The International, Prospective COSMOS (CytOSorb ® TreatMent Of Critically Ill PatientS) Registry: Results from the first 300 patients

The International, Prospective COSMOS (CytOSorb ® TreatMent Of Critically Ill PatientS) Registry: Results from the first 300 patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The International, Prospective COSMOS (CytOSorb ® TreatMent Of Critically Ill PatientS) Registry: Results from the first 300 patients Ricard Ferrer, Matthias Thielmann, Moritz Unglaube, Thomas Kirschning, and 25 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8036793/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Introduction Blood purification techniques are being investigated as adjunctive options in critically ill patients not only to treat severe inflammation but also to remove harmful substances such as myoglobin in rhabdomyolysis. Yet, the available evidence is limited, and further research is needed to clarify their clinical benefits. Methods The international prospective COSMOS Registry (NCT05146336, 23 Nov 2021) tracks CytoSorb® (CS) utilization patterns and outcomes in critical care settings. Clinical assessment was performed before, during, and after CS treatment, with a 90-day follow-up. At least “possibly device-related” adverse effects were reported by investigators as the safety evaluation. Data were analyzed according to a pre-specified statistical plan using descriptive statistics and paired tests to compare pre- and post-treatment values, with subgroup and safety analyses performed. Results A total of 300 adult patients (30.3% female, mean age 59 ± 15 years) from 22 sites were included in this analysis. The most common indications for CS therapy (multiple indications possible per patient) were septic shock (48.3%), rhabdomyolysis (12.8%), cardiogenic shock (11.5%), liver failure (11.5%), and acute respiratory distress syndrome (ARDS; 5.0%). On average, each patient received 3.3 ± 3.3 adsorbers, with 27.9% of patients receiving 4 or more adsorbers. CS was integrated in conjunction with kidney replacement therapy (75.6%), standalone hemoperfusion (7.1%), intermittent hemodialysis (IHD; 10.6%), extracorporeal membrane oxygenation (ECMO; 3.9%), and sustained low-efficiency daily dialysis (SLEDD; 4.9%).At baseline, median (interquartile range, IQR) APACHE II and SOFA scores were 24 [18, 30] and 12 [9, 15], respectively. Fluid balance improved from + 1,675 [141, 3,348] mL pre-CS to + 115 [–1,100, 1,495] mL post-CS, and norepinephrine requirements decreased from 0.21 [0.09, 0.40] µg/kg/min to 0.08 [0.02, 0.22] µg/kg/min (p < 0.0001 for both). Ratio of partial pressure of oxygen in arterial blood to the fraction of inspiratory oxygen concentration (P/F ratio) improved from 120 [72, 208] to 176 [115, 255] (p < 0.0001). Platelet counts decreased from 123 [76, 185] to 72 [42, 118] x10 9 /L (p < 0.0001), while albumin levels remained stable from 2.6 [2.3, 3.1] to 2.5 [2.3, 3.0] g/dL (p = 0.112). ICU mortality was 33.1%, which was lower than predicted by the scoring systems. No serious adverse effects related to the device or device deficiencies were reported. Conclusions Real-world CytoSorb® use as part of standard care in critically ill patients showed an association with significant improvements in key therapeutic outcomes, including reduced norepinephrine, fluid requirements, and improved oxygenation. Observed mortality was lower than predicted by risk scores. CytoSorb hemoadsorption hemoperfusion adsorption blood purification hyperinflammation sepsis septic shock liver failure rhabdomyolysis registry Figures Figure 1 Figure 2 Introduction CytoSorb® (CS) is a hemoadsorption cartridge consisting of porous polymer beads that can remove a wide range of small and middle-sized hydrophobic substances, including cytokines, toxins, and other harmful substances from whole blood ( 1 ). This mechanism has been particularly beneficial in conditions like sepsis and other inflammatory diseases like acute respiratory distress syndrome (ARDS), where excess cytokines are a major driver of organ dysfunction ( 2 , 3 ). Additionally, the ability to also remove bilirubin and bile acids as well as myoglobin expands the spectrum of critical care indications for CS to include acute and acute-on-chronic liver failure (ALF/ACLF), secondary liver dysfunction or rhabdomyolysis ( 4 , 5 ). However, much of the evidence to date comes from small, single center studies without control groups, leaving gaps in knowledge about the real-world performance of this therapy in diverse patient populations. While randomized controlled trials are considered the gold standard for evaluating clinical interventions, real-world evidence (RWE) is increasingly recognized for its critical role in understanding the practical applications of therapies outside the controlled environment of clinical trials ( 6 ). RWE provides insights into how therapies perform in routine clinical practice, where patient characteristics, comorbidities, and institutional practices can vary widely. This is especially relevant for CS since it can be used in a wide range of critical care conditions. Furthermore, RWE collection is necessary for post-market surveillance as required by Medical Device Regulations ( 7 ). The COSMOS ( CytoSorb® Treat M ent O f Critically Ill Patient S ) Registry is an international, prospective multicenter data collection platform designed to capture the real-world effectiveness and safety of CS in critically ill patients ( 8 ). This planned interim report from the first 300 adult patients enrolled in the registry aims to provide a comprehensive overview of utilization patterns and clinical performance of CS in the real world. Understanding how CS performs across such varied conditions is crucial for assessing its broader applicability in critical care. In this context, real-world evidence from the COSMOS registry can help clinicians better understand potential benefits but also potential limitations of CS therapy, refine patient selection criteria, and guide future research directions in the field of hemoadsorption therapy. Methods Registry study design The COSMOS Registry is an international, prospective, single-arm observational study conducted in countries where the device is approved for routine clinical use ( 8 ). Sites are selected based on their research credentials and capabilities, routine use of the device, patient enrollment capacity, and interest in participation. Device use should follow applicable current best practice ( 9 – 11 ) and all site personnel receive training to ensure proper use. Investigators are encouraged to review the latest device Instructions for Use for contraindications and precautions. To minimize selection bias, sites are asked to enroll consecutive eligible patients. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approval was secured at every site and informed consent obtained from all participants before data collection. The current interim analysis focuses on the first 300 adult patients (age ≥ 18 years old) enrolled in the COSMOS registry from 22 hospitals across Germany, Italy, Spain, Austria, and Portugal. These patients were treated with CS as part of their clinical management for a variety of indications, including septic shock, cardiogenic shock, rhabdomyolysis, and acute liver failure. Study Population Patients were eligible if they were treated with CytoSorb® 300 mL during their ICU stay and if an informed consent for prospective registry participation was obtained by the patient or legally authorized representative. Exclusion criteria included the use of the CytoSorb® for antithrombotic removal only or intra-operatively during cardiac surgery only. The registry collects data across a broad range of clinical indications of CS hemoadsorption. These include hyperinflammatory conditions such as septic shock, HLH, cytokine release syndrome (CRS) and CAR-T–related CRS, cardio-pulmonary settings like cardiogenic shock, ARDS, and ECMO/ECLS, and liver or kidney dysfunction including ALF, ACLF, secondary liver dysfunction, and rhabdomyolysis with multiple indications for CS being possible. Further recorded indications are infectious diseases such as COVID-19, influenza, and dengue, as well as post-operative vasoplegic shock, burns, pancreatitis, and drug overdose removal. Data collection and study outcomes Data are systematically collected at defined time points, including screening, 24 hours before CS initiation, 24 hours after completion, at ICU and hospital discharge, and again at 90-day follow-up. An overview of the baseline characteristics, therapeutic interventions, biomarker, clinical measurements, and outcome as well as safety variables assessed in this analysis is provided in Table 1 below. The registry assessed ICU mortality as the primary endpoint, with secondary outcomes including key laboratory, hemodynamic, and clinical parameters, longer-term mortality, and device safety. Table 1 Baseline characteristics and study outcomes Domain Variables / Parameters Screening/Baseline Characteristics Demographics : • Age • Sex Comorbid Disease / Risk Scores : • APACHE II score (Acute Physiology and Chronic Health Evaluation) • SOFA score (Sequential Organ Failure Assessment) • Charlson Comorbidity Index Treatment Characteristics • Indication for CS • Type of extracorporeal circuit used • Need for kidney replacement therapy (KRT) • Number of CS adsorbers used per patient • Duration of CS treatment • Timing of CS therapy initiation relative to ICU admission Primary Outcome Parameter ICU mortality Secondary Outcome Parameters Laboratory Biomarkers (Pre- versus Post-CS) : • Interleukin-6 (IL-6) • C-Reactive Protein (CRP) • Procalcitonin • Lactate • Creatinine • pH • Platelet count • Albumin Clinical Parameters (Pre- versus Post-CS) : • Norepinephrine dosage • Fluid balance • Oxygenation (P/F ratio, ratio of partial pressure of oxygen in arterial blood to the fraction of inspiratory oxygen concentration) • Mean arterial pressure (MAP) • MAP/Norepinephrine (MAP/NE) index Other Outcomes : • 90-day mortality • ICU length of stay (in survivors) • Hospital length of stay Safety Parameters : • Serious device-related adverse events • Device deficiencies • Bleeding events • Need for albumin substitution Statistical Analysis A pre-specified statistical analysis plan was followed to summarize and analyze the data. For continuous variables, either the median with first and third quartiles [Q1, Q3] or the mean with standard deviation (SD) were reported. For categorical variables, counts and proportions were provided. Baseline data were defined as the time of ICU admission and included demographic information and most commonly used risk scores for critically ill patients. The pre-CS therapy period was defined as the 24 hours prior to the start of CS therapy and included assessments for vasopressor use, fluid balance, with the latest available lab and blood gas values. The post-CS therapy period was defined as the 24 hours following the end of CS therapy for vasopressor use and fluid balance with the earliest available measurements for lab and blood gas values. Absolute change from the pre-CS period was calculated as the post-CS measurement minus