Hypotension is the most common complication of spinal anesthesia for cesarean delivery and can be associated with considerable morbidity.1 Despite multiple techniques for preventing spinal anesthesia–induced hypotension, including fluid loading, left uterine displacement, and treatment of the hypotension with bolus doses of vasoactive medications, no single method is uniformly successful.2 Current data support the preemptive use of vasopressors, along with fluid coloading (rapid bolus of intravenous [IV] fluid at time of initiation of spinal anesthesia) to reduce the severity of spinal anesthesia–induced hypotension.3–5 In the past decade, phenylephrine has replaced ephedrine as the preferred vasopressor for healthy parturients because it is equally effective as ephedrine in treating hypotension and it is associated with higher umbilical artery pH.6–8 However, almost all vasopressor studies addressing spinal anesthesia–induced hypotension have enrolled healthy women undergoing scheduled cesarean delivery.
Preeclampsia complicates up to 5%–7% of pregnancies and is a significant contributor to maternal morbidity and mortality.9 Uteroplacental insufficiency, a hallmark of preeclampsia, results in considerable fetal morbidity and mortality. Many women with preeclampsia require cesarean delivery; spinal anesthesia is generally considered safe and preferable to general anesthesia.10 Several studies have demonstrated that women with preeclampsia experience less hypotension after spinal anesthesia than their healthy counterparts11–13; however, it is arguably more important to prevent and treat the hypotension in women with preeclampsia given the potential adverse effects to mother and fetus.
Two retrospective studies have investigated the use of phenylephrine compared with ephedrine for the treatment of spinal anesthesia–induced hypotension in women with preeclampsia; neither demonstrated a difference in fetal outcomes.14,15 The aim of the current randomized controlled trial was to compare IV infusion regimens of phenylephrine versus ephedrine for the prevention of spinal anesthesia–induced hypotension in nonlaboring preeclamptic patients undergoing cesarean delivery. We hypothesized that phenylephrine compared to ephedrine would result in higher umbilical artery pH when used for the prevention of hypotension in women with preeclampsia undergoing cesarean delivery with spinal anesthesia. The primary outcome variable was umbilical artery blood pH.
The study was approved by the institutional review board for human subjects at Northwestern University (STU00014037). The protocol was registered at ClinicalTrials.gov (NCT00458003), principal investigator Cynthia A. Wong, registration date April 4, 2007. This manuscript adheres to the Consolidated Standards of Reporting Trials (CONSORT) guidelines. The study was a double-blind, randomized controlled trial conducted at Prentice Women’s Hospital of Northwestern Medicine. Inclusion criteria were English-speaking American Society of Anesthesiologists physical status II and III women with singleton or twin pregnancies scheduled for cesarean delivery with single-shot spinal anesthesia and a diagnosis of preeclampsia. Before late 2013, preeclampsia was defined as new onset of hypertension and proteinuria after 20 weeks of gestation and further delineated as mild or severe based on blood pressure criteria and presence of end-organ dysfunction. After 2013, preeclampsia was defined as described by the American College of Obstetricians and Gynecologist Taskforce on Hypertension in Pregnancy.16 Exclusion criteria included chronic hypertension, labor or failed trial of labor, body mass index ≥40 kg/m2, resting heart rate <60 bpm, eclampsia, known fetal anomalies, contraindications to spinal anesthesia, and emergency procedures.
A convenience sample of eligible women was screened and approached shortly after admission to the Labor and Delivery Unit. Women meeting inclusion criteria provided informed written consent for study participation. Subjects were randomly allocated to receive either a phenylephrine or an ephedrine infusion commencing at the initiation of spinal anesthesia. Before the study commencement, 2-group block randomization (1:1) using randomly selected block sizes of 4 and 8 was performed by an investigator (R.J.M.) using a computer-generated allocation list.17 Group allocations were concealed in sequentially numbered opaque envelopes that were opened by the research nurse after obtaining informed consent.
