This clinical study was approved by the Hospital Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University and was registered in the clinical trial registration center of China (ChiCTR1900022780). Informed consent was obtained from all individual participants included in the study. This study adhered to CONSORT guidelines.
This study was based on medical records of ASA I-II patients aged 18 to 65 who underwent an outpatient GI endoscopy (diagnostic esophagogastroduodenoscopy and colonoscopy, without therapeutic procedures) and requiring anesthesia in endoscopy center from May to July of 2019, and an operation time within 30 min. Patients were excluded from the study based on the following criterion: not willing or unable to finish the whole study, acute upper respiratory tract infections, hepatitis, and renal failure, habitual sedative or analgesic use, analgesic use for acute pain, chronic fatigue syndrome, low potassium, myasthenia gravis, psychiatric disease and allergy to butorphanol, sufentanil or propofol.
This study was divided into two parts: 1. determination of the ED95 of butorphanol and sufentanil; 2. comparison of clinical efficacy of butorphanol with equivalent sufentanil.
ED95 of butorphanol and sufentanil
All the patients were completed routine gastrointestinal preparation before endoscopy, fasting from solids for 8 hr and liquids for 2 hr before the operation. Anesthesia machine was inspected, and intravenous access was established. Standard monitoring was applied before the induction of anesthesia in the outpatient operating room, including non-invasive blood pressure (BP), electrocardiogram (ECG), and oxygen saturation (SpO2), and the patients were placed in the left lateral position. All the patients received supplemental oxygen inhalation through nasal 3 L per minute and hold the facial mask by themselves.
Butorphanol (Batch number: 190411BP Jiangsu Hengrui Pharmaceutical Co, Ltd .) or sufentanil (Batch number: 3018511505 Yichang Humanwell Pharmaceutical Co, Ltd .) was slowly injected intravenously. Given the 3 min onset time, propofol (Batch number: 1811236 Beijing Fresenius Kabi Pharmaceutical Co., Ltd.) was administrated intravenously at a constant speed until the patient lost consciousness and dropped the hand-held mask, followed by a continuous intravenous infusion at a rate of 50–150 µg•kg− 1•min− 1. Monitoring bispectral index (BIS Complete Monitoring System, Covidien.co), controlled BIS value between 50–60 by adjusting propofol speed; then, the endoscopy began (operated by the same gastroenterologist). If the patient showed “failure sedation” (definition of failure sedation: occurrence of gag reflex [11], coughing, or body movement during esophagogastroduodenoscopy, or body movement during colonoscopy) during the GI, additional propofol of 0.5-1 mg/kg was administrated. Once the SpO2 fell to 90%, assisted ventilation by a facial mask with oxygen was applied. If the heart rate was less than 45 beats per minute, atropine (0.5 mg) was applied. If the mean arterial pressure was less than 50 mmHg, ephedrine 5–10 mg was used. After surgery, the patients were transported to the PACU (postanesthesia care unit) to have a rest and recovery.
Dixon up-and-down method
The dose of butorphanol to each patient was determined by the Dixon up-and-down method [12]. According to geometric progression, the dose gradient was divided into 6 steps: 12.00 µg/kg, 10.00 µg/kg, 8.33 µg/kg, 6.94 µg/kg, 5.79 µg/kg, 4.82 µg/kg. In a preliminary experiment, the ED95 of butorphanol of “successful sedation” (definition of successful sedation: without gag reflex, coughing, or body movement in esophagogastroduodenoscopy and body movement in colonoscopy) with propofol in outpatient GI endoscopy was 9.8 µg/kg. So, the primal patient received a prescription dose of 10.00 µg/kg. The does grade was increased or decreased by using the up-down method based on the failure or successful sedation in the previous patient. This process was repeated until there were nine cross-over pairs [13] (i.e., one successful sedation, followed by one failure sedation).
The dose of sufentanil to each patient was also determined by the Dixon up-and-down method. According to geometric progression, the dose gradient was divided into 6 steps: 0.12 µg/kg, 0.1 µg/kg, 0.083 µg/kg, 0.069 µg/kg, 0.058 µg/kg, 0.048 µg/kg. In a preliminary experiment, the ED95 of sufentanil of “successful sedation” with propofol in outpatient GI endoscopy was 0.085 µg/kg. So, the primal patient received a prescription dose of 0.083 µg/kg. The following process was also pretreated similarly to testing the ED95 of butorphanol.
Comparison with sufentanil
Groups. Two hundred cases of painless GI patients were recruited. The patients were randomly divided into two groups, including the butorphanol group (group B, n = 100) and the sufentanil group (group S, n = 100).
Anesthesia methods. In this part, this was a double-blind, randomized study. The patients were grouped according to the envelope method. The dispensing nurse dispensed the medicine to the anesthetist. The preoperative preparation and anesthesia methods were the same as in the first part performed by the anesthetist. The ED95 dose of butorphanol (9.07 µg/kg) was administered in group B. The ED95 dose of sufentanil (0.1 µg/kg) was administered in group S. ED95 dose of butorphanol and sufentanil were achieved in the first part. Postoperative indications in the PACU were evaluated and recorded by another postoperative observer who was blinded to the group division.
Efficacy measurements and variables. Our primary outcome in this study was the recovery time that represented the time between completion of the examination and departure from the PACU). The standard of leaving the hospital is our outpatient operation standard [14] (including vital signs, pain, orientation, dizziness, and walking). Secondary outcomes included the demographic and medical data, including the incidence of respiratory depression (respiratory rate < 10 beats/min or SpO2 < 90% in nasal catheter oxygenation with 3 L/min), the incidence of circulatory inhibition (MAP < 50 mmHg or HR < 45 beats /min), dosage of propofol, the incidence of failed sedation, fatigue severity scores (assessed an 11-point (0–10) scale [15] 15 min after awakening time ), VAS score of abdominal pain (15 min after awakening time), value of hand grip strength before and 15 min after operation ( by an electronic hand dynamometer (EH101, Camry Co. Zhongshan, China)), the incidence of nausea and vomiting, and dizziness after awakening.
Statistical analysis.
SPSS statistical software (IBM Corporation, version 19) was used for statistical analysis. The median effective dose (ED50) and ED95 and the 95% confidence intervals (CI) of butorphanol and sufentanil were determined by binary regression (probit) [16].
The sample size of part two was evaluated by PASS 11.0. The primary indicator was recovery time. The pre-experimental measurement showed that the recovery time in the butorphanol group was 22.12 ± 7.9 min, and in the sufentanil group was 25.57 ± 8.1 min. A sample size of 93 in each group was determined to be required for a β value of 0.10 and an α value of 0.05. Considering the loss of data and the patients who could not be interviewed after endoscopy, 100 patients were selected in each group to ensure that the experiment had a large enough sample size.
Normally distributed data were analyzed with the Mean ± standard deviation, and a two independence sample t-test was used to evaluate the differences between the two groups in this condition. The non-parametric data were analysed using the median (Q1, Q3) or ratio, and a non-parametric test was used to evaluate the differences between the two groups in this condition. The rate comparison of complications was using a four-square table chi-square test. P-value < 0.05 was considered to indicate statistical significance.