Two-center randomized controlled trial comparing oral chloral hydrate and intranasal combination of dexmedetomidine and ketamine for procedural sedation in children: study protocol

We shall randomly allocate patients to the intervention group (intranasal combination of dexmedetomidine 2μg/kg and ketamine 3 mg/kg, IN DEXKET) and the control group (chloral hydrate 50 mg/kg). We chose oral chloral hydrate of 50 mg/kg as the comparator because it is commonly used for pediatric sedation without an intravenous line worldwide. There is conflicting evidence regarding the efficacy and safety of chloral hydrate and alternative sedatives in pediatric patients.

Patients will follow the hospital fasting guidelines before sedation, and the type and time of the last meal will be checked (Table 1). The baseline heart rate (HR) and oxygen saturation (SpO₂) will be measured before the induction of sedation and continuously monitored during sedation. If the patient shows irritability or cries, HR and SpO₂ measured in a calm, relaxed state will be used as baseline. On-site trial members will administer sedatives according to the group allocation. In the intervention (IN DEXKET) group, the parents will clear the patient’s nose and hold them in their arm to keep the head supine to facilitate intranasal absorption. After administering a combination of dexmedetomidine 2 μg/kg (100 μg/mL) and ketamine 3 mg/kg (50 mg/mL) using an intranasal mucosal atomizer device (SEDACO, Doowon Meditec, Gyeonggi, Republic of Korea), the nose will be gently massaged to enhance absorption. In the control group, chloral hydrate syrup 50 mg/kg (100 mg/mL) will be administrated orally. Patient acceptance of drug administration will be assessed using a 4-point scale (1 = excellent, can be administered without difficulty; 2 = good, brief tears or grimacing, but can be administered; 3 = fair, does not cooperate but can be administered; 4 = poor, refusal of medication).

If continuing the study protocol affects patient safety, the allocated intervention will be discontinued. If the parents withdraw the informed consent, or if the reliability of data is compromised, the participants will be dropped from the study.

Not applicable; the designated intervention will be applied in a single procedural sedation.

Not applicable; no relevant concomitant care will be permitted or prohibited.

The principal investigator has clinical trial liability insurance that is in accordance with the legal requirements in Korea. This insurance provides coverage for any damage to the research participants through injury or death caused by the study. Insurance applies to damages that become apparent during the study or within 1 year after the end of the study. The principal investigator has clinical trial liability insurance following the legal requirements of the Republic of Korea. This insurance covers medical damage caused by the study to research participants through injury or death. The insurance applies to damages that occurred during the study protocol or within 2 h after the end of sedation.

The primary outcome will be the success rate of sedation (Pediatric Sedation State Scale, PSSS = 1, 2, or 3) within 15 min of sedative administration [40]. We contacted the developers of the PSSS, obtained permission to translate it into Korean, and adapted it to the participating hospitals. The PSSS was educated on pediatric sedation providers including 7 pediatric anesthesiologists and 6 pediatric sedation nurses. All raters were given 30 min of PowerPoint presentation including 8 video clips showing variable sedation states.

Secondary outcomes include PSSS and vital signs during sedation, overall sedation profile, and adverse outcomes during sedation. The detailed secondary outcomes are presented in Table 2.

Participant timeline is shown in Fig. 1.

The primary outcome is the success rate of sedation (PSSS = 1, 2, or 3) within 15 min of sedative administration. Previous studies have reported that the success rate of sedation with oral choral hydrate (50 mg/kg) within 30 min is 65–75% [4‐6]. We assumed that the success rate of oral chloral hydrate sedation within 15 min is 55%, and the success rate in the intervention group is 80%. With an alpha error of 5% and a power of 85%, 122 patients with a 1:1 allocation to the intervention and control groups will be required. Assuming a dropout rate of 10%, we planned to enroll 136 patients.

On-site trial members with a medical doctor’s license (YE Jang, EY Ju) will make a list of patients scheduled to undergo procedural sedation at Seoul National University Hospital and the Asan Medical Center on the day of sedation. They will visit the candidate’s parents in the wards or outpatient clinic, check the inclusion and exclusion criteria, explain the study protocol, provide at least 20 min of pondering, and obtain written informed consent from the parents or guardians.

The Medical Research Collaborating Center (MRCC) of Seoul National University Hospital offers a web-based randomization solution (https://​mrcc.​snuh.​org/​). Stratified block randomization will be performed according to age (< 1 year and 1–7 years) and location (Seoul National University Hospital and Asan Medical Center) with an allocation ratio of 1:1.

A nurse who is not participating in the study will keep the randomization table on a web-based randomization site. The allocation will be concealed until the last participant’s study protocol ends.

After enrollment of a participant, a nurse who is not participating in the study will log into the web-based randomization site and check the inclusion and exclusion criteria of the participant. After verifying the date of birth and the inclusion and exclusion criteria, the results of randomization will be detected and stored on the web-based randomization site. The nurse will prepare the studied drug according to the group allocation.

An independent outcome assessor, a pediatric sedation nurse not involved in group randomization or drug administration, will record the HR and SpO₂ and assess sedation level using a 6-point PSSS. Care providers and data analysts will be blinded to the group allocation.

On-site trial members who administer sedatives will not be blinded. Unblinding is allowed for the occurrence of any serious adverse event that forces the participant to drop out of the study and is determined by the trial steering committee. When the unblinding of a specific patient is decided, the on-site trial member who can access the web-based randomization table will be asked to review the table and tell the group allocation to the trial steering committee and caregivers.

An independent outcome assessor, a pediatric sedation nurse not involved in group randomization or drug administration, will record the HR and SpO₂ and will assess sedation level using a 6-point PSSS (Table 2) [40]. PSSS = 4 and 5 are defined as awake states and PSSS = 1, 2, and 3 are defined as sedated states (Table 3). After administering sedatives, the HR, SpO₂, and PSSS will be recorded every 10 min. In addition, HR, SpO₂, and PSSS will be recorded 15 min after administration of sedative (primary outcome), at the induction of sedation (the first time of PSSS ≤ 3), at recovery from sedation (PSSS ≥ 4), and when the cardiorespiratory event occurs. The primary outcome is sedation induction (PSSS ≤ 3) within 15 min of sedative administration. If the PSSS is 0, 4, or 5 after 30 min, it is defined as a failure to induce sedation.

If the sedation level is inadequate (PSSS = 4 or 5) for procedures or examinations, the attending medical staff will decide on the method of rescue sedation. As pain during blood pressure measurement can wake up the patient, blood pressure will be measured when the HR is less than 70% of the baseline value. If the patient shows significant bradycardia or hypotension (− 30% from baseline), the trial member will offer hemodynamic intervention, such as fluid management and intravenous medication. If the patient shows apnea for ≥ 20 s or a significant decrease in pulse oxygen saturation (SpO2 < 95% or < 90% from baseline value ≥ 10 s) occurs, the trial member will secure the airway and apply appropriate stimulation for recovery.

Before the examination or procedure, separation anxiety will be evaluated using a 4-points scale (1 = easy, easily separated from parent; 2 = whimper, whimpering but separated; 3 = crying and reluctant to separate but not clinging; and 4 = crying and cling to parents; crying and clinging to parent). Successful completion of the procedure will be recorded, and if stopped, the reason will be recorded. Physician satisfaction will be evaluated using 4 scales. (1 = excellent, fearless, and cooperative with the test; 2 = good, showing some fear but reassuring quickly when appeased; 3 = fair, showing fear and not being appeased; 4 = poor, showing fear or crying or resistance to tests or procedures). When the examination or procedure ends, the patient will be transferred to the recovery room or ward bed. The time when PSSS = 4 will be recorded to check the duration of sedation.

The study timeline will be completed on the day of sedation. There is no follow-up.

On-site investigators (YE Jang at Seoul National University Hospital and EY Ju at Asan Medical Center) are responsible for recruiting patients, conducting the study, and recording data on the worksheet (paper-based case report form). The records will be submitted to the Internet-based Clinical Research and Trial Management System (http://​icreat.​nih.​go.​kr), an electronic case report form (eCRF), by the National Institute of Health, Korea. The patients will be identified using a unique numeric code, and all patient data will be anonymized to ensure patient confidentiality. All eCRF data management will be conducted by the MRCC, Seoul, Korea. Data monitoring (verification) of paper-based case report form and eCRF will be conducted when every 10 patients are enrolled, by the Clinical Research Coordinator and the LSK Site Management Organization, a Contract Research Organization in Seoul, Korea. Data validation will be performed using automatic query by SAS edit checks and manual query, data clarification, and query resolution by MRCC. External data handling will be performed by checking the consistency of the web-based randomization, protocol deviation log, and eCRF data. The latest version of the data management plan is 1.1 (June 7, 2021), and that of the data validation specification is 1.1 (April 8, 2022) (Fig. 2).

Patients will only be referred to by the number of participants. Written informed consent and paper-based case report forms will be stored separately. Data will be stored within a double-locker until the expiration of the storage period and will only be accessible to trial members. After a storage period of 3 years, we shall destroy the data.

Not applicable. No biological specimen will be collected for laboratory testing during the trial.

All data will be expressed as mean ± standard deviation or median (interquartile range [IQR]) unless otherwise specified. We shall test distribution using the Shapiro-Wilk normality test and evaluate the baseline characteristics of the study population using the independent t-test and Mann-Whitney U test. We shall analyze outcomes according to the intention-to-treat principle. The primary outcome (the success rate of sedation (PSSS = 1, 2, or 3) within 15 min of sedative administration) will be evaluated using the χ² test, while secondary outcomes will be evaluated using the χ² test, independent t-test, and Mann-Whitney U test. Statistical analyses will be performed using IBM® SPSS® Statistics 23 (IBM Corp., Armonk, NY, USA) and R software (version 3.4.4; R Foundation for Statistical Computing, Austria). Statistical significance shall be set as a two-sided p < 0.05. To evaluate safety, we shall monitor and collect HR, SpO₂, and RR throughout the study as secondary outcomes. For repeated-measured data, analysis using a mixed model shall be performed to compare the two groups over time. It is expected that there will be a few missing values for the primary endpoint, and missing values will not be substituted for primary and secondary evaluations.

No interim analysis will be conducted during this trial.

Not applicable; no additional analysis is intended for this study.

Not applicable; the written informed consent and all data will be obtained on the day of sedation. There will be no non-adherence issue in this study.

Sharing the data can be considered by the corresponding author on reasonable request.

The coordinating center is the Department of Anesthesiology and Pain Medicine of Seoul National University Hospital, Seoul, Korea. The trial steering committee consists of the principal investigator (JT Kim) and other investigators (YE Jang and EY Ju) who are responsible for recruiting patients, conducting the study, and data entry.

Data monitoring (verification) will be conducted by the clinical research coordinator and the LSK site management organization, a contract research organization in Seoul, Korea. Data validation and external data handling (web-based randomization) will be conducted by statisticians and data managers at the MRCC in Seoul, Korea. The safety of the participants and the appropriateness of the data will be monitored and reported every three months and under the supervision of the principal investigator.

The principal investigators (JT Kim at Seoul National University Hospital, and EY Ju at Asan Medical Center) will report any serious adverse events to each institutional review board within 15 days of the notice. Mild adverse events will be reported every 3 months. When reporting adverse events or harm, we shall equally report causalities, time of occurrence, severity, seriousness, provided management, and the relationship to the present clinical trial.

Self-auditing will be performed by the site management organization every three months. The trial may be audited at any time by the Ministry of Food and Drug Safety of Korea or the institution’s quality assurance team.

Any amendment to the protocol will be reviewed by the Institutional Review Board of Seoul National University Hospital and the Asan Medical Center Institutional Review Board. After approval, the changes will be reported and reviewed by the Ministry of Food and Drug Safety of Korea. These changes will be reflected in the public registry site (https://​clinicaltrials.​gov/​ct2/​show/​NCT04820205).

The results will be disseminated via publication in a peer-reviewed journal, available at the registry site (https://​clinicaltrials.​gov/​ct2/​show/​NCT04820205) and presented at scientific meetings.