A 16-gauge IV catheter was placed in an upper extremity using local anesthesia in the preoperative holding area and an infusion of lactated Ringer’s solution was initiated at a minimal rate to maintain vein patency. Subjects were allowed to rest undisturbed for several minutes in the left lateral tilt position; during this period, heart rate and blood pressure were measured every 2.5 minutes for at least 3 measurements until the variability among the 3 most recent measurements was <10%. Baseline heart rate and systolic blood pressure (SBP) were defined as the mean of these 3 measurements. Pulmonary aspiration prophylaxis with IV metoclopramide 10 mg and ranitidine 150 mg was administered at least 30 minutes before initiation of anesthesia, and 0.3 M sodium citrate 30 mL was administered orally immediately before initiation of anesthesia.
On arrival in the operating room, standard monitors were applied, including automated noninvasive blood pressure monitoring in an upper extremity. Fetal heart rate was assessed by external cardiotocography until the time of surgical preparation. Lactated Ringer’s solution was administered as a 500-mL bolus concurrently with the start of the spinal anesthesia procedure. Thereafter, fluid administration was at the discretion of the anesthesia team. Spinal anesthesia was induced with patients in the sitting position. After sterile skin preparation and draping, the skin was infiltrated with lidocaine, a 25-gauge Whitacre needle was inserted at the estimated L3–L4 or L4–L5 vertebral interspace and hyperbaric 0.75% bupivacaine 12 mg, fentanyl 15 µg, and morphine 150 µg were injected intrathecally. The patient was positioned supine with left uterine displacement. Blood pressure and heart rate were measured every minute beginning 1 minute after intrathecal injection for 10 minutes, then every 2.5 minutes for the remainder of the surgical procedure. Hemodynamic variables were recorded throughout the procedure. Five minutes after the intrathecal injection, the sensory level of anesthesia was assessed by loss-of-pinprick discrimination. Preincision antibiotics, magnesium sulfate, and uterotonic agents were administered intraoperatively per routine practice.
The unblinded research nurse prepared the solution of phenylephrine 100 µg/mL or ephedrine 8 mg/mL, depending on group assignment. The concentration of the phenylephrine and ephedrine solutions was chosen based on the relative potency ratio of 80:1 as described by Saravanan et al.18 The solution was prepared in a 20-mL syringe labeled “study medication” and placed in a syringe pump; the infusion tubing was attached to the mainline IV fluid at the IV catheter-tubing interface. The investigator administrating the study infusion, anesthesiologist, and patient were blinded to the contents of the syringe.
The infusion protocol was modeled after the protocol described by Ngan Kee et al.19,20 The infusion was initiated immediately after completion of the spinal injection at the rate of 1 mL/min for 2 minutes, after which the infusion was stopped, continued, or increased based on the SBP measurement. For purposes of this study, hypotension was defined as a 20% decrease from SBP baseline. The goal was to maintain SBP ≥80% baseline, but <160 mm Hg. If the baseline SBP >160 mm Hg, the infusion was not started until the SBP decreased to 160 mm Hg. After each measurement of SBP, the infusion was stopped if SBP was greater than baseline or greater than 160 mm Hg and continued unchanged if the SBP was between 80% and 100% of baseline. If the SBP was <80% baseline, a 1-mL bolus was administered and the infusion was increased by 1 mL/min, or restarted if it had been stopped. Bradycardia (heart rate <60 bpm) associated with an SBP equal or greater than 80% of baseline SBP was treated by stopping the study drug infusion and bradycardia associated with SBP <80% baseline was treated with IV atropine 0.4 mg. At the discretion of the attending anesthesiologist, hypotension unresponsive to study medication was treated with IV 1-mL boluses of epinephrine 10 µg/mL until correction of the hypotension. Nausea and/or vomiting not associated with hypotension were treated with IV ondansetron 4 mg. Oxygen was routinely administered via nasal cannula at 2–4 L/min.
The drug protocol was continued until delivery, after which further management to maintain SBP was at the discretion of the anesthesiologist. The total volume of the study solutions given by infusion and bolus up to the time of delivery was recorded. One- and 5-minute Apgar scores were assessed by the nurse or pediatrician blinded to subject group assignment. Arterial and venous blood samples were drawn immediately from a double-clamped segment of the umbilical cord for blood gas analysis.
