The administration of a prophylactic phenylephrine infusion significantly reduces the incidence of hypotension associated with spinal anesthesia.1–3 When administered with a fluid coload, hypotension is virtually eliminated.4 However, concerns have been raised about the safety of this technique in terms of the frequent incidence of reactive hypertension and bradycardia.5 Although it has been suggested that phenylephrine at a dose of 100 μg/min should be titrated to maintain maternal arterial blood pressure at or near baseline, there are no studies comparing this with other dosing regimens of prophylactic phenylephrine infusions.2
We designed a double-blind, placebo-controlled study to determine the dose of phenylephrine that, when administered as a prophylactic fixed rate continuous infusion, is associated with the least number of physician interventions needed to maintain maternal systolic blood pressure (SBP) within a set criteria during cesarean delivery under spinal anesthesia.
After receiving IRB approval, ASA physical status I and II pregnant women with singleton gestation at a gestational age of >36 weeks scheduled for elective cesarean delivery under spinal anesthesia were recruited. All patients provided written informed consent. We excluded women who were in labor, had a body mass index >45 kg/m2, Type 1 diabetes mellitus, hypertensive disease, cardiac disease, a fetus with severe congenital anomalies, history of monoamine oxidase inhibitor use, or those who were included in any other anesthesia drug studies.
Patients were admitted to the preoperative holding area on the morning of their cesarean delivery. They had an 18-gauge IV cannula inserted into a dorsal hand vein, which was then connected to a Y-connector flushed with normal saline. A fluid preload was not administered. Baseline arterial blood pressure and heart rate (HR) were measured in the supine position with left uterine displacement. We determined baseline SBP by calculating the mean of 3 consecutive SBP measurements taken 5 minutes apart when the patient was left undisturbed. The baseline SBP was then used to determine the acceptable range of ±20% outside of which a physician intervention would be indicated by study protocol. We used a lower limit of 90 mm Hg in patients in whom a 20% reduction in maternal baseline SBP was <90 mm Hg.
Patients were randomly allocated to a placebo group (PE 0) or 4 fixed rate phenylephrine infusion regimens: phenylephrine 25 μg/min (PE 25), phenylephrine 50 μg/min (PE 50), phenylephrine 75 μg/min (PE 75), and phenylephrine 100 μg/min (PE 100). Each syringe was identified by a study number according to a computer-generated randomization in blocks of 20. To maintain blinding, the infusions were prepared in identical 50-mL syringes containing normal saline (PE 0), or phenylephrine at a concentration of 25, 50, 75, and 100 μg/mL by a physician not involved in the study.
Patients were transferred to the operating room and after the administration of 30 mL oral sodium citrate, standard noninvasive monitoring was applied, including pulse oximetry, electrocardiography, and noninvasive blood pressure. Spinal anesthesia was performed in the sitting position at the L3-4 or L4-5 interspace using a 25-gauge Pencan® spinal needle (B Braun Medical, Inc., Bethlehem, PA) with fentanyl 15 μg, preservative-free morphine 150 μg, and 0.75% hyperbaric bupivacaine 1.6 mL. Immediately after the injection of the intrathecal medication, infusion of study drug was started at 60 mL/h in combination with a fluid coload. The study drug infusion was connected to the most distal drug administration port and a pressurized 1-L bag of room temperature lactated Ringer solution was infused, with the aim of administering at least 2 L before delivery of the baby. Patients were immediately laid supine with left uterine displacement. Noninvasive blood pressure readings were taken every minute for the first 10 minutes after spinal injection and every 2.5 minutes thereafter. After delivery, 5 U oxytocin was administered IV as a bolus followed by an infusion over the next 2 hours (25 U in 1 L lactated Ringer solution). The study drug was infused until 10 minutes after delivery, after which the study ended and further management was at the discretion of the anesthesiologist. The surgical technique was standardized and included uterine exteriorization.
