The application of therapeutic plasma exchange in sepsis and septic shock: A narrative review

Abstract

Sepsis, characterized by a dysregulated host response to infection that leads to life-threatening organ dysfunction, remains a leading cause of mortality in the intensive care unit (ICU). Despite continuous optimization of treatment strategies, mortality rates remain high. Therapeutic plasma exchange (TPE) has emerged as a promising adjunctive therapy, offering benefits through the removal of harmful substances and the replenishment of essential plasma components. The key mechanisms of TPE include replenishing deficient plasma components, clearing inflammatory cytokines, improving thrombotic microangiopathy, regulating immune imbalance, and enhancing vascular endothelial function. Although the efficacy of TPE in sepsis and septic shock management shows promise, the current evidence is predominantly derived from retrospective studies and small-scale randomized controlled trials (RCTs). As a result, the overall therapeutic effectiveness is inconclusive. The guidelines from the American Society for Apheresis and the Surviving Sepsis Campaign offer cautious recommendations for the use of TPE, particularly in patients with sepsis and multiple organ failure. Emerging RCTs suggest that early initiation of TPE can stabilize hemodynamics, reduce vasopressor requirements, and improve organ function, especially in cases of refractory septic shock. However, safety concerns need to be carefully considered, including hypotension and the potential for blood–borne infections. Future research should focus on larger RCTs to provide robust evidence supporting the role of TPE in sepsis and septic shock management. This review aims to summarize related research results to provide evidence for clinicians to use TPE in treating sepsis and septic shock.

Introduction

Sepsis is defined as a dysregulated host response to infection that leads to life-threatening organ dysfunction. ¹ Characterized by a complex pathogenesis and rapid progression, sepsis often progresses to septic shock and multiple organ dysfunction syndrome, making it one of the leading causes of mortality in the intensive care unit (ICU) patients. Research by Marta et al. ² suggests that uncontrolled inflammatory responses and endothelial dysfunction are central mechanisms in sepsis progression, leading to multiple organ failure and microcirculatory thrombosis. These pathological changes significantly increase the risk of death and are considered the primary causes of sepsis-related mortality. Studies estimate approximately 48.9 million cases of sepsis annually, with around 11 million sepsis-related deaths worldwide. ³ Since being recognized as a global health priority by the World Health Organization in 2017, sepsis has imposed a substantial economic burden. ⁴ Despite continuous optimization of treatment strategies, including early goal-directed therapy, as outlined in international guidelines for sepsis and septic shock in recent years, mortality rates have not significantly declined.

Continuous renal replacement therapy (CRRT) has been recommended for the treatment of septic shock. Among the available modalities, continuous veno-venous hemofiltration (CVVH) and continuous veno-venous hemodiafiltration (CVVHDF) are the most commonly used blood purification techniques in sepsis. These methods primarily aim to remove excess fluid, small- and medium-sized metabolic toxins, and inflammatory mediators. However, despite their widespread use, sepsis-related mortality remains high as their primary role is fluid and solute clearance in acute kidney injury rather than targeted cytokine removal. In contrast, therapeutic plasma exchange (TPE), though still considered an adjunctive therapy, is gaining increasing recognition for its potential benefits in sepsis management. ⁵ As an extracorporeal blood purification technique, TPE can remove pathogenic substances while replenishing essential procoagulant and anticoagulant factors, thereby restoring physiological homeostasis and coagulation balance.^6,7 Additionally, TPE has been shown to clear inflammatory cytokines, modulate immune imbalance, improve vascular endothelial function, stabilize hemodynamics, and reduce vasopressor requirements. This review aims to summarize current evidence on the use of TPE in sepsis and septic shock, providing clinicians with a comprehensive evaluation of its therapeutic potential. The review follows the Scale for the Assessment of Narrative Review Articles (SANRA) guidelines to ensure methodological rigor. ⁸

Current status of TPE in the treatment of sepsis

The concept of TPE was first introduced by Abel in 1914. ⁹ Its clinical application in sepsis began in 1979 when it was used to treat meningococcal bacteremia-induced septic shock, demonstrating promising efficacy. ¹⁰ Over the past two decades, TPE technology has advanced significantly and been widely used in critical care settings for managing conditions such as autoimmune diseases, toxic exposures, multiorgan failure (MOF), and sepsis spanning multiple medical specialties, including neurology, nephrology, and hematology.

Despite its expanding use, clinical studies on TPE in sepsis—both pediatric and adult populations—remain limited, with most available data derived from retrospective analyses. The scarcity of high-quality evidence has led to uncertainty regarding TPE's overall therapeutic benefit in sepsis. While some studies suggest that TPE may improve organ dysfunction in septic patients, its definitive efficacy remains inconclusive. According to the American Society for Apheresis guidelines, TPE is classified as a category III, grade 2A intervention for sepsis with MOF. ¹¹ This classification reflects that the role of plasmapheresis in sepsis is not yet firmly established, and its use should be guided by individualized clinical judgment, supported by a moderate-weak recommendation.

Globally, several studies have preliminarily explored the therapeutic value of TPE in pediatric patients with sepsis-induced thrombocytopenia-associated multiple organ failure (TAMOF). Among these, two retrospective cohort studies^12,13 and one small-sample randomized controlled trial (RCT) ¹⁴ suggested that TPE was associated with reduced mortality. Notably, the largest retrospective observational study to date, involving 81 pediatric sepsis patients, demonstrated that TPE reduced the 28-day mortality in pediatric sepsis patients with TAMOF. ¹⁵ However, shortly after the publication, a commentary in the same journal questioned the study’s conclusions, arguing that the results were insufficient to establish a definitive causal relationship between TPE and improved outcomes. ¹⁶ Consequently, the 2020 Surviving Sepsis Campaign International Guidelines do not recommend TPE for pediatric patients with septic shock or sepsis-related organ dysfunction without TAMOF (GRADE: weak recommendation, very-low-quality evidence). In contrast, TPE may be considered in cases complicated by TAMOF. ¹⁷ The guidelines also highlight the need for further clinical research to clarify TPE’s role in pediatric sepsis with TAMOF. ¹⁸ A 2022 RCT ¹⁹ provided additional insights, demonstrating that early TPE application in refractory septic shock rapidly improved hemodynamic stability, significantly reducing norepinephrine (NE) dosage and lactate levels. Furthermore, TPE markedly decreased the levels of procalcitonin and harmful inflammatory mediators while replenishing protective factors. Notably, in patients with lactate levels > 3 mmol/L, TPE further reduced NE dependency. These findings suggest that supportive TPE may help stabilize hemodynamics in refractory septic shock.

Mechanisms and clinical efficacy of TPE in sepsis management

Mechanism of TPE in treating sepsis

Compared to other CRRT modes used in sepsis such as CVVH and CVVHDF, the therapeutic efficacy of TPE primarily stems from two key mechanisms: (1) the infusion of fresh plasma and (2) the removal of harmful mediators. In principle, TPE ameliorates sepsis-induced organ dysfunction and improves prognosis through multiple pathways (Figure 1).

Figure 1.

Mechanism of TPE in treating sepsis and septic shock. TPE: therapeutic plasma exchange.

Replenishing plasma component deficiencies

The infusion of fresh frozen plasma (FFP) compensates for critical deficiencies in sepsis. Sepsis triggers tissue factor activation, endothelial injury, and suppression of endogenous anticoagulants (e.g. antithrombin and activated protein C). ⁶ TPE directly replenishes these components, thereby restoring the balance between procoagulant and anticoagulant pathways. ⁷ Specifically, FFP provides all essential clotting factors, and anticoagulant proteins such as ADAMTS13 (A Disintegrin and Metalloprotease with Thrombospondin Motifs-13).

Clearance of inflammatory cytokines

TPE effectively removes small- and medium-sized inflammatory cytokines, as well as larger molecular-weight inflammatory mediators (e.g. endotoxins, albumin-bound IL-10, and immune complexes) that CVVH and CVVHDF fail to eliminate. This process significantly attenuates systemic inflammation. ²⁰ Knaup et al. ²¹ monitored inflammatory cytokines in sepsis patients before and after TPE, demonstrating significant reductions in IL-6 and IL-8 levels post-treatment. Similar findings were reported in COVID-19 studies, where TPE led to decrease IL-6 and IL-8 concentrations. ²² Bengsch et al. ²³ conducted a study involving 15 septic shock patients who underwent 83 TPE sessions. Post-TPE analyses revealed marked reductions in C-reactive protein, IL-6, and fibrinogen levels. These findings collectively substantiate TPE’s efficacy in removing inflammatory mediators, thereby ameliorating systemic inflammatory responses in sepsis patients.

Improvement in thrombotic microangiopathy

In sepsis/septic shock patients progressing to TAMOF, reduced ADAMTS13 activity leads to widespread microthrombi formation. The mechanism of TPE in coagulation regulation contains removing antifibrinolytic molecules (e.g. ultra-large von Willebrand factor [ULvWF] fragments, ADAMTS13 autoantibodies) and restoring ADAMTS13 activity, thereby improving coagulation and endothelial function.^24,25

Regulation of immune imbalance

Sepsis is characterized by a paradoxical coexistence of hyperinflammation and compensatory immunosuppression. TPE’s immunomodulatory effects contain removing excess immunosuppressive mediators, replenishing essential immune components, including complement proteins, immunoglobulins, and other bioactive substances, restoring immune cell function and activity, promoting immune homeostasis.^26,27 Clinical evidences demonstrates that TPE reduces acute-phase proteins and IL-2 receptor α/cluster of differentiation 25 (IL-2Rα/CD25) while exerting minimal effects on core proinflammatory cytokines. ²⁸ This selective immunomodulatory mechanism may explain the observed hemodynamic improvements in septic shock patients.

Improvement of vascular endothelial function

TPE removes inflammatory mediators and endothelium-damaging substances such as extracellular histone proteins and neutrophil extracellular traps. This process mitigates endothelial injury, reduces vascular permeability, enhances endothelial function, and ultimately improves organ perfusion. ²⁹ In septic shock, severe degradation of the endothelial glycocalyx (eGC) occurs alongside impaired function of heparanase-2 (Hpa-2), a protective regulatory enzyme. TPE may exert a dual protective effect on endothelial homeostasis by clearing harmful mediators released during eGC breakdown and partially restoring acquired Hpa-2 deficiencies. ³⁰

Clinical efficacy of TPE in sepsis management

Current international authoritative guidelines have not provided definitive conclusions regarding the efficacy of TPE in the treatment of sepsis and septic shock. Moreover, there are few large-scale RCTs evaluating TPE for septic shock or sepsis-related organ dysfunction. However, in recent years, studies conducted by scholars worldwide on the use of TPE for septic shock have shown promising results in improving patient outcomes.

Impact of TPE on hemodynamics

TPE improves hemodynamic stability and the inflammatory response in patients with septic shock, thereby promoting circulatory stability. Yu et al. ³¹ demonstrated that patients who received early TPE required a shorter duration of vasopressor use compared to those who received delayed TPE. This was accompanied by a progressive increase in systemic vascular resistance (SVR) and a concomitant decrease in lactate levels. Unfortunately, the study lacked hemodynamic monitoring. In a retrospective study, Stahl et al. ³² pointed out that the TPE group showed a significant reduction in the concentrations of tissue factor (TF) and TF pathway inhibitor (TFPI), while the standard of care (SOC) group showed no significant changes. The ratio of TF to TFPI remained unchanged in both the SOC and TPE groups. Thus, it was concluded that adjunctive TPE mediated the clearance of TF and TFPI in septic shock, which may contribute to the early hemodynamic improvement observed in patients. Additionally, Ahmed et al. ³³ further confirmed that the early initiation of TPE better improved the hemodynamic parameters in patients with severe septic shock. David et al. ³⁴ demonstrated that a single session of TPE administered within 24 hours of septic shock onset significantly reduced the NE dosage requirements within 6 hours.

Impact of TPE on organ function

TPE shows potential in improving organ function. In pediatric sepsis patient, the administration of TPE has been associated with statistically significant reductions in both Acute Physiology and Chronic Health Evaluation (APACHE II) scores and Sequential Organ Failure Assessment (SOFA) scores, along with a decrease in the number of failing organs. ³⁵ In a study by Nguyen et al., ¹⁴ 10 children with sepsis were randomly divided into TPE group and standard treatment group. The TPE group showed restoration of ADAMTS13 activity and a survival rate compared to the control group. These findings suggest that TPE may temporarily enhance organ function and increase the 7-day survival rate in pediatric sepsis, although the sample size was small.

Some adult studies also support the use of TPE for septic shock and sepsis-related organ dysfunction. A meta-analysis by Rimmer et al. ³⁶ found that TPE was associated with reduced mortality in adult sepsis patients. Busund et al. ³⁷ conducted an RCT involving 106 adults with septic shock, randomly dividing them into TPE group and SOC group. The TPE group showed a 20.5% reduction in 28-day mortality compared to the SOC group, supporting its role as an adjunctive therapy for sepsis and septic shock. Another meta-analysis that incorporated 5 RCTs and 15 multicenter studies (MCSs), encompassing 937 patients with sepsis-induced organ dysfunction, showed a significant reduction in short-term mortality rate among TPE recipients. ³⁸ Several studies have demonstrated survival benefits associated with TPE in critically ill adults with sepsis, showing a reduction in 28-day mortality.^39–41 All studies consistently documented improvements in secondary outcomes, including hemodynamics, inflammation, coagulation function, and vascular endothelial permeability. These findings suggest that TPE may accelerate improvements in clinical outcomes and prognosis among sepsis patients. Although these findings are encouraging, large-scale RCTs are still imperative before widespread clinical implementation. Moreover, the therapeutic efficacy of TPE remains controversial. Lee et al. ⁴² found no difference in mortality outcomes for adults with septic shock who received TPE support. Additionally, Aygün et al. ³⁵ concluded that neither CRRT nor TPE significantly reduced mortality in pediatric sepsis patients. This discrepancy could be explained by the complexity of pediatric cases and the multifactorial determinants of therapeutic efficacy. These conflicting findings highlight the need for further investigation to clarify the role of TPE in reducing mortality in adult and pediatric sepsis patients.

Leonhardt et al. ⁴³ found that patients with septic shock complicated with severe liver failure generally had cholestasis, and their serum bile acid levels were significantly elevated. This metabolic disorder may be related to the pathological process of endotoxemia and liver failure. Stahl et al. ⁴⁴ found that the level of soluble urokinase plasminogen activator receptor was positively correlated with the severity of the disease, multiple organ dysfunction, and the activation status of endothelial cells in patients with sepsis. These studies provide important insights, which may be the key points to focus on when exploring the role of TPE in improving organ function metabolism in the future.

The application of TPE in special populations

Fortenberry et al. ¹² carried out a prospective multicenter observational cohort study involving 81 children with sepsis. The study showed that TPE was associated with a reduced 28-day mortality and improved Pediatric Logistic Organ Dysfunction (PELOD) scores. A Turkish retrospective cohort study ¹³ revealed that the 28-day mortality in the TPE group was significantly lower than that in the non-TPE group. However, in a retrospective cohort study by Lima et al., ⁴⁵ more than 49,000 pediatric sepsis patients were analyzed, and only 2% of them received TPE. The TPE group had a higher mortality rate compared to the non-TPE group. After multivariable adjustment for patient characteristics, comorbidities, and organ dysfunction, this difference in mortality still remained statistically significant. The substantial discrepancy might be due to several factors. Firstly, patients who received TPE may have had more severe MOF. Secondly, there was a lack of standardized criteria for initiating TPE. Thirdly, the procedure itself is inherently complex.

Safety and side effects of TPE

Despite achieving some significant therapeutic effects in septic shock, most studies primarily focus on traditional TPE. The traditional TPE procedure involves withdrawing blood extracorporeally, followed by the removal of pathogenic substances through membrane separation or centrifugal processing. After discarding the separated plasma, blood cellular components are reinfused along with FFP or replacement fluid. The need for large volumes of FFP in conventional TPE contributes to procedure-related complications. Adverse reactions associated with TPE include the depletion of beneficial molecules, as well as catheter- and operation-related events. ⁴⁶ In contemporary practice, the reported incidence of TPE-associated adverse events has declined to 5% to 6%.^47,48 It is reported that 0.4% to 1.6% of the patients have catheter-related infections, pneumothorax, and local hemorrhage.^49,50 In critically ill populations, while hemorrhagic complications remain uncommon (＜10%), catheter-associated events are the predominant adverse outcomes (32%). ⁵¹ Life-threatening complications (1%–2%), mainly anaphylaxis and refractory hypotension, have been documented in critically ill patients undergoing TPE.^51,52 Additionally, citrate anticoagulation is a risk factor for hypocalcemia. ⁵³ Albumin-based replacement fluids unable to replenish depleted coagulation factors and immunoglobulins, potentially increasing the hemorrhagic risk and immunosuppression. These safety considerations may influence clinical decision making regarding the use of TPE. Notwithstanding these risks, substantial clinical evidence supports the therapeutic efficacy of TPE in appropriately selected cases. A 2024 systematic review by Hernández et al. ⁵⁴ emphasizes the necessity of rigorous risk-benefit analysis for TPE-associated metabolic disturbances, including hypocalcemia and citrate toxicity. TPE has emerged as an adjunctive intervention for refractory sepsis, particularly in cases with multiorgan dysfunction. Notably, current evidence shows no specific adverse events linking TPE to sepsis apart from the well-known common complications. Current meta-analyses evaluating TPE in adult sepsis populations have demonstrated safety profiles comparable to those in other indications. ⁴²

Current research predominantly focuses on dual plasma exchange (DPE) application in fluid-restricted critically ill patients under plasma resource constraints, with limited investigation into early therapeutic initiation. Emerging evidence from single-center prospective studies suggests DPE potentially mitigates acute hemodynamic complications in critically ill patients, including sudden increases in circulating blood volume, edema, bleeding, and allergic reactions. However, due to the limited sample sizes, these observations need to be verified through multicenter RCTs. With an advancing understanding of disease pathogenesis and therapeutic efficacy profiles, novel treatment modalities and combination therapies, such as double filtration plasma apheresis (DFPP), have emerged. DFPP is a highly selective therapeutic modality for eliminating macromolecular pathogenic substances while preserving a substantial amount of allogeneic plasma, thus significantly reducing transfusion-related infection risks. ⁵⁵ Further research is warranted to clarify its clinical applications and underlying mechanisms.

Sorbent therapies in sepsis

Cytosorb^® is a whole blood adsorber featuring a large adsorption surface area. It primarily consists of polystyrene-divinylbenzene porous microspheres, whose surfaces are covered with polyvinylpyrrolidone. As a nonselective adsorption column, Cytosorb^® can remove a variety of molecules with a molecular weight ranging from 5000 to 60,000 D from the blood. These molecules include various pro-inflammatory and anti-inflammatory cytokines, bilirubin, and bile acids. Numerous studies have demonstrated the value of Cytosorb^®. It has been shown to reduce the demand for vasopressors, extract cytokines from the blood, and potentially lower mortality.^56–58 However, other studies have reported that while Cytosorb^® clears cytokines, it may also result in a significant loss of certain therapeutic drugs and plasma proteins. ⁵⁹ The nonspecific removal of circulating cytokines might actually be harmful to the resolution of inflammation and could even exacerbate inflammatory damage. Therefore, in the future, more efforts should be directed toward the development of selective cytokine adsorption devices.

Coupled plasma filtration adsorption (CPFA) is a blood purification model. It combines synthetic resin hemoperfusion columns, which can eliminate medium and large molecules, with hemofiltration, which is capable of removing small molecules. The aim is to address the inflammatory mediators and toxins that trigger systemic inflammation in conditions like septic shock. The CPFA process is carried out in two stages: plasma separation and adsorption. In a prospective multicenter trial, Livigni et al. ⁶⁰ found that although CPFA could improve the early hemodynamics of patients, it did not reduce mortality or improve other major clinical outcomes. Garbero et al. ⁶¹ reported that the mortality rate was higher in the CPFA group compared to the control group, especially among patients without severe renal failure. This is related to the insufficient dosage of antibiotics when using adsorption therapy. Some researchers have pointed out that insufficient antibiotic doses can be more dangerous than the potential side-effects of antibiotics themselves. ⁶²

Conclusion

TPE serves as a crucial adjunctive therapy in sepsis and septic shock. It has two key functions: eliminating large molecular weight inflammatory mediators and modulating coagulation function. A large body of evidence supports the safety and feasibility of TPE in sepsis management. However, its clinical application depends on multiple factors, including the severity of the disease, patient demographics (such as gender and age), and other comorbidities. To optimize TPE protocols, systematic investigations through rigorous clinical studies are necessary. These studies should focus on aspects like therapeutic regimens, therapeutic timing, and indication criteria. Despite ongoing debates about its efficacy, the well-established safety profile of TPE justifies its early incorporation into evidence-based sepsis management bundles for critically ill patients. Multiple studies have shown that TPE can effectively reduce inflammatory responses, maintain hemodynamic stability, and improve organ function and prognosis. Although current evidence-based medical evidence for TPE in sepsis and septic shock remains limited, the potential of TPE in treating sepsis and septic shock is promising. Future clinical research should concentrate on conducting multicenter RCTs to provide more robust support for its use.