the pre-CS value. The Wilcoxon signed-rank test was used to compare paired pre- and post-CS data to assess changes associated with CS treatment. We applied the Wilcoxon signed-rank test universally because several lab parameters had small sample sizes, non-normal distributions, or extreme outliers, making this test more robust than the paired t-test until larger sample sizes reduce these limitations. P-values less than 0.0001 were reported as < 0.0001 in tables, all other p-values were rounded and displayed using three decimals. Subgroup analyses were performed for clinically relevant categories, e.g., septic shock, KRT use. Kaplan-Meier plots illustrated the probability of survival over time (from the start of CytoSorb up to 90-day) by the subgroups, along with log-rank p-value. A separate analysis of ICU survivors and non-survivors was also performed. Device safety was evaluated based on investigator-reported adverse events related to the device, recorded until either ICU discharge or death, whichever occurred first. All analyses were performed using SAS 9.4 (SAS, Cary, NC). Results Patient Characteristics A total of 300 adult patients enrolled at 22 sites in Germany, Spain, Italy, Austria, and Portugal were included in this analysis. Patients’ mean age was 59 ± 15 years, with 30% being female (Table 2). Median baseline Acute Physiology and Chronic Health Evaluation (APACHE) II score was 24, with an interquartile range (IQR) of 18 to 30 and median Sequential Organ Failure Assessment (SOFA) score was 12, with IQR of 9 to 15. In the septic shock cohort patients (n=155) APACHE II score was 24 [18, 29] and SOFA 12 [9, 15]. Table 2. Baseline characteristics of the first 300 patients in COSMOS Registry (n and percent shown for categorial variables, Median [Q1, Q3] for continuous variables except age which is presented as mean and standard deviation). Not all patients’ data available at time of the interim data lock. Baseline characteristics All Patients (n=300) ICU survivors (n=180) ICU non-survivors (n=89) Age (years) Mean ± SD 59 ± 15 57 ± 16 64 ± 13 Age Group, n (%) >=65 18-65 131/300 (43.7%) 70/180 (38.9%) 45/89 (50.6%) 169/300 (56.3%) 110/180 (61.1%) 44/89 (49.4%) Gender, n (%) Male Female 209/300 (69.7%) 124/180 (68.9%) 60/89 (67.4%) 91/300 (30.3%) 56/180 (31.1%) 20/89 (32.6%) Weight (kg) N Median [Q1, Q3] 292 176 86 85 [72, 98] 85 [70, 100] 85 [75, 95] BMI (kg/m2) N Median [Q1, Q3] 290 176 84 27.2 [24.2, 31.2] 26.8 [24.0, 31.2] 27.4 [24.7, 32.5] Charlson Comorbidity Score N Median [Q1, Q3] 279 173 75 4 [2, 5] 3 [2, 5] 5 [3, 6] APACHE II Score N Median [Q1, Q3] 242 149 85 24 [18, 30] 23 [18, 28] 25 [18, 32] SOFA Score N Median [Q1, Q3] 238 156 75 12 [9, 15] 12 [9, 15] 13 [10, 15] Legend: APACHE – Acute Physiology And Chronic Health Evaluation, SD – Standard Deviation, BMI – Body mass Index, SOFA – Sequential Organ Failure Assessment, Q1 – First Quartile, Q3 – Third Quartile Treatment Modalities and Indications of CytoSorb Therapy The therapeutic use of CS in the COSMOS registry covers a wide spectrum of clinical conditions, with a predominant focus on the treatment of hyperinflammation and organ failure. Also, multiple indications for some patients were possible. Indication for CS included septic shock (n=155, 48.3% of all indications), cardiogenic shock (n=37, 11.5%), rhabdomyolysis (n=41, 12.8%), acute or acute on chronic liver failure (ALF/ACLF) or secondary liver dysfunction (n=37, 11.6%), acute respiratory distress syndrome (ARDS; n=16, 5.0%) and other (n=35, 10.9%). Mean number of adsorbers used per patient was 3.3 ± 3.3, with 28% receiving 4 or more adsorbers. Information on extracorporeal platforms used for CS integration was available for 283 patients and included chronic renal replacement therapy (n=214, 75.6% of all available info on circuits), standalone hemoperfusion (n=20, 7.1%), intermittent hemodialysis (IHD; n=30, 10.6%), extracorporeal membrane oxygenation (ECMO; n=11, 3.9%), and sustained low-efficiency daily dialysis (SLEDD; n=14, 4.9%). Primary and Secondary Outcomes The primary outcome of ICU mortality was 33.1% overall and 32.9 % in septic shock cohort. Mortality at 90 days was 46.0% for 248 patients with the completion of follow-up. Median length of ICU stay for survivors was 22 [12, 38] days. Table 3 shows an overview of mortality rates in relation to the onset of CS therapy. Survival was numerically higher when CS therapy was initiated within 1 day of ICU admission onset compared to initiation after more than 1 day (see also Figure 1). Note that the Kaplan–Meier curve accounts for censored data, unlike incidence rates, which exclude patients lost to follow-up. However, it cannot accurately estimate ICU mortality because patients have varying ICU lengths of stay. Furthermore, patients with immediate CS onset had shorter ICU stay (16 vs. 27 days, p<0.0001) and hospital stay (30 vs. 42 days, p=0.005). Table 3. Mortality of patients according to onset of CS Therapy in relation to ICU admission Onset of CS within 0-1 day of ICU admission Delayed onset (>=2 days after ICU admission) P-value ICU mortality 22.3% (25/112) 29.8% (39/131) 0.189 Hospital Mortality 27.3% (30/110) 32.3% (40/130) 0.396 Mortality at 90-day FU 34.7% (35/101) 44.3% (54/122) 0.145 Table 4 summarizes biomarker data pre versus post CS use. Of note, in patients where CS was integrated into ECMO or used in hemoperfusion mode without KRT (n=31) creatinine (1.9 [1.1, 3.0] to 1.3 [0.8, 2.0] mg/dL, p<0.0001) and lactate (2.1 [1.2, 2.6] to 1.4 [1.1, 1.6] mmol/L, p=0.037) were also significantly reduced. Table 4. Overview of laboratory findings before versus after CS therapy. Biomarkers Median levels [IQR] before CS Median levels [IQR] after CS p-value Interleukin - 6 pg/mL, n=58 563 [187, 14,168] 104 [52, 1,299] <0.0001 C-Reactive Protein mg/dL, n=159 13.0 [3.5, 22.1] 10.8 [4.3, 19.1] 0.082 Procalcitonin ng/mL, n=98 9.4 [2.1, 47.0] 3.3 [1.2, 16.0] <0.0001 pH, n=233 7.35 [7.30, 7.42] 7.40 [7.36, 7.45] <0.0001 Lactate mmol/L, n=231 2.4 [1.4, 4.9] 1.4 [1.0, 2.2] <0.0001 Creatinine mg/dL, n=231 2.1 [1.4, 3.1] 1.4 [0.9, 2.1] <0.0001 Albumin g/dL, n=122 2.6 [2.3, 3.1] 2.5 [2.3, 3.0] 0.112 Platelets x10 9 /L, n=237 123 [76, 185] 72 [42, 118] <0.0001 Legend: CS: CytoSorb; IQR; Interquartile range Secondary outcomes including 24-hour fluid balance, norepinephrine requirements (NE) and P/F ratio all significantly improved post CS treatment (p<0.0001 for all, Figure 2). Significant improvements were also noted post treatment for MAP/NE index (287 [157, 635] to 681 [302, 1,400] mmHg·kg·min/µg, p<0.0001). Change in fluid balance was also significant in patients without KRT from +1,383 [0, 3,700] to -227 [-1,390, 497] mL (p=0.034). SOFA Score improved from 12 [9, 15] to 11 [8, 14] over course of CS treatment in the whole cohort (p=0.001), and equally from 12 [10, 15] to 11 [9, 14] in patients with septic shock (p=0.003). Figure 2 summarizes the most important findings before versus after CS treatment. Safety Platelet counts decreased during CS treatment (123 [76, 185] to 72 [42, 118] x10 9 /L, p<0.0001), an effect primarily driven by platelet count reductions in the septic cohort (122 [86, 182] to 65 [36, 121] x10⁹/L, p<0.0001), while platelets did not significantly decrease in patients with cardiogenic shock (102 [60, 164] to 69 [39, 107] x10 9 /L, p=0.137) or liver failure (85 [42, 149] to 66 [43, 99] x10 9 /L, p=0.322). 31% of overall patients (n=93) received platelet transfusion concomitantly with CS therapy. No major bleeding events were reported. Median albumin levels did not change significantly during treatment (2.6 [2.3, 3.1] g/dL pre- versus 2.5 [2.3, 3.0] post-CS (p=0.112), however with 43.7% of patients receiving albumin substitution. No Serious Adverse Device Effects or Device Deficiencies were reported by the time this interim analysis was performed. Discussion In this interim analysis of 300 patients, CS therapy was applied across diverse critical care indications. Observed improvements in hemodynamics, oxygenation, and fluid balance, along with lower-than-predicted ICU mortality, suggest potential benefit, although these findings should be interpreted cautiously given the observational design. These results are consistent with results from previous interim analyses ( 12 ). Notably, the broad range of indications highlights its increasing role beyond septic shock, with emerging applications particularly in liver failure ( 13 , 14 ) and rhabdomyolysis ( 10 ). Further research is needed to clarify its role in these different contexts. The mean number of adsorbers used reveals a high degree of variability in clinical practice, with 28% of patients receiving four or more devices. This underscores one of the major values of the registry, which enables a more comprehensive understanding of how clinicians indicate and apply CS therapy in real-world settings. As enrollment numbers in the COSMOS Registry continue to increase, dedicated subgroup analyses may help clarify how treatment intensity (e.g., number of adsorbers or exchange intervals) relates to clinical outcomes in different patient groups ( 9 , 15 ). Moreover, such analyses may identify specific subgroups that derive the greatest clinical benefit from CS therapy. Patients included in this analysis had a baseline APACHE II score of 24, corresponding to an expected mortality in nonoperative patients of 40% ( 16 ) and SOFA median of 12, which as an initial score in the general ICU population corresponds to a mortality risk of 95.2% ( 17 ). A more recent study focusing on adults with suspected infection predicted for a SOFA of 12 an in-hospital mortality of around 50% ( 18 ). In the current analysis, ICU mortality was 33.1% (32.9% in septic shock) despite high baseline disease severity. These findings are further supported by a recent systematic review and meta-analysis in septic shock patients, which showed that CS use significantly reduced both in-hospital and 28–30-day mortality in 744 critically ill patients ( 19 ). While the design of this study does not allow for causal conclusions, these results may suggest a potential benefit of CS therapy in improving outcomes in critically ill patients, especially when used in appropriately selected patients and with adequate treatment regimens. The observed median ICU stay of 22 days is notable in the context of healthcare resource utilization and cost. The potential clinical benefits – such as hemodynamic stabilization, improved oxygenation, and fluid balance – may translate into shorter ICU stays and reduced resource utilization if validated in larger controlled studies. Further cost-effectiveness analyses are warranted to determine its economic impact, especially in resource-intensive settings ( 20 ). Norepinephrine requirements decreased significantly over the course of CS treatment resulting in hemodynamic stabilization, an observation that is consistent with prior evidence ( 21 ). While the underlying pathophysiologic mechanism may be linked to improved vascular function and a reduction in the inflammatory burden ( 22 ), observed decreased vasopressor requirements with CS therapy may contribute to minimizing organ hypoperfusion and ischemia ( 23 , 24 ). Importantly, hemodynamic