The primary outcome was umbilical artery blood pH. The secondary outcome was umbilical artery base excess. Exploratory analyses included the incidence of fetal acidosis (umbilical artery pH <7.2), maternal hypotension (defined as SBP <80% baseline), the incidence of reactive hypertension (defined as an increase in SBP ≥20% above baseline), bradycardia (heart rate <60 bpm), nausea and vomiting, requirement for supplemental intraoperative analgesia, total intraoperative IV fluids, estimated blood loss, Apgar scores, and admission of the neonate to the intensive care unit.
The umbilical artery pH was compared between groups using the Mann-Whitney U test. In women with twin deliveries, the blood gases values of both twins were used in the analysis. Because pH data are a log-normal distribution, the geometric mean and the standard deviation (SD) were used as point estimates.21 Differences and ratios of the geometric means of phenylephrine and ephedrine, and the 95% confidence intervals (CIs) for the differences and ratios, were calculated using the generalized pivotal method.22 Sensitivity analyses of umbilical artery pH between phenylephrine and ephedrine groups were performed by stratifying by the maternal magnesium sulfate therapy and the severity of preeclampsia. In addition, umbilical artery pH, adjusted for infant gender and the gestational age at delivery to a gestational age of 37 weeks using population-based reference curves for umbilical artery pH, was compared between phenylephrine and ephedrine groups.23
Umbilical artery base excess was compared between groups using the Mann-Whitney U test. The median difference and 95% CI of the difference were calculated using a 10,000 sample bootstrap. Exploratory nominal outcome data were compared using the Fisher exact test; continuous and interval outcomes were compared between groups with the Mann-Whitney U test. CIs for differences in proportions were calculated using the Pearson-Klopper method. Differences in medians and 95% CI of the median difference were calculated using a 10,000 sample bootstrap. Analysis was per protocol. A P < .05 was required to reject the null hypothesis. Data analysis was performed using RStudio version 1.0.143 (RStudio: Integrated Development for R; RStudio, Inc, Boston, MA, http://www.rstudio.com/) and R version 3.4.1, release date 6/30/2017 (The R Foundation for Statistical Computing, Vienna, Austria).
A sample of 51 patients per group was calculated to have 80% power at the 5% significance level to detect an increase of 0.03 in mean of the umbilical artery pH of the phenylephrine group compared to the ephedrine group, assuming mean pH = 7.28 in the ephedrine group and a group SD of 0.05 (2-sided Mann-Whitney U test).8,24 These results were based on 2000 Monte Carlo samples from a log-normal distribution. The estimated phenylephrine:ephedrine pH ratio, based on prior studies, was 1.004.8 Calculations were performed using PASS 2005 (NCSS, LLC, Kaysville, UT). To allow for potential dropouts, we planned recruitment of 110 patients.
Subject flow is shown in the CONSORT diagram (Figure); 110 patients provided informed written consent to participate in the study and were randomized to study groups between September 27, 2006, and May 10, 2014. Fifty-four subjects in each group received the intervention and were included in the analysis of maternal outcomes. Seventy-four infants were delivered in the ephedrine group and 72 were delivered in the phenylephrine group. Umbilical artery blood gases were included in the analysis for 66 infants in the ephedrine and 61 in the phenylephrine groups. There were no clinically important differences in baseline or intraoperative characteristics between groups (Tables 1 and 2). Spinal anesthesia was successfully initiated in all study subjects. All women in both groups initially received the study drug; the infusion was stopped and not restarted after 2 minutes in 32 women (30%).
Umbilical cord blood gas values and infant outcomes are shown in Table 3. The phenylephrine:ephedrine ratio for umbilical artery pH was 1.002 (95% CI, 0.997–1.007). Mean [SD] umbilical artery pH was not different between the ephedrine 7.20 [0.10] and phenylephrine 7.22 [0.07] groups (mean difference −0.02, 95% CI of the difference −0.06 to 0.07; P = .38). Median (first, third quartiles) umbilical artery base excess was −3.4 mEq/L (−5.7 to −2.0 mEq/L) in the ephedrine group and −2.8 mEq/L (−4.6 to −2.2 mEq/L) in the phenylephrine group (P = .10). Sensitivity analyses of umbilical artery pH are shown in Table 4. Umbilical artery pH adjusted for infant gender and gestational age did not differ between groups. There were no differences in the umbilical artery pH stratified by magnesium therapy or severity of preeclampsia.
