The effect of therapeutic plasma exchange on the inflammatory response in septic shock: a secondary analysis of the EXCHANGE-1 trial

Abstract

Background: Sepsis and septic shock, defined by a profound immune dysregulation, are among the leading causes of death in the intensive care unit (ICU). Despite advances in understanding the underlying pathophysiology, evidence for specific immunomodulatory treatment does not exist to date. Therapeutic plasma exchange (TPE) represents an adjunctive treatment approach to rebalance immune homeostasis. In the EXCHANGE-1 trial, we recently demonstrated a rapid hemodynamic improvement, possibly caused by the removal of harmful mediators and the replacement of protective plasma proteins. The aim of this secondary analysis is to further characterize the underlying immunomodulatory effects and to identify biomarkers that may predict treatment response.

Methods: This secondary analysis included patients in early septic shock (< 24 h duration) and a norepinephrine (NE) dose of ≥ 0.4 μg/kg/min. Patients were randomized 1:1 to receive standard of care (SOC) or SOC + one single TPE and plasma samples were collected before and after TPE. Within-group and between group effects of circulating levels of acute-phase proteins [CRP and Pentraxin3 (PTX3)], inflammatory mediators (IL-4, IL-6, IL-8, IL-10, TNF-α, IL-2Rα/CD25) and damage-associated molecular pattern (DAMP) [cell-free DNA (cfDNA)] were analyzed via paired t test or Wilcoxon signed-rank test and a mixed-effects model. Multivariate mixed-effects modeling of NE and lactate reduction was performed to investigate if cfDNA could be associated with treatment response to TPE.

Results: TPE led to a significant reduction in circulating acute-phase protein levels (CRP p = 0.00976, PTX3 p = 0.0001). Pro-inflammatory cytokines, such as circulating TNF-α-, IL-6- und IL-8-levels, were significantly reduced in both groups with no significant difference between treatment groups except for IL-2Rα/CD25 (p ≤ 0.0001). In a multivariate mixed-effects model, rising cfDNA levels over the first 6 h indicated refractoriness to SOC treatment regarding NE (p = 0.004) and lactate (p = 0.001), whereas those receiving TPE demonstrated sustained reductions in both parameters.

Conclusions: In this secondary analysis of the EXCHANGE-1 trial adjunctive TPE is associated with the reduction of acute-phase proteins and IL-2Rα/CD25, however not with the reduction of pro-inflammatory cytokines. This phenomenon could contribute to the observed enhancement in hemodynamics among patients with septic shock. Furthermore, TPE may be particularly beneficial for patients with septic shock who exhibit rising levels of cfDNA.

Keywords: Blood purification; Cell-free nucleic acids; Damage-associated molecular pattern molecules; Extracorporeal treatment; Fresh frozen plasma; Immune response; Plasmapheresis; Precision medicine; Sepsis.

Fig. 1

Flow chart of the study participants. Shown are screening, inclusion and randomization of patients. Inclusion criteria were early (< 24 h) and severe (noradrenaline (NE) dose ≥ 0.4 μg/kg/min despite adequate fluid resuscitation) septic shock. The study compared standard of care (SOC) with SOC + a single therapeutic plasma exchange (TPE) performed immediately after a 1:1 randomization

Fig. 2

Effect of therapeutic plasma exchange on CRP and PTX3 levels in early septic shock. Box and whisker plots of CRP (a) and PTX3 (b) serum concentrations at randomization and 6 h after in patients with septic shock who received either standard of care (SOC) alone or SOC in combination with therapeutic plasma exchange (TPE)

Fig. 3

Effect of therapeutic plasma exchange on inflammatory mediator levels in patients with septic shock. Box and whisker plots of proinflammatory cytokines TNF-α (a), IL-6 (b), IL-8 (c), anti-inflammatory cytokines IL-4 (d), IL-10 (e) and inflammatory mediator IL-2Rα/CD25 (f) serum concentrations at randomization and 6 h after in patients with septic shock who received either standard of care (SOC) alone or SOC in combination with therapeutic plasma exchange (TPE)

Fig. 4

Predicted NE dose and lactate level response to therapeutic plasma exchange stratified by cfDNA change. The overall predicted response of a NE and b lactate over time to TPE is presented. Furthermore, the mediating effect of cfDNA changes over the initial 6 h on c NE and d lactate response are presented. Estimated values were calculated using a triple interaction model with TPE/SOC and time, as well as all simple interactions terms between fixed effects. The model indicates that SOC patients with increasing delta cfDNA levels experienced diminishing NE dose and lactate level reductions over 24 h in contrast to patients under TPE which experienced sustained NE reductions across all levels of cfDNA (NE: p = 0.004, lactate: p = 0.001). The thresholds for cfDNA changes represent the mean ± one standard deviation. Solid lines represent predicted mean effects with their 95% confidence interval depicted as shaded area