Artificial liver support with CytoSorb and continuous veno- venous hemodiafiltration and advanced organ support (ADVOS) for critically ill patients with hyperbilirubinemia: a retrospective analysis

Artificial liver support with CytoSorb and continuous veno- venous hemodiafiltration and advanced organ support (ADVOS) for critically ill patients with hyperbilirubinemia: a retrospective analysis | 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 Artificial liver support with CytoSorb and continuous veno- venous hemodiafiltration and advanced organ support (ADVOS) for critically ill patients with hyperbilirubinemia: a retrospective analysis Kristina Schönfelder, Luisa Katharina Hirsch, Andreas Kribben, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6195702/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Aug, 2025 Read the published version in BMC Nephrology → Version 1 posted 14 You are reading this latest preprint version Abstract Background: As many as 30% of critically ill patients in intensive care units experience acute liver dysfunction with hyperbilirubinemia as a part of multiorgan failure that is associated with poor outcome. This retrospective cohort study was aimed at comparing CytoSorb and ADVOS in terms of bilirubin removal and overall survival among critically ill patients with hyperbilirubinemia ≥ 7 mg/dL. Methods: At the University Hospital Essen, between January 2021 and March 2024, 71 patients were treated with CytoSorb integrated in a continuous veno-venous hemodiafiltration (CVVHDF) circuit, and 71 patients were treated with ADVOS. Each therapy session lasted 24 hours. Results: The first single sessions of both CytoSorb with CVVHDF and ADVOS were associated with a statistically significant decrease in total serum bilirubin levels (Cytosorb, 20 to 14 mg/dL, p<0.0001; ADVOS, 16 to 14 mg/dL, p<0.0001), but the percentage bilirubin reduction was more pronounced for CytoSorb treatment (26% vs. 17%, p=0.0002). The number of days of treatment was similar for both groups (3 vs. 4, p=0.07). After completion of therapy, serum levels of total bilirubin had decreased significantly; 19.9 to 11.3 mg/dl (p<0.0001) in the CytoSorb group and 16.3 to 14.0 mg/dL (p=0.003) in the ADVOS group. The relative bilirubin reduction was significantly higher after application of CytoSorb than after treatment with ADVOS (35% (IQR 19,54) vs. 15% (IQR -11;54), p<0.0001). The relative removal of creatinine and urea nitrogen was significantly higher after ADVOS treatment than after CytoSorb with CVVHD treatment. Courses of treatment with CytoSorb and ADVOS reduced similarly platelet counts, hemoglobin levels, and C-reactive protein levels. CytoSorb treatment led to a significant decline in procalcitonin levels. Seven-day or in-hospital mortality rates were high among critically ill patients in both liver support groups. Conclusions: Our results showed that CytoSorb and CVVHDF treatment performed better than ADVOS in bilirubin removal among critically ill patients with hyperbilirubinemia caused by acute liver dysfunction. ADVOS was more efficient in eliminating creatinine and urea nitrogen than was CVVHDF with CytoSorb. Additional prospective randomized controlled trials are warranted to investigate the efficacy of hemoperfusion with CytoSorb for liver disease indications among critically ill patients. CytoSorb ADVOS bilirubin acute-on-chronic liver failure secondary acquired liver dysfunction continuous veno-venous hemodiafiltration Figures Figure 1 Figure 2 Figure 3 1. Background Acute impairment of liver function is a common life-threatening condition among critically ill patients admitted to intensive care units (ICUs). The incidence of acute liver dysfunction is as high as 30% among critically ill patients during the course of their illness ( 1 ). The manifestations of acute liver dysfunction among critically ill patients vary but may include acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). ALF is related to viral infections, hepatotoxic drugs, or hypoxemia resulting in rapid necrosis of liver tissue and therefore an increase in bilirubin levels ( 2 – 3 ). Patients with ALF are at risk of multiorgan failure with a mortality rate of 50% ( 2 ). ACLF is a consequence of decompensation of chronic liver cirrhosis, causing hepatic and extrahepatic organ failure, and is also characterized by excessive short-term mortality rates ( 4 ). Systemic hyperinflammation is involved in the pathogenesis of both ALF and ACLF ( 5 ); however, secondary acquired acute liver failure occurs more often among critically ill patients ( 6 ). Inflammation in the context either of sepsis and multiorgan failure or of exposure to toxic substances predominantly triggers the development of secondary acquired liver failure ( 3 , 7 ). Release of inflammatory mediators induces downregulation of specific transporters of bile acids and bilirubin on the surface of hepatocytes, provoking non-obstructive formation and accumulation of bile acids and bilirubin because of impaired secretion ( 3 , 7 ). Thus, the mortality rate among critically ill patients with secondary acquired liver dysfunction is 11% ( 8 ). Hyperbilirubinemia reflects early hepatic dysfunction among critically ill patients ( 9 ). Thus, the serum bilirubin level has been established as an appropriate surrogate marker for the assessment of deterioration of excretory liver function and the development of acute forms of liver dysfunction, and it is a part of several scores ( 10 ). Although bilirubin itself does not exhibit any direct toxic effect on hepatocytes, in several studies the elevation of circulating bilirubin concentrations was shown to correlate with an increase in the risk of mortality among critically ill patients ( 11 – 12 ). So far, there is no specific therapy for the management of acute liver dysfunction with hyperbilirubinemia among critically ill patients, and treatment protocols are often center-specific. Liver transplant is the only curative therapy option, but only 4.5% of patients undergo liver transplant because most transplant candidates are considered “too sick to transplant” persistent infections and multiorgan failure ( 13 ). Several artificial extracorporeal devices have been tested for replacing hepatic function and bridging patients to liver transplant or recovery ( 14 ). Hemoperfusion using the cytokine adsorber CytoSorb is a new artificial liver support method ( 3 ). This medical device was primarily developed for cytokine removal to control hyperinflammation in septic shock ( 15 ). The adsorber can be implemented in a continuous renal replacement therapy (CRRT) circuit ( 15 ). CytoSorb has a large adsorption capacity because of its surface area of 45,000 qm, and it is reported to eliminate hydrophobic substances with a molecular size of 5 to 55 kD ( 15 ). The molecular weight of bilirubin falls within the aforementioned range of adsorption; thus, the combination of CRRT with CytoSorb absorber can be used for extracorporeal purification of bilirubin from the blood of in critically ill patients with acute kidney injury and hyperbilirubinemia ( 3 , 15 – 16 ). Some case reports and retrospective studies indicate that CytoSorb is efficient in reducing bilirubin levels among critically ill patients with liver failure ( 3 , 16 ). As described in the meta-analysis by Turan et al., CytoSorb is a feasible and safe approach for treating critically ill patients with acute liver dysfunction ( 3 ). Advanced organ support (ADVOS) is also an artificial liver support tool ( 17 ). It is an extracorporeal multiple organ support system that enables simultaneous replacement of multiple organs, such as liver, kidney, and lungs, with a unified device ( 17 ). ADVOS as part of an advanced hemodialysis system combines three extracorporeal circuits: the extracorporeal blood circuit, the dialysate circuit, and the albumin multicircuit ( 17 ). As a new albumin-dialysis procedure using a recirculating and recyclable albumin-enriched solution, ADVOS allows detoxification of water-soluble and albumin-bound molecules ( 17 ). ADVOS is licensed in Germany for patients with acute kidney failure and hyperbilirubinemia in the setting of critical illness ( 17 ). Published clinical evidence demonstrates that the first ADVOS treatment session produces a statistically significant reduction in bilirubin levels ( 17 ). On the basis of this background information, we decided to perform a retrospective comparison of two artificial systems for liver support: CytoSorb integrated in a continuous veno-venous hemodiafiltration (CVVHDF) circuit, and ADVOS. The aim of this retrospective analysis was to determine and to compare the effects of both liver support modalities in the elimination of bilirubin, liver function and disease severity in a cohort of critically ill patients with acute kidney failure and hyperbilirubinemia caused by diverse forms of acute liver dysfunction. 2. Methods 2.1 Study population This monocentric retrospective study compared two approaches for extracorporeal liver support: 1) the combination of the cytokine adsorber CytoSorb (CytoSorbents Europe GmbH, Berlin, Germany) plus CVVHDF, and 2) ADVOS (ADVITOS GmbH, Munich, Germany), in critically ill patients with hyperbilirubinemia in terms of bilirubin elimination and effects on clinical scores and overall survival rates. This study enrolled adult patients with hyperbilirubinemia (total serum bilirubin levels 7 mg/dL or higher) and acute kidney injury requiring CRRT. Exclusion criteria were the use liver support systems other than CytoSorb or ADVOS and the use of several liver support systems during the ICU stay. Patients were divided into two groups. One group consisted of 71 critically ill patients who were treated with a combination of CVVHDF and CytoSorb between January 2021 and March 2024 at the University Hospital Essen. The other group consisted of 71 patients who underwent ADVOS therapy during their stay in the ICU of the University Hospital Essen between January 2021 and March 2024. Indications for liver support were ALF or ACLF with hyperbilirubinemia or with hyperbilirubinemia caused by secondary liver dysfunction in the context of sepsis and multiorgan failure. ALF and ACLF were defined in accordance with the European Association for the Study of the Liver guidelines. All included patients received at least one session of treatment with CytoSorb or ADVOS over 24 hours. An extracorporeal liver support session was considered to be a single treatment with either CVVHDF plus CytoSorb or ADVOS. Extracorporeal liver support therapy was provided in addition to standard medical care. The type of artificial liver support therapy used, either CytoSorb or ADVOS, and the time point of treatment initiation were decided by the attending treating physician. The local ethics committee of the University Duisburg-Essen approved this retrospective study (23-11563-BO, 23-11170-BO). All laboratory variables were determined by standard clinical chemistry tests in the Institute of Laboratory Medicine Essen and were obtained from the laboratory information system within the first 24 hours before the initiation of liver support therapy, defined as day 0 (d0), and after 24, 48, and 72 hours of treatment, as well as at the end of treatment. Demographic and clinical data were collected from patient information systems by retrospective electronic medical record review. 2.2 Study setting Patients in the CytoSorb group were treated with with the high-flux F60S dialyzer (effective surface area, 1.3-qm; Fresenius, Medical Care AG, Bad Homburg, Germany), and the CytoSorb adsorber was placed upstream of the dialyzer. The duration of a single CytoSorb application was 24 hours; the adsorber was exchanged every 24 hours. The initial settings for CVVHDF were the following: blood flow of 100 mL/min, dialysate flow of 1000 to 3000 mL/min, and predilution with a 5% glucose solution at 600 to 800 mL/min. The entire CVVHDF circuit was exchanged regularly every 72 hours. Anticoagulation was performed with regional citrate. The duration of a single ADVOS session was 24 hours. The ADVOS system consisted of three extracorporeal circuits: blood circuit, dialysate circuit, and ADVOS multicircuit ( 18 ). In the extracorporeal blood circuit the patient’s blood was cleaned by two high-flux polyethersulfone dialyzers (SURELYZER PES-190 DH, Nipro D. Med Germany GmbH, Hamburg, Germany) with a 1.9-qm effective surface for each dialyzer ( 18 ). The dialysate circuit and ADVOS multicircuit were necessary for eliminating water-soluble and protein-bound toxins from the patient’s blood ( 18 ). The dialysate contained a mixture of alkaline concentrate (mainly NaOH), an acid concentrate (mainly HCl), osmosis water, and 200 mL of 20% pharmaceutical grade albumin, and it was recirculated with a flow of 800 mL/min in the second circuit ( 18 ). For this recirculating procedure, the dialysate was divided in two paths, in which acidic or basic concentrates were added with a concentrate flow of 160 or 320 mL/min to change the pH and to provoke the release of anionic or cationic albumin-bound substances and, in this way, to regenerate albumin-binding capacity ( 18 ). The pH of the dialysate can be adjusted between 7.2 and 9.0 by modifying the ratio of acidic and basic concentrates ( 18 ). The released anionic or cationic substances were further filtered by convection through two polynephron high-flux dialyzers (ELISIO-13H, Nipro D. Med Germany GmbH, Hamburg, Germany) with a 1.3-qm effective surface for each dialyzer ( 18 ). Each dialyzer was installed in either an acidic or a basic path of the ADVOS multicircuit ( 18 ). The removed filtrate was continuously replaced by permeate (i.e., osmosis water) and acidic and basic concentrates ( 18 ). ADVOS therapy was conducted at the following initial settings: blood flow, 100 mL/min; concentrate flow, 160 mL/min; dialysate pH, 7.8. Blood anticoagulation was maintained by the application of regional citrate. 2.3 Statistical analysis Categorical variables were presented as numbers and percentages, and continuous variables were given as medians with interquartile ranges. The two-tailed χ 2 test for categorical variables and the Mann-Whitney test for not normally distributed quantitative data were used to detect differences between the CytoSorb and ADVOS groups. The differences between variables obtained at the start of liver support therapy and those obtained at the completion of therapy were analyzed with the Wilcoxon test. Survival was assessed by Kaplan-Meier analysis, and the p values were determined by the log-rank test. All p values are two-tailed, and statistical significance was assumed for p values ≤ 0.05. All statistical analyses were performed with GraphPad Prism version 6 (GraphPad Software, Inc., La Jolla, CA, USA) and IBM SPSS Statistics version 23 (IBM Corp., Armonk, NY, USA). 3. Results 3.1 Patient characteristics Table 1 illustrates patients’ demographic characteristics and laboratory values measured immediately before the initiation of liver support. ACLF was significantly more frequent in the ADVOS group than in the CytoSorb group, whereas secondary acquired acute liver dysfunction occurred significantly more often among patients treated with CytoSorb than among patients treated with ADVOS. Patients from the CytoSorb group stayed significantly longer in an ICU before the initiation of liver support therapy; they also exhibited a significantly higher Sequential Organ Failure Assessment (SOFA) score at baseline than did those patients who underwent ADVOS treatment. Model for End-Stage Liver Disease (MELD) scores at study inclusion were significantly higher among patients in the ADVOS group than among those in the CytoSorb group. With regard to biochemical data, patients in the CytoSorb group exhibited significantly higher baseline levels of liver transaminases, lactate dehydrogenase (LDH), prothrombin time, hemoglobin, C-reactive protein, and procalcitonin. Indeed, baseline partial thromboplastin times (PTT) were higher for patients treated with ADVOS than for those treated with CytoSorb. Baseline total serum bilirubin levels did not differ significantly between the treatment groups. Table 1 Comparison of baseline clinical and laboratory values between 71 patients treated with a combination of CytoSorb plus continuous veno-venous hemodiafiltration and 71 patients treated with the ADVOS system. All patients were admitted to the intensive care unit of the University Hospital Essen between January 2021 and March 2024 because of critical illness with hyperbilirubinemia and acute kidney injury. Values are presented as medians. Variable CytoSorb n = 71 ADVOS n = 71 RR (CI) p value Age (years) 58 55 0.55 Women, (%) 30 (42) 30 (42) 1.0 (0.7–1.5) 0.99 Number of sessions, (range) 3 ( 1 – 18 ) 4 (1–56) 0.07 Duration of CRRT (hours), (range) 72 (24–576) 96 (24-1344) 0.07 ACLF, (%) 31 (44) 66 (93) 0.5 (0.4–0.6) 0.0001 ALF, (%) 5 ( 7 ) 5 ( 7 ) 1.0 (0.3–3.1) 0.99 Secondary acquired liver dysfunction, (%) 35 (49) 0 (0) infinity (2.0-infinity) 0.0001 Days in ICU before therapy 9 1 0.0001 Continous dialysis before therapy, (%) 35 (49) 32 (45) 1.1 (0.8–1.6) 0.61 SOFA (points) 19 18 0.04 SAPS II (points) 81 77 0.06 MELD (points) 30 33 0.04 Laboratory values at baseline Bilirubin (mg/dL) 19.9 13.6 0.08 ALT (U/L) 88 63 0.06 AST (U/L) 172 139 0.04 GGT (U/L) 111 67 0.009 LDH (U/L) 511 347 0.0006 Leukocytes (/nL) 15.6 15.0 0.42 Hemoglobin (g/dL) 8.9 7.8 0.004 Platlets (/nL) 87 65 0.26 Prothrombin time (%) 50 33 0.0001 PTT (sec) 41 55 0.0001 Serum creatinine (mg/dL) 2.1 2.0 0.75 Blood urea nitrogen (mg/dL) 57 54 0.81 Lactate (mmol/L) 2.3 2.6 0.45 pH 7.39 7.38 0.82 Base excess -0.2 -2.2 0.20 C-reactive protein (mg/dL) 14 8 0.0001 Procalcitonin (ng/mL) 5.2 2.2 0.0001 ACLF, acute-on-chronic liver failure; ADVOS, advanced organ support; ALF, acute liver failure; ALT, alanine transaminase; AST, aspartate transaminase; CI, confidence interval; CRRT, continuous renal replacement therapy; ICU, intensive care unit; GGT, gamma-glutamyltransferase; L, liter; LDH, lactate dehydrogenase; MELD, Model for End-Stage Liver Disease; PTT, partial thromboplastin time; RR, relative risk; SAPS II, Simplified Acute Physiology Score II; SOFA, Sequential Organ Failure Assessment; U, unit. 3.2 Use of CytoSorb was associated with significantly higher clearance of bilirubin than was ADVOS First, we compared the two liver support methods in eliminating total serum bilirubin. Both devices significantly decreased bilirubin concentrations at the end of the first treatment session lasting 24 hours (CytoSorb plus CVVHDF, 20 to 14 mg/dL, p < 0.0001; ADVOS, 16 to 14 mg/dL, p < 0.0001) (Fig. 1 A). However, the relative median reduction of total bilirubin levels achieved by CytoSorb within the first 24 hours of treatment was significantly higher than that after the first use of ADVOS over 24 hours (26% vs. 17%, p = 0.0002) (Fig. 1 B). A full course of treatment with either liver support mode significantly reduced total bilirubin levels, but this end-of-treatment reduction was more pronounced in the CytoSorb group (19.9 to 11.3 mg/dl, p < 0.0001) than in the ADVOS group (16.3 to 14.0 mg/dL, p = 0.003) (Fig. 1 C). The median duration of a full course of treatment with CytoSorb was 72 hours (range 24–432 hours) and with ADVOS 96 hours (range 24-1344 hours), respectively (p = 0.07). As was true for the results of the single session, the elimination of bilirubin after the completion of liver support treatment was significantly higher among patients in the CytoSorb group (35%) than among those in the ADVOS group (15%) (p < 0.0001) (Fig. 1 D). As shown in Fig. 1 B, the highest value of relative bilirubin reduction was achieved after the first day of treatment with either liver support option. After 48 and 72 hours of treatment, both liver support modalities exhibited a decrease in the elimination capacity of bilirubin among critically ill patients who survived longer than one day (Fig. 1 B). However, the relative removal of bilirubin by CytoSorb was significantly higher than the relative removal by ADVOS at all time points of treatment (Fig. 1 B). Next, we separately analyzed the subgroup of 97 patients for whom ACLF was the cause of liver dysfunction with hyperbilirubinemia (Supplementary Fig. 1). The initial total bilirubin levels (CytoSorb, 17.6 mg/dL; ADVOS, 15.7 mg/dL; p = 0.1) and the number of sessions (CytoSorb, 3 sessions; ADVOS, 4 sessions; p = 0.2) were similar for patients in both groups. The median duration of the liver support (72 (range 24–240 hours) vs. 96 hours (range 24-1344 hours); p = 0.15), as well as the median duration of continuous renal replacement therapy (72 (range 24–576 hours) vs. 96 hours (range 24-1344 hours); p = 0.14) were also comparable in both groups. The results achieved by the analysis of bilirubin clearance for this subgroup were similar to those achieved by analysis of the entire cohort (Supplementary Fig. 1A-D). Again, the relative reductions in total bilirubin levels after the first single session (Supplementary Fig. 1C) and at the end of treatment (Supplementary Fig. 1D) were significantly higher in the CytoSorb group than in the ADVOS group. 3.3 Changes in biochemical variables during liver support with CytoSorb versus ADVOS Changes between pretreatment and posttreatment laboratory values in the two patient groups are depicted in Fig. 2 . The full course of treatment with CytoSorb was associated with a significant decrease in gamma-glutamyl transferase (GGT) activity, in prothrombin time, and in creatinine, blood urea nitrogen, platelet count, hemoglobin, C-reactive protein, and procalcitonin levels, and with a significant increase of in PTT and lactate levels (Fig. 2 ). Treatment with ADVOS led to a significant decrease in levels of creatinine, blood urea nitrogen, prothrombin time, platelet count, hemoglobin, and C-reactive protein and to a significant elevation of transaminase activity, lactate dehydrogenase (LDH) activity, PTT, lactate levels, and pH (Fig. 2 ). The intergroup comparison showed a significantly higher relative reduction of serum creatinine and urea nitrogen among patients treated with ADVOS than among those treated with the combination of CVVHDF and CytoSorb (Fig. 2 ). Application of ADVOS also led to a significantly higher relative increase in pH values than did treatment with CytoSorb (Fig. 2 ). A percentage increase in posttreatment transaminase activity and LDH activity occurred in the ADVOS group but not in the CytoSorb group (Fig. 2 ). The relative reduction of procalcitonin levels was significantly higher in the CytoSorb group than in the ADVOS group, a finding suggesting that ADVOS treatment did not influence procalcitonin levels. As indicated in Supplementary Tables 1 through 3, an additional focus on the subgroup of ACLF patients showed alterations in relevant laboratory values similar to those achieved with the entire cohort. In summary, ADVOS treatment led to a larger relative reduction of serum creatinine und blood urea nitrogen levels and to a greater improvement of pH values than did CytoSorb treatment, but it was related to an additional deterioration of liver function with a corresponding additional increase in liver enzyme activity during the treatment course (Supplementary Table 3). In contrast to ADVOS therapy, CytoSorb treatment led to stable liver function values and a significant decrease in procalcitonin concentrations at the end of treatment (Supplementary Table 3). 3.4 Clinical scoring and short-term mortality under CytoSorb and ADVOS With respect to prognostic clinical scores, in the CytoSorb group we found no changes between pretreatment and posttreatment SOFA scores or Simplified Acute Physiology Score II (SAPS II) scores (Fig. 3 A). In the ADVOS group SOFA scores further increased and SAPS II scores remained unchanged after the completion of adjuvant liver support (Fig. 3 A). We found a significant improvement in MELD scores after treatment with both liver support devices (Fig. 3 A). Comparison of relative reduction of clinical scores between the two liver support systems showed no differences between the groups in SAPS II and MELD scores (Fig. 3 A). Compared to patients treated with CytoSorb, patients in the ADVOS group experienced a significant worsening of SOFA scores during the posttreatment period (Fig. 3 A). For the subgroup of ACLF patients, none of the three clinical scores was influenced by CytoSorb therapy (Supplementary Table 1). ADVOS led to a further elevation in the SOFA score and a decrease in the MELD score after treatment (Supplementary Table 2). Results of the relative changes in clinical scores among critically ill ACLF patients completely reproduced the results achieved for the entire cohort (Supplementary Table 3). We examined short-term mortality among critically ill patients with hyperbilirubinemia due to acute liver dysfunction who received the two different liver support approaches (Fig. 3 B-C). There were no significant differences between the CytoSorb and the ADVOS group in seven-day or in-hospital mortality rates (Fig. 3 B-C). In-hospital mortality rates reached 88% for both devices (Fig. 3 C). Separate analysis of ACLF patients for each liver support method showed that seven-day and in-hospital mortality rates were similar to those obtained for the entire study population; there were no significant differences between the two tested liver support devices (Supplementary Fig. 1E). 5. Discussion Our retrospective study compared the effects of two artificial liver support systems, CytoSorb and ADVOS, applied in addition to standard treatment for critically ill patients with hyperbilirubinemia of ≥ 7 mg/dL. We found a more pronounced reduction of total serum bilirubin by CytoSorb integrated into CVVHDF circuit than by ADVOS therapy as early as after one therapy session and also after the completion of treatment. ADVOS was significantly more effective in eliminating water-soluble molecules such as serum creatinine and blood urea nitrogen and in correcting pH alterations than was CytoSorb integrated into a CVVHDF circuit. Platelet counts and hemoglobin and C-reactive protein levels decreased significantly after therapy with both devices, whereas only CytoSorb resulted in a significant decrease in procalcitonin levels. Neither device improved other laboratory liver-function parameters, such as transaminases or plasmatic coagulation. SOFA and SAPS II scores also did not improve after treatment with either liver support method. Our analysis showed high post treatment mortality among critically ill patients treated with the two different liver support modalities. The results of laboratory and clinical outcomes tests obtained from a separate analysis of the subgroup of ACLF patients were similar to those for the entire cohort. The evidence of the effectiveness of CytoSorb in removal of total serum bilirubin of patients with hyperbilirubinemia is still scarce and is based on case presentations, three observational studies, and one registry analysis ( 3 ). We detected a median decrease of total bilirubin of 6 mg/dL as early as after the first individual session of CytoSorb. The median relative reduction of bilirubin levels after the full course of treatment with CytoSorb was 35%. These findings are consistent with existing reports ( 3 , 16 ). Most of the previous studies and case series involved small sample sizes and retrospectively collected data ( 3 , 16 , 19 – 20 ). The CytoSorb International Registry presented by Ocskay et al. analyzed a total of 109 patients who were treated for the liver indication with hyperbilirubinemia; this is the largest dataset obtained in a prospective multicenter fashion ( 16 ). Both Ocskay’s study and the pooled data metaanalysis conducted by Turan et al. reported a mean difference of 5 mg/dL between pretreatment and posttreatment bilirubin levels ( 3 , 16 ). The studies of Scharf et al. and Geimel et al. found that the use of CytoSorb led to a median relative reduction in bilirubin levels ranging between 23% and 32%, a finding very similar to our results ( 19 – 20 ). In a subset of patients with ACLF, Haselwanter et al. showed a much higher reduction in the relative bilirubin level of 48% after CytoSorb treatment ( 21 ). However, our current study found a median relative reduction rate in the total bilirubin level of 35% among the entire study population as well as among the subgroup of patients with ACLF at the end of CytoSorb therapy. It is worth noting that Geimel et al observed a relative bilirubin reduction of 32% within the first 6 hours of therapy with CytoSorb, whereas a relative bilirubin decrease of only 4% occurred after 6 hours ( 20 ). This rapid decline of relative bilirubin clearance during treatment with CytoSorb suggests saturation of the CytoSorb adsorber ( 20 ). Alternatively, Geimel and colleagues hypothesized that the release of bilirubin from the adsorber into the blood circulation during the procedure might explain this phenomenon ( 20 ). In the current study settings the CytoSorb adsorber was replaced after 24 hours. Therefore, we assume that because of the potential saturation of the CytoSorb adsorber we may have underestimated the bilirubin elimination, and this underestimation may have prevented us from achieving the same high relative reduction rates as those demonstrated by Haselwanter et al. ( 21 ). In contrast to our study, which already included patients with hyperbilirubinemia of ≥ 7 mg/dl, all other studies enrolled patients with slightly higher total bilirubin concentrations of more than 10 mg/dL ( 3 , 16 , 19 – 21 ). Thus, higher concentration gradients may have enabled a faster and more efficient bilirubin removal attributed to the concentration-dependent bilirubin elimination manner of CytoSorb. As shown by recent reports, CytoSorb was not inferior to several other available artificial liver support methods ( 3 , 19 , 22 – 23 ). In vitro experiments revealed that CytoSorb yielded a significantly stronger reduction in bilirubin levels than did the Molecular Adsorbent Recirculating System (MARS) ( 24 ). Popescu et al. reported that 15 patients with liver failure treated with CytoSorb exhibited a more pronounced bilirubin removal than did 15 critically ill patients from a corresponding group that underwent MARS therapy ( 22 ). Scharf et al. compared CytoSorb and ADVOS administered to patients admitted to an ICU with acute liver dysfunction; this group identified an equivalent relative bilirubin reduction of 23% for both liver support systems ( 19 ). However, for this comparison only 6 patients were treated with ADVOS, whereas 33 patients were treated with CytoSorb ( 19 ). Hence, the documented results on bilirubin elimination should be interpreted with caution ( 19 ). On the other hand, Scharf et al. assumed that they might have underestimated the effect of CytoSorb on bilirubin elimination and postulated ongoing accumulation of bilirubin during CytoSorb treatment because of significant increase in bilirubin levels prior to CytoSorb start indicating persistent hepatic injury with worsening of the liver dysfunction. Indeed, in the ADVOS group bilirubin levels already decreased before initiation of CytoSorb ( 19 ). We saw a markedly higher relative reduction of total bilirubin levels among 71 critically ill patients treated with Cytosorb than among 71 patients treated with ADVOS. These observations did not support the previous results of the research group of Scharf et al. ( 19 ). Reports on bilirubin removal achieved by ADVOS are rare to date, mostly deriving from real-life treatment experience ( 17 – 18 , 25 ). Fuhrmann et al. reported only a moderate median decrease in bilirubin levels from 6.9 to 6.5 mg/dL among 18 patients treated with ADVOS in the context of a multicenter registry ( 17 ). A case series of 34 critically ill patients treated with ADVOS found a relative bilirubin reduction of 17%, a finding comparable to our finding of a relative reduction of 15% at the end of ADVOS therapy ( 17 ). Additionally, a concentration-dependent removal of bilirubin was previously described ( 26 ). The contradiction between our study and that of Scharf et al. in the difference in bilirubin clearance among patients treated with CytoSorb and those treated with ADVOS may also be explained by the studies’ different inclusion criteria ( 19 ). The study by Scharf and colleges involved a homogenous patient cohort with secondary acquired acute liver dysfunction ( 19 ). Indeed, in the present study we requited critically ill patients with hyperbilirubinemia caused by various types of liver function impairment without differentiation between ALF, ACLF, or secondary acquired acute liver dysfunction associated with critical illness and multiorgan failure. Thus, our study population was heterogeneous, with different diagnostic and prognostic characteristics in the two treatment groups. Hence, in the CytoSorb group secondary acquired acute liver dysfunction was the most common underlying entity of liver failure, whereas in the ADVOS group ACLF clearly dominated and acute liver dysfunction was missing. This clear imbalance between the two treatment groups is attributable to the fact that, in the current retrospective study, supportive therapy for liver failure was performed as part of the clinical routine; therefore, the choice of which liver support procedure was used was a part of the clinical decision of the attending physician, because consensus and protocols on this issue are lacking so far. In the case of ACLF, the use of ADVOS instead of CytoSorb was favored and recommended in our center, and this fact may have introduced a significant bias into the comparison of the effect of the two supportive therapies on bilirubin elimination. To counteract the aforementioned problem, we additionally performed a separate analysis of the subgroup of ACLF patients for the CytoSorb and ADVOS device. This analysis provided results that were in line with observations achieved in the entire cohort. However, most of the patients in the ADVOS group were admitted to the ICU with advanced ACLF stages for which treatment with ADVOS and subsequent bilirubin clearance may be less effective because of the progression of irreversible multiorgan failure and persistent release of bilirubin that may provoke a permanent supply of bilirubin or an additional increase instead of a decrease in bilirubin levels. Studies of the use of CytoSorb and other available liver support modes in separate groups sharing the same indication for liver support and the same entity of liver dysfunction may be helpful in defining which specific types of acute liver dysfunction may profit from CytoSorb. Prospective randomized clinical trials comparing CytoSorb with various other liver support devices are warranted to clarify the beneficial effects of CytoSorb on bilirubin reduction and improvement of liver function. CYTOHEP was the first prospective single center, open-label, randomized controlled intervention pilot trial on this topic involving patients with ACLF and containing three arms: CRRT with CytoSorb, CCRT without CytoSorb, and no CRRT ( 27 ). Unfortunately, the trial was terminated early because of difficulties in recruiting eligible participants and the high severity of ACLF ( 27 ). Each of the three arms involved only three patients ( 27 ). Taking into account the small sample size, the authors observed a trend toward a better bilirubin adsorption capacity in the CytoSorb group in comparison to the other two control groups ( 27 ). Dhokia et al. and Scharf et al. found a significant improvement in liver function tests including a decrease in liver transaminase and GGT activity after the completion of CytoSorb therapy ( 19 , 28 ). Additionally, Popescu et al. noted that LDH and ammonia levels decreased after CytoSorb treatment with no significant changes in transaminase activity ( 22 ). Because the molecular size of these aforementioned liver variables exceeds CytoSorb’s maximum pore size of 17 kD, it is unlikely that hemoadsorption by CytoSorb is directly responsible for the decrease in the activity of liver transaminases, GGT, and LDH ( 19 ). It is conceivable that the improvement in these clinical values is related to the potential improvement and recovery of liver function under liver support therapy ( 19 ). To resolve this issue, the levels of these substances of interest should be measured upstream and downstream of the CytoSorb adsorber so that clearance by hemoadsorption can be assessed. ADVOS therapy cannot directly remove and modulate liver enzymes ( 17 – 18 ). Our data stand in contrast to those of these other reports and do not demonstrate a paraclinical improvement in the CytoSorb group or the ADVOS group. Liver transaminase activity remained stable or further increased in both groups, as indicated by negative relative reduction values in both treatment groups; this finding leads us again to hypothesize that the severe progressive acute liver dysfunction of a different origin exhibited by our critically ill patients was that seems to be irreversible and to contribute to the further deterioration of liver function in most patients. However, elevation of liver transaminase activity during the course of treatment was significantly stronger in the ADVOS group than in CytoSorb group, mainly referring to a severe ACLF disease state among patients in the ADVOS group. Regarding blood coagulation markers, the degree of worsening PTT and prothrombin time and the significant drop of in platelet counts were of similar extent for both tested liver support methods in our study. A number of other studies have documented depletion of platelets as an adverse effect of CytoSorb use; the degree of this depletion may depend on multiple factors, such as the activation of platelets by the extracorporeal CRRT circuit and the aggregation of platelets within the CytoSorb adsorber or the CRRT dialyzer ( 21 – 21 , 29 ). A reduction in the platelet count was reported to occur during ADVOS therapy ( 17 ). But the observed decrease of platelet counts in our study may also reflect further damage of liver tissue and loss of liver function, especially among patients with advanced ACLF. To explain the alterations in plasmatic coagulation parameters at the end of treatment with both liver support systems, we again suspect the progression of liver disease rather than device-related effects. Patients in the CytoSorb group experienced a stronger reduction of hemoglobin concentrations after therapy than did those in the ADVOS group. Popescu et al. found similar hemoglobin changes after CytoSorb treatment ( 22 ). Erythrocyte entrapment, destruction within the CytoSorb adsorber or the CRRT dialyzer, and an accompanying phenomenon for critical illness or frequent blood withdrawal during CVVHDF in the ICU should be discussed as potential causes ( 22 , 30 – 31 ). A systemic hyperinflammatory state is a known hallmark of various causes of acute liver dysfunction ( 5 , 7 ). Haselwanter et al. found that treating ACLF patients with CytoSorb resulted in a reduction of procalcitonin levels after CytoSorb treatment ( 21 ). Moreover, Popescu et al. found a mild decrease in C-reactive protein and procalcitonin levels as standard inflammatory markers among patients treated with CytoSorb ( 22 ). Similarly, we detected a significant decrease in C-reactive protein and procalcitonin levels under CytoSorb therapy. ADVOS also led to a decrease in C-reactive protein levels without influencing procalcitonin levels. It is unclear whether these findings are related to the standard medial treatment of sepsis and infection or to the hemoadsorption. A single study pointed out no significant modifications of proinflammatory cytokine levels by ADVOS ( 32 ). Thus, to rule out the real extent of device-specific clearance of inflammatory markers by CytoSorb or ADVOS, additional studies quantifying diverse proinflammatory and antiinflammatory cytokines after these liver support methods would be useful. Unfortunately, due to the retrospective nature of the present study, which involved patients in routine clinical settings, we could not estimate specific cytokine levels. Determining the role of different liver support devices in rebalancing the inflammatory response during liver dysfunction should be the aim of ongoing studies. The current study showed that ADVOS therapy was superior to the combination of CVVHDF plus CytoSorb in clearing creatinine and blood urea nitrogen levels, and in improving acidosis. Few existing case series have shown that critically ill patients treated with ADVOS developed successful reduction of creatinine and blood urea nitrogen levels ( 17 – 18 , 25 ). The integration of two high-flux dialyzers with a large surface area of 1.9 qm for each dialyzer into the blood circuit of the ADVOS machine provides an advantage over conventional CVVHDF which uses only one dialyzer. This difference may have substantially contributed to the greater elimination of water-soluble toxins in the ADVOS group than in the CytoSorb group ( 17 – 18 ). However, the same blood flow of 100 mL/min was applied in both liver support modalities. Otherwise, we observed a slight trend toward higher median duration of CRRT using ADVOS lasting 96 hours in comparison to the median duration of continuous hemodialysis treatment among patients in the CytoSorb group lasting only 72 hours, that might partly explain a better removal of serum creatinine and blood urea nitrogen under ADVOS than under CytoSorb with CVVHDF. Thanks to the adjustable dialysate composition in the ADVOS system, a relevant pH increase can be achieved, and severe metabolic disorders refractory to conventional CCRT can be corrected ( 17 – 18 ). Previous real-world clinical experience reports indicated that the pH value of the dialysate can be set between 7.2 and 9.0; this setting allows an automatic modification of the dialysate composition according to the amount of acid and basic concentrate being supplied. It also allows adaptation of metabolic control on the individual patient’s needs ( 17 – 18 ). Although CytoSorb was significantly better than ADVOS in reducing bilirubin levels, reduction capability of CytoSorb treatment was not associated with ameliorated seven-day or in-hospital survival rates or with improvement in clinical scores such as SOFA and SAPS II. SOFA and SAPS II scores did not decrease in either liver support group after the full course of treatment, probably because these critically ill patients with hyperbilirubinemia were at a late stage of advanced liver disease and multiorgan failure at the time of treatment. The observations of prognostic clinical scores are consistent with the findings of Popescu et al. ( 22 ), who maintained that SOFA scores did not change significantly after treatment with CytoSorb or MARS ( 22 ). Like us, they observed a decrease in MELD scores in the CytoSorb group ( 22 ). A reduction in posttreatment MELD scores was documented for both liver support devices in our study; this finding may be explained by the reduction of bilirubin values that are included in the quantification of the MELD score. In-hospital mortality rates were comparably high in both groups, at 88%. In agreement with our findings, Scharf et al. described in-hospital mortality rate of 82% for their cohort of critically ill patients with secondary acquired acute liver dysfunction ( 19 ). Indeed, the CytoSorb International Registry analysis by Ocskay et al. found a lower in-hospital mortality rate of only 60% among 109 critically ill patients treated with CytoSorb for a liver indication ( 16 ). In our opinion, the very high mortality rates observed in our study and in the study of Scharf et al. were probably the result of the inclusion of extremely ill patients with advanced disease state in our study population, as reflected by high MELD, SOFA, and SAPS II scores in both analyses ( 19 ). Gräfe et al. investigated differences in mortality rates between 30 critically ill patients treated with CytoSorb and 52 patients without CytoSorb use who served as a control group ( 33 ). The authors stated no significant differences in mortality rates between the CytoSorb treatment group and the control group ( 33 ). Multivariate analysis also showed no independent effects of CytoSorb therapy on the survival of critically ill patients with hyperbilirubinemia ( 33 ). The present study did not provide an appropriate control group composed of critically ill patients with hyperbilirubinemia who were not treated with a liver support device in addition to standard medical treatment; the absence of a control group complicates the estimation of the real effects of CytoSorb and ADVOS on mortality rates. However, several aspects may play a role in explaining why long-term effects of CytoSorb on mortality rates are not achieved despite a positive effect on total serum bilirubin levels. Hemoadsorption using CytoSorb is not able to completely restore all liver function; it is only an adjuvant treatment option that supports liver function, but does not eliminate the cause of liver failure, or cure acute liver dysfunction. The acute liver dysfunction indicated by hyperbilirubinemia is only one component of a complex disease state and is often accompanied by multiorgan failure. Numerous other factors are involved in the death of critically ill patients with multiorgan failure in ICUs, and one liver support device cannot manage all of these factors. On the other hand, achieving a relevant prognostic improvement in our study population was difficult due to the fact that critically ill patients in both treatment groups mostly exhibited advanced liver dysfunction and multiorgan failure; it was impossible to reverse these conditions by using adjuvant liver support therapies that might be provided too late. Thus, our study results emphasize the urgent need for the application of CytoSorb, ADVOS, or another liver support system at early disease stages to prevent disease progression. In general, the effects on clinical outcomes, in particular mortality rates associated with various liver support devices that were designed for liver detoxification and are currently in clinical use, are controversial and under debate ( 22 , 34 – 36 ). Popescu et al. found that CytoSorb did not perform better then MARS with respect to twenty-eight day survival rates of ICU patients ( 22 ). No benefit on survival rates was reported by comparison of diverse artificial liver support devices, such as MARS, Prometheus, and single-pass albumin dialysis with standard medical care, in retrospective studies and a prospective randomized trial involving ACLF patients ( 34 – 36 ). For patients with ALF, a metaanalysis detected a significant positive effect on overall survival for a high-volume plasma exchange group in comparison to a group treated with standard medical care, but not for other alternative liver support possibilities ( 21 , 34 ). Until there is no longer a lack of hard evidence about clinical outcomes after hemoadsorption with CytoSorb, there will be an urgent need for randomized, controlled prospective trials addressing this question. We are aware of several limitation of our study. The data were obtained retrospectively in clinical routines from a single center. Hence, missing laboratory values or slight deviation in time points cannot be excluded. We were not able to determine other important variables, such as cytokine levels that are not usually measured as part of clinical routine. Because the study did not include an appropriate control group, it is problematic to account for spontaneous changes in characteristic variables of liver function and to judge the advantages in survival and recovery from acute liver dysfunction. Our study may also involve selection bias because of heterogeneity in diagnosis and prognosis in both treatment groups and deviant composition in terms of forms of acute liver dysfunction in the CytoSorb group as compared with the ADVOS group; this bias may have been induced because the choice of a suitable liver support device was based on the decision and opinion of an attending physician in our institution. Significant differences in clinical and biochemical baseline features between the CytoSorb group and the ADVOS group may also have induced selection bias. Nevertheless, compared with a number of other recent studies and case series, the current study involved a large patient number and dataset in both liver support therapy groups. 6. Conclusions In conclusion, both liver support devices, CytoSorb and ADVOS, efficiently reduced bilirubin levels among critically ill patients with hyperbilirubinemia caused by various forms of acute liver dysfunction and among critically ill patients with ACLF. Although CytoSorb use led to a significantly more extensive relative reduction of total serum bilirubin levels than did ADVOS, ADVOS therapy was associated with better elimination of water-soluble substances such as creatinine and blood urea nitrogen and with a better rebalancing of acid abnormalities than was CytoSorb. Neither of the liver support modalities improved liver function and short-term mortality rates of critically ill patients with hyperbilirubinemia or ACLF patients were comparable between the two extracorporeal liver support approaches. Artificial liver support devices such as ADVOS are time- and cost-intensive, and their use is complex, requiring experienced healthcare personnel ( 17 – 18 ). In contrast, CytoSorb as a liver support approach is cheaper, easier to handle, and readily available for installation in conventional hemodialysis circuits ( 16 ). In addition, our findings support the opinion that CytoSorb has beneficial effects on bilirubin elimination and is not disadvantageous compared to ADVOS. Therefore, the CytoSorb adsorber may be a promising tool for treating critically ill patients with acute liver dysfunction and hyperbilirubinemia in small centers. Otherwise, the combination of ADVOS and CytoSorb incorporates the advantages of both devices, such as bilirubin clearance, elimination of water-soluble toxins, and correction of metabolic disorders, this combination merits investigation in ongoing studies involving critically ill patients with acute liver dysfunction. Abbreviations ACLF, acute-on-chronic liver failure; ADVOS, advanced organ support ALF, acute liver failure ALT, alanine transaminase AST, aspartate transaminase CI, confidence interval CRP, C-reactive protein CRRT, continuous renal replacement therapy CVVHDF, continuous veno-venous hemodiafiltration d, day ICU, intensive care unit GGT, gamma-glutamyltransferase L, liter LDH, lactate dehydrogenase MARS, Molecular Adsorbent Recirculating System MELD, Model for End-Stage Liver Disease PTT, partial thromboplastin time RR, relative risk SAPS II, Simplified Acute Physiology Score II SOFA, Sequential Organ Failure Assessment U, unit urea-N, urea nitrogen Declarations Ethics approval and consent to participate: The study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of the University Hospital Essen (23-11563-BO, 23-11170-BO). Informed consent was obtained from all subjects. Consent for publication: Not applicable. Availability of data and materials: All data generated or analyzed during this study are included in this published article and its supplementary information files. Competing interests: The authors declare that they have no competing interests. Funding: No funding. Authors' contributions: J.F.K., B.T. and A.K. developed the idea and the concept of the project. J.F.K. and K.S. were responsible for project administration. J.F.K., L.K.H., B.T., M.J. and K.S. performed data collection. J.F.K. and K.S. analyzed the data and prepared the figures and tables. J.F.K. wrote the manuscript. All authors reviewed the manuscript. Clinical trial number: not applicable. Acknowledgments: Editorial assistance was provided by Flo Witte, PhD, of Bluegrass Editorial Services Team, LLC, Lexington, KY, USA. References Jonsdottir S, Arnardottir MB, Andresson JA, Bjornsson HK, Lund SH, Bjornsson ES. Prevalence, clinical characteristics and outcomes of hypoxic hepatitis in critically ill patients. 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Blood Purif. 2023;52(11–12):849–56. Ocskay K, Kanjo A, Gede N, Szakács Z, Pár G, Erőss B, et al. Uncertainty in the impact of liver support systems in acute-on-chronic liver failure: a systematic review and network meta-analysis. Ann Intensive Care. 2021;11(1):10. Abbas N, Rajoriya N, Elsharkawy AM, Chauhan A. Acute-on-chronic liver failure (ACLF) in 2022: Have novel treatment paradigms already arrived? Expert Rev Gastroenterol Hepatol. 2022;16(7):639–52. Thompson J, Jones N, Al-Khafaji A, Malik S, Reich D, Munoz S, et al. Extracorporeal cellular therapy (ELAD) in severe alcoholic hepatitis: A multinational, prospective, controlled, randomized trial. Liver Transpl. 2018;24(3):380–93. Additional Declarations No competing interests reported. Supplementary Files SupplementaryFigure1.tif Supplementary Figure 1. Effects on biochemical and clinical outcomes of adjuvant extracorporeal liver support treatment for critically ill patients with acute-on-chronic liver failure (ACLF). Patients were treated either with a combination of CytoSorb plus continuous veno-venous hemodiafiltration or with the ADVOS system. Shown are changes in total bilirubin concentrations after the first single therapy session (A) and after the completion of therapy (B) with CytoSorb or with ADVOS. Also shown are comparisons of relative bilirubin reduction achieved after the first single therapy session (C) and at the end of treatment (D) between critically ill patients treated with CytoSorb and those treated with ADVOS. (E) Short-term seven-day mortality rates and in-hospital mortality rates for critically ill patients with ACLF treated with CytoSorb or with ADVOS. *, p<0.05; **, p =0.01; ****, p≤0.0001. ADVOS, advanced organ support; d, day; L, liter. Supplementarytables.docx Cite Share Download PDF Status: Published Journal Publication published 04 Aug, 2025 Read the published version in BMC Nephrology → Version 1 posted Editorial decision: Revision requested 05 Jun, 2025 Reviews received at journal 26 May, 2025 Reviewers agreed at journal 19 May, 2025 Reviewers agreed at journal 15 May, 2025 Reviews received at journal 15 Apr, 2025 Reviews received at journal 08 Apr, 2025 Reviewers agreed at journal 02 Apr, 2025 Reviewers agreed at journal 02 Apr, 2025 Reviewers agreed at journal 01 Apr, 2025 Reviewers invited by journal 01 Apr, 2025 Editor assigned by journal 27 Mar, 2025 Editor invited by journal 25 Mar, 2025 Submission checks completed at journal 24 Mar, 2025 First submitted to journal 24 Mar, 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. 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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-6195702","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":445881295,"identity":"e96f58c4-0481-43c9-83d6-e672d77064e3","order_by":0,"name":"Kristina Schönfelder","email":"","orcid":"","institution":"University of Duisburg-Essen, University Hospital Essen","correspondingAuthor":false,"prefix":"","firstName":"Kristina","middleName":"","lastName":"Schönfelder","suffix":""},{"id":445881296,"identity":"aea0e152-b239-42ee-85f7-930a59e803f0","order_by":1,"name":"Luisa Katharina Hirsch","email":"","orcid":"","institution":"University of Duisburg-Essen, University Hospital Essen","correspondingAuthor":false,"prefix":"","firstName":"Luisa","middleName":"Katharina","lastName":"Hirsch","suffix":""},{"id":445881297,"identity":"b5c2bea4-cffa-4df0-8281-091eb46feaef","order_by":2,"name":"Andreas Kribben","email":"","orcid":"","institution":"University of Duisburg-Essen, University Hospital Essen","correspondingAuthor":false,"prefix":"","firstName":"Andreas","middleName":"","lastName":"Kribben","suffix":""},{"id":445881298,"identity":"59917ed4-556a-49c5-a986-79d36f0f617a","order_by":3,"name":"Michael Jahn","email":"","orcid":"","institution":"University of Duisburg-Essen, University Hospital Essen","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Jahn","suffix":""},{"id":445881299,"identity":"a760ea89-b13e-4a3e-8c90-bb04fe038814","order_by":4,"name":"Bartosz Tyczynski","email":"","orcid":"","institution":"University Hospital Essen","correspondingAuthor":false,"prefix":"","firstName":"Bartosz","middleName":"","lastName":"Tyczynski","suffix":""},{"id":445881300,"identity":"6a6da8c3-ed54-4823-9251-4112dd158b57","order_by":5,"name":"Justa Friebus-Kardash","email":"data:image/png;base64,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","orcid":"","institution":"University of Duisburg-Essen, University Hospital Essen","correspondingAuthor":true,"prefix":"","firstName":"Justa","middleName":"","lastName":"Friebus-Kardash","suffix":""}],"badges":[],"createdAt":"2025-03-10 12:53:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6195702/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6195702/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12882-025-04342-6","type":"published","date":"2025-08-04T15:57:11+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82054342,"identity":"a0b13e71-06ac-4fe8-ae21-b0fc27757eea","added_by":"auto","created_at":"2025-05-06 10:21:22","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":911065,"visible":true,"origin":"","legend":"\u003cp\u003eClearance of total serum bilirubin among 71 critically ill patients treated with a combination of CytoSorb plus continuous veno-venous hemodiafiltration and among 71 critically ill patients treated with the ADVOS system. (A) Changes in total bilirubin concentrations after the first single therapy session of 24 hours with CytoSorb or with ADVOS. (B) Comparison of relative bilirubin reduction (related to baseline [d0] levels or not) during the first three days of treatment with CytoSorb or with ADVOS. (C) Changes in total bilirubin concentrations after the completion of therapy with CytoSorb or with ADVOS. (D) Comparison of relative bilirubin reduction achieved at the end of treatment between critically ill patients treated with CytoSorb and those treated with ADVOS. *, p\u0026lt;0.05; **, \u003cem\u003ep\u003c/em\u003e=0.01; ***, p=0.001; ****, p≤0.0001.\u003c/p\u003e\n\u003cp\u003eADVOS, advanced organ support; d, day; L, liter.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6195702/v1/27d25b725009f98417eb9855.png"},{"id":82057300,"identity":"5c696960-e624-4221-89a7-c4ae72cae47f","added_by":"auto","created_at":"2025-05-06 10:45:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1929266,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in absolute values and relative reductions in relevant biochemical variables after adjuvant extracorporeal liver support treatment of critically ill patients with hyperbilirubinemia and acute kidney injury. Patients were treated either with a combination of CytoSorb plus continuous veno-venous hemodiafiltration or with the ADVOS system. **, \u003cem\u003ep\u003c/em\u003e=0.01; ***, p=0.001.\u003c/p\u003e\n\u003cp\u003eADVOS, advanced organ support; ALT, alanine transaminase; AST, aspartate transaminase; CRP, C-reactive protein; d, day; GGT, gamma-glutamyltransferase; L, liter; LDH, lactate dehydrogenase; PTT, partial thromboplastin time; urea-N, urea nitrogen.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6195702/v1/9b7500a0e1fa58c677626544.png"},{"id":82054349,"identity":"132170bb-3cf7-44a5-a3ac-3fd46f4b7334","added_by":"auto","created_at":"2025-05-06 10:21:23","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1003210,"visible":true,"origin":"","legend":"\u003cp\u003eEffects on clinical outcomes of adjuvant extracorporeal liver support treatment of critically ill patients with hyperbilirubinemia and acute kidney injury. Patients were treated either with a combination of CytoSorb plus continuous veno-venous hemodiafiltration or with the ADVOS system. (A) Alterations in absolute values and relative reductions in prognostic clinical scores (SOFA, SAPS II, and MELD scores) at the end of treatment with CytoSorb or with ADVOS. Short-term seven-day mortality rates (B) and in-hospital mortality rates (C) for critically ill patients with hyperbilirubinemia treated either with CytoSorb or with ADVOS. *, p\u0026lt;0.05; **, \u003cem\u003ep\u003c/em\u003e=0.01; ***, p=0.001; ****, p≤0.0001.\u003c/p\u003e\n\u003cp\u003eADVOS, advanced organ support; d, day; MELD, Model for End-Stage Liver Disease; SAPS II, Simplified Acute Physiology Score II; SOFA, Sequential Organ Failure Assessment.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-6195702/v1/5ca20e53d1f9042fa857ba60.png"},{"id":88814107,"identity":"5c34d4f2-c5e1-46f0-a5b4-3c16bb7cd04e","added_by":"auto","created_at":"2025-08-11 16:06:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4962442,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6195702/v1/d966c667-4b74-4a1b-a85a-d7791b261168.pdf"},{"id":82054348,"identity":"9460897e-eaba-4582-9da5-dd6273534d66","added_by":"auto","created_at":"2025-05-06 10:21:23","extension":"tif","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":631804,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure 1. \u003c/strong\u003eEffects on biochemical and clinical outcomes of adjuvant extracorporeal liver support treatment for critically ill patients with acute-on-chronic liver failure (ACLF). Patients were treated either with a combination of CytoSorb plus continuous veno-venous hemodiafiltration or with the ADVOS system. Shown are changes in total bilirubin concentrations after the first single therapy session (A) and after the completion of therapy (B) with CytoSorb or with ADVOS. Also shown are comparisons of relative bilirubin reduction achieved after the first single therapy session (C) and at the end of treatment (D) between critically ill patients treated with CytoSorb and those treated with ADVOS. (E) Short-term seven-day mortality rates and in-hospital mortality rates for critically ill patients with ACLF treated with CytoSorb or with ADVOS. \u0026nbsp;*, p\u0026lt;0.05; **, \u003cem\u003ep\u003c/em\u003e=0.01; ****, p≤0.0001.\u003c/p\u003e\n\u003cp\u003eADVOS, advanced organ support; d, day; L, liter.\u003c/p\u003e","description":"","filename":"SupplementaryFigure1.tif","url":"https://assets-eu.researchsquare.com/files/rs-6195702/v1/de3c21c595669e2f300846a1.tif"},{"id":82055885,"identity":"e575492e-d7f7-4874-bd72-adc1c732effc","added_by":"auto","created_at":"2025-05-06 10:29:23","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":50874,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6195702/v1/491abff1233ec2b1617aa62c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Artificial liver support with CytoSorb and continuous veno- venous hemodiafiltration and advanced organ support (ADVOS) for critically ill patients with hyperbilirubinemia: a retrospective analysis","fulltext":[{"header":"1. Background","content":"\u003cp\u003eAcute impairment of liver function is a common life-threatening condition among critically ill patients admitted to intensive care units (ICUs). The incidence of acute liver dysfunction is as high as 30% among critically ill patients during the course of their illness (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The manifestations of acute liver dysfunction among critically ill patients vary but may include acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). ALF is related to viral infections, hepatotoxic drugs, or hypoxemia resulting in rapid necrosis of liver tissue and therefore an increase in bilirubin levels (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Patients with ALF are at risk of multiorgan failure with a mortality rate of 50% (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). ACLF is a consequence of decompensation of chronic liver cirrhosis, causing hepatic and extrahepatic organ failure, and is also characterized by excessive short-term mortality rates (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSystemic hyperinflammation is involved in the pathogenesis of both ALF and ACLF (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e); however, secondary acquired acute liver failure occurs more often among critically ill patients (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Inflammation in the context either of sepsis and multiorgan failure or of exposure to toxic substances predominantly triggers the development of secondary acquired liver failure (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Release of inflammatory mediators induces downregulation of specific transporters of bile acids and bilirubin on the surface of hepatocytes, provoking non-obstructive formation and accumulation of bile acids and bilirubin because of impaired secretion (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Thus, the mortality rate among critically ill patients with secondary acquired liver dysfunction is 11% (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHyperbilirubinemia reflects early hepatic dysfunction among critically ill patients (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Thus, the serum bilirubin level has been established as an appropriate surrogate marker for the assessment of deterioration of excretory liver function and the development of acute forms of liver dysfunction, and it is a part of several scores (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Although bilirubin itself does not exhibit any direct toxic effect on hepatocytes, in several studies the elevation of circulating bilirubin concentrations was shown to correlate with an increase in the risk of mortality among critically ill patients (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). So far, there is no specific therapy for the management of acute liver dysfunction with hyperbilirubinemia among critically ill patients, and treatment protocols are often center-specific. Liver transplant is the only curative therapy option, but only 4.5% of patients undergo liver transplant because most transplant candidates are considered \u0026ldquo;too sick to transplant\u0026rdquo; persistent infections and multiorgan failure (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSeveral artificial extracorporeal devices have been tested for replacing hepatic function and bridging patients to liver transplant or recovery (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Hemoperfusion using the cytokine adsorber CytoSorb is a new artificial liver support method (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). This medical device was primarily developed for cytokine removal to control hyperinflammation in septic shock (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). The adsorber can be implemented in a continuous renal replacement therapy (CRRT) circuit (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). CytoSorb has a large adsorption capacity because of its surface area of 45,000 qm, and it is reported to eliminate hydrophobic substances with a molecular size of 5 to 55 kD (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). The molecular weight of bilirubin falls within the aforementioned range of adsorption; thus, the combination of CRRT with CytoSorb absorber can be used for extracorporeal purification of bilirubin from the blood of in critically ill patients with acute kidney injury and hyperbilirubinemia (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Some case reports and retrospective studies indicate that CytoSorb is efficient in reducing bilirubin levels among critically ill patients with liver failure (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). As described in the meta-analysis by Turan et al., CytoSorb is a feasible and safe approach for treating critically ill patients with acute liver dysfunction (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAdvanced organ support (ADVOS) is also an artificial liver support tool (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). It is an extracorporeal multiple organ support system that enables simultaneous replacement of multiple organs, such as liver, kidney, and lungs, with a unified device (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). ADVOS as part of an advanced hemodialysis system combines three extracorporeal circuits: the extracorporeal blood circuit, the dialysate circuit, and the albumin multicircuit (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). As a new albumin-dialysis procedure using a recirculating and recyclable albumin-enriched solution, ADVOS allows detoxification of water-soluble and albumin-bound molecules (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). ADVOS is licensed in Germany for patients with acute kidney failure and hyperbilirubinemia in the setting of critical illness (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Published clinical evidence demonstrates that the first ADVOS treatment session produces a statistically significant reduction in bilirubin levels (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOn the basis of this background information, we decided to perform a retrospective comparison of two artificial systems for liver support: CytoSorb integrated in a continuous veno-venous hemodiafiltration (CVVHDF) circuit, and ADVOS. The aim of this retrospective analysis was to determine and to compare the effects of both liver support modalities in the elimination of bilirubin, liver function and disease severity in a cohort of critically ill patients with acute kidney failure and hyperbilirubinemia caused by diverse forms of acute liver dysfunction.