Assessing circadian rhythms during prolonged midazolam infusion in the pediatric intensive care unit (PICU) children Agnieszka Bienert 1 , Alicja Bartkowska-Œniatkowska 2 , Pawe³ Wiczling 3 , Jowita Rosada-Kurasiñska 2 , Ma³gorzata Grzeœkowiak 2 , Czes³aw ¯aba 4 , Artur Te¿yk 4 , Anna Soko³owska 1 , Roman Kaliszan 3 , Edmund Grzeœkowiak 1 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 nonlin- ear 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 ade- quately 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. Key words: midazolam, pharmacokinetics, children, critically ill, circadian rhythms, mechanical ventilation Introduction Both undersedation and oversedation have an obvious effect on morbidity and mortality in critically ill pa- tients [44]. Midazolam is one of the most commonly used sedative agents in the pediatric intensive care unit (PICU) [8]. Its pharmacokinetics (PK) and phar- macodynamics (PD) has been studied on intensive care unit (ICU) patients, including infants and chil- dren [8, 13, 37, 51, 58]. However, there are still many open questions regarding both disposition and phar- macological response of midazolam in the ICU. Com- 107