There were no differences in any maternal or neonatal exploratory outcome except the median umbilical vein Paco2 was greater in the phenylephrine group. The overall incidence of fetal acidosis (umbilical artery pH <7.2) was 34% (ephedrine group 37%, phenylephrine group 31%; difference 6% [95% CI, 12%–24%; P = .25]). The incidence of fetal acidosis was 28% in women with a single fetus and 37% in women with a multiple gestation (P = .38).
Maternal hypotension (SBP <80% of baseline) occurred in 50% of the ephedrine and 46% of the phenylephrine group, difference 4%, 95% CI, 17%–25%, P = .84. Two subjects in each group received epinephrine, and 2 subjects in the ephedrine group received atropine. There were no cases of reactive hypertension in either group. Five patients, 2 (4%) in the phenylephrine group and 3 (6%) in the ephedrine group, received extra vasopressor boluses outside of the study protocol.
The important finding of this study is that a phenylephrine infusion used to prevent hypotension immediately after the initiation of spinal anesthesia was not superior to an ephedrine infusion for the outcome of umbilical artery pH in nonlaboring women with preeclampsia undergoing cesarean delivery, although the study lacked power to identify a small difference in this outcome. Similarly, we were also unable to demonstrate a clinically important difference in umbilical artery base excess between phenylephrine and ephedrine. These findings are in contrast to the results of studies performed in healthy parturients.
Historically, ephedrine was considered the vasopressor of choice to treat spinal anesthesia–induced hypotension; however, in the past several decades, multiple studies in healthy parturients undergoing elective cesarean delivery with spinal anesthesia have shown that phenylephrine compared with ephedrine results in a more favorable fetal acid-base status.8 Thus, phenylephrine has emerged as the vasopressor of choice to prevent spinal anesthesia–induced hypotension in healthy parturients undergoing cesarean delivery. Several mechanisms may explain the advantage of phenylephrine. First, phenylephrine is a direct α-adrenergic agonist and potent vasoconstrictor. Hypotension after spinal anesthesia is primarily due to an abrupt decrease in systemic vascular resistance.25 Phenylephrine directly counteracts this mechanism of hypotension. Second, phenylephrine crosses the placenta to a lesser extent, and is more rapidly metabolized by the fetus, than ephedrine.26 Ephedrine, via its β-adrenergic stimulating effects, may stimulate metabolism in the fetus, resulting in an increased incidence of absolute fetal acidosis compared with phenylephrine.7,27 In contrast to healthy parturients, women with preeclampsia have diffuse vascular endothelial dysfunction, including placental vasculature.9 Arteriolar resistance in the uteroplacental bed is greater, resulting in decreased uteroplacental perfusion and less reserve.9 Thus, it is conceivable that women with preeclampsia, and their fetuses, may react differently to maternal vasopressor administration than healthy women.
The optimal intervention for spinal anesthesia–induced hypotension in preeclamptic patients has not been well studied. Cooper et al14 retrospectively examined outcomes in women who underwent nonelective cesarean delivery under spinal anesthesia for fetal indications (nonreassuring fetal heart rate tracing, dystocia, pregnancy-induced hypertension, growth restriction, hemorrhage, prolonged rupture of membranes, or cord prolapse). Phenylephrine infusions were standardized, but ephedrine infusions were not common and not standardized. The authors found no difference in umbilical artery pH between ephedrine and phenylephrine. Ngan Kee et al28 randomized women undergoing nonelective cesarean delivery with spinal anesthesia to receive ephedrine or phenylephrine boluses for treatment of spinal anesthesia-induced hypotension. There were no differences in umbilical artery pH or other neonatal outcomes. However, women with hypertension were excluded from this study. Mohta et al29 randomized women undergoing emergency cesarean delivery for fetal compromise with spinal anesthesia to receive either ephedrine or phenylephrine boluses and also found no differences in umbilical artery pH, incidence of fetal acidosis, and Apgar scores between the groups. Again, women with preeclampsia were excluded from this study. Ituk et al15 retrospectively studied women with preeclampsia who had spinal anesthesia for cesarean delivery and received bolus dose phenylephrine or ephedrine to treat hypotension. The investigators found no differences in umbilical artery pH.
