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Background The CytoSorb hemoadsorption device has been demonstrated to be capable of clearing inflammatory cytokines, but has not yet been shown to attenuate plasma cytokine concentrations. We investigated the effects of CytoSorb hemoperfusion on plasma levels of various cytokines using the repeated human experimental endotoxemia model, a highly standardized and reproducible human in vivo model of systemic inflammation and immunological tolerance induced by administration of bacterial lipopolysaccharide (LPS). Methods Twenty-four healthy male volunteers (age 18–35) were intravenously challenged with LPS (a bolus of 1 ng/kg followed by continuous infusion of 0.5 ng/kg/hr for three hours) twice: on day 0 to quantify the initial cytokine response and on day 7 to quantify the degree of endotoxin tolerance. Subjects either received CytoSorb hemoperfusion during the first LPS challenge (CytoSorb group), or no intervention (control group). Plasma cytokine concentrations and clearance rates were determined serially. This study was registered at ClinicalTrials.gov (NCT04643639, date of registration November 24th 2020). Results LPS administration led to a profound increase in plasma cytokine concentrations during both LPS challenge days. Compared to the control group, significantly lower plasma levels of tumor necrosis factor (TNF, − 58%, p  < 0.0001), interleukin (IL)-6 ( − 71%, p  = 0.003), IL-8 ( − 48%, p  = 0.02) and IL-10 ( − 26%, p  = 0.03) were observed in the CytoSorb group during the first LPS challenge. No differences in cytokine responses were observed during the second LPS challenge. Conclusions CytoSorb hemoperfusion effectively attenuates circulating cytokine concentrations during systemic inflammation in humans in vivo, whereas it does not affect long-term immune function. Therefore, CytoSorb therapy may be of benefit in conditions characterized by excessive cytokine release.

Background Rhabdomyolysis is frequently occurring in critically ill patients, resulting in a high risk of acute kidney injury (AKI) and potentially permanent kidney damage due to increased myoglobin levels. The extracorporeal elimination of myoglobin might be an approach to prevent AKI, but its molecular weight of 17 kDa complicates an elimination with conventional dialysis membranes. Question of interest is, if myoglobin can be successfully eliminated with the cytokine adsorber Cytosorb® (CS) integrated in a high-flux dialysis system. Methods Patients were included between 10/2014 and 05/2020 in the study population if they had an anuric renal failure with the need of renal replacement therapy, if CS therapy was longer than 90 min and if myoglobin level was > 5.000 ng/ml before treatment. The measurement times of the laboratory values were: d-1 = 24–36 h before CS, d0 = shortly before starting CS and d1 = 12–24 h after starting CS treatment. Statistical analysis were performed with Spearman’s correlation coefficient, Wilcoxon test with associated samples and linear regression analysis. Results Forty-three patients were included in the evaluation (median age: 56 years, 77% male patients, 32.6% ECMO therapy, median SAPS II: 80 points and in-hospital mortality: 67%). There was a significant equilateral correlation between creatine kinase (CK) and myoglobin at all measurement points. Furthermore, there was a significant reduction of myoglobin ( p  = 0.03, 95% confidence interval (CI): − 9030, − 908 ng/ml) during CS treatment, with a median relative reduction of 29%. A higher median reduction of 38% was seen in patients without ongoing rhabdomyolysis (CK decreased during CS treatment, n  = 21). In contrast, myoglobin levels did not relevantly change in patients with increasing CK and therefore ongoing rhabdomyolysis ( n  = 22, median relative reduction 4%). Moreover, there was no significant difference in myoglobin elimination in patients with and without ECMO therapy. Conclusion Blood purification with Cytosorb® during high-flux dialysis led to a significant reduction of myoglobin in patients with severe rhabdomyolysis. The effect might be obscured by sustained rhabdomyolysis, which was seen in patients with rising CK during treatment. Prospective clinical trials would be useful in investigating its benefits in avoiding permanent kidney damage.

