I. INTRODUCTION
Sepsis and septic shock are serious conditions that are common in intensive care units (ICUs) and are associated with high mortality and significant medical costs [1,2]. These conditions are characterized by an excessive inflammatory response and a cytokine storm, which can lead to MODS (multiple organ dysfunction syndrome) [3,4]. ICU nurses play a pivotal role in the continuous monitoring and early detection of clinical deterioration in these patients, as they are at the frontline of patient care 24 hours a day. Traditional treatments include antibiotics, fluid therapy, and vasoconstrictors; however, these treatments are often not enough[5,6].
Recently, extracorporeal blood purification technology has attracted attention as an adjuvant treatment for sepsis[7]. Among these, CytoSorb® (CytoSorbents Corporation, NJ USA) is a specialized hemoperfusion device utilizing highly porous polymer beads with specific pore size distribution (250-600μm) and surface modification. Unlike traditional blood purification methods such as CRRT which primarily removes small molecular weight substances through filtration, or ECMO which provides cardiopulmonary support, CytoSorb uniquely removes medium molecular weight molecules(5-60kDa) through selective adsorption [8-10]. The device's versatility allows it to be used either as a standalone treatment or integrated into existing extracorporeal circuits(CRRT/ECMO), though considerations include the need for anti-coagulation and higher treatment costs. CytoSorb modulates inflammatory responses, improves hemodynamic stability, and ultimately enhances patient outcomes[11,12].
Although the clinical safety of CytoSorb is relatively well-established, evidence regarding its clinical efficacy remains questionable. Clinical studies have demonstrated various outcomes, such as mortality reduction (ranging from 28% to 65%), significant improvements in hemodynamic stability with vasopressor requirement reductions of 30-50%, and organ function improvement as measured by SOFA score decreases of 3-4 points [13,14]. However, other studies have not found significant clinical efficacy in terms of mortality reduction or hemodynamic improvement[15,16]. Moreover, uncertainty remains regarding the optimal timing of CytoSorb use, duration of treatment, and which patient groups may benefit most [17,18].
This study aims to perform a systematic review and meta-analysis that evaluate the efficacy of CytoSorb in patients with sepsis or septic shock. Therefore, this study focuses on key clinical outcomes, including mortality, changes in critical inflammatory markers (Procalcitonin [PCT] - an early diagnostic marker for bacterial infection and sepsis severity[19]; C-Reactive Protein [CRP] - an acute phase protein indicating systemic inflammation; and Interleukin-6 [IL-6] - a key proinflammatory cytokine central to the inflammatory cascade[20]), organ dysfunction scores, vasopressor requirements, time to weaning from mechanical ventilation, and length of hospital stay.
II. METHODS
This systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The study protocol was registered in (International Prospective Register of Systematic Reviews)(registration number: CRD 42024600394).
2.1. Information source and Search strategy
The eligibility criteria for this study were as follows: studies involving adult patients with sepsis or septic shock aged ≥18 years were included, and extracorporeal cytokine removal therapy using CytoSorb was compared with standard care. The primary endpoints were 28-day and in-hospital mortality, and the secondary endpoints included changes in blood cytokine levels, organ failure scores, vasopressor requirements, time to ventilator weaning, ICU length of stay, and hospital length of stay. Randomized controlled trials, non-randomized controlled trials, prospective cohort studies, and retrospective cohort studies were considered for inclusion. Animal studies, case reports, review articles, letters to the editor, and papers written in languages other than English were excluded.
Literature retrieval was performed using the PubMed, Embase, Web of Science, and CINAHL databases, covering the period from the inception of each database to September 25, 2024. The following Medical Subject Heading keywords and their combinations were used: ‘sepsis,’ ‘septic shock,’ ‘CytoSorb, ‘hemadsorption,’ and ‘extracorporeal cytokine removal,’ tailored to each database.
Two independent reviewers screened the titles and abstracts to identify potentially eligible studies, followed by a full-text review to determine the final inclusion. Disagreements were resolved through discussion with a third researcher. Data from the selected studies were extracted in a standardized form, capturing information on study characteristics, participant details, intervention specifics, outcome measures, and results.
2.2. Quality assessment
To assess the risk of bias in individual studies, two independent reviewers performed a quality assessment using the Cochrane Risk of Bias 2 (RoB 2) tool for randomized controlled trials and the ROBINS-I tool for non-randomized studies. Disagreements between the reviewers were resolved through discussion.
