Ephedrine Versus Phenylephrine Boluses
The use of phenylephrine boluses of 100 μg for the treatment of hypotension was associated with a lower incidence of IONV than was ephedrine 6 to 10 mg despite a similar incidence and frequency of hypotension.14,15 The lower incidence of IONV with the use of phenylephrine might be related to the faster onset of pressor effect compared with ephedrine (mean onset 61 seconds vs 89 seconds),16 leading to more rapid correction of hypotension. The use of lower doses of phenylephrine of 40 to 80 μg, however, failed to reduce the incidence of IONV compared with ephedrine 5 to 10 mg,17,18 with the 40-μg dose being associated with a higher incidence of hypotension than ephedrine 5 mg.18 Similarly, the addition of 20 μg of phenylephrine to a 5-mg ephedrine bolus for the treatment of hypotension was not effective in reducing the incidence of hypotension or IONV compared to ephedrine alone.19
Ephedrine Versus Phenylephrine Infusions
In contrast to treating established hypotension, the use of a prophylactic vasopressor infusion might be more effective in reducing the incidence of hypotension and IONV. The use of prophylactic phenylephrine infusions ranging from 33 to 100 μg/min has been more effective in reducing the incidence of hypotension and IONV than prophylactic ephedrine infusions 1 to 8 mg/min.12,20,21 However, the use of a lower infusion rate of phenylephrine at 10 μg/min was not better than ephedrine 1 to 2 mg/min in reducing the incidence of hypotension or IONV.22 Reactive hypertension has been reported with the use of prophylactic vasopressor infusions11,12,20,23–26; however, this is usually transient and responds quickly to stopping the infusion.
Combined Ephedrine and Phenylephrine Infusions
The addition of phenylephrine 10 μg/min to an ephedrine infusion at 2 mg/min resulted in a significantly lower incidence of hypotension and IONV than did ephedrine alone.25 In contrast, the addition of ephedrine to a phenylephrine infusion did not result in any extra benefit over phenylephrine alone in terms of lower incidence of hypotension or IONV,12,21 with 1 study reporting the incidence of IONV increasing from 17% with phenylephrine alone to 55% when ephedrine was added to phenylephrine, despite similar arterial blood pressure control.21 Cooper et al. suggested that this might be secondary to phenylephrine-induced venoconstriction, reducing preload and avoiding excessive β-adrenergic stimulation.21 This in turn decreases the risk of increased vagal tone that might lead to IONV with spinal anesthesia. Furthermore, another study comparing various combinations of phenylephrine and ephedrine infusions reported that as the proportion of phenylephrine decreased and the proportion of ephedrine increased, hemodynamic control worsened and the incidence of IONV increased.12 In this study, the groups contained the proportional potency equivalent of 100%, 75%, 50%, 25%, or 0% of phenylephrine and 0%, 25%, 50%, 75%, or 100%, respectively, of ephedrine, assuming 100 μg phenylephrine to be equipotent to 8 mg ephedrine.
Phenylephrine Bolus Versus Phenylephrine infusion
Administration of phenylephrine as a prophylactic infusion was associated with an incidence of hypotension of 13%–23% compared to an incidence of 85%–88% when phenylephrine boluses of 100 μg were used to treat a 20% decrease in arterial blood pressure.11,27 Infusions compared to bolus administration were also associated with a lower incidence of IONV.11 Allen et al.,26 however, did not find a reduction in the incidence of IONV with the use of prophylactic phenylephrine infusions at 25, 50, 75, and 100 μg/min compared to treatment of hypotension with 100 μg phenylephrine boluses, despite a significantly lower incidence of hypotension with the infusion regimens. Data collection in this latter study continued for 10 minutes after delivery, and therefore exteriorization of the uterus, visceral manipulation, and administration of oxytocin might have contributed to a higher overall incidence of nausea in all groups. In another study, the administration of a single prophylactic phenylephrine bolus of 50 μg was less effective than a prophylactic infusion in reducing the incidence of hypotension and IONV.27
Comparison of Different Phenylephrine Infusion Regimens
A phenylephrine infusion at 100 μg/min combined with a 2-L crystalloid coload was associated with a lower incidence of hypotension, compared to a similar regimen with fluid administered at a minimal rate (1.9% vs 23.8%).23 The incidence of IONV was low and not different between the groups. In another study by the same group of investigators, a similar phenylephrine infusion regimen initiated at 100 μg/min was titrated to maintain systolic blood pressure at 80%, 90%, or 100% of baseline.24 The incidence of IONV was lowest in the group with the blood pressure goal of 100% of baseline. Stewart et al. reported a dose-related reduction in the incidence of IONV as the infusion rate increased from phenylephrine 25 μg/min (25% incidence) to 50 μg/min (4%) and 100 μg/min (0%). There was also a significant dose-related increase in systolic blood pressure in this study.28 These studies stopped data collection at delivery or uterine incision.23,24,28 Allen et al. however collected data up to 10 minutes after delivery and reported a higher incidence of IONV, ranging from 32% to 40%, with phenylephrine infusions of 25, 50, 75, and 100 μg/min; there was no significant difference among groups.26 Although the incidence of hypotension was higher in the lower-infusion-rate groups, the differences were not statistically significant, and the study was not powered for this endpoint.