The primary end point was the number of physician interventions needed to maintain maternal SBP within 20% of baseline and to treat bradycardia during the study period. Physician interventions were triggered by a change in any of the following hemodynamic variables: a decrease in SBP >20% of baseline or SBP <90 mm Hg was treated by administering a 100-μg bolus of phenylephrine; an increase in the SBP to >20% of baseline was treated by stopping the infusion. Infusions were only restarted when the SBP decreased to below the upper limit of the target range (>20% above baseline). Glycopyrrolate 0.4 mg was administered for bradycardia defined as HR <50 bpm. If the study drug infusion had to be stopped on 3 occasions, then it was stopped permanently and blood pressure was maintained with phenylephrine boluses for the remainder of the study. We recorded the number of patients who experienced any episode of hypotension (SBP <20% below baseline), reactive hypertension (SBP >20% above baseline), and bradycardia (HR <50 bpm) in each group. We also recorded the number of hypotensive and hypertensive episodes per patient in each group.
The cephalad extent of the sensory block at 5, 10, and 20 minutes after placement of the spinal anesthetic was recorded using loss of pinprick sensation. Patients were asked to rate the severity of their nausea at 5, 10, and 15 minutes after spinal injection and at the end of the study using an 11-point verbal rating scale (0 = no nausea, 10 = worst possible nausea). They were also asked to report nausea occurring at any other time. Intraoperative nausea or vomiting not related to hypotension was treated with ondansetron 4 mg IV. Intraoperative nausea or vomiting occurring immediately before or after a 20% reduction in maternal SBP was recorded as hypotension-induced nausea or vomiting.
Apgar scores at 1 and 5 minutes were recorded. Blood samples were collected from a double-clamped segment of the umbilical cord for the measurement of umbilical artery and umbilical vein blood gases. Samples were either read immediately or placed in an ice bath and read within 30 minutes of collection using a blood gas analyzer (ABL735 Blood Gas Analyzer; Radiometer America, Inc., Cleveland, OH).
Based on data from a pilot study, we estimated that a sample size of 18 patients per group would provide 80% power to detect a mean difference of 2.5 interventions among groups in pairwise comparisons at α = 0.05 adjusted for multiple comparisons. To compensate for possible patient withdrawals, we aimed to recruit at least 20 patients per group.
Numeric measures such as gestational age, number of interventions required, and changes in blood pressure were compared among treatment groups using Kruskal-Wallis rank tests. Categorical outcomes such as the incidence of hypertension or bradycardia were compared using χ2 tests. Where an overall test of difference among groups was significant, rank sum or χ2 tests compared groups pairwise, with adjustments for multiple tests using a step-down permutation method. Outcomes of hypotension and hypertension are presented as overall incidence (yes/no) as well as number of measurements when the SBP was >20% of baseline (hypertension) or <20% of baseline or <90 mm Hg (hypotension). Times to the first SBP measured outside the 20% target range were analyzed using the log-rank test with a Kaplan-Meier analysis. We analyzed data on an intention-to-treat basis.
To further compare the accuracy of blood pressure control among groups, we compared the performance among the different infusion regimens using parameters previously described for assessing the performance of computer-controlled infusion pumps and adapted for closed loop infusions.6–10 The following parameters were calculated.
Percentage Performance Error
Percentage performance error was defined as the difference between each measured value of SBP and the baseline value, expressed as a percentage of the baseline value and was calculated for each patient as follows:
where percentage PEij is the percentage performance error for the ith patient at the jth minute, meaSBPij is the measured SBP for the ith patient at the jth minute, and basSBPi is the baseline SBP in the ith patient.
Median Performance Error
Median performance error (MDPE) is a measure of bias and describes the median of performance error for each patient's performance error values. These differences have a direction that may be positive, indicating SBP above baseline or negative, indicating an SBP below baseline. MDPE was calculated as follows:
where MDPEi is the MDPE for the ith patient and Ni is the number of values for the performance error obtained for the ith patient.
Median Absolute Performance Error
Median absolute performance error (MDAPE) is similar to MDPE except that it only considers the magnitude of the difference between the measured and baseline SBP and not the direction. It is a measure of inaccuracy and is summarized as the median of the absolute values of the performance error for each patient as follows:
where MDAPEi is the MDAPE for the ith patient.
Wobble is a measure of the intraindividual variability of performance error and it is directly related to the ability of a computer-controlled infusion to achieve a stable effect. It is calculated as follows:
where wobblei is the wobble for the ith patient.
