Comparison of phenylephrine infusion regimens for maintaining maternal blood pressure during spinal anaesthesia for Caesarean section{dagger}

W. D. Ngan Kee*, K. S. Khaw and F. F. Ng

Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong,Prince of Wales Hospital, Shatin, Hong Kong, China

*Corresponding author. E-mail: warwick@cuhk.edu.hk
{dagger}This article is accompanied by Editorial I.Presented as a poster at the Australian Society of Anaesthetists and the New Zealand Society of Anaesthetists Combined National Scientific Congress, Melbourne, Australia, October 2–5, 2003.

Accepted for publication: November 6, 2003


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. During spinal anaesthesia for Caesarean section, the optimal phenylephrine regimen and the optimal blood pressure (BP) to which it should be titrated are undetermined. The ideal regimen would balance efficacy for maintaining uteroplacental perfusion pressure against potential for uteroplacental vasoconstriction, both of which may affect fetal acid–base status. We compared phenylephrine infusion regimens based on three different BP thresholds.

Methods. After intrathecal injection, we infused phenylephrine 100 µg min–1 for 2 min. Then, until delivery, we infused phenylephrine whenever systolic BP (SBP), measured every 1 min, was below a randomly assigned percentage of baseline: 100% (Group 100, n=25), 90% (Group 90, n=25) or 80% (Group 80, n=24). We compared umbilical blood gases, Apgar scores and maternal haemodynamics and symptoms.

Results. Patients in Group 100 had fewer episodes [median 0 (range 0–8)] of hypotension (SBP <80% baseline) compared with Group 80 [5 (0–18)] and Group 90 [2 (0–7)] (P<0.001 in each instance). Total dose of phenylephrine was greater in Group 100 [median 1520 µg (interquartile range 1250–2130 µg)] compared with Group 90 [1070 (890–1360) µg] and Group 80 [790 (590–950) µg]. Umbilical arterial pH was greater in Group 100 [mean 7.32 (95% confidence interval 7.31–7.34)] than in Group 80 [7.30 (7.28–7.31)] (P=0.034). No patient had umbilical arterial pH <7.2. In Group 100, 1/24 (4%) patients had nausea or vomiting compared with 4/25 (16%) in Group 90 and 10/25 (40%) in Group 80 (P=0.006).

Conclusions. For optimal management, phenylephrine should be titrated to maintain maternal BP at near-baseline values.

Br J Anaesth 2004; 92: 469–74

Keywords: anaesthetic techniques, subarachnoid; complications, hypotension; surgery, Caesarean section; sympathetic nervous system, phenylephrine


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Recent data support the use of {alpha}-agonists such as phenylephrine to maintain maternal arterial blood pressure (BP) during spinal anaesthesia for Caesarean section.13 However, the optimal regimen for administration of phenylephrine is undetermined. As phenylephrine is highly efficacious, it can be titrated to maintain arterial pressure over a wide range of values. However, the threshold or level of BP that should be targeted or treated is unknown. Previously, it has been recommended that vasopressors be administered when BP decreases below various arbitrary definitions of hypotension; for example, to less than 70–80% of baseline or below 90–100 mm Hg systolic pressure.4 However, few data are available to support this practice. In theory, the ideal vasopressor regimen would balance the efficacy of phenylephrine in maintaining uteroplacental perfusion pressure against its potential to cause uteroplacental vasoconstriction, both of which may affect fetal acid–base status. The aim of our study was to compare i.v. phenylephrine infusion regimens based on three different thresholds of BP. The main outcome measure we compared was the umbilical artery pH.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
After obtaining approval from the Clinical Research Ethics Committee of the Chinese University of Hong Kong, we recruited 75 ASA physical status I and II women with term singleton pregnancies scheduled for elective Caesarean section under spinal anaesthesia. All patients gave written informed consent. We excluded patients with pre-existing or pregnancy-induced hypertension, cardiovascular or cerebrovascular disease, known fetal abnormalities or contraindications to spinal anaesthesia.

Patients were premedicated with famotidine 20 mg orally the night before and on the morning of surgery. On arrival in the operating theatre, sodium citrate 0.3 M, 30 ml was given orally. Standard monitoring, using the integrated monitors of the anaesthetic machine (Narkomed 4; North American Dräger, Telford, PA, USA) was attached, including non-invasive BP, electrocardiography and pulse oximetry. Fetal heart rate was monitored by external cardiotocography until the time of surgical preparation. We allowed patients to rest undisturbed in the supine position for several minutes, during which time BP was measured every 1–2 min. Left uterine displacement was achieved by tilting the operating table to the left. Blood pressure measurements were continued until they became consistent (three successive measurements of systolic blood pressure (SBP) that had a difference of no more than 10%). Baseline SBP and heart rate (HR) were taken as the mean of the three recordings.