INTRAOPERATIVE HEART RATE AND CARDIAC OUTPUT
Heart Rate Changes
Phenylephrine has both direct and indirect sympathomimetic effects; it primarily functions as an α-adrenergic receptor agonist. The indirect effect results from norepinephrine release from nerve terminals' storage sites.29 Unlike ephedrine, it lacks direct inotropic or chronotropic effects. Phenylephrine administration is associated with reflex bradycardia. Studies have consistently reported a slower heart rate with phenylephrine than with ephedrine.12,14–17,20,21,30 Use of prophylactic phenylephrine infusions is associated with an overall slower heart rate compared to treatment of hypotension with phenylephrine boluses.11,31 Comparison of different phenylephrine infusion rates demonstrate dose-related reductions in heart rate.24,28 Bradycardia occurring during administration of a prophylactic phenylephrine infusion should be managed by reducing the rate or stopping the infusion, unless accompanied by hypotension. Administration of an anticholinergic to treat bradycardia in the absence of hypotension results in significant hypertension.26,32
Cardiac Output Changes
Initiation of spinal anesthesia is associated with changes in cardiac output. Robson et al. used intermittent suprasternal Doppler flow measurements at 5, 10, and 15 minutes after spinal anesthesia with 10 to 12.5 mg hyperbaric bupivacaine in 16 women receiving a prophylactic ephedrine infusion.33 Stroke volume was significantly decreased in 16 patients, and cardiac output was reduced in 12; the decrease in cardiac output exceeded 1 L/min in 9 subjects. More recently, Langesaeter et al. measured cardiac output continuously using pulse waveform analysis after spinal anesthesia using bupivacaine 7 to 10 mg with or without a phenylephrine infusion at 0.25 μg/kg/min, and reported an initial decrease in systemic vascular resistance together with a concomitant increase in cardiac output after the initiation of spinal anesthesia31; such an increase may be missed in studies using intermittent measurements starting several minutes after initiation of the spinal anesthetic.
Studies investigating cardiac output changes associated with phenylephrine suggest that heart rate changes parallel changes in cardiac output. An earlier study using intermittent suprasternal Doppler for 15 minutes after intrathecal injection reported no overall changes in cardiac output with ephedrine 5 mg compared to phenylephrine 100 μg for the treatment of hypotension.30 This study, however, did not specifically report cardiac output changes immediately after vasopressor administration. Furthermore, atropine was used in 58% of patients who received phenylephrine. More recently, Dyer et al. measured cardiac output continuously using pulse waveform analysis and thoracic bioimpedance. In patients who required a vasopressor to treat a 20% decrease in mean arterial blood pressure, there was a 35% decrease in systemic vascular resistance compared to baseline, accompanied by a 12% increase in heart rate, 9% increase in stroke volume, and 23% increase in cardiac output before vasopressor administration. Cardiac output and heart rate were significantly lower during the 150 seconds after administration of a phenylephrine bolus of 80 μg compared to ephedrine 10 mg for the treatment of hypotension, but cardiac output values after phenylephrine administration [mean ± SD (5.2 ± 1.5 L/min)] were still numerically higher than baseline values (4.6 ± 0.9 L/min).16 In comparison with prevasopressor values, cardiac output increased by 5% with ephedrine and decreased by 14% with phenylephrine. Stroke volume was not different between the groups. Heart rate was slower in patients receiving phenylephrine and strongly correlated with cardiac output. The authors suggested that maintaining heart rate at baseline might therefore be a surrogate for maintaining baseline cardiac output.