These measures of blood pressure stability were compared among the treatment groups using Kruskal-Wallis rank tests, followed by adjusted pairwise comparisons, as described previously. In addition, the Pearson correlation between these measures and dose was used as a test of trend to determine whether variability tended to increase with larger doses. Linearity of the trend was checked with Spearman and Jonckheere-Terpstra tests. Data were analyzed using SAS version 9.1 (SAS Institute, Cary, NC). P < 0.05 was considered statistically significant.
One hundred nine patients were initially recruited for this study. Eight patients did not complete the study because of inadequate or failed spinal anesthesia. Insufficient samples were obtained for umbilical cord blood gases for patients in all groups because of insufficient samples, clotted samples, or sampling errors (1 sample in PE 0, 2 in PE 25, 2 in PE 50, 1 in PE 75, and 5 in PE 100).
There were no significant differences among the groups in patient demographic characteristics, maximum height of the sensory block, skin incision to delivery time, uterine incision to delivery time, volume of lactated Ringer solution infused, and the estimated blood loss (Table 1). The dose of phenylephrine administered was significantly different among the groups with the largest doses administered in the PE 75 and PE 100 groups.
Hemodynamic data are presented in Table 2. Doses of phenylephrine of 25 and 50 μg/min were associated with significantly fewer interventions to maintain target blood pressure compared with a dose of 100 μg/min. However, there were no differences in the number of interventions needed to maintain SBP within our target range among patients in the control group and those receiving phenylephrine infusions. The incidence of predelivery hypotension was significantly lower in groups PE 50, 75, and 100 compared with the control group. Hypotensive episodes were more frequent in the control group compared with all the PE groups. Both groups PE 75 and PE 100 were associated with a significantly higher incidence of predelivery hypertension compared with the control group. The incidence of predelivery hypertension was also significantly higher in the PE 100 group compared with PE 25. Similarly, hypertensive episodes were significantly more frequent in groups PE 100 and PE 75 compared with both lower infusion regimen groups PE 0 and PE 25. Hypertensive episodes were also more frequent in group PE 100 compared with PE 50. Infusions were permanently stopped for reactive hypertension in 15 patients (68%) in the PE 100 group compared with 3 patients (15%) in the PE 50 group. There were no significant differences in the incidence of postdelivery hypotension or hypertension among the groups.
Figure 1 presents the percentage performance error over time for all patients in each of the 5 groups. The performance measurements were calculated for each patient and the data for each group are presented in Figures 2 and 3. The MDPE was <0 in the PE 0 and PE 25 groups and >0 in the other 3 groups. MDPE was significantly different among the groups (Fig. 2). Pairwise comparisons of MDPE among the groups showed that MDPEs in the control and PE 25 groups were significantly less than baseline when compared with all the other groups. The PE 75 and PE 100 groups were significantly above baseline when compared with the PE 0 and the PE 25 groups. The MDPE of the PE 50 group was also significantly less than that of the PE 100. The MDAPE was different among the groups (Fig. 3). The PE 50 group had the smallest MDAPE among all the groups but was only significantly different from PE 100 after correction for multiple comparisons. Significant Pearson correlations for both MDPE (P < 0.001) and MDAPE (P = 0.006) showed that the measures of SBP distance from baseline tended to increase with increasing dose. The trend was linear with no significant nonlinearity. Wobble was also significantly different among the groups (P = 0.0024). Pairwise comparisons showed that wobble was significantly higher in the PE 100 group compared with all the other groups (P < 0.001 vs PE 0, P = 0.0075 vs PE 25, P < 0.001 vs PE 50, and P = 0.0017 vs PE 75). Phenylephrine infused at 25 and 50 μg/min was associated with longer times to the first SBP measured outside the 20% target range when compared with the higher doses of 75 and 100 μg/min, but there were no differences when compared with the control group (Fig. 4).
There were no differences in the incidence of bradycardia among the groups. Glycopyrrolate was administered to 1 patient in the control group, 3 patients in group PE 25, 2 patients in group PE 75, and 7 patients in group PE 100. When those patients who received glycopyrrolate for the treatment of bradycardia were excluded from the analysis, only the PE 25 group was associated with significantly fewer interventions than the PE 100 group (P = 0.02), whereas the comparison with the PE 50 group was no longer statistically significant (P = 0.06).