improvement was not achieved at the cost of additional fluid overload but was instead accompanied by significantly reduced need for fluid resuscitation which seems to be relevant also in the context of the observed improved oxygenation. These effects are clinically relevant, as intravenous fluid resuscitation can lead to dilutional coagulopathy, fluid overload, and the development of pathogenic edema in the lungs and other organs ( 25 ). The observed reductions in lactate, creatinine, and fluid balance in patients not receiving KRT indicate that these effects are likely linked to CS treatment, rather than consequences of concomitant KRT. The observed improvements may reflect, at least in part, a potential endothelial protective effect of CS by removing circulating inflammatory factors known to impair endothelial function, contributing to enhanced vascular function and fluid homeostasis ( 22 ). Finally, the current analysis reinforces the favorable safety profile of CS therapy, with no serious adverse device effects or deficiencies reported. The observed decrease in platelet counts, primarily in septic shock patients, should be interpreted cautiously, as thrombocytopenia is a common feature in sepsis ( 26 ). It is however reassuring, that despite the observed drops in platelet counts there were no bleeding events reported ( 27 ). Clinical Implications Timely removal of circulating harmful substances, such as overshooting cytokines ( 1 ) or myoglobin in rhabdomyolysis ( 5 ), are critical goals in the management of critically ill patients. Patients eligible for CS therapy should preferably be treated within 24 hours of ICU admission. The hemoadsorption properties of CS enable efficient elimination of these and other inflammatory mediators, potentially contributing to the stabilization of the endothelial barrier ( 22 ) and attenuation of systemic hyperinflammation. COSMOS Registry data suggest that CS may be associated with improvements in hemodynamics, fluid balance, and oxygenation. For physicians, this underlines the role of CS in supporting hemodynamic recovery in shock states, particularly vasoplegic shock in sepsis. Furthermore, improved fluid balance reduces risks associated with fluid overload, such as worsening respiratory distress reinforcing the potential benefit of CS therapy in managing patients with capillary leak and ARDS. Moreover, CS therapy was safely used in conjunction with renal replacement therapy, ECMO or standalone hemoperfusion, underlining its versatility. For decision-makers, these findings offer a rationale for further integration of CS therapy into standard care pathways while supporting ongoing research to maximize its clinical utility. While these results are promising, further investigations are necessary, particularly controlled trials in dedicated indications, that compare outcomes with the addition of CS therapy to established treatment standards. Such studies will help refine clinical indications, optimize treatment protocols, and further establish the role of CS in improving outcomes for critically ill patients. Importantly, observations from this registry may serve as a valuable source for hypothesis generation, guiding the design and focus of future clinical trials. Limitations A key limitation common to all observational single-arm registries, including COSMOS, is the absence of a control group, which prevents establishing definitive causality between the intervention and the outcomes observed. As such, the findings should be interpreted with caution as suggestive rather than conclusive evidence. A second limitation is that at the time of this interim analysis, some patient datasets were incomplete, leading to a reduced sample size for certain analyses. Furthermore, another limitation is the lack of standardized use of CS therapy across participating centers. The registry encompasses a heterogeneous population in which CS is applied for multiple indications. The therapeutic approach (treatment initiation, duration, and dosing strategies) may therefore differ according to the underlying indication and was left to the discretion of the treating physicians. In addition, there was no standardized measurement of predefined parameters, which may have introduced heterogeneity and limited comparability of outcomes across sites. Conclusions This interim analysis of the international, real-world COSMOS Registry reports significant improvements in key therapeutic targets that might be associated with the use of CS as part of standard clinical practice across multiple critical care indications. Specifically, integration of CS was observed to be associated with hemodynamic stabilization and improved fluid balance and oxygenation resulting in observed ICU mortality lower than predicted by established risk scores. These findings provide valuable insights into the potential clinical benefits of CS in real-world settings and warrant further investigation. Abbreviations 90-day FU 90 days Follow-up ACLF Acute-On-Chronic Liver Failure ALF Acute Liver Failure APACHE Acute Physiology And Chronic Health Evaluation ARDS Acute Respiratory Distress Syndrome BMI Body Mass Index CRP C-Reactive Protein CRS Cytokine Release Syndrome CS CytoSorb® DD Device Deficiencies ECLS Extracorporeal Life Support System ECMO Extracorporeal Membrane Oxygenation FU Follow-up GCP Good Clinical Practice HLH Hemophagocytic Lymphohistiocytosis ICF Informed Consent Form ICH International Conference on Harmonization ICU Intensive Care Unit IEC Independent Ethics Committee IL-6 Interleukin-6 IQR Interquartile Range IRB Institutional Review Board ISO International Organization for Standardization KRT Kidney Replacement Therapy MAP Mean Arterial Pressure NE Norepinephrine P/F ratio Ratio of partial pressure of oxygen in arterial blood to the fraction of inspiratory oxygen concentration RWE Real-World Evidence SD Standard Deviation SLEDD Sustained low-efficiency daily dialysis SOFA Sequential Organ Failure Assessment Declarations Clinical Trial Number The COSMOS Registry was registered on Clinicaltrials.gov, NCT05146336, since November 23, 2021. Ethics Approval The Registry is being conducted in compliance with ISO 14155:2020, the Declaration of Helsinki, and the principles of Good Clinical Practice (GCP), as outlined in the International Conference on Harmonization (ICH) E6 Guidelines for GCP, along with all relevant local legal requirements. Before the Registry begins, approval must be obtained from the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) for the study protocol, sample informed consent form (ICF), and any documents related to patient information or recruitment methods, such as advertisements. Any subsequent amendments to the protocol or changes to the ICF must also be submitted for approval by the IRB/IEC. The initial international ethics approval was from IRB ‘Comité de Ética de Investigación con Medicamentos del Hospital Universitario Vall d’Hebron’ with the approval number PR(AG)86/2022 (28 March 2022). Each participating center is required to obtain approval from its respective IRB before study activation. Consent to participate Written informed consent was obtained from all subjects or legally authorized representatives involved in the study. Consent for Publication Not applicable. Availability of Data and Materials The data are available upon reasonable written request and with written permission of CytoSorbents Corporation. Data Management Plan and Informed Consent Forms are available upon request. Competing Interests FST, GB, JH, AK, JLT, DT, and RF have consulting contracts with CytoSorbents Corporation and CytoSorbents Medical Inc. AB has received reimbursements for travelling expenses and honoraria for presentations from CytoSorbents Europe GmbH. JK has received honoraria for presentation from CytoSorbents Europe GmbH. TeK and JS are full-time employees of CytoSorbents Europe GmbH. END and WF are full-time employees of CytoSorbents Corporation and CytoSorbents Medical Inc. Funding CytoSorbents Corporation and CytoSorbents Medical Inc. are the funding sources. Author Contributions Conceptualization, FST, TK, JS and RF; methodology, FST, TK and RF; writing, original draft preparation, TK and RF; writing, review and editing, MT, MU, TKi, AB, BT, AK, UG, JK, DH, MB, AE-E, NG, TG, PH, CS, PCS, MMF, MK, GB, FA, DT; statistics, WF; visualization, TK, WF; supervision, FST, JH, JLT, END, RF. All authors have read and agreed to the published version of the manuscript. Acknowledgments The authors would like to thank Dr. Marie-Christin Pawlik, Robert Wilke and Antje Fechner for operational management of the Registry as well as Harriet Adamson for support with literature search. References Jansen A, Waalders NJB, van Lier DPT, Kox M, Pickkers P. CytoSorb hemoperfusion markedly attenuates circulating cytokine concentrations during systemic inflammation in humans in vivo. Crit Care. 2023;27(1):117. Ronco C, Tetta C, Mariano F, Wratten ML, Bonello M, Bordoni V, et al. 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Use of the CytoSorb adsorber in patients with acute-on-chronic liver failure. Sci Rep. 2024;14(1):11309. Ferrer R, Thielmann M, Kribben A, Unglaube M, Tyczynski B, Kreutz J, et al. The international, prospective CytOSorbⓇ treatMent Of critically ill patientS (COSMOS) registry: Interim results from the first 150 patients. Journal of Intensive Medicine. 2025. Grafe C, Paal M, Winkels M, Irlbeck M, Liebchen U, Scharf C. Correlation between Bilirubin Elimination with the Cytokine Adsorber CytoSorb(R) and Mortality in Critically Ill Patients with Hyperbilirubinemia. Blood Purif. 2023;52(11-12):849-56. Scharf C, Liebchen U, Paal M, Becker-Pennrich A, Irlbeck M, Zoller M, et al. Successful elimination of bilirubin in critically ill patients with acute liver dysfunction using a cytokine adsorber and albumin dialysis: a pilot study. Sci Rep. 2021;11(1):10190. Berlot G, Carocci P, Votrico V, Iacoviello B, Taverna N, Gerini U, et al. 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Hemoadsorption Using CytoSorb((R)) in Patients with Infective Endocarditis: A German-Based Budget Impact Analysis. J Cardiovasc Dev Dis. 2023;10(9):366. Rao C, Hawchar F, Akil A, Rugg C, Mehta Y, Scheier J, et al. Reducing vasopressor requirements with hemoadsorption in the critically ill: a systematic review. ISICEM; Sept 2nd 2021; Brussels: Crit Care; 2021. p. 55. Papp M, Ince C, Bakker J, Molnar Z. Endothelial Protection and Improved Micro- and Macrocirculation with Hemoadsorption in Critically Ill Patients. J Clin Med. 2024;13(23):7044. Jesani S, Elkattawy S, Noori MAM, Ayad S, Abuaita S, Gergis K, et al. Vasopressor-Induced Digital Ischemia. Cureus. 2021;13(7):e16595. Jozwiak M, Geri G, Laghlam D, Boussion K, Dolladille C, Nguyen LS. Vasopressors and Risk of Acute Mesenteric Ischemia: A Worldwide Pharmacovigilance Analysis and Comprehensive Literature Review. Front Med (Lausanne). 2022;9:826446. Self WH, Semler MW, Bellomo R, Brown SM, deBoisblanc BP, Exline MC, et al. Liberal Versus Restrictive Intravenous Fluid Therapy for Early Septic Shock: Rationale for a Randomized Trial. Ann Emerg Med. 2018;72(4):457-66. Cox D. Sepsis - it is all about the platelets. Front Immunol. 