Clinical trial NCT02990910
Conditions: Analgesia
Keywords: respiratory adverse events adenotonsillectomy opioid analgesia children
Sponsor: Children's Hospital of Fudan University
Start date: 2016-11-01; Completion date: 2017-02-01
Enrollment: 280 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A high incidence of respiratory morbidity after adenotonsillectomy is reported in children with obstructive sleep apnea syndrome (OSAS). So we designed a prospective, double-blind, randomized controlled study to determine the effects of individualized opioid analgesia compared with conventional opioid analgesia on respiratory morbidity after adenotonsillectomy in Children with OSAS.

Detailed description:
All children were randomized 2 groups based on a computer-generated random number. The main interventions were occurred in post anesthetic care unit (PACU). In the operating room, all patients received a standardized anesthetic regimen by one anesthetist. Sevoflurane was used for maintenance without any opioids. Before the end of the procedure, spontaneous respiratory was recovered. All the patients were given 1 mcg/kg fentanyl intravenous injection after the end of the procedure. The positive result was defined as spontaneous respiratory rate decreased more than 50%, the others were defined as negative result. The result of fentanyl test submitted to assistant, and prepared the rescue analgesic drugs according to this result. One group: positive result 10μg/kg morphine; negative result 50μg/kg morphine. Another group: all received 25μg/kg morphine .The trachea was extubated when patients were awake, and then transported to the PACU. Patients with a Children's Hospital of Eastern Ontario Pain Scale score\>6 received rescue analgesic drugs and observe respiratory morbidity in each group.

Arms: arm 1: One group: positive result 10μg/kg morphine; negative result 50μg/kg morphine.Scored every 10 minutes until CHEOPS\<=6 and Aldrete score\>9. arm 2: Another group: all received 25μg/kg morphine .Scored every 10 minutes until CHEOPS\<=6 and Aldrete score\>9.
Interventions: intervention 1: Individualized opioid analgesia intervention 2: conventional opioid analgesia
Intervention descriptions: intervention 1: (a）positive result 10μg/kg morphine; negative result 50μg/kg morphine. intervention 2: (b) all received 25μg/kg morphine

Protocol documents:
Prot_005.pdf: 
 
 
NCT02990910 
 
 
 
 
 
 
 
The effect of individualized analgesia 
on respiratory adverse events after 
adenotonsillectomy in Children 
—randomized double-blind controlled trial 
 
 
 
 
 
 
                                          2017-2-15 
 
 
 
 


Study protocol 
Study background  
Adenotonsillectomy in children is a common operation in Department of 
ENT, and it is also the main method for treatment of obstructive sleep 
apnea syndrome (OSAS). Clinically, there are a considerable number of 
children with OSAS who underwent adenotonsillectomy, some of which 
are severe OSAS.  
Recurrent nocturnal hypoxemia occurred in children with severe OSAS. 
Their susceptibility to opioids increased and the quantity of opioid 
needed for no pain after operation was less than that of mild children . 
Therefore, the dosage of opioids for postoperative analgesia in children 
with different severity is different. If all children are treated with a small 
dose of opioid analgesics, the analgesic efficacy of mild or non OSAS 
children is not sufficient; if a large dose is used, then severe children are 
prone to respiratory adverse events . Studies have shown that the 
incidence of respiratory adverse events in children with severe OSAS is 
as high as 29.6%, which is about 10 times that of children with mild 
OSAS.Therefore, it is very important to differentiate the patients with 
severe and mild OSAS for targeted individualized use of analgesics in 
children with adenotonsillectomy .  
Since children with severe OSAS have an increased susceptibility to 
opioids, we hypothesized that the sensitivity of children to opioids could 


be judged by the response of respiratory rate to small doses of opioids, 
which can guide the use of long-acting opioids after surgery to reduce 
the incidence of respiratory adverse events. Based on our previous 
studies, we found that the fentanyl test results were correlated with the 
postoperative morphine requirement. Children with positive fentanyl 
test need less morphine requirement (median morphine use was 
30μg/kg), and negative children need less postoperative morphine 
requirement (median morphine use was 50μg/kg) . It shows that the 
conventional analgesic dose (25 μg/kg) is larger for some of the children 
with positive fentanyl, which may increase the incidence of 
postoperative respiratory adverse events . It is small for the children 
with negative fentanyl test, there is a lack of pain relief, which extends 
the duration of pain in children. Fentanyl test cannot identify the 
severity of OSAS, but it can be used to identify children with different 
morphine requirements. Therefore, we hypothesized that individual 
analgesia should be performed according to the results of fentanyl test. 
More amount of morphine in children with positive fentanyl test and 
less amount of morphine in children with negative fentanyl test can 
reduce the incidence of postoperative adverse events in children ,and 
improve the analgesic efficacy of children.  
Objective  
The aim of this study was to verify the hypothesis that individualized 


