Study design and registration
Our study was a prospective, randomized, double-blind, controlled clinical trial conducted in the Liaocheng People’s Hospital, Shandong, China, between December 2020 and May 2021. The study was approved by the Ethics Committee of Liaocheng People’s Hospital. Written informed consent was obtained from the guardians of each recruited pediatric patient. This study was registered in the Chinese Clinical Trial Registry on 08/12/2020 (ChiCTR, https://www.chictr.org.cn/index.aspx; Registration Number ChiCTR2000040739).
Participant selection and group assignment
Male or female pediatric patients aged 1–6 years, weighing 10–30 kg, in ASA (American Society of Anesthesiology) class I or II, and scheduled for elective tonsillectomy or adenoidectomy were recruited. Children with a history of allergic reactions to esketamine or ketamine; abnormal cardiac, lung, liver, and kidney function; or with systemic or congenital diseases, abnormal intellectual development, history of neuronal or mental diseases, prior establishment of intravenous access, or other types of surgery were excluded from the study.
Eligible pediatric patients were assigned to either a placebo control group (group C), esketamine 1 mg.kg-1 group (group EK1), or esketamine 2 mg.kg-1 group (group EK2) based on a random number generated in MS Excel software (Microsoft Corporation, Redmond, WA, USA). The group assignment was blinded to the investigators, clinical physicians, pediatric patients, and their families.
Study protocol and interventions
Patients fasted from midnight prior to the surgery date. Heart rate (HR), respiratory rate (RR), electrocardiogram (ECG), and oxygen saturation (SpO2) were monitored after the pediatric patient entered the preoperative room. A dedicated nurse prepared the esketamine solution (Hengrui Pharma, Jiangsu, China) and orally administered it to the patients based on their group assignment. Pediatric patients in groups EK1 and EK2 received 10% glucose solution (0.2 ml.kg-1) containing 1 mg.kg-1 or 2 mg.kg-1 esketamine, respectively. Group C patients received a 10% glucose solution (0.2 ml.kg-1). The parent–child separation was performed approximately 15 min after oral medication administration, which was followed by venipuncture. After a successful venipuncture, the pediatric patients were transferred to the operating room. Then, every child received general anesthesia induction and tracheal intubation from the same anesthesia team. A nursing staff member who was blinded to the group assignment was responsible for recording vital signs and outcome scores during the perioperative period.
Outcome measurements
The primary outcome was the analgesic score during venipuncture (supplementary Table S1). The secondary outcomes were parent–child separation cooperation, venipuncture cooperation, and sedation (supplementary Table S1). The onset time of medication was based on the mental changes (i.e., being quiet, blurred eyes, or sleepy blinking) of pediatric patients after medication was administered. The Ramsay Sedation Scale was used to assess the level of sedation. The details of these evaluations are described in the literature[9–11].
In addition, we also measured the Ramsay sedation scores, HR, RR, and SpO2 before and 5, 10, 15, 20, 25, and 30 min after medication administration. Incidences of adverse events (including nausea or vomiting), increased secretion, nystagmus, dizziness, and molar accompanied involuntary head swing were recorded from esketamine administration until the end of the recovery period.
Statistical analyses
The sample size was calculated based on the analgesic scores. According to the preliminary experimental results, the analgesic scores of group C, group EK1, and group EK2 were 3.0±1.1, 2.5±1.1, and 2.0 ±1.1, respectively. At α=0.05 and 1-β=90%, a two-sided ANOVA (analysis of variance) would require 22 participants in each of the groups C, EK1, and EK2. Taking into account a 20% lost-to-follow-up ratio, at least 28 cases were therefore recruited into each group (PASS [version 11.0] software; NCSS LLC, Kaysville, UT, USA).
Statistical analyses were conducted using SPSS (version 23.0) software (IBM, New York, NY, USA). Categorical data are expressed as numbers (percentage) and compared using the Chi-squared test. Continuous data are expressed as mean ± standard deviation (
±s) and compared by one-way ANOVA. Intergroup comparisons were performed using one-way ANOVA with repeated measures. P<0.05 was considered statistically significant.