Historically, anesthesiologists were concerned that spinal anesthesia for cesarean delivery in women with preeclampsia would result in a higher risk of clinically significant hypotension compared to epidural anesthesia. Thus, it was not until the last 2 decades that spinal anesthesia in these patients gained popularity and is now considered safe and preferable, especially compared with general anesthesia.10,30 Evidence suggests that women with preeclampsia have a lower incidence of spinal anesthesia–induced hypotension, and require less vasopressor to treat hypotension than normotensive parturients.11–13
The lack of a difference in umbilical artery pH between the groups observed in our study may be due, in part, to the small total dose of ephedrine administered to study participants (range, 10–30 mg). Ephedrine most likely induces fetal acidosis through a direct β-adrenergic–mediated mechanism and its adverse effects are dependent on total dose and duration of exposure.31
The incidence of hypotension in our study was approximately 50%. Given that women with preeclampsia are known to have less hypotension than healthy women, and that all women in the current study received a prophylactic vasopressor regimen, the incident appears high. For example, in 1 study in healthy women undergoing elective cesarean delivery with spinal anesthesia (bupivacaine dose 10 mg), the incidence of hypotension (defined as a 20% decrease in SBP from baseline) was 2% in women randomized to receive a fluid bolus and prophylactic phenylephrine infusion.5 In 2 studies assessing variable doses of prophylactic phenylephrine infusions, the incidence of hypotension (defined as a 20% decrease in baseline blood pressure) ranged from 0% to 30%.32,33 However, compared to studies in women with preeclampsia, our definition of hypotension was conservative—20% below baseline—and the spinal bupivacaine dose was higher. In 2 observational studies by Aya et al,11,12 the incidence of hypotension after spinal anesthesia, defined as a 30% decrease in mean blood pressure, was 17% and 25%,12 respectively. (The mean spinal bupivacaine doses were 10.0–10.6 mg.) Using a threshold of a 30% decrease in SBP, Sharwood-Smith et al34 reported an incidence of hypotension of 45% in women with preeclampsia with severe features (bupivacaine dose 13.5 mg). Finally, using a threshold of a 25% decrease in blood pressure, Xiao et al35 and Nikooseresht et al36 reported a 55% and 68% incidence of hypotension, respectively, in women with preeclampsia with severe features (bupivacaine dose 10 mg in both studies). Clinicians caring for patients in our study were limited in the vasopressor dose and regimen used to treat hypotension by the study protocol. It is possible that they would have used higher doses in normal clinical practice and the incidence of hypotension would have been correspondingly lower. Approximately 40% of women in our study had received prior antihypertensive and/or magnesium therapy, which may also contribute to hypotension.
The incidence of fetal acidosis (umbilical artery pH <7.2) in the women who received phenylephrine in our study (28%) was generally higher than observed in studies of healthy parturients, most likely due to the underlying uteroplacental insufficiency associated with preeclampsia. For example, in the study by Cooper et al,7 the incidence of fetal acidosis in the phenylephrine group was 4%, and in a study by Ngan Kee et al,31 the incidence of fetal acidosis in the phenylephrine group was 0%. Nonetheless, the pH values in the current study mimic those found by Dyer et al37 in a randomized controlled trial comparing spinal to general anesthesia (ephedrine used to treat hypotension) in women with preeclampsia with nonreassuring fetal heart tracings. Our study was underpowered to determine whether a difference exists in this outcome between groups; the 95% CI of the difference in incidence of fetal acidosis was wide (−12% to 24%). A larger study is necessary to determine whether this difference (favoring phenylephrine) is real and clinically significant.
