IntroductionWhile evidence on the pharmacokinetics of midazolam in children in increasing, there is only limited information on the pharmacokinetic-pharmacodynamic relation of midazolam in critically ill children. In this study, we explored the relation between midazolam concentrations and level of sedation using data from a multi-institutional clinical trial1 comparing Daily Sedation Interruption (DSI) with protocolised sedation versus protocolised sedation alone (i.e DSI + PS vs. PS) in critically-ill, mechanically ventilated paediatric ICU (P-ICU) patients.MethodsPharmacokinetic information on midazolam use along with COMFORT and NISS scores from 113 mechanically ventilated P-ICU patients (median age 3 months, range: 0 to 17 years) admitted between 2010 and 2014 were used from the original study.1 Midazolam plasma concentrations at the time of each COMFORT score were calculated using a pharmacokinetic model published on the same dataset.2 Sedation scores were categorised into under-, adequate- and over-sedated categories according to the study protocol.3ResultsIn total, 6662 COMFORT scores were elicited (3112 and 3550 records for DSI+PS and PS arms, respectively). Patients were observed to be adequately sedated in 4232 (64%) scores, and under- and over-sedated in 720 scores (10%) and 1710 (26%) scores, respectively. For all three sedation categories, median midazolam concentrations were significantly lower in the DSI+PS arm compared to PS (P < 0.001). Generalized multivariate linear mixed-effects modelling identified previously reported over-sedation scores (P < 0.001) in combination with high log-transformed midazolam concentrations (P < 0.001) as predictors of over-sedation in patients. Prior under-sedation, but not individual predicted midazolam concentration, predicted current under-sedation (P < 0.001).ConclusionThese preliminary results suggest a role of previous sedation scores in subsequent sedation scores. Further exploration of these data using Markov modelling seems required to identity the relation between midazolam concentrations and level of sedation in mechanically ventilated P-ICU patients.ReferencesVet NJ, de Wildt SN, Verlaat CW, et al. A randomized controlled trial of daily sedation interruption in critically ill children. Intensive care medicine 2016;42(2):233–44. doi: 10.1007/s00134-015-4136-z [published Online First: 2015/11/26]Vet NJ, Brussee JM, de Hoog M, et al. Inflammation and organ failure severely affect midazolam clearance in critically ill children. American journal of respiratory and critical care medicine 2016;194(1):58–66. doi: 10.1164/rccm.201510-2114OC [published Online First: 2016/01/23]Vet NJ, de Wildt SN, Verlaat CW, et al. Daily interruption of sedation in critically ill children: study protocol for a randomized controlled trial. Trials 2014;15:55. doi: 10.1186/1745-6215-15-55 [published Online First: 2014/02/15]Disclosure(s)Conflict of interest statement: The original trial was supported by project grants from the Netherlands Organization for Health Research and Development, ZonMw Priority Medicines for Children (grant numbers 113202002 and 92003549) and Erasmus MC Cost-Effectiveness Research.
Study protocol for a phase II dose evaluation randomized controlled trial of cholecalciferol in critically ill children with vitamin D deficiency (VITdAL-PICU study)
