Early therapeutic plasma exchange in septic shock: a prospective open-label nonrandomized pilot study focusing on safety, hemodynamics, vascular barrier function, and biologic markers

Abstract

Background: Given the pathophysiological key role of the host response to an infection rather than the infection per se, an ideal therapeutic strategy would also target this response. This study was designed to demonstrate safety and feasibility of early therapeutic plasma exchange (TPE) in severely ill individuals with septic shock.

Methods: This was a prospective single center, open-label, nonrandomized pilot study enrolling 20 patients with early septic shock (onset < 12 h) requiring high doses of norepinephrine (NE; > 0.4 μg/kg/min) out of 231 screened septic patients. Clinical and biochemical data were obtained before and after TPE. Plasma samples were taken for ex-vivo stimulation of human umbilical vein endothelial cells (HUVECs) to analyze barrier function (immunocytochemistry and transendothelial electrical resistance (TER)). Cytokines were measured by cytometric bead array (CBA) and enzyme-linked immunosorbent assays (ELISAs). An immediate response was defined as > 20% NE reduction from baseline to the end of TPE.

Results: TPE was well tolerated without the occurrence of any adverse events and was associated with a rapid reduction in NE (0.82 (0.61-1.17) vs. 0.56 (0.41-0.78) μg/kg/min, p = 0.002) to maintain mean arterial pressure (MAP) above 65 mmHg. The observed 28-day mortality was 65%. Key proinflammatory cytokines and permeability factors (e.g., interleukin (IL)-6, IL-1b, and angiopoietin-2) were significantly reduced after TPE, while the protective antipermeability factor angiopoietin-1 was not changed. Ex-vivo stimulation of HUVECs with plasma obtained before TPE induced substantial cellular hyperpermeability, which was completely abolished with plasma obtained after TPE.

Conclusions: Inclusion of early septic shock patients with high doses of vasopressors was feasible and TPE was safe. Rapid hemodynamic improvement and favorable changes in the cytokine profile in patients with septic shock were observed. It has yet to be determined whether early TPE also improves outcomes in this patient cohort. An appropriately powered multicenter randomized controlled trial is desirable.

Trial registration: Clinicaltrials.gov, NCT03065751 . Retrospectively registered on 28 February 2017.

Keywords: Blood purification; Endothelium; Extracorporeal treatment; Fresh frozen plasma; Plasmapheresis.

Conflict of interest statement

Ethics approval and consent to participate

The ethical committee of Hannover Medical School approved the protocol (no. 2786–2015), and written informed consent was obtained from participants or authorized representatives. The study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. This study was designed to prove feasibility of a planned multicenter RCT (clinicaltrials.gov NCT03065751).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Flow chart of study participants. NE norepinephrine, TPE therapeutic plasma exchange

Fig. 2

Hemodynamic improvements upon TPE. Box and whisker blots showing a the dose of norepinephrine (NE; μg/kg/min) immediately before the start of plasma exchange (pre) and after TPE (post) (p = 0.0002), and b the ratio of mean arterial pressure (MAP) over NE dose (p < 0.0001). c Peri-interventional (−60 to +105 min) longitudinal course of NE doses over the therapeutic plasma exchange (TPE) procedure assessed every 15 min (**p < 0.001, ***p < 0.0001, compared with time-point 0 highlighted in black). d Box and whisker blot of stroke volume variance (SVV) as a dynamic preload surrogate. Grey area highlights the reference range for healthy individuals (p = 0.008). e Box and whisker blot for fluid requirements 6 h before (pre) plasma exchange and 6 h after (post) TPE (p = 0.007)

Fig. 3

Twenty-eight-day survival. Kaplan Meier graphs showing the 28-day survival course in a the overall cohort showing an observed mortality of 65%, b immediate responders (n = 10) and nonresponders (n = 10) to plasma exchange (defined as norepinephrine reduction of > 20%), as well as c sustained responders (n = 7) and nonresponders (n = 13) to plasma exchange (defined as any reduction in SOFA score within 48 h following plasma exchange). HR hazard ratio

Fig. 4

Ex-vivo effect of plasma obtained from patients with septic shock on endothelial morphology and function. a HUVECs were incubated for 30 min with patients plasma obtained immediately before (left panel) and after (right panel) therapeutic plasma exchange (TPE) ex vivo. Immunofluorescent cytochemistry for the cell-cell contact protein VE-cadherin (green) and the cytoskeletal component f-actin (red) show severe alterations of the endothelial architecture and the formation of paracellular gaps (i.e., the cellular correlate of the clinical capillary leakage syndrome). Incubation of HUVECs with the same patients plasma obtained after TPE did not induce these changes any more. This assay was performed with plasma from all patients. Shown are images from a representative patient. b Transendothelial electrical resistance (TER), a highly quantitative method to assess permeability in real time in vitro, revealed that 60% (12/20) of patients plasma did induce a severe drop in resistance (grey dots). The same patients plasma after TPE did not induce permeability any more (white bars). c 40% (8/20) of patients did not show any response to therapeutic TPE with regard to TER before and after the procedure