The role of cytokine adsorption in post-cardiac arrest syndrome (PCAS): a 10-year literature narrative review

Abstract

Background

Post-cardiac arrest syndrome (PCAS) is a critical condition arising from systemic inflammation and ischemia-reperfusion injury, often leading to poor outcomes despite advanced supportive therapies. Cytokine adsorption has been proposed as a therapeutic approach to mitigate the inflammatory response and improve survival and recovery in PCAS patients.

Materials and methods

This narrative review aims to synthesize and critically evaluate recent literature (2013–2024) on the role of cytokine adsorption in PCAS management, focusing on inflammatory modulation, clinical outcomes, and safety. A comprehensive search of PubMed, Cochrane Library, Embase, Medline Complete, Scopus and Web of Science identified 17 studies investigating cytokine adsorption in PCAS. Inclusion criteria encompassed clinical trials, observational studies, and preclinical investigations.

Results

Cytokine adsorption reduces inflammatory markers, particularly interleukin-6 (IL-6), in patients with PCAS. While some studies report modest improvements in hemodynamic stability and reduced vasopressor requirements, survival benefits remain inconsistent across the literature.

Conclusions

Cytokine adsorption appears to be a safe and feasible intervention in PCAS, with potential benefits in inflammatory modulation and hemodynamic support. However, its impact on long-term survival and neurological recovery remains unclear. Future large-scale randomized controlled trials are needed to establish definitive clinical guidelines for its use in PCAS management.

Introduction

Post-cardiac arrest syndrome (PCAS) is a multifaceted clinical condition that arises after successful resuscitation from cardiac arrest. It is characterized by a confluence of systemic inflammatory response syndrome (SIRS), myocardial dysfunction, and hemodynamic issues, neurological injury, and ischemia-reperfusion response [1], challenging clinician’s resuscitation strategy (Targeted Temperature Management “TTM”, restore hemodynamic stability, splanchnic dysfunction, and endotoxemia, hormonal dysfunction) [2]. Together, these phenomena result in high morbidity and mortality, with survivors often experiencing long-term neurological deficits and diminished quality of life. Despite advancements in critical care and resuscitation strategies, including the integration of Extracorporeal Cardiopulmonary Resuscitation (ECPR) and Extracorporeal Membrane Oxygenation (ECMO), mortality rates in PCAS remain stubbornly high, ranging from 40 to 70% depending on the severity of initial injury and clinical context [3]. The inflammatory dysregulation central to PCAS is often driven by a “cytokine storm,” an excessive release of pro-inflammatory mediators such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1β (IL-1β) [4] and together with complement system activation, endothelial injury, and glycocalyx shedding may help stratifying the level of inflammatory status and thus prognosis severity [5]. The systemic inflammation driven by the level of IL-6 (even more than the level of C-reactive protein “CPR” and procalcitonin “PCT”) was associated with increased need for vasopressor support as demonstrated by its correlation with the Cumulative Vasopressor Index (CVI) [6]. The inflammatory response after cardiac arrest was not modified by TTM at 33 °C or 36 °C [7]. This uncontrolled immune “sepsis-like” response is precipitated by ischemia-reperfusion injury, which occurs during the restoration of blood flow following resuscitation. The subsequent endothelial damage, capillary leak syndrome, and microvascular dysfunction exacerbate systemic inflammation, leading to secondary organ injury, hemodynamic instability, and impaired recovery [8] and thus also play a role in PCAS-associated cardiovascular dysfunction: endothelial biomarkers (thrombomodulin, sE-selectin, syndecan-1, and VE-cadherin) correlated with CVI at 72 h after cardiac arrest [6]. These inflammatory processes not only complicate immediate post-resuscitation care but also limit long-term survival and functional recovery in patients. Traditional strategies to mitigate the inflammatory cascade in PCAS, such as supportive care and therapeutic hypothermia, have shown variable effectiveness [9]. In this context, extracorporeal blood purification techniques, particularly cytokine adsorption, have emerged as promising adjunctive therapies. Cytokine adsorption involves the extracorporeal removal of circulating cytokines and other inflammatory mediators using hemoadsorption devices, such as CytoSorb® [10]. These devices are designed to modulate the immune response by restoring a balance between pro- and anti-inflammatory mediators, thereby mitigating hemodynamic instability, reducing organ dysfunction, and potentially improving survival and neurological outcomes [11]. The integration of cytokine adsorption into ECMO or standalone circuits has shown promise in reducing the levels of inflammatory cytokines such as IL-6 and TNF-α, both of which have been implicated in poor outcomes in PCAS. Moreover, accumulating evidence from preclinical studies indicates that cytokine adsorption does not act in isolation but may exert enhanced benefits when used in combination with therapeutic hypothermia or other established neuroprotective interventions. This synergistic interaction underscores the potential of cytokine adsorption as part of a multimodal therapeutic approach, where the integration of complementary strategies could more effectively attenuate neuro-inflammation, limit secondary brain injury, and ultimately preserve neurological function [12]. Despite its theoretical benefits and initial clinical application, the evidence supporting the routine use of cytokine adsorption in PCAS remains limited. Studies have reported mixed results, with some demonstrating reductions in inflammatory biomarkers and improved hemodynamic parameters, while others have failed to show significant survival or recovery benefits [13]. The heterogeneity in study designs, patient populations, and therapeutic protocols underscores the need for a comprehensive analysis of the existing literature to delineate the true clinical utility of cytokine adsorption [14]. This narrative review aims to critically evaluate the role of cytokine adsorption in PCAS by synthesizing data from recent studies published between 2013 and 2024. The review will focus on the mechanisms of action, clinical outcomes, safety profile, and potential applications of cytokine adsorption in the management of PCAS. By exploring the current evidence, this review seeks to provide a deeper understanding of cytokine adsorption as a therapeutic modality and to identify gaps in knowledge that warrant further investigation.

