title: Assessing circadian rhythms during prolonged midazolam infusion in the pediatric intensive care unit (PICU) children.
abstract: BACKGROUND
  This study evaluates possible circadian rhythms during prolonged midazolam infusion in 27 pediatric intensive care unit (PICU) children under mechanical ventilation.
  
  
  METHODS
  Blood samples for midazolam and 1-OH-midazolam assay were collected throughout the infusion at different times of the day. The blood pressure, heart rate and body temperature were recorded every hour for the rhythms analysis. Population nonlinear mixed-effect modeling with NONMEM was used for data analysis.
  
  
  RESULTS
  A two-compartment model for midazolam pharmacokinetics and a one-compartment model for midazolam metabolite adequately described the data. The 24 h profiles of all monitored physiological parameters were greatly disturbed/abolished in comparison with the well-known 24 h rhythmic patterns in healthy subjects. There was no significant circadian rhythm detected with respect to midazolam pharmacokinetics, its active metabolite pharmacokinetics and all monitored parameters.
  
  
  CONCLUSIONS
  We concluded that the light-dark cycle did not influence midazolam pharmacokinetics in intensive care units children. Also, endogenous rhythms in critically ill and sedated children are severely disturbed and desynchronized. Our results confirmed that it is necessary to adjust the dose of midazolam to the patient's body weight. The low value of midazolam clearances observed in our study was probably caused by mechanical ventilation, which was shown to decrease the cardiac output.
authors.affiliation: Department of Clinical Pharmacy and Biopharmacy, Karol Marcinkowski University of Medical Sciences, Marii Magdaleny 14, PL 61-861 Poznań, Poland. agnbienert@op.pl.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Bienert
authors.forename: Alicja
authors.initials: A
authors.lastname: Bartkowska-Sniatkowska
authors.forename: Paweł
authors.initials: P
authors.lastname: Wiczling
authors.forename: Jowita
authors.initials: J
authors.lastname: Rosada-Kurasińska
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Grześkowiak
authors.forename: Czesław
authors.initials: C
authors.lastname: Zaba
authors.forename: Artur
authors.initials: A
authors.lastname: Teżyk
authors.forename: Anna
authors.initials: A
authors.lastname: Sokołowska
authors.forename: Roman
authors.initials: R
authors.lastname: Kaliszan
authors.forename: Edmund
authors.initials: E
authors.lastname: Grześkowiak
mesh_terms: D000293:Adolescent; D001794:Blood Pressure; D001831:Body Temperature; D001835:Body Weight; D002302:Cardiac Output; D002648:Child; D002675:Child, Preschool; D002940:Circadian Rhythm; D016638:Critical Illness; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007223:Infant; D007262:Infusions, Intravenous; D015278:Intensive Care Units, Pediatric; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D008954:Models, Biological; D017711:Nonlinear Dynamics; D012121:Respiration, Artificial; D013997:Time Factors
chemical_list: D006993:Hypnotics and Sedatives; C040081:1-hydroxymethylmidazolam; D008874:Midazolam