Dataset Information

Effect of therapeutic plasma exchange on endothelial activation and coagulation-related parameters in septic shock.

ABSTRACT: BACKGROUND:A dysbalanced coagulation system is part of the pathological host response to infection in sepsis. Activation of pro-coagulant pathways and attenuation of anti-coagulant activity ultimately lead to microvascular stasis and consequent organ failure. No treatment approaches specifically targeting this axis are available. We explored the effects of therapeutic plasma exchange (TPE) on microvascular coagulation dysbalance in septic shock. METHODS:We conducted a prospective single-center study enrolling 31 patients with early septic shock (onset ?0.4??g/kg/min). Clinical and biochemical data, including measurement of protein C; a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS13); and von Willebrand factor antigen (vWF:Ag), were obtained before and after TPE against fresh frozen plasma. RESULTS:Antithrombotic acting proteins such as antithrombin-III (ATIII) and protein C were markedly reduced in septic patients, but their activity increased after TPE (ATIII, 51% (41-61) vs. 63% (48-70), p?=?0.029; protein C, 47% (38-60) vs. 62% (54-69), p?=?0.029). Median ADAMTS13 activity was increased by TPE from 27 (21-42) % before to 47 (38-62) % after TPE (p?

SUBMITTER: Stahl K

PROVIDER: S-EPMC7053051 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effect of therapeutic plasma exchange on endothelial activation and coagulation-related parameters in septic shock.

Stahl Klaus K Schmidt Julius J JJ Seeliger Benjamin B Schmidt Bernhard M W BMW Welte Tobias T Haller Hermann H Hoeper Marius M MM Budde Ulrich U Bode Christian C David Sascha S

Critical care (London, England) 20200302 1

<h4>Background</h4>A dysbalanced coagulation system is part of the pathological host response to infection in sepsis. Activation of pro-coagulant pathways and attenuation of anti-coagulant activity ultimately lead to microvascular stasis and consequent organ failure. No treatment approaches specifically targeting this axis are available. We explored the effects of therapeutic plasma exchange (TPE) on microvascular coagulation dysbalance in septic shock.<h4>Methods</h4>We conducted a prospective ...[more]

PMID: 32122366

Similar Datasets

Project description:BackgroundDisruption of the endothelial glycocalyx (eGC) is observed in septic patients and its injury is associated with multiple-organ failure and inferior outcomes. Besides this biomarker function, increased blood concentrations of shedded eGC constituents might play a mechanistic role in septic organ failure. We hypothesized that therapeutic plasma exchange (TPE) using fresh frozen plasma might influence eGC-related pathology by removing injurious mediators of eGC breakdown while at the time replacing eGC protective factors.MethodsWe enrolled 20 norepinephrine-dependent (NE > 0.4 μg/kg/min) patients with early septic shock (onset < 12 h). Sublingual assessment of the eGC via sublingual sidestream darkfield (SDF) imaging was performed. Plasma eGC degradation products, such as heparan sulfate (HS) and the eGC-regulating enzymes, heparanase (Hpa)-1 and Hpa-2, were obtained before and after TPE. A 3D microfluidic flow assay was performed to examine the effect of TPE on eGC ex vivo. Results were compared to healthy controls.ResultsSDF demonstrated a decrease in eGC thickness in septic patients compared to healthy individuals (p = 0.001). Circulating HS levels were increased more than sixfold compared to controls and decreased significantly following TPE [controls: 16.9 (8-18.6) vs. septic patients before TPE: 105.8 (30.8-143.4) μg/ml, p < 0.001; vs. after TPE: 70.7 (36.9-109.5) μg/ml, p < 0.001]. The Hpa-2 /Hpa-1 ratio was reduced in septic patients before TPE but normalized after TPE [controls: 13.6 (6.2-21.2) vs. septic patients at inclusion: 2.9 (2.1-5.7), p = 0.001; vs. septic patients after TPE: 13.2 (11.2-31.8), p < 0.001]. Ex vivo stimulation of endothelial cells with serum from a septic patient induced eGC damage that could be attenuated with serum from the same patient following TPE.ConclusionsSeptic shock results in profound degradation of the eGC and an acquired deficiency of the protective regulator Hpa-2. TPE removed potentially injurious eGC degradation products and partially attenuated Hpa-2 deficiency. Trial registration clinicaltrials.gov NCT04231994, retrospectively registered 18 January 2020.

Project description:BackgroundGiven 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.MethodsThis 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.ResultsTPE 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.ConclusionsInclusion 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 registrationClinicaltrials.gov, NCT03065751 . Retrospectively registered on 28 February 2017.