Materials and methods

This narrative review was conducted to synthesize and critically evaluate recent literature on the use of cytokine adsorption in post-cardiac arrest syndrome (PCAS). A structured and comprehensive approach was used to identify and analyze studies relevant to the topic, focusing on publications from 2013 to 2024. This section outlines the criteria and methodology used for literature selection, analysis, and synthesis.

Search strategy

This article is based on a narrative review of the literature, which was chosen as the most suitable approach to provide a broad and integrative overview of current knowledge on The Role of Cytokine Adsorption in Post-Cardiac Arrest Syndrome (PCAS). We performed a comprehensive search of the Cochrane Library, Embase, Medline Complete, Scopus, and Web of Science databases between January 2013 and December 2024 using the search terms [“cytokine adsorption,” AND/OR “post-cardiac arrest syndrome,” “hemoadsorption,” “CytoSorb,” “extracorporeal cardiopulmonary resuscitation,” “ECMO,” and “inflammation.”].

Selection process

The initial database search yielded 507 articles. Two reviewers independently screened titles and abstracts for relevance. After initial screening, 18 articles were selected for full-text review. Following the application of inclusion and exclusion criteria, a final set of 17 articles was included in this narrative review. Any discrepancies during the selection process were resolved through discussion and consensus.

Data extraction and organization

Key information from each included study was extracted and categorized into the following domains:

• Study characteristics: design, population, and intervention details.

• Outcomes: cytokine levels, endothelial damage, hemodynamic stability, survival, neurological recovery and safety profiles.

• Study strengths and limitations.

The extracted data were organized into thematic sections for narrative synthesis, focusing on:

1. Mechanisms of action of cytokine adsorption in PCAS.

2. Evidence on clinical and preclinical outcomes.

3. Safety and feasibility.

Approach to synthesis

As a narrative review, the emphasis was on providing a cohesive summary of findings rather than a quantitative meta-analysis. The results were synthesized thematically to highlight key trends, areas of agreement or controversy, and gaps in the literature. The aim was to integrate findings across studies to offer a comprehensive understanding of the potential role of cytokine adsorption in PCAS management.

Ethical considerations

This review is based solely on previously published studies, and no new data collection involving human or animal subjects was conducted. As such, ethical approval was not required. The review adhered to best practices for conducting narrative reviews, ensuring transparency and rigor in methodology. By adopting these structured and professional criteria, this review provides a robust and coherent synthesis of the current evidence on cytokine adsorption in PCAS, contributing to a deeper understanding of its clinical potential and limitations.

Results

The review analyzed 17 studies published between 2013 and 2024, focusing on the application of cytokine adsorption in post-cardiac arrest syndrome (PCAS).

When analyzing these studies, an important preliminary consideration must be made: since patients continue to produce IL-6, systemic plasma measurements alone are not the most reliable indicators of a sorbent’s efficacy. These measurements do not account for ongoing cytokine production or for the redistribution of IL-6 from the interstitial space into the bloodstream.

The only definitive method for assessing whether a sorbent is effective involves the simultaneous measurement of IL-6 concentrations before and after the sorbent cartridge. This allows for a mass balance analysis and provides a direct quantification of the cytokines removed.

While a decrease in systemic cytokine levels does confirm that the sorbent is functioning, the absence of a systemic reduction does not necessarily imply that the sorbent is ineffective. For this reason, in studies where systemic cytokine levels decrease, we can be confident in the sorbent’s efficacy. However, in studies — such as the Cyter study — where systemic levels remain unchanged, definitive conclusions cannot be drawn without pre- and post-cartridge measurements.

The results of the proof-of-concept study published by Jansen et Al [15]. consistently demonstrated the ability of cytokine adsorption to modulate inflammatory markers, particularly interleukin-6 (IL-6), a key driver of the inflammatory cascade also in PCAS. In the CYTER trial (2022), IL-6 levels decreased in the cytokine adsorption group compared to controls, though the reduction was not statistically significant (p = 0.48). As the CYTER authors themselves stated, several limitations must be considered when interpreting these findings. First, the study included a limited number of patients, and as such, the results should be viewed as preliminary until validated in larger populations. Second, key prognostic indicators following cardiac arrest — namely IL-6 levels, blood lactate, and arterial pH — were more unfavorable at baseline in the intervention group compared to the control group. Given the small sample size, random variability may have led to an uneven distribution of these factors between the groups. As a result, these initial imbalances could have negatively influenced survival outcomes in the intervention group, potentially contributing to the lower survival rate observed. Similarly, Monard et al. [8] reported a median IL-6 reduction of 75% at 48 h in patients receiving cytokine adsorption, compared to a 5% reduction in the standard care group (p = 0.06). Nonetheless, the study by Monard presents several noteworthy limitations. Firstly, no pre- and post-cartridge measurements were performed to directly assess cytokine removal. Additionally, approximately half of the enrolled patients had very low baseline IL-6 levels (< 100 pg/mL), which may have limited the potential for observing a meaningful reduction. Despite this, the observed decrease in IL-6 was nearly statistically significant compared to the control group.

Moreover, the study was not designed or powered to detect differences in mortality or cytokine reduction. Randomization appears to have been suboptimal, resulting in an uneven distribution of cardiac arrest characteristics known to be associated with worse outcomes. The authors also did not report neurological outcomes, which are notable given that hemoadsorption may potentially offer neuroprotective benefits. Elevated IL-6 levels in Cerebrospinal Fluid (CSF) have previously been linked to poor neurological prognosis, and since IL-6 can cross the blood–brain barrier, a reduction in plasma IL-6 through hemoadsorption might also lower CSF concentrations, potentially supporting neurological recovery.

Furthermore, the study utilized only a single hemoadsorption cartridge, which may have limited the treatment’s efficacy. Lastly, the study population was highly heterogeneous with respect to baseline IL-6 plasma levels at the time of randomization, adding further variability to the outcomes. Preclinical studies, such as those by Zhai et al. [9], corroborated these findings, demonstrating robust reductions in IL-6, TNF-α, and IL-1β, highlighting the therapy’s potential to suppress inflammation at a molecular level. Clinical outcomes related to hemodynamic stability and survival were more variable. Some studies reported reductions in vasopressor requirements and improvements in vasoactive-inotropic scores (VIS), indicating improved circulatory support. For instance, Pieri et al. [3], the largest ever trial performed in this setting, documented a significant decrease not only in VIS during cytokine adsorption therapy in ECMO-supported patients but also improvement in Lactic Dehydrogenase (LDH), creatine phosphokinase (CPK), CRP, bilirubin, lactate, and creatinine levels, with an Intensive Care Unit (ICU) mortality (57%), 30-day mortality (49%), and hospital mortality (62%) significantly lower than predicted from both Simplified Acute Physiology Score II (SAPS II) and Sequential Organ Failure Assessment (SOFA). However, findings in other studies on other hemodynamic markers, such as lactate clearance and mean arterial pressure, were inconsistent: Lother et al. [16] suggested a weak advantage of cytokine adsorption to VA-ECMO therapy during post-cardiac arrest care when taking into account fluid balance and arterial lactate lowering levels [16].

Regarding survival, the CYTER trial found no significant improvement in 30-day survival (14% in the cytokine adsorption group vs. 42% in the control group, HR 1.85, p = 0.10), because of the limitations listed above. Observational studies suggested that early initiation of cytokine adsorption might benefit certain subgroups, but these findings were not uniformly replicated. Akin et al. [14] reported higher 30-day mortality in the cytokine adsorption group compared to controls, underscoring the need for further investigation into patient selection criteria. Indeed, the plasma removal of inflammatory mediators using high cut-off continuous veno-venous hemodialysis (HCO-CVVHD) in cardiac arrest did not decrease the length of post-resuscitation shock and had no significant effect on hemodynamic profile in the Guillame Geri et al. [17] HYPERDIA trial [17].

In a very recent published study, Kreutz et Al [18]. presents the first evidence that CytoSorb® therapy is linked to a notable decrease in inflammatory markers, along with enhancements in hemodynamic stability and tissue/organ perfusion in patients with Cardiogenic Shock (CS) undergoing various forms of Mechanical Circulatory Support (MCS). A marked reduction in the vasoactive-inotropic score (VIS) and improved cardiovascular stability were recorded. Additionally, declines in lactate, PCT, and myoglobin levels point to the therapy’s potential in supporting metabolic recovery and reducing endothelial and kidney injury. These findings indicate that CytoSorb® may serve as a valuable component in a comprehensive, multimodal treatment strategy for severe CS, especially when used alongside MCS. These results are due to the personalized hemoadsorption protocol, chosen according to the severity of the patients, treated with ECMO, Impella, or ECMELLA.

Neurological recovery outcomes were limited in the reviewed studies. Preclinical research indicated that cytokine adsorption, especially when combined with therapeutic hypothermia, reduced neuro-inflammation and preserved neuronal integrity. Zhai et al. [9] demonstrated this effect in animal models, but clinical data on neurological outcomes remain sparse and inconclusive, signaling a significant gap in current research. The safety profile of cytokine adsorption was favorable across studies. Regarding coagulation, mild thrombocytopenia and transient coagulopathy, including a trend toward increased Activated Partial Thromboplastin Time (aPTT), were observed in some patients [8]. However, no severe adverse events, such as device-related complications, were reported. The integration of cytokine adsorption devices like CytoSorb® into ECMO circuits was described as straightforward, with therapy initiation feasible within 18–24 h of intensive care unit admission.

In summary, cytokine adsorption consistently reduced inflammatory cytokines, particularly IL-6, and showed potential hemodynamic benefits, though survival and neurological outcomes were variable. The therapy was well-tolerated with a low incidence of adverse events, supporting its feasibility in critically ill patients (Table 1) [1–9]. These findings highlight the need for larger, randomized trials or studies conducted with statistical matching (i.e. propensity score) to confirm efficacy and define optimal patient selection and treatment protocols.

Table 1.

Summary of studies on cytokine adsorption in PCAS

Study	Key Findings	Clinical Outcomes	Safety Profile
CYTER Trial (2022) [10]	IL-6 levels reduced but no significant survival benefit (14% survival in cytokine group vs. 42% in control, p=0.10)	Modest inflammatory modulation; no significant hemodynamic or survival improvement	No severe adverse events reported
Zahn et el. (2024) [1]	No significant differences in neutrophil and monocyte surface molecule expression nor in circulating platelet–monocyte complexes	No relevant effect of cytokine adsorption on neutrophil and monocyte activation	Safety not assessed (subgroup study of CYTER RCT)
Monard et al. (2023) [8]	75% median reduction in IL-6 vs. 5% in control (p=0.06); mild thrombocytopenia observed	Effective IL-6 reduction; hemodynamic parameters not assessed	Mild thrombocytopenia and transient coagulopathy (increased aPTT)
Pieri et al. (2023) [3]	Reduction in vasoactive-inotropic score (VIS), limited impact on lactate clearance	Improved circulatory stability; inconsistent findings on tissue perfusion	No device-related complications
Haertel et al. (2023) ECMOsorb trial [4]	Data under development (?)	Hypothesized reduction in cytokine levels leading to faster weaning from inotropic and mechanical circulatory support, and ultimately improved recovery	Safety evaluation encompasses air embolisms, allergic reactions, peripheral ischemic complications, vascular complications, bleeding incidents, and stroke occurrences
Zhai et al. (2022) [9]	Reduced neuroinflammation and preserved neuronal integrity in animal models	Neuroprotection demonstrated in preclinical animal models	Safety not assessed (preclinical study)
Akin et al. (2020) [14]	Higher 30-day mortality in cytokine adsorption group; no significant improvement in survival	No survival benefit; requires further investigation for patient selection criteria	No specific adverse events reported
Supady et al. (2022) [12]	Survival to discharge from ICU was 17.4% (4/23) in the cytokine adsorption group and 21.7% in the control group (5/23, P > 0.99). Favorable neurologic outcome in both groups	In both groups, lactate levels and volume demand dropped significantly. Comparing the two groups directly, values for the cytokine adsorption group were lower, but except for fluid balance at the time interval 48–54 hours, no significant between-group differences could be detected.	No significant differences were discovered in platelet count, INR, number (units) of concentrated red blood cells, thrombocyte concentrates, and fresh–frozen plasma transfused between cytokine adsorption and control groups
Geri et al. (2021) HYPERDIA trial [17]	No difference was observed at any time points between the 2 groups for all pro- and anti-inflammatory cytokines over the first 72 hours	Overall day-7 mortality was 68.7%: 11/17 (64.7%) and 13/18 (72.2%) in the intervention and control groups, respectively (p=0.725). No difference was observed regarding the length of post-resuscitation shock, the daily-dose of vasopressors, arterial pressure profile and fluid balance.	Regarding adverse events, we observed 6 circuit coagulations and no other serious adverse event.
Jozwiak et al (2020) [2]	Compared to conventional renal replacement therapy, the use of high-volume hemofiltration was associated with a better survival	No significant effect on the cytokines levels explained by several mechanisms: (1) the lower cytokines level at ICU admission (compared to patients with septic shock), (2) the quick decrease in cytokines level after the initial and transient increase at the time of ROSC, and/or (3) the membrane fouling, resulting in a progressive better removal of molecules with lower molecular weights despite the use of high cut-offs membranes.	No specific adverse events reported
Langeland et al. (2022) [5]	Patients that presented with high levels of TCC and IL-6 at admission had increased 30-days mortality.	A systemic inflammatory response, including complement activation, cytokine release and endothelial glycocalyx injury, is associated with cardiac arrest and circulatory failure	No specific adverse events reported.
BroJeppesena et al. (2017) [6]	In comatose survivors after OHCA, increasing systemic inflammation and endothelial injury was associated with increased need of vasopressor support	Systemic inflammation, in particular IL-6, was consistently associated with vasopressor support	No specific adverse events reported.
BroJeppesena et al. (2014) [7]	Level of inflammatory response was associated with severity of PCAS	IL-6 being consistently and more strongly associated with severity of PCAS than the inflammatory markers CRP and PCT.	No specific adverse events reported.
Napp et al. (2021) [11]	Hemoadsorber represents a potentially useful therapeutic tool in patients on ECMO	Parameters for decision-making should include, but shall not be restricted to, signs of shock, vasopressor dosage, IL-6, lactate clearance, bilirubin, and myoglobin plasma levels	Hemoadsorber has been used more than 130.000 times to date, and there are no robust data beyond this single study which demonstrate adverse clinical outcomes with Hemoadsorber use.
Redant et al. (2021) [13]	The authors have focused our review upon the potential role of blood purification in attenuating the consequences of the post-resuscitation syndrome.	Blood purification can decrease the cytokine storm. Blood purification can decrease the cytokine storm particularly when using a Hemoadsorber. Acrylonitrile 69-based oXiris membranes can remove endotoxin and high-mobility group box 1 protein. Blood purification techniques can quickly induce hypothermia. Blood purification can be used with veno-arterial extracorporeal membrane oxygenation to remove excess water.	No specific adverse events reported.
Lother et al. (2019) [16]	These data suggest that incorporation of cytokine adsorption into the management of critically ill patients requiring continued ECMO support is feasible and easy to handle.	Whether cytokine removal improves clinical outcome in ECMO-treated patients after cardiac arrest should be investigated in a prospective clinical trial.	Indicators for adverse effects of cytokine adsorption during ECMO therapy. Platelet count (A) and international normalized ratio (INR, B)
Kreutz et al. (2025) [18]	The results of this study underline that hemoadsorber therapy can be considered a useful “component” in the complex management of CS, especially when combined with MCS.	During hemoadsorber therapy in CS, a significant reduction in VIS was demonstrated, resulting in improved organ perfusion	Adverse effects such as thrombocytopenia and anemia are defined only as potential.
Jansen et all (2023) [15]	Hemoperfusion effectively attenuates circulating cytokine concentrations during systemic inflammation in humans in vivo, whereas it does not affect long-term immune function.	Therapy may be of benefit in conditions characterized by excessive cytokine release.	Twenty-four healthy male volunteers were included in this study. All procedures and symptoms associated with the experimental endotoxemia and hemoperfusion procedures were well tolerated by all subjects, and no serious adverse events occurred during the study.

Discussion

The findings of this review underscore both the potential and limitations of cytokine adsorption as an adjunctive therapy in the management of post-cardiac arrest syndrome (PCAS). The ability of cytokine adsorption to effectively reduce inflammatory mediators, particularly interleukin-6 (IL-6), suggests its potential to modulate the systemic inflammatory response that underpins much of the pathophysiology of PCAS. Monard et al. [8] demonstrated a median reduction of IL-6 by 75%, corroborating preclinical findings by Zhai et al. [9], which highlighted significant suppression of cytokines such as IL-6, TNF-α, and IL-1β. Despite these promising results, the lack of consistent correlation between inflammatory modulation and improvements in clinical outcomes such as survival or neurological recovery raises questions about whether targeting inflammation alone is sufficient to alter the trajectory of PCAS. Hemodynamic stabilization is another key area where cytokine adsorption has shown potential, with some studies reporting reduced vasopressor requirements and improved vasoactive-inotropic scores [3]. These findings suggest a beneficial role for cytokine adsorption in supporting circulatory function during the critical post-resuscitation period. However, other studies, such as the CYTER trial (2022), failed to demonstrate significant improvements in hemodynamic markers like mean arterial pressure or lactate clearance, highlighting variability in the clinical impact of this therapy. The discrepancies between studies may reflect differences in patient selection, timing of intervention, and underlying severity of organ dysfunction. Survival outcomes remain a contentious issue, with mixed results across studies. While the CYTER trial reported no significant survival benefit (14% vs. 42% survival in the cytokine adsorption and control groups, respectively, p = 0.10), smaller observational studies suggested improved survival in select patient subgroups, particularly when cytokine adsorption was initiated early. Conversely, Akin et al. [14] observed higher 30-day mortality in the cytokine adsorption group, suggesting that indiscriminate application of the therapy may be detrimental in certain populations. These findings underscore the need for better patient stratification and the importance of identifying those most likely to benefit from cytokine adsorption. Neurological recovery, a critical outcome in PCAS, remains underexplored in clinical studies. Preclinical models provide compelling evidence for the neuroprotective effects of cytokine adsorption, particularly when combined with therapeutic hypothermia. Zhai et al. [9] demonstrated reduced neuro-inflammation and preservation of neuronal integrity in animal models, highlighting the potential of cytokine adsorption to protect the brain. However, clinical studies have largely focused on inflammatory and hemodynamic outcomes, with limited assessment of neurological recovery, signaling a significant gap in the current evidence base. The safety profile of cytokine adsorption is reassuring, with most studies reporting minimal adverse events. Mild thrombocytopenia and transient coagulopathy, including a trend toward increased activated partial thromboplastin time (aPTT), were noted in some patients [8], but these effects were not clinically significant. No severe device-related complications were reported, and the integration of cytokine adsorption devices like CytoSorb® into ECMO circuits was described as straightforward and feasible. This favorable safety profile supports the practicality of cytokine adsorption in critically ill patients, although close monitoring for coagulopathy remains essential, particularly in those with pre-existing bleeding risks.

The heterogeneity of study designs, small sample sizes, and variability in outcome measures present significant limitations in the current evidence base. Most studies were underpowered to detect meaningful differences in survival or neurological outcomes. Furthermore, the lack of standardized protocols for timing, duration, and patient selection complicates the interpretation and generalizability of results. These limitations emphasize the need for large-scale, randomized controlled trials to determine the clinical efficacy of cytokine adsorption and to establish evidence-based guidelines for its use. Future research should prioritize the standardization of protocols to optimize treatment timing, duration, and patient selection. Investigating the synergistic effects of cytokine adsorption with other therapies, such as therapeutic hypothermia, may further enhance its efficacy. Additionally, studies should focus on robust assessments of neurological outcomes, incorporating biomarkers and long-term functional measures to provide a more comprehensive evaluation of its impact. Identifying specific cytokine profiles or biomarkers that predict patient responsiveness to cytokine adsorption could enable a more personalized approach to therapy [1–17]. It is increasingly recognized that the clinical efficacy of extracorporeal blood purification therapies, including hemoadsorption with sorbents, is highly contingent upon several critical factors: appropriate patient selection, optimal timing of therapy initiation, and the administered “dose” — commonly reflected by the volume of blood processed and the quantity of sorbent material utilized. A review of prior studies (e.g., Cyter and Monard et al.) reveals significant methodological limitations that may have impacted the interpretability and generalizability of their findings. These include heterogeneous study populations, imprecise or delayed initiation of therapy, empirically determined and often subtherapeutic dosing regimens, and inadequate biochemical monitoring — particularly the lack of pre- and post-cartridge cytokine measurements and absence of mass balance assessments. Additionally, critical operational parameters, such as sorbent exchange intervals, were frequently undefined, and study designs were not adequately powered or structured to assess definitive clinical endpoints such as mortality.

Given these limitations, there is a growing consensus that mortality, as a distal and multifactorial outcome, may not be the most appropriate primary endpoint for evaluating the efficacy of hemoadsorption. Instead, intermediate and mechanistically relevant endpoints — such as vasopressor requirement, serum lactate levels, organ dysfunction scores (e.g., SOFA), and ICU length of stay — should be prioritized in future investigations. Emerging evidence, including findings from the Kreutz study, suggests that when hemoadsorption therapy is tailored to individual patient profiles — accounting for dynamic clinical variables and inflammatory burden — clinical outcomes are notably improved. This aligns with contemporary expert opinion advocating for a paradigm shift towards personalized and precision-based approaches in the application of extracorporeal therapies.

Conclusions

Cytokine adsorption represents a promising adjunctive therapy in the management of post-cardiac arrest syndrome (PCAS), particularly for its ability to modulate the inflammatory response and support hemodynamic stability. The reviewed studies demonstrated consistent reductions in inflammatory cytokines, such as interleukin-6 (IL-6), and showed potential benefits in reducing vasopressor requirements and improving circulatory parameters. However, the impact of cytokine adsorption on survival and neurological recovery remains inconclusive, with mixed results across clinical trials and observational studies. The therapy was generally safe and feasible, with minimal adverse events, making it a practical option for integration into critical care protocols, particularly in patients requiring extracorporeal membrane oxygenation (ECMO) or extracorporeal cardiopulmonary resuscitation (ECPR). Despite these encouraging findings, the variability in outcomes highlights the need for further research to clarify its clinical efficacy and identify patient populations most likely to benefit from this intervention. Future large-scale randomized controlled trials are essential to establish definitive evidence on the role of cytokine adsorption in PCAS management. Personalized protocols regarding timing, duration, and patient selection criteria should be developed to optimize therapeutic outcomes. The inherent heterogeneity of this kind of patients presents a substantial obstacle to the execution of conventional randomized controlled trials (RCTs) in this area. While RCTs are considered the gold standard for evaluating therapeutic efficacy, they typically yield an average treatment effect across a broad population, offering limited insight into which subgroups of patients derive meaningful benefit—or to what degree. This limitation is particularly pronounced in the context of extracorporeal blood purification, where variability in patient phenotypes, therapeutic timing, dosing strategies, and device modalities further complicates trial design and interpretation.

Given these constraints, there is a growing recognition that the advancement of blood purification therapies may depend less on large, generalized RCTs and more on the development of adaptive, precision-based study designs. These would prioritize well-defined inclusion criteria, objective biomarkers, and standardized treatment protocols to better identify patient subsets most likely to respond to therapy. Crafting randomized trials that account for the clinical and biological diversity of septic populations — while preserving methodological rigor — remains a significant yet necessary challenge in the pursuit of meaningful clinical progress in this field.

Moreover, studies focusing on long-term survival, neurological recovery, and quality of life are crucial to assess the broader impact of this therapy. Until such data are available, cytokine adsorption should be considered a supportive therapy with potential benefits in select cases, but its routine use in PCAS requires further validation.

Authors’ contributions

All authors collaborate equally. All authors have read and agreed to the published version of the manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

No datasets were generated or analysed during the current study.

Competing interests

The authors declare no competing interests.