Parth J. Upadhyay (1), Nienke J. Vet(2), Sebastiaan C. Goulooze(1), Elke H.J. Krekels(1), Saskia N. de Wildt(2,3), Catherijne A.J. Knibbe(1,4)
1Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands 2 Department of Paediatrics, St Antonius hospital, Nieuwegein, 3 Department of Pharmacology & Toxicology, Radboud University Medical Center, Nijmegen, 4 Department of Clinical Pharmacy, St Antonius hospital, Nieuwegein, the Netherlands
Objectives: Sedation during mechanical ventilation in critically-ill children is crucial to ensure patient comfort and reduce adverse events such as self-extubation. Midazolam is used as a first line sedative in these patients, however a relationship between midazolam exposure and sedation is difficult to quantify in mechanically ventilated critically-ill children due to the administration of multiple sedative and analgesic drugs. In this study, we analysed data from a randomised blinded clinical trial assessing daily sedation interruption (DSI) versus midazolam control in critically-ill children [1] using parametric time to event analysis. The study offered a unique opportunity to assess the influence of midazolam and other determinants on the duration of blinded placebo or midazolam infusion during a DSI.
Methods: A parametric time to event (PTTE) analysis assessed the time to midazolam reinfusion during the DSI phase in the study population. An event was defined as the cessation of blinded infusion and the restart of an unblinded midazolam infusion because of inadequate sedation. A simultaneous constant hazard model assessing dropout was also constructed for patients extubated prior to ceasing the blinded infusion. A smaller group of participants in whom midazolam plasma concentrations were not available, were separated from model development and used as a validation cohort. The relationship between time and event was tested using various constant and time varying baseline hazards. The influence of study arm (placebo or midazolam), patient specific variables such as age, weight, disease severity scores (PRISM II and PIM II), number of failing organs, and midazolam exposure during the study period were tested on the baseline hazard as covariates.
Results: In total, 138 events from 79 individuals (42 receiving blinded placebo and 37 blinded midazolam) informed the PTTE analysis and 75 events from 42 patients were used for validation. A constant baseline hazard best described the risk of ceasing the blinded infusion and switching to unblinded midazolam infusion due to inadequate sedation. Compared to blinded placebo, blinded midazolam treatment significantly lowered the hazard of switching to unblinded midazolam by 51%, while there was no influence of midazolam exposure. Additionally, we identified a decreasing hazard for ceasing the blinded infusion with increasing severity of illness (PRISM II scores). Simultaneous covariate analysis did not identify any influence on extubation prior to ceasing the blinded infusion and therefore dropout was considered uninformative for quantifying event hazard.
In this study, we assessed the role of midazolam for optimal sedation in mechanically ventilated children using a PTTE analysis. While receiving midazolam resulted in substantial lower hazard for switch to unblinded midazolam treatment compared to placebo, we could not identify an influence of midazolam concentration on this hazard. Furthermore, we found that increasing disease severity leads to reduced sedation requirements, which has been reported before for critically-ill adults.[2]
Conclusions: Midazolam reduced the risk of additional sedation requirements in mechanically ventilated critically-ill children. Also, sedation requirements were lower in patients with a higher disease severity score.
References:
[1] Vet NJ et al. Intensive Care Med, 42(2):233-44, 2016
[2] Peeters MY et al. Clin Pharmacol Ther, 83(3):443-51, 2008
Reference: PAGE () Abstr 9307 [www.page-meeting.org/?abstract=9307]
Poster: Drug/Disease Modelling - Paediatrics