A physiological model of the inflammatory‐thermal‐pain‐cardiovascular interactions during an endotoxin challenge

Abstract

Key points Inflammation in response to bacterial endotoxin challenge impacts physiological functions, including cardiovascular, thermal and pain dynamics, although the mechanisms are poorly understood. We develop an innovative mathematical model incorporating interaction pathways between inflammation and physiological processes observed in response to an endotoxin challenge. We calibrate the model to individual data from 20 subjects in an experimental study of the human inflammatory and physiological responses to endotoxin, and we validate the model against human data from an independent study. Using the model to simulate patient responses to different treatment modalities reveals that a multimodal treatment combining several therapeutic strategies gives the best recovery outcome. Abstract Uncontrolled, excessive production of pro‐inflammatory mediators from immune cells and traumatized tissues can cause systemic inflammatory conditions such as sepsis, one of the ten leading causes of death in the USA, and one of the three leading causes of death in the intensive care unit. Understanding how inflammation affects physiological processes, including cardiovascular, thermal and pain dynamics, can improve a patient's chance of recovery after an inflammatory event caused by surgery or a severe infection. Although the effects of the autonomic response on the inflammatory system are well‐known, knowledge about the reverse interaction is lacking. The present study develops a mathematical model analyzing the inflammatory system's interactions with thermal, pain and cardiovascular dynamics in response to a bacterial endotoxin challenge. We calibrate the model with individual data from an experimental study of the inflammatory and physiological responses to a one‐time administration of endotoxin in 20 healthy young men and validate it against data from an independent endotoxin study. We use simulation to explore how various treatments help patients exposed to a sustained pathological input. The treatments explored include bacterial endotoxin adsorption, antipyretics and vasopressors, as well as combinations of these. Our findings suggest that the most favourable recovery outcome is achieved by a multimodal strategy, combining all three interventions to simultaneously remove endotoxin from the body and alleviate symptoms caused by the immune system as it fights the infection.

A Kinetic Response Model for Standardized Regression Analyses of Inflammation-Triggered Hypothermic Body Temperature-Time Courses in Mice

“…The kinetic parameters, particularly the parameters p 0 and k , may actually depend on the LPS dosage. LPS-induced inflammation triggers a cascade of pro-inflammatory and inhibitory signaling via cytokine production, which gives rise to complex physiological regulation processes (Dobreva et al, 2021 ). Therefore, our model has to be conceived as a phenomenological “summary process” with different kinetic processes aggregated into a manageable number of parameters.…”

Predicting the neuro‐cardio‐haemodynamic outcomes of sepsis and its pharmacological interventions: Get to the future through numerical equations

“…Interestingly, the inflammation model in BioGears was optimised using murine data employed for human predictions, which is problematic because murine inflammatory pathways are different from those found in humans (Dobreva et al . 2021 ). Next, Zhao et al .…”

“…In a recent study published in the The Journal of Physiology , Dobreva et al . ( 2021 ) developed a mathematical model simulating the response to one‐time bacterial endotoxin lipopolysaccharide (LPS) injection. The system‐level model integrated three submodels: the inflammatory response to endotoxin; the effect of inflammation on temperature, pain perception and nitric oxide (NO); and their impact on the cardiovascular system.…”

“…Dobreva et al . ( 2021 ) elegantly demonstrated how system‐level mathematical modelling could elucidate the complex inflammation, neurological, cardiovascular and haemodynamic interactions following transient and sustained endotoxemia, which could provide new insight into the management of sepsis, including the discovery of new druggable targets. They employed the perfect control and observability offered by mathematical modelling to untangle the individual contributions of sepsis determinants.…”

“…Overall, the in silico study conducted by Dobreva et al . ( 2021 ) exemplifies the value of mathematical modelling in identifying major determinants of a complex disease state (e.g. sepsis) and potentially providing an opportunity to support clinical decision‐making processes.…”