A Personalized Signature and Chronotherapy-Based Platform for Improving the Efficacy of Sepsis Treatment

Abstract

Sepsis remains a major therapeutic challenge and is associated with a high rate of morbidity and mortality. It is a dynamic condition in which multiple parameters change over time, rendering it difficult to overcome the various injurious responses, which worsen the prognosis in these patients. The prognosis of sepsis is associated with a disbalance of compensatory responses to infectious triggers, part of which can be deleterious. Marked inter- and intra-patient variability characterizes the mechanisms that underlie sepsis progression and determine the response to therapy. In this paper, we review some of the data on the use of chronopharmacological approaches for the treatment of patients with sepsis and discuss the role of the autonomic nervous system in the mechanisms associated with immune response and chronotherapy in these patients. We describe the implementation of an individualized platform that is based on the personalized autonomic nervous system, immune, and chronobiology-derived parameters for generating a patient-tailored therapeutic regimen. The notion of overcoming the deleterious compensatory response in a highly dynamic system in sepsis is presented to ensure an improved response to current therapies.

Keywords: chronobiology; chronotherapy; compensatory mechanisms; drug resistance; sepsis.

FIGURE 1

(A) A schematic presentation of the bidirectional effect of sepsis and chronobiology. Examples of biological rhythms influence on the inflammatory response during sepsis (right side) and of the alteration of those rhythms (chronodisruption) by the inflammatory process itself (left side) (ICU, intensive care unit). (B) A schematic representation of the potential use of HRV from the diagnosis and risk stratification through personalizing the therapy to match relevant chronobiological patterns, and finally in the post-sepsis observation period (HRV, heart rate variability). (C) A schematic representation of establishing a platform that implements different signatures that are relevant to sepsis, including circadian rhythm, immune-, and ANS-based parameters (I). These are implemented into a variability-based therapeutic regimen (II). Finally, the generation of a patient-based closed loop, which responds to the continuous changes is implemented (III) (HRV, heart rate variability).