A limitation of our study is that we assumed the potency of phenylephrine to ephedrine was 80:1 based on previous work by Saravanan et al.18 Ngan Kee et al31 questioned whether the potency ratio is actually lower. Ephedrine is more difficult to titrate as an infusion because of its slower onset and longer duration of action than phenylephrine; thus, a direct comparison of the 2 drugs using a similar titration technique may not be appropriate. A second limitation is that we measured baseline blood pressure on the day of the procedure. Patients are understandably anxious on the day of surgery and this may have falsely elevated their resting baseline blood pressure measurements. A third limitation is that the definition of preeclampsia, as defined by the American College of Obstetricians and Gynecologists, was modified during the study period.16 It is unclear how this change in definition may have changed our study population, but the potential for patients with more (or less) severe preeclampsia being enrolled in the later part of the study exists.
Despite a small sample size and a high-volume obstetric setting, this study took several years to complete. The primary reason for the long study duration was the study design inclusion criteria. We included women with the diagnosis of preeclampsia requiring cesarean delivery without evidence of labor. This limited the patient population to nonlaboring women with previous cesarean delivery(ies), fetal breech presentation, contraindications to vaginal trial of labor (eg, cavity-entering myomectomy, uterine abnormalities), or presumed fetal intolerance to labor. We excluded women in labor from the study because laboring women have a lower incidence of hypotension compared with nonlaboring women, and this might have confounded the study results. However, there is no reason to think the results might be different in laboring women, as they generally require lower doses of vasopressor. Our institution’s protocols for managing cesarean delivery anesthesia did not change over the period of the study. However, the obstetric management of women with preeclampsia may have evolved over this period (eg, criteria for magnesium therapy).
Our study was based on the infusion protocol used by Ngan Kee et al19,20 in previous studies; however, the protocol for titrating the vasoactive infusions is labor intensive. Many clinicians now start prophylactic infusions with lower phenylephrine doses and titrate to effect.32 Future studies should explore vasopressor regimens that are easier to implement and prevent hypotension without causing reactive hypertension in women with preeclampsia.
In conclusion, this study did not identify evidence of superiority of phenylephrine compared with ephedrine for the outcome of umbilical artery pH when used to prevent spinal anesthesia–induced hypotension during cesarean delivery in women with preeclampsia. Thus, phenylephrine may not offer the same benefit with respect to fetal acid-base status in women with preeclampsia compared with healthy women.
Name: Nicole Higgins, MD.
Contribution: This author helped in the study design, collection of data, participation in data analysis, preparation of the manuscript, and final approval of the version to be published.
Conflicts of Interest: None.
Name: Paul C. Fitzgerald, RN.
Contribution: This author helped in collection of data, participation in data analysis, preparation of the manuscript, and final approval of the version to be published.
Conflicts of Interest: None.
Name: Dominique van Dyk, FCA (SA).
Contribution: This author helped in the study design, preparation of the manuscript, and final approval of the version to be published.
Conflicts of Interest: None.
Name: Robert A. Dyer, FCA (SA), PhD.
Contribution: This author helped in the study design, preparation of the manuscript, and final approval of the version to be published.
Conflicts of Interest: None.
Name: Natalie Rodriguez, BS.
Contribution: This author helped in collection of data, participated in data analysis, preparation of the manuscript, and final approval of the version to be published.
Conflicts of Interest: None.
Name: Robert J. McCarthy, PharmD.
Contribution: This author helped in study design, collection of data, participated in data analysis, preparation of the manuscript, and final approval of the version to be published. This author also agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Conflicts of Interest: R. J. McCarthy is currently a Senior Editor for Anesthesia & Analgesia.
Name: Cynthia A. Wong, MD.
Contribution: This author helped in study design, collection of data, participation in data analysis, preparation of the manuscript, and final approval of the version to be published.
Conflicts of Interest: C. A. Wong was the Section Editor for Obstetric Anesthesiology for Anesthesia & Analgesia until December 2015. C. A. Wong was Vice Chair of the Department of Anesthesiology and Section Chief for Obstetric Anesthesiology at Northwestern University at the time of the study.
This manuscript was handled by: Jill M. Mhyre, MD.
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