Physiological modelling of agitation-sedation dynamics including endogenous agitation reduction

Sedation administration and agitation management are fundamental activities in any intensive care unit. A lack of objective measures of agitation and sedation, as well as poor understanding of the underlying dynamics, contribute to inefficient outcomes and expensive healthcare. Recent models of agitation-sedation pharmacodynamics have enhanced understanding of the underlying dynamics and enable development of advanced protocols for semi-automated sedation administration. However, these initial models do not capture all observed dynamics, particularly periods of low sedative infusion. A physiologically representative model that incorporates endogenous agitation reduction (EAR) dynamics is presented and validated using data from 37 critical care patients. High median relative average normalised density (RAND) values of 0.77 and 0.78 support and minimum RAND values of 0.51 and 0.55 for models without and with EAR dynamics respectively show that both models are valid representations of the fundamental agitation-sedation dynamics present in a broad spectrum of intensive care unit (ICU) patients. While the addition of the EAR dynamic increases the ability of the model to capture the observed dynamics of the agitation-sedation system, the improvement is relatively small and the sensitivity of the model to the EAR dynamic is low. Although this may represent a limitation of the model, the inclusion of EAR is shown to be important for accurately capturing periods of low, or no, sedative infusion, such as during weaning prior to extubation.