Adsorption of Pathogens and Blockade of Sepsis Cascade

Objective To discuss the rationale, hypothesis, modality of extracorporeal blood purification (EBP) techniques for the critically ill animal models or patients, and to summarize the experimental and clinical studies with inconsistent data which explored the EBP's efficacy in the areas of critical care medicine. Data sources Articles referred in this review were collected from the database of PubMed published in English up to June 2014. Study selection We had done a literature search by using the term “(sepsis OR acute lung injury OR acute respiratory distress syndrome) AND (extracorporeal blood purification OR hemofiltration OR hemoperfusion OR plasma exchange OR plasmapheresis OR adsorpiton)”. Related original or review articles were included and carefully analyzed. Results Acute cellular and humoral immune disturbances occur in both sepsis and acute respiratory distress syndrome (ARDS). Treatments aimed at targeting one single pro-/anti-inflammatory mediator have largely failed with no proven clinical benefits. Such failure shifts the therapeutic rationale to the nonspecific, broad-spectrum methods for modulating the over-activated inflammatory and anti-inflammatory response. Therefore, EBP techniques have become the potential weapons with high promise for removing the circulating pro-/anti-inflammatory mediators and promoting immune reconstitution. Over the years, multiple extracorporeal techniques for the critically ill animal models or patients have been developed, including hemofiltration (HF), high-volume hemofiltration (HVHF), high-cutoff hemofiltration (HCO-HF), hemo-perfusion or -adsorption (HP/HA), coupled plasma filtration adsorption (CPFA), and plasma exchange (PE). These previous studies showed that EBP therapy was feasible and safe for the critically ill animal models or patients. However, data on their efficacy (especially on the clinical benefits, such as mortality) were inconsistent. Conclusions It is not now to conclude that EBP intervention can purify septic or ARDS patients with high clinical efficacy from current experimental and clinical practice. Prospective, randomized controlled, and well-designed clinical or experimental studies and most suitable EBP modalities should be further developed.

Background and aims: Hypercytokinemia is believed to be harmful and reducing cytokine levels is considered beneficial. Extracorporeal blood purification (EBP) techniques have been studied for the purpose of cytokine reduction. We aimed to study the efficacy of various EBP techniques for cytokine removal as defined by technical measures. Method: We conducted a systematic search for human clinical trials which focused on technical measures of cytokine removal by EBP techniques. We identified 41 articles and analyzed cytokine removal according to clearance (CL), sieving coefficient (SC), ultrafiltrate (UF) concentration and percentage removed. Results: We identified the following techniques for cytokine removal: standard hemofiltration, high volume hemofiltration (HVHF), high cut-off (HCO) hemofiltration, plasma filtration techniques, and adsorption techniques, ultrafiltration (UF) techniques relating to cardiopulmonary bypass (CPB), extracorporeal liver support systems and hybrid techniques including combined plasma filtration adsorption. Standard filtration techniques and UF techniques during CPB were generally poor at removing cytokines (median CL for interleukin 6 [IL-6]: 1.09 mL/min, TNF-alpha 0.74 mL/min). High cut-off techniques consistently offered moderate cytokine removal (median CL for IL-6: 26.5 mL/min, interleukin 1 receptor antagonist [IL-1RA]: 40.2 mL/min). Plasma filtration and extracorporeal liver support appear promising but data are few. Only one paper studied combined plasma filtration and adsorption and found low rates of removal. The clinical significance of the cytokine removal achieved with more efficacious techniques is unknown. Conclusion: Human clinical trials indicate that high cut-off hemofiltration techniques, and perhaps plasma filtration and extracorporeal liver support techniques are likely more efficient in removing cytokines than standard techniques.