Background Septic shock, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, is a highly lethal condition that causes substantial morbidity and mortality among critically ill patients. One of the hallmarks of sepsis is the excessive release of cytokines and other inflammatory mediators causing refractory hypotension, tissue damage, metabolic acidosis and ultimately multiple organ failure. In this context, cytokine reduction by hemoadsorption represents a new concept for blood purification, developed to attenuate the overwhelming systemic levels of pro-inflammatory and anti-inflammatory mediators released in the early phase of sepsis. Methods In the present case series, we evaluated the impact of a new hemoadsorption device (CytoSorb) used as adjunctive therapy, on hemodynamics and clinically relevant outcome parameters in 26 critically ill patients with septic shock and in need of renal replacement therapy. Results We found that treatment of these patients with septic shock was associated with hemodynamic stabilization and a reduction in blood lactate levels. Actual mortality in the overall patient population was lower than mortality predicted by acute physiology and chronic health evaluation II (APACHE II). These effects seem to be more pronounced in patients in whom therapy started within 24 h of sepsis diagnosis, whereas a delay in the start of therapy was associated with a poor response to therapy in terms of reduction of catecholamine demand and survival. Moreover, from our patient population, medical patients seemed to benefit more than post-surgical patients in terms of survival. Treatment using the CytoSorb device was safe and well-tolerated with no device-related adverse events during or after the treatment sessions. Conclusion Hemoadsorption using CytoSorb resulted in rapid hemodynamic stabilization and increased survival, particularly in patients in whom therapy was started early. Given the positive clinical experience of this case series, randomized controlled trials are urgently needed to define the potential benefits of this new treatment option.

Background and aims Innovative treatment modalities have not yet shown a clinical benefit in patients with septic shock. To reduce severe cytokinaemia, CytoSorb as an add-on to continuous renal replacement therapy (CRRT) showed promising results in case reports. However, there are no clinical trials investigating outcomes. Methods In this investigator-initiated retrospective study, patients with septic shock were treated with CRRT + CytoSorb ( n  = 67) or CRRT alone ( n  = 49). The primary outcome was the 28-day all-cause mortality rate. Patients were weighted by stabilized inverse probability of treatment weights (sIPTW) to overcome differences in baseline characteristics. Results At the start of therapy, CytoSorb-treated patients had higher lactate levels ( p  < 0.001), lower mean arterial pressure ( p  = 0.007) and higher levels of noradrenaline ( p  < 0.001) compared to the CRRT group. For CytoSorb, the mean predicted mortality rate based on a SOFA of 13.8 ( n  = 67) was 75% (95%CI 71–79%), while the actual 28-day mortality rate was 48% (mean difference − 27%, 95%CI − 38 to − 15%, p  < 0.001). For CRRT, based on a SOFA of 12.8 ( n  = 49), the mean predicted versus observed mortality was 68% versus 51% (mean difference − 16.9% [95%CI − 32.6 to − 1.2%, p  = 0.035]). By sIPTW analysis, patients treated with CytoSorb had a significantly lower 28-day mortality rate compared to CRRT alone (53% vs. 72%, respectively, p  = 0.038). Independent predictors of 28-day mortality in the CytoSorb group were the presence of pneumosepsis (adjusted odds ratio [aOR] 5.47, p  = 0.029), higher levels of lactate at the start of CytoSorb (aOR 1.15, p  = 0.031) and older age (aOR per 10 years 1.67, p  = 0.034). Conclusions CytoSorb was associated with a decreased observed versus expected 28-day all-cause mortality. By IPTW analysis, intervention with CytoSorb may be associated with a decreased all-cause mortality at 28 days compared to CRRT alone.

The aim of this proof of concept, prospective, randomized pilot trial was to investigate the effects of extracorporeal cytokine removal (CytoSorb®) applied as a standalone treatment in patients with septic shock. 20 patients with early (<24 h) onset of septic shock of medical origin, on mechanical ventilation, norepinephrine>10 μg/min, procalcitonin (PCT) > 3 ng/mL without the need for renal replacement therapy were randomized into CytoSorb (n = 10) and Control groups (n = 10). CytoSorb therapy lasted for 24 h. Clinical and laboratory data were recorded at baseline (T0), T12, T24, and T48 hours. Overall SOFA scores did not differ between the groups. In the CytoSorb-group norepinephrine requirements and PCT concentration decreased significantly (norepinephrine: CytoSorb: T0 = 0.54[IQR:0.20–1.22], T48 = 0.16[IQR:0.07–0.48], p = .016; Controls: T0 = 0.43[IQR:0.19–0.64], T48 = 0.25[IQR:0.08–0.65] μg/kg/min; PCT: CytoSorb: T0 median = 20.6[IQR: 6.5–144.5], T48 = 5.6[1.9–54.4], p = .004; Control: T0 = 13.2[7.6–47.8], T48 = 9.2[3.8–44.2]ng/mL). Big-endothelin-1 concentrations were also significantly lower in the CytoSorb group (CytoSorb: T0 = 1.3 ± 0.6, *T24 = 1.0 ± 0.4, T48 = 1.4 ± 0.8, *p = .003; Control: T0 = 1.1 ± 0.7, T24 = 1.1 ± 0.6, T48 = 1.2 ± 0.6 pmol/L, p = .115). There were no CytoSorb therapy-related adverse events. This is the first trial to investigate the effects of early extracorporeal cytokine adsorption treatment in septic shock applied without renal replacement therapy. It was found to be safe with significant effects on norepinephrine requirements, PCT and Big-endothelin-1 concentrations compared to controls. Trial registration: The study has been registered on ClinicalTrials.gov, under the registration number of NCT02288975, registered 13 November 2014. •First randomized trial on one single 24-hour period of standalone CytoSorb treatment•Medical patients with septic shock were randomized (CytoSorb treated or control)•Patients were treated for 24 h with CytoSorb in addition to standard treatment•Significant reduction (70%) in norepinephrine requirement, PCT and Big Endothelin-1

