Efficacy and Safety of Dexmedetomidine Combined With Butorphanol Tartrate for Postoperative Analgesia and Breastfeeding in Cesarean Section
Phase: PHASE4
Conditions: Breast Feeding, Analgesia Obstetrical, Postoperative Pain
Sponsor: The First Affiliated Hospital with Nanjing Medical University

Study Protocol and Statistical Analysis Plan 
 
Efficacy and Safety of Dexmedetomidine Combined With Butorphanol Tartrate 
for Postoperative Analgesia and Breastfeeding in Cesarean Section 
Registration number: NCT03065530 
December 21, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

This study was registered at www.ClinicalTrials.gov (registration number: 
NCT03065530). The study protocol was approved by the Ethics Committee of The 
First Affiliated Hospital of Nanjing Medical University (Nanjing, Jiangsu province, 
China) and written consent was obtained from all participants. The study was 
conducted at The First Affiliated Hospital of Nanjing Medical University, Nanjing, 
China between February 2017 and October 2017. 
 
Patients were randomly allocated to one of four groups immediately after delivery 
of the newborn and cord clamping. Patients in group C received 30 ml 0.9% sodium 
chloride, whereas patients in group D1, D2, and D3 received 0.5 μg·kg-1 intravenous 
DEX diluted to 30 ml in 0.9% sodium chloride. Their PCIA protocol was programmed 
with 3 μg·kg-1·h-1 butorphanol in group C, while with 3 μg·kg-1·h-1 butorphanol 
combined with 0.03, 0.05, and 0.08 μg·kg-1·h-1 DEX in groups D1, D2, and D3, 
respectively. The settings for PCIA were a basal infusion at a rate of 2 ml·h-1 and 0.5 
ml of boluses with a lock-out interval of 15 min (butorphanol and DEX in these PCIA 
protocols were calculated based on patient weight and infusion rate). 
None of the parturients received any medication before the induction of anesthesia. 
On arrival to the operating room, a 20-gauge intravenous cannula was inserted into a 
peripheral vein on the arm, and five-lead electrocardiogram (ECG), noninvasive blood 
pressure (NIBP), and oxygen saturation on pulse oximetry (SpO2) were continuously 
monitored. NIBP was measured every 2 min during the operation. The parturients were 
positioned in the lateral decubitus position with knees bent toward the chest and the 
epidural space was identified at the L2 to L3 interspace. After loss-of-resistance 
confirmed that the tip of the epidural needle was in the epidural space, the epidural 
catheter was inserted into the space and 3 ml 1.5% lidocaine combined with 5 μg·ml-1 
epinephrine was administered via the epidural catheter as a test. All parturients were 
administered 0.75% ropivacaine with 2 μg·ml-1 fentanyl, and were in supine to the left 
lateral position. Surgery commenced when T4 to T6 sensory block was achieved. 
Oxygen was administered at 5 L·min-1 via facemask, hypotension (systolic blood 
pressure [SBP] ≤ 90 mmHg or > 20% decline from baseline) was treated with 

intravenous phenylephrine. Parturients received the “study drug” immediately, which 
was intravenously administered for 20 min when the umbilical cord was clamped. 
When the obstetrician closed the peritoneum, 50 mg flurbiprofen axetil and 10 mg 
azasetron hydrochloride was injected in every parturient as a loading dose. No other 
analgesics were administered post-cesarean section except the study drugs. 
Immediately after surgery, the PCIA pumps were attached at a rate of 2 ml·h-1, which 
was 0.5 ml per demand with lock-out intervals of 15 min, and the mother was 
transferred to the ward after a 1 h stay in the recovery room. NIBP was measured every 
30 min for the first 6 h, and every 1 h until 48 h after the operation, with continuous 
HR and SpO2 monitoring.  
Side effects, such as hypotension (SBP < 90 mmHg), bradycardia (HR < 60 
beasts/min), hypoxemia (SpO2 < 90%), respiratory rate (RR, < 10 breaths/min, lasting > 
10 min), and nausea and vomiting were recorded during the period starting from the 
end of surgery until 48 h after surgery. Respiratory depression was treated with oxygen 
and naloxone until RR reached >15 breaths/min. Severe nausea and vomiting were 
treated with azasetron or dexamethasone, whereas hypotension was treated with fluid 
loading, intravenous ephedrine or phenylephrine. Bradycardia was treated with atropine. 
Breast milk samples were collected on primary lactation (the start of which was from 
delivery to when > 5 ml of breast milk was expressed by massaging and compressing 
both breasts) for 48 h, and the time was also recorded. All samples were stored at -30°C. 
DEX levels in breast milk were quantified using high-performance liquid 
chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis and liquid-liquid 
extraction. 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parturients with a singleton underwent elective caesarean delivery under epidural 
anesthesia (n=176) 
120 patients were randomized 
Excluded (n=56) 
Not meeting inclusion criteria (n=39) 
Declined to participate (n=14) 
Other reasons (n=13) 
Allocated to intervention 
(n=30) 
Allocated to intervention 
(n=30) 
Allocated to intervention 
(n=30) 
Allocated to intervention 
(n=30) 
Second surgery in 
48 h (n=1) 
Failure to epidural 
anesthesia (n=1) 
Hemorrhage need  
transfusion (n=1) 
Inadvertent PCIA 
suspended ()n=1 
Failure to epidural 
anesthesia (n=1) 
Hemorrhage need  
transfusion (n=1) 
Eligible for Analysis 
(n=28) 
Eligible for Analysis 
(n=29) 
Eligible for Analysis 
(n=29) 
Eligible for Analysis 
(n=28) 
0.9% sodium chloride 30 
mL loading dose 
+ 
butorphanol 3μg/kg/h in 
PCIA 
dexmedetomidine 
0.5μg/kg diluted to 30 mL 
loading dose 
+ 
butorphnol 3μg/kg/h plus 
dexmedetomidine 0.03μ
g/kg/h in PCIA 
dexmedetomidine 
0.5μg/kg diluted to 30 mL 
loading dose 
+ 
butorphnol 3μg/kg/h plus 
dexmedetomidine 0.05μ
g/kg/h in PCIA 
dexmedetomidine 
0.5μg/kg diluted to 30 mL 
loading dose 
+ 
butorphnol 3μg/kg/h plus 
dexmedetomidine 0.08μ
g/kg/h in PCIA 

Statistical Analysis Plan 
 
The primary outcome was the VAS-R at 6 h after delivery. When designing the 
study, the sample size was calculated on the basis of an initial pilot study measuring 
VAS-R 6 h after surgery in 20 patients, and the standard deviation (SD) among the four 
groups was 1.4. The authors hypothesized that differences in VAS among the four 
groups and the SDs would be 15%. A power analysis suggested that 80% power would 
be required to detect differences at an α level of 0.05 (two-tailed), including 24 
individuals per treatment group. Considering an anticipated attrition rate of 25%, 30 
parturients were eventually recruited for each group. Secondary outcomes included 
VAS-M, VAS-C, RSS, RID, and satisfaction with analgesia after surgery. 
GraphPad Prism version 7 (GraphPad, La Jolla, California, USA) was used to 
perform statistical analysis. Patient characteristics were analyzed using one-way 
analysis of variance (ANOVA). Patient satisfaction was analyzed using the chi-squared 
test and Kruskal-Wallis rank sum test. RID, VAS, and RSS were analyzed using the 
Kruskal-Wallis rank sum test. Dunn’s multiple comparison tests were also used for 
multiple comparisons (post hoc test). P < .05 was considered to be statistically 
significant (P<.0083 was considered to be statistically significant when the post hoc 
test was used).