In women receiving phenylephrine infusions at 25, 50, and 100 μg/min after spinal anesthesia with 11 mg hyperbaric bupivacaine, there were significant dose-related and time-related reductions in heart rate and cardiac output measured using suprasternal Doppler for 20 minutes after intrathecal injection.28 Stroke volume remained stable with no significant differences among the groups, suggesting that cardiac output changes were mainly due to heart rate reduction. In another study using lower doses of intrathecal bupivacaine (7 and 10 mg), Langesaeter et al. randomized patients to receive a prophylactic low-dose phenylephrine infusion (0.25 μg/kg/min, equivalent to about 20 μg/min) or placebo. Hypotension was treated with phenylephrine boluses of 30 μg. The investigators reported that heart rate and cardiac output were also significantly lower in patients receiving the phenylephrine infusion.31 The initial increase in cardiac output seen after initiation of spinal anesthesia was obtunded with phenylephrine. Similar to other studies, stroke volume was not different between groups.
Cardiac Output Changes in Women with Pre-Eclampsia
Tihtonen et al. measured cardiac output using bioimpedance in 10 pre-eclamptic women undergoing cesarean delivery under spinal anesthesia and compared hemodynamic variables with those of healthy parturients.34 At baseline, mean arterial blood pressure and systemic vascular resistance index were higher, while stroke index and cardiac index were lower in pre-eclamptic women. Systemic vascular resistance index and mean arterial blood pressure decreased in both groups after spinal anesthesia, while cardiac index and stroke index were not changed. Hypotension, defined as a decrease in systolic arterial blood pressure to 80% of baseline or <100 mm Hg, occurred in 3 patients with pre-eclampsia and was treated with ephedrine, which increased both mean arterial blood pressure and systemic vascular resistance index. In another observational study involving 15 women with severe pre-eclampsia undergoing cesarean delivery under spinal anesthesia,35 Dyer et al. reported that cardiac output was higher than baseline when women were placed supine before lateral tilt immediately after spinal placement, and then was not different from baseline until it increased after delivery and oxytocin administration. In this study, 10 patients received phenylephrine 50 μg boluses for the treatment of a 20% decrease in mean arterial blood pressure. Phenylephrine administration was associated with a significant decrease in heart rate, a trend toward a reduction in cardiac output, and no change in stroke volume.
Assessments of Uteroplacental Perfusion
A few studies compared the effects of ephedrine to phenylephrine and other α-agonists on uteroplacental circulation using ultrasound measurements. These studies reported on the pulsatility index in maternal and fetal vessels, which is calculated as the difference between the peak systolic and end-diastolic flow velocity divided by the average flow velocity.36 Alahuhta et al. administered a bolus of ephedrine 5 mg or phenylephrine 100 μg followed by an infusion of ephedrine 50 mg/h or phenylephrine 1000 μg/h when the level of spinal block reached T5.36 The investigators reported that compared to baseline, mean maternal uterine and placental arcuate arteries pulsatility index values were increased in patients receiving phenylephrine but not those receiving ephedrine, suggesting an increase in vascular resistance with phenylephrine. In contrast, the pulsatility index in fetal renal arteries decreased with phenylephrine. There was no change in fetal umbilical artery pulsatility in either group. In another study in which hypotension was treated with boluses of ephedrine 5 mg or phenylephrine 100 μg,30 there was also no difference in umbilical artery pulsatility index measured at baseline and 15 minutes after initiation of spinal anesthesia. Similarly, Ngan Kee et al. reported no difference in uterine artery pulsatility index in parturients who received a prophylactic ephedrine or metaraminol infusion initiated immediately after induction of spinal anesthesia.37
Apgar Scores and Umbilical Cord Blood Gases
Neonatal assessments were performed in most studies using Apgar scores and umbilical cord blood gas and pH analysis, with the latter commonly being the primary outcome of the study. While Apgar scoring is widely used in clinical practice, and provides a useful assessment of the condition of the infant in the first minutes after birth, its usefulness as a predictor of neonatal outcome continues to be debated. For instance, low Apgar scores alone are not sufficient evidence of hypoxia that might cause neurological damage.38 Poor correlation between Apgar scores and umbilical cord pH has been observed.39 On the other hand, umbilical cord blood gas and pH provide an indication of the fetal condition immediately before delivery, and might therefore be more useful than Apgar scores when assessing perfusion and the impact of vasopressors on the fetus. While pH is most commonly quoted, the scale is logarithmic. Therefore, the base excess, which is also adjusted for PCO2, provides a more linear measure of metabolic acid accumulation. Low arterial cord pH may be associated with clinically significant neonatal outcomes.40 While umbilical artery pH of 7.2 was historically considered the lower limit of normal,41 the use of this threshold value has been challenged. It has been suggested that pH values of 7.02 to 7.18 represent the lower limit of normal umbilical artery pH.42 In fact, a pH<7.0 seems to be a better threshold value since significant adverse outcomes in the neonate are rare with umbilical artery pH >7.0 or base excess >−12 mmol/L.43