There were no significant differences among groups with respect to the incidence of intraoperative nausea, vomiting, highest nausea scores, and the need for rescue antiemetics (Table 3). However, phenylephrine at a dose of 100 μg/min significantly reduced the incidence of hypotension-induced nausea when compared with the control group.
Three patients experienced adverse effects during the study period. Two of these were patients in the PE 100 group. Both events occurred after the administration of glycopyrrolate for the treatment of bradycardia, which was then followed by reactive hypertension. One patient developed headache and the other patient developed neck pain. Both events resolved spontaneously. One patient in the PE 50 group experienced an episode of ventricular bigeminy, which was not associated with any hemodynamic instability. The PE infusion was stopped but bigeminy persisted intraoperatively and resolved spontaneously in the postanesthesia care unit.
There were no significant differences in umbilical cord gases or in 1- and 5-minute Apgar scores among the groups (Table 4). There were also no differences in the incidence of fetal acidosis (umbilical artery pH <7.2) among the groups.
Although current evidence supports the use of phenylephrine as the vasopressor of choice for low-risk elective cesarean delivery, the dosing and mode of administration of this drug still remain an area warranting further research.1–4,11–17 In this study, we found greater hemodynamic stability with the lower doses of phenylephrine administered as fixed rate infusions (25 and 50 μg/min) compared with the higher doses (75 and 100 μg/min). Of these regimens, phenylephrine at a dose of 50 μg/min was associated with a significant reduction in the incidence of predelivery hypotension and the number of hypotensive episodes compared with the control group. In addition, whereas the 25 μg/min infusion regimen had a lower incidence of predelivery hypertension when compared with the 100 μg/min group, both the lower infusion rates of 25 and 50 μg/min were associated with fewer episodes of reactive hypertension when compared with 100 μg/min. However, there were no differences in the number of interventions needed to maintain SBP within our target range among patients in the control group and those receiving phenylephrine infusions.
In a comparison of all the infusion regimens, there was a bias (MDPE) toward maintaining SBP below baseline with placebo and phenylephrine infused at 25 μg/min and a bias toward maintaining SBP above baseline with 50, 75, and 100 μg/min. This suggests that although increasing doses of phenylephrine reduce maternal hypotension, they also significantly increase the incidence of hypertension. Patients who received phenylephrine 50 μg/min had the fewest number of physician interventions and also had the lowest degree of inaccuracy (MDAPE) for SBP control of all the regimens; the median magnitude of the absolute performance error between each measured value of SBP and the target SBP was 6.5%. The performance of this regimen compares favorably with a previously described computer-controlled feedback algorithm used to provide hemodynamic support during cesarean delivery under spinal anesthesia.7 Patients receiving the highest infusion rate of 100 μg/min had the greatest variability in performance error (wobble) compared with those receiving 25 to 75 μg/min and phenylephrine boluses only. These results suggest that an infusion regimen of 100 μg/min provides less maternal hemodynamic control and stability compared with all the other regimens studied. There were no differences in MDAPE between those patients receiving phenylephrine boluses and those receiving infusions, suggesting that the administration of phenylephrine by a fixed rate continuous infusion may not improve the accuracy of blood pressure control when compared with bolus administration.
Reactive hypertension can be a problem and is a concern with the use of prophylactic phenylephrine infusions.4,5 Ideally, the infusion should be stopped before reactive hypertension occurs. However, because factors predicting response to vasopressor administration are not clear, it is difficult to predict if and when a patient will develop reactive hypertension. In fact, even patients in the bolus group and 25 μg/min group developed reactive hypertension in this study. The incidence of hypertension was dose dependent, ranging from 25% to 82%. The administration of glycopyrrolate for the management of bradycardia may have also contributed to this. We elected to include this intervention in our treatment algorithm because we had a control group and bradycardia may be associated with hypotension and is not always a result of reactive hypertension. Phenylephrine administration has also been associated with profound bradycardia and hypotension.2 In retrospect, managing bradycardia by stopping the phenylephrine infusion and restricting the administration of glycopyrrolate to cases of bradycardia associated with hypotension may have reduced its administration and limited the incidence and magnitude of hypertension. When we repeated the analysis on the number of physician interventions, by excluding patients who received glycopyrrolate, statistical significance remained only between the 25 and 100 μg/min groups. However, because a larger proportion of patients was excluded from the 100 μg/min group compared with the other groups (Pearson exact P = 0.03), this reduced the power to show statistical significance compared with the 50 μg/min group.
