Revisiting the impact of endotoxin clearance on survival in the euphrates trial

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Conference Proceeding

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Introduction: Sepsis is a diverse disease. The EUPHRATES TRIAL conducted in a subset of septic shock patients with elevated endotoxin activity levels (EAA) at baseline greater than 0.6 Units were randomized to receive Polymyxin B Hemoperfusion (PMXBHP) or a SHAM treatment. PMXBHP targets the reduction of circulating endotoxin, thought to be a continued trigger for a dysregulated host response. PMXBHP may aid reduction in EAA levels and treatment responders may have improved survival rates.

Methods: This is a post hoc analysis of the EUPHRATES trial focusing on dynamic changes in EAA levels examined at time points (Baseline, Day 1, Day 2, and Day 3). To evaluate changes between the time points the endotoxin clearance (EAAC) was calculated [EAAC = (EAA Time1- EAA Time2)/ EAA Time1]. Values < 0% indicate increasing EAA values, values > 0% indicate reduction in measured EAA values. Chi2 test was used to compare mortality between increasing versus decreasing EAA values. P values of 0.05 were considered significant.

Results: The primary end-point analysis of EUPHRATES did not show a mortality benefit with PMXBHP for all patients enrolled or patients with a Multiple Organ Dysfunction Syndrome (MODS) score of > 9. By using an EAAC assessments approach dynamic EAA changes can be observed. Positive EAAC indicates a response to PMXBHP from day 2 to day 3 and has a positive impact on survival. There is a significant 12.1% difference in mortality between the PMXBHP responders and PMXBHP non-responders. (Table 1) Increasing EAA (negative EEAC) has higher mortality in the PMXBHP and the Sham treated patients. PMXBHP treated patients with positive EAAC from day 2 to 3 have a 9.3% lower 28-day mortality compared to SHAM patients with positive EAAC. This difference in mortality is however not statistical significant with a Chi2 of 2.64 and a p-value of 0.10.

Conclusions: All EUPHRATES trial patients regardless of MODS score, who responded to treatment with PMXBHP with reduction in EAA levels from day 2 to day 3, have an impactful mortality reduction of 12.1% over the non-responders treated with PMXBHP. The observed mortality benefit between PMXBHP and SHAM group with positive EAAC did not reach statistical significance and may be based on the small subgroup size. Future research should focus on optimization of EAA dynamics and optimization of EAA clearance rates do aid resolution of the dysregulated host response.



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