2.3. Statistical analysis
The meta-analysis was performed using Review Manager software(RevMan). For binary outcomes, risk ratios (RR) were calculated with 95% confidence intervals (CI), whereas for continuous outcomes, mean differences(MD) were calculated with 95% CI. Statistical heterogeneity was assessed using the I2 statistic with a random-effects model applied in cases of substantial heterogeneity(I2＞ 50%). Publication bias was evaluated using funnel plots and Egger's test.
III. RESULTS
3.1. Study search and characteristics
In total, 423 articles were identified from the four databases. The search results are as follows: CINAHL (n=164), Embase (n=75), Web of Science (n=116), and PubMed (n=68). After excluding 31 duplicate studies, 392 studies remained. According to the systematic screening procedure under the PRISMA guidance, title and abstract reviews were performed for the remaining 392 studies after the 31 duplicated studies were excluded, of which 382 were re-excluded for not meeting the eligibility criteria. After a full-text review, 10 studies were finally included, resulting in the final inclusion of 10 studies in this systematic review and meta-analysis[11,16,18,21-27] Figure 1.
3.2. Methodological bias risk assessment
The risk of bias for each included study was assessed using credible tools based on the study design. Two randomized controlled trials were assessed using the Cochrane RoB2 tool, whereas eight non-randomized controlled trials, including cohort studies, were assessed using the ROBINS-I tool. Two independent reviewers performed the assessments, and disagreements between them were resolved through discussion and consultation with a third reviewer.
3.3. Risk of bias in randomized controlled trials
The risk of bias in two studies, Hawchar et al.[18] and Schä dler et al.[16], was assessed across five domains(D1-D5). The risk factors are shown in Figure 2-A. The other eight studies were non-randomized, including retrospective and prospective cohort studies. These risk factors are shown in Figure 2-B. For non-randomized studies, the major concerns were related to confounding factors and selection bias. Most studies have attempted to address confounding factors through statistical methods such as propensity score matching or adjustment, but residual confounding factors might remain a concern. The retrospective characteristics of some studies also present the potential for selection bias. The measurement of outcomes was generally considered to have a moderate risk of bias because the blinding in the outcome assessment was insufficient.
3.4. CytoSorb in Sepsis and Septic Shock
This systematic review included ten studies [enrolling] that focused on patients with sepsis or septic shock. The study participants ranged from small cohorts (9 patients) to larger groups (502 patients), with varying distributions between the CytoSorb and control groups. For example, Brouwer et al.[11] included 116 patients (67 CytoSorb, 49 controls), whereas Akil et al.[23] studied 20 patients(13 CytoSorb, seven controls). The total number of patients in the 10 studies was 759, of whom 517 were included in the CytoSorb intervention group.
The primary intervention focused on hemoadsorption therapy with CytoSorb, which is usually applied in combination with various treatments such as ECMO, CRRT, or standard care. The duration of CytoSorb application varied significantly across studies, with some studies specifying 24h[16,18,22]. Key outcome measures included: 1) mortality (28-day, 30-day, and in-hospital), 2) inflammatory markers (PCT, CRP, and IL-6), 3) vasopressor requirements, 4) organ dysfunction scores (SOFA), and 5) length of stay.
The results of this study revealed various outcomes. Some studies have reported positive results. Brouwer et al.[11] found decreased mortality in patients with septic shock, Rugg et al. [25] reported reduced catecholamine requirements and in-hospital mortality, and Schultz et al.[26] noted improved survival with high-dose CytoSorb treatment. Kogelmann et al.[24] developed a Dynamic Scoring System (DSS) and found that the early initiation of CytoSorb therapy in patients with high DSS scores was associated with improved survival. In contrast, other studies showed neutral results: Schä dler et al.[16] found no significant difference in IL-6 removal or clinical outcomes, and Schittek et al.[21] reported no significant reduction in mortality.
The conclusions of this study reflect this evidence. While some studies strongly support CytoSorb's effectiveness (e.g., Akil et al.,[23] found it effective in preventing sepsis escalation when combined with ECMO), others were more cautious or found no significant benefits. The basic characteristics of the included studies are summarized in Table 1.
Table 1.
Basic characteristics of the included studies: CytoSorb in Sepsis and Septic Shock
3.5. Patient outcomes
The three patient-related outcomes that showed statistical significance were mortality, ICU stay, and cytokine levels in Figure 3-A, B, and C. The ORs, Standard Mean Difference, and 95% CI for these patient outcomes are shown in Table 2.
Table 2.
Patient Outcomes: Mortality, ICU Length of Stay, and Cytokine Level(IL-6)
3.6. Effectiveness of CytoSorb in Sepsis and Septic Shock
The meta-analysis for mortality included 7 studies with 481 and 335 patients in the experimental and control groups, respectively. The overall effect size, represented by the pooled risk ratio, was 0.99 (95% confidence interval: 0.75-1.30). This suggests that CytoSorb treatment showed no significant difference in mortality compared with the control group (p=0.93). The I2 statistic, which indicates heterogeneity among studies, was 64%, indicating substantial heterogeneity (chi2=16.79, df=6, p=0.01) Figure 3-A.
The meta-analysis for ICU length of stay included six studies with 528 patients in the experimental group and 246 patients in the control group. The overall effect size, represented by the standardized mean difference, was 0.06(95% confidence interval: −0.09 to 0.22). This suggests that CytoSorb treatment was associated with a nonsignificant difference in ICU length of stay compared with the control group (p=0.44). The I2 statistic was 0%, indicating no heterogeneity between the studies (Chi2=3.99, df=5, p=0.55) Figure 3-B.
The analysis of IL-6 levels included three studies with 89 patients in both the experimental and control groups. The overall effect size, represented by the standardized mean difference, was −0.43 (95% confidence interval: −0.83 to −0.03). This indicated that CytoSorb treatment was associated with a significant reduction in IL-6 levels compared to the control group(p=0.04). The I2 statistic was 36%, suggesting low-to-moderate heterogeneity among the studies (P=0.21) Figure 3-C.
3.7. Publication Bias
Despite having 10 studies in this meta-analysis, publication bias assessment was performed according to the recommendations of the Cochrane Handbook. The funnel plots in Figure 3-D, E, and F show three separate analyses of(D) mortality (RR), (E) ICU length of stay (SMD), and (F) IL-6 levels (SMD). In Figure 3-D, the studies were distributed asymmetrically, with one study showing a notable deviation in the lower left region, suggesting a possible publication bias for mortality outcomes. Figure 3–E shows a relatively even distribution of studies around the vertical line for the ICU length of stay, although with some clustering toward the bottom half. Figure 3-F contains only three studies on IL-6 levels, making it difficult to draw meaningful conclusions regarding publication bias for this outcome.
IV. DISCUSSION
This systematic review and meta-analysis aimed to evaluate the effectiveness of CytoSorb hemoadsorption therapy in patients with sepsis and septic shock, with a focus on clinical outcomes and cytokine levels. This analysis encompassed 10 studies involving 759 patients (517 patients with CytoSorb and 242 controls), providing comprehensive insights into both the clinical effectiveness and mechanistic aspects of this innovative therapy. Among the various inflammatory markers examined, IL-6 is considered the main indicator of therapeutic efficacy.
This meta-analysis showed a significant reduction in IL-6 levels in the CytoSorb group (SMD: −0.43, 95% CI: −0.83 to −0.03, p=0.04), with relatively low heterogeneity (I2=36%, p=0.21). This important outcome validates the primary therapeutic mechanism of CytoSorb, that is, the effective removal of excess cytokines from the bloodstream. The ability of the device to significantly reduce IL-6, a key proinflammatory mediator in sepsis or septic shock, suggests its potential to modulate the inflammatory response during the critical phases of illness. This cytokine reduction capability becomes specifically relevant given IL-6's main role in the inflammatory cascade of sepsis or septic shock.
The underlying effectiveness of CytoSorb can be understood from a biomedical engineering perspective and represents a significant advancement in blood purification technology. The innovative design of the device utilizes highly porous polymer beads with a specific pore size distribution and surface modification, allowing the selective adsorption of medium-molecular-weight molecules, including various inflammatory mediators[10]. This targeted approach for cytokine removal represents a considerable improvement over traditional, less selective blood purification techniques, as highlighted by Rimmelé and Kellum[7].
Besides cytokine reduction, several studies have reported improvements in hemodynamic parameters, particularly in vasopressor requirements. Rugg, Klose [25] demonstrated reduced catecholamine requirements and improved in-hospital mortality rates after CytoSorb treatment. These observations suggest that CytoSorb may provide benefits in addition to cytokine removal, contributing to improved organ function and hemodynamic stability.
The varying clinical outcomes observed across studies underscore an important aspect of CytoSorb therapy: the critical role of proper patient selection and timing of intervention. These findings have been further corroborated by a recent systematic review by Saldañ a-Gastulo et al.[28], which also highlighted the significance of appropriate patient selection and early intervention. Our study not only confirms these observations but also provides evidence for the clinical utility of the Dynamic Scoring System in predicting treatment response. Kogelmann et al. [24] developed a Dynamic Scoring System and found that early initiation of CytoSorb therapy in patients with high DSS scores was associated with improved survival. Similarly, Brouwer et al. [11] reported improved survival rates when CytoSorb therapy was initiated early in an appropriate patient population. This finding particularly emphasizes the crucial role of ICU nurses in the timely initiation of therapy through their continuous patient assessment, careful monitoring of hemodynamic changes and cytokine levels, and effective interdisciplinary communication. These findings suggest that optimal utilization of CytoSorb may depend on careful patient stratification, timing strategies, and specialized nursing interventions including meticulous device management and prevention of potential complications.
Although this meta-analysis showed no significant difference in overall mortality (RR 0.99, 95% CI: 0.75-1.30, p=0.93). This finding aligns with a recent meta-analysis by Becker et al.[29] (RR 1.07[0.88; 1.31]). However, our study focused not only on mortality but also demonstrated significant improvements in IL-6 levels and hemodynamic parameters. This is particularly relevant in light of the recent consensus statement by Mitzner et al.[30], which emphasizes the importance of treatment timing and appropriate dosing.
The evaluation of medical devices for critical care, particularly sepsis management, presents unique methodological considerations that differ from those in traditional pharmaceutical trials. This methodological challenge was also noted in Heymann et al.'s[31] recent meta-analysis, particularly regarding the heterogeneity of study designs and patient populations. However, our analysis demonstrates a consistent correlation between IL-6 reduction and hemodynamic improvement, providing important insights into the mechanism of action. The complexity of sepsis pathophysiology, the heterogeneity of patient populations, and the dynamic nature of critical illness necessitate comprehensive evaluation approaches that can capture the full spectrum of clinical responses. The positive outcomes observed in several well-designed observational studies included in our analysis, such as those reported by Brouwer, Duran[11] and Kogelmann, Hübner [24], demonstrate the value of diverse clinical evidence for understanding therapeutic effectiveness. These studies, conducted in clinical settings across various patient populations, provide important insights into the potential benefits of CytoSorb in real-world medical practice.
The primary strengths of this study are its comprehensive analytical approach and robust methodology. This analysis included diverse clinical settings and patient populations and provided a broad perspective on the therapeutic applications of CytoSorb. The inclusion of randomized and observational studies allowed for a more complete understanding of the effects of therapy across different clinical scenarios. Furthermore, this systematic evaluation of multiple outcome measures, from cytokine levels to clinical end- points, provided a multifaceted view of the impact of CytoSorb on sepsis management.
This meta-analysis has several limitations. The observed heterogeneity in treatment protocols, patient characteristics, and outcome measurements across the included studies may have affected the generalizability of our findings. The funnel plots suggested some asymmetry, particularly in the mortality outcomes, indicating a possible publication bias that could influence the interpretation of treatment effects. Additionally, variations in the timing and duration of CytoSorb application across studies may have affected the observed outcomes, highlighting the need for more standardized treatment protocols. These limitations should be considered in-depth to provide valuable insights for future research.
Future studies of CytoSorb therapy should address several interconnected issues. Most importantly, it is important to establish an optimal treatment protocol, especially with regard to the timing and duration of treatment, as these factors are crucial for treatment success. This process should be complemented by the identification of reliable biomarkers for patient selection and treatment response prediction, including but not limited to cytokine profiles and clinical scoring systems. Based on this basic understanding, investigation of potential synergies with other sepsis therapies may open new the- rapeutic possibilities. Although mid- to long- term follow-up studies will provide important insights into the sustained benefits of CytoSorb treatment, parallel studies on cost-effectiveness and resource utilization will help convert these clinical findings into more realistic and pragmatic health policies.
V. CONCLUSION
This systematic review and meta-analysis demonstrated the effectiveness of CytoSorb in reducing IL-6 levels during sepsis treatment, with promising effects on hemodynamic stability. Although the mortality benefit has not yet been fully established, several studies have suggested that optimal patient selection and timing of intervention are critical for maximizing treatment outcomes. The unique adsorption properties of CytoSorb make it a promising approach for cytokine removal, potentially mitigating the detrimental effects of cytokine storms. By addressing the limitations identified in this study and exploring personalized treatment strategies, future studies are expected to unlock the full potential of CytoSorb in improving outcomes in patients with severe sepsis, which has the potential to convert the approach to sepsis management in the future. Thus, future research focusing on optimized treatment protocols and patient selection criteria will help to realize the full therapeutic potential of this innovative technology.
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