Background and Objective: Midazolam is used to sedate children during extracorporeal membrane oxygenation (ECMO). Pharmacokinetic changes are expected because of extracorporeal circulation and maturation. We present a population pharmacokinetic model for midazolam and its major metabolites in neonates during venoarterial ECMO. Methods: We studied 20 neonates on venoarterial ECMO, with a median postnatal age of 0.79 (range 0.17-5.8) days and a bodyweight of 3.0 (range 2.7-3.9) kg at the onset of ECMO. The median ECMO duration was 124 (range 70-275) hours. Serum concentrations were measured at the initiation and discontinuation of the midazolam infusion (100-300 μg/kg/h). Analysis of concentrations of midazolam, 1-hydroxymidazolam and its glucuronide were performed using nonlinear mixed-effects modelling. A two-compartment model for midazolam and a one-compartment model for the metabolites 1-hydroxymidazolam and hydroxymidazolam glucuronide adequately described the data, with allometric scaling of all parameters. Results: Following the start of ECMO, the volume of distribution of midazolam increased from 4.29 to 14.6L/3 kg, with an elimination half-life of 1.85 hours. The median midazolam and 1-hydroxymidazolam clearance values increased 3-fold within the first 5 days (up to 1.38 and 5.31L/h/3 kg, respectively), whereas hydroxymidazolam glucuronide clearance remained constant at 0.18 L/h/3 kg. Interpatient variability estimates of midazolam, 1-hydroxymidazolam and hydroxymidazolam glucuronide clearance and midazolam and hydroxymidazolam glucuronide volumes of distribution varied between 87% and 129%. Concomitant inotropic infusion increased hydroxymidazolam glucuronide clearance by 23%. Conclusion: After allometric scaling, clearance of midazolam and 1-hydroxymidazolam increases as a result of maturation or recovery from critical illness. InECMO patients weighing 2.7-3.9 kg, continuously infused midazolam doses of 300 μg/kg/h for 6 hours and 150 μg/kg/h thereafter provide adequate serum concentrations for sedation. The dose must be increased substantially after 5-7 days. Hydroxymidazolam glucuronide accumulates during ECMO, providing an increased proportion of the overall effect, up to 34% after 7 days.Large unexplained interpatient variability warrants careful titration of sedation and adverse effects.

Additional Metadata
Persistent URL dx.doi.org/10.2165/11319970-000000000-00000, hdl.handle.net/1765/27908
Journal Clinical Pharmacokinetics
Citation
Ahsman, M.J, Hanekamp, M.N, Wildschut, E.D, Tibboel, D, & Mathot, R.A. (2010). Population pharmacokinetics of midazolam and its metabolites during venoarterial extracorporeal membrane oxygenation in neonates. Clinical Pharmacokinetics, 49(6), 407–419. doi:10.2165/11319970-000000000-00000