Introduction
Advancements in perioperative management, and surgical equipment and techniques, have significantly increased the prevalence of high-complexity surgical procedures. With rising life expectancy and improvements in healthcare standards, the proportion of elderly, and high-risk patients undergoing such complex surgeries has also increased. Consequently, the incidence of severe perioperative complications is on the rise. This highlights the growing importance and concerns around effective management and treatment strategies for these complications.
Among perioperative complications, intra-abdominal infections are the most common, with Gram-negative bacteria being the predominant causative pathogens. However, Gram-positive species, fungi, and various other microorganisms can also lead to severe intra-abdominal infections. For septic shock resulting from intra-abdominal infections, the reported mortality rates range from 28% to 48% [1,2]. In particular, immediately after surgery, the physiological status of the patient is unstable and the disruption of barriers (such as tissues and blood vessels) due to surgical intervention, make the translocation of intra-abdominal pathogens into the systemic circulation more likely. This risk is further exacerbated by postoperative fluid loss, and a pronounced systemic inflammatory response, significantly increasing the likelihood of progression to clinical deterioration, and multi-organ failure.
Among these patients, those in refractory shock who fail to respond to general shock management strategies, such as fluid resuscitation, broad-spectrum antibiotics, inotropes, or vasopressors, often experience poor outcomes despite successful source control. In these cases, pathogens that infiltrate the bloodstream through damaged biological barriers release excessive amounts of endotoxins which circulate within the body, and lead to significant damage to vital organs. In addition, these pathogens and the endotoxins they release continuously stimulate the immune system and result in the overproduction of both proinflammatory and anti-inflammatory cytokines [3,4]. This phenomenon has been identified as a major contributor to the high mortality rate which is associated with septic shock [3,4]. The excessive release of inflammatory cytokines into the bloodstream and the level of endotoxin ultimately impairs the host’s regulatory mechanisms, triggering a cytokine storm [5]. This condition is characterized by refractory hypotension and secondary immune paralysis during the early stages of the infection, which can progressively lead to multi-organ failure or dysfunction, culminating in increased mortality [4]. Therefore, in patients with refractory septic shock, typically successful emergency interventions and surgical procedures may not be sufficient to address the overwhelming response to pathogens that have infiltrated the bloodstream. Consequently, various extracorporeal blood purification therapies have been proposed as adjunct treatment approaches for septic shock, in addition to fundamental source control through surgical interventions and conventional standard treatment strategies. These therapies aim to effectively eliminate cytokine excess and circulating endotoxins from the bloodstream to correct the dysregulated immune response.
Since the approval of blood purification therapy, for patients with sepsis, using polymyxin B hemoperfusion [polymyxin B hemoperfusion (PMX-HP, Toraymyxin™, Toray Medical Co. Ltd., Tokyo, Japan)], in Japan in 1994, several therapies, such as CytoSorb (CytoSorb®, CytoSorbents Inc, New Jersey, USA) and AN69-Oxiris (AN69-Oxiris®, Baxter, IL, USA), have been developed and introduced into clinical practice. These therapies are used in the clinical setting to promote early recovery and improve outcomes to enhance the prognosis of patients with refractory septic shock. Despite their therapeutic potential, hemoperfusion treatments for septic shock lack standardized guidelines. This may be due to several critical challenges in clinical research, standardization, and implementation. Conflicting clinical outcomes regarding their effectiveness have been reported [6–10]. Small-scale studies and observational data suggest potential benefits, yet these studies fail to provide consistent evidence [7,8]. Each hemoperfusion modality has distinct mechanisms of action, advantages, and limitations. A significant gap remains in clinical studies that directly compare their efficacy. One major barrier to standardization is the lack of large-scale, high-quality randomized controlled trials (RCTs). The establishment of a standard operating procedure to produce robust evidence to supports the efficacy and safety of hemoperfusion in septic shock is essential. The variability in study designs, patient populations, and outcome measures has led to inconsistent findings across studies, making it difficult to develop universally accepted treatment protocols. In addition, the heterogeneity of septic shock pathophysiology complicates patient selection for hemoperfusion therapy. Septic shock results from a complex interplay of immune dysregulation, pathogen burden, and organ dysfunction, yet not all patients exhibit endotoxin-driven pathophysiology. The primary target of some hemoperfusion devices, such as PMX-HP, is the treatment of endotoxin-driven pathophysiology. Without precise biomarker-driven selection criteria, identifying the appropriate candidates for therapy remains challenging. This further contributes to the lack of standardized treatment protocols. Furthermore, cost constraints and limited accessibility in certain healthcare settings also hinder the widespread adoption of hemoperfusion therapy. These factors collectively contribute to the significant challenges in developing standardized guidelines for hemoperfusion treatment in septic shock patients, and their adoption by surgical clinicians, to manage critically ill patients, remains limited.
This review aimed to examine the mechanisms of action and specific advantages of 3 representative extracorporeal blood purification therapies, CytoSorb, PMX-HP, and AN69-Oxiris. In addition, this review compared the advantages and limitations of PMX-HP and AN69-Oxiris, which are currently the most widely utilized modalities for the simultaneous removal of endotoxins and cytokines in patients with refractory septic shock. Furthermore, specific criteria and considerations were explored to propose a framework for selecting the most appropriate modality based on the clinical characteristics and conditions of patients with refractory septic shock.
Extracorporeal Blood Purification Therapies
Extracorporeal blood purification utilizes mass separation mechanisms: (1) diffusion, as utilized in standard hemodialysis; (2) convection, as seen in hemofiltration; (3) a combination of both diffusion and convection [11,12]; and (4) solute adsorption, as used for hemoperfusion [using a solid agent (sorbent)] [13].
Solute adsorption blood purification therapy promotes early recovery in refractory septic shock and enhances the prognosis of patients. Sorbent particles are manufactured and packed into devices (cartridges) to create a tortuous pathway (sorbent bed) through which blood flows. As blood or plasma passes through the sorbent bed, solutes are adsorbed onto the surface of the beads. Blood purification, specifically hemoperfusion, in sepsis or septic shock remains a critical focus of research due to the belief that soluble mediators of injury play a significant role in morbidity and mortality among severe septic patients [14]. The mediators of septic shock, diverse in molecular size, can be potentially removed through hemoperfusion. Two distinct approaches to hemoperfusion in sepsis exist: (1) selective adsorption targeting specific molecules such as endotoxins; and (2) nonselective adsorption of molecules including cytokines.
Endotoxin, a toxic component of lipopolysaccharide (LPS) located on the outer membrane of Gram-negative bacteria, plays a pivotal role in sepsis pathophysiology. When bacteria die or their cell walls disintegrate endotoxins are released into the bloodstream where they bind to Toll-like receptor-4 on immune cells [15]. This action triggers an intense proinflammatory response, a cascade which leads to the release of cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β, contributing to systemic inflammation, endothelial dysfunction, and multiorgan failure [16]. The levels of endotoxin in the blood are expressed as endotoxin activity and are categorized as follows: values < 0.4 are defined as mild endotoxemia, values between 0.4 and 0.6 indicate moderate endotoxemia, and values > 0.6 signify severe endotoxemia. Clinically, endotoxin activity assay (EAA) values are stratified as low (< 0.4), intermediate (0.4–0.6), or high (> 0.6), with higher values correlating with increased mortality, organ dysfunction, and prolonged Intensive Care Unit stays. A high EAA value may also indicate the need for extracorporeal blood purification therapies such as PMX-HP to remove endotoxins and improve hemodynamic stability. In addition, EAA value serves as a prognostic tool for assessing disease severity and as a guide to early therapeutic interventions [17].
