Pediatric Pharmacodynamics of Midazolam Oral Syrup

Abstract

In this study, the authors evaluate the pharmacodynamics, safety, and acceptability of a new cherry-flavored oral syrup formulation of midazolam. This randomized, double-blind, parallel-group, dose-ranging clinical trial of oral midazolam was conducted at seven U.S. health care institutions focused on pediatric clinical pharmacology research (i.e., the PPRU Network). Pediatric patients (n = 85, ages 6 months through 15 years) underwent invasive procedures and were randomized to a single oral dose of midazolam syrup (0.25, 0.5, or 1.0 mg/kg). Patient taste acceptability of midazolam syrup was evaluated at the time of oral administration. Pharmacodynamic measurements included (1) sedation score using a 5-point scale at baseline and 10-, 20-, and 30-minute postdose intervals and (2) anxiety score using a 4-point scale at the time of separation from caretakers and, when applicable, at the time of mask anesthetic induction. Midazolam and alpha-hydroxymidazolam plasma concentrations were measured at all pharmacodynamic measurement time points. Adverse events were monitored continuously during the study. Most patients (99%) accepted the syrup without difficulty. Satisfactory sedation was achieved within 30 minutes by 81% of patients. The anxiety score at the time of caretaker separation and mask anesthetic induction was satisfactory for 87% and 91% of patients, respectively. A significant linear relationship between plasma drug concentration and maximal sedation score, but not anxiety score, was observed. The occurrence of adverse events was consistent with the known safety profile of midazolam. The most commonly reported adverse events were hiccoughing, hypoxemia, nausea, and emesis. It was concluded that a new oral syrup formulation of midazolam, 0.25 to 1.0 mg/kg, effectively induced rapid-onset, dose-related, adequate, and safe sedation and anxiolysis in pediatric patients who underwent operative procedures. Sedative effects were related to plasma concentrations of both midazolam and the primary metabolite, alpha-hydroxymidazolam. Oral midazolam, 1.0 mg/kg, administered within 30 minutes of the expected procedure or anesthetic induction should provide safe and effective sedation to a majority of children ages 6 months to 16 years.

Is premedication with midazolam more effective by the sublingual than the oral route?

“…[710] Sublingual route has an advantage of mucosal absorption directly into the systemic circulation with no first pass hepatic metabolism due to the rich blood supply of oral mucosa, is easy to administer, has rapid action, reliable predictable effect and the drug is not destroyed by the gastrointestinal enzymes. [1112]…”

Inosine monophosphate dehydrogenase activity in paediatrics: age-related regulation and response to mycophenolic acid

“…However, little is known about the effect of human ontogeny on pharmacodynamics. Data on warfarin [6], cyclosporine [7] and midazolam [8,9] indicate that there is a true developmental change in the interaction between the drug and its specific receptor or in the relation between the plasma level and the pharmacological effect of a given drug.…”

Sedation and Analgesia in Children with Developmental Disabilities and Neurologic Disorders

“…Midazolam does not cause local irritation after injection (unlike diazepam) and can be readily mixed with other medications for intravenous, intramuscular, oral, intranasal, or rectal administration. Rapid redistribution from the brain to other tissues, and rapid metabolism by the liver, accounts for a short duration of action and an elimination half life of 1 to 2 hours [20]. …”