Premedication of nalbuphine benefits children gastrointestinal endoscopy screening under sedation: a randomized, controlled, double-blinded clinical trial

Backgrounds : Nalbuphine may be a useful opioid for postoperative use in children, but exact efficacy of premedication of nalbuphine in gastrointestinal endoscopy (e.g. compared to other commonly used opioids) has not been determined yet. This study aims to compare the benefits between premedication with nalbuphine and fentanyl on children undergoing gastrointes tinal endoscopy screening under sedation with propofol. Methods: A total of 460 children with age 3-10 years old, undergoing elective gas ‐ trointestinal endoscopy screening with ASA I -II were randomly assigned to fentanyl group or nalbuphine group, and then they were all subsequently ad ministrated propofol through target-controlled infusion (TCI) with an effect-site concentration of 3.5 ug/ml, before and during the procedure. We compared postoperative pain, the total consumption of propofol, the cardiovascular parameters, satisfaction scores of patients’ parents, adverse events in patients, injection pain scores and recovery time. Results: The postoperative pain score at time of entering PACU and 10min later in nalbuphine group were lower than that in fentanyl group(1.75±1.87 vs 2.29±2.22 p0.05) (1.67±1.81 vs 2.12±1.99 p0.05), but the injection pain of propofol and the recovery time is approximate. Patients in two groups had similarly stable hemodynamics. The consumption of propofol was higher in fentanyl group than nalbuphine group (78.7± 13.6 mg vs 71.2 ± 13.9 mg, P <0.05). The incidence of bucking/hiccupping was lower than in the nalbuphine group than that in the fentanyl group (6% vs 14.3%, P <0.005). The incidence of body movement was also lower in the nalbuphine group than the fentanyl group (7.9% vs 18.7%, P<0.005). The satisfaction scores by patients ’parents were higher in the nalbuphine group than fentanyl

Conclusion: Premedication of nalbuphine in children for endoscopy screening sedation has many benefits. The analgesic effect of nalbuphine is superior to that of fentanyl.

Backgrounds
Propofol is often used as a sedative agent in children and adults gastrointestinal endoscopy screening, but its adverse effects including hypotension, bradycardia, and respiratory depression, injection pain has also been reported [1,2]. In addition, pediatric patients undergo invasive examination the same as adult patients, but generally because of excessive concerns about the side effects of analgesics, lower doses of analgesics per body weight are prescribed compared with those for adult patients, which results in inadequate management of perioperative pain. And several surveys in recent years demonstrated that perioperative pain in children is still a relevant problem [3,4].
Nalbuphine is an opioid analgesic agent widely used for control of mild-to-severe pain.
And the analgesic potency were already reported in adults [5] and in children [6]. Its analgesic potency is equivalent to that of morphine on a milligram basis in adults.
Nalbuphine hydrochloride is a synthetic narcotic agonist-antagonist analgesic of the phenanthrene series with a duration of analgesia of 2-6 h [5,7]. As nalbuphine was a kappa-receptor agonist and µ-receptor antagonist, it can relive µ receptor -related adverse reactions respiratory depression and opioid -induced adverse events such as pruritus, nausea and vomiting in theory. Compared with morphine, nalbuphine could induce less respiratory depression at high doses because of its ceiling effect [8]. What's more, it had less effect on arterial pressure [9] and it could reduce the incidence of vomiting [10]and pruritus. [11,12] This study was performed to evaluate whether premedication with nalbuphine can bring much benefits for children gastrointestinal endoscopy screening under sedation with TCI of propofol. 4

Methods
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.

Study design
It's a prospective, randomized, double-blinded, and placebo-controlled clinical trial and the allocation ratio is 1:1 in the project.

Participants
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 24h; (3) preoperative body temperature was higher than 38℃ or suffering from upper respiratory infection in 24h;(4)suffered from bronchial asthma;(5) suffering from severe obstructive sleep apnea syndrome and arrhythmia;(6)having difficult airway. had abnormal surgery or anesthesia recovery; (7) intracranial hypertension;(8)suffering from mental disease or can't express their mind exactly.(9) BMI≥27.5kg/m2 or ≤13.0kg/m2 or body weight 12kg.

Interventions
Anesthesia induction: the subjects weren't administration any other sedatives or analgesics as premedication expect fentanyl or nalbuphine. The baseline of vital signs (HR, RR) were acquired at the calm station of subjects entering into operating room. An 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 6 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.

Outcomes
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 [13] Table 1.
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 10s 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 7 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, 240 samples were decided to be enrolled into each group. Finally,425 samples statistics were useful to make analysis.

Statistical analysis
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.10mg nalbuphine hydrochloride injection and 0.1mg fentanyl citrate injection were diluted into 10ml with saline respectively. Nalbuphine hydrochloride injection and fentanyl citrate injection was similar in appearance, extrinsic feature, color and weight. In addition, the preparing process of clinical trial medicine is unknown to researcher and patient.

Results
A total of 460 patients were enrolled, with 35 dropouts or violating the protocol, 209 patients were recruited to analyze in fentanyl group and 216 in nalbuphine group finally, the patient flowchart is presented in Figure 1. None of the patients involving had severe complications. All the measurement data was recorded as Mean±SD. The characteristic of the patients is presented in Table 2. There is no difference in these parameters including the proportion of genders, the mean age, BMI, weight and height in two groups (all P>0.05).
The postoperative pain score in accordance with FLACC is lower in nalbuphine group compared with fentanyl group presented in Table 3. No statistically significant difference was noted in injection pain of propofol according to the scoring standard as Table 4, respiratory depression rate, nausea and vomiting rate, but the incidence of bucking/hiccupping, body movement and pruritus were lower in the nalbuphine group compared to fentanyl group, presented in Table 5 and Table 6. In addition, there were also no significant difference for vital signs including heart rate, respiratory rate presented in Figure 2. The consumption of propofol is higher in fentanyl group than that in nalbuphine group and satisfaction scores is lower in fentanyl group compared with nalbuphine group.

Discussion
The ideal perioperative pain relief for pediatric patients should be easy to administer and should have sufficient analgesic effects as well as enough safety [14]. Nalbuphine may be a suitable analgesic agent for children because of its ceiling effect, the dose of maximum analgesic action is 0.3-0.4 mg kg-1. Higher doses neither increase the analgesic effects nor substantially increase the risk of respiratory failure. A neonate mistakenly administered a dose ten-fold higher than required has been described and resulted in only a prolonged sedation without respiratory failure [15]. What's more, nalbuphine can reverse the opioid -induced respiratory depression [16].
The study outcome showed that the postoperative analgesia effect of premedication with nalbuphine is superior to the fentanyl, but the analgesia effect to relief the injection pain of propofol is similar to fentanyl. It may be because of the time of nalbuphine approaching to peak effect of analgesia effect and it has sedative effect [5]. The reason can also explain that the total consumption of propofol and incidence of adverse effect such as 9 bucking /hiccupping and body movement is less in nalbuphine group compared to fentanyl group. The advantage of relief incidence respiratory depression is not obvious. Maybe because the usage dose of two groups is not enough. In addition, the study outcome showed that nalbuphine has less incidence of pruritus than fentanyl, which could be explained by its characteristic. [5] Nalbuphine was proved to be a relative efficient agent. It can decrease the tourniquet pain when added to intravenous regional anesthesia There were few limitations in our study. Firstly, we used only a single low dose of nalbuphine and thus did not compare the effects of different doses. Secondly, we only considered the postoperative pain scored according to FLACC, when calculating the sample size, which may not be adequately powered for injection pain of propofol. Future studies should consider it, while calculating the sample size. Thirdly, we don't record the sedation degree which possibly made influence on pain score.

Conclusion 10
In conclusion, premedication of nalbuphine has many benefits to children gastrointestinal endoscopy screening under sedation.

Ethics declarations
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Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.  Tables   Table 1. Questionnaire table   14 The satisfaction survey of patients' parents    Table 4. Pain scale for evaluation of propofol-induced injection pain   Verbalisation scale  Response to propofol injection Pain score  0  No vocalisation  1  Purposeless moaning  2  Explicit protest  3 Screams, cries nalbuphine group vs fentanyl group *P<0.05  Figure 1 The flowchart is the process from recruitment to statistical analysis of the trial

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