The study adheres to the applicable CONSORT2010 guidelines. This prospective, randomized, double-blind, placebo-controlled, single-center clinical trial was done at The Ningbo City First Hospital (Ningbo, Zhejiang Province, China). The study was registered with the Chinese Clinical Trial Registry (ChiCTR1900023082). The trial was approved by Ethics Committee of Ningbo City First Hospital (2018-R16). The parents or legal guardians of each patient were supplied with comprehensive information by one of the investigators, regarding the study’s risk, benefits, objectives, and procedures. The parents/legal guardians signed informed consent before the patient’s inclusion in the study.
It’s a prospective, randomized, double-blinded, and placebo-controlled clinical trial and the allocation ratio is 1:1 in the project.
We enrolled 460 children (age 3–10 years old) whose American Society of Anesthesiologists physical status was I or II and who were scheduled for elective gastrointestinal endoscopy (esophagogastroduodenoscopy followed by colonoscopy) in endoscopy center of The Ningbo City First Hospital during the period from May 10 to December 5, 2019. Exclusion criteria:(1) be allergic to nalbuphine, its components and opioid medicine;(2)preoperative using analgesic, sedatives, antiemetics or antipruritic in 24 h; (3) preoperative body temperature was higher than 38℃ or suffering from upper respiratory infection in 24 h;(4)suffered from bronchial asthma;(5) suffering from severe obstructive sleep apnea syndrome and arrhythmia;(6)had abnormal surgery; (7) intracranial hypertension;(8)suffering from mental disease or can’t express their mind exactly.(9) BMI ≥ 27.5 kg/m2 or ≤ 13.0 kg/m2 or body weight༜12 kg.
Anesthesia induction: the subjects weren’t administration any other sedatives or analgesics as premedication except fentanyl or nalbuphine. The baseline of vital signs (HR, RR) were acquired at the calm state of subjects entering into operating room. An intravenous cannula was placed in the peripheral vein of right hand for fluid infusion and medicine administration. Oxygen at a rate of 3L/min was delivered via Venturi mask when patients entered the endoscopy unit. Monitors included blood pressure (NIBP), electrocardiogram (ECG), peripheral oxygen saturation (SpO2), CO2 exhalation and respiratory rate (the Intelli Vue MP50; Philips, Shanghai, China). Vital signs were recorded every three minutes. Vital signs 10-minutes after patients lying down on the mobile operating table and administrated with clinical trial medicine were defined as the baselines.
Either nalbuphine(0.1 mg/kg) or fentanyl(1ug/kg) were administered through peripheral vein access which was established preoperatively with a intravenous cannula by the same supervising nurse. Five minutes later, Propofol infusion is initiated via a TCI system with pediatric model (CONCERT-CL, Guangxi Veryark Technology Co. Ltd, Nanning, Guangxi, China). Before the TCI system was started, the pediatric age, weight, height and the effect-site concentration were needed to be set in the TCI system machine. The effect-site concentration was set as 3.5ug/ml. During the procedure, various standard interventions were employed depending on the clinical situation including (i) administration of a 0.5 mg/kg bolus of propofol if the patient moved; (ii) use of a jaw-thrust to open the airway and/or mask ventilation if the patients develop respiratory depression as determined by the anesthesiologist; and (iii) administration of 0.01 mg/mg atropine if the HR was reduced to lower than 20% of baseline.
Once anesthesia induction was achieved, which was confirmed by the loss of eyelid reflex, the same senior endoscopist executed the gastrointestinal endoscopy, starting with esophagogastroduodenoscopy, then colonoscopy. When the colonoscope is at the ileocecal valve and prepared to be removed, the infusion of propofol by TCI system was terminated. Both the endoscopist and the anesthesiologist were blinded to the grouping information.
The primary indicator was pain scores of patients’ awaking time point(t1) and 10 minutes later of recovery time(t2). The secondary indicators included the total consumption of propofol, injection pain scores of propofol, satisfaction scores of patients, recovery time and adverse events such as bucking/hiccupping, body movement. The satisfaction scores of patients ’parents were acquired by a survey (1–5 points, representing Not Satisfied At All to Highly Satisfied) when the endoscopy was completed. Patients were fully oriented as determined by if patient could tell who is his or her parents. RR, HR at 6 different time-points were recorded. The six different time-points were, T1, the time-point after induction; T2, the time-point of insertion of gastroscope into oropharynx. T3, the time-point of the gastroscope removal from the mouth; T4, the time-point of colonoscope entry into the anus; and T5, the time point of the colonoscope reaching the ileocecal valve; T6, the recovery time-point. Besides, the vital signs (HR, RR) at the station of inhaling air in the PACU and the satisfactory degree of parents of children were also as secondary indicators. The general analgesic satisfaction of patients and discomfort was acquired through the questionnaire as Table 1.
The satisfaction survey of patients’ parents
1.On a scale of 1–5`how satisfied are you with this process of postoperative analgesic.
Circle your answer below
1 2 3 4 5
(Not satisfied at all) (Highly satisfied)
The discomfort survey of patients
1.Are you feel pruritus in the process of postoperative analgesic? Circle yes or no.
2.Are you feel nausea and vomiting in the process of postoperative analgesic? Circle yes or no
3.Do you feel any other discomfort in the process of postoperative analgesic? Circle yes or no
Adverse effects such as delayed recovery, respiratory depression (That respiratory rate is lower than 10 per minute or SPO2 is lower than 92% and interval time is longer than 10 s is characteristic as respiratory depression), low blood pressure(20% and more lower than baseline of BP), bradycardic, nausea and vomiting, pruritus were needed to be noted in detail.
Samples size calculation
Because this study was a non-inferiority clinical trial, the sample size was calculated with PASS according to the reference literature in which the non-inferiority value is 1 and standard deviation is 3.189 samples for each group met the requirement of α = 0.05 and power = 0.9.But with the consideration of 20% dropping-out of samples, 230 samples were decided to be enrolled into each group. Totally, 460 samples were collected. With the drop-out or other reasons ,425 samples statistics were useful to make analysis at last.
The measurement data with normal distribution was analyzed with independent 2-sample t-test and the measurement data with abnormal distribution was analyzed with nonparametric test. The count data expressed as frequency or rate was compared using Chi-Square test or Fisher’s exact test .The recording P value was 2-sided,with P༜0.05 considered statistically significant. All the data was analyzed with SPSS23.
Random and double-blind
A total of 460 subjects were randomly distributed in the nalbuphine or fentanyl group according to the random number table generated by Dr Yong Li by using SPSS23. One stable nurse prepared the clinical trial medicine according to the random number table.10 mg nalbuphine hydrochloride injection and 0.1 mg fentanyl citrate injection were diluted into 10 ml with saline respectively. Nalbuphine hydrochloride injection and fentanyl citrate injection were similar in appearance, extrinsic feature, color and weight. In addition, the preparing process of clinical trial medicine is unknown to researcher and patient.