Hypotension associated with spinal anesthesia is a common complication during cesarean delivery and can result in adverse effects for both mother and infant.1,2 Many preventive measures have been suggested, including IV fluid administration,3 low-dose spinal anesthesia,4 and various vasopressor regimens.5 However, a Cochrane review concluded that although these interventions may reduce the incidence of hypotension, none has been shown to eliminate the need for close monitoring and early treatment of maternal hypotension.6
Standard monitoring during cesarean delivery under spinal anesthesia includes serial Noninvasive arterial blood pressure (BP) assessment as frequently as every minute. With the advent of various minimally invasive and Non-invasive cardiac output (CO) monitors, we are now becoming more aware of the effects that our interventions have upon the patients’ complete hemodynamic profile. Minimally invasive techniques, such as lithium dilution and pulse wave analysis,7 and Noninvasive suprasternal Doppler flow techniques8 have recently been used to investigate the effect of various vasopressor regimens on CO during cesarean delivery under spinal anesthesia. This information has not yet yielded a convincing answer as to what vasopressor regimen is superior in maintaining baseline maternal BP while preserving baseline maternal CO.
Bioreactance, a development from impedance technology, is also emerging as an accessible mode of continuous CO monitoring in the operating room and can provide valuable insight into the hemodynamic effects of our interventions.9 This method of monitoring provides continuous CO, stroke volume (SV) and heart rate (HR) monitoring, and intermittent BP and systemic vascular resistance assessments at 1-minute intervals. This enables the user to measure the effects of an intervention on multiple hemodynamic variables simultaneously.
In recent years, phenylephrine has become the vasopressor of choice to prevent and treat maternal hypotension during cesarean delivery.10 The optimal regimen for administration of phenylephrine is undetermined, and current practice includes both phenylephrine infusion and intermittent bolus administration. These drug administration methods have been studied in terms of their effect on baroreceptor sensitivity,11–13 but have not been directly compared in terms of their effect on maternal CO or their success in maintaining maternal BP at baseline during cesarean delivery under spinal anesthesia.
This study used a Noninvasive CO monitor based on bioreactance technology (NICOM, Cheetah Medical, Portland, OR) to directly compare the hemodynamic profiles created by an infusion and a bolus regimen of phenylephrine for the maintenance of maternal BP at baseline, during cesarean delivery under spinal anesthesia.
Our hypothesis was that the phenylephrine infusion regimen would cause a smaller reduction in maternal CO and result in less maternal hypotension, as compared to the phenylephrine bolus regimen, in the setting of an elective cesarean delivery under spinal anesthesia.
This randomized and double-blind study was conducted with institutional research ethics board approval and was registered with the www.clinicaltrials.gov protocol registration system (NCT00996190). Participants were required to be ASA physical status I/II, aged 18 years and older, weigh between 50 and 100 kg, and have a height between 150 and 180 cm. Exclusion criteria included patient refusal, inability to communicate in English, allergy or hypersensitivity to phenylephrine, hypertension, cardiovascular or cerebrovascular disease, fetal abnormalities, diabetes (excluding gestational diabetes), or contraindications to spinal anesthesia.
Written informed consent was obtained from all participants. Randomization was performed using a computer-generated random number table. The patient and the attending anesthesiologist were blinded to the group allocation. Group allocations were placed in sealed, opaque envelopes on initial randomization. After the patient had agreed to participate and signed the informed consent, the allocation envelope was opened and the syringes were prepared by an anesthesiologist not involved with the clinical care of the patient, according to instructions contained within each sealed envelope. Two syringes, one 20-mL bolus syringe and one 60-mL infusion syringe, were prepared for each patient. One syringe contained 120 μg/mL phenylephrine and the second syringe contained saline. Both syringes were labeled “phenylephrine/placebo,” and “bolus syringe,” and “infusion syringe,” respectively.
All patients fasted for at least 8 hours before induction of spinal anesthesia. An 18-G IV catheter was placed in a peripheral vein in the patient’s upper limb while in the holding area, and an infusion of lactated Ringer’s solution was started at a minimal rate to keep the vein open.