We then inserted a 16 gauge i.v. catheter under local anaesthesia. No i.v. prehydration was given.58 We started an i.v. infusion of lactated Ringer’s solution at a minimal rate to maintain vein patency. The fluid infusion was continued at this rate throughout the study without adjustment, regardless of maternal haemodynamic changes. Spinal anaesthesia was induced with patients in the right lateral position. After skin infiltration with lidocaine, a 25 gauge Whitacre needle was inserted at what was estimated to be the L2–3 or L3–4 vertebral interspace and hyperbaric bupivacaine 0.5%, 2.0 ml (10 mg) and fentanyl 15 µg were injected intrathecally. Patients were then immediately turned supine with left uterine displacement. Blood pressure was measured at 1-min intervals beginning 1 min after spinal injection. Haemodynamic data were downloaded to a computer from the anaesthetic machine at 5-s intervals using software developed within our department.

We prepared a solution of phenylephrine 100 µg ml–1, which we infused using a syringe pump (Graseby 3500 Anaesthesia Pump; Graseby Medical, Watford, UK) via a three-way stopcock attached to the i.v. cannula. We started the infusion at 100 µg min–1 (60 ml h–1) immediately after completion of intrathecal injection and continued it for a minimum of 2 min. Subsequently, until the time of uterine incision, we adjusted the infusion according to each 1-min measurement of SBP. We continued to infuse phenylephrine at 100 µg min–1 each minute if SBP was less than or equal to a randomly assigned percentage of baseline: 100% (Group 100), 90% (Group 90) or 80% (Group 80). The infusion was turned off if the SBP was greater than the assigned value. Randomization was according to computer-generated randomization codes contained in sealed, sequentially numbered envelopes. Replacement randomization was used when the codes were generated to ensure equal numbers in each group.9 The rate and timing of phenylephrine infusion were chosen according to our previous experience.10

Patients were not informed of the group to which they were allocated. However, it was not considered practical to blind the investigator responsible for titrating the phenyl ephrine infusion. We did not routinely give oxygen unless the arterial oxyhaemoglobin saturation decreased to less than 95%, when we gave oxygen 5 litres min–1 by clear facemask. If SBP did not increase above the assigned level after three successive BP measurements, we gave a rescue bolus of phenylephrine 100 µg i.v. from a separate syringe. We treated bradycardia (defined as HR <50 beats min–1) that was associated with SBP greater than or equal to baseline by stopping the phenylephrine infusion, and treated bradycardia that was associated with SBP less than baseline with i.v. atropine 0.6 mg. We recorded any incidences of nausea (reported by patients) or vomiting (observed by investigators).

Five minutes after intrathecal injection, we measured the upper sensory level of anaesthesia by assessing loss of pinprick discrimination and then invited the surgeon to scrub. Further checks of the block height were made as required before the start of surgery but these levels were not recorded as part of the study. We recorded the times of skin incision, uterine incision and delivery with a stopwatch. We continued the phenylephrine infusion protocol until the time of uterine incision, after which further management was at the discretion of the attending anaesthetist. We recorded the total dose of phenylephrine given up to the time of uterine incision as measured by the syringe pump.

After delivery, we gave oxytocin 5–10 IU by slow i.v. injection. The attending paediatrician, who was blinded to the patient’s group, assessed Apgar scores 1 and 5 min after delivery. We took arterial and venous blood samples from a double-clamped segment of umbilical cord for immediate blood gas analysis using a Ciba-Corning 278 Blood Gas System blood gas analyser (Ciba-Corning, Medfield, MA, USA).

Prospective power analysis was based on the primary outcome, which was defined as the umbilical artery pH. Using data from our previous studies, we calculated that a sample size of 23 patients per group would have 90% power at the 5% significance level to detect a difference in umbilical arterial pH of 0.03 units among groups. To allow for potential dropouts, we decided to recruit a total of 25 patients per group. Secondary outcomes that we compared included the incidence, frequency and magnitude of hypotension (defined for the analysis as a decrease in SBP below baseline by more than 20%), the incidence of reactive hypertension (defined for the analysis as an increase in SBP above baseline by more than 20%), the incidence of bradycardia, and the incidence of nausea or vomiting. We compared data using one-way ANOVA, ANOVA for repeated measures and the Kruskal–Wallis test, with post hoc comparisons using Tukey’s honestly significant difference test and the Mann–Whitney U test. We compared nominal data using the {chi}2 test. We applied modified Bonferroni corrections for post hoc multiple comparisons as appropriate. P<0.05 was considered significant. All analyses were performed using SPSS 10.1.4 for Windows (SPSS, Chicago, IL, USA).


