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

Abstract

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.

• Authors: Maurice J Ahsman, Manon Hanekamp, Enno D Wildschut, Dick Tibboel, Ron A A Mathot
• Journal: Clinical pharmacokinetics (Clin Pharmacokinet) Vol. 49 Issue 6 Pg. 407-19 (Jun 2010) ISSN: 1179-1926 [Electronic] Switzerland
• PMID: 20481651 (Publication Type: Journal Article)

Chemical References

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

Topics

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