Upon arrival to the operating room, patients were placed in the supine position, slightly tilted to the left. Four NICOM® sensors were applied to the patient’s chest, 2 below the clavicle in the midclavicular line, and 2 at the costal margin in the midclavicular line. Baseline systolic arterial BP (SBP) was measured by averaging 3 readings taken 1 minute apart using an automated device for Noninvasive BP assessment, after which 80% and 120% of the mean baseline value were calculated.
Spinal anesthesia was performed in the sitting position. Hyperbaric bupivacaine 13.5 mg mixed with preservative-free fentanyl 10 μg and morphine 100 μg was injected over 30 seconds. After the intrathecal injection, the patient was positioned supine, with left uterine displacement. Concomitantly to the intrathecal injection the patient received 10 mL/kg of lactated Ringer’s solution (maximum 1000 mL) under pressure of 250 mm Hg. After the initial bolus infusion, the rate of administration of IV fluids was reduced to keep vein open until the delivery of the infant. BP, HR, and pulse oximetry (SpO2) were assessed every minute during the study period, which began immediately on completion of intrathecal injection. CO and SV were recorded continuously. Total peripheral resistance (TPR) was calculated at 1-minute intervals.
The attending anesthesiologist received 1 syringe of infusion solution and 1 syringe of bolus solution. The study drug infusion was started immediately on completion of the intrathecal injection, at a rate of 1 mL/min, and continued for a minimum of 2 minutes. The infusion was connected to the main IV line at the most proximal port to the patient, approximately 6 cm from the IV cannula. The infusion was continued if maternal SBP ≤ baseline. If maternal BP was higher than baseline, the infusion was discontinued and the BP reassessed in 1 minute. The patient also received 1 mL of the bolus solution every time the SBP was ≤ baseline. The bolus was administered into the port nearest to the patient each time. The bolus dose was not administered when the SBP was above baseline. If, at any time, maternal SBP was <80% baseline, a rescue dose of 5 mg ephedrine was used. If the SBP remained below 80% baseline after 1 minute, a second 10 mg bolus of ephedrine was administered.
Bradycardia was defined as a HR <60 bpm for 2 consecutive readings 1-minute apart. If a patient developed bradycardia and the SBP was at or less than baseline, 0.6 mg atropine was administered. Bradycardia with SBP > baseline resulted in discontinuation of the infusion and reassessment in 1 minute.
Upon delivery of the fetus, oxytocin was administered as a bolus of 0.5 IU over 5 seconds, followed by an infusion of 40 mIU/min.
Data collection was complete 10 minutes after delivery. Additional data obtained included maternal age, weight, and height; cephalad sensory block level at delivery; neonatal weight; 1- and 5-minute Apgar scores; and umbilical cord blood gases obtained from a double-clamped segment of umbilical cord upon delivery. During the preoperative assessment, patients were instructed to inform the attending anesthesiologist of any nausea during the procedure. The presence of nausea and vomiting in the predelivery and postdelivery periods was documented when the patient complained of feeling sick or vomited. The severity of nausea was not documented. No prophylactic antiemetic medication was administered to the patients.
The primary outcome was the maximum change in CO in the predelivery period. Secondary outcomes included the incidence of hypotension (SBP <80% baseline) and hypertension (SBP >120% baseline), the maximum decrease in HR, the incidence of nausea and vomiting, the incidence of bradycardia (HR <60 beats per minute), and the total dose of phenylephrine administered in the predelivery and postdelivery periods.
The primary objective of this study was to examine changes in CO. Based on data from Doherty et al.,9 sample sizes of 30 per group would achieve 80% power to detect a 1.2 L/minute CO absolute difference in maximum CO change between treatment groups over the predelivery period; this is between a 10% and 25% difference in maximum CO change from baseline. We assumed absolute differences of 25% or more in maximum CO change to be clinically relevant. Given a SD of differences of 1.6L/min, a 1.2L/min difference is a moderate effect size. This calculation assumed a 2-tailed type I error rate (α) of 0.05 and a SD of 1.60 L/min maximum change in both treatment arms. Seventy-two study subjects were randomized in 12 blocks of 6 subjects. Analyses of the additional hemodynamic components and overall profile were considered secondary; however, this sample size was sufficient to detect a moderate effect size (Cohen’s d) of 0.75 for any outcome.
