Population pharmacokinetics of midazolam and its metabolites during venoarterial extracorporeal membrane oxygenation in neonates

Clin Pharmacokinet. 2010 Jun;49(6):407-19. doi: 10.2165/11319970-000000000-00000.


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 microg/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 14.6 L/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 5.31 L/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. In ECMO patients weighing 2.7-3.9 kg, continuously infused midazolam doses of 300 microg/kg/h for 6 hours and 150 microg/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.

MeSH terms

  • Dose-Response Relationship, Drug
  • Extracorporeal Membrane Oxygenation*
  • Female
  • Glucuronides / pharmacokinetics
  • Half-Life
  • Humans
  • Hypnotics and Sedatives / administration & dosage
  • Hypnotics and Sedatives / pharmacokinetics*
  • Infant, Newborn
  • Male
  • Midazolam / administration & dosage
  • Midazolam / analogs & derivatives
  • Midazolam / pharmacokinetics*
  • Models, Biological*
  • Nonlinear Dynamics
  • Time Factors
  • Tissue Distribution


  • Glucuronides
  • Hypnotics and Sedatives
  • 1-hydroxymethylmidazolam
  • Midazolam