We acknowledge the fact that sepsis and septic shock are induced, sustained and perpetuated with the help of circulating molecules released from various activated inflammatory cells. This has shifted focus of management of sepsis from virulence of microbes to the dysregulated host immune response. The drivers of dysregulated immune responses constitute circulating substances like cytokines, chemokines and endotoxins. Extracorporeal blood purification (EBP) is a blood purification technique where blood or its components circulate in the extracorporeal (EC) circuit with the help of a specialised or standard dialysis machine. The blood is purified with clearance of inflammatory mediators and/or toxins aimed at suppressing inflammatory mediators in the various phases of sepsis. The purified blood/component gets recirculated back to the patient. But, presently we do not have any established guidelines for the use of EBP therapies. Hence, the use of EBP therapies is largely based on the judgement of the treating physician influenced by local practice and expertise levels. The literature is hopeful about the theoretical advantages of using multiple novel extracorporeal blood purification techniques with equivocal outcomes in clinical trials.

Clinically, it is highly challenging to promote recovery in patients with acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). Despite recent advances in understanding the underlying mechanisms of ALF and ACLF, standard medical therapy remains the primary therapeutic approach. Liver transplantation (LT) is considered the last option, and in several cases, it is the only intervention that can be lifesaving. Unfortunately, this intervention is limited by organ donation shortage or exclusion criteria such that not all patients in need can receive a transplant. Another option is to restore impaired liver function with artificial extracorporeal blood purification systems. The first such systems were developed at the end of the 20th century, providing solutions as bridging therapy, either for liver recovery or LT. They enhance the elimination of metabolites and substances that accumulate due to compromised liver function. In addition, they aid in clearance of molecules released during acute liver decompensation, which can initiate an excessive inflammatory response in these patients causing hepatic encephalopathy, multiple-organ failure, and other complications of liver failure. As compared to renal replacement therapies, we have been unsuccessful in using artificial extracorporeal blood purification systems to completely replace liver function despite the outstanding technological evolution of these systems. Extracting middle to high-molecular-weight and hydrophobic/protein-bound molecules remains extremely challenging. The majority of the currently available systems include a combination of methods that cleanse different ranges and types of molecules and toxins. Furthermore, conventional methods such as plasma exchange are being re-evaluated, and novel adsorption filters are increasingly being used for liver indications. These strategies are very promising for the treatment of liver failure. Nevertheless, the best method, system, or device has not been developed yet, and its probability of getting developed in the near future is also low. Furthermore, little is known about the effects of liver support systems on the overall and transplant-free survival of these patients, and further investigation using randomized controlled trials and meta-analyses is needed. This review presents the most popular extracorporeal blood purification techniques for liver replacement therapy. It focuses on general principles of their function, and on evidence regarding their effectiveness in detoxification and in supporting patients with ALF and ACLF. In addition, we have outlined the basic advantages and disadvantages of each system.

Sepsis, a dysregulated immune response due to life-threatening organ dysfunction, caused by drug-resistant pathogens, is a major global health threat contributing to high disease burden. Clinical outcomes in sepsis depend on timely diagnosis and appropriate early therapeutic intervention. There is a growing interest in the evaluation of nanotechnology-based solutions for sepsis management due to the inherent and unique properties of these nano-sized systems. This review presents recent advancements in nanotechnology-based solutions for sepsis diagnosis and management. Development of nanosensors based on electrochemical, immunological or magnetic principals provide highly sensitive, selective and rapid detection of sepsis biomarkers such as procalcitonin and C-reactive protein and are reviewed extensively. Nanoparticle-based drug delivery of antibiotics in sepsis models have shown promising results in combating drug resistance. Surface functionalization with antimicrobial peptides further enhances efficacy by targeting pathogens or specific microenvironments. Various strategies in nanoformulations have demonstrated the ability to deliver antibiotics and anti-inflammatory agents, simultaneously, have been reviewed. The critical role of nanoformulations of other adjuvant therapies including antioxidant, antitoxins and extracorporeal blood purification in sepsis management are also highlighted. Nanodiagnostics and nanotherapeutics in sepsis have enormous potential and provide new perspectives in sepsis management, supported by promising future biomedical applications included in the review.

The development of new extracorporeal blood purification (EBP) techniques has led to increased application in clinical practice but also inconsistencies in nomenclature and misunderstanding. In November 2022, an international consensus conference was held to establish consensus on the terminology of EBP therapies. It was agreed to define EBP therapies as techniques that use an extracorporeal circuit to remove and/or modulate circulating substances to achieve physiological homeostasis, including support of the function of specific organs and/or detoxification. Specific acute EBP techniques include renal replacement therapy, isolated ultrafiltration, hemoadsorption, and plasma therapies, all of which can be applied in isolation and combination. This paper summarizes the proposed nomenclature of EBP therapies and serves as a framework for clinical practice and future research.