All data were summarized using means and standard deviations for continuous factors, and frequencies and proportions for categorical factors. Demographic characteristics and secondary outcomes were compared between intervention arms using Student’s t-tests (unequal variances formula) for continuous factors and Fisher’s exact tests for categorical factors. For each outcome, 95% confidence intervals (CI) of the difference were calculated between intervention arms assuming unequal variances for continuous factors and using Wilson-based methods for differences in proportions. Each hemodynamic component (e.g., CO, SV, HR, SBP, TPR) was compared between intervention arms using mixed linear models with an autoregressive 1 correlation structure. The Akaike Information Criterion correlation was used to assess the statistical models and verify the best correlation structure. In addition, a profile analysis was conducted comparing the overall hemodynamic profile between intervention arms. In this context, profile analysis examines whether the overall pattern exhibited by several dependent variables together (e.g., hemodynamic components) over time is similar between treatment arms.14 All analyses examining hemodynamic components were completed separately for the predelivery and postdelivery period. For the purposes of analysis and reporting, the predelivery period was limited to the first 20 minutes after the intrathecal injection, because the number of mothers who had not delivered by 20 minutes was small, and thus the added reliability of summary estimates past 20 minutes was poor.
One hundred twenty-six women presenting for elective cesarean delivery under spinal anesthesia were assessed for eligibility from October 2009 to August 2010. Figure 1 shows the CONSORT flow chart detailing patient recruitment. Data analysis was performed on 2 groups of 30 patients.
Details of maternal demographic characteristics are summarized in Table 1. The 2 groups were similar with respect to maternal age, weight, height, parity, and gestational age. The time from induction of spinal anesthesia to delivery was similar in both groups (range from 14 to 69 minutes), as was the sensory level by pinprick at the time of delivery (Table 2). Baseline hemodynamic variables are detailed in Table 3. There were no significant differences between the groups.
There was no significant difference in the maximum change in CO between the 2 treatment arms: mean (SD) maximum decrease in CO in the bolus group was 1.87 (1.68) L/min versus 1.9 (1.46) L/min in the infusion group (P = 0.94). The mean difference and 95% CI was −0.03 L/min, 95% CI, −0.84 to 0.78 L/min.
Analysis of the evolving hemodynamic profiles in each group with respect to time showed significant differences between the groups in the maintenance of SBP in the first 6 minutes of the predelivery period (P = 0.007) (Fig. 2). In the infusion group, there was a decrease in mean SBP>10% from baseline in the initial 6 minutes after intrathecal injection followed by a recovery to baseline. In the bolus group, the mean SBP was maintained within 5% of baseline during this time.
Figure 3 shows the hemodynamic profiles in each group during the postdelivery period. There were no significant differences between groups during the postdelivery period.
The incidences of nausea and vomiting, hyper- and hypotension, bradycardia, and rescue interventions are presented in Table 4. Given the wide CI in the differences in incidences between groups for these outcomes, no definitive conclusions can be drawn regarding these outcomes. The infusion group received significantly more phenylephrine during the procedure to maintain SBP at baseline. All patients in the bolus group received at least 1 bolus of phenylephrine. The median (range) of boluses delivered in the bolus group was 7 (3–16). There were no significant differences in neonatal weight, Apgar scores, and umbilical cord blood gases (Table 5).
Our study suggests that the hemodynamic effects of intermittent bolus and fixed-rate infusion regimens of phenylephrine are very similar. There are subtle differences between the 2 regimens, such as greater stability in maternal SBP control in the initial 6 minutes of the spinal block with the bolus regimen; however, these are not clinically significant.
