A two-compartment mathematical model of endotoxin-induced inflammatory and physiologic alterations in swine

Objective: To gain insights into individual variations in acute inflammation and physiology. Design: Large-animal study combined with mathematical modeling. Setting: Academic large-animal and computational laboratories. Subjects: Outbred juvenile swine. Interventions: Four swine were instrumented and subjected to endotoxemia (100 μg/kg), followed by serial plasma sampling. Measurements and Main Results: Swine exhibited various degrees of inflammation and acute lung injury, including one death with severe acute lung injury (PaO2/FIO2 ratio μ200 and static compliance μ10 L/cm H2O). Plasma interleukin-1β, interleukin-4, interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor-α, high mobility group box-1, and NO₂/NO₃ were significantly (p μ .05) elevated over the course of the experiment. Principal component analysis was used to suggest principal drivers of inflammation. Based in part on principal component analysis, an ordinary differential equation model was constructed, consisting of the lung and the blood (as a surrogate for the rest of the body), in which endotoxin induces tumor necrosis factor-α in monocytes in the blood, followed by the trafficking of these cells into the lung leading to the release of high mobility group box-1, which in turn stimulates the release of interleukin-1β from resident macrophages. The ordinary differential equation model also included blood pressure, PaO₂, and FIO ₂, and a damage variable that summarizes the health of the animal. This ordinary differential equation model could be fit to both inflammatory and physiologic data in the individual swine. The predicted time course of damage could be matched to the oxygen index in three of the four swine. Conclusions: The approach described herein may aid in predicting inflammation and physiologic dysfunction in small cohorts of subjects with diverse phenotypes and outcomes.