opioid analgesia regimen according to fentanyl test could decrease the 
incidence of postoperative respiratory adverse events and improve the 
effect of analgesia compared with conventional opioid analgesia 
regimen after adenotonsillectomy in children. 
Materials and Methods 
The study received approval from the Institutional Review Board of the 
Children’s Hospital Fudan university (Human Research Review 
Committee Approval No.2016189) and written parental informed 
consent. In this prospective, double-blind, randomized, controlled 
clinical trial, 280 children scheduled for adenotonsillectomy under 
general anesthesia at the Children’s Hospital from November 2016 
through February 2017 were selected and were randomly divided into 
two groups. One group was conventional opioid analgesia regimen 
group, another was individualized opioid analgesia regimen group. The 
two groups had the same anesthesia regimen. Intubation was performed 
without muscle relaxants after induction with inhaled sevoflurane 
combined with propofol. Anesthesia was maintained with sevoflurane 
and N2O without opioids during the operation. Before extubation, 
spontaneous respiration was recovered, and respiratory rate were 
monitored after administration of 1µg/kg fentanyl intravenously. A 
positive result was defined as a decrease of more than 50% in 
spontaneous respiratory rate. Otherwise it was defined as a negative 


result. Extubation was performed when patients were fully awake, and 
they were transferred to the post-anesthesia care unit (PACU). Pain was 
evaluated based on the Children’s Hospital of Eastern Ontario Pain Score 
(CHEOPS) upon admission into the PACU, and every 10 minutes 
thereafter. Morphine was administered repeatedly every 10 minutes 
until a CHEOPS of 6 was attained. Patients in the individualized group 
with positive results of fentanyl test received morphine 10μg/kg 
intravenously, while patients with negative results received morphine 
50μg/kg intravenously. In the conventional group all patients received 
25μg/kg morphine. The main observation indexes was the incidence of 
respiratory adverse events in PACU, the ratio was the number of 
children who occurred respiratory adverse events to the total number of 
children. Respiratory adverse events were defined as an intervention 
requiring a nurse to maintain the SPO2 ≥95%. Interventions include 
blow-by-oxygen mask, jaw thrust, change the body position, pressure 
ventilation, the need to establish artificial airway (oropharyngeal or 
nasopharyngeal airway, laryngeal mask, the endotracheal tube), drug 
administration 
(succinylcholine 
or 
propofol 
ease 
laryngospasm, 
salbutamol inhalation ease bronchospasm, etc.).Secondary indexes were 
the pain score of children in two groups, and analyzed the persistent 
pain state of children in the two groups by Kaplan-Meier survival 
analysis. 


Statistical Analysis 
the SPSS 23.0（Statistical Package for Social Sciences，IBM）was used to 
analyze the data. The measurement data are tested by normality, and 
the normal distribution is expressed as the mean± standard deviation; 
if the distribution is not normal, it is represented by the median and 
range interquartile. The measurement data with normal distribution and 
homogeneity of variance uses t test, if heterogeneity of variance, use the 
nonparametric test; Chi square test was used to compare the count data. 
Results  
The rate of postoperative respiratory adverse events were the main  
observation indexes, comparative the differences， RR (relative risk) and 
the NNT (number need to treat)。We also compare the median survival 
time of CHEOPS> 6 in the individualized group and conventional group. 
At 20 minutes in the PACU, the proportion of children who reached a 
score of CHEOPS ≤ 6 in the individualized group and conventional 
group . p < 0.05 was considered statistically significant. 
Summary 
There are few studies on how to guide the opioid analgesic dosage in 
children with OSAS according to their sensitivity to opioids. In our study , 
the individualized analgesic regimen guided by fentanyl test may reduce 
the incidence of respiratory adverse events after adenotonsillectomy  
and improve the postoperative safety of children.  

SAP_003.pdf: 
 
 
NCT02990910 
 
 
 
 
 
 
 
The effect of individualized analgesia 
on respiratory adverse events after 
adenotonsillectomy in Children 
—randomized double-blind controlled trial 
 
 
 
 
 
 
                                          2017-2-15 
 
 
 
 


Statistical Analysis Plan 
 
In this study, the SPSS 23.0（Statistical Package for Social Sciences，IBM）
was used to analyze the data.The measurement data are tested by 
normality, and the normal distribution is expressed as the 
mean±standard deviation;if the distribution is not normal, it is 
represented by the median and range interquartile.The measurement 
data with normal distribution and homogeneity of variance uses t test,if 
heterogeneity of variance, use thenonparametric test;Chi square test 
was used to compare the count data.The data of heart rate, blood 
pressure and pain score were analyzed by variance analysis of repeated 
measurement data.Kaplan-Meier method was used to analyze the 
survival status of two groups patients with postoperative pain status 
after operation,plot the survival curve and compare the median survival 
time of Cheops > 6. 

ICF_004.pdf: 
 
 
NCT02990910 
 
 
 
 
 
 
 
The effect of individualized analgesia 
on respiratory adverse events after 
adenotonsillectomy in Children 
—randomized double-blind controlled trial 
 
 
 
 
 
 
                                         2017-2-15 
 
 
 
 


 
Informed Consent Form 
 
Research name: The effect of individualized analgesia on respiratory 
adverse events after adenotonsillectomy in Children—randomized 
double-blind controlled trial  
Project leader: Wang Xuan Phone : 18017591058  
The children's Hospital of Fudan University  
You are invited to participate in this project. This notification provides 
information about this study to know. If you agree to participate, you 
will be asked to sign the informed notice.  
1. Research purpose  
The aim of this study was to verify the hypothesis that individualized 
opioid analgesia regimen according to fentanyl test could decrease the 
incidence of postoperative respiratory adverse events and improve the 
effect of analgesia compared with conventional opioid analgesia 
regimen after adenotonsillectomy in children.  
2. Research programme  
In this prospective, double-blind, randomized, controlled clinical trial, 
280 children scheduled for adenotonsillectomy under general anesthesia 
at the Children’s Hospital of Fudan University from November 2016 
through February 2017 were selected. If your child decides to participate 
in this study you will need to take about 10 minutes of preoperative 


interview. You will be asked about their children at night and if daily 
respiratory abnormalities. Preoperative random allocation group is 
based on the analgesia of fentanyl in postoperative test individual, 
according to conventional methods of analgesia in the control group. 
Pain management in the recovery room, has a dedicated staff of child's 
pain scores, according to the grouping and scoring intravenous 
morphine analgesia, compared between the two groups the incidence of 
adverse respiratory events. When pain scores and aldrete score was 
reached, the children will be sent back to the ward.  
3. Possible risks  
And like a regular check, data collection may have some risks, including 
recurrent laryngeal spasms, nausea, vomiting, aspiration, and so on. If 
these conditions occur, will be processed in a timely manner.  
4. Possible benefits  
You will receive regular follow-up of our health, and are ready to provide 
you with health and treatment of nocturnal sleep respiratory disorder 
syndromes in children information and advice.  
5. Research related injury compensation and treatment  
We will carefully assess your damage as a result of the study, 
and provide the proper treatment in order to preserve your 
rights. Fudan University children's Hospital anesthesia 
Department will provide you with insurance, if there is damage 


due to studies, Fudan University children's Hospital 
anesthesia Department will provide the necessary treatment 
costs as well as appropriate financial compensation.  
6. Study on confidentiality of records  
We require each participating staff to sign confidentiality 
agreements, to ensure that our researchers do not give out your 
information. All research data is locked in a file cabinet, 
absolute confidentiality, only the project researchers have 
access to the information. Your examination and treatment 
information at scientific meetings or used in the literature, 
but not your personal information.  
7. Right to object  
You can volunteer to participate in this study, and withdraw 
from the study at any time without any consequences, 
participants in this study is without prejudice to any existing 
rights to your. You will receive a copy of the signed "informed 
notice" and "informed consent" copies. If you have any 
questions about this study, you can contact the project leader 
Wang Xuan, telephone number is 18017591058. You can also 
contact with Fudan University children's Hospital Research 
Ethics Board, telephone 021-64931913, which represents your 
interests. 


Informed consent 
 
1. Informed consent or authorized signature  
I have read or someone else has to read to me and understand 
the above information and content. All my questions have been 
satisfied with the answer. My participation in this research 
is voluntary,  
 
I would like to participate in this study  
Name: _______________________ Date __________________  
Guardian signature: _____________________ Date 
_________________  
2. Investigators statement  
I have already explained to the participants in this study and 
answer all the questions. I believe he is independently decided 
to participate in the study. I promise you, if the study found 
the drug's new use or others have found new adverse reaction, 
you will be informed in a timely manner.  
Inspector  signature: __________________________  
Date :_________________