Effectiveness of Multiple Blood-Cleansing Interventions in Sepsis, Characterized in Rats

Abstract

Sepsis is a serious, life-threatening condition that presents a growing problem in medicine, but there is still no satisfying solution for treating it. Several blood cleansing approaches recently gained attention as promising interventions that target the main site of problem development-the blood. The focus of this study is an evaluation of the theoretical effectiveness of hemoadsorption therapy and pathogen reduction therapy. This is evaluated using the mathematical model of Murine sepsis, and the results of over 2,200 configurations of single and multiple intervention therapies simulated on 5,000 virtual subjects suggest the advantage of pathogen reduction over hemoadsorption therapy. However, a combination of two approaches is found to take advantage of their complementary effects and outperform either therapy alone. The conducted computational experiments provide unprecedented evidence that the combination of two therapies synergistically enhances the positive effects beyond the simple superposition of the benefits of two approaches. Such a characteristic could have a profound influence on the way sepsis treatment is conducted.

Figure 1. The efficacy of 744 configurations of HA therapies on 5,000 virtual subjects over a range of starting times and duration.

Each pixel color represents the rate of subjects rescued using that configuration of starting time and duration. Warmer tones represent higher, and the colder tones lower survival rates (1 corresponds to 100% rescue). Earlier and longer treatments tend to save more subjects.

Figure 2. The efficacy of 744 configurations of PR therapies on 5,000 virtual subjects over a range of starting times and duration.

Each pixel color represents the rate of subjects rescued using that configuration of starting time and duration. Warmer tones represent higher, and the colder tones lower survival rates (1 corresponds to 100% rescue). Earlier start and longer treatments tend to rescue more subjects.

Figure 3. The efficacy of combined therapies on 5,000 virtual subjects when starting therapy within 60 hours of infection and limited the total therapy to 24 hours.

Each pixel color represents the rate of subjects rescued using that configuration of starting time and duration. Warmer tones represent higher, and the colder tones lower survival rates (1 corresponds to 100% rescued rate). The blue line represents the maximum percentage of rescued subjects. Combined therapies where pathogen reduction therapy is much longer than hemoadsorption were the most effective.

Figure 4. The most effective combination of therapies on 5,000 virtual subjects.

The most effective combined therapy is presented by the blue line. Hemoadsorption and pathogen reduction parts of the corresponding combined therapy are depicted with green and red color, respectively. The black line shows accumulated performance of individual therapies. The blue line above the black line provides evidence that there is a synergistic effect when therapies are applied together.

Figure 5. Isobologram of pathogen reduction and hemoadsorption blood cleansing interventions on 5,000 virtual subjects.

The isobole (black dotted) lines are representing the expected case of no interaction between the interventions. Empirical lines corresponding to computed lines of targeted efficacy levels for a combined therapy (red lines) show large positive interaction between the components.