British Journal of Anaesthesia, 2002, Vol. 89, No. 3 428-437
© 2002 The Board of Management and Trustees of the British Journal of Anaesthesia
research-article |
Contribution of midazolam and its 1-hydroxy metabolite to preoperative sedation in children: a pharmacokinetic-pharmacodynamic analysis
1 University of Sheffield, Academic Unit of Molecular Pharmacology and Pharmacogenetics, Division of Clinical Sciences (South), The Royal Hallamshire Hospital Sheffield S10 2JF, UK
2 Department of Anaesthesia, Children's Hospital Sheffield S10 2TH, UK
3 University of Sheffield, Academic Unit of Child Health, Children's Hospital Sheffield S10 2TH, UK
*Corresponding author
Background. Oral midazolam is widely used for preoperative sedation in children. We have studied the pharmacokinetics (PK) of both midazolam and its active l-hydroxy metabolite and their contributions to sedative effect in 45 children attending for day surgery.
Methods. Blood samples (two per individual) were collected at the beginning and end of the surgical procedure. Plasma midazolam and l-hydroxymidazolam (I-OHMDZ) were measured by HPLC. Sedation score (score: I =awake, 2=drowsy/asleep) was recorded at the same time as the first blood sample. The population-PK software P-Pharm was used to analyse the data. Age, weight, sex, concomitant drugs, and the metabolic ratio, l-OHMDZ/midazolam were investigated as co-variates of the PK of midazolam and I-OHMDZ. The pharmacokineticpharmacodynamic (PK-PD) modelling of the score in relation to plasma midazolam and I-OHMDZ was performed using logistic regression analysis.
Results. A median dose of 0.5 mg kg–1 was given to the children, median age 5 yr (range from 9 months to 12 yr) and weight 21 kg (range 8–75 kg). Average concentrations of midazolam 150 ng ml–1 and I-OHMDZ 90 ng ml–1 were observed in the first plasma samples. These concentrations resulted in an odds ratio of 4 in favour of score 2 vs I. The best PK-PD model included both midazolam and I-OHMDZ as active moieties and predicted correct scores in 86% of cases.
Conclusion. Studies of midazolam should evaluate the contribution of I-OHMDZ to the overall PD effect. The metabolite I-OHMDZ has approximately half the activity of the parent drug and can compensate for at least part of the decreased effect due to increased midazolam metabolism.
hypnotics benzodiazepine, midazolam pharmacokinetics, midazolam pharmacodynamics sedation, preoperative anaesthesia, paediatric
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. B Hawcutt and R. L Smyth One size does not fit all: getting drug doses right for children Arch. Dis. Child., March 1, 2008; 93(3): 190 - 191. [Full Text] [PDF]
|
|