2023;14:1210219. Brozat CI, Zoller M, Frank S, Bruegel M, Grafe C, Rebholz D, et al. Albumin and Platelet Loss during the Application of CytoSorb(R) in Critically Ill Patients: A post hoc Analysis of the Cyto-SOLVE Trial. Blood Purif. 2025;54(2):93-101. Additional Declarations Competing interest reported. FST, GB, JH, AK, JLT, DT, and RF have consulting contracts with CytoSorbents Corporation and CytoSorbents Medical Inc. AB has received reimbursements for travelling expenses and honoraria for presentations from CytoSorbents Europe GmbH. JK has received honoraria for presentation from CytoSorbents Europe GmbH. TeK and JS are full-time employees of CytoSorbents Europe GmbH. END and WF are full-time employees of CytoSorbents Corporation and CytoSorbents Medical Inc. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 29 Dec, 2025 Reviews received at journal 05 Dec, 2025 Reviews received at journal 24 Nov, 2025 Reviewers agreed at journal 23 Nov, 2025 Reviewers agreed at journal 17 Nov, 2025 Reviewers invited by journal 17 Nov, 2025 Editor assigned by journal 14 Nov, 2025 Submission checks completed at journal 14 Nov, 2025 First submitted to journal 05 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8036793","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":550145965,"identity":"ecce1fd5-fb9c-4b3b-9503-f2bc835afa39","order_by":0,"name":"Ricard 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06:55:32","extension":"html","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":126110,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8036793/v1/9078954aff6d71116393a6e2.html"},{"id":96967573,"identity":"3254dd16-a712-40d9-9c93-cb07c39108a2","added_by":"auto","created_at":"2025-11-28 06:55:32","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":128748,"visible":true,"origin":"","legend":"\u003cp\u003eAssociation of time of CS initiation and survival percentage\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8036793/v1/bb30f4f6fe39300c8f5133d0.png"},{"id":96967568,"identity":"939597e7-afdb-473b-92b8-17ce3fcdcd52","added_by":"auto","created_at":"2025-11-28 06:55:32","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":88755,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in norepinephrine, fluid balance, P/F ratio, interleukin-6 and pH in 24 h periods before (grey) versus after CytoSorb® treatment (blue), data are presented as median and interquartile range, Legend: P/F ratio – ratio of partial pressure of oxygen in arterial blood to the fraction of inspiratory oxygen concentration\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8036793/v1/263531a387c76773d612371b.png"},{"id":97144664,"identity":"e41c9bfc-57a3-4497-8a4d-8fd823279bb6","added_by":"auto","created_at":"2025-12-01 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FST, GB, JH, AK, JLT, DT, and RF have consulting contracts with CytoSorbents Corporation and CytoSorbents Medical Inc. AB has received reimbursements for travelling expenses and honoraria for presentations from CytoSorbents Europe GmbH. JK has received honoraria for presentation from CytoSorbents Europe GmbH. TeK and JS are full-time employees of CytoSorbents Europe GmbH. END and WF are full-time employees of CytoSorbents Corporation and CytoSorbents Medical Inc.","formattedTitle":"The International, Prospective COSMOS (CytOSorb ® TreatMent Of Critically Ill PatientS) Registry: Results from the first 300 patients","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCytoSorb\u0026reg; (CS) is a hemoadsorption cartridge consisting of porous polymer beads that can remove a wide range of small and middle-sized hydrophobic substances, including cytokines, toxins, and other harmful substances from whole blood (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). This mechanism has been particularly beneficial in conditions like sepsis and other inflammatory diseases like acute respiratory distress syndrome (ARDS), where excess cytokines are a major driver of organ dysfunction (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Additionally, the ability to also remove bilirubin and bile acids as well as myoglobin expands the spectrum of critical care indications for CS to include acute and acute-on-chronic liver failure (ALF/ACLF), secondary liver dysfunction or rhabdomyolysis (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). However, much of the evidence to date comes from small, single center studies without control groups, leaving gaps in knowledge about the real-world performance of this therapy in diverse patient populations.\u003c/p\u003e\u003cp\u003eWhile randomized controlled trials are considered the gold standard for evaluating clinical interventions, real-world evidence (RWE) is increasingly recognized for its critical role in understanding the practical applications of therapies outside the controlled environment of clinical trials (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). RWE provides insights into how therapies perform in routine clinical practice, where patient characteristics, comorbidities, and institutional practices can vary widely. This is especially relevant for CS since it can be used in a wide range of critical care conditions. Furthermore, RWE collection is necessary for post-market surveillance as required by Medical Device Regulations (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe COSMOS (\u003cb\u003eCytoSorb\u0026reg;\u003c/b\u003e Treat\u003cb\u003eM\u003c/b\u003eent \u003cb\u003eO\u003c/b\u003ef Critically Ill Patient\u003cb\u003eS\u003c/b\u003e) Registry is an international, prospective multicenter data collection platform designed to capture the real-world effectiveness and safety of CS in critically ill patients (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). This planned interim report from the first 300 adult patients enrolled in the registry aims to provide a comprehensive overview of utilization patterns and clinical performance of CS in the real world. Understanding how CS performs across such varied conditions is crucial for assessing its broader applicability in critical care. In this context, real-world evidence from the COSMOS registry can help clinicians better understand potential benefits but also potential limitations of CS therapy, refine patient selection criteria, and guide future research directions in the field of hemoadsorption therapy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eRegistry study design\u003c/h2\u003e\u003cp\u003eThe COSMOS Registry is an international, prospective, single-arm observational study conducted in countries where the device is approved for routine clinical use (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Sites are selected based on their research credentials and capabilities, routine use of the device, patient enrollment capacity, and interest in participation. Device use should follow applicable current best practice (\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) and all site personnel receive training to ensure proper use. Investigators are encouraged to review the latest device Instructions for Use for contraindications and precautions. To minimize selection bias, sites are asked to enroll consecutive eligible patients. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approval was secured at every site and informed consent obtained from all participants before data collection.\u003c/p\u003e\u003cp\u003eThe current interim analysis focuses on the first 300 adult patients (age\u0026thinsp;\u0026ge;\u0026thinsp;18 years old) enrolled in the COSMOS registry from 22 hospitals across Germany, Italy, Spain, Austria, and Portugal. These patients were treated with CS as part of their clinical management for a variety of indications, including septic shock, cardiogenic shock, rhabdomyolysis, and acute liver failure.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy Population\u003c/h3\u003e\n\u003cp\u003ePatients were eligible if they were treated with CytoSorb\u0026reg; 300 mL during their ICU stay and if an informed consent for prospective registry participation was obtained by the patient or legally authorized representative. Exclusion criteria included the use of the CytoSorb\u0026reg; for antithrombotic removal only or intra-operatively during cardiac surgery \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eonly.\u003c/span\u003e\u003c/p\u003e\u003cp\u003eThe registry collects data across a broad range of clinical indications of CS hemoadsorption. These include hyperinflammatory conditions such as septic shock, HLH, cytokine release syndrome (CRS) and CAR-T\u0026ndash;related CRS, cardio-pulmonary settings like cardiogenic shock, ARDS, and ECMO/ECLS, and liver or kidney dysfunction including ALF, ACLF, secondary liver dysfunction, and rhabdomyolysis with multiple indications for CS being possible. Further recorded indications are infectious diseases such as COVID-19, influenza, and dengue, as well as post-operative vasoplegic shock, burns, pancreatitis, and drug overdose removal.\u003c/p\u003e\n\u003ch3\u003eData collection and study outcomes\u003c/h3\u003e\n\u003cp\u003eData are systematically collected at defined time points, including screening, 24 hours before CS initiation, 24 hours after completion, at ICU and hospital discharge, and again at 90-day follow-up. An overview of the baseline characteristics, therapeutic interventions, biomarker, clinical measurements, and outcome as well as safety variables assessed in this analysis is provided in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e below. The registry assessed ICU mortality as the primary endpoint, with secondary outcomes including key laboratory, hemodynamic, and clinical parameters, longer-term mortality, and device safety.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline characteristics and study outcomes\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDomain\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eVariables / Parameters\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eScreening/Baseline Characteristics\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eDemographics\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e\u0026bull; Age\u003c/p\u003e\u003cp\u003e\u0026bull; Sex\u003c/p\u003e\u003cp\u003e\u003cb\u003eComorbid Disease / Risk Scores\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e\u0026bull; APACHE II score (Acute Physiology and Chronic Health Evaluation)\u003c/p\u003e\u003cp\u003e\u0026bull; SOFA score (Sequential Organ Failure Assessment)\u003c/p\u003e\u003cp\u003e\u0026bull; Charlson Comorbidity Index\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTreatment Characteristics\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026bull; Indication for CS\u003c/p\u003e\u003cp\u003e\u0026bull; Type of extracorporeal circuit used\u003c/p\u003e\u003cp\u003e\u0026bull; Need for kidney replacement therapy (KRT)\u003c/p\u003e\u003cp\u003e\u0026bull; Number of CS adsorbers used per patient\u003c/p\u003e\u003cp\u003e\u0026bull; Duration of CS treatment\u003c/p\u003e\u003cp\u003e\u0026bull; Timing of CS therapy initiation relative to ICU admission\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePrimary Outcome Parameter\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eICU mortality\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSecondary Outcome Parameters\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eLaboratory Biomarkers (Pre- versus Post-CS)\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e\u0026bull; Interleukin-6 (IL-6)\u003c/p\u003e\u003cp\u003e\u0026bull; C-Reactive Protein (CRP)\u003c/p\u003e\u003cp\u003e\u0026bull; Procalcitonin\u003c/p\u003e\u003cp\u003e\u0026bull; Lactate\u003c/p\u003e\u003cp\u003e\u0026bull; Creatinine\u003c/p\u003e\u003cp\u003e\u0026bull; pH\u003c/p\u003e\u003cp\u003e\u0026bull; Platelet count\u003c/p\u003e\u003cp\u003e\u0026bull; Albumin\u003c/p\u003e\u003cp\u003e\u003cb\u003eClinical Parameters (Pre- versus Post-CS)\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e\u0026bull; Norepinephrine dosage\u003c/p\u003e\u003cp\u003e\u0026bull; Fluid balance\u003c/p\u003e\u003cp\u003e\u0026bull; Oxygenation (P/F ratio, ratio of partial pressure of oxygen in arterial blood to the fraction of inspiratory oxygen concentration)\u003c/p\u003e\u003cp\u003e\u0026bull; Mean arterial pressure (MAP)\u003c/p\u003e\u003cp\u003e\u0026bull; MAP/Norepinephrine (MAP/NE) index\u003c/p\u003e\u003cp\u003e\u003cb\u003eOther Outcomes\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e\u0026bull; 90-day mortality\u003c/p\u003e\u003cp\u003e\u0026bull; ICU length of stay (in survivors)\u003c/p\u003e\u003cp\u003e\u0026bull; Hospital length of stay\u003c/p\u003e\u003cp\u003e\u003cb\u003eSafety Parameters\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e\u0026bull; Serious device-related adverse events\u003c/p\u003e\u003cp\u003e\u0026bull; Device deficiencies\u003c/p\u003e\u003cp\u003e\u0026bull; Bleeding events\u003c/p\u003e\u003cp\u003e\u0026bull; Need for albumin substitution\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eA pre-specified statistical analysis plan was followed to summarize and analyze the data. For continuous variables, either the median with first and third quartiles [Q1, Q3] or the mean with standard deviation (SD) were reported. For categorical variables, counts and proportions were provided. Baseline data were defined as the time of ICU admission and included demographic information and most commonly used risk scores for critically ill patients. The pre-CS therapy period was defined as the 24 hours prior to the start of CS therapy and included assessments for vasopressor use, fluid balance, with the latest available lab and blood gas values. The post-CS therapy period was defined as the 24 hours following the end of CS therapy for vasopressor use and fluid balance with the earliest available measurements for lab and blood gas values. Absolute change from the pre-CS period was calculated as the post-CS measurement minus the pre-CS value. The Wilcoxon signed-rank test was used to compare paired pre- and post-CS data to assess changes associated with CS treatment. We applied the Wilcoxon signed-rank test universally because several lab parameters had small sample sizes, non-normal distributions, or extreme outliers, making this test more robust than the paired t-test until larger sample sizes reduce these limitations. P-values less than 0.0001 were reported as \u0026lt;\u0026thinsp;0.0001 in tables, all other p-values were rounded and displayed using three decimals. Subgroup analyses were performed for clinically relevant categories, e.g., septic shock, KRT use. Kaplan-Meier plots illustrated the probability of survival over time (from the start of CytoSorb up to 90-day) by the subgroups, along with log-rank p-value. A separate analysis of ICU survivors and non-survivors was also performed. Device safety was evaluated based on investigator-reported adverse events related to the device, recorded until either ICU discharge or death, whichever occurred first. All analyses were performed using SAS 9.4 (SAS, Cary, NC).\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003ePatient Characteristics\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eA total of 300 adult patients enrolled at 22 sites in Germany, Spain, Italy, Austria, and Portugal were included in this analysis. Patients\u0026rsquo; mean age was 59 \u0026plusmn; 15 years, with 30% being female (Table 2). Median baseline Acute Physiology and Chronic Health Evaluation (APACHE) II score was 24, with an interquartile range (IQR) of 18 to 30 and median Sequential Organ Failure Assessment (SOFA) score was 12, with IQR of 9 to 15. In the septic shock cohort patients (n=155) APACHE II score was 24 [18, 29] and SOFA 12 [9, 15].\u003c/p\u003e\n\u003cp\u003eTable 2. Baseline characteristics of the first 300 patients in COSMOS Registry (n and percent shown for categorial variables, Median [Q1, Q3] for continuous variables except age which is presented as mean and standard deviation). Not all patients\u0026rsquo; data available at time of the interim data lock.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"689\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline characteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll Patients\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=300)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eICU survivors (n=180)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eICU non-survivors (n=89)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (years)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e59 \u0026plusmn; 15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e57 \u0026plusmn; 16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e64 \u0026plusmn; 13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge Group, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026gt;=65\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e18-65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e131/300 (43.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e70/180 (38.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e45/89 (50.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e169/300 (56.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e110/180 (61.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e44/89 (49.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e209/300 (69.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e124/180 (68.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e60/89 (67.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e91/300 (30.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e56/180 (31.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e20/89 (32.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeight (kg)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003cp\u003eMedian [Q1, Q3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e292\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e176\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e86\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e85 [72, 98]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e85 [70, 100]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e85 [75, 95]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI (kg/m2)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003cp\u003eMedian [Q1, Q3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e290\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e176\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e84\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e27.2 [24.2, 31.2]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e26.8 [24.0, 31.2]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e27.4 [24.7, 32.5]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharlson Comorbidity Score\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003cp\u003eMedian [Q1, Q3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e279\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e173\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e4 [2, 5]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e3 [2, 5]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e5 [3, 6]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAPACHE II Score\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003cp\u003eMedian [Q1, Q3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e242\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e149\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e85\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e24 [18, 30]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e23 [18, 28]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e25 [18, 32]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSOFA Score\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003cp\u003eMedian [Q1, Q3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e238\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e156\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e12 [9, 15]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e12 [9, 15]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e13 [10, 15]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eLegend: APACHE \u0026ndash; Acute Physiology And Chronic Health Evaluation, SD \u0026ndash; Standard Deviation, BMI \u0026ndash; Body mass Index, SOFA \u0026ndash; Sequential Organ Failure Assessment, Q1 \u0026ndash; First Quartile, Q3 \u0026ndash; Third Quartile\u003c/p\u003e\n\u003ch2\u003eTreatment Modalities and Indications of CytoSorb Therapy\u003c/h2\u003e\n\u003cp\u003eThe therapeutic use of CS in the COSMOS registry covers a wide spectrum of clinical conditions, with a predominant focus on the treatment of hyperinflammation and organ failure. Also, multiple indications for some patients were possible. Indication for CS included septic shock (n=155, 48.3% of all indications), cardiogenic shock (n=37, 11.5%), rhabdomyolysis (n=41, 12.8%), acute or acute on chronic liver failure (ALF/ACLF) or secondary liver dysfunction (n=37, 11.6%), acute respiratory distress syndrome (ARDS; n=16, 5.0%) and other (n=35, 10.9%). Mean number of adsorbers used per patient was 3.3 \u0026plusmn; 3.3, with 28% receiving 4 or more adsorbers. Information on extracorporeal platforms used for CS integration was available for 283 patients and included chronic renal replacement therapy (n=214, 75.6% of all available info on circuits), standalone hemoperfusion (n=20, 7.1%), intermittent hemodialysis (IHD; n=30, 10.6%), extracorporeal membrane oxygenation (ECMO; n=11, 3.9%), and sustained low-efficiency daily dialysis\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e(SLEDD; n=14, 4.9%).\u003c/p\u003e\n\u003ch2\u003ePrimary and Secondary Outcomes\u003c/h2\u003e\n\u003cp\u003eThe primary outcome of ICU mortality was 33.1% overall and 32.9 % in septic shock cohort. Mortality at 90 days was 46.0% \u0026nbsp;for 248 patients with the completion of follow-up. Median length of ICU stay for survivors was 22 [12, 38] days. Table 3 shows an overview of mortality rates in relation to the onset of CS therapy. Survival was numerically higher when CS therapy was initiated within 1 day of ICU admission onset compared to initiation after more than 1 day (see also Figure 1). Note that the Kaplan\u0026ndash;Meier curve accounts for censored data, unlike incidence rates, which exclude patients lost to follow-up. However, it cannot accurately estimate ICU mortality because patients have varying ICU lengths of stay. Furthermore, patients with immediate CS onset had shorter ICU stay (16 vs. 27 days, p\u0026lt;0.0001) and hospital stay (30 vs. 42 days, p=0.005).\u003c/p\u003e\n\u003cp\u003eTable 3. Mortality of patients according to onset of CS Therapy in relation to ICU admission\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 154px;\"\u003e\n \u003cp\u003eOnset of CS within 0-1 day of ICU admission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 207px;\"\u003e\n \u003cp\u003eDelayed onset (\u0026gt;=2 days after ICU admission)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003eICU mortality\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 154px;\"\u003e\n \u003cp\u003e22.3% (25/112)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 207px;\"\u003e\n \u003cp\u003e29.8% (39/131)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e0.189\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003eHospital Mortality\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 154px;\"\u003e\n \u003cp\u003e27.3% (30/110)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 207px;\"\u003e\n \u003cp\u003e32.3% (40/130)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e0.396\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003eMortality at 90-day FU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 154px;\"\u003e\n \u003cp\u003e34.7% (35/101)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 207px;\"\u003e\n \u003cp\u003e44.3% (54/122)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e0.145\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 4 summarizes biomarker data pre versus post CS use. Of note, in patients where CS was integrated into ECMO or used in hemoperfusion mode without KRT (n=31) creatinine (1.9 [1.1, 3.0] to 1.3 [0.8, 2.0] mg/dL, p\u0026lt;0.0001) and lactate (2.1 [1.2, 2.6] to 1.4 [1.1, 1.6] mmol/L, p=0.037) were also significantly reduced.\u003c/p\u003e\n\u003cp\u003eTable 4. Overview of laboratory findings before versus after CS therapy.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"678\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBiomarkers\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian levels [IQR] before CS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian levels [IQR] after CS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInterleukin\u003c/strong\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003cstrong\u003e6 pg/mL, n=58\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e563 [187, 14,168]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e104 [52, 1,299]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eC-Reactive Protein mg/dL, n=159\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e13.0 [3.5, 22.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e10.8 [4.3, 19.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.082\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProcalcitonin ng/mL, n=98\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e9.4 [2.1, 47.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e3.3 [1.2, 16.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u003cstrong\u003epH, n=233\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e7.35 [7.30, 7.42]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e7.40 [7.36, 7.45]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLactate mmol/L, n=231\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e2.4 [1.4, 4.9]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.4 [1.0, 2.2]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCreatinine mg/dL, n=231\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e2.1 [1.4, 3.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1.4 [0.9, 2.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAlbumin g/dL, n=122\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e2.6 [2.3, 3.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e2.5 [2.3, 3.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.112\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlatelets x10\u003csup\u003e9\u003c/sup\u003e/L, n=237\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e123 [76, 185]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e72 [42, 118]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eLegend: CS: CytoSorb; IQR; Interquartile range\u003c/p\u003e\n\u003cp\u003eSecondary outcomes including 24-hour fluid balance, norepinephrine requirements (NE) and P/F ratio all significantly improved post CS treatment (p\u0026lt;0.0001 for all, Figure 2). Significant improvements were also noted post treatment for MAP/NE index (287 [157, 635] to 681 [302, 1,400] mmHg\u0026middot;kg\u0026middot;min/\u0026micro;g, p\u0026lt;0.0001). Change in fluid balance was also significant in patients without KRT from +1,383 [0, 3,700] to -227 [-1,390, 497] mL (p=0.034). SOFA Score improved from 12 [9, 15] to 11 [8, 14] over course of CS treatment in the whole cohort (p=0.001), and equally from 12 [10, 15] to 11 [9, 14] in patients with septic shock (p=0.003). Figure 2 summarizes the most important findings before versus after CS treatment.\u003c/p\u003e\n\u003ch2\u003eSafety\u003c/h2\u003e\n\u003cp\u003ePlatelet counts decreased during CS treatment (123 [76, 185] to 72 [42, 118] x10\u003csup\u003e9\u003c/sup\u003e/L, p\u0026lt;0.0001), an effect primarily driven by platelet count reductions in the septic cohort (122 [86, 182] to 65 [36, 121] x10⁹/L, p\u0026lt;0.0001), while platelets did not significantly decrease in patients with cardiogenic shock (102 [60, 164] to 69 [39, 107] x10\u003csup\u003e9\u003c/sup\u003e/L, p=0.137) or liver failure (85 [42, 149] to 66 [43, 99] x10\u003csup\u003e9\u003c/sup\u003e/L, p=0.322). 31% of overall patients (n=93) received platelet transfusion concomitantly with CS therapy. No major bleeding events were reported. Median albumin levels did not change significantly during treatment (2.6 [2.3, 3.1] g/dL pre- versus 2.5 [2.3, 3.0] post-CS (p=0.112), however with 43.7% of patients receiving albumin substitution. No Serious Adverse Device Effects or Device Deficiencies were reported by the time this interim analysis was performed.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this interim analysis of 300 patients, CS therapy was applied across diverse critical care indications. Observed improvements in hemodynamics, oxygenation, and fluid balance, along with lower-than-predicted ICU mortality, suggest potential benefit, although these findings should be interpreted cautiously given the observational design.\u003c/p\u003e\u003cp\u003eThese results are consistent with results from previous interim analyses (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Notably, the broad range of indications highlights its increasing role beyond septic shock, with emerging applications particularly in liver failure (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) and rhabdomyolysis (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Further research is needed to clarify its role in these different contexts.\u003c/p\u003e\u003cp\u003eThe mean number of adsorbers used reveals a high degree of variability in clinical practice, with 28% of patients receiving four or more devices. This underscores one of the major values of the registry, which enables a more comprehensive understanding of how clinicians indicate and apply CS therapy in real-world settings. As enrollment numbers in the COSMOS Registry continue to increase, dedicated subgroup analyses may help clarify how treatment intensity (e.g., number of adsorbers or exchange intervals) relates to clinical outcomes in different patient groups (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Moreover, such analyses may identify specific subgroups that derive the greatest clinical benefit from CS therapy.\u003c/p\u003e\u003cp\u003ePatients included in this analysis had a baseline APACHE II score of 24, corresponding to an expected mortality in nonoperative patients of 40% (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) and SOFA median of 12, which as an initial score in the general ICU population corresponds to a mortality risk of 95.2% (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). A more recent study focusing on adults with suspected infection predicted for a SOFA of 12 an in-hospital mortality of around 50% (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). In the current analysis, ICU mortality was 33.1% (32.9% in septic shock) despite high baseline disease severity. These findings are further supported by a recent systematic review and meta-analysis in septic shock patients, which showed that CS use significantly reduced both in-hospital and 28\u0026ndash;30-day mortality in 744 critically ill patients (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). While the design of this study does not allow for causal conclusions, these results may suggest a potential benefit of CS therapy in improving outcomes in critically ill patients, especially when used in appropriately selected patients and with adequate treatment regimens.\u003c/p\u003e\u003cp\u003eThe observed median ICU stay of 22 days is notable in the context of healthcare resource utilization and cost. The potential clinical benefits \u0026ndash; such as hemodynamic stabilization, improved oxygenation, and fluid balance \u0026ndash; may translate into shorter ICU stays and reduced resource utilization if validated in larger controlled studies. Further cost-effectiveness analyses are warranted to determine its economic impact, especially in resource-intensive settings (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eNorepinephrine requirements decreased significantly over the course of CS treatment resulting in hemodynamic stabilization, an observation that is consistent with prior evidence (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). While the underlying pathophysiologic mechanism may be linked to improved vascular function and a reduction in the inflammatory burden (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e), observed decreased vasopressor requirements with CS therapy may contribute to minimizing organ hypoperfusion and ischemia (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Importantly, hemodynamic improvement was not achieved at the cost of additional fluid overload but was instead accompanied by significantly reduced need for fluid resuscitation which seems to be relevant also in the context of the observed improved oxygenation. These effects are clinically relevant, as intravenous fluid resuscitation can lead to dilutional coagulopathy, fluid overload, and the development of pathogenic edema in the lungs and other organs (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). The observed reductions in lactate, creatinine, and fluid balance in patients not receiving KRT indicate that these effects are likely linked to CS treatment, rather than consequences of concomitant KRT. The observed improvements may reflect, at least in part, a potential endothelial protective effect of CS by removing circulating inflammatory factors known to impair endothelial function, contributing to enhanced vascular function and fluid homeostasis (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eFinally, the current analysis reinforces the favorable safety profile of CS therapy, with no serious adverse device effects or deficiencies reported. The observed decrease in platelet counts, primarily in septic shock patients, should be interpreted cautiously, as thrombocytopenia is a common feature in sepsis (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). It is however reassuring, that despite the observed drops in platelet counts there were no bleeding events reported (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eClinical Implications\u003c/h2\u003e\u003cp\u003eTimely removal of circulating harmful substances, such as overshooting cytokines (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) or myoglobin in rhabdomyolysis (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), are critical goals in the management of critically ill patients. Patients eligible for CS therapy should preferably be treated within 24 hours of ICU admission. The hemoadsorption properties of CS enable efficient elimination of these and other inflammatory mediators, potentially contributing to the stabilization of the endothelial barrier (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) and attenuation of systemic hyperinflammation. COSMOS Registry data suggest that CS may be associated with improvements in hemodynamics, fluid balance, and oxygenation. For physicians, this underlines the role of CS in supporting hemodynamic recovery in shock states, particularly vasoplegic shock in sepsis. Furthermore, improved fluid balance reduces risks associated with fluid overload, such as worsening respiratory distress reinforcing the potential benefit of CS therapy in managing patients with capillary leak and ARDS. Moreover, CS therapy was safely used in conjunction with renal replacement therapy, ECMO or standalone hemoperfusion, underlining its versatility. For decision-makers, these findings offer a rationale for further integration of CS therapy into standard care pathways while supporting ongoing research to maximize its clinical utility.\u003c/p\u003e\u003cp\u003eWhile these results are promising, further investigations are necessary, particularly controlled trials in dedicated indications, that compare outcomes with the addition of CS therapy to established treatment standards. Such studies will help refine clinical indications, optimize treatment protocols, and further establish the role of CS in improving outcomes for critically ill patients. Importantly, observations from this registry may serve as a valuable source for hypothesis generation, guiding the design and focus of future clinical trials.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eLimitations\u003c/h2\u003e\u003cp\u003eA key limitation common to all observational single-arm registries, including COSMOS, is the absence of a control group, which prevents establishing definitive causality between the intervention and the outcomes observed. As such, the findings should be interpreted with caution as suggestive rather than conclusive evidence. A second limitation is that at the time of this interim analysis, some patient datasets were incomplete, leading to a reduced sample size for certain analyses. Furthermore, another limitation is the lack of standardized use of CS therapy across participating centers. The registry encompasses a heterogeneous population in which CS is applied for multiple indications. The therapeutic approach (treatment initiation, duration, and dosing strategies) may therefore differ according to the underlying indication and was left to the discretion of the treating physicians. In addition, there was no standardized measurement of predefined parameters, which may have introduced heterogeneity and limited comparability of outcomes across sites.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis interim analysis of the international, real-world COSMOS Registry reports significant improvements in key therapeutic targets that might be associated with the use of CS as part of standard clinical practice across multiple critical care indications. Specifically, integration of CS was observed to be associated with hemodynamic stabilization and improved fluid balance and oxygenation resulting in observed ICU mortality lower than predicted by established risk scores. These findings provide valuable insights into the potential clinical benefits of CS in real-world settings and warrant further investigation.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp dir=\"LTR\"\u003e90-day FU\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;90 days Follow-up\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eACLF\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Acute-On-Chronic Liver Failure\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eALF\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Acute Liver Failure\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eAPACHE\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Acute Physiology And Chronic Health Evaluation\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eARDS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Acute Respiratory Distress Syndrome\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eBMI\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Body Mass Index\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eCRP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;C-Reactive Protein\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eCRS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Cytokine Release Syndrome\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eCS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;CytoSorb®\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eDD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Device Deficiencies\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eECLS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Extracorporeal Life Support System\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eECMO\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Extracorporeal Membrane Oxygenation\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eFU\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Follow-up\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eGCP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Good Clinical Practice\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eHLH\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Hemophagocytic Lymphohistiocytosis\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eICF\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Informed Consent Form\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eICH\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;International Conference on Harmonization\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eICU\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Intensive Care Unit\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eIEC\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Independent Ethics Committee\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eIL-6\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Interleukin-6\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eIQR\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Interquartile Range\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eIRB\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Institutional Review Board\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eISO\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;International Organization for Standardization\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eKRT\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Kidney Replacement Therapy\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eMAP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Mean Arterial Pressure\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eNE\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Norepinephrine\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eP/F ratio\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Ratio of partial pressure of oxygen in arterial blood to the fraction of inspiratory oxygen concentration\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eRWE\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Real-World Evidence\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eSD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Standard Deviation\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eSLEDD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Sustained low-efficiency daily dialysis\u0026nbsp;\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eSOFA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Sequential Organ Failure Assessment\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eClinical Trial Number\u003c/h2\u003e\n\u003cp\u003eThe COSMOS Registry was registered on Clinicaltrials.gov, NCT05146336, since November 23, 2021.\u003c/p\u003e\n\u003ch2\u003eEthics Approval\u003c/h2\u003e\n\u003cp\u003eThe Registry is being conducted in compliance with ISO 14155:2020, the Declaration of Helsinki, and the principles of Good Clinical Practice (GCP), as outlined in the International Conference on Harmonization (ICH) E6 Guidelines for GCP, along with all relevant local legal requirements. Before the Registry begins, approval must be obtained from the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) for the study protocol, sample informed consent form (ICF), and any documents related to patient information or recruitment methods, such as advertisements. Any subsequent amendments to the protocol or changes to the ICF must also be submitted for approval by the IRB/IEC. The initial international ethics approval was from IRB ‘Comité de Ética de Investigación con Medicamentos del Hospital Universitario Vall d’Hebron’ with the approval number PR(AG)86/2022 (28 March 2022). Each participating center is required to obtain approval from its respective IRB before study activation.\u003c/p\u003e\n\u003ch2\u003eConsent to participate\u003c/h2\u003e\n\u003cp\u003eWritten informed consent was obtained from all subjects or legally authorized representatives involved in the study.\u003c/p\u003e\n\u003ch2\u003eConsent for Publication\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eAvailability of Data and Materials\u003c/h2\u003e\n\u003cp\u003eThe data are available upon reasonable written request and with written permission of CytoSorbents Corporation. Data Management Plan and Informed Consent Forms are available upon request.\u003c/p\u003e\n\u003ch2\u003eCompeting Interests\u003c/h2\u003e\n\u003cp\u003eFST, GB, JH, AK, JLT, DT, and RF have consulting contracts with CytoSorbents Corporation and CytoSorbents Medical Inc. AB has received reimbursements for travelling expenses and honoraria for presentations from CytoSorbents Europe GmbH. JK has received honoraria for presentation from CytoSorbents Europe GmbH. TeK and JS are full-time employees of CytoSorbents Europe GmbH. END and WF are full-time employees of CytoSorbents Corporation and CytoSorbents Medical Inc.