given, as required, according to the following protocol. If the systolic arterial pressure was between 0.80 times baseline (or 90 mm Hg, whichever higher) and baseline, and the infusion was already on the maximum rate, 1 ml boluses of trial solution were given. If the systolic arterial pressure was between 0.60 times baseline (or 70 mm Hg, whichever higher) and 0.80 times baseline (or 90 mm Hg, whichever higher), 1 ml boluses of trial solution were given. If the systolic arterial pressure was below 0.60 times baseline (or 70 mm Hg, whichever higher), 2 ml boluses of trial solution were given. If the systolic arterial pressure remained below 0.80 times baseline (or 90 mm Hg, whichever higher) for a further two readings, boluses of trial solution were replaced with the same volume boluses of rescue solution.
The maximum total volume of trial solution that could be given, including any additional boluses, was 20 ml (equating to 2 mg phenylephrine for the phenylephrine group, or 90 mg ephedrine for the ephedrine group). Thereafter, boluses of rescue solution were given, as required, to maintain systolic arterial pressure: 1 ml boluses were given if systolic arterial pressure was between 0.80 times baseline (or 90 mm Hg, whichever higher) and baseline, 2 ml boluses were given if systolic arterial pressure was below 0.80 times baseline (or 90 mm Hg, whichever higher).
The study continued for 90 min after spinal anaesthesia, or until the end of the operation, whichever was longer. At 15, 30, 60, and 90 min post-spinal, the volumes of trial solution and rescue solution given were recorded. The upper dermatomes blocked to cold and light touch sensation, and the ability to raise either knee, were also recorded at these times. Ethyl chloride spray was used to assess cold sensation (first awareness of the spray feeling cold) and light touch sensation (first awareness of the spray). The spray was moved from the lower abdomen, upwards, and the patient placed her finger where she was first aware of the spray. This was then repeated for where she was first aware of the spray feeling cold. A standard dermatomal chart was referred to. If T4 was not blocked to cold on both sides by 15 min, the patient was tilted head-down, with lateral tilt towards whichever side was least well blocked, for 1 min, repeated as necessary. At the end of the operation, the pain score was recorded for the worst pain experienced during the operation (on a 0–100 mm visual analogue score, where 0 = no pain and 100 = the worst pain imaginable). Anaesthesia was defined as being inadequate if T6 was not blocked to cold sensation by 30 min, if either knee could be raised at 30 min, if there was a pain score of more than 30 mm during the operation, if analgesic supplementation was required, or if general anaesthesia was required because of pain.
At delivery, the surgeon obtained umbilical artery and vein blood samples from a segment of umbilical cord double-clamped before the baby's first breath. A Rapidlab 248 blood gas analyser (Bayer Healthcare, Newbury, UK) was used for blood gas analysis. Supplemental oxygen was not given to the mother before childbirth. A midwife recorded Apgar scores at 1 and 5 min after delivery. Newborn infants were not studied beyond the immediate post-delivery period.
The protocol for additional boluses of vasopressor solution was modified after patient 14 because of concerns about an unexpectedly high incidence of fetal acidosis. From patient 15 onwards, additional boluses of trial solution were no longer given. Instead, boluses of trial solution were replaced with the same volume boluses of rescue solution. This was to limit fetal exposure to ephedrine, which we considered to be the most likely cause of the excessive fetal acidosis, based upon previous experience with prophylactic vasopressor infusions.6 Boluses of rescue solution were only given if the systolic arterial pressure was less than 0.80 times baseline (or 90 mm Hg, whichever was higher). The protocol for the trial solution infusion was not modified.
Statistical analysis
The study was originally designed to have an 80% chance of detecting a one-dermatome difference in block height to cold sensation at 15 min post-spinal, at P = 0.05 (two-sided). This would have required a total of 126 patients, based on a standard deviation of two for block height observed from a previous study.6 However, early in the study there were concerns about a relatively high overall incidence of fetal acidosis. The protocol for additional boluses of vasopressor was modified after patient 14 to reduce the risk of acidosis and an interim analysis was planned after another 40 patients. A total of 54 patients gave the study a 96% chance of detecting a two-dermatome difference in block height, based on a standard deviation of two. Two dermatomes was the difference in block height to cold sensation that we had found in the previous study of plain levobupivacaine.1 After 54 patients had been studied, the overall incidence of acidosis remained higher than expected, so a third party, who was not involved with the study, broke the code for fetal acidosis. The incidence of acidosis in the ephedrine group was considered to be unacceptably high by the chief investigator, both before and after the modification to the additional bolus protocol. The study was therefore stopped and the code was broken for the remainder of the data. Data were analysed using a statistical software package (SPSS). The 
2 test and the Mann–Whitney U-test were used to compare results between groups. Pearson correlation coefficient and backward stepwise regression were also used to analyse data. P < 0.05 was considered to be significant.