Cytokines are secreted as part of the immune response to pathogens. The host immune response to external pathogens relies on both innate and adaptive immune components. The innate immune system includes complement proteins, natural killer cells, and sentinel phagocytes which play a crucial role in activating and regulating the adaptive immune system. The adaptive immune system, including B cells, broadly recognize antigens by detecting pathogen-associated molecular patterns of carbohydrates located on the surface of pathogens [18]. Following cellular injury, caused by burns, trauma, ischemia-reperfusion injury, or major surgery, the mitochondria release damage-associated molecular patterns, and these molecules have significant similarity to those released during bacterial infection [19]. Physiologically, the innate immune response aims to eradicate both pathogen-associated molecular patterns and damage-associated molecular patterns, subsequently leading to an adaptive immune response. However, in severe infections such as septic shock, excessive secretion of circulating proinflammatory and anti-inflammatory cytokines (including TNF-α, IL-1, IL-6, IL-8, and IL-10) frequently occurs, and can trigger a cytokine storm. In addition, an imbalance between proinflammatory and anti-inflammatory responses is likely to develop, and contribute to exaggerated immune dysregulation. These pathological processes ultimately lead to cellular, tissue, organ, and organ system dysfunction, with fatal outcomes in septic shock patients if left untreated [20]. Theoretically, the removal of excessive levels of cytokine mediators using a hemoadsorption device could be beneficial in the treatment of sepsis. However, the differences in filters and cartridges used for each modality lead to variations in the target substances primarily adsorbed or removed by each device. Consequently, the strengths and limitations of each modality differ, therefore, clinicians must understand these differences to select the most appropriate hemoperfusion modality for each patient.
1. CytoSorb
CytoSorb represents an advanced extracorporeal blood purification modality, employing adsorption as its primary mechanism to remove cytokines and other proinflammatory mediators from the blood which are present in hyperinflammatory states. The effect of CytoSorb has been assessed and it has the capacity to lower cytokine toxicity during systemic inflammatory response syndrome caused by sepsis, following burns, infections, or major trauma, which can lead to severe immunosuppression and multiple organ dysfunction [21]. The CytoSorb cartridge, which is single use, is composed of biocompatible, highly porous polymer beads, was were specifically engineered to enable selective adsorption of medium-sized molecules (10–60 kDa) over a maximum surface area [22]. This range of molecular weights encompasses a wide array of cytokines and inflammatory proteins [22]. The adsorption process is predominantly driven by hydrophobic interactions, facilitating the effective binding of hydrophobic cytokines such as IL-6, TNF-α, and high-mobility group box-1, within the hydrophilic environment of blood plasma. The beads uniquely designed microporous structure enhance molecular selectivity enabling the efficient sequestration of inflammatory mediators whilst preserving nontargeted components. Compared with traditional blood purification methods such as dialysis or filtration, CytoSorb cartridges have several distinct advantages. These include molecular weight selectivity optimized for most cytokines, concurrent removal of both proinflammatory and anti-inflammatory mediators to help restore immune homeostasis, and minimal interference with platelet activation or coagulation cascades (due to the inert biocompatible polymer composition which ensures hemodynamic stability during prolonged operation times). It was reported that CytoSorb therapy significantly reduced norepinephrine requirements and procalcitonin levels in patients with septic shock, whereas no significant reductions were observed in the control group [6]. However, CytoSorb lacks the capacity to remove endotoxins (unlike other hemoperfusion modalities such as PMX-HP or AN69-Oxiris) which may limit in its application for refractory septic shock management. An advantage of the CytoSorb hemoadsorption is its capacity for continuous renal replacement therapy (CRRT) or extracorporeal membrane oxygenation. The device performance is influenced by critical factors such as blood flow rates, saturation kinetics, and patient-specific cytokine profiles. For instance, excessive flow rates may reduce adsorption efficiency by limiting contact time within the cartridge, necessitating precise regulation of flow dynamics. In addition, the hemoadsorption of CytoSorb can be modulated by the pathophysiological context of the patient, with the removal of specific cytokines playing a pivotal role in determining clinical outcomes
2. PMX-HP
PMX-HP is commonly utilized in patients with Gram-negative sepsis, particularly those with refractory septic shock who are unresponsive to conventional therapies. It is specifically designed for the treatment of endotoxemia, a critical component in the pathogenesis of sepsis and septic shock. It employs a polymyxin B-immobilized fiber column to selectively adsorb endotoxins from the bloodstream (Figure 1). Polymyxin B is an antibiotic with a high affinity for the lipid A component of LPS. The PMX-HP cartridge contains polymyxin B molecules which are covalently immobilized on the surface of porous fibers. As blood flows through the cartridge, LPS binds to the polymyxin B on the fibers, effectively removing endotoxins from the bloodstream without exerting an antibiotic effect. By removing free endotoxins, the therapy interrupts their interaction with toll-like receptor-4, reducing downstream signaling pathways responsible for the systemic inflammatory response. In addition to this, by reducing endotoxin levels, PMX-HP can modulate cytokine production to lead to a decrease in proinflammatory cytokines, and may mitigate the cytokine storm frequently observed in conditions such as sepsis and septic shock. Furthermore, the suppression of systemic inflammation contributes to improved vascular tone resulting in enhanced hemodynamic stability, and a reduced need for vasopressor support. Moreover, PMX-HP therapy may have indirect benefits beyond its primary mechanism of endotoxin removal, specifically, it may contribute to the preservation of endothelial integrity by attenuating endotoxin-induced endothelial activation, thereby maintaining vascular barrier function, and potentially reducing capillary leakage. Similarly, it plays a role in mitigating organ injury by interrupting inflammatory signaling pathways, which limit the extent of organ damage, particularly in vital organs such as the kidneys and liver, which are often affected in septic shock. Although PMX-HP does not directly reduce bacterial load or resolve the underlying infection, its capacity to modulate the host immune response and suppress endotoxin-driven inflammation represents a critical adjunctive strategy in the comprehensive management of sepsis. Garcia-Ramos et al [7] showed that PMX-HP treatment reduce mortality in postoperative patients with abdominal septic shock to 25% significantly lower than the 57.98% predicted by the APACHE II score. Other studies have investigated the effectiveness of Toraymyxin in managing septic patients with endotoxemia and among these studies, the EUPHRATES trial, one of the most extensive RCTs evaluating PMX-HP, did not find a statistically significant reduction in 28-day mortality across the entire study population [8]. A post hoc analysis of the EUPHRATES trial identified a substantial reduction in mortality in a subset of patients who had moderate to severe endotoxemia (defined by an EAA value between 0.6 and 0.9) [9]. In another study the use of postoperative PMX HP therapy markedly enhanced in-hospital survival rates in patients with moderate or higher endotoxemia, characterized by an EAA value of 0.54 or above as compared with the conventional treatment [10]. These findings suggest that appropriate patient selection, based on endotoxin activity, could be critical in optimizing outcomes. Despite its potential, PMX-HP has limitations. Its use is associated with high costs, and the need for specialized equipment and training may limit its availability of use. Moreover, while the therapy is generally well-tolerated, complications such as thrombocytopenia and hypotension during hemoperfusion have been reported [23]. To further validate the role of Toraymyxin in sepsis management, additional trials are necessary to refine patient selection criteria, optimize treatment protocols, and establish its cost-effectiveness. Combining PMX-HP with other sepsis therapies, such as targeted antibiotics or immunomodulatory agents, may enhance its therapeutic impact. Advances in biomarkers for endotoxemia could also improve the identification of patients most likely to benefit from PMX-HP therapy.
3. AN69-Oxiris
The development of the AN69-Oxiris hemoperfusion is rooted in decades of progress in the field of extracorporeal blood purification. The hollow-fiber AN69 membrane, used in the AN69-Oxiris device, has a unique filter structure with a 3-layer membrane (Figure 2). The 1st layer has an AN69 copolymer hydrogel structure that facilitates cytokine adsorption such as TNF-α, interferon-γ, IL-6, and IL-8. The 2nd layer has multiple layers of polyethyleneimine which are of higher density and positively charged to enable robust adsorption of endotoxins. The 3rd layer is pretreated with heparin (4,500 IU/m2) to reduce the risk of thrombosis, extend filter lifespan, and enhance CRRT efficiency [24]. The AN69-Oxiris device can provide renal support (with acid-base and electrolyte correction) and volume control for CRRT, in addition to its immunomodulatory support. Both in vitro and in vivo studies have demonstrated that AN69-Oxiris effectively lowers levels of procalcitonin, endotoxins, cytokines, and various inflammatory mediators. These reductions have been correlated with decreased vasopressor requirements, and notable improvements in the Sequential Organ Failure Assessment score [25], reflecting its therapeutic usefulness in critical care settings. A recent RCT demonstrated improved renal function during the early phase of treatment with AN69-Oxiris in critically ill patients with acute kidney injury (AKI) Stages 2–3 [26]. However, the lack of large-scale clinical trials and comprehensive studies limit definitive conclusions on the use of AN69-Oxiris therapy, and no consensus guidelines have yet been developed regarding its clinical application. In addtion, several concerns remain regarding the effectiveness of AN69-Oxiris at removing endotoxins in refractory septic shock patients with high endotoxin levels. Furthermore, the negative impact of AN69-Oxiris on the plasma concentration of antibiotics, limit its use. Antibiotics are a cornerstone of standard therapy for patients with septic shock and play a critical, and indispensable role in treatment. Beyond its capacity to adsorb endotoxins and inflammatory mediators, hemofilter membranes can also adsorb antibiotics. However, there are no clear guidelines for adjusting antibiotic dosages during CRRT, and the optimal therapeutic plasma concentrations of antibiotics have not been clearly defined. Notably, the use of hemofilters such as AN69-Oxiris may further decrease the effective plasma concentration of antibiotics [5]. This reduction poses a potential risk of exacerbating the condition of septic shock patients where precise antibiotic administration and maintenance of adequate therapeutic levels are critical. This warrants further clinical investigation to mitigate these risks. However, the AN69-Oxiris hemofilter is a specialized device that combines the capability to remove both endotoxins and cytokines with the fluid removal function for CRRT [5]. Considering that AKI occurs in approximately 50% of patients with sepsis, and is associated with significantly higher mortality rates [27], AN69-Oxiris appears to be particularly well-suited for patients with AKI who require simultaneous CRRT. In addition, given the role of kidney dysfunction in mediating crosstalk with other organ systems, leading to further organ damage, the use of AN69-Oxiris offers distinct advantages in such scenarios. Future research should prioritize identifying the optimal timing for initiating AN69-Oxiris therapy, determining the appropriate duration of use, and establishing criteria for filter replacement. Such studies are crucial in optimizing the clinical application of AN69-Oxiris, and in the assurance of safe and effective use in the management of refractory septic shock patients.
Considerations for Choosing between PMX-HP and AN69-Oxiris
The differences in performance observed between the 2 modalities may be attributed to variations in their filters’ capacity to remove endotoxins. In an in vitro study [28], it was reported that PMX-HP had a substantially greater endotoxin clearance rate within the first 30 minutes compared with AN69-Oxiris. Another in vitro study showed that after 4 hours, AN69-Oxiris achieved only a 10% clearance rate, whereas PMX-HP had a clearance rate of 70% [29]. The endotoxin adsorption capacity of these devices differed significantly. PMX-HP removed 64 μg of endotoxin from whole blood compared with AN69-Oxiris which only removed 1–8 μg of endotoxin [29]. These findings support the hypothesis that PMX-HP may be more suitable for patients with elevated endotoxin levels, as it can rapidly and efficiently reduce endotoxin burden as compared with AN69-Oxiris.
Faster endotoxin removal can expedite the resolution of symptoms of severe shock including hypotension, and facilitate a rapid reduction in vasopressor use, thereby minimizing complications associated with prolonged vasopressor therapy. This indicates that in this situation, PMX-HP would be the appropriate modality of choice. In addition to the inferior endotoxin adsorption capacity of AN69-Oxiris, it has been reported to adsorb antibiotics, including vancomycin and amikacin, which could lower circulating antibiotic levels to below the therapeutic threshold [24]. These characteristic may limit the capacity of AN69-Oxiris as an appropriate modality in patients with severe endotoxemia or high disease severity, where maintaining effective antibiotic concentrations is critical.
AN69-Oxiris therapy demonstrates greater cost-effectiveness in blood purification therapy compared with PMX-HP therapy. The pricing of these filters varies across countries, however, the AN69-Oxiris filter is generally more affordable than the PMX-HP filter. In South Korea, the PMX-HP filter is approximately 3.2 times more expensive than the AN69-Oxiris filter, whilst in Taiwan, it costs around twice as much. In European nations, the cost of PMX-HP filter is roughly 2.25–3 times higher than the AN69-Oxiris filter. In addition, AN69-Oxiris therapy integrates CRRT functionality, whereas PMX-HP therapy necessitates an additional CRRT device for renal replacement therapy (RRT), further increasing its overall cost. Therefore, AN69-Oxiris therapy may be a more advantageous option for patients with sepsis or septic shock characterized by relatively mild endotoxemia, as it delivers comparable clinical outcomes over time with a significantly lower financial burden.
Close examination of the 2 modalities reveals significant differences in their specific target substances, the types of membranes utilized, associated limitations, and cost-effectiveness, although both hemoperfusion modalities share the common feature of primary (or secondary) removal of endotoxins and cytokines. These distinctions highlight the need for careful consideration when selecting the appropriate modality for clinical use. Given that PMX-HP therapy is superior in filtering high endotoxin blood, it may be a particularly suitable option for patients with refractory septic shock characterized by moderate to severe disease severity. This includes cases defined by moderate or high endotoxemia with EAA values of 0.6 or higher, lactate levels exceeding 8–10 mmol/L, and the requirement for 2 or more vasopressors. In contrast, for patients with surgical septic shock characterized by mild endotoxemia with EAA values below 0.6, lactate levels under 5–8 mmol/L, or moderate or lower vasopressor requirements, AN69-Oxiris may serve as a more efficient hemoperfusion option, particularly in cases of significant fluid imbalance during the perioperative period or in the early postoperative phase. This is especially applicable to patients with accompanying AKI or a history of chronic renal failure who are anticipated to require RRT. Considering the implementation of RRT, such as CRRT, along with cost-effectiveness, AN69-Oxiris presents itself as a more viable and practical choice in these clinical scenarios. However, additional prospective studies are needed to establish definitive, evidence-based criteria for choosing to use PMX-HP therapy over AN69-Oxiris.
Conclusion
Extracorporeal blood purification therapies such as CytoSorb, PMX-HP, and AN69-Oxiris are emerging as potential treatment options for patients with refractory septic shock, particularly when Gram-negative bacteria are identified as the predominant cause, as in cases of intra-abdominal infections. These therapies may be considered for patients whose condition does not improve despite surgical source control of the infection. Considering the high cost of these devices and the absence of well-established treatment protocols, their application to all patients with surgical septic shock remains challenging. However, for refractory septic shock patients who continue to exhibit a critical condition, despite effective source control through emergency surgery or other interventions, these specialized therapies may offer a valuable means of improving outcomes. Notably, except for contraindications such as severe thrombocytopenia, or hypersensitivity to polymyxin B in the case of PMX-HP, these therapies can be regarded as safe and feasible options for critically ill postoperative patients.
In South Korea, the adoption of these therapies for surgical patients remains limited, partly due to limited awareness among healthcare professionals, high costs, and the lack of insurance reimbursement. Despite these challenges, blood purification treatments hold the potential to serve as “silver bullets” for patients with severe, life-threatening conditions who fail to recover after surgery, and progress rapidly to multi-organ failure. Particularly, in refractory septic shock patients who continue to deteriorate clinically or face life-threatening conditions, despite standardized sepsis management (including massive fluid resuscitation, and the early administration of broad-spectrum antibiotics or antifungal agents, as well as effective source control through surgery or interventional procedures). In these cases, extracorporeal blood purification therapy may be considered a salvage treatment option. Although definitive criteria or guidelines regarding the optimal timing of application have not yet been established, early intervention may provide benefits by reducing endotoxin burden and suppressing excessive cytokine activity, thereby serving as a prevention of organ failure. Given these potential advantages, it would be preferable to initiate treatment as early as possible to maximize clinical improvement. Ideally, this therapy should be applied immediately after the completion of source control, through surgery or intervention, or at the moment when such high-risk patients are identified. This would achieve the most favorable outcome. To fully realize the potential of these therapies, it is essential to develop a comprehensive understanding of the mechanisms of action and efficacy for each device. Tailored treatment strategies should be established by considering individual patient factors such as endotoxin levels, renal function, the severity of septic shock and illness, and the financial burden. Based on such evidence, standardized guidelines for the application of blood purification therapies should be developed to optimize their use and improve the outcomes in critically ill patients.
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