Comparison of a pH-adjusted intranasal midazolam spray with off-label intranasal use of midazolam injection as preoperative sedation among pediatric patients undergoing inguinal hernia surgery: a randomized clinical trial

Preoperative anxiety in pediatric patients can lead to significant psychological consequences. Midazolam, a fast-acting benzodiazepine, can be administered intranasally. However, the injectable solution, when used intranasally, may cause mucosal irritation. This study aimed to compare the efficacy and clinical acceptability of a specially formulated intranasal midazolam spray versus the intranasal use of midazolam injection in children scheduled for inguinal hernia surgery. This open-label, randomized clinical trial with a blinded assessor, was conducted on children aged 1 to 8 years old undergoing unilateral inguinal hernia surgery at Namazi Hospital in Shiraz, from December 2024 to May 2025. Patients were randomly assigned into two groups to receive either an intranasal midazolam spray or intranasal midazolam injection administered 30 min before surgery at a dose of 0.2–0.3 mg/kg. Sedation level based on Ramsey sedation scale was considered as the primary outcome with the Houpt Behavioral Scale as a secondary outcome assessing behavioral parameters including sleep, movement, crying, and overall behavior. Of 105 eligible children, 101 were enrolled (88 boys, 13 girls) and allocated to intranasal midazolam spray ( n = 52) or intranasal administration of the midazolam injection( n = 49). Doses were rounded to the nearest deliverable unit (2 mg per puff in the spray group; 0.5 mg increments in the injection group). The median (IQR) dose was 4 (2) mg vs. 3 (1.65) mg, respectively ( P = 0.07). The onset of sedation was significantly faster in the spray group compared to the group that received intranasal midazolam injection (median 3 (2) vs. 4 (2) minutes, P = 0.009). To assess whether the faster onset in the spray group could be attributed to the slightly higher dose in this group, a post-hoc analysis of covariance (ANCOVA) was performed. The ANCOVA revealed that the adjusted mean onset time remained significantly shorter in the spray group after controlling for dose (adjusted mean difference: 1.1 min; 95% CI: 0.3 to 1.9; P = 0.012). This suggests that the faster onset in the spray group is driven by formulation and delivery characteristics rather than dose alone. Sedation levels, as assessed by Ramsey Sedation Scale and Houpt Overall Behavior, were comparable between the two groups. However, nasal burning was significantly more common in the intranasal injection group ( p value = 0.001). Additionally, anesthesiologist satisfaction was significantly higher in the spray group ( p value = 0.001). Our results showed that the formulated intranasal midazolam spray with optimized pH provided not only similar sedative effects to the injectable form but also superior tolerability. These findings suggest that the pH-adjusted spray is a promising alternative that warrants further evaluation in multicenter studies. IRCT20120731010453N6. Registration date: 2024-12-15.