Study Results

• A total of 30,731 patients (4,766 with PMX and 25,965 without) met the selection criteria and were included in the analysis. As a result of propensity score (PS) matching, 4,141 pairs of patients in each group were created.
• The survival rate at 28 days after the onset of shock was 77.9% in the PMX group and 71.1% in the control group, which was significantly higher in the PMX group (p＜0.0001).
• Noradrenaline-, CHDF-, and ventilator-free days at day 28 (median, interquartile range) were 24 (11-26) days in the PMX group and 22 (0-25) days in the control group (p＜0.0001), 24 (9-28) days in the PMX group and 22 (0-28) days in the control group (p＜0.0001), and 20 (1-28) days in the PMX group and 14 (0-28) days in the control group (p＜0.0001), respectively, all of which were significantly longer in the PMX group.
• The odds ratio of survival with and without PMX was examined in four subgroups stratified by the maximum noradrenaline dose per day. The survival rate of the PMX group was significantly higher in the three groups with doses of less than 20 mg/day, but there was no significant difference in the group with dose of 20 mg/day or higher.

• “Effects of Polymyxin B Hemoperfusion on Septic Shock Patients Requiring Noradrenaline: Analysis of a Nationwide Administrative Database in Japan.”
  Fujimori K et al. Blood Purif(Feb 12, 2021 online) PubMed

Multi-centered, double blind, randomized controlled study

• Control arm：standard medical care
• PMX arm：standard medical care plus 2 sessions of PMX hemoperfusion

Septic shock patients with age >= 18, who meets all of the following criteria

• Septic shock requiring vasopressor support
• At least 1 new onset organ dysfunction
• Endotoxemia (≥ 0.60 Endotoxin Activity Assay)
• Multiple Organ Dysfunction Score (MODS) > 9 (Criteria added after interim analysis)

• 450 patients met the inclusion criteria and randomized (ITT population). Among them, 294 patients were MODS > 9. 375 patients completed the planned two sessions of treatment (Per Protocol population). Among them, 245 were MODS > 9.
• Mortality at 28 day in ITT population was 37.7% for PMX arm and 34.5% for control arm.
• Mortality at 28 day in ITT population with MODS > 9 was 44.5% for PMX arm and 43.9% for control arm.
• Mortality at 28 day in Per Protocol population was 28.9% for PMX arm and 29.2% for control arm.
• Mortality at 28 day in Per Protocol population with MODS > 9 was 33.0% for PMX arm and 36.4% for control arm.
• Increase in mean arterial pressure (from baseline to 72h) was significantly higher in PMX arm compared to control arm (in ITT population, PMX arm:9.4mmHg vs control arm：4.1mmHg, p<0.005, in MODS>9 population, PMX arm:8.1mmHg vs control arm：3.9mmHg, p=0.02）. In addition, the ventilator free days in the patient group of MODS> 9 was significantly longer in PMX group (PMX arm: 12.7 days vs. sham arm: 9.8 days, p = 0.02).
• There were a total of 264 serious adverse events, with a frequency of 65.1% in the PMX arm and 57.3% in the control arm. Common serious adverse events were worsening of sepsis (PMX arm: 10.8% vs. control arm: 9.1%) and septic shock (PMX arm: 6.6% vs. control arm: 7.7%).
• As a result of subgroup analysis, a high effect of PMX was found in the group of 194 patients in the range of EAA value 0.6-0.89. In this group of patients, the mortality after 28 days was 26.8% for PMX arm and 36.8% for control arm. Logistic regression analysis adjusted with baseline mean arterial pressure and APACHE II score showed significant differences between groups.

• “The EUPHRATES trial (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock): study protocol for a randomized controlled trial.”
  Klein DJ et al. Trials (2016) 15:218 PubMed
• “Effect of Targeted Polymyxin B Hemoperfusion on 28-Day Mortality in Patients With Septic Shock and Elevated Endotoxin Level: The EUPHRATES Randomized Clinical Trial.”
  Dellinger RP et al. JAMA (2018) 320:1455-63 PubMed
• “Polymyxin B hemoperfusion in endotoxemic septic shock patients without extreme endotoxemia: a post hoc analysis of the EUPHRATES trial.”
  Klein DJ et al. Intensive Care Med (2018) 44:2205-12 PubMed