Studies examining Apgar scores and fetal acid-base status have consistently reported no difference in Apgar scores, but a higher umbilical artery pH and base excess with IV phenylephrine compared with ephedrine in low-risk parturients undergoing elective cesarean delivery (Table 3). This result has been reported whether the vasopressors were administered as a bolus for the treatment of established hypotension or as a prophylactic infusion. The higher fetal pH has been attributed to a greater placental transfer of ephedrine compared to phenylephrine (median umbilical vein/maternal artery concentration ratio of 1.13 compared with 0.17) and less early metabolism or redistribution in the fetus of the more lipid soluble ephedrine.20 In turn, fetal ephedrine stimulates fetal β-adrenergic receptors, therefore increasing metabolic activity,20,21,44 and resulting in higher umbilical artery and vein PCO2, lower fetal pH, and increased fetal concentrations of lactate, glucose, epinephrine, and norepinephrine.20,21,45 The difference in pH is usually in the range of 0.01 to 0.08 pH units. It is unclear whether this difference is clinically relevant in low-risk pregnancies.
Some studies have reported a lower umbilical artery and umbilical vein PO2 with phenylephrine compared with ephedrine, possibly related to greater vasoconstriction of the uteroplacental circulation with resultant reduced flow and increased oxygen extraction.12,14,20 This does not appear to have a detrimental effect on the neonate. Sheep studies suggest that this lack of adverse effect is due to greater uterine blood flow relative to what is required to meet fetal oxygen demand under normal physiologic conditions.46
All the above studies were conducted in women with low-risk pregnancies undergoing elective cesarean delivery. In women undergoing nonelective cesarean delivery, there was no difference in acid-base status when hypotension was treated with ephedrine or phenylephrine boluses, but fetal lactate concentrations were higher with ephedrine.14 Similarly, in a retrospective study, Cooper et al. reported no difference in umbilical artery pH with the use of ephedrine or phenylephrine for arterial blood pressure control in high-risk cesarean deliveries.47
When comparing different regimens of phenylephrine administration, there was no difference in neonatal acid-base status when phenylephrine was administered as a bolus for the treatment of hypotension or as a prophylactic infusion, despite a lower incidence of maternal hypotension with the infusion.11,26 This is probably due to prompt treatment and short duration of hypotension. However, infusions titrated to maintain maternal systolic blood pressure at baseline were associated with a small (0.02 pH unit difference) but statistically significantly higher umbilical artery pH compared to infusion rates titrated to maintain blood pressure at 80% or 90% of baseline.24
Optimum Dosing and Administration Regimen of Phenylephrine
The optimal administration regimen for phenylephrine is unknown. Treatment of established hypotension by bolus administration is simple but associated with more hypotension and more IONV than prophylactic infusions.11,26 Conversely, prophylactic administration is associated with a higher incidence of reactive hypertension and bradycardia. Studies have generally used phenylephrine bolus doses ranging from 40 to 100 μg. Doses of 40 to 80 μg were associated with a higher incidence of hypotension and failed to reduce the incidence of IONV compared with ephedrine in some studies.17,18 Furthermore, 2 recent dose-finding studies using an up–down sequential allocation methodology suggested that a dose of phenylephrine higher than what is routinely used in practice and in previous studies may be needed for bolus administration. Tanaka et al. reported that the ED95 of a prophylactic bolus dose of phenylephrine to prevent hypotension or nausea, when given immediately after intrathecal injection of 12 mg hyperbaric bupivacaine, was 159 μg (95% confidence interval: 122 to 371 μg).48 For the treatment of established hypotension after intrathecal administration of a similar dose of bupivacaine, George et al. estimated that the ED90 of a bolus dose of phenylephrine was 147 μg (95% confidence interval: 98 to 222 μg).49 It is important to note that both studies estimated the dose needed early after intrathecal injection when the sympathectomy was evolving; this might differ from the dose required to treat hypotension later, once the block has stabilized.