There were no differences in umbilical cord blood gas values among the groups despite a significantly higher incidence of maternal predelivery hypotension in the control group, probably because of the brief nature of those hypotensive episodes and their rapid treatment. This is in agreement with the results of a previous study showing no difference in fetal outcomes between patients receiving phenylephrine as a bolus or infusion.3
Whereas previous studies investigating the use of prophylactic phenylephrine infusions ended after uterine incision,2–4,18 we decided to continue the infusions postdelivery to attenuate the potential hemodynamic changes associated with the administration of IV oxytocin.19,20 Although the incidence of postdelivery hypotension was reduced from 45% in the control group to 5% to 25% in the phenylephrine groups, this difference was not statistically significant. However, our study was not powered to detect such a difference.
Hypotension has been identified as an important etiological factor for intraoperative nausea and vomiting.21 Several studies have identified a reduction in the incidence of nausea and vomiting when using phenylephrine for cesarean delivery under spinal anesthesia.1–3,6,22 The mechanism of this may be related to the attenuation of the increase in vagal tone accompanying the rapid decrease in preload associated with spinal anesthesia.1,23 Even though all prophylactic infusion regimens reduced the incidence of hypotension-induced nausea compared with the control group, the result was only statistically significant in the 100 μg/min group. Our study was not powered to detect these differences. Overall, there were no significant reductions in the incidence of intraoperative nausea, vomiting, highest nausea scores, or the need for rescue antiemetics among the groups.
The current study has limitations. First, we investigated the use of simple fixed rate phenylephrine infusion regimens in conjunction with a 2-L crystalloid coload. Our findings may not be applicable to clinical situations in which IV fluids are not coadministered or an alternative volume of crystalloid or colloid is administered. The simple fixed rate infusion regimen used in this study was stopped when maternal SBP exceeded the set limits and lacked titration. In clinical practice, however, titrating the infusion rate in response to changes in blood pressure may be more appropriate. Such variable infusion rates could improve the accuracy of hemodynamic control over bolus administration. Furthermore, the best infusion rate for a fixed rate regimen might not be the best initial rate for a titrated infusion. Physician interventions were our primary end point and served as a surrogate marker of hemodynamic stability, but we did not measure other hemodynamic variables such as maternal cardiac output.18 For the purposes of this study, we collected hemodynamic data at 1-minute intervals for the first 10 minutes only and then every 2.5 minutes until the end of the study period, and may have missed opportunities in this later time period to intervene to maintain maternal SBP within the target range, ultimately affecting our final outcome. In retrospect, the measurement of maternal blood pressure at 1-minute intervals during the entire study period, as has previously been described, would have been more appropriate.4,6 For those practitioners using phenylephrine infusions, we recommend frequent blood pressure measurements, especially in patients receiving higher infusion rates and after the administration of oxytocic drugs.
In conclusion, prophylactic fixed rate infusions did not reduce the number of physician interventions needed to maintain maternal SBP within 20% of baseline or the accuracy of hemodynamic control when compared with placebo. However, prophylactic phenylephrine infusions reduced the incidence and severity of maternal predelivery hypotension. Among the fixed rate phenylephrine infusion regimens investigated, 25 and 50 μg/min were associated with greater maternal hemodynamic stability compared with 75 and 100 μg/min. Therefore, if a prophylactic fixed rate infusion is used in conjunction with a fluid coload, the lower rates are more appropriate. Future studies are needed to investigate variable rate infusion regimens for the prevention of hypotension in this patient population.
TKA, RBG, and ASH helped in study design, conduct of study, data collection, and manuscript preparation; WDW helped in study design, data analysis, and manuscript preparation; and HAM helped in study design, conduct of study, and manuscript preparation.
The authors acknowledge the contribution of Barbara L. Fouse, MS, MT (ASCP), SC (Technical Manager, Clinical Pediatric Laboratory, Duke University Health System) and Kristin E. Weaver, BS, for their assistance in facilitating collection and analysis of the umbilical cord gas samples presented in this article.
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© 2010 International Anesthesia Research Society
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