Severe rhabdomyolysis frequently results in acute kidney injury (AKI) due to myoglobin accumulation with the need of kidney replacement therapy (KRT). The present study investigated whether the application of Cytosorb® (CS) led to an increased rate of kidney recovery in patients with KRT due to severe rhabdomyolysis. Adult patients with a myoglobin-concentration >10,000 ng/ml and KRT were included from 2014 to 2021. Exclusion criteria were chronic kidney disease and CS-treatment before study inclusion. Groups 1 and 2 were defined as KRT with and without CS, respectively. The primary outcome parameter was independence from KRT after 30 days. Propensity score (PS) matching was performed (predictors: myoglobin, SAPS-II, and age), and the chi2-test was used. 35 pairings could be matched (mean age: 57 vs. 56 years; mean myoglobin: 27,218 vs. 26,872 ng/ml; mean SAPS-II: 77 vs. 76). The probability of kidney recovery was significantly (p = .04) higher in group 1 (31.4 vs. 11.4%, mean difference: 20.0%, odds ratio (OR): 3.6). Considering patients who survived 30 days, kidney recovery was also significantly (p = .03) higher in patients treated with CS (61.1 vs. 23.5%, mean difference: 37.6%, OR: 5.1). In conclusion, the use of CS might positively affect renal recovery in patients with severe rhabdomyolysis. A prospective randomized controlled trial is needed to confirm this hypothesis.

Hemoadsorption with CytoSorb® offers a possible therapeutic approach in septic shock, but modes of application and dosing are still undetermined. Data from surgical patients with septic shock, treated with hemoadsorption adjunctive to renal replacement therapy were analyzed retrospectively. The 28-day mortality was compared to predicted mortality. In 70 patients (70.6 ± 13.3 years), hemoadsorption was applied for 85.6 ± 53.8 h. The APACHE ll (30.2 ± 6.3) calculated to a predicted mortality of 73.3%, while the observed mortality was significantly lower (50%, p < 0.05). The amount of blood purified was higher in survivors than in non-survivors (8.5 ± 4.4 vs. 6.1 ± 3.6 l/kgBW, p = 0.017). We identified three clusters of <6 l/kgBW, 6-13 l/kgBW and ≥ 13 l/kgBW with a linear dose-response relation between blood purification volume and survival, which was best in the highest volume cluster (83.3%; p = 0.045). The application of CytoSorb® seems to be effective in various conditions of septic shock. In a cohort of most severely ill patients the observed mortality was lower than predicted and decreased linearly with blood purification volumes inadvertently exceeding 6 l/kg BW. These results suggest that hemoadsorption might improve survival provided that the applied dose is high enough. [Display omitted] •Excessive cytokine overshoot contributes to mortality in septic shock and severe inflammatory response syndrome•Hemoadsorption with Cytosorb is a new treatment targeting the cytokine storm•The effects of hemoadsorption on mortality are related to the applied dose•The amount of blood purified ≥13 l/kg was associated with better outcome•Hemoadsorption may improve survival provided that the applied dose is high enough

