Journal Club - Recent Additions

October - 2018

   

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Effect of Targeted Polymyxin B Hemoperfusion on 28-Day Mortality in Patients With Septic Shock and Elevated Endotoxin Level: The EUPHRATES Randomized Clinical Trial

R.P. Dellinger, S.M.Bagshaw, M Antonelli, et al for the EUPHRATES Trials Investigators JAMA, 2018, 320(14):1455-1463

Comment

We all know endotoxin is a problem - it activates the inflammatory response, leads to systemic damage external to primary infection sites, and can be hard to turn off. 

We have tried to modify this and failed - monoclonal human and mouse antibody, recombinant bacterial permeability–increasing protein, phospholipid emulsion, antagonist of the TLR4 receptor.

We also know sepsis trials enrol heterogenous groups of patients, and possibly missed benefits in targeted subgroups.

So, what about removing endotoxin from the blood of critically ill patients with septic shock and documented high levels of endotoxin activity through selective adsorption using high-affinity polymyxin B hemoperfusion? 

The Italian EUPHAS trial reported improved hemodynamics associated with early polymyxin B HP in septic shock, while the French ABDOMIX trial reported no difference in 28-d mortality in patients with peritonitis and septic shock undergoing emergency surgery. 

Enter the EUPHRATES (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized Controlled trial of Adults Treated for Endotoxemia and Septic Shock) trial;

  • multicenter, randomized, clinical trial
  • 450 adults with septic shock (fluid, vasopressors, antibiotics, at least 1 organ dysfunction) and high circulating endotoxin activity (circulating level 0.60 or higher)
  • Intervention of polymyxin B hemoperfusion (2 treatments of 2-hours in 1st 24 hrs enrolment) vs sham hemoperfusion (basically set up through cut vascath bandaged to skin)
  • After interim analysis DSMB recommended restricting to patients with higher mortality risk, ie excluded patients with MODS of 9 or less.
  • At baseline patients were well matched
  • Primary outcome 28-day mortality did not significantly decrease 37.7% PBH vs 34.5% sham, RD 3.15; 95% CI,−5.73 to 12.04; RR 1.09; 95% CI, 0.85-1.39; P = .49.
  • Primary outcome restricted to MODS >9, 28-d mortality was 44.5% vs 43.9%, p=0.92.
  • There was no difference in endotoxin activity between baseline and day 203 between groups in all or MODS 

Polymyxin B hemoperfusion was not effective in reducing 28-d mortality in septic shock in patients with elevated endotoxin activity. Why did it fail? Perhaps it was applied for to short a duration and to late, perhaps it simply doesn’t reduce endotoxin at all, or enough. For now, it should not be applied as a therapy in this setting.

 

Abstract

Importance  Polymyxin B hemoperfusion reduces blood endotoxin levels in sepsis. Endotoxin activity can be measured in blood with a rapid assay. Treating patients with septic shock and elevated endotoxin activity using polymyxin B hemoperfusion may improve clinical outcomes.

Objective  To test whether adding polymyxin B hemoperfusion to conventional medical therapy improves survival compared with conventional therapy alone among patients with septic shock and high endotoxin activity.

Design, Setting, and Participants  Multicenter, randomized clinical trial involving 450 adult critically ill patients with septic shock and an endotoxin activity assay level of 0.60 or higher enrolled between September 2010 and June 2016 at 55 tertiary hospitals in North America. Last follow-up was June 2017.

Interventions  Two polymyxin B hemoperfusion treatments (90-120 minutes) plus standard therapy completed within 24 hours of enrollment (n = 224 patients) or sham hemoperfusion plus standard therapy (n = 226 patients).

Main Outcomes and Measures  The primary outcome was mortality at 28 days among all patients randomized (all participants) and among patients randomized with a multiple organ dysfunction score (MODS) of more than 9.

Results  Among 450 eligible enrolled patients (mean age, 59.8 years; 177 [39.3%] women; mean APACHE II score 29.4 [range, 0-71 with higher scores indicating greater severity), 449 (99.8%) completed the study. Polymyxin B hemoperfusion was not associated with a significant difference in mortality at 28 days among all participants (treatment group, 84 of 223 [37.7%] vs sham group 78 of 226 [34.5%]; risk difference [RD], 3.2%; 95% CI, −5.7% to 12.0%; relative risk [RR], 1.09; 95% CI, 0.85-1.39; P = .49) or in the population with a MODS of more than 9 (treatment group, 65 of 146 [44.5%] vs sham, 65 of 148 [43.9%]; RD, 0.6%; 95% CI, −10.8% to 11.9%; RR, 1.01; 95% CI, 0.78-1.31; P = .92). Overall, 264 serious adverse events were reported (65.1% treatment group vs 57.3% sham group). The most frequent serious adverse events were worsening of sepsis (10.8% treatment group vs 9.1% sham group) and worsening of septic shock (6.6% treatment group vs 7.7% sham group).

Conclusions and Relevance  Among patients with septic shock and high endotoxin activity, polymyxin B hemoperfusion treatment plus conventional medical therapy compared with sham treatment plus conventional medical therapy did not reduce mortality at 28 days.

October


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