Project description:BackgroundThere is no gold standard to diagnose septic shock-induced disseminated intravascular coagulation (DIC). The objective of our multicenter prospective study was to assess the performances of the different major scoring systems in terms of mortality prediction and DIC diagnosis. The JAAM-DIC 2016 score, the ISTH overt-DIC 2001 score, the associations of sepsis-induced coagulopathy (SIC) score with JAAM-DIC 2016 or ISTH overt-DIC scores were tested in patients within 12 h of their admission in ICU for septic shock (day 1) and at day 2.Results582 patients were enrolled in the study. 182/567 (32.1%) were diagnosed with DIC according to ISTH overt-DIC score, and 193/561 (34.4%) according to JAAM-DIC score; 486/577 patients (84.2%) were diagnosed with a coagulopathy according to SIC score. A moderate concordance was observed between ISTH overt-DIC and JAAM-DIC [κ = 0.67 (0.60, 0.73), p < 0.001]. The delay of positivity of the scores for early DIC patients was not different between JAAM-DIC and ISTH overt-DIC scores. Although it was positive earlier, SIC score had worse diagnosis specificity, as 84.2% of the patients with septic shock were diagnosed with "coagulopathy". The specificity of SIC score alone to predict mortality was very low [0.18 (0.15; 0.22)], compared to the ones of JAAM-DIC score [0.71 (0.67; 0.75)], and of ISTH overt-DIC score [0.76 (0.72; 0.80)], p < 0.001. The sensitivity of SIC score to predict mortality was 0.95 [0.89; 0.98], and the ones of JAAM-DIC score and ISTH overt-DIC score were 0.61 [0.50; 0.70] and 0.68 [0.58; 0.77], respectively. There was no benefit in sensitivity and specificity in combining SIC score to JAAM-DIC score or to ISTH overt-DIC score, compared to JAAM-DIC score or ISTH overt-DIC score alone.ConclusionsOur data suggest that the added value of SIC score alone or combined with other scores is limited, and that both JAAM-DIC score and ISTH overt-DIC score can be used in septic shock patients. Trial registration clinicaltrial; Trial registration number: NCT02391792; Date of registration: 18/03/2015; URL of trial registry record: https://clinicaltrials.gov/ct2/show/NCT02391792?term=meziani&draw=4&rank=1.

Project description:BackgroundRecently, 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.MethodsIn 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.ResultsA 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).ConclusionsAdjunctive 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 ).

Project description:IntroductionICU-acquired muscle weakness commonly occurs in patients with septic shock and is associated with poor outcome. Although atrophy is known to be involved, it is unclear whether ligands in plasma from these patients are responsible for initiating degradation of muscle proteins. The aim of the present study was to investigate if plasma from septic shock patients induces skeletal muscle atrophy and to examine the time course of plasma-induced muscle atrophy during ICU stay.MethodsPlasma was derived from septic shock patients within 24 hours after hospital admission (n = 21) and healthy controls (n = 12). From nine patients with septic shock plasma was additionally derived at two, five and seven days after ICU admission. These plasma samples were added to skeletal myotubes, cultured from murine myoblasts. After incubation for 24 hours, myotubes were harvested and analyzed on myosin content, mRNA expression of E3-ligase and Nuclear Factor Kappa B (NF?B) activity. Plasma samples were analyzed on cytokine concentrations.ResultsMyosin content was approximately 25% lower in myotubes exposed to plasma from septic shock patients than in myotubes exposed to plasma from controls (P < 0.01). Furthermore, patient plasma increased expression of E3-ligases Muscle RING Finger protein-1 (MuRF-1) and Muscle Atrophy F-box protein (MAFbx) (P < 0.01), enhanced NF?B activity (P < 0.05) and elevated levels of ubiquitinated myosin in myotubes. Myosin loss was significantly associated with elevated plasma levels of interleukin (IL)-6 in septic shock patients (P < 0.001). Addition of antiIL-6 to septic shock plasma diminished the loss of myosin in exposed myotubes by approximately 25% (P < 0.05). Patient plasma obtained later during ICU stay did not significantly reduce myosin content compared to controls.ConclusionsPlasma from patients with septic shock induces loss of myosin and activates key regulators of proteolysis in skeletal myotubes. IL-6 is an important player in sepsis-induced muscle atrophy in this model. The potential to induce atrophy is strongest in plasma obtained during the early phase of human sepsis.

Dataset Information

Effect of therapeutic plasma exchange on endothelial activation and coagulation-related parameters in septic shock.

Publications

Effect of therapeutic plasma exchange on endothelial activation and coagulation-related parameters in septic shock.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets