Clinical and biochemical endpoints and predictors of response to plasma exchange in septic shock: results from a randomized controlled trial

Abstract

Background: Recently, a randomized controlled trial (RCT) demonstrated rapid but individually variable hemodynamic improvement with therapeutic plasma exchange (TPE) in patients with septic shock. Prediction of clinical efficacy in specific sepsis treatments is fundamental for individualized sepsis therapy.

Methods: In the original RCT, patients with septic shock of < 24 h duration and norepinephrine (NE) requirement ≥ 0.4 μg/kg/min received standard of care (SOC) or SOC + one single TPE. Here, we report all clinical and biological endpoints of this study. Multivariate mixed-effects modeling of NE reduction was performed to investigate characteristics that could be associated with clinical response to TPE.

Results: A continuous effect of TPE on the reduction in NE doses over the initial 24 h was observed (SOC group: estimated NE dose reduction of 0.005 µg/kg/min per hour; TPE group: 0.018 µg/kg/min per hour, p = 0.004). Similarly, under TPE, serum lactate levels, continuously decreased over the initial 24 h in the TPE group, whereas lactate levels increased under SOC (p = 0.001). A reduction in biomarkers and disease mediators (such as PCT (p = 0.037), vWF:Ag (p < 0.001), Angpt-2 (p = 0.009), sTie-2 (p = 0.005)) along with a repletion of exhausted protective factors (such as AT-III (p = 0.026), Protein C (p = 0.012), ADAMTS-13 (p = 0.008)) could be observed in the TPE but not in the SOC group. In a multivariate mixed effects model, increasing baseline lactate levels led to greater NE dose reduction effects with TPE as opposed to SOC (p = 0.004).

Conclusions: Adjunctive TPE is associated with the removal of injurious mediators and repletion of consumed protective factors altogether leading to preserved hemodynamic stabilization in refractory septic shock. We identified that baseline lactate concentration as a potential response predictor might guide future designing of large RCTs that will further evaluate TPE with regard to hard endpoints. Trial registration Retrospectively registered 18th January 2020 at clinicaltrials.gov (Identifier: NCT04231994 ).

Keywords: Blood purification; Endothelium; Extracorporeal treatment[; Fresh frozen plasma; Personalized medicine; Plasmapheresis; Precision medicine; Sepsis.

Fig. 1

Flowchart of study participants. Shown are screening, enrollment and randomization of patients. Inclusion criteria were early (< 24 h) and severe (norepinephrine (NE) dose ≥ 0.4 μg/kg/min despite adequate fluid resuscitation) septic shock. The study compared standard of care (SOC) to SOC + a singular therapeutic plasma exchange (TPE), performed immediately following 1:1 envelope-based randomization

Fig. 2

Secondary biochemical endpoints. Box and whisker blots showing A Procalcitonin (PCT), B Antithrombin-III (AT-III), C Protein C, D A disintegrin and metalloprotease with thrombospondin-1-like domains 13 (ADAMTS13), E von Willebrand factor antigen (vWF:Ag), F vWF:Ag/ADAMTS13 ratio, G Angiopoietin-2 (Angpt-2), H soluble receptor of tyrosine kinase with immunoglobulin-like and EGF-like domains (sTie-2) for patients receiving standard of care (SOC) treatment as well as patients receiving additive therapeutic plasma exchange (TPE). Compared are results both at randomization and 6 h after randomization and between-group differences

Fig. 3

Modulation of TPE effect on norepinephrine dose and lactate concentrations. Shown are both observed A, C and estimated B, D norepinephrine doses (NE) as well as lactate concentrations for the standard of care (SOC) and therapeutic plasma exchange (TPE) group during the first 24 h since randomization. Estimated values were calculated using a linear mixed-effects model. The models indicated a continuous effect of TPE on the reduction in NE doses (p = 0.004) and lactate concentrations (p = 0.001) over the initial 24 h

Fig. 4

Prediction of effect of TPE on norepinephrine dose by baseline lactate concentration. Shown are estimated norepinephrine (NE) doses for both the standard of care (SOC) and therapeutic plasma exchange (TPE) group stratified by different lactate concentrations at randomization. Estimated values were calculated using a triple interaction model with TPE/ SOC and time, as well as all simple interaction terms between fixed effects. The model indicated that patients with increasing baseline lactate levels experienced diminishing NE dose reductions over 24 h when under SOC, in contrast to patients under TPE which experienced sustained NE reductions across all levels of lactate (p = 0.004). At baseline lactate concentrations of 2 mmol/l, both groups showed a reduction in NE (left panel). Above 4.5 mmol/l, patients under SOC experienced no NE dose reduction, whereas NE reduction in the TPE group remained conserved (middle panel). Above 7 mmol/l, patients in the SOC group showed increasing NE doses over time, while NE reduction was conserved in the TPE group (right panel). The thresholds for baseline lactate concentration employed were chosen post hoc in order to best illustrate the continuous effect of lactate within the model