Towards in silico models of decomplexification in human endotoxemia

Heart rate (HR) variability (HRV) is an important variable in determining the state of a critically ill patient. This motivates the quantitative understanding of the mechanisms giving rise to changes in HRV, particularly in the context of critical illness. Human endotoxemia, a clinical model of systemic inflammation, has been modeled previously to characterize its complex dynamics. This model is extended to incorporate a semi-mechanistic model of signal transduction leading from the well-established processes at the cellular and molecular levels in the inflammatory response to systemic changes in HR and HRV as governed by the autonomic nervous system's response to inflammation. This is accomplished with an integral pulse frequency modulation model that translates the continuous, deterministic model dynamics into a series of discrete, variable heart beats. Thus, homeostatic variability and the mechanisms leading from cellular processes to systemic changes in variability under endotoxemia are assessed.