In pregnant women at term, spinal anesthesia typically causes hypotension and an increase in CO, because of an increase in SV and HR, to compensate for a decreasing vascular resistance.15 The administration of phenylephrine in high doses, to increase vascular tone and maintain BP, results in a baroreceptor-mediated decrease in HR, which can decrease CO. It also increases the splanchnic arterial tone resulting in decreased splanchnic bloodflow and decreased venous return, and SV may decrease as a result, further reducing CO.16 However, myocardial contractility may also increase in the face of increased vascular resistance, which may help to maintain SV. This is known as the Anrep effect.17
HR is now regarded as the best surrogate marker for CO during cesarean delivery under spinal anesthesia.7 The activation of the baroreflex by a rapid increase in BP has been shown, in nonpregnant subjects, to produce a greater decrease in HR than with a more gradual increase in BP.11
In our study, the delivery regimen of phenylephrine did not impact significantly upon the CO changes. Changes in HR did not differ significantly between the groups. Our results are in agreement with Ferguson et al.12 who found an equivalent decrease in HR using comparable bolus and infusion regimens in nonpregnant subjects. However, Sullebarger et al. found that, in nonpregnant subjects, the baroreflex-induced response to a gradual increase in BP was less than that with a rapid increase.13 Our contrasting results may be explained by differences in the infusion regimen. Whereas Sullebarger et al. used a 10-minute continuous infusion to assess the HR response, we used a fixed-rate infusion that was intermittently switched off when the patient’s BP was higher than baseline. This may have mitigated centrally mediated baroreceptor adaptation. It is this central adaptive response that decreases the baroreceptor sensitivity, and the heart then slows to a lesser extent for a given pressure increase. CO was not assessed in either of the above studies.
Our results suggest that when administering a phenylephrine infusion a “less is more” approach may have better effect, minimizing the decrease in HR and venous return and optimizing CO. We found that the use of a 120 μg/min infusion regimen of phenylephrine in our study required a higher total dose to maintain maternal BP at baseline. The dose-dependent effects of phenylephrine were studied by Stewart et al., using suprasternal Doppler at 5-minute intervals.8 They assessed the hemodynamic effects of 3 fixed-rate continuous infusions of phenylephrine (25, 50, and 100 μg/min), supplemented with 100 μg phenylephrine boluses when the maternal SBP decreased to 80% of baseline. The investigators found a dose-dependent decrease in CO and HR, while SV was maintained during the study period. CO decreased by up to 20% using a 100 μg/min phenylephrine infusion. Significantly more phenylephrine was required in the group receiving the higher dose regimen to maintain maternal BP at baseline. Dyer and Reed, in an editorial, suggested that the requirement for a higher total dose of phenylephrine, when using a higher dose infusion, is consistent with a dose-related decrease in venous return.16 Allen et al. also studied 4 fixed-rate infusion regimens of phenylephrine (0, 25, 50, 75, 100 μg/min infusion) with respect to maternal BP control.18 A rescue bolus of phenylephrine 100 μg was administered when maternal SBP decreased to 80% of baseline or <90 mm Hg. The primary outcome was the number of physician interventions required to maintain maternal SBP within 20% of baseline. There was no difference among the groups in the number of interventions required. There was greater BP stability using a low-dose infusion regimen supplemented with boluses when maternal BP decreased to <80% of baseline. There were no significant differences among groups with respect to the incidence of nausea and vomiting and the need for rescue antiemetics.
