Polymyxin B hemoperfusion in endotoxemic septic shock patients without extreme endotoxemia: a post hoc analysis of the EUPHRATES trial

Abstract

Purpose: The 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.

Methods: Post-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.

Results: At 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.

Conclusions: These 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 registration: Clinicaltrials.gov Identifier: NCT01046669. Funding Spectral Medical Incorporated.

Keywords: Endotoxemia; Endotoxin; Hemoperfusion; Polymyxin B; Precision medicine; Sepsis; Septic shock.

Conflict of interest statement

Dr. Klein served as the medical monitor for the sponsor for the EUPHRATES trial and is a consultant to Spectral Medical. Dr. Walker and D. Foster are employees of Spectral Medical. H. Mekonnen is an employee of Amarex Clinical Research LLC, the contract research organization that ran the EUPHRATES trial.

Figures

Fig. 1

Consort diagram

Fig. 2

Time to death within 90 days for PMX versus sham. Kaplan-Meier estimates of the probability of survival to day 90 among 194 per-protocol patients with MODS > 9 and EAA between 0.6 and 0.89, by treatment groups. The 90-day results of Cox proportional hazards adjusted for baseline MAP and APACHE II score are the hazard ratio [0.57, 95% CI (0.35, 0.93), P value = 0.02]. The vertical line represents the 28-day interval. The 28-day adjusted Cox proportional hazard ratio for death in the PMX group compared with the sham group is 0.58 (95% CI, 0.35 to 0.98; P = 0.04). TRT treatment, 25th 25th percentile at 90 days