Abstract
AimIn critically ill mechanically ventilated children, midazolam is used first line for sedation, however its exact sedative effects have been difficult to quantify. In this analysis, we use parametric time-to-event (PTTE) analysis to quantify the effects of midazolam in critically ill children.MethodsIn the PTTE analysis, data was analyzed from a published study in mechanically ventilated children in which blinded midazolam or placebo infusions were administered during a sedation interruption phase until, based on COMFORT-B and NISS scores, patients became undersedated and unblinded midazolam was restarted. Using NONMEM® v.7.4.3., restart of unblinded midazolam was analysed as event. Patients in the trial were divided into internal and external validation cohorts prior to analysis.ResultsData contained 138 events from 79 individuals (37 blinded midazolam; 42 blinded placebo). In the PTTE model, the baseline hazard was best described by a constant function. Midazolam reduced the hazard for restart of unblinded midazolam due to undersedation by 51%. In the blinded midazolam group, time to midazolam restart was 26 h versus 58 h in patients with low versus high disease severity upon admission (PRISM II < 10 versus > 21), respectively. For blinded placebo, these times were 14 h and 33 h, respectively. The model performed well in an external validation with 42 individuals.ConclusionThe PTTE analysis effectively quantified the effect of midazolam in prolonging sedation and also the influence of disease severity on sedation in mechanically ventilated critically ill children, and provides a valuable tool to quantify the effect of sedatives.Clinical trial number and registry URL: Netherlands Trial Register, Trial NL1913 (NTR2030), date registered 28 September 2009 https://www.trialregister.nl/trial/1913.
Highlights
Sedation of critically ill children during mechanical ventilation in paediatric intensive care units (PICU) ensures patient comfort and reduces the incidence of adverse events like accidental self-extubation
Instead, expressing sedative efficacy as cumulative mg/kg dosing [3], duration in PICU stay [4], duration of mechanical ventilation [5], number of ventilator free days [6], or proportion of time at target sedation [7] is used which provides a general estimate of sedative efficacy, yet fail to take into account the changing circumstances around the patient in PICU that may contribute to the varying patient level of sedation
We applied parametric time-to-event (PTTE) modelling to analyse the efficacy of midazolam in maintaining adequate sedation in critically ill children
Summary
Sedation of critically ill children during mechanical ventilation in paediatric intensive care units (PICU) ensures patient comfort and reduces the incidence of adverse events like accidental self-extubation. Pharm Res ventilated paediatric patients, quantifying the effect of midazolam in adequately sedating critically ill children proved to be challenging [1, 2]. A pharmacodynamic analysis of sedatives in critically ill children is complicated due to the multitude of patient intrinsic and extrinsic factors that can influence sedation and the removal of patients from studies due to discharge. Rather than analysing absolute sedation scores, TTE analyses only assess the occurrence (or lack thereof) of clinically relevant events (e.g. need for rescue sedatives) over time. This data analysis method allows the assessment of multiple constant (e.g. diagnosis) or time-varying (changing disease severity) covariates, and it can handle censoring and small sample sizes [9]
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