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study population\u003c/h2\u003e \u003cp\u003eThis monocentric retrospective study compared two approaches for extracorporeal liver support: 1) the combination of the cytokine adsorber CytoSorb (CytoSorbents Europe GmbH, Berlin, Germany) plus CVVHDF, and 2) ADVOS (ADVITOS GmbH, Munich, Germany), in critically ill patients with hyperbilirubinemia in terms of bilirubin elimination and effects on clinical scores and overall survival rates. This study enrolled adult patients with hyperbilirubinemia (total serum bilirubin levels 7 mg/dL or higher) and acute kidney injury requiring CRRT. Exclusion criteria were the use liver support systems other than CytoSorb or ADVOS and the use of several liver support systems during the ICU stay. Patients were divided into two groups. One group consisted of 71 critically ill patients who were treated with a combination of CVVHDF and CytoSorb between January 2021 and March 2024 at the University Hospital Essen. The other group consisted of 71 patients who underwent ADVOS therapy during their stay in the ICU of the University Hospital Essen between January 2021 and March 2024. Indications for liver support were ALF or ACLF with hyperbilirubinemia or with hyperbilirubinemia caused by secondary liver dysfunction in the context of sepsis and multiorgan failure. ALF and ACLF were defined in accordance with the European Association for the Study of the Liver guidelines. All included patients received at least one session of treatment with CytoSorb or ADVOS over 24 hours. An extracorporeal liver support session was considered to be a single treatment with either CVVHDF plus CytoSorb or ADVOS. Extracorporeal liver support therapy was provided in addition to standard medical care. The type of artificial liver support therapy used, either CytoSorb or ADVOS, and the time point of treatment initiation were decided by the attending treating physician. The local ethics committee of the University Duisburg-Essen approved this retrospective study (23-11563-BO, 23-11170-BO).\u003c/p\u003e \u003cp\u003eAll laboratory variables were determined by standard clinical chemistry tests in the Institute of Laboratory Medicine Essen and were obtained from the laboratory information system within the first 24 hours before the initiation of liver support therapy, defined as day 0 (d0), and after 24, 48, and 72 hours of treatment, as well as at the end of treatment. Demographic and clinical data were collected from patient information systems by retrospective electronic medical record review.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Study setting\u003c/h2\u003e \u003cp\u003e Patients in the CytoSorb group were treated with with the high-flux F60S dialyzer (effective surface area, 1.3-qm; Fresenius, Medical Care AG, Bad Homburg, Germany), and the CytoSorb adsorber was placed upstream of the dialyzer. The duration of a single CytoSorb application was 24 hours; the adsorber was exchanged every 24 hours. The initial settings for CVVHDF were the following: blood flow of 100 mL/min, dialysate flow of 1000 to 3000 mL/min, and predilution with a 5% glucose solution at 600 to 800 mL/min. The entire CVVHDF circuit was exchanged regularly every 72 hours. Anticoagulation was performed with regional citrate.\u003c/p\u003e \u003cp\u003eThe duration of a single ADVOS session was 24 hours. The ADVOS system consisted of three extracorporeal circuits: blood circuit, dialysate circuit, and ADVOS multicircuit (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). In the extracorporeal blood circuit the patient\u0026rsquo;s blood was cleaned by two high-flux polyethersulfone dialyzers (SURELYZER PES-190 DH, Nipro D. Med Germany GmbH, Hamburg, Germany) with a 1.9-qm effective surface for each dialyzer (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). The dialysate circuit and ADVOS multicircuit were necessary for eliminating water-soluble and protein-bound toxins from the patient\u0026rsquo;s blood (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). The dialysate contained a mixture of alkaline concentrate (mainly NaOH), an acid concentrate (mainly HCl), osmosis water, and 200 mL of 20% pharmaceutical grade albumin, and it was recirculated with a flow of 800 mL/min in the second circuit (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFor this recirculating procedure, the dialysate was divided in two paths, in which acidic or basic concentrates were added with a concentrate flow of 160 or 320 mL/min to change the pH and to provoke the release of anionic or cationic albumin-bound substances and, in this way, to regenerate albumin-binding capacity (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). The pH of the dialysate can be adjusted between 7.2 and 9.0 by modifying the ratio of acidic and basic concentrates (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). The released anionic or cationic substances were further filtered by convection through two polynephron high-flux dialyzers (ELISIO-13H, Nipro D. Med Germany GmbH, Hamburg, Germany) with a 1.3-qm effective surface for each dialyzer (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Each dialyzer was installed in either an acidic or a basic path of the ADVOS multicircuit (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). The removed filtrate was continuously replaced by permeate (i.e., osmosis water) and acidic and basic concentrates (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). ADVOS therapy was conducted at the following initial settings: blood flow, 100 mL/min; concentrate flow, 160 mL/min; dialysate pH, 7.8. Blood anticoagulation was maintained by the application of regional citrate.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Statistical analysis\u003c/h2\u003e \u003cp\u003eCategorical variables were presented as numbers and percentages, and continuous variables were given as medians with interquartile ranges. The two-tailed \u003cem\u003eχ\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e test for categorical variables and the Mann-Whitney test for not normally distributed quantitative data were used to detect differences between the CytoSorb and ADVOS groups. The differences between variables obtained at the start of liver support therapy and those obtained at the completion of therapy were analyzed with the Wilcoxon test. Survival was assessed by Kaplan-Meier analysis, and the p values were determined by the log-rank test. All p values are two-tailed, and statistical significance was assumed for p values\u0026thinsp;\u0026le;\u0026thinsp;0.05. All statistical analyses were performed with GraphPad Prism version 6 (GraphPad Software, Inc., La Jolla, CA, USA) and IBM SPSS Statistics version 23 (IBM Corp., Armonk, NY, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003e3.1 Patient characteristics\u003c/h2\u003e\n \u003cp\u003eTable \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates patients\u0026rsquo; demographic characteristics and laboratory values measured immediately before the initiation of liver support. ACLF was significantly more frequent in the ADVOS group than in the CytoSorb group, whereas secondary acquired acute liver dysfunction occurred significantly more often among patients treated with CytoSorb than among patients treated with ADVOS. Patients from the CytoSorb group stayed significantly longer in an ICU before the initiation of liver support therapy; they also exhibited a significantly higher Sequential Organ Failure Assessment (SOFA) score at baseline than did those patients who underwent ADVOS treatment. Model for End-Stage Liver Disease (MELD) scores at study inclusion were significantly higher among patients in the ADVOS group than among those in the CytoSorb group. With regard to biochemical data, patients in the CytoSorb group exhibited significantly higher baseline levels of liver transaminases, lactate dehydrogenase (LDH), prothrombin time, hemoglobin, C-reactive protein, and procalcitonin. Indeed, baseline partial thromboplastin times (PTT) were higher for patients treated with ADVOS than for those treated with CytoSorb. Baseline total serum bilirubin levels did not differ significantly between the treatment groups.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eComparison of baseline clinical and laboratory values between 71 patients treated with a combination of CytoSorb plus continuous veno-venous hemodiafiltration and 71 patients treated with the ADVOS system. All patients were admitted to the intensive care unit of the University Hospital Essen between January 2021 and March 2024 because of critical illness with hyperbilirubinemia and acute kidney injury. Values are presented as medians.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCytoSorb\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;71\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eADVOS\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;71\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRR (CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWomen, (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 (42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 (42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.0 (0.7\u0026ndash;1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNumber of sessions, (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (1\u0026ndash;56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDuration of CRRT (hours), (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e72 (24\u0026ndash;576)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e96 (24-1344)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eACLF, (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31 (44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e66 (93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.5 (0.4\u0026ndash;0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eALF, (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.0 (0.3\u0026ndash;3.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSecondary acquired liver dysfunction, (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35 (49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003einfinity (2.0-infinity)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDays in ICU before therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eContinous dialysis before therapy, (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35 (49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32 (45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.1 (0.8\u0026ndash;1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.61\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSOFA (points)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.04\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSAPS II (points)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMELD (points)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.04\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLaboratory values at baseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBilirubin (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eALT (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAST (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e172\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e139\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.04\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGGT (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e111\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.009\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLDH (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e511\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e347\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0006\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLeukocytes (/nL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHemoglobin (g/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatlets (/nL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProthrombin time (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePTT (sec)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSerum creatinine (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.75\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBlood urea nitrogen (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.81\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLactate (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBase excess\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eC-reactive protein (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProcalcitonin (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eACLF, acute-on-chronic liver failure; ADVOS, advanced organ support; ALF, acute liver failure; ALT, alanine transaminase; AST, aspartate transaminase; CI, confidence interval; CRRT, continuous renal replacement therapy; ICU, intensive care unit; GGT, gamma-glutamyltransferase; L, liter; LDH, lactate dehydrogenase; MELD, Model for End-Stage Liver Disease; PTT, partial thromboplastin time; RR, relative risk; SAPS II, Simplified Acute Physiology Score II; SOFA, Sequential Organ Failure Assessment; U, unit.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003e3.2 Use of CytoSorb was associated with significantly higher clearance of bilirubin than was ADVOS\u003c/h2\u003e\n \u003cp\u003eFirst, we compared the two liver support methods in eliminating total serum bilirubin. Both devices significantly decreased bilirubin concentrations at the end of the first treatment session lasting 24 hours (CytoSorb plus CVVHDF, 20 to 14 mg/dL, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; ADVOS, 16 to 14 mg/dL, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eA). However, the relative median reduction of total bilirubin levels achieved by CytoSorb within the first 24 hours of treatment was significantly higher than that after the first use of ADVOS over 24 hours (26% vs. 17%, p\u0026thinsp;=\u0026thinsp;0.0002) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eB).\u003c/p\u003e\n \u003cp\u003eA full course of treatment with either liver support mode significantly reduced total bilirubin levels, but this end-of-treatment reduction was more pronounced in the CytoSorb group (19.9 to 11.3 mg/dl, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) than in the ADVOS group (16.3 to 14.0 mg/dL, p\u0026thinsp;=\u0026thinsp;0.003) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eC). The median duration of a full course of treatment with CytoSorb was 72 hours (range 24\u0026ndash;432 hours) and with ADVOS 96 hours (range 24-1344 hours), respectively (p\u0026thinsp;=\u0026thinsp;0.07). As was true for the results of the single session, the elimination of bilirubin after the completion of liver support treatment was significantly higher among patients in the CytoSorb group (35%) than among those in the ADVOS group (15%) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eD). As shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eB, the highest value of relative bilirubin reduction was achieved after the first day of treatment with either liver support option. After 48 and 72 hours of treatment, both liver support modalities exhibited a decrease in the elimination capacity of bilirubin among critically ill patients who survived longer than one day (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eB). However, the relative removal of bilirubin by CytoSorb was significantly higher than the relative removal by ADVOS at all time points of treatment (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eB).\u003c/p\u003e\n \u003cp\u003eNext, we separately analyzed the subgroup of 97 patients for whom ACLF was the cause of liver dysfunction with hyperbilirubinemia (Supplementary Fig.\u0026nbsp;1). The initial total bilirubin levels (CytoSorb, 17.6 mg/dL; ADVOS, 15.7 mg/dL; p\u0026thinsp;=\u0026thinsp;0.1) and the number of sessions (CytoSorb, 3 sessions; ADVOS, 4 sessions; p\u0026thinsp;=\u0026thinsp;0.2) were similar for patients in both groups. The median duration of the liver support (72 (range 24\u0026ndash;240 hours) vs. 96 hours (range 24-1344 hours); p\u0026thinsp;=\u0026thinsp;0.15), as well as the median duration of continuous renal replacement therapy (72 (range 24\u0026ndash;576 hours) vs. 96 hours (range 24-1344 hours); p\u0026thinsp;=\u0026thinsp;0.14) were also comparable in both groups. The results achieved by the analysis of bilirubin clearance for this subgroup were similar to those achieved by analysis of the entire cohort (Supplementary Fig.\u0026nbsp;1A-D). Again, the relative reductions in total bilirubin levels after the first single session (Supplementary Fig.\u0026nbsp;1C) and at the end of treatment (Supplementary Fig.\u0026nbsp;1D) were significantly higher in the CytoSorb group than in the ADVOS group.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003e3.3 Changes in biochemical variables during liver support with CytoSorb versus ADVOS\u003c/h2\u003e\n \u003cp\u003eChanges between pretreatment and posttreatment laboratory values in the two patient groups are depicted in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. The full course of treatment with CytoSorb was associated with a significant decrease in gamma-glutamyl transferase (GGT) activity, in prothrombin time, and in creatinine, blood urea nitrogen, platelet count, hemoglobin, C-reactive protein, and procalcitonin levels, and with a significant increase of in PTT and lactate levels (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Treatment with ADVOS led to a significant decrease in levels of creatinine, blood urea nitrogen, prothrombin time, platelet count, hemoglobin, and C-reactive protein and to a significant elevation of transaminase activity, lactate dehydrogenase (LDH) activity, PTT, lactate levels, and pH (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The intergroup comparison showed a significantly higher relative reduction of serum creatinine and urea nitrogen among patients treated with ADVOS than among those treated with the combination of CVVHDF and CytoSorb (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Application of ADVOS also led to a significantly higher relative increase in pH values than did treatment with CytoSorb (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). A percentage increase in posttreatment transaminase activity and LDH activity occurred in the ADVOS group but not in the CytoSorb group (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The relative reduction of procalcitonin levels was significantly higher in the CytoSorb group than in the ADVOS group, a finding suggesting that ADVOS treatment did not influence procalcitonin levels.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eAs indicated in Supplementary Tables\u0026nbsp;1 through 3, an additional focus on the subgroup of ACLF patients showed alterations in relevant laboratory values similar to those achieved with the entire cohort. In summary, ADVOS treatment led to a larger relative reduction of serum creatinine und blood urea nitrogen levels and to a greater improvement of pH values than did CytoSorb treatment, but it was related to an additional deterioration of liver function with a corresponding additional increase in liver enzyme activity during the treatment course (Supplementary Table\u0026nbsp;3). In contrast to ADVOS therapy, CytoSorb treatment led to stable liver function values and a significant decrease in procalcitonin concentrations at the end of treatment (Supplementary Table\u0026nbsp;3).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003e3.4 Clinical scoring and short-term mortality under CytoSorb and ADVOS\u003c/h2\u003e\n \u003cp\u003eWith respect to prognostic clinical scores, in the CytoSorb group we found no changes between pretreatment and posttreatment SOFA scores or Simplified Acute Physiology Score II (SAPS II) scores (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA). In the ADVOS group SOFA scores further increased and SAPS II scores remained unchanged after the completion of adjuvant liver support (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA). We found a significant improvement in MELD scores after treatment with both liver support devices (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA). Comparison of relative reduction of clinical scores between the two liver support systems showed no differences between the groups in SAPS II and MELD scores (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA). Compared to patients treated with CytoSorb, patients in the ADVOS group experienced a significant worsening of SOFA scores during the posttreatment period (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA).\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eFor the subgroup of ACLF patients, none of the three clinical scores was influenced by CytoSorb therapy (Supplementary Table\u0026nbsp;1). ADVOS led to a further elevation in the SOFA score and a decrease in the MELD score after treatment (Supplementary Table\u0026nbsp;2). Results of the relative changes in clinical scores among critically ill ACLF patients completely reproduced the results achieved for the entire cohort (Supplementary Table\u0026nbsp;3).\u003c/p\u003e\n \u003cp\u003eWe examined short-term mortality among critically ill patients with hyperbilirubinemia due to acute liver dysfunction who received the two different liver support approaches (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eB-C). There were no significant differences between the CytoSorb and the ADVOS group in seven-day or in-hospital mortality rates (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eB-C). In-hospital mortality rates reached 88% for both devices (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eC). Separate analysis of ACLF patients for each liver support method showed that seven-day and in-hospital mortality rates were similar to those obtained for the entire study population; there were no significant differences between the two tested liver support devices (Supplementary Fig.\u0026nbsp;1E).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"5. Discussion","content":"\u003cp\u003eOur retrospective study compared the effects of two artificial liver support systems, CytoSorb and ADVOS, applied in addition to standard treatment for critically ill patients with hyperbilirubinemia of \u0026ge;\u0026thinsp;7 mg/dL. We found a more pronounced reduction of total serum bilirubin by CytoSorb integrated into CVVHDF circuit than by ADVOS therapy as early as after one therapy session and also after the completion of treatment. ADVOS was significantly more effective in eliminating water-soluble molecules such as serum creatinine and blood urea nitrogen and in correcting pH alterations than was CytoSorb integrated into a CVVHDF circuit. Platelet counts and hemoglobin and C-reactive protein levels decreased significantly after therapy with both devices, whereas only CytoSorb resulted in a significant decrease in procalcitonin levels. Neither device improved other laboratory liver-function parameters, such as transaminases or plasmatic coagulation. SOFA and SAPS II scores also did not improve after treatment with either liver support method. Our analysis showed high post treatment mortality among critically ill patients treated with the two different liver support modalities. The results of laboratory and clinical outcomes tests obtained from a separate analysis of the subgroup of ACLF patients were similar to those for the entire cohort.\u003c/p\u003e \u003cp\u003eThe evidence of the effectiveness of CytoSorb in removal of total serum bilirubin of patients with hyperbilirubinemia is still scarce and is based on case presentations, three observational studies, and one registry analysis (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). We detected a median decrease of total bilirubin of 6 mg/dL as early as after the first individual session of CytoSorb. The median relative reduction of bilirubin levels after the full course of treatment with CytoSorb was 35%. These findings are consistent with existing reports (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Most of the previous studies and case series involved small sample sizes and retrospectively collected data (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). The CytoSorb International Registry presented by Ocskay et al. analyzed a total of 109 patients who were treated for the liver indication with hyperbilirubinemia; this is the largest dataset obtained in a prospective multicenter fashion (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Both Ocskay\u0026rsquo;s study and the pooled data metaanalysis conducted by Turan et al. reported a mean difference of 5 mg/dL between pretreatment and posttreatment bilirubin levels (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). The studies of Scharf et al. and Geimel et al. found that the use of CytoSorb led to a median relative reduction in bilirubin levels ranging between 23% and 32%, a finding very similar to our results (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). In a subset of patients with ACLF, Haselwanter et al. showed a much higher reduction in the relative bilirubin level of 48% after CytoSorb treatment (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). However, our current study found a median relative reduction rate in the total bilirubin level of 35% among the entire study population as well as among the subgroup of patients with ACLF at the end of CytoSorb therapy. It is worth noting that Geimel et al observed a relative bilirubin reduction of 32% within the first 6 hours of therapy with CytoSorb, whereas a relative bilirubin decrease of only 4% occurred after 6 hours (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). This rapid decline of relative bilirubin clearance during treatment with CytoSorb suggests saturation of the CytoSorb adsorber (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Alternatively, Geimel and colleagues hypothesized that the release of bilirubin from the adsorber into the blood circulation during the procedure might explain this phenomenon (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). In the current study settings the CytoSorb adsorber was replaced after 24 hours. Therefore, we assume that because of the potential saturation of the CytoSorb adsorber we may have underestimated the bilirubin elimination, and this underestimation may have prevented us from achieving the same high relative reduction rates as those demonstrated by Haselwanter et al. (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). In contrast to our study, which already included patients with hyperbilirubinemia of \u0026ge;\u0026thinsp;7 mg/dl, all other studies enrolled patients with slightly higher total bilirubin concentrations of more than 10 mg/dL (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Thus, higher concentration gradients may have enabled a faster and more efficient bilirubin removal attributed to the concentration-dependent bilirubin elimination manner of CytoSorb.\u003c/p\u003e \u003cp\u003eAs shown by recent reports, CytoSorb was not inferior to several other available artificial liver support methods (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). \u003cem\u003eIn vitro\u003c/em\u003e experiments revealed that CytoSorb yielded a significantly stronger reduction in bilirubin levels than did the Molecular Adsorbent Recirculating System (MARS) (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Popescu et al. reported that 15 patients with liver failure treated with CytoSorb exhibited a more pronounced bilirubin removal than did 15 critically ill patients from a corresponding group that underwent MARS therapy (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Scharf et al. compared CytoSorb and ADVOS administered to patients admitted to an ICU with acute liver dysfunction; this group identified an equivalent relative bilirubin reduction of 23% for both liver support systems (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). However, for this comparison only 6 patients were treated with ADVOS, whereas 33 patients were treated with CytoSorb (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Hence, the documented results on bilirubin elimination should be interpreted with caution (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). On the other hand, Scharf et al. assumed that they might have underestimated the effect of CytoSorb on bilirubin elimination and postulated ongoing accumulation of bilirubin during CytoSorb treatment because of significant increase in bilirubin levels prior to CytoSorb start indicating persistent hepatic injury with worsening of the liver dysfunction. Indeed, in the ADVOS group bilirubin levels already decreased before initiation of CytoSorb (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe saw a markedly higher relative reduction of total bilirubin levels among 71 critically ill patients treated with Cytosorb than among 71 patients treated with ADVOS. These observations did not support the previous results of the research group of Scharf et al. (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Reports on bilirubin removal achieved by ADVOS are rare to date, mostly deriving from real-life treatment experience (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Fuhrmann et al. reported only a moderate median decrease in bilirubin levels from 6.9 to 6.5 mg/dL among 18 patients treated with ADVOS in the context of a multicenter registry (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). A case series of 34 critically ill patients treated with ADVOS found a relative bilirubin reduction of 17%, a finding comparable to our finding of a relative reduction of 15% at the end of ADVOS therapy (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Additionally, a concentration-dependent removal of bilirubin was previously described (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). The contradiction between our study and that of Scharf et al. in the difference in bilirubin clearance among patients treated with CytoSorb and those treated with ADVOS may also be explained by the studies\u0026rsquo; different inclusion criteria (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). The study by Scharf and colleges involved a homogenous patient cohort with secondary acquired acute liver dysfunction (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Indeed, in the present study we requited critically ill patients with hyperbilirubinemia caused by various types of liver function impairment without differentiation between ALF, ACLF, or secondary acquired acute liver dysfunction associated with critical illness and multiorgan failure. Thus, our study population was heterogeneous, with different diagnostic and prognostic characteristics in the two treatment groups. Hence, in the CytoSorb group secondary acquired acute liver dysfunction was the most common underlying entity of liver failure, whereas in the ADVOS group ACLF clearly dominated and acute liver dysfunction was missing. This clear imbalance between the two treatment groups is attributable to the fact that, in the current retrospective study, supportive therapy for liver failure was performed as part of the clinical routine; therefore, the choice of which liver support procedure was used was a part of the clinical decision of the attending physician, because consensus and protocols on this issue are lacking so far. In the case of ACLF, the use of ADVOS instead of CytoSorb was favored and recommended in our center, and this fact may have introduced a significant bias into the comparison of the effect of the two supportive therapies on bilirubin elimination. To counteract the aforementioned problem, we additionally performed a separate analysis of the subgroup of ACLF patients for the CytoSorb and ADVOS device. This analysis provided results that were in line with observations achieved in the entire cohort. However, most of the patients in the ADVOS group were admitted to the ICU with advanced ACLF stages for which treatment with ADVOS and subsequent bilirubin clearance may be less effective because of the progression of irreversible multiorgan failure and persistent release of bilirubin that may provoke a permanent supply of bilirubin or an additional increase instead of a decrease in bilirubin levels. Studies of the use of CytoSorb and other available liver support modes in separate groups sharing the same indication for liver support and the same entity of liver dysfunction may be helpful in defining which specific types of acute liver dysfunction may profit from CytoSorb.\u003c/p\u003e \u003cp\u003eProspective randomized clinical trials comparing CytoSorb with various other liver support devices are warranted to clarify the beneficial effects of CytoSorb on bilirubin reduction and improvement of liver function. CYTOHEP was the first prospective single center, open-label, randomized controlled intervention pilot trial on this topic involving patients with ACLF and containing three arms: CRRT with CytoSorb, CCRT without CytoSorb, and no CRRT (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Unfortunately, the trial was terminated early because of difficulties in recruiting eligible participants and the high severity of ACLF (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Each of the three arms involved only three patients (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Taking into account the small sample size, the authors observed a trend toward a better bilirubin adsorption capacity in the CytoSorb group in comparison to the other two control groups (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDhokia et al. and Scharf et al. found a significant improvement in liver function tests including a decrease in liver transaminase and GGT activity after the completion of CytoSorb therapy (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). Additionally, Popescu et al. noted that LDH and ammonia levels decreased after CytoSorb treatment with no significant changes in transaminase activity (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Because the molecular size of these aforementioned liver variables exceeds CytoSorb\u0026rsquo;s maximum pore size of 17 kD, it is unlikely that hemoadsorption by CytoSorb is directly responsible for the decrease in the activity of liver transaminases, GGT, and LDH (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). It is conceivable that the improvement in these clinical values is related to the potential improvement and recovery of liver function under liver support therapy (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). To resolve this issue, the levels of these substances of interest should be measured upstream and downstream of the CytoSorb adsorber so that clearance by hemoadsorption can be assessed. ADVOS therapy cannot directly remove and modulate liver enzymes (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Our data stand in contrast to those of these other reports and do not demonstrate a paraclinical improvement in the CytoSorb group or the ADVOS group. Liver transaminase activity remained stable or further increased in both groups, as indicated by negative relative reduction values in both treatment groups; this finding leads us again to hypothesize that the severe progressive acute liver dysfunction of a different origin exhibited by our critically ill patients was that seems to be irreversible and to contribute to the further deterioration of liver function in most patients. However, elevation of liver transaminase activity during the course of treatment was significantly stronger in the ADVOS group than in CytoSorb group, mainly referring to a severe ACLF disease state among patients in the ADVOS group.\u003c/p\u003e \u003cp\u003eRegarding blood coagulation markers, the degree of worsening PTT and prothrombin time and the significant drop of in platelet counts were of similar extent for both tested liver support methods in our study. A number of other studies have documented depletion of platelets as an adverse effect of CytoSorb use; the degree of this depletion may depend on multiple factors, such as the activation of platelets by the extracorporeal CRRT circuit and the aggregation of platelets within the CytoSorb adsorber or the CRRT dialyzer (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). A reduction in the platelet count was reported to occur during ADVOS therapy (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). But the observed decrease of platelet counts in our study may also reflect further damage of liver tissue and loss of liver function, especially among patients with advanced ACLF. To explain the alterations in plasmatic coagulation parameters at the end of treatment with both liver support systems, we again suspect the progression of liver disease rather than device-related effects.\u003c/p\u003e \u003cp\u003ePatients in the CytoSorb group experienced a stronger reduction of hemoglobin concentrations after therapy than did those in the ADVOS group. Popescu et al. found similar hemoglobin changes after CytoSorb treatment (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Erythrocyte entrapment, destruction within the CytoSorb adsorber or the CRRT dialyzer, and an accompanying phenomenon for critical illness or frequent blood withdrawal during CVVHDF in the ICU should be discussed as potential causes (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA systemic hyperinflammatory state is a known hallmark of various causes of acute liver dysfunction (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Haselwanter et al. found that treating ACLF patients with CytoSorb resulted in a reduction of procalcitonin levels after CytoSorb treatment (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Moreover, Popescu et al. found a mild decrease in C-reactive protein and procalcitonin levels as standard inflammatory markers among patients treated with CytoSorb (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Similarly, we detected a significant decrease in C-reactive protein and procalcitonin levels under CytoSorb therapy. ADVOS also led to a decrease in C-reactive protein levels without influencing procalcitonin levels. It is unclear whether these findings are related to the standard medial treatment of sepsis and infection or to the hemoadsorption. A single study pointed out no significant modifications of proinflammatory cytokine levels by ADVOS (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Thus, to rule out the real extent of device-specific clearance of inflammatory markers by CytoSorb or ADVOS, additional studies quantifying diverse proinflammatory and antiinflammatory cytokines after these liver support methods would be useful. Unfortunately, due to the retrospective nature of the present study, which involved patients in routine clinical settings, we could not estimate specific cytokine levels. Determining the role of different liver support devices in rebalancing the inflammatory response during liver dysfunction should be the aim of ongoing studies.\u003c/p\u003e \u003cp\u003eThe current study showed that ADVOS therapy was superior to the combination of CVVHDF plus CytoSorb in clearing creatinine and blood urea nitrogen levels, and in improving acidosis. Few existing case series have shown that critically ill patients treated with ADVOS developed successful reduction of creatinine and blood urea nitrogen levels (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). The integration of two high-flux dialyzers with a large surface area of 1.9 qm for each dialyzer into the blood circuit of the ADVOS machine provides an advantage over conventional CVVHDF which uses only one dialyzer. This difference may have substantially contributed to the greater elimination of water-soluble toxins in the ADVOS group than in the CytoSorb group (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). However, the same blood flow of 100 mL/min was applied in both liver support modalities. Otherwise, we observed a slight trend toward higher median duration of CRRT using ADVOS lasting 96 hours in comparison to the median duration of continuous hemodialysis treatment among patients in the CytoSorb group lasting only 72 hours, that might partly explain a better removal of serum creatinine and blood urea nitrogen under ADVOS than under CytoSorb with CVVHDF. Thanks to the adjustable dialysate composition in the ADVOS system, a relevant pH increase can be achieved, and severe metabolic disorders refractory to conventional CCRT can be corrected (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Previous real-world clinical experience reports indicated that the pH value of the dialysate can be set between 7.2 and 9.0; this setting allows an automatic modification of the dialysate composition according to the amount of acid and basic concentrate being supplied. It also allows adaptation of metabolic control on the individual patient\u0026rsquo;s needs (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlthough CytoSorb was significantly better than ADVOS in reducing bilirubin levels, reduction capability of CytoSorb treatment was not associated with ameliorated seven-day or in-hospital survival rates or with improvement in clinical scores such as SOFA and SAPS II. SOFA and SAPS II scores did not decrease in either liver support group after the full course of treatment, probably because these critically ill patients with hyperbilirubinemia were at a late stage of advanced liver disease and multiorgan failure at the time of treatment. The observations of prognostic clinical scores are consistent with the findings of Popescu et al. (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e), who maintained that SOFA scores did not change significantly after treatment with CytoSorb or MARS (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Like us, they observed a decrease in MELD scores in the CytoSorb group (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). A reduction in posttreatment MELD scores was documented for both liver support devices in our study; this finding may be explained by the reduction of bilirubin values that are included in the quantification of the MELD score. In-hospital mortality rates were comparably high in both groups, at 88%. In agreement with our findings, Scharf et al. described in-hospital mortality rate of 82% for their cohort of critically ill patients with secondary acquired acute liver dysfunction (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Indeed, the CytoSorb International Registry analysis by Ocskay et al. found a lower in-hospital mortality rate of only 60% among 109 critically ill patients treated with CytoSorb for a liver indication (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). In our opinion, the very high mortality rates observed in our study and in the study of Scharf et al. were probably the result of the inclusion of extremely ill patients with advanced disease state in our study population, as reflected by high MELD, SOFA, and SAPS II scores in both analyses (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Gr\u0026auml;fe et al. investigated differences in mortality rates between 30 critically ill patients treated with CytoSorb and 52 patients without CytoSorb use who served as a control group (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). The authors stated no significant differences in mortality rates between the CytoSorb treatment group and the control group (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). Multivariate analysis also showed no independent effects of CytoSorb therapy on the survival of critically ill patients with hyperbilirubinemia (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). The present study did not provide an appropriate control group composed of critically ill patients with hyperbilirubinemia who were not treated with a liver support device in addition to standard medical treatment; the absence of a control group complicates the estimation of the real effects of CytoSorb and ADVOS on mortality rates. However, several aspects may play a role in explaining why long-term effects of CytoSorb on mortality rates are not achieved despite a positive effect on total serum bilirubin levels. Hemoadsorption using CytoSorb is not able to completely restore all liver function; it is only an adjuvant treatment option that supports liver function, but does not eliminate the cause of liver failure, or cure acute liver dysfunction. The acute liver dysfunction indicated by hyperbilirubinemia is only one component of a complex disease state and is often accompanied by multiorgan failure. Numerous other factors are involved in the death of critically ill patients with multiorgan failure in ICUs, and one liver support device cannot manage all of these factors. On the other hand, achieving a relevant prognostic improvement in our study population was difficult due to the fact that critically ill patients in both treatment groups mostly exhibited advanced liver dysfunction and multiorgan failure; it was impossible to reverse these conditions by using adjuvant liver support therapies that might be provided too late. Thus, our study results emphasize the urgent need for the application of CytoSorb, ADVOS, or another liver support system at early disease stages to prevent disease progression. In general, the effects on clinical outcomes, in particular mortality rates associated with various liver support devices that were designed for liver detoxification and are currently in clinical use, are controversial and under debate (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan additionalcitationids=\"CR35\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). Popescu et al. found that CytoSorb did not perform better then MARS with respect to twenty-eight day survival rates of ICU patients (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). No benefit on survival rates was reported by comparison of diverse artificial liver support devices, such as MARS, Prometheus, and single-pass albumin dialysis with standard medical care, in retrospective studies and a prospective randomized trial involving ACLF patients (\u003cspan additionalcitationids=\"CR35\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). For patients with ALF, a metaanalysis detected a significant positive effect on overall survival for a high-volume plasma exchange group in comparison to a group treated with standard medical care, but not for other alternative liver support possibilities (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). Until there is no longer a lack of hard evidence about clinical outcomes after hemoadsorption with CytoSorb, there will be an urgent need for randomized, controlled prospective trials addressing this question.\u003c/p\u003e \u003cp\u003eWe are aware of several limitation of our study. The data were obtained retrospectively in clinical routines from a single center. Hence, missing laboratory values or slight deviation in time points cannot be excluded. We were not able to determine other important variables, such as cytokine levels that are not usually measured as part of clinical routine. Because the study did not include an appropriate control group, it is problematic to account for spontaneous changes in characteristic variables of liver function and to judge the advantages in survival and recovery from acute liver dysfunction. Our study may also involve selection bias because of heterogeneity in diagnosis and prognosis in both treatment groups and deviant composition in terms of forms of acute liver dysfunction in the CytoSorb group as compared with the ADVOS group; this bias may have been induced because the choice of a suitable liver support device was based on the decision and opinion of an attending physician in our institution. Significant differences in clinical and biochemical baseline features between the CytoSorb group and the ADVOS group may also have induced selection bias. Nevertheless, compared with a number of other recent studies and case series, the current study involved a large patient number and dataset in both liver support therapy groups.\u003c/p\u003e"},{"header":"6. Conclusions","content":"\u003cp\u003eIn conclusion, both liver support devices, CytoSorb and ADVOS, efficiently reduced bilirubin levels among critically ill patients with hyperbilirubinemia caused by various forms of acute liver dysfunction and among critically ill patients with ACLF. Although CytoSorb use led to a significantly more extensive relative reduction of total serum bilirubin levels than did ADVOS, ADVOS therapy was associated with better elimination of water-soluble substances such as creatinine and blood urea nitrogen and with a better rebalancing of acid abnormalities than was CytoSorb. Neither of the liver support modalities improved liver function and short-term mortality rates of critically ill patients with hyperbilirubinemia or ACLF patients were comparable between the two extracorporeal liver support approaches. Artificial liver support devices such as ADVOS are time- and cost-intensive, and their use is complex, requiring experienced healthcare personnel (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). In contrast, CytoSorb as a liver support approach is cheaper, easier to handle, and readily available for installation in conventional hemodialysis circuits (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). In addition, our findings support the opinion that CytoSorb has beneficial effects on bilirubin elimination and is not disadvantageous compared to ADVOS. Therefore, the CytoSorb adsorber may be a promising tool for treating critically ill patients with acute liver dysfunction and hyperbilirubinemia in small centers. Otherwise, the combination of ADVOS and CytoSorb incorporates the advantages of both devices, such as bilirubin clearance, elimination of water-soluble toxins, and correction of metabolic disorders, this combination merits investigation in ongoing studies involving critically ill patients with acute liver dysfunction.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eACLF, acute-on-chronic liver failure;\u003c/p\u003e\n\u003cp\u003eADVOS, advanced organ support\u003c/p\u003e\n\u003cp\u003eALF, acute liver failure\u003c/p\u003e\n\u003cp\u003eALT, alanine transaminase\u003c/p\u003e\n\u003cp\u003eAST, aspartate transaminase\u003c/p\u003e\n\u003cp\u003eCI, confidence interval\u003c/p\u003e\n\u003cp\u003eCRP, C-reactive protein\u003c/p\u003e\n\u003cp\u003eCRRT, continuous renal replacement therapy\u003c/p\u003e\n\u003cp\u003eCVVHDF, continuous veno-venous hemodiafiltration\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ed, day\u003c/p\u003e\n\u003cp\u003eICU, intensive care unit\u003c/p\u003e\n\u003cp\u003eGGT, gamma-glutamyltransferase\u003c/p\u003e\n\u003cp\u003eL, liter\u003c/p\u003e\n\u003cp\u003eLDH, lactate dehydrogenase\u003c/p\u003e\n\u003cp\u003eMARS, Molecular Adsorbent Recirculating System \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMELD, Model for End-Stage Liver Disease\u003c/p\u003e\n\u003cp\u003ePTT, partial thromboplastin time\u003c/p\u003e\n\u003cp\u003eRR, relative risk\u003c/p\u003e\n\u003cp\u003eSAPS II, Simplified Acute Physiology Score II\u003c/p\u003e\n\u003cp\u003eSOFA, Sequential Organ Failure Assessment\u003c/p\u003e\n\u003cp\u003eU, unit\u003c/p\u003e\n\u003cp\u003eurea-N, urea nitrogen\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eThe study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of the University Hospital Essen (23-11563-BO, 23-11170-BO). Informed consent was obtained from all subjects.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eAll data generated or analyzed during this study are included in this published article and its supplementary information files.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e No funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJ.F.K., B.T. and A.K. developed the idea and the concept of the project. J.F.K. and K.S. were responsible for project administration. J.F.K., L.K.H., B.T., M.J. and K.S. performed data collection. J.F.K. and K.S. analyzed the data and prepared the figures and tables. J.F.K. wrote the manuscript. All authors reviewed the manuscript. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number:\u003c/strong\u003e not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eEditorial assistance was provided by Flo Witte, PhD, of Bluegrass Editorial Services Team, LLC, Lexington, KY, USA. \u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eJonsdottir S, Arnardottir MB, Andresson JA, Bjornsson HK, Lund SH, Bjornsson ES. Prevalence, clinical characteristics and outcomes of hypoxic hepatitis in critically ill patients. Scand J Gastroenterol. 2022;57(3):311\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrek A, Arasi L. Acute Liver Failure. 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World J Clin Cases. 2023;11(17):3932\u0026ndash;48.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerez Ruiz de Garibay A, Leonhardt J, Zipprich A, Bauer M. Critical care hepatology: definitions, incidence, prognosis and role of liver failure in critically ill patients. Crit Care. 2022;26(1):289.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKluge M, Tacke F. Liver impairment in critical illness and sepsis: The dawn of new biomarkers? Ann Transl Med. 2019;7(Suppl S8):S258.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKramer L, Jordan B, Druml W, Bauer P, Metnitz P, DEAA for the Austrian Epidemiologic Study on Intensive Care, ASDI Study Group. Incidence and prognosis of early hepatic dysfunction in critically ill patients\u0026mdash;A prospective multicenter study. Crit Care Med. 2007;35(4):1099\u0026ndash;104.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoseley RH. Sepsis and cholestasis. Clin. Liver Dis. 2004;8(1):83\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVincent JL, Moreno R, Takala J, Willatts S, De Mendon\u0026ccedil;a A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22(7):707\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHan HS, Park CM, Lee DS, Sinn DH, Gil E. Evaluating mortality and recovery of extreme hyperbilirubinemia in critically ill patients by phasing the peak bilirubin level: a retrospective cohort study. PLoS ONE. 2021;16(8):e0255230.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOng KL, llison MA, Cheung BM, Wu BJ, Barter PJ, Rye KA. The relationship between total bilirubin levels and total mortality in older adults: The United States National Health and Nutrition Examination Survey (NHANES) 1999\u0026ndash;2004. PLoS ONE. 2014;9(4):e94479.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeiss EM, Saner FM, Asrani SKM, Biancofiore GM, Blasi A, Lerut JM, et al. When Is a Critically Ill Cirrhotic Patient Too Sick to Transplant? Development of Consensus Criteria by a Multidisciplinary Panel of 35 International Experts. Transplantation. 2021;105(3):561\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTandon R, Froghi S. Artificial liver support systems. J Gastroenterol Hepatol. 2021;36(5):1164\u0026ndash;79.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePoli EC, Rimmele T, Schneider AG. Hemoadsorption with CytoSorb\u0026reg;. Intensive Care Med. 2019;45(2):236\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOcskay K, Tomescu D, Faltlhauser A, Jacob D, Friesecke S, Malbrain M, et al. Hemoadsorption in liver indication\u0026rsquo;-analysis of 109 patients data from the CytoSorb international registry. J Clin Med. 2021;10(21):5182.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFuhrmann V, de Garibay APR, Faltlhauser A, Tyczynski B, Jarczak D, Lutz J, et al. Registry on extracorporeal multiple organ support with the advanced organ support (ADVOS) system. Med (Baltim). 2021;100(7):e24653.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFuhrmann V, Weber T, Roedl K, Motaabbed J, Tariparast A, Jarczak D, et al. Advanced organ support (ADVOS) in the critically ill: first clinical experience in patients with multiple organ failure. Ann Intensive Care. 2020;10(1):96.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\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/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGreimel A, Habler K, Gr\u0026auml;fe C, Maciuga N, Brozat CI, Vogeser M, et al. Extracorporeal adsorption of protective and toxic bile acids and bilirubin in patients with cholestatic liver dysfunction: a prospective study. Ann Intensive Care. 2023;13(1):110.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\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/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePopescu M, David C, Marcu A, Olita MR, Mihaila M, Tomescu D. Artificial Liver Support with CytoSorb and MARS in Liver Failure: A Retrospective Propensity Matched Analysis. J Clin Med. 2023;12(6):2258.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDominik A, Stange J. Similarities, Differences, and Potential Synergies in the Mechanism of Action of Albumin Dialysis Using the MARS Albumin Dialysis Device and the CytoSorb Hemoperfusion Device in the Treatment of Liver Failure. Blood Purif. 2021;50(1):119\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMonard C, Rimmel\u0026eacute; T, Ronco C. Extracorporeal Blood Purification Therapies for Sepsis. Blood Purif. 2019;47(Suppl S3):2\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSommerfeld O, Neumann C, Becker J, von Loeffelholz C, Roth J, Kortgen A, et al. Extracorporeal albumin dialysis in critically ill patients with liver failure: Comparison of four different devices-A retrospective analysis. Int J Artif Organs. 2023;46(8\u0026ndash;9):481\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaps L, Ahlbrand CJ, Gadban R, Nagel M, Labenz C, Klimpke P, et al. Applicability and safety of discontinuous ADVanced Organ Support (ADVOS) in the treatment of patients with acute-on-chronic liver failure (ACLF) outside of intensive care. PLoS ONE. 2021;16(4):e0249342.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSekandarzad A, Weber E, Prager EP, Graf E, Betting D, Wengenmayer T, et al. Cytokine adsorption in patients with acute-on-chronic liver failure (CYTOHEP)-a single center, open-label, three-arm, randomized, controlled intervention trial. Trials. 2022;23(1):222.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDhokia VD, Madhavan D, Austin A, Morris CG. Novel use of Cytosorb\u0026trade; haemadsorption to provide biochemical control in liver impairment. J Intensiv Care Soc. 2019;20(2):74\u0026ndash;181.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlharthy A, Faqihi F, Memish ZA, Balhamar A, Nasim N, Shahzad A, et al. Continuous renal replacement therapy with the addition of CytoSorb cartridge in critically ill patients with COVID-19 plus acute kidney injury: A case-series. Artif Organs. 2021;45(5):E101\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAl-Dorzi HM, Alhumaid NA, Alwelyee NH, Albakheet NM, Nazer R, Aldakhil SK et al. Anemia, Blood Transfusion, and Filter Life Span in Critically Ill Patients Requiring Continuous Renal Replacement Therapy for Acute Kidney Injury: A Case-Control Study. Crit Care Res Pract. 2019:2019:3737083.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJu\u0026aacute;rez-Vela R, Andr\u0026eacute;s-Esteban EM, Gea-Caballero V, S\u0026aacute;nchez-Gonz\u0026aacute;lez JL, Marcos-Neira P, Serrano-L\u0026aacute;zaro A, et al. Related Factors of Anemia in Critically Ill Patients: A Prospective Multicenter Study. J Clin Med. 2022;11(4):1031.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaps L, Schleicher EM, Montano CM, Bros M, Gairing SJ, Ahlbrand CJ, et al. Influence of Advanced Organ Support (ADVOS) on Cytokine Levels in Patients with Acute-on-Chronic Liver Failure (ACLF). J Clin Med. 2022;11(10):2782.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGr\u0026auml;fe C, Paal M, Winkels M, Irlbeck M, Liebchen U, Scharf C. Correlation between Bilirubin Elimination with the Cytokine Adsorber CytoSorb\u0026reg; and Mortality in Critically Ill Patients with Hyperbilirubinemia. Blood Purif. 2023;52(11\u0026ndash;12):849\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOcskay K, Kanjo A, Gede N, Szak\u0026aacute;cs Z, P\u0026aacute;r G, Erőss B, et al. Uncertainty in the impact of liver support systems in acute-on-chronic liver failure: a systematic review and network meta-analysis. Ann Intensive Care. 2021;11(1):10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbbas N, Rajoriya N, Elsharkawy AM, Chauhan A. Acute-on-chronic liver failure (ACLF) in 2022: Have novel treatment paradigms already arrived? Expert Rev Gastroenterol Hepatol. 2022;16(7):639\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThompson J, Jones N, Al-Khafaji A, Malik S, Reich D, Munoz S, et al. Extracorporeal cellular therapy (ELAD) in severe alcoholic hepatitis: A multinational, prospective, controlled, randomized trial. Liver Transpl. 2018;24(3):380\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e\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":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"CytoSorb, ADVOS, bilirubin, acute-on-chronic liver failure, secondary acquired liver dysfunction, continuous veno-venous hemodiafiltration","lastPublishedDoi":"10.21203/rs.3.rs-6195702/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6195702/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e As many as 30% of critically ill patients in intensive care units experience acute liver dysfunction with hyperbilirubinemia as a part of multiorgan failure that is associated with poor outcome. This retrospective cohort study was aimed at comparing CytoSorb and ADVOS in terms of bilirubin removal and overall survival among critically ill patients with hyperbilirubinemia ≥ 7 mg/dL.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e At the University Hospital Essen, between January 2021 and March 2024, 71 patients were treated with CytoSorb integrated in a continuous veno-venous hemodiafiltration (CVVHDF) circuit, and 71 patients were treated with ADVOS. Each therapy session lasted 24 hours.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e The first single sessions of both CytoSorb with CVVHDF and ADVOS were associated with a statistically significant decrease in total serum bilirubin levels (Cytosorb, 20 to 14 mg/dL, p\u0026lt;0.0001; ADVOS, 16 to 14 mg/dL, p\u0026lt;0.0001), but the percentage bilirubin reduction was more pronounced for CytoSorb treatment (26% vs. 17%, p=0.0002). The number of days of treatment was similar for both groups (3 vs. 4, p=0.07). After completion of therapy, serum levels of total bilirubin had decreased significantly; 19.9 to 11.3 mg/dl (p\u0026lt;0.0001) in the CytoSorb group and 16.3 to 14.0 mg/dL (p=0.003) in the ADVOS group. The relative bilirubin reduction was significantly higher after application of CytoSorb than after treatment with ADVOS (35% (IQR 19,54) vs. 15% (IQR -11;54), p\u0026lt;0.0001). The relative removal of creatinine and urea nitrogen was significantly higher after ADVOS treatment than after CytoSorb with CVVHD treatment. Courses of treatment with CytoSorb and ADVOS reduced similarly platelet counts, hemoglobin levels, and C-reactive protein levels. CytoSorb treatment led to a significant decline in procalcitonin levels. Seven-day or in-hospital mortality rates were high among critically ill patients in both liver support groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eOur results showed that CytoSorb and CVVHDF treatment performed better than ADVOS in bilirubin removal among critically ill patients with hyperbilirubinemia caused by acute liver dysfunction. ADVOS was more efficient in eliminating creatinine and urea nitrogen than was CVVHDF with CytoSorb. Additional prospective randomized controlled trials are warranted to investigate the efficacy of hemoperfusion with CytoSorb for liver disease indications among critically ill patients.\u003c/p\u003e","manuscriptTitle":"Artificial liver support with CytoSorb and continuous veno- venous hemodiafiltration and advanced organ support (ADVOS) for critically ill patients with hyperbilirubinemia: a retrospective analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-06 10:21:18","doi":"10.21203/rs.3.rs-6195702/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-05T04:50:50+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-26T19:33:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"25277049410911141693230440878306160690","date":"2025-05-19T17:17:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"334663537849582278830733025579253857705","date":"2025-05-15T14:00:22+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-15T10:43:11+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-08T13:54:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"264310180040619751567620285736878653562","date":"2025-04-02T12:41:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"78181688083094923487311137361513313398","date":"2025-04-02T06:05:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"325983348765625251084891156507470604102","date":"2025-04-01T16:58:46+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-01T11:49:57+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-27T11:15:55+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-03-25T17:14:35+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-24T12:15:22+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nephrology","date":"2025-03-24T12:14:15+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"823db749-6866-426c-8046-4da76100e81b","owner":[],"postedDate":"May 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-11T15:59:44+00:00","versionOfRecord":{"articleIdentity":"rs-6195702","link":"https://doi.org/10.1186/s12882-025-04342-6","journal":{"identity":"bmc-nephrology","isVorOnly":false,"title":"BMC Nephrology"},"publishedOn":"2025-08-04 15:57:11","publishedOnDateReadable":"August 4th, 2025"},"versionCreatedAt":"2025-05-06 10:21:18","video":"","vorDoi":"10.1186/s12882-025-04342-6","vorDoiUrl":"https://doi.org/10.1186/s12882-025-04342-6","workflowStages":[]},"version":"v1","identity":"rs-6195702","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6195702","identity":"rs-6195702","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}