Pharmacokinetics and clinical efficacy of lorazepam in children with severe malaria and convulsions Academic Article uri icon

abstract

  • WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

    • Lorazepam (LZP) may be a more useful anticonvulsant to stop convulsions in children with severe malaria (SM) than diazepam, since it has a longer duration of action and can be given by other routes, such as intramuscular (i.m.).

    • There are no studies describing both the pharmacoknetics and clinical efficacy of LZP in African children, particularly those with SM.

    • We have undertaken a study with LZP, administered either intravenously (i.v.) or i.m., to children with SM and convulsions in order to describe and compare the pharmacokinetic profiles of LZP following administration via both routes and determine whether the currently recommended dose of LZP (0.1 mg kg−1) is effective in terminating convulsions in this group.

    WHAT THIS STUDY ADDS

    • Administration of LZP (i.v. or i.m.) at the currently recommended dose (0.1 mg kg−1) resulted in rapid achievement of plasma LZP concentrations within the reported effective therapeutic range without clinically significant cardiorespiratory effects.

    • A single dose of LZP was effective in the rapid termination of convulsions in all children, and prevention of seizure recurrence for >72 h in 11 of 15 (73%) children and 10 of 11 (91%) children after i.v. and i.m. administration, respectively.

    AIM

    To investigate the pharmacokinetics and clinical efficacy of intravenous (i.v.) and intramuscular (i.m.) lorazepam (LZP) in children with severe malaria and convulsions.

    METHODS

    Twenty-six children with severe malaria and convulsions lasting ≥5 min were studied. Fifteen children were given a single dose (0.1 mg kg−1) of i.v. LZP and 11 received a similar i.m. dose. Blood samples were collected over 72 h for determination of plasma LZP concentrations. Plasma LZP concentration–time data were fitted using compartmental models.

    RESULTS

    Median [95% confidence interval (CI)] LZP concentrations of 65.1 ng ml−1 (50.2, 107.0) and 41.4 ng ml−1 (22.0, 103.0) were attained within median (95% CI) times of 30 min (10, 40) and 25 min (20, 60) following i.v. and i.m. administration, respectively. Concentrations were maintained above the reported therapeutic concentration (30 ng ml−1) for at least 8 h after dosing via either route. The relative bioavailability of i.m. LZP was 89%. A single dose of LZP was effective for rapid termination of convulsions in all children and prevention of seizure recurrence for >72 h in 11 of 15 children (73%, i.v.) and 10 of 11 children (91%, i.m), without any clinically apparent respiratory depression or hypotension. Three children (12%) died.

    CONCLUSION

    Administration of LZP (0.1 mg kg−1) resulted in rapid achievement of plasma LZP concentrations within the reported effective therapeutic range without significant cardiorespiratory effects. I.m administration of LZP may be more practical in rural healthcare facilities in Africa, where venous access may not be feasible.

publication date

  • 2008