When given as a prophylactic infusion, phenylephrine doses ranging from 10 to 100 μg/min have been used; however, the 10 μg/min dose was ineffective with a 90% incidence of hypotension.22 Two recent dose–response studies investigated fixed phenylephrine infusion doses ranging from 25 to 100 μg/min.26,28 Both groups of investigators recommended the use of lower infusion rates of 25 to 50 μg/min because these were associated with less reactive hypertension,26 bradycardia,28 and reduction in cardiac output28 compared to higher-dose infusions. The 50 μg/min rate was also associated with the fewest number of physician interventions needed to maintain arterial blood pressure within the target range and had the lowest degree of inaccuracy of systolic blood pressure control compared to the 25, 75, and 100 μg/min rates; the differences were, however, only statistically significant when compared to the 100 μg/min group.26 The choice of a starting infusion rate balances the risk of hypotension versus reactive hypertension. For instance, the 25 μg/min rate has been associated with an incidence of hypotension of 30%–40%, compared to 15%–20% with 50 μg/min.26,28 However, the incidence of reactive hypertension was 40% and 25% with the 50 and 25 μg/min doses, respectively.26,50
With the exception of the study by Cooper at al,21 most of the published studies to date have investigated a fixed-rate infusion regimen that is switched on and off based on blood pressure response.11,12,20,22–24,26,28 While this technique is simple, a variable rate infusion titrated to blood pressure changes may allow more accurate blood pressure control. Recently, Ngan Kee et al. reported that a closed-loop variable rate algorithm provided tighter and more accurate blood pressure control compared to the manual on/off technique, but with no difference in other maternal or neonatal outcomes.51 More studies investigating variable rate phenylephrine infusions are needed.
An additional difficulty is that studies have used different goals for blood pressure control with a prophylactic phenylephrine infusion. For instance, while some studies have switched the infusion off when the blood pressure exceeded baseline,28 others have used the same target but allowed a 20% blood pressure increase in the first 2 to 3 minutes,11,12,20,23 or allowed a 20%–25% increase in blood pressure from baseline throughout the duration of the infusion.21,22,26 Allowing an increase in blood pressure from baseline increased the incidence of reactive hypertension with higher infusion rates of 100 μg/min, but not with rates of 25 and 50 μg/min.26,50 It is not clear, however, if different targets have an impact on the occurrence of hypotension, IONV, or need to make frequent adjustments to the infusion rate. Most studies have also allowed a 20% decrease in blood pressure. A study by Ngan Kee et al., however, reported that the incidence of IONV is lowest and fetal pH highest when blood pressure is maintained at 100% of baseline compared to allowing a 10%–20% decrease in blood pressure.24
Fluid administration regimens also varied among the studies. This should be considered when comparing the results of different studies to determine the optimum administration regimen for phenylephrine. For instance, in women receiving a prophylactic phenylephrine infusion, administering a 2 L crystalloid coload was associated with a lower incidence of hypotension and reduced phenylephrine requirements compared with administering fluids at a minimal rate.23
The optimum duration of phenylephrine infusion is also not known. Most studies have stopped the infusion at uterine incision,11,12,20,21,23,28 while Allen at al.26 continued the infusion for 10 minutes after delivery to counteract oxytocin induced hypotension.
Both ephedrine and phenylephrine are effective in managing spinal anesthesia-induced hypotension. Phenylephrine may be associated with a lower incidence of IONV, and higher umbilical artery pH and base excess compared with ephedrine. However, the difference in pH is small and unlikely to be clinically relevant in low-risk deliveries. Administration of phenylephrine as a prophylactic infusion is more effective in reducing the incidence of hypotension and IONV compared with bolus administration. However, phenylephrine use is associated with a decrease in maternal cardiac output. The clinical significance of this reduction in healthy low-risk parturients is unclear. Studies suggest that such changes do not appear to have any consequences in healthy mothers. The optimum phenylephrine administration regimen is unclear. Studies addressing the use of phenylephrine in high-risk pregnancies, such as those complicated by placental insufficiency, preeclampsia, and growth restriction, are needed.
Name: Ashraf S. Habib, MBBCh, MSc, MHS, FRCA.
Contribution: This author helped analyze the data and write the manuscript.
Attestation: Ashraf S. Habib approved the final manuscript.
This manuscript was handled by: Cynthia A. Wong, MD.
a McGlennan A, Patel N, Sujith B, Bell R. A survey of pre-loading and vasopressor use during regional anaesthesia for caesarean section. Int J Obstet Anesth 2007;16:S27.
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