The Ethical Committee of the Women’s Hospital, Zhejiang University School of Medicine (Hangzhou, China) approved this study on April 5, 2018 (No. 20180010). This study was registered on the Chinese Clinical Trial Register (ChiCTR1800015532).
The study was performed at the Women’s Hospital, Zhejiang University School of Medicine from April 9 to July 31, 2018. After providing written informed consent, 150 healthy term parturients scheduled for elective CD were enrolled in this prospective, randomized, triple-blinded, placebo-controlled, dose-finding study. The present study adhered to CONSORT guideline.
Inclusion criteria were American Society of Anaesthesiologists Physical Status II, age 18–40 years old, body mass index < 40 kg/m2, singleton pregnancy, ≥37 weeks’ gestation age, elective CD planned with a Pfannenstiel incision, and planning epidural anaesthesia. Parturients were only recruited if the individual performing the CD was 1 of 5 experienced obstetricians who agreed to have their patients participate in this study. Exclusion criteria included maternal refusal, emergency CD, active labor, ruptured membranes, pregnancy-induced hypertension, placental abnormalities (including placenta previa), multiple gestation, uterine fibroids, history of prior peripartum hemorrhage, coagulation disorders, oxytocin allergy, contraindication to epidural anaesthesia, and the need for pharmacological anxiolysis.
Prior to initiation of this study, sealed, opaque envelopes were prepared using the Microsoft Excel RAND function to determine study subject allocation. Participants were randomized to oxytocin infusion at a rate of 0, 1, 2, 3, 5, or 8 IU h− 1, to be given for a total of 1 h. On the day of surgery, an anaesthetist not involved in the study prepared an oxytocin infusion according to the randomization assignment. After filling a syringe with the total number of units of oxytocin that were to be administered during the hour-long infusion (e.g. if the patient were randomized to receive 8 IU h− 1, a total of 8 IU were drawn into the syringe), the syringe was filled with normal saline to make a total volume of 50 ml. This syringe was then given to the anaesthetist of record with instructions to administer the infusion at 50 ml over 1 h. By having all study subjects receive the same infusion rate (50 ml h− 1) but with a different total dose of oxytocin, the study subject, obstetrician, and anaesthetist responsible for the care of the patient were all blinded to the actual dose of oxytocin.
Upon entry into the operation room, an 18-gauge i.v. catheter was placed in the study subject’s lower forearm and 500 ml lactated Ringer’s solution was administered. With the parturient in the left lateral decubitus position, an epidural catheter was placed at the L1–2 interspace by an anaesthetist not involved in the study. Lidocaine 2% with epinephrine 1:200,000 was administered in 5 ml increments to a total of 15–20 ml until a T6 sensory level to pinprick was obtained.
Upon initiation of epidural anaesthesia, non-invasive blood pressure (NIBP) and maternal heart rate (HR) were measured at 3-min intervals. An i.v. bolus of ephedrine 5 mg was administrated when hypotension was accompanied by bradycardia (HR < 50 beats min− 1), and an i.v. bolus of phenylephrine 100 μg was administrated when hypotension occurred without bradycardia. Hypotension was defined as a decrease in systolic blood pressure greater than 20% from baseline, which had been previously estimated upon admission by the averaging of three consecutive measurements.
Surgery commenced with onset of adequate surgical anaesthesia. After clamping of the umbilical cord and delivery of the infant, all parturients were given an i.v. bolus of oxytocin 1 IU over 15 s as previously recommended , after which the oxytocin infusion previously prepared according to the randomization scheme was initiated at 50 ml h− 1.
After initiation of the oxytocin infusion, uterine tone (UT) was assessed by the obstetrician as adequate or inadequate every 3 min until the peritoneum was closed based on previously described methods [5,6,7]. If UT was assessed as inadequate, an i.v. bolus of oxytocin 1 U was administered. If UT was still judged to be inadequate after two such oxytocin boluses, then secondary uterotonic agents (i.m. carboprost tromethamine 0.25 mg or i.v. carbetocin 0.1 mg) were administered upon the obstetrician’s request. The oxytocin infusion was continued until discharge from the post anaesthetic care unit (PACU). If another syringe was needed in PACU, the same dose of oxytocin as the original was prepared.
The primary study outcome was adequacy of UT during the CD. Secondary outcomes included estimated blood loss (EBL), hemoglobin (Hb) and haematocrit (HCT) levels (at time of PACU discharge and on postoperative day 1), proportion of participants requiring administration of supplemental oxytocin boluses or alternative uterotonic agents, and side effects (hypotension, bradycardia, tachycardia [defined as HR ≥120 beats min− 1], nausea, vomiting, flushing, chest pain, or dyspnea). Postpartum hemorrhage (PPH), defined as EBL > 1000 ml , and the need for perioperative blood transfusion were also noted. EBL was estimated using the following formula [4, 9]: EBL (mL) = [(preoperative HCT - postoperative HCT)/preoperative HCT] × (weight in kilograms) × 85.
Data are expressed as mean ± SD, median (inter-quartile range), or n (%) where appropriate. Data were assessed for normal distribution of variance using the Kolmogorov-Smirnov test. Normally distributed data were assessed by one-way analysis of variance. Nonnormally distributed data were assessed by the Kruskal-Wallis test. Categorical variables were assessed using the Chi-square test or Fisher exact test where appropriate. The Chi-square trend test (linear-by-linear association) was used to analyze the frequency of administration of additional uterotonic agents in the six groups. Statistical analyses were performed using SPSS version 16.0 (SPSS Inc., Chicago, IL, USA). P < 0.05 was considered statistically significant.
The dose-response relation for oxytocin infusion was determined using probit regression [10, 11]. An effective oxytocin infusion rate (success) was defined as a rate that provided adequate UT throughout the CD, from initiation of the oxytocin infusion to closure of the peritoneum, in the absence of administration of additional uterotonic agents. Data for successful responses for each infusion rate were used to plot a sigmoid dose-response curve. The ED50 and ED95 of an effective oxytocin infusion rate were then determined.
Sample size calculation
The sample size was estimated using the Cochran-Armitage Test for the trend in proportions using PASS® (Version 11.0.7, NCSS, LLC, Kaysville, UT). Based on pilot data in which the proportion of parturients with adequate UT was 0.5, 0.5, 0.7, 0.8, 0.85, and 0.9 in those receiving oxytocin infusions at a rate of 0, 1, 2, 3, 5, or 8 IU h− 1, respectively, a total sample of 78 subjects (13 per group) were required to achieve 90% power to detect a liner trend using a two-sided Z test with continuity correction and a significance level of 0.05. We planned to recruit150 subjects to account for potential attrition.