Our study found no difference between the groups in the number of ephedrine or atropine boluses required. This suggests that the use of a fixed-rate infusion may not improve BP control in the setting of a cesarean delivery under spinal anesthesia. The bolus regimen of vasopressor administration resulted in a smaller decrease from baseline of maternal SBP in the initial minutes after intrathecal injection. This regimen allows faster delivery of an effective dose of phenylephrine allowing rapid recovery of maternal vascular resistance during the establishment of spinal blockade. The delay in effective control of the immediate hemodynamic changes using a fixed-rate infusion regimen was previously noted by Langesaeter et al. using the minimally invasive LiDCOplus monitor.19
The dose of phenylephrine used in our study was based on the ED95 of phenylephrine as calculated by Tanaka et al.20 They studied the phenylephrine dose required to prevent maternal hypotension during spinal anesthesia using an intermittent bolus regimen and found it to be at least 120 μg (the lowest limit of the 95% CI). We chose this dose as we aimed to maintain maternal BP at the baseline. We used a dose of 120 μg/min in our infusion regimen to make the bolus and infusion regimens comparable, and make the mode of delivery of the drug the primary variable.
The incidence of hypotension in the predelivery period was similar in both groups (approximately 25%) and similar to that reported by Ngan Kee et al. using an intermittent infusion regimen of phenylephrine at 100 μg per minute.21 The incidence of maternal nausea/vomiting (between 17% and 37%) in our study was, however, much higher than that reported by Ngan Kee et al. (4%). We are unable to find an explanation for these contrasting results.
We did not observe the typical hemodynamic effect of oxytocin, but rather a blunted hemodynamic effect was noted in the postdelivery period. Oxytocin induces a brief, but significant, decrease in maternal BP due to vasodilation. This in turn results in an increase in HR, CO, and myocardial contractile force.22 Phenylephrine administration prevents both a significant decrease in TPR and increase in HR.7 CO increased similarly in both groups due to increased stroke volume. SBP was maintained.
The optimal vasopressor regimen for the maintenance of maternal BP during cesarean delivery under spinal anesthesia has yet to be determined. As studies progress, it is becoming apparent that the use of BP alone as an accurate marker of CO and utero-placental perfusion may be unreliable. Some investigators suggest the use of HR as a surrogate marker for CO in the context of phenylephrine use.16 An accurate, user-friendly, Noninvasive CO monitor may provide valuable information about the trends in maternal CO during cesarean delivery. This could be valuable in the setting of an already compromised fetus, where the maintenance of CO and not just maternal BP is desirable. We used a Noninvasive CO monitor based on bioreactance to continuously assess maternal CO throughout the study period. Bioreactance is a technology derived from bioimpedance, however, the CO measurement does not use the static impedance and does not depend on the distance between the electrodes for the calculations of stroke volume and CO, which significantly reduces the uncertainty in the result. Its readings were shown to correlate well with results derived from pulmonary artery catheter measurement of CO.23 In addition, it has also been shown that the Noninvasive CO measurement (NICOM®) system has acceptable accuracy, precision, and responsiveness for CO monitoring in patients experiencing a wide range of circulatory situations24,25 and has recently been used in the obstetric population.9,26
There are some limitations in our study. The dose of phenylephrine used is higher than in other centers and our results may apply only to the particular dose we used. The bioreactance technology has been extensively validated in many clinically challenging situations and patient populations; however, it has not yet been validated in pregnancy. Another minor limitation is that we waited for the patient to report any nausea and vomiting although they had been told to report any sensation of nausea before coming to the operating room.
In conclusion, the fixed-rate infusion regimen of phenylephrine did not result in a smaller reduction in baseline maternal CO or provide greater BP stability as compared to the bolus regimen, in the setting of elective cesarean delivery under spinal anesthesia. The bolus regimen of vasopressor administration resulted in a smaller decrease from baseline of maternal SBP in the initial minutes after intrathecal injection; however this did not result in a better clinical outcome for mother or infant. Our findings are consistent with recent studies suggesting that high-dose fixed-rate infusions of phenylephrine ultimately require a higher total dose to be administered to maintain maternal BP at baseline.
Name: Anne Doherty, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Anne Doherty has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Yayoi Ohashi, MD, PhD.
Contribution: This author helped design the study, conduct the study, and write the manuscript.
Attestation: Yayoi Ohashi has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Kristi Downey, MSc.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Kristi Downey has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Jose C. A. Carvalho, MD, PhD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Jose C. A. Carvalho has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
This manuscript was handled by: Cynthia A. Wong, MD.
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