Premedication of Pediatric Cardiac Population with Midazolam: Comparison of Oral and Sublingual Administration Regarding Plasma Midazolam Concentration, Clinical Effectiveness, Hemodynamic and Behavioral Outcomes

Background: Midazolam is widely used as a pediatric premedication, but evidence from direct comparisons of oral and sublingual administration in children with congenital heart disease remains limited, particularly that from pharmacokinetic and physiologic data analyzed together. Methods: We conducted a single-center prospective randomized study comparing oral midazolam 0.5 mg/kg with sublingual midazolam 0.3 mg/kg in children undergoing cardiac surgery or catheterization procedures under general anesthesia. Plasma midazolam and 1-hydroxymidazolam concentrations were measured approximately 30 min after administration. Log-transformed concentrations were compared using regression/ANCOVA models adjusted for dose and age. Changes in mean arterial pressure (MAP), heart rate (HR), and oxygen saturation (SpO₂) were analyzed from baseline to 15 and 30 min. Behavioral outcomes included the sedation score, separation from parents, and mask acceptance. Results: Sixty-eight children were randomized; 65 had evaluable pharmacokinetic samples and formed the complete-case pharmacokinetic cohort. Adjusted plasma midazolam concentrations did not differ significantly between the groups, with an adjusted geometric mean ratio for sublingual versus oral administration of 0.98 (95% CI 0.53-1.79; unadjusted p = 0.940; Holm-adjusted p = 1.000). The corresponding ratio for 1-hydroxymidazolam was 1.37 (95% CI 0.55-3.41; unadjusted p = 0.494; Holm-adjusted p = 1.000). HR and SpO₂ changes were non-significant between the groups. At 30 min, sublingual administration was associated with a lower adjusted change in MAP compared with oral administration (adjusted difference -12.08 mmHg, 95% CI -19.74 to -4.42; unadjusted p = 0.002, Holm-adjusted p = 0.012). Behavioral outcomes did not differ significantly between the groups. Conclusions: In this prospective randomized pediatric cardiac cohort, oral midazolam 0.5 mg/kg and sublingual midazolam 0.3 mg/kg produced comparable plasma concentrations and similar behavioral outcomes. Sublingual administration was not associated with worse HR or SpO₂ responses, although an isolated lower MAP change at 30 min warrants confirmation in larger studies. Sublingual midazolam may represent a feasible lower-dose alternative for premedication in this population.