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Spinal anaesthesia was successful in all patients. No patient complained of significant intraoperative pain and no patient required intraoperative supplementation with analgesics or sedatives. One patient in Group 100 was excluded because severe shivering prevented accurate measurement of BP. Umbilical cord blood gases could not be measured for technical reasons in two patients in Group 80 and three patients in Group 100. The total dose of phenylephrine was different among groups (Table 1). One patient in Group 80 required a single i.v. rescue bolus of phenylephrine; in all other patients, whenever hypotension occurred it was rectified within 2 min of continuing or restarting the phenylephrine infusion. One patient in Group 100 and three patients in Group 80 required supplementary oxygen. By chance, patients in Group 90 were shorter than patients in Group 80 [mean difference 4 (95% confidence interval 1–7) cm, P=0.01] and patients in Group 100 [3 (0–7) cm] (P=0.037). There was no difference among groups in block height at 5 min or other patient characteristics (Table 1).


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Table 1 Patient characteristics, surgical times and phenylephrine consumption. Values are mean (range) for age, mean (SD) or median (interquartile range)
 
Neonatal outcome is shown in Table 2. The primary outcome measure, umbilical artery pH, was significantly different among groups (P=0.036). Post hoc tests showed that umbilical artery pH was greater in Group 100 [mean 7.32 (95% confidence interval 7.31–7.34)] than in Group 80 [7.30 (7.28–7.31)] (P=0.034). No patient in any group had umbilical artery pH <7.2. One infant in Group 100 had a 1 min Apgar score of 6; all other Apgar scores at 1 min were >=7 and all Apgar scores at 5 min were >=9.


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Table 2 Neonatal outcome. Values are mean (SD) or number (%). NS = not significant
 
Maternal haemodynamic changes are shown in Figs 1 and 2 and Table 3. As the time from induction to delivery varied among patients, serial haemodynamic changes were only compared up to the earliest time of uterine incision, which was 14 min. Changes in SBP and HR over time were significantly different among groups (P<0.001). SBP was greater over time in Group 100 compared with Group 80 (P<0.001) and Group 90 (P=0.009). The number of patients with hypotension and the number of episodes of hypotension were different among groups (P<0.001) and smallest in Group 100. The incidence of reactive hypertension was similar among groups. Bradycardia occurred in several patients in each group; the incidence was similar among groups and only two patients required treatment with atropine. The incidence of nausea and vomiting was different among groups (P=0.006) and was smaller in Group 100 than in Group 80.



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Fig 1 Serial changes in systolic blood pressure. Data are mean and standard deviation. Changes over time were significantly different among groups (P<0.001).

 


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Fig 2 Serial changes in heart rate. Data are mean and standard deviation. Changes over time were significantly different among groups (P<0.001).

 

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Table 3 Maternal haemodynamic changes and side-effects. Values are number (%) or median (range). *Systolic blood pressure <80% of baseline. **Systolic blood pressure >120% of baseline
 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The results of our study showed that umbilical artery pH was greatest and the incidence of nausea and vomiting was smallest when phenylephrine was titrated with the aim of maintaining maternal BP at 100% of baseline. Despite giving a median total phenylephrine dose of 1.5 mg in Group 100, there was no evidence of any detrimental effect on neonatal outcome as assessed clinically and biochemically.

Although we found a statistically significant difference among groups in umbilical artery pH, the difference was small and all values were within the range seen after normal uncomplicated deliveries.11 Therefore, the difference in itself is unlikely to be of clinical importance. Nonetheless, the finding that umbilical artery pH was greatest in Group 100 is reassuring and provides evidence for the safety of using phenylephrine in doses required to maintain haemodynamic stability and prevent maternal symptoms. In particular, nausea and vomiting is a frequent and unpleasant symptom of hypotension; our study showed that its incidence can be effectively and safely reduced by tight control of BP using phenylephrine.