Background Cardiopulmonary bypass (CPB) is often associated with degrees of complex inflammatory response mediated by various cytokines. This response can, in severe cases, lead to systemic hypotension and organ dysfunction. Cytokine removal might therefore improve outcomes of patients undergoing cardiac surgery. CytoSorb® (Cytosorbents, NJ, USA) is a recent device designed to remove cytokine from the blood using haemoadsorption (HA). This trial aims to evaluate the potential of CytoSorb® to decrease peri-operative cytokine levels in cardiac surgery. Methods We have conducted a single-centre pilot randomized controlled trial in 30 patients undergoing elective cardiac surgery and deemed at risk of complications. Patients were randomly allocated to either standard of care ( n  = 15) or CytoSorb® HA ( n  = 15) during cardiopulmonary bypass (CPB). Our primary outcome was the difference between the two groups in cytokines levels (IL-1a, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-10, TNF-α, IFN-γ, MCP-1) measured at anaesthesia induction, at the end of CPB, as well as 6 and 24 h post-CPB initiation. In a consecutive subgroup of patients (10 in HA group, 11 in control group), we performed cross-adsorber as well as serial measurements of coagulation factors’ activity (antithrombin, von Willebrand factor, factor II, V, VIII, IX, XI, and XII). Results Both groups were similar in terms of baseline and peri-operative characteristics. CytoSorb® HA during CPB was not associated with an increased incidence of adverse event. The procedure did not result in significant coagulation factors’ adsorption but only some signs of coagulation activation. However, the intervention was associated neither with a decrease in pro- or anti-inflammatory cytokine levels nor with any improvement in relevant clinical outcomes. Conclusions CytoSorb® HA during CPB was not associated with a decrease in pro- or anti-inflammatory cytokines nor with an improvement in relevant clinical outcomes. The procedure was feasible and safe. Further studies should evaluate the efficacy of CytoSorb® HA in other clinical contexts. Trial registration ClinicalTrials.gov NCT02775123 . Registered 17 May 2016.

Background Cardiopulmonary bypass (CPB) surgery initiates a systemic inflammatory response, which is associated with postoperative morbidity and mortality. Hemoadsorption (HA) of cytokines may suppress inflammatory responses and improve outcomes. We tested a new sorbent used for HA (CytoSorb™; CytoSorbents Europe GmbH, Berlin, Germany) installed in the CPB circuit on changes of pro- and anti-inflammatory cytokines levels, inflammation markers, and differences in patients’ perioperative course. Methods In this first pilot trial, 37 blinded patients were undergoing elective CPB surgery at the Medical University of Vienna and were randomly assigned to HA (n = 19) or control group (n = 18). The primary outcome was differences of cytokine levels (IL-1β, IL-6, IL-18, TNF-α, and IL-10) within the first five postoperative days. We also analyzed whether we can observe any differences in ex vivo lipopolysaccharide (LPS)-induced TNF-α production, a reduction of high-mobility box group 1 (HMGB1), or other inflammatory markers. Additionally, measurements for fluid components, blood products, catecholamine treatment, bioelectrical impedance analysis (BIA), and 30-day mortality were analyzed. Results We did not find differences in our primary outcome immediately following the HA treatment, although we observed differences for IL-10 24 hours after CPB (HA: median 0.3, interquartile range (IQR) 0–4.5; control: not traceable, P  = 0.0347) and 48 hours after CPB (median 0, IQR 0–1.2 versus not traceable, P  = 0.0185). We did not find any differences for IL-6 between both groups, and other cytokines were rarely expressed. We found differences in pretreatment levels of HMGB1 (HA: median 0, IQR 0–28.1; control: median 48.6, IQR 12.7–597.3, P  = 0.02083) but no significant changes to post-treatment levels. No differences in inflammatory markers, fluid administration, blood substitution, catecholamines, BIA, or 30-day mortality were found. Conclusions We did not find any reduction of the pro-inflammatory response in our patients and therefore no changes in their perioperative course. However, IL-10 showed a longer-lasting anti-inflammatory effect. The clinical impact of prolonged IL-10 needs further evaluation. We also observed strong inter-individual differences in cytokine levels; therefore, patients with an exaggerated inflammatory response to CPB need to be identified. The implementation of HA during CPB was feasible. Trial registration ClinicalTrials.gov: NCT01879176 , registration date: June 7, 2013.

The “normal” immune response to an insult triggers a highly regulated response determined by the interaction of various immunocompetent cells with pro- and anti-inflammatory cytokines. Under pathologic conditions, the massive elevation of cytokine levels (“cytokine storm”) could not be controlled until the recent development of hemoadsorption devices that are able to extract a variety of different DAMPs, PAMPs, and metabolic products from the blood. CytoSorb® has been approved for adjunctive sepsis therapy since 2011. This review aims to summarize theoretical knowledge, in vitro results, and clinical findings to provide the clinician with pragmatic guidance for daily practice. English-language and peer-reviewed literature identified by a selective literature search in PubMed and published between January 2016 and May 2021 was included. Hemoadsorption can be used successfully as adjunct to a complex therapeutic regimen for various conditions. To the contrary, this nonspecific intervention may potentially worsen patient outcomes in complex immunological processes. CytoSorb® therapy appears to be safe and useful in various diseases (e.g., rhabdomyolysis, liver failure, or intoxications) as well as in septic shock or cytokine release syndrome, although a conclusive assessment of treatment benefit is not possible and no survival benefit has yet been demonstrated in randomized controlled trials.