Effect of Intranasal Dexmedetomidine or Midazolam for Premedication on the Occurrence of Respiratory Adverse Events in Children Undergoing Tonsillectomy and Adenoidectomy

Key Points Question Do preoperative sedatives such as midazolam and dexmedetomidine have a protective effect against perioperative respiratory adverse events (PRAEs) while achieving adequate sedative effect? Findings In this randomized clinical trial that included 384 children undergoing tonsillectomy and adenoidectomy, the incidence of PRAEs was 24.2% in the dexmedetomidine (2.0 μg/kg) group, 56.5% in the midazolam (0.1 mg/kg) group, and 40.8% in the normal saline group. Meaning Intranasal midazolam used for premedication was associated with increased incidence of PRAEs, whereas premedication with dexmedetomidine was associated with reduced incidence of PRAEs.

This supplemental material has been provided by the authors to give readers additional information about their work.

Further detail on statistical analyses
Primary outcome was analyzed using Chi-square test or Fisher exact test, the crude odds ratio (OR) and 95% CI reported were calculated.
Adjusted odds ratio (aOR) and 95% CI were calculated for both primary and secondary outcomes.
Age, sex, American Society of Anesthesiologists physical status, Body Mass Index(BMI), Upper Respiratory Infection(URI), passive smoking and Obstructive Sleep Apnea(OSA) were adjusted for using binary logistic regression, age and BMI adjusted in the models as continuous variables.

Intention-to-treat analysis AND as-per-protocol analysis
Outcome analyses were performed in the intention-to-treat population, a per-protocol analysis was also performed for the primary endpoint.
We excluded 33 cases in as-per-protocol analysis: 10 patients were preoperatively sedated for less than 30 minutes, 6 patients were preoperatively sedated for more than 60 minutes, 8 patients still accepted intravenous midazolam during the anesthesia induction period, 9 patients refused a preoperative nasal drip(figure 1), these cases violated the protocol of the trial, excluding them would destroy the balance among groups and be inconsistent with actual clinical practice, but the intention-to-treat analysis may underestimate the efficacy and increase the possibility of type II error, so we reported the ITT in the main results, and the PP in the eResult.

Post hoc analysis
We conducted a post hoc analysis for children with upper respiratory tract infections(URI) in the previous 4 weeks, previous studies have found that approximately 30% of children undergoing elective surgery have active URI symptoms. URI is associated with an increased risk for PRAEs, the most common reason for delaying surgery in children is due to upper respiratory tract infection. The incidence of PRAEs was reported to be 2-3 times higher in children with URTI than without URTI.

As-per-protocol analysis
The incidence of PRAEs among the three groups are shown in eTable 1, the crude and adjusted OR were presented. Consistent with the intention-to-treat analysis, children in midazolam group were more likely to experience PRAEs than those in normal saline group after adjusting for age, sex, ASA, BMI, OSA, URI and passive smoking (65/

Post hoc analysis
The occurrence of URI was 33.0%, the incidence of PRAEs in midazolam group was 64.4% (vs. 56.5% in general population), while dexmedetomidine was 20.0% (vs. 24.2% in general population).
The risk of PRAEs in the midazolam group was higher than that in the control group (

Secondary outcomes
Sedation success rate FUNK score was recorded when entering the operating room, it assess sedative effects in anxiolysis, separation, puncture, mask induction, the score of 1 or 2 is considered ineffective sedation, whlie a score of 3 or 4 is considered effective sedation, total funk score ≥12 is considered clinically effective sedation.
Success rates for anxiolysis, separation, puncture, mask induction and clinically effective sedation before induction of anesthesia among groups are shown in eFigure 2. Both dexmedetomidine group and midazolam group had higher success rates in anxiolysis, separation and mask induction compared normal saline group, dexmedetomidine may be better than midazolam in reducing anxiety. There was no significant difference in the success rate of clinical effective sedation between dexmedetomidine and midazolam group (68.5% vs. 77.4%, P＞.017).
The heart rate of dexmedetomidine group and midazolam group was slightly lower than that of normal saline group after sedation, but no bradycardia was observed. At the time of extubation (T9), the heart rate of dexmedetomidine group was lower than that of normal saline group and midazolam group (P<.017). There were no significant difference between the groups in other moments (P>.017).
When comparing within group, compared with the baseline value (T0), the heart rates of the three groups significantly decreased after induction (T7) and after intubation (T8) (P<.001), and the heart rates of normal saline and midazolam group significantly decreased after extubation (T9) than the baseline value (T0) (P＜.001), whlie dexmedetomidine can suppress a sharp increase in heart rate during extubation..