Importance of Endotoxin Clearance in Endotoxemic Septic Shock: An Analysis From the Evaluating Use of PolymyxinB Hemoperfusion in a Randomized Controlled Trial of Adults Treated for Endotoxemic Septic Shock (EUPHRATES) Trial

To investigate the relationship between survival and treatment-related reduction in endotoxin activity for patients in the Evaluating Use of PolymyxinB Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock trial with baseline endotoxin activity assay greater than or equal to 0.60 to less than 0.90 units. DESIGN: Post hoc analysis of a multicenter randomized controlled clinical trial. SETTING: Fifty-five tertiary hospitals in North America. PATIENTS: Patients with septic shock and endotoxin activity assay level greater than or equal to 0.60 to less than 0.90 and multiple organ dysfunction syndrome greater than 9. INTERVENTIONS: Two polymyxin B hemoperfusion treatments or Sham. MEASUREMENTS AND MAIN RESULTS: One-hundred ninety-four patients were included (88 polymyxin B and 106 Sham). We evaluated the impact of changes in endotoxin activity assay based on comparison to the median reduction from baseline to day 3 and a second method where a target post-treatment endotoxin activity assay level (day 3) was established. The population median reduction in endotoxin activity assay level was 10.4%. In patients with a greater than median reduction, there was trend toward lower mortality with polymyxin B (17.1% vs 33.3%; p = 0.07) and a significant increase in mechanical ventilation-free days (20 vs 13.5; p = 0.04). The pressure adjusted heart rate showed a significant improvement in the polymyxin B group (p = 0.02). For patients who achieved an endotoxin activity assay of less than 0.65 at day 3, the polymyxin B treated group had a trend toward a mortality reduction compared to Sham (16% vs 33%;p = 0.06) and a significant increase in ventilation-free day (20 vs 16; p = 0.05). Kaplan-Meier analysis showed a 17% reduction in mortality with polymyxin B (p = 0.04). CONCLUSIONS: These findings suggest that reducing endotoxin activity assay levels with polymyxin B as measured by comparison to a median reduction or when a treatment target is established, may result in improvements in mortality and organ function outcomes. This article is the first to report endotoxin activity assay measurements in response to polymyxin B use versus Sham in patients with septic shock and elevated endotoxin activity assay. These findings are considered to be hypothesis generating and will need to be prospectively validated.