Pharmacokinetics and clinical efficacy of midazolam in children with severe malaria and convulsions

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Midazolam (MDZ), a water-soluble benzodiazepine, can be administered via several routes, including intravenously (IV), intramuscularly (IM) and buccal routes to terminate convulsions. It may be a suitable alternative to diazepam to stop convulsions in children with severe malaria, especially at peripheral healthcare facilities. The pharmacokinetics of MDZ have not been described in African children, in whom factors such as the aetiology and nutritional status may influence the pharmacokinetics. WHAT THIS STUDY ADDS• Administration of MDZ (IV, IM, or buccal) at the currently recommended dose (0.3 mg kg -1 ) resulted in rapid achievement of median maximum plasma concentrations of MDZ within the range 64-616 ng ml -1 , with few clinically significant cardio-respiratory effects. A single dose of MDZ rapidly terminated (within 10 min) seizures in all (100%), 9/12 (75%) and 5/8 (63%) children following IV, IM and buccal administration, respectively. Although IM and buccal MDZ may be the preferred treatment for children in the pre-hospital settings the efficacy appears to be poorer. AIMTo investigate the pharmacokinetics and clinical efficacy of intravenous (IV), intramuscular (IM) and buccal midazolam (MDZ) in children with severe falciparum malaria and convulsions. METHODSThirty-three children with severe malaria and convulsions lasting Ն5 min were given a single dose of MDZ (0.3 mg kg -1 ) IV (n = 13), IM (n = 12) or via the buccal route (n = 8). Blood samples were collected over 6 h post-dose for determination of plasma MDZ and 1′-hydroxymidazolam concentrations. Plasma concentration-time data were fitted using pharmacokinetic models. RESULTS Median (range) MDZ CONCLUSIONSAdministration of MDZ at the currently recommended dose resulted in rapid achievement of therapeutic MDZ concentrations. Although IM and buccal administration of MDZ may be more practical in peripheral healthcare facilities, the efficacy appears to be poorer at the dose used, and a different dosage regimen might improve the efficacy.Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

Growing up with Midazolam in the Neonatal and Pediatric Intensive Care

“…In neonates there is a decreased volume of distribution of lipophilic drugs resulting in higher peak drug concentrations. With increasing age, the volume of distribution of midazolam increases from approximately 1 l/kg in neonates to 1.3 l/kg in children of 5 years of age and 2 l/kg in teenagers, with large differences between different study populations [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. This indicates that changes in body composition have a moderate influence on the pharmacokinetic disposition of midazolam [12].…”

Inter-individual variation in midazolam clearance in children

“…Seven used a two compartment model,11 12 14 15 17 18 21 one used a three compartment model,31 one used both one and two compartment model17 and five used a non-compartment model 1316 24 25 28 Ethnicity was described in only four studies 1516 24 30 All studies except two were population PK studies.…”

Comparative Study of Buccal Midazolam and I.V Diazepam for Acute Treatment of Seizure in Pediatrics Age Group

“…In our study, mean time taken by drug, from its administration to cessation of seizures in group A was 90.00 ± 150 seconds (168 min), and it was 80 ± 130 seconds (1.4 min) in group B. In the study by Talukdar et al [5] [8] used…”