Ethical considerations
This study was approved by the Capital Medical University Institutional Review Board on January 23, 2019 (IRB # 2019-058). Written informed consent was obtained from all participants. The study was registered at ClinicalTrials.gov (http://clinicaltrials.gov; NCT-03833895) on February 1, 2019. Participant recruitment was performed from February 2019 to October 2019. Our methodology followed the international guidelines for randomized clinical studies according CONSORT Guidelines.
Study design and participants
This was a prospective, single- center, randomized, controlled clinical study conducted from February 2019 to October 2019 in the Xuanwu Hospital, Beijing, China. Parturient meeting the following inclusion criteria were recruited: 1) healthy singleton pregnancy; 2) scheduled elective CD under combined spinal-epidural anesthesia (CSEA); 3) American Society of Anesthesiologists physical status I/II; and 4) age between 20 and 45 years. The exclusion criteria were as follows: 1) history of mental disorder, epilepsy, or other central nervous system disease; 2) tricyclic or imipramine antidepressant use; 3) preexisting or pregnancy-induced hypertension; 4) lumbar injury; 5) severe hypovolemia; 6) allergy or history of hypersensitivity to vasopressors; 7) body mass index >40 kg/m2; and 8) infection at the puncture site.
Randomization and blinding
Randomization was performed using computer-generated randomized numbers and allocation concealment was ensured using sequentially numbered opaque sealed envelopes. An anesthesiologist not involved in parturient care was responsible for opening the envelopes and preparing the study medicine.
The study medicine and sealed wrapping instructions were delivered to the operating room before the time of CD. The study medicine was prepared in 50 mL syringes containing phenylephrine, norepinephrine, or placebo, marked with a randomization number. The dose of each medicine was calculated according to the participant’s standard weight, defined as the actual height minus 110 cm 13, and then the medicine was diluted to 50 mL at different concentrations. The three groups were infused in the same speed at 20ml/h. Anesthesiologists involved in infusion of the medicine or parturient care were blinded to the group allocation. Randomization codes were not revealed to the blinded anesthesiologists until all measurements and calculations had been entered into the database and statistical methods had been specified.
Anesthesia protocol
On arrival in the operating room, standard monitoring was initiated, including noninvasive blood pressure (BP) measurement, heart rate (HR) measurement, pulse oximetry, and electrocardiography. Patients were asked to rest still for 5 min. Subsequently, hemodynamic parameters were measured thrice at 2-min intervals, and the mean value was considered the baseline. Next, venous access was established using a 16-gauge intravenous (IV) cannula and 10 mL/kg lactated Ringer’s solution (LR) was infused in all groups before CSEA.
CSEA was performed with the patient in the right lateral position using 0.5% bupivacaine (7.5 mg, 1.5 mL, isobaric, 1.0 mL/10 s) injected into the subarachnoid space at the L2–L3 interspace. An epidural catheter was inserted cephalad for a rescue SA. Immediately after anesthesia induction, patients were placed in the supine position with 15° left lateral tilt. The sensory block level before surgical incision was T4.
Intraoperatively, maintenance LR (3 ml/kg/h) was provided for all groups according to the parturients’ standard weight. Additionally, parturients received a continuous infusion of the study drug according to the group allocation. After delivery of the fetus, a bolus of 5 IU oxytocin was administered IV followed by a slow infusion of another 5 IU over the remainder of the operation in all three groups.
Interventions
In the phenylephrine group, parturients received a continuous infusion of phenylephrine at the rate of 0.25 μg/kg/min according to their standard weight.14 In the norepinephrine group, parturients received a continuous infusion of norepinephrine at the rate of 0.05 μg/kg/min according to their standard weight.8 In the control group, parturients received a continuous infusion of LR as the same speed.
Hypotension was defined if the systolic BP (SBP) reduced by 30% relative to the baseline value or an absolute SBP value of <100 mm Hg. The time interval for BP measurement was set at 3 min. The shortest interval for vasopressor administration was every 1 min. In case of severe hypotension (SBP reduced by more than 30% relative to the baseline value), additional bolus of vasopressor was given; 25 μg of phenylephrine in the phenylephrine group or 4 μg of norepinephrine in the norepinephrine group. In the control group, additional bolus of 4 μg norepinephrine was administered in case of hypotension combined with a HR >60 bpm and additional bolus of 25 μg phenylephrine was administered in case of hypotension combined with a HR <60 bpm. In this study, 0.5mg atropine was administered continually for 3 min only in case of simple bradycardia (HR <50 bpm). The vasopressor infusion was stopped if the SBP increased to >150 mm Hg for over 3 min.
Outcome measurement
LiDCOrapid Pulse Contour Analysis System (LiDCO Ltd., London, UK) was used in all three groups to measure the hemodynamic parameters at each time point. The hemodynamic parameters included stroke volume (SV), cardiac output (CO), systemic vascular resistance (SVR), SBP, diastolic blood pressure (DBP), mean arterial pressure (MAP), and HR. All parameters were measured at baseline (T1), at the time of spinal injection (T2), at placement in supine position (T3), 3 min following norepinephrine/phenylephrine/LR administration (T4), 5 min following norepinephrine/phenylephrine/LR administration (T5), at the time of incision (T6), immediately after fetus delivery (T7), at the time of placental expulsion (T8), 5 min after placental expulsion (T9), and at discharge to the postoperative unit (T10).
Blood samples were taken from the UA, UV, and PV for analysis by the blood gas analyzer (Radiometer ABL800 FLEX analyzer, Radiometer A/S, Copenhagen, Denmark) immediately after delivery. The measured parameters included oxygen partial pressure (PO2), oxygen saturation (SO2), carbon dioxide partial pressure (PCO2), glucose and lactate levels, base excess (BE), pH, and anion gap (AG). Intraoperative fluid input and output were recorded. The postoperative incidence of maternal complications, such as hypotension, tachycardia, bradycardia, nausea and vomiting, breathing difficulty, and dizziness was also recorded.
The primary outcome of the study was the SBP as important one of hemodynamic parameters in each group at different time point. The secondary outcomes included hemodynamic parameters (DBP, MAP, HR, SV, CO, SVR), the blood gas indices (PO2, SO2, PCO2, BE, pH, AG) in UV, UA, and PV blood samples, and the incidence of complications.
Sample size calculation
In our pilot study (n=20), the increase of systolic blood pressure (SBP) in the norepinephrine and phenylephrine compare with control groups were ∆31 mmHg and ∆20 mmHg respectively. Using PASS 15.0, a sample size of 71 in the phenylephrine group and 70 in the norepinephrine group was required for α (Type I error) of 0.05 and β (Type II error) of 0.2. Considering a 10% withdrawal rate, the sample size was calculated at 79 per group.
Statistical analysis
Statistical analyses were performed using SPSS (version 22.0, SPSS Inc., Chicago, IL, USA). Categorical data were expressed as number of episodes/participants counts and compared among the three groups by the Chi-squared test. Intergroup comparisons of the mean values of parameters and the mean variations using the Tukey Kramer multiple comparison test. In the time-series data in each group was determined using one-way repeated measures ANOVA during the whole operation. All data were analyzed by the Shapiro-Wilk test for normality of distribution. Normally distributed quantitative variables were presented as means ± standard deviation. A P value of <0.05 was considered statistically significant.