Study setting {9}
The study will be conducted among pediatric patients undergoing tonsillectomy and adenoidectomy at the following 12 medical centers: 1). Zhongda Hospital Southeast University, Nanjing, China; 2). Children's Hospital of Nanjing Medical University, Nanjing,China; 3). Xuzhou Central Hospital, Xuzhou, China; 4). Tongling People's Hospital, Tongling, China; 5). Xishan People's Hospital, Wuxi, China; 6). Xuyi People's Hospital, Suqian, China; 7). Nanjing Gaochun People's Hospital, Nanjing, China; 8). Haikou People's Hospital, Hainan, China; 9). Nanjing Lishui People's Hospital, Nanjing, China; 10). The First Hospital of Jiaxing, Jiaxing, China; 11). The People's Hospital of Leshan, Leshan, China; 12). Pizhou Traditional Chinese Medicine Hospital, Xuzhou, China. The geographical distribution of these medical centers is illustrated in Figure 1.
Eligibility criteria {10}
The inclusion and exclusion criteria for participants in this study are as follows:
Inclusion criteria:
- American Society of Anesthesiologists (ASA) score of Ⅰ to Ⅲ;
- Age ≤ 12 years;
- Proposed elective general anesthesia tonsil and/or adenoidectomy.
Exclusion criteria:
- Congenital conditions or abnormalities of liver and kidney function;
- Chronic lung diseases (pulmonary cystic fibrosis, bronchial dysplasia, pulmonary hypertension, etc.);
- Severe preoperative upper respiratory tract infection;
- Neuromuscular disorders, cerebral palsy, epilepsy;
- Intubated, or undergoing tracheotomy;
- Patients expected to require ICU admission postoperatively;
- Difficult airway;
- If the attending anesthesiologist suggests a specific anesthetic maintenance plan and advises against random allocation;
- Relatives or guardians declining participation.
Who will take informed consent? {26a}
Before the surgery, an investigator reviewed a surgical application form to assess whether the individual met the necessary criteria for recruitment. If they were found eligible, children and their family members or guardians were then informed about the study in detail by the investigator. Any concerns or doubts from the child’s family members or guardians were addressed, and an informed consent form was signed by the family members or guardians. Additionally, if the subject was 8 years or older, their consent was also obtained at the appropriate time. This process ensures that everyone involved has a clear understanding of the study and provides their voluntary agreement to participate.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Before obtaining the informed consent of the participants, we will explain the implementation of anesthesia program, and account for the preoperative,intraoperative,and postoperative data needing to be collected. The specific content of methods and data will also be listed in the informed consent form. This study will not involve the collection of biological specimens.
Interventions
Explanation for the choice of comparators {6b}
This is a parallel controlled study comparing propofol intravenous anesthesia maintenance, sevoflurane inhalation anesthesia maintenance, and propofol-sevoflurane combination anesthesia maintenance for children undergoing tonsil adenoidectomy. Although these are all commonly used in clinical practice in China, the specific effect on postoperative respiratory adverse events in this context isn't clear. The study is aimed at determining whether propofol-sevoflurane combination anesthesia maintenance could potentially provide greater benefits compared to the other methods. It's important to carefully analyze the results of this study to gain insights into the comparative effectiveness of these anesthesia maintenance approaches for this specific surgical procedure in pediatric patients.
Intervention description {11a}
After the induction of anesthesia and intubation, the maintenance phase of anesthesia commenced, with the implementation of appropriate protocols according to the allocated results for each group.
Group A (Propofol intravenous anesthesia maintenance): propofol was administered intravenously at a dosage of 6-12 mg/kg/h.
Group B (Propofol-sevoflurane combination anesthesia maintenance): sevoflurane at 1% concentration was administered via the anesthesia machine, while propofol was infused intravenously at a dosage of 4-6 mg/kg/h.
Group C (Sevoflurane inhalation anesthesia maintenance): sevoflurane at a concentration of 2-3% was administered via the anesthesia machine.
Intraoperatively, adjustments to propofol dosage in group A and B, and to sevoflurane concentration in group C, were made based on the monitoring of anesthesia depth (BIS) and hemodynamic changes. Anesthesiologists, drawing on their clinical experience, modified anesthesia depth to maintain a BIS between 40-60, ensuring an adequate depth of anesthesia.
Criteria for discontinuing or modifying allocated interventions {11b}
The investigator will terminate the experiment for this participant if one of the following occurs during the experiment:
- An intraoperative allergic reaction to propofol or sevoflurane.
- The child develops a new upper respiratory tract infection, or a pre-existing mild upper respiratory tract infection worsens.
- The child or guardian opts for temporary withdrawal from the study.
Strategies to improve adherence to interventions {11c}
The intervention in this study occurs post-induction of anesthesia, at which point the child is unconscious. On the first preoperative day, the principal investigator (SPH) conducts a pre-anesthetic evaluation in strict adherence to the exclusion and inclusion criteria. This is followed by a detailed explanation to the child and their guardian about the study’s nature and the importance of cooperation.
Relevant concomitant care permitted or prohibited during the trial {11d}
All study participants are guaranteed postoperative care, whether in the operating room, the post-anesthesia care unit (PACU), or the ward, delivered by the standard medical staff. To further support the child's comfort and cooperation with medical procedures and the study, a family member or guardian is permitted to accompany the child during preoperative preparation and upon awakening from anesthesia.
Provisions for post-trial care {30}
The intervention measures in this study are all commonly used protocols in clinical practice internationally, thus they will not cause additional harm to the children involved. Standard clinical care will be administered at each center following routine procedures. In case of any adverse events related to this study,the investigator are dedicated to providing the necessary care. If there is postoperative damage or death related to this study, the investigator will promptly provide treatment, cover the costs of appropriate treatment, and offer relevant financial compensation.
Outcomes {12}
Primary outcome
The postoperative respiratory adverse events, any one or more of which occurred between the phase of post-extubation and departure from the recovery room, were categorized as endpoint events:
- Laryngospasm: Complete airway obstruction with associated muscle rigidity of the abdominal and chest walls.
- Bronchospasm: Increased respiratory effort, particularly during expiration and wheeze on auscultation.
- Oxygen desaturation: Less than 95% more than 10s, or less than 90%.
- Coughing: A series of pronounced, persistent severe coughs lasting more than 10s.
- Airway obstruction: Presence of airway obstruction in combination with a snoring noise and/or respiratory efforts.
- Stridor(recovery): High-pitched sound during breathing in the postoperative period.
Secondary outcomes
- The frequency of each specific respiratory adverse event.
- Postoperative delirium agitation quantified by the PAED score.
- Post-extubation pain score evaluated using the Wong-Baker scale.
- The quality of anesthesia maintenance ( factors such as hemodynamic changes, presence or absence of swallowing, and limb movement).
- Sevoflurane exhalation minimum alveolar concentration (MAC) value at extubation in conjunction with BIS value.
- Brainwave forms (including σ, θ, α, and β-waves) upon awakening.
- The incidence of adverse events other than perioperative respiratory adverse events.
Participant timeline {13}
The participant timeline is shown in Figure 2.
Sample size {14}
According to the outcomes of our preliminary study, the rates of postoperative respiratory adverse events stood at 10%, 40%, and 25% for patients administered with intravenous, inhalation, and intravenous-inhalation combined anesthesia, respectively. A difference between groups that reached 15% was considered clinically meaningful. After adjusting for multiplicity from making 3 pairwise comparisons, a sample size of 215 per group at a P < .017 two-sided significance level provided an 80% power to detect a 20% difference in the rate of PRAEs among the 3 groups using the χ2 test. Allowing for 10% loss of cases because of unusable or missing data, we aimed to recruit 239 participants in each group, or 717 cases in total.
Recruitment {15}
Participants will be selected from individuals who have undergone tonsil adenoidectomy at 12 medical centers, ensuring a robust pool of children for potential enrollment. Before the surgery, an investigator reviewed a surgical application form to assess whether the individual met the necessary criteria for recruitment. If they were found eligible, children and their family members or guardians were then informed about the study in detail by the investigator. Any concerns or doubts from the child’s family members or guardians were addressed, and an informed consent form was signed by the family members or guardians. Additionally, if the subject was 8 years or older, their consent was also obtained at the appropriate time. The trial is presently in the recruitment phase, with patients undergoing rigorous screening in accordance with the defined recruitment criteria.
Assignment of interventions: allocation
Sequence generation {16a}
In this study, dynamic stratified block randomization was employed, supplemented by central randomization. Stratification was based on center (12 centers) and age groups (0-6 years, 7-12 years), with zone group randomization executed within each stratum. Specifically, random zone group sequences, each with a zone group size of 6 or 9, were pre-generated and incorporated into the pool of random sequences. Upon enrollment of a patient in a stratum, a zone sequence is randomly selected by the center and assigned to that stratum. This process continues until the selected random sequence for a stratum is exhausted, after which another zone sequence is randomly chosen. Recruitment concludes once all zone sequences in the sequence pool are assigned.
Concealment mechanism {16b}
Random sequences were pre-generated by the working committee, and a designated investigator (WC-I) was assigned to provide specific random numbers to each center; WC-I had no role in the process at each center beyond the assignment of random numbers. Each center was assigned a nurse anesthetist specifically dedicated to the task of random assignment. The randomization process was carried out in real time by the WC-I and the nurse anesthetists at each center without the knowledge of others.
Implementation {16c}
Following the determination of patient eligibility for recruitment, the WC-I assigned serial numbers based on center and age group once patients were admitted to the operating room. The nurse anesthetist then informed the attending anesthesiologist of the assigned randomization group. Subsequently, the attending anesthesiologist administered anesthesia maintenance according to the given protocols, remaining blind to the study hypotheses and endpoints.
Assignment of interventions: Blinding
Who will be blinded {17a}
Blinding was maintained for the investigator, the child, and their family or guardian. On the day of surgery, upon the child’s entry into the operating room, the nurse anesthetist responsible for receiving the randomization number obtained the centrally assigned randomization sequence results. This nurse then informed the attending anesthesiologist of the assignment, who subsequently implemented the appropriate maintenance protocol, unaware of the study’s hypotheses and outcomes. An opaque sheet covered the intraoperative anesthesia workstation, including the anesthesia machine and drug infusion pump, ensuring visibility only for the anesthesiologist, who adjusted the anesthesia depth as clinically required, rendering it invisible to the data-collecting researcher, while an independent researcher collected postoperative data.
Procedure for unblinding if needed {17b}
- The intraoperative depth of anesthesia cannot be precisely controlled to match the expected value.
- Allergic reactions to sevoflurane and propofol were observed.
- In the event of intraoperative complications, including uncontrollable bleeding, cardiac arrhythmia, allergic reactions, or cardiac arrest, further action may be required to manage these unforeseen circumstances effectively.
Data collection and management
Plans for assessment and collection of outcomes {18a}
Data will be collected at three time points: preoperative, intraoperative, and postoperative, and recorded on a Case Record Form (CRF). The SPH will conduct a preanesthetic evaluation to ascertain eligibility for recruitment, document general information about the child, and secure informed consent for participation in the study. The attending anesthesiologist executes the intervention and manages intraoperative care, remaining uninformed about the study’s hypotheses and endpoints. One researcher records intraoperative data within the operating room. Postoperative data collectors and data analysts maintain independence and are unaware of the study’s subgroup allocations. All data will be collected in the CRF, the investigation will be conducted by investigators who are trained and qualified, employing standard definitions for each indicator. Furthermore, all assessors at each center will undergo training before the start of the study to mitigate assessor bias.
Plans to promote participant retention and complete follow-up {18b}
Prior to commencement of the study, children and their family members or guardians were comprehensively informed by the investigator, addressing any concerns or doubts to minimize participant dropout. Throughout the study duration, interventionists and data collectors received rigorous training to minimize protocol deviations and data loss.
Data management {19}
Upon completion of CRF collection, the original records will become unalterable. Completed CRFs will be promptly submitted to the data monitoring committee (DMC) for review, and then transcribed into Microsoft Excel by the researcher not involved in study. Data input and management will be overseen by Data Monitoring Committees, committee members have no conflicting interests related to this study. The study will be conducted safely in accordance with the protocol, adhering to Good Clinical Practice and relevant regulatory requirements, ensuring proper execution of data collection.
Confidentiality {27}
The randomization lists and paper CRFs shall be securely stored in the clinical research office of each center and expediently transmitted to the Data Monitoring Committee. During this process, access is to be strictly limited to members of the Data Monitoring Committee alone. De-identified data will be meticulously entered into Microsoft Excel, with access codes established, and then stored on locked computers only accessible to authorized investigators. All subsequent publications shall exclude any patient identifying information or study sequence numbers. DMC members shall conduct regular and independent evaluations of the safety, validity, and integrity of the randomized parallel control study biweekly. The DMC shall convene on a monthly basis, or more often as required.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Not applicable, there will be no biological specimens collected.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Statistical analyses were conducted using SPSS software (version 26.0), graphs were generated using GraphPad Prism (version 8.0.2), and EEG data were analyzed using MATLAB. The Kolmogorov-Smirnov test was employed to ascertain whether continuous data adhered to a normal distribution. Continuous data conforming to a normal distribution within groups were presented as mean ± standard deviation (`x ± s), while non-normally distributed data were depicted as median (M) and interquartile range (IQR). Categorical variables were represented using proportions. For the comparison of normally distributed continuous data across different time points within the three groups, repeated measures analysis of variance (ANOVA) was utilized, and for comparison at the same time point across the three groups, one-way ANOVA was employed. The Bonferroni correction was utilized for pairwise comparisons to adjust the P-value. For non-normally distributed continuous data within the three groups, the Kruskal-Wallis H test was employed, and the Mann-Whitney U test was utilized for pairwise comparisons among non-normally distributed data. The association among unordered categorical data across the three groups was evaluated using a chi-square test for difference analysis, opting for either the Pearson chi-square test or Fisher’s exact test based on the sample size and the minimum expected frequency to ascertain if there was an association between groups and outcome variables. The level of significance was established at (alpha = 0.05), with a P-value of < 0.05 being considered statistically significant.
Outcome analyses were performed in the intention-to-treat population, and a per-protocol analysis was also performed for the primary end point. The primary outcome was analyzed using χ2 test or Fisher exact test, and the crude odds ratio (OR) and 95% CI were calculated. The adjusted OR(aOR) and 95% CI were calculated for both primary and secondary outcomes(the frequency of each specific respiratory adverse event.
Interim analyses {21b}
Not applicable, no interim analyses are planned.
Methods for additional analyses (e.g. subgroup analyses) {20b}
We plan to conduct a secondary analysis to develop a machine learning model for predicting postoperative respiratory adverse events in children undergoing tonsillectomy and adenoidectomy. Boruta was employed to identify feature variables based on their importance. The optimal model was established by integrating ten machine learning classification models, and personalized risk assessment was facilitated through an interpretation using Shapley Additive explanations (SHAP).
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Given that we will explain the intervention in detail and emphasize the importance of cooperation to the patients during the pre-anesthesia evaluation and the process of obtaining informed consent, we anticipate that few patients will exhibit non-adherence to the protocol. Outcome analyses were performed in the intention-to-treat population, and a per-protocol analysis was also performed for the primary end point. If needed, multiple imputation will be used for the analysis of missing data, and sensitivity analysis will be performed.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
This is a principal investigator-initiated trial. Access to the full protocol and participant-level data will be considered upon submission of a reasonable request to, and with the consent from, the principal investigator.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
(1) Exective Committee
The Exective Committee comprises principal investigators and representatives from each participating center. It oversees the formulation of strategies and guidelines for the entire clinical trial, monitors the trial’s overall progression, addresses critical issues emerging during the trial, and ratifies the final draft of the research protocol along with all substantial amendments.
(2) Steering Committee
The Steering Committee is comprised of experts in clinical research, statisticians, and ethics specialists. It offers professional guidance and advice to safeguard the scientific and ethical integrity of the trial design, and aids in resolving professional dilemmas encountered throughout the research process.
(3) Operations Committee
The Operations Committee consists of project managers, data managers, and biostatisticians. It manages the day-to-day operations and oversight, encompassing data collection, quality assurance, and report generation, to guarantee the seamless execution of the clinical trial.
(4) Data Monitoring Committee (DMC)
The Data Monitoring Committee is made up of independent experts in clinical trials, statisticians, and ethics specialists. It oversees the safety and integrity of the trial data, regularly reviews trial data to ensure participant safety, and evaluates whether there is a need to prematurely terminate or adjust the trial design.
(5) Safety Monitoring Committee
The Safety Monitoring Committee comprises experts in medicine, pharmacology, statistics, and ethics, focusing particularly on safety issues within the trial. It monitors adverse event reports and assesses whether these adverse events are related to the trial interventions.
(6) Endpoint Committee
The Endpoint Committee consists of independent experts who conduct a blind review of the clinical trial results without involvement in other aspects of the trial. They are responsible for objectively evaluating primary and secondary endpoint events to ensure consistency and accuracy in the evaluation.
Composition of the data monitoring committee, its role and reporting structure {21a}
The Data Monitoring Committee (DMC), its main functions are to safeguard participant safety, ensure data integrity, monitor the treatment's efficacy, and make recommendations about the trial's continuation, adjustment, or termination. DMC members are independent experts in clinical trials, statisticians, and ethics specialists, who report their findings directly to the trial's sponsor or a steering committee, maintaining confidentiality. They meet regularly or at significant trial milestones to review data, guided by regulations and international standards to protect participants and ensure the trial's scientific validity.
Adverse event reporting and harms {22}
Adverse events occurring in this trial shall be recorded on the CRF and reported to the Principal Investigator. Each adverse event shall be assessed for its character (expected versus unexpected), severity (serious versus non-serious), and relevance to the intervention (relevant versus irrelevant). Serious and unexpected adverse events shall be promptly reported to the Ethics Committee. The Principal Investigator shall conduct regular cumulative reviews of all adverse events and convene an Investigator Meeting as necessary.
Frequency and plans for auditing trial conduct {23}
The Exective Committee, Steering Committee, Opreations Committee, Data Monitoring Committee (DMC), and Safety Monitoring Committee conduct regular meetings,Monitoring online visits will include reviewing regulatory compliance and conducting data verification. This involves reviewing a variety of documents such as regulatory files, case report forms (CRFs), informed consent forms (ICFs), medical and laboratory reports, site study intervention storage records, and training records, while ensuring protocol and Good Clinical Practice (GCP) compliance. Both on-site and off-site monitoring, central review of data collection, and remote source data verification are permissible.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
The Ethics Committee of Zhongda Hospital Southeast University has reviewed the protocol and agreed to conduct the trial as the protocol. No protocol amendments will be made unless permitted by the Exective Committee.
Dissemination plans {31a}
Following the completion of the study, the results will be published in a scientific journal.