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

"Limitations of the study: The limitations of this study include: (i) a non-randomized study design which potentially may have introduced selection bias in the allocation of patients into the different routes of MDZ administration; and (ii) the small numbers in each group limits the comparison between the groups. Further studies are required to compare the efficacy and frequency of adverse events between the different routes of administration.: In conclusion, the pharmacokinetic data presented in this study show a high bioavailability and reliable plasma concentrations following IM and buccal MDZ. Administration of MDZ (IV, IM or buccal) at the currently recommended dose resulted in rapid attainment of maximum plasma concentrations of MDZ above 60 ng ml−1 but it was associated with a high incidence of respiratory depression. Although IV MDZ terminated seizures in all children with severe malaria, there was a high rate of recurrence of seizures. Intramuscular and buccal administration of MDZ may be more practical in most rural healthcare facilities in sub-Saharan Africa, but the efficacy appears to be poorer at the dose used, and a different dosage regimen might improve the efficacy of IM and buccal MDZ. We recommend that MDZ (0.3 mg kg−1) should be administered IV, but in peripheral health centres with no facilities for IV cannulation, then IM and buccal MDZ may be used cautiously as an alternative. Ideally, MDZ should be administered together with a long acting anticonvulsant in children with severe malaria and convulsions.: Competing interests: The authors declare that they have no competing interests. The Wellcome Trust (UK) and WHO (TDR/MIM) financially supported this work. They had no role in the collection, analysis and interpretation of data or in the writing of the manuscript.: We would like to thank the medical, nursing, laboratory and other staff of the pediatric high-dependency unit at the Kenya Medical Research Institute for their dedication and valuable support. We are indebted to the children and their parents/guardians, for participating in this study. We thank Professor Kevin Marsh and Dr Norbert Peshu (KEMRI/Wellcome Trust Research Programme, Kilifi) for their support. Professor Gilbert O. Kokwaro was supported by a Research Capability Strengthening Grant from WHO (TDR/MIM grant nos. 980074 and A50071). Dr Simon Ndirangu Muchohi was a PhD student in clinical pharmacology supported by The Wellcome Trust of Great Britain. Professor Charles R.J.C. Newton is a Wellcome Trust Senior Clinical Research Fellow (grant no. 070114/Z/02/Z). This paper is published with permission from the Director of KEMRI."

"We would like to thank the medical, nursing, laboratory and other staff of the pediatric high-dependency unit at the Kenya Medical Research Institute for their dedication and valuable support. We are indebted to the children and their parents/guardians, for participating in this study. We thank Professor Kevin Marsh and Dr Norbert Peshu (KEMRI/Wellcome Trust Research Programme, Kilifi) for their support. Professor Gilbert O. Kokwaro was supported by a Research Capability Strengthening Grant from WHO (TDR/MIM grant nos. 980074 and A50071). Dr Simon Ndirangu Muchohi was a PhD student in clinical pharmacology supported by The Wellcome Trust of Great Britain. Professor Charles R.J.C. Newton is a Wellcome Trust Senior Clinical Research Fellow (grant no. 070114/Z/02/Z). This paper is published with permission from the Director of KEMRI."