2.1. Patient Selection.
This study was approved by the Ethics Committee of The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University (LCKY2018-56) and registered on http://www.chictr.org.cn: (registration number: ChiCTR1800019965). Every participant provided a written informed consent. Inclusion criteria included parturients planned for elective cesarean section under epidural anesthesia with 18 to 35 years of age, American Society of Anesthesiologists (ASA) physical status I or II, body mass index (BMI) 20 to 25 kg/m2, 37 to 42 weeks of gestation age, and B-ultrasonography showed intrauterine single live fetus without umbilical cord around the neck, congenital malformation or other abnormal conditions. The exclusion criteria included parturients with history of liver dysfunction or kidney dysfunction or cardiopulmonary diseases, parturients with mental and neurological diseases, parturients with history of allergy, parturients who were complicated with hypertension and eclampsia and parturients who were not suitable for epidural anesthesia. Parturients would be dropped out if hemabate was used or the hemorrhage exceeded 500mL during delivery.
2.2. Anesthesia Procedure
The trial was conducted from December 15, 2018 to April 30, 2019 in the operation room of The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University. 160 parturients planned for elective CS under EA were enrolled and 158 of them were included and randomly allocated to 4 groups: Group A (n=39, receiving butorphanol 7.5ug/kg), Group B (n=40, receiving butorphanol 5.0ug/kg), Group C (n=40, receiving butorphanol 2.5ug/kg), and Group D (n=39, without butorphanol). None of the parturients was given any other premedications. Parturients were monitored by electrocardiography (ECG), noninvasive blood pressure (NIBP), and pulse oxygen saturation (SpO2) every five minutes. The operating room temperature was maintained to 24~26°C and the humidity was maintained to 40%~60%.
Venous access was obtained in the upper limb with a 20G catheter. After the venous access was established, each group of parturients received corresponding intravenous medication: Group A (butorphanol 7.5ug/kg), Group B (butorphanol 5.0ug/kg), Group C (butorphanol 2.5ug/kg) and Group D (without butorphanol). After that, epidural puncture was performed at L2-L3, and 3 ml of 2% lidocaine was injected into the epidural catheter. If there was no sign of subarachnoid block after 5 minutes, 8~12ml of 0.75% ropivacaine and 0.2 mg (0.1 mg/ml) hydromorphone would be given for epidural anesthesia. Parturients’ positions were adjusted to control the level of anesthesia at T6. Subsequently, parturients were placed in the supine position, and underwent segmental cesarean section.
A blinded observer was involved in the data collection. The incidence, intensity and duration of shivering were recorded as main parameters. Shivering severity was graded by Wrench standard scale (0 = no shivering; 1 = One or more of the following: piloerection, peripheral vasoconstriction, peripheral cyanosis with no other cause, but no muscle activity; 2 = visible muscular activity confined to one muscle group; 3 = visible muscular activity in more than one muscle group; 4 = muscular activity involving the whole body). Shivering was observed from the start of intravenous administration of butorphanol to two hours after surgery. Pulse oxygen saturation (SpO2), systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), respiratory rate (RR) and sedation score (1=fully awake and oriented; 2=drowsy; 3=eyes closed, but open on command; 4=eyes closed, but open on physical stimulation; 5=eyes closed and unresponsive to physical stimulation.) were recorded at six points which were respectively before intravenous administration (T0), 5 min after intravenous administration (T1), 10 min after intravenous administration (T2), 15 min after intravenous administration (T3), 20 min after intravenous administration (T4) and 30 min after intravenous administration (T5). Apgar scores of newborn were recorded at 1 min, 5 min, and 10 min after delivery and cord blood were collected for blood gas analysis. Occurrence of nausea, vomiting, chest tightness, dyspnea, dizziness and other complications were also recorded during study.
Hypotension (systolic BP <90 mmHg or >30% drop from the baseline BP) was treated with intravenous ephedrine (5–10 mg). Decrease in the heart rate (<50 beats per min) was treated with intravenous atropine (0.3–0.5mg). Respiratory depression (pulse oxygen saturation <90% or >10% drop from the baseline) was treated with mask oxygen inhalation. Cephalic position was taken to flank side for parturient with nausea and vomiting, and intravenous administration of 8 mg ondansetron was given to those with severe vomiting. The amount of intravenous administration of any drug were recorded.
Any other important harms or unintended effects happened in any group would also be recorded.
2.3. Statistical Analysis.
Sample size estimates were done using PASS 11 software (PASS, Kaysville, UT, USA). In our pilot experiment, the incidence of shivering was 45% which decreased to 10% after the administration of intravenous butorphanol 7.5ug/kg. Assuming a <5% probability for a type I error, (i.e., significance level α=0.05) and <20% for a type II error (i.e., accepting a null hypothesis when it is false, β=0.20), the required sample size in each group was estimated to be 32. Allowing for 10% withdrawals, we recruited 40 parturients in each group.
Participants were randomly divided into four groups by using a computer generated random-number sequence. Wendong Lin generated the random allocation sequence. Shuying Fu enrolled participants and assigned participants to interventions and prepared the drugs. Liang Qi performed Epidural puncture and drugs administration. Bing Zhang and Mingpin Hu recorded and assessed the outcomes. Bing Zhang, Mingpin Hu and Participants were blinded after assignment to interventions.
The statistical analysis was performed using IBM SPSS Statistics 22.0 for Windows software (IBM Corp, Armonk, NY). Normal distribution of continuous varialbes data was tested by the Shapiro–Wilk test. Data pertaining to normally distributed continuous variables (age, weight, height etc.) were presented as a mean ± standardand deviation and analyzed using one-way ANOVA. Measurement data of non-normal distribution (BMI, gestational weeks etc.) were presented as a median (Q1, Q3) and analyzed with the Kruskal-Wallis H test. Categorical data were presented as numbers and proportions, and tested by the chi-square test or Fisher’s exact test as appropriate. Continuous variables at different time points were compared by using repeated measures design analysis of variance. A value of P<0.05 was considered a statistically significant difference.