The reason why umbilical artery pH was slightly greater in Group 100 is uncertain. Theoretically, it could be explained by better maintenance of uteroplacental perfusion pressure and blood flow. Although there was a trend towards a smaller uterine incision-to-delivery time in Group 100 compared with the other groups, the difference was small, and probably not clinically important. Of note, base excess was similar among groups, which suggests a predominantly respiratory component in the difference in umbilical artery pH. Previously, it has been reported that acute uteroplacental insufficiency is associated with fetal respiratory acidaemia.12 In our study, the trends towards smaller values for umbilical artery PCO2 and greater values for umbilical artery PO2 in Group 100 would support an effect on uteroplacental blood flow as the explanation for the difference in umbilical artery pH. However, without directly measuring uteroplacental blood flow, this explanation remains speculative. In our study, we titrated the phenyl ephrine infusion according to maternal BP. Concurrent measurement of cardiac output would probably have yielded more useful information, but this is difficult to perform in the clinical setting.

The results of our study contrast markedly with those of studies where ephedrine has been used to maintain BP during spinal anaesthesia for Caesarean section. Prophylactic ephedrine, even in large doses, has limited efficacy and does not reduce the incidence of fetal acidosis.13 Historical recommendations that ephedrine was the vasopressor of choice were based on animal experiments that had questionable applicability to clinical obstetric practice. More recent clinical studies have shown that {alpha}-agonists such as phenylephrine and metaraminol are associated with better fetal acid–base status than ephedrine.13 Early papers suggested that vasopressors had detrimental effects on uteroplacental circulation and that their use should therefore be avoided until other measures of maintaining maternal BP had failed.14 The resulting reluctance to use vasopressors liberally has resulted in an emphasis on non-pharmacological methods for maintaining BP, such as i.v. fluid prehydration; however, recent data show that this has poor efficacy.6 7 The results of our present study argue further against this approach and suggest that it is safe to titrate phenylephrine, as required, to maintain maternal BP at values near normal.

Although we found that phenylephrine appeared safe from a fetal perspective, there may be some concern about its propensity to cause maternal bradycardia. In the present study, we found that maternal HR was relatively low in most patients (Fig. 2) and in approximately one-fifth of all patients it transiently decreased to less than 50 beats min–1. As this was not associated with hypotension in most cases and HR in most patients increased after stopping phenyl ephrine administration, the decrease in HR most likely reflected a physiological baroreceptor reflex. As there were no detrimental effects on neonatal outcome, this indicates that relatively low maternal HRs are well tolerated if maternal BP is maintained. However, it should be noted that, in two patients, bradycardia was accompanied by hypotension and treatment with atropine was required. Theoretically, glycopyrrolate may have been a more appropriate anticholinergic agent as its quaternary structure limits placental transfer,15 but unfortunately this drug is not available in Hong Kong. An alternative approach that has been described recently would be to combine phenylephrine with ephedrine.2 16 However, although this technique potentially might decrease the incidence of maternal bradycardia, it has been associated with a large incidence of fetal acidosis16 and a greater incidence of nausea and vomiting compared with phenylephrine alone.2

We chose not to administer prehydration before induction of spinal anaesthesia. Although controversial, this practice is supported by recent reports.58 For example, in a previous study we used an infusion of metaraminol to maintain arterial blood pressure in women having spinal anaesthesia for Caesarean section with or without prehydration with 20 ml kg–1 lactated Ringer’s solution.8 We found that although prehydration reduced the maximum rate of metaraminol required and the dose given in the first 5 min, the total overall dose of vasopressor, haemodynamic changes, incidence of hypotension, incidence of nausea and vomiting, Apgar scores and fetal acid–base status were similar regardless of whether prehydration was given. Other authors have reported similar findings and have suggested that routine crystalloid prehydration is not necessary.6 7

By chance, patients in Group 90 were shorter than patients in the other groups. However, there was no difference in block height measured at 5 min. Therefore, the difference in height is unlikely to have been a significant confounding factor in our analysis.

In conclusion, our study suggests that when phenylephrine is infused to maintain maternal BP during spinal anaesthesia for Caesarean section, the optimal regimen is to titrate it with the aim of maintaining maternal BP at values near baseline.


    Acknowledgements
 
We thank the midwives of the Labour Ward, Prince of Wales Hospital, Shatin, Hong Kong, for their help and cooperation with this study.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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14 James FM, III, Greiss FCJ, Kemp RA. An evaluation of vasopressor therapy for maternal hypotension during spinal anesthesia. Anesthesiology 1970; 33: 25–34[ISI][Medline]

15 Ali-Melkkila T, Kaila T, Kanto J, Iisalo E. Pharmacokinetics of glycopyrronium in parturients. Anaesthesia 1990; 45: 634–7[ISI][Medline]

16 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[ISI][Medline]