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eCytoSorbents Corporation and CytoSorbents Medical Inc. are the funding sources.\u003c/p\u003e\n\u003ch2\u003eAuthor Contributions\u003c/h2\u003e\n\u003cp\u003eConceptualization, FST, TK, JS and RF; methodology, FST, TK and RF; writing, original draft preparation, TK and RF; writing, review and editing, MT, MU, TKi, AB, BT, AK, UG, JK, DH, MB, AE-E, NG, TG, PH, CS, PCS, MMF, MK, GB, FA, DT; statistics, WF; visualization, TK, WF; supervision, FST, JH, JLT, END, RF. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgments\u003c/h2\u003e\n\u003cp\u003eThe authors would like to thank Dr. Marie-Christin Pawlik, Robert Wilke and Antje Fechner for operational management of the Registry as well as Harriet Adamson for support with literature search.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eJansen A, Waalders NJB, van Lier DPT, Kox M, Pickkers P. CytoSorb hemoperfusion markedly attenuates circulating cytokine concentrations during systemic inflammation in humans in vivo. Crit Care. 2023;27(1):117.\u003c/li\u003e\n\u003cli\u003eRonco C, Tetta C, Mariano F, Wratten ML, Bonello M, Bordoni V, et al. Interpreting the mechanisms of continuous renal replacement therapy in sepsis: the peak concentration hypothesis. Artif Organs. 2003;27(9):792-801.\u003c/li\u003e\n\u003cli\u003eRimmele T, Kellum JA. Clinical review: blood purification for sepsis. Crit Care. 2011;15(1):205.\u003c/li\u003e\n\u003cli\u003eTomescu D, Popescu M, David C, Sima R, Dima S. Haemoadsorption by CytoSorb(R) in patients with acute liver failure: A case series. Int J Artif Organs. 2021;44(8):560-4.\u003c/li\u003e\n\u003cli\u003eGrafe C, Liebchen U, Greimel A, Maciuga N, Bruegel M, Irlbeck M, et al. The effect of cytosorb(R) application on kidney recovery in critically ill patients with severe rhabdomyolysis: a propensity score matching analysis. Ren Fail. 2023;45(2):2259231.\u003c/li\u003e\n\u003cli\u003eBlonde L, Khunti K, Harris SB, Meizinger C, Skolnik NS. Interpretation and Impact of Real-World Clinical Data for the Practicing Clinician. Adv Ther. 2018;35(11):1763-74.\u003c/li\u003e\n\u003cli\u003eInternational Organization for Standardization (ISO). ISO 14155:2020 Clinical investigation of medical devices for human subjects \u0026mdash; Good clinical practice. https://www.iso.org/standard/71690.html; 2020.\u003c/li\u003e\n\u003cli\u003eTaccone FS, Brunkhorst FM, Bottari G, Hidalgo J, Kribben A, Teboul JL, et al. The COSMOS Registry of CytoSorb Hemoadsorption Therapy in Critically Ill Patients: Protocol for an International, Prospective Registry. JMIR Res Protoc. 2024;13:e55880.\u003c/li\u003e\n\u003cli\u003eMitzner S, Kogelmann K, Ince C, Molnar Z, Ferrer R, Nierhaus A. Adjunctive Hemoadsorption Therapy with CytoSorb in Patients with Septic/Vasoplegic Shock: A Best Practice Consensus Statement. J Clin Med. 2023;12(23):7199.\u003c/li\u003e\n\u003cli\u003eForni L, Aucella F, Bottari G, Buttner S, Cantaluppi V, Fries D, et al. Hemoadsorption therapy for myoglobin removal in rhabdomyolysis: consensus of the hemoadsorption in rhabdomyolysis task force. BMC Nephrol. 2024;25(1):247.\u003c/li\u003e\n\u003cli\u003eHaselwanter P, Scheiner B, Balcar L, Semmler G, Riedl-Wewalka M, Schmid M, et al. Use of the CytoSorb adsorber in patients with acute-on-chronic liver failure. Sci Rep. 2024;14(1):11309.\u003c/li\u003e\n\u003cli\u003eFerrer R, Thielmann M, Kribben A, Unglaube M, Tyczynski B, Kreutz J, et al. The international, prospective CytOSorbⓇ treatMent Of critically ill patientS (COSMOS) registry: Interim results from the first 150 patients. Journal of Intensive Medicine. 2025.\u003c/li\u003e\n\u003cli\u003eGrafe C, Paal M, Winkels M, Irlbeck M, Liebchen U, Scharf C. Correlation between Bilirubin Elimination with the Cytokine Adsorber CytoSorb(R) and Mortality in Critically Ill Patients with Hyperbilirubinemia. Blood Purif. 2023;52(11-12):849-56.\u003c/li\u003e\n\u003cli\u003eScharf C, Liebchen U, Paal M, Becker-Pennrich A, Irlbeck M, Zoller M, et al. Successful elimination of bilirubin in critically ill patients with acute liver dysfunction using a cytokine adsorber and albumin dialysis: a pilot study. Sci Rep. 2021;11(1):10190.\u003c/li\u003e\n\u003cli\u003eBerlot G, Carocci P, Votrico V, Iacoviello B, Taverna N, Gerini U, et al. Real-World Outcomes of Hemoadsorption with CytoSorb((R)) in Patients with Septic Shock: Insights from a Single-Center Study. J Intensive Care Med. 2025;40(9):993-1000.\u003c/li\u003e\n\u003cli\u003eKnaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13(10):818-29.\u003c/li\u003e\n\u003cli\u003eFerreira FL, Bota DP, Bross A, Melot C, Vincent JL. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA. 2001;286(14):1754-8.\u003c/li\u003e\n\u003cli\u003eRaith EP, Udy AA, Bailey M, McGloughlin S, MacIsaac C, Bellomo R, et al. Prognostic Accuracy of the SOFA Score, SIRS Criteria, and qSOFA Score for In-Hospital Mortality Among Adults With Suspected Infection Admitted to the Intensive Care Unit. JAMA. 2017;317(3):290-300.\u003c/li\u003e\n\u003cli\u003eSteindl D, Schroeder T, Krannich A, Nee J. Hemoadsorption in the Management of Septic Shock: A Systematic Review and Meta-Analysis. J Clin Med. 2025;14(7):2285.\u003c/li\u003e\n\u003cli\u003eRao C, Preissing F, Thielmann M, Wendt D, Haidari Z, Kalisnik JM, et al. Hemoadsorption Using CytoSorb((R)) in Patients with Infective Endocarditis: A German-Based Budget Impact Analysis. J Cardiovasc Dev Dis. 2023;10(9):366.\u003c/li\u003e\n\u003cli\u003eRao C, Hawchar F, Akil A, Rugg C, Mehta Y, Scheier J, et al. Reducing vasopressor requirements with hemoadsorption in the critically ill: a systematic review. ISICEM; Sept 2nd 2021; Brussels: Crit Care; 2021. p. 55.\u003c/li\u003e\n\u003cli\u003ePapp M, Ince C, Bakker J, Molnar Z. Endothelial Protection and Improved Micro- and Macrocirculation with Hemoadsorption in Critically Ill Patients. J Clin Med. 2024;13(23):7044.\u003c/li\u003e\n\u003cli\u003eJesani S, Elkattawy S, Noori MAM, Ayad S, Abuaita S, Gergis K, et al. Vasopressor-Induced Digital Ischemia. Cureus. 2021;13(7):e16595.\u003c/li\u003e\n\u003cli\u003eJozwiak M, Geri G, Laghlam D, Boussion K, Dolladille C, Nguyen LS. Vasopressors and Risk of Acute Mesenteric Ischemia: A Worldwide Pharmacovigilance Analysis and Comprehensive Literature Review. Front Med (Lausanne). 2022;9:826446.\u003c/li\u003e\n\u003cli\u003eSelf WH, Semler MW, Bellomo R, Brown SM, deBoisblanc BP, Exline MC, et al. Liberal Versus Restrictive Intravenous Fluid Therapy for Early Septic Shock: Rationale for a Randomized Trial. Ann Emerg Med. 2018;72(4):457-66.\u003c/li\u003e\n\u003cli\u003eCox D. Sepsis - it is all about the platelets. Front Immunol. 2023;14:1210219.\u003c/li\u003e\n\u003cli\u003eBrozat CI, Zoller M, Frank S, Bruegel M, Grafe C, Rebholz D, et al. Albumin and Platelet Loss during the Application of CytoSorb(R) in Critically Ill Patients: A post hoc Analysis of the Cyto-SOLVE Trial. Blood Purif. 2025;54(2):93-101.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-anesthesia-analgesia-and-critical-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Journal of Anesthesia, Analgesia and Critical Care](https://janesthanalgcritcare.biomedcentral.com/)","snPcode":"44158","submissionUrl":"https://submission.nature.com/new-submission/44158/3","title":"Journal of Anesthesia, Analgesia and Critical Care","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"CytoSorb, hemoadsorption, hemoperfusion, adsorption, blood purification, hyperinflammation, sepsis, septic shock, liver failure, rhabdomyolysis, registry ","lastPublishedDoi":"10.21203/rs.3.rs-8036793/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8036793/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIntroduction\u003c/p\u003e\u003cp\u003eBlood purification techniques are being investigated as adjunctive options in critically ill patients not only to treat severe inflammation but also to remove harmful substances such as myoglobin in rhabdomyolysis. Yet, the available evidence is limited, and further research is needed to clarify their clinical benefits.\u003c/p\u003e\u003cp\u003eMethods\u003c/p\u003e\u003cp\u003eThe international prospective COSMOS Registry (NCT05146336, 23 Nov 2021) tracks CytoSorb\u0026reg; (CS) utilization patterns and outcomes in critical care settings. Clinical assessment was performed before, during, and after CS treatment, with a 90-day follow-up. At least \u0026ldquo;possibly device-related\u0026rdquo; adverse effects were reported by investigators as the safety evaluation. Data were analyzed according to a pre-specified statistical plan using descriptive statistics and paired tests to compare pre- and post-treatment values, with subgroup and safety analyses performed.\u003c/p\u003e\u003cp\u003eResults\u003c/p\u003e\u003cp\u003eA total of 300 adult patients (30.3% female, mean age 59\u0026thinsp;\u0026plusmn;\u0026thinsp;15 years) from 22 sites were included in this analysis. The most common indications for CS therapy (multiple indications possible per patient) were septic shock (48.3%), rhabdomyolysis (12.8%), cardiogenic shock (11.5%), liver failure (11.5%), and acute respiratory distress syndrome (ARDS; 5.0%). On average, each patient received 3.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3 adsorbers, with 27.9% of patients receiving 4 or more adsorbers. CS was integrated in conjunction with kidney replacement therapy (75.6%), standalone hemoperfusion (7.1%), intermittent hemodialysis (IHD; 10.6%), extracorporeal membrane oxygenation (ECMO; 3.9%), and sustained low-efficiency daily dialysis (SLEDD; 4.9%).At baseline, median (interquartile range, IQR) APACHE II and SOFA scores were 24 [18, 30] and 12 [9, 15], respectively.\u003c/p\u003e\u003cp\u003eFluid balance improved from +\u0026thinsp;1,675 [141, 3,348] mL pre-CS to +\u0026thinsp;115 [\u0026ndash;1,100, 1,495] mL post-CS, and norepinephrine requirements decreased from 0.21 [0.09, 0.40] \u0026micro;g/kg/min to 0.08 [0.02, 0.22] \u0026micro;g/kg/min (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 for both). Ratio of partial pressure of oxygen in arterial blood to the fraction of inspiratory oxygen concentration (P/F ratio) improved from 120 [72, 208] to 176 [115, 255] (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Platelet counts decreased from 123 [76, 185] to 72 [42, 118] x10\u003csup\u003e9\u003c/sup\u003e/L (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), while albumin levels remained stable from 2.6 [2.3, 3.1] to 2.5 [2.3, 3.0] g/dL (p\u0026thinsp;=\u0026thinsp;0.112). ICU mortality was 33.1%, which was lower than predicted by the scoring systems. No serious adverse effects related to the device or device deficiencies were reported.\u003c/p\u003e\u003cp\u003eConclusions\u003c/p\u003e\u003cp\u003eReal-world CytoSorb\u0026reg; use as part of standard care in critically ill patients showed an association with significant improvements in key therapeutic outcomes, including reduced norepinephrine, fluid requirements, and improved oxygenation. 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