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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.

ABSTRACT: 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.

SUBMITTER: Rachoin JS

PROVIDER: S-EPMC7069594 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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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.

Rachoin Jean-Sebastien JS Foster Debra D Giese River R Weisberg Lawrence S LS Klein David J DJ

Critical care explorations 20200224 2

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.<h4>Design</h4>Post hoc analysis of a multicenter randomized controlled clinical trial.<h4>Setting</h4>Fifty-five tertiary hospitals in North America.< ...[more]

PMID: 32211615

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Project description:PurposeThe EUPHRATES trial examined the impact of polymyxin B hemoperfusion (PMX) on mortality in patients with septic shock and endotoxemia, defined as EAA ≥ 0.60. No difference was found in 28-day all-cause mortality. However, the trial showed that in some patients with septic shock the burden of endotoxin activity was extreme (EAA ≥ 0.9). In a post hoc analysis, we evaluated the impact of PMX use in patients with septic shock and endotoxin activity measured between 0.6-0.89.MethodsPost-hoc analysis of the EUPHRATES trial for the 194 patients with EAA ≥ 0.6-0.89 who completed two treatments (PMX or sham). The primary end point was mortality at 28 days adjusted for APACHE II score and baseline mean arterial pressure (MAP). Additional end points included changes in MAP, cumulative vasopressor index (CVI), median EAA reduction, ventilator-free days (VFD), dialysis-free days (DFD) and hospital length of stay. Subpopulations analyzed were site and type of infection and those with norepinephrine dose > 0.1 mcg/kg/min at baseline.ResultsAt 28 days, 23 patients of 88 (26.1%) in the PMX group died versus 39 of 106 (36.8%) in the sham group [risk difference 10.7%, OR 0.52, 95% CI (0.27, 0.99), P = 0.047]. When unadjusted for baseline variables, P = 0.11. The 28-day survival time in the PMX group was longer than for the sham group [HR 0.56 (95% CI 0.33, 0.95) P = 0.03]. PMX treatment compared with sham showed greater change in MAP [median (IQR) 8 mmHg (- 0.5, 19.5) vs. 4 mmHg (- 4.0, 11) P = 0.04] and VFD [median (IQR) 20 days (0.5, 23.5) vs. 6 days (0, 20), P = 0.004]. There were no significant differences in other end points. There was a significant difference in mortality in PMX-treated patients with no bacterial growth on culture [PMX, 6/30 (20%) vs. sham, 13/31 (41.9%), P = 0.005]. The median EAA change in the population was - 12.9% (range: increase 49.2%-reduction 86.3%). The mortality in the above median EAA change group was PMX: 6/38 (15.7%) vs. sham 15/49 (30.6%), P = 0.08.ConclusionsThese hypothesis-generating results, based on an exploratory post hoc analysis of the EUPHRATES trial, suggest measurable responses in patients with septic shock and an EAA ≥ 0.6 to 0.89 on changes in mean arterial pressure, ventilator-free days and mortality.Trial registrationClinicaltrials.gov Identifier: NCT01046669. Funding Spectral Medical Incorporated.

Project description:ImportancePolymyxin 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.ObjectiveTo 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 participantsMulticenter, 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.InterventionsTwo 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 measuresThe 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.ResultsAmong 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 relevanceAmong 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.Trial registrationClinicalTrials.gov Identifier: NCT01046669.

Project description:Severe sepsis and septic shock are common in intensive care and carry high mortality rates. In patients with Gram-negative infections, early and extensive removal of endotoxin may limit the inflammatory response that characterizes septic shock. The Alteco® LPS Adsorber (hereafter referred to cited as the lipopolysaccharide (LPS) Adsorber) can be used for endotoxin removal and attenuate the deleterious inflammatory and clinical responses seen in septic shock.The Abdominal Septic Shock - Endotoxin Adsorption Treatment (ASSET) trial is a pilot study investigating the feasibility and safety of LPS Adsorber therapy. This pilot, multicenter, stratified, parallel, double-blinded, randomized, phase IIa, feasibility clinical investigation will be performed in five Scandinavian intensive care units. Thirty-two subjects with early septic shock and organ failure, following adequate resuscitation, will be randomized to receive either: extracorporeal veno-venous hemoperfusion therapy with the LPS Adsorber or veno-venous hemoperfusion therapy with a placebo adsorber (without active LPS-binding peptide). Patients will be stratified by infection focus such that 20 subjects with an abdominal focus (stratum A) and 12 subjects with a urogenital focus (stratum B) will be included in a parallel design. Thereafter, an interim analysis will be performed and an additional 12 patients may be included in the study. The study is designed as adaptive a priori: the patients from this study can be included in a later phase IIb study. The aim of the study is to investigate the feasibility of LPS Adsorber therapy commenced early in the time-course of septic shock. The primary endpoint will be a characterization of all reported unanticipated serious adverse device effects and anticipated serious adverse device effects. Secondary outcomes are decrease in endotoxin plasma concentration, impact on clinical outcome measures and impact on inflammatory response by LPS Adsorber therapy, as well as detailed description of the relevant mediators bound to the LPS Adsorber. Recruitment of patients will start in September 2015.The ASSET trial will give insight into the feasibility and safety of this LPS Adsorber therapy and preliminary data on its potential clinical effects in septic shock. Moreover, this pilot trial will provide with necessary data for designing future studies.ClinicalTrials.gov Identifier NCT02335723 . Registered on 28 November 2014.

Project description:Septic shock-associated mortality in intensive care units (ICUs) remains high, with reported rates ranging 30-50%. In particular, Gram-negative bacilli (GNB), which induce significant inflammation and consequent multiple organ failure, are the etiological bacterial agent in 40% of severe sepsis cases. Hemoperfusion using polymyxin B-immobilized fiber (PMX), which adsorbs endotoxin, is expected to reduce the inflammatory sepsis cascade due to GNB. However, the clinical efficacy of this treatment has not yet been demonstrated. Here, we aimed to verify the efficacy of endotoxin adsorption therapy using PMX through a retrospective analysis of 413 patients who received broad spectrum antimicrobial treatment for GNB-related septic shock between January 2009 and December 2012 in 11 ICUs of Japanese tertiary hospitals. After aligning the patients' treatment time phases, we classified patients in two groups depending on whether PMX hemoperfusion (PMXHP) therapy was administered or not within 24 hours after ICU admission (PMXHP group: n = 134, conventional group: n = 279). The primary study endpoint was the mortality rate at 28 days after ICU admission. The mean age was 72.4 (standard deviation: 12.6) years, and the mean Sequential Organ Failure Assessment score at ICU admission was 9.9 (3.4). The infection sites included intra-abdominal (38.0%), pulmonary (18.9%), and urinary tract (32.2%), and two thirds of all patients had GNB-related bacteremia. Notably, the mortality at 28 days after ICU admission did not differ between the groups (PMXHP: 29.1% vs. conventional: 29.0%, P = 0.98), and PMXHP therapy was not found to improve this outcome in a Cox regression analysis (hazard ratio = 1.16; 95% confidence interval, 0.81-1.64, P = 0.407). We conclude that PMX-based endotoxin adsorption within 24 hours from ICU admission was not associated with mortality among patients with septic shock due to GNB.Trial registrationUniversity Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR ID: UMIN000012748).

Dataset Information

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.

Publications

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.

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