Extracorporeal blood purification (EBP) techniques provide support for critically ill patients with single or multiple organ dysfunction. Continuous renal replacement therapy (CRRT) is the modality of choice for kidney support for those patients and orchestrates the interactions between the different artificial organ support systems. Intensive care teams should be familiar with the concept of sequential extracorporeal therapy and plan on how to incorporate new treatment modalities into their daily practices. Importantly, scientific evidence should guide the decision-making process at the bedside and provide robust arguments to justify the costs of implementing new EBP treatments. In this narrative review, we explore the extended indications for CRRT as an adjunctive treatment to provide support for the heart, lung, liver, and immune system. We detail practicalities on how to run the treatments and how to tackle the most frequent complications regarding each of the therapies, whether applied alone or integrated. The physicochemical processes and technologies involved at the molecular level encompassing the interactions between the molecules, membranes, and resins are spotlighted. A clinical case will illustrate the timing for the initiation, maintenance, and discontinuation of EBP techniques.

Extracorporeal blood purification techniques (EBTs) are emerging as beneficial interventions in the management of sepsis. Although the combination of different EBTs has also been suggested as a potentially effective approach in the early phases of sepsis [1, 2], no data are available for pediatric septic shock.

Severe liver failure is common in Low-and-Medium Income Countries (LMIC) and is associated with a high morbidity, mortality and represents an important burden to the healthcare system. In its most severe state, liver failure is a medical emergency, that requires supportive care until either the liver recovers or a liver transplant is performed. Frequently the patient requires intensive support until their liver recovers or they receive a liver transplant. Extracorporeal blood purification techniques can be employed as a strategy for bridging to transplantation or recovery. The most common type of extracorporeal support provided to these patients is kidney replacement therapy (KRT), as acute kidney injury is very common in these patients and KRT devices more readily available. However, because most of the substances that the liver clears are lipophilic and albumin-bound, they are not cleared effectively by KRT. Hence, there has been much effort in developing devices that more closely resemble the clearance function of the liver. This article provides a review of various non-biologic extracorporeal liver support devices that can be used to support these patients, and our perspective keeping in mind the needs and unique challenges present in the LMIC of Latin America.

Extracorporeal blood purification is proposed as an adjuvant therapy for sepsis, aiming at controlling the associated dysregulation of the immune system, which is known to induce organ dysfunctions. Different therapies have been developed to address certain steps of the immune dysregulation. Most of the available blood purification devices focus on a single target, such as the endotoxin that triggers the immune cascade, or the cytokine storm that causes organ damages. However, the highly adsorptive membrane named oXiris® is a unique 4-in-1 device that combines cytokine and endotoxin removal properties, renal replacement function, and antithrombogenic properties. More recently, promising treatments that focus on the pathogen itself or the immune cells have been developed and are currently under investigation. In this review, we aim to summarize, according to their target, the different extracorporeal blood purification techniques that are already available for use. We will also briefly introduce the most recent techniques that are still under development. Because of its unique ability to remove both endotoxins and cytokines, we will particularly discuss the highly adsorptive preheparinized oXiris® membrane. We will present its properties, advantages, pitfalls, as well as therapeutic perspectives based on experimental and clinical data. Video Journal Club “Cappuccino with Claudio Ronco” at https://www.karger.com/Journal/ArticleNews/223997?sponsor=52

A resurgence of interest in adsorbents for medical application is now being seen. In extracorporeal blood purification techniques, the application of unselective adsorbents has been proven to increase remarkably the removal of plasma solutes accumulated as a result of renal and liver failure. The present technology for appropriately modifying several intrinsic characteristics of the adsorbents - such as chemical nature, particle and pore-size distribution and the surface area offered to adsorption - has helped to fine-tune extracorporeal devices for more defined clinical applications. These properties, together with improved biