This was a single-center, double-blind, placebo-controlled, randomized study. The study protocol was approved by the Ethics Committee of Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China (Chairperson Prof Guojun Zhang) on 23 March 2021 (2021-E-015-Y-001). All methods were performed according to relevant guidelines and regulations. The study was conducted at the Beijing Children’s Hospital, China, from April to June 2021. Written informed consent was obtained from the parents or guardians before the study procedures were performed. The study was registered with the Chinese Clinical Trial Registry (number: ChiCTR2100045128, date: 07/04/2021). This article adhered to the Consolidated Standards of Reporting Trials guidelines.
We enrolled patients aged 3–9 years with an American Society of Anesthesiologists risk score of I–II undergoing elective tonsillectomy with or without adenoidectomy. Children with an abnormal electrolyte balance, previous analgesic treatment, allergy to the study drugs, hepatic, renal, neurological, or neuromuscular disease; craniofacial abnormalities; respiratory or cardiac disease; and patients who chose not to participate were excluded.
Randomization, intervention, and anesthesia management
Patients were randomly assigned in a 1:1 ratio to receive intravenous ibuprofen or placebo. The treatment allocation order was generated by permuted block randomization with a block size of 6 and was concealed with sequentially numbered sealed envelopes. On the day of the study, a third-party participant opened the envelope and prepared the study drug, which was indistinguishable from each other and marked with a randomization code known only to the participant. Patients and clinical investigators who collected clinical information were blinded to the patient grouping until the final data analysis.
Upon patient arrival in the operating room, conventional monitoring, including electrocardiography, noninvasive blood pressure measurement, pulse oximetry, and bispectral index (BIS) monitoring (BIS Monitor Model A-2000 Aspect Medical Systems Inc., USA), was performed. Anesthesia was administered intravenously with propofol 2 mg·kg−1, fentanyl 2 mcg·kg−1, and cisatracurium 0.1 mg·kg−1 to facilitate endotracheal intubation. After the induction of anesthesia, patients in the treatment group received a dose of 10 mg·kg−1 of intravenous ibuprofen slowly over 15 min, whereas in the control group, a volume-matched normal saline infusion was slowly administered. Anesthesia was maintained with propofol and remifentanil, beginning with propofol 10 mg·kg−1·h−1, followed by an adjustment in dose depending on BIS measurements (40–60), and remifentanil 0.3–0.4 mcg·kg−1·min−1), with the dose adjusted to analgesic requirements (systolic blood pressure changed within 20% of baseline values). After the completion of surgery, the patients were transferred to the post-anesthesia care unit (PACU) and extubated once adequate spontaneous breathing was observed. Extubation time was defined as the time interval between discontinuation of anesthetics and extubation.
Data collection and outcomes
Previous studies have revealed that the incidence rate of EA in pediatric patients undergoing tonsillectomy with propofol anesthesia ranges between 41.4% and 48.3% in the PACU. We assumed that the average incidence rate of EA in this study was 45%. Based on our pilot study, we supposed that a reduction in the incidence rate of > 25% in the ibuprofen group would indicate a signiﬁcant eﬀect. The sample size was calculated using the tests for a two-proportion design model (one-sided, α=0.05, β=0.8, 10% dropout rate), with a group allocation of 1:1 using PASS (NCSS Statistical Software, UT). This resulted in a required sample size of 45 patients per group. Histograms and the Kolmogorov–Smirnov tests were used to assess normality. Continuous variables are expressed as mean ± standard deviation or median (interquartile interval), as appropriate. To assess the differences between the two groups, the t-test was used for normally distributed continuous variables, whereas the Wilcoxon rank-sum test was used for non-normally distributed continuous variables. For categorical variables, the χ2 test and Fisher’s exact test were used. Secondary analyses were used to build multivariate logistic regression models to assess the association between EA and perioperative variables. Odds ratios (ORs) with 95% confidence intervals (CIs) for each factor were calculated using logistic regression. Variables with statistically significant values (P < 0.1) in the univariate model were entered into the multivariate model. Predictors tested included age, sex, body mass index (BMI), pre-anesthesia score, use of ibuprofen, anesthesia time, and extubation time. Model diagnostics were also reported, including the Hosmer–Lemeshow goodness-of-fit test, a receiver operating characteristic (ROC) curve, and the area under the curve (C-index). Statistical analysis was performed using the International Business Machines Statistical Package for the Social Sciences (SPSS) Statistics version 19.0 (SPSS Inc., Chicago, IL) and GraphPad Prism 9.1 (GraphPad Software Company, San Diego, CA). We selected a significance threshold of P < 0.05, for comparisons between groups.