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Results |
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Twenty-seven patients received phenylephrine and 27 received ephedrine. The groups were similar in age, height, weight, systolic arterial pressure, heart rate, gestation, breech presentation, previous Caesarean delivery, and fetal weight (Table 1). The groups were similar in uterine incision-delivery intervals, and the times from spinal anaesthesia to incision, to delivery, and to the end of operation (Table 1). Blood gas values were not available for four phenylephrine group patients and one ephedrine group patient. Data are presented as median (inter-quartile range), unless stated otherwise.
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From 0 to 15 min, the volumes of vasopressor given, and systolic arterial pressure, were similar for the two groups (Table 2). This contrasted with the 15 to 30 min time period, where the phenylephrine group required relatively more trial and rescue solution, and systolic arterial pressure was significantly lower than in the ephedrine group.
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Block height was similar in the two groups for both sensory modalities tested at all of the assessment times (Figs 1 and 2). The standard deviation for block height to cold sensation at 15-min post-spinal was two dermatomes, which was the same as in the study upon which the power analysis was based.6 Two phenylephrine group patients and one ephedrine group patient were given head down tilt because T4 was not blocked to cold sensation by 15 min post-spinal. All three of these patients had adequate anaesthesia. There was no difference in pain scores, or in the incidence of inadequate anaesthesia between the two groups. The worst pain experienced in the phenylephrine group was 0 mm (0–3), compared with 0 mm (0–0) in the ephedrine group (P = 0.21). Three patients, two in the phenylephrine group, and one in the ephedrine group were classified as having inadequate anaesthesia because they required additional analgesia. No patient required general anaesthesia.
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After 14 patients had been studied (six phenylephrine group and eight ephedrine group), the overall incidence of acidosis (umbilical artery pH < 7.20) was high, at 50% [95% confidence interval (CI), 23–77]. After 54 patients had been studied the overall incidence of fetal acidosis remained relatively high, at 31% (95% CI, 19–43). This compared with an overall incidence of fetal acidosis of 11% (95% CI, 5–17) in the combined phenylephrine and ephedrine groups of our previous study of vasopressors and fetal acidosis.6
Umbilical artery pH was higher with phenylephrine than with ephedrine (Table 3). Two of 23 (9%) of the phenylephrine group fetuses were acidotic, compared with 13 of 26 (50%) of the ephedrine group (P = 0.002). The lowest umbilical artery pH in the phenylephrine group was 7.19, whereas three ephedrine group fetuses had an umbilical artery pH of less than 7.00, of which two followed the modification to the protocol for additional boluses of vasopressor. Both umbilical artery PCO2 and base deficit were greater with ephedrine than with phenylephrine. The umbilical arterio-venous PCO2 difference with phenylephrine was approximately half of that with ephedrine (Table 3). We observed a strong negative correlation between umbilical artery pH and umbilical arterio-venous PCO2 difference, but only with ephedrine: phenylephrine group, r2 = 0.01 (P = 0.64), and ephedrine group, r2 = 0.52 (P < 0.0001). We also observed a strong negative correlation between umbilical artery pH and spinal-delivery interval, but only with ephedrine (Figs 3 and 4).
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To investigate which factors may have affected umbilical artery pH, backward stepwise regression was performed for uterine incision-delivery interval, spinal-delivery interval, total ephedrine dose, total phenylephrine dose, lowest systolic arterial pressure recorded, and duration of hypotension (systolic arterial pressure less than 0.80 times baseline). In the phenylephrine group, uterine incision-delivery interval was the only factor associated with umbilical artery pH (Table 4). In the ephedrine group, spinal-delivery interval and the total dose of ephedrine were the only factors associated with umbilical artery pH (Table 5).
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One-minute Apgar scores were similar in the phenylephrine group [9 (9–9)] and the ephedrine group [9 (9–9)] (P = 0.43). However, 5-min Apgar scores were higher in the phenylephrine group [10 (9–10)] than in the ephedrine group [9 [9–9)] (P = 0.009). In the phenylephrine group, 15 of 27 newborns [56% (95% CI, 37–75)] had a 5-min Apgar score of 10, compared with only 5 of 27 [19% (95% CI, 4–34)] in the ephedrine group (P = 0.005).
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Discussion |
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This study did not find a difference in rostral spread of spinal hyperbaric bupivacaine during Caesarean delivery when phenylephrine was used to maintain maternal arterial pressure, compared with ephedrine. The study was stopped after an interim analysis, at 54 patients, because of an unexpectedly high incidence of fetal acidosis in the ephedrine group. However, the lack of difference in block height between the two groups was unlikely to have been a type II error. With 54 patients, the study had a 96% chance of detecting a two-dermatome difference in block height, which was the difference that we had found in the previous study of plain levobupivacaine.1
What was the reason for the similar spread of spinal hyperbaric bupivacaine anaesthesia in this study of phenylephrine and ephedrine, compared with their differing effects on the spread of spinal plain levobupivacaine in the previous study?1 It is possible that the differences in block height in the levobupivacaine study were type I errors. We consider this to be unlikely because the study was performed to investigate a strong clinical observation10 and the differences were highly statistically significant. However, until this has been confirmed by further study, a type I error cannot be excluded.
The design of this study of hyperbaric bupivacaine was very similar to the study of plain levobupivacaine, but there were significant differences. First, a higher concentration of ephedrine (4.5 mg ml –1) was used in this study than in the previous one (3 mg ml –1). This was unlikely to have been the reason for the difference in the findings, since systolic arterial pressure control in the first 15-min of this study of hyperbaric bupivacaine, and the first 20-min of the plain levobupivacaine study, was similar for both groups.
Secondly, a simple spinal anaesthetic was used in this study, whereas a combined spinal-epidural anaesthetic, which included 10-ml of epidural saline, was given in the previous study of plain levobupivacaine. Epidural saline is thought to enhance the spread of spinal anaesthetic (epidural volume enhancement) by compressing the dural sac and reducing lumbosacral cerebrospinal fluid volume.11 12 We have previously speculated that i.v. phenylephrine may constrict engorged lumbosacral epidural veins to a greater degree than ephedrine,1 which may cause a relative increase in epidural space compliance with phenylephrine. If so, the efficacy of epidural volume enhancement may have been reduced with phenylephrine, which would have contributed to the difference between the groups in the plain levobupivacaine study and, therefore, to the difference between the two studies.
Thirdly, hyperbaric local anaesthetic solution was used in this study, whereas plain solution was used in the previous study of levobupivacaine. We consider this to be the most likely reason for the differing effects of i.v. phenylephrine and ephedrine on the spread of spinal anaesthesia between the two studies. In the supine position, gravity assists rostral spread of spinal hyperbaric local anaesthetic solution until the thoracic curve of the vertebral canal is reached, which limits further spread.12 In contrast, rostral spread of plain anaesthetic solution is more dependent upon other factors, such as bulk flow of CSF, and its spread is not limited by the thoracic curve of the vertebral canal. We have previously suggested that during spinal anaesthesia in pregnancy, compared with ephedrine, prophylactic phenylephrine reduces the bulk flow of CSF that occurs from the lumbosacral region to the cranial region, in the supine position.1 We suggest that vasopressor-induced differences in bulk flow of cerebrospinal fluid have a lesser effect on the spread of hyperbaric bupivacaine than on plain levobupivacaine because spread of hyperbaric bupivacaine is more dependent upon the effects of gravity.
The dose of hyperbaric bupivacaine chosen for this study was relatively large because we used a single-shot spinal anaesthetic technique. With a smaller dose of hyperbaric bupivacaine, rostral spread would not have been as great, so the influence of the thoracic curve of the vertebral canal on spread would have been less. A smaller dose of hyperbaric bupivacaine may, therefore, have increased the chance of finding a vasopressor-induced difference in the spread of spinal anaesthesia. However, this would have required a backup epidural catheter, so the results would have been less relevant to the impact of choice of vasopressor upon the efficacy of the more popular single-shot spinal anaesthetic technique.
This study was primarily designed to compare the effect of vasopressors on the spread of spinal hyperbaric bupivacaine anaesthesia. However, we made other observations of interest regarding the incidence of fetal acidosis, and the relationship between spinal-delivery interval and fetal acidosis.
The 50% (95% CI, 31–69) incidence of fetal acidosis with prophylactic ephedrine was remarkably high for the low-risk population studied. It was higher than the 21% (95% CI, 10–32) incidence of fetal acidosis that we had previously encountered with prophylactic ephedrine,6 but it was close to that observed in two other studies of prophylactic ephedrine in low-risk patients.4 5 In contrast, the incidence of fetal acidosis that we observed in a higher risk population of 250 women having urgent Caesarean delivery during spinal anaesthesia, where ephedrine was given as required, rather than prophylactically, was only 17% (95% CI, 12–22).13 This adds weight to the suggestion that we should eliminate or drastically limit the use of ephedrine during spinal anaesthesia for Caesarean delivery.2 Five-minute Apgar scores were lower with ephedrine, but this was unlikely to have been clinically significant because scores were good in both groups.
Increasing spinal-delivery intervals were strongly associated with decreasing umbilical artery pH, but only in the ephedrine group. This may simply have been because ephedrine group patients with longer spinal-delivery intervals received more ephedrine. However, multiple regression analysis found both spinal-delivery interval, and the total dose of ephedrine given, to be significant factors for fetal acidaemia. Unpublished multiple regression analysis of data from our previous study of vasopressors and fetal acidosis6 also found spinal-delivery interval to be a significant factor, in addition to the total dose of ephedrine given.
We have previously suggested that ephedrine can cause fetal acidosis by increasing fetal oxygen demand and carbon dioxide production, secondary to a beta-adrenergic mediated increase in fetal metabolic rate.6 As supportive evidence, we cited the strong association that we had observed between fetal acidaemia and increasing umbilical arterio-venous PCO2 difference with ephedrine, but not phenylephrine. We have again observed a similar strong association between these two variables with ephedrine, but not phenylephrine. The prophylactic use of ephedrine, combined with relatively long spinal-delivery intervals, and a relatively large dose of spinal hyperbaric bupivacaine, probably contributed to the high incidence of fetal acidosis in the ephedrine group by increasing both total dose and duration of fetal exposure to ephedrine.
Rostral spread of spinal hyperbaric bupivacaine was similar with phenylephrine and with ephedrine during Caesarean delivery. This contrasted with our previous study of plain levobupivacaine, where rostral spread was less with phenylephrine than with ephedrine.1 To explain this difference, we suggest that vasopressor-induced differences in bulk flow of cerebrospinal fluid have a lesser effect on the spread of hyperbaric bupivacaine, than on plain levobupivacaine, because spread of hyperbaric bupivacaine is more dependent upon the effects of gravity. We also found evidence that longer spinal-delivery intervals increase the risk of fetal acidosis developing with prophylactic ephedrine, but not phenylephrine.
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This work is attributed to Department of Anaesthesia, James Cook University Hospital, Middlesbrough, Cleveland TS4 3BW, UK. Financial support was received from the South Tees National Health Service Trust.
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1 Cooper DW, Jeyaraj L, Hynd R, et al. Evidence that intravenous vasopressors can affect rostral spread of spinal anesthesia in pregnancy. Anesthesiology (2004) 101:28–33.[CrossRef][Web of Science][Medline]
2 Riley ET. Editorial I: spinal anaesthesia for Caesarean delivery: keep the pressure up and don't spare the vasoconstrictors. Br J Anaesth (2004) 92:459–61.
3 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) 94:920–6.
4 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. Anesthesiology (2001) 95:307–13.[CrossRef][Web of Science][Medline]
5 Mercier FJ, Riley ET, Frederickson WL, Roger-Christoph S, Benhamou D, Cohen SE. Phenylephrine added to prophylactic ephedrine infusion during spinal anesthesia for elective cesarean section. Anesthesiology (2001) 95:668–74.[CrossRef][Web of Science][Medline]
6 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) 97:1582–90.[CrossRef][Web of Science][Medline]
7 Akerman N, Saxena S, Wilson R, Columb M, Lyons G. Effect of intrathecal diamorphine on block height during spinal anaesthesia for Caesarean section with bupivacaine. Br J Anaesth (2005) 94:843–7.
8 Russell IF. Levels of anaesthesia and intra-operative pain at Caesarean section under regional block. Int J Obstet Anesth (1995) 4:71–7.[CrossRef][Medline]
9 Saravanan S, Robinson APC, Qayoum Dar A, Columb MO, Lyons GR. Minimum dose of intrathecal diamorphine required to prevent intraoperative supplementation of spinal anaesthesia for Caesarean section. Br J Anaesth (2003) 91:368–72.
10 Cooper DW, Mowbray P. Can choice of vasopressor therapy affect rostral spread of spinal anaesthetic? (letter). Anesthesiology (2003) 98:1524.[CrossRef][Web of Science][Medline]
11 Blumgart CH, Ryall D, Dennison B, Thompson-Hill LM. Mechanism of extension of spinal anaesthesia by extradural injection of local anaesthetic. Br J Anaesth (1992) 69:457–60.
12 Hocking G, Wildsmith JA. Intrathecal drug spread. Br J Anaesth (2004) 93:568–78.
13 Cooper DW, Gowni RR. Impact of changing from ephedrine to phenylephrine as the first-line vasopressor during urgent caesarean section. Int J Obstet Anesth (2006) 15:339–40.[CrossRef][Web of Science][Medline]
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