• Of 1,723 eligible patients, 522 had received PMX-HP. Propensity score matching created 262 matched pairs (i.e., 262 patients in each of the non-PMX-HP and PMX-HP groups).
• The proportion of all-cause hospital mortality was significantly lower in the PMX-HP group than in the non-PMX-HP group (32.8% vs. 41.2%; odds ratio (OR): 0.681; 95% confidence interval (CI): 0.470–0.987; P = 0.042).
• The number of ICUFD in the first 28 days was significantly higher in the PMX-HP group than in the non-PMX-HP group (18 (0-22) vs. 14 (0-22) days, respectively; P = 0.045).
• there was no significant difference in ICU mortality between the two groups (21.8% vs. 24.4%; OR:0.844; CI: 0.548–1.300; P = 0.443).

• “Potential survival benefit of polymyxin B hemoperfusion in patients with septic shock: a propensity-matched cohort study.”
  Nakamura Y et al. Crit Care (2017) 21:134 PubMed

• Data between 2010 and 2014 were analyzed. Registry is ongoing.
• 357 cases were registered from 57 centers (Europe: 46, Asia (India): 11).
• Of the 357 cases, 305 were septic shock. Main infection sites were the abdomen (44%) and the lungs (17.6%).
• Adverse events were recorded in 26 out of a total of 576 sessions, which includes tachycardia: 2, blood pressure reduction: 10, hemorrhage: 1, and column coagulation: 13. None of these adverse events caused clinical worsening or death of the patients.
• After 72 h from the first cycle of PMX-HP, SOFA score improved significantly (before treatment:12.4±4.2, 72h:10.5±5.3, P<0.001). Also, cardiovascular, respiratory and renal SOFA score significantly improved. Inotropic score and lactate levels decreased significantly. Coagulation SOFA significantly increased, reflecting the reduction of platelet counts.
• Overall 28-day survival rate was 54.5 %. Patients with abdominal infection treated with PMX-HP within 24 h from the diagnosis of septic shock had a 28-day survival rate of 64.5 %. Patients showing a significantly cardiovascular improvement after PMX-HP had a 28-survival rate of 75 % in comparison to the 39 % of patients who did not (p < 0.001).

• “Polymyxin‑B hemoperfusion in septic patients: analysis of a multicenter registry.” Cutuli SL et al. Ann Intensive Care (2016) 6:77 PubMed

• Of 3,759 eligible patients, 1,068 received PMX. Propensity-score matching produced a matched cohort of 978 pairs.
• The 28-day mortality was 40.2% (393/978) in the PMX group and 46.8% (458/978) in the control group (p = 0.003).
• Logistic regression analysis revealed a significant association between the use of PMX and decreased 28-day mortality　(adjusted OR 0.75; 95% CI 0.62–0.91).
• When differentiating the number of PMX sessions (1 or 2) incorporated in the multivariable logistic regression model, the adjusted OR of 28-day mortality was 0.83 (95% CI 0.67–1.02) for the one PMX session group and 0.64 (95% CI 0.49–0.83) for the 2 PMX session group as compared with the no PMX group.

• “Potential Survival Benefit of Polymyxin B Hemoperfusion in Septic Shock Patients on Continuous Renal Replacement Therapy: A Propensity-Matched Analysis.”
  Iwagami M et al. Blood Purif (2016) 42:9-17 PubMed

Multi-centered randomized, open-label study

• Control arm：standard medical care
• PMX arm：standard medical care plus 2 sessions of PMX hemoperfusion

A total of 938 patients were screened, and 243 were randomized. Eleven patients were excluded due to withdrawal of consent, and 119 patients in the PMX group and 113 patients in the control group were included in the final analysis.
The 28-day mortality rate was 33/119 (27.7%) in the PMX group and 22/113 (19.5%) in the control group, with no significant difference (p=0.14).
There was no difference between groups in secondary endpoints, including mortality at 3, 7, 14, and 90 days, as well as changes in SOFA score. The frequency of adverse events was also similar between the groups.

Of the 119 patients in the PMX group, 3 could not complete the first session, and 12 could not complete the second session. Of the 220 PMX treatments performed, 25 (11%) were incomplete, primarily due to circuit clotting. A total of 81/119 (69.8%) patients completed both PMX sessions.“

• “Early use of polymyxin B hemoperfusion in patients with septic shock due to peritonitis: a multicenter randomized control trial.”
  Payen DM et al. Intensive Care Med (2015) 41:975-84 PubMed

Several commentaries on the ABDO-MIX Study have highlighted issues to consider when interpreting the results:

1. The mortality rate in the control group was significantly lower than expected. As a result, the statistical power to detect a mortality difference between the groups was insufficient.".
2. Endotoxin levels were not measured during patient selection, and approximately one-quarter of patients did not have confirmed gram-negative bacterial infections. It is believed that some relatively less severe patients without high endotoxemia may have been included.
3. Among the 119 patients in the PMX group, 81 completed two sessions of therapy as per protocol, meaning about one-third of patients did not complete the treatment. Circuit clotting was the main reason for this, suggesting that the anticoagulation method may not have been optimal.
4. There was an imbalance in the PMX group, with a higher proportion of patients in whom fungi were detected, which may have been associated with poorer patient outcomes.

• "Balancing the "Humors" in Severe Sepsis: Still a Role for Extracorporeal Therapies?"
  Darmon M et al. Intensive Care Med (2015) 41:1132-4 PubMed
• “Polymyxin B Hemoperfusion in Sepsis: Growing Body of Evidence and Occasional Conflicting Results"
  Antonelli M and Ronco C Blood Purif (2015) 39:I-II PubMed
• “Polymyxin B Haemoperfusion in Septic Shock Patients"
  Shime N and MacLaren G Intensive Care Med (2015) 41:2033 PubMed
• “Polymyxin B Hemoperfusion in Septic Shock: Just Look at the Evidence!”
  Antonelli M et al. Intensive Care Med (2015) 41:1731-2 PubMed

Multi-centered randomized, open-label study

• Control arm：standard medical care
• PMX arm：standard medical care plus 2 sessions of PMX hemoperfusion

A total of 34 patients were enrolled in the PMX group, and 30 patients were enrolled in the standard care group.
At 72 hours, the PMX group showed an increase in the mean arterial pressure, a decrease in the Inotropic Score (vasopressor dose index), and an improvement in the PaO2/FiO2 ratio. These significant changes were not observed in the standard treatment group.
The 28-day mortality rate was 11/34 (32%) in the PMX group and 16/30 (53%) in the standard treatment group. The in-hospital mortality rate was 14/30 (41%) in the PMX group and 20/30 (67%) in the standard treatment group. A comparison of the change in the SOFA score from baseline to 72 hours revealed a significantly greater reduction in the PMX treatment group (p<0.001).

• “Early Use of Polymyxin B Hemoperfusion in Abdominal Septic Shock.”
  Cruz DN et al. JAMA (2009) 301:2445-52 PubMed

Regarding the EUPHAS Study, several commentaries have pointed out the following issues that should be considered when interpreting the results:

• Based on the recognition of the treatment‘s effectiveness, the trial was prematurely terminated by the decision of the ethics committee for ethical reasons. However, this decision resulted in the absence of a clear answer regarding the effect on survival improvement.
• The difference in mortality rates between the groups was not statistically significant at 28 days (53% vs. 32%), and the significant difference observed in the hazard ratio analysis should be interpreted as an extension of the time to death, rather than a definitive survival benefit.
• An imbalance was observed in the higher frequency of Gram-positive bacterial isolation in the PMX group.

• “International Differences in the Treatment of Sepsis: Are They Justified?”
  Kellum JA and Uchino S JAMA (2009) 301:2496-7 PubMed
• “Polymyxin B Hemoperfusion and Mortality in Abdominal Septic Shock”
  Amaral AC JAMA (2009) 302:1968-9 PubMed
• “Polymyxin B Hemoperfusion and Mortality in Abdominal Septic Shock”
  Vincent JL JAMA (2009) 302:1968 PubMed
• “Polymyxin B Hemoperfusion and Mortality in Abdominal Septic Shock”
  Kida Y JAMA (2009) 302:1969 PubMed
• “Polymyxin B Hemoperfusion and Mortality in Abdominal Septic Shock - Reply”
  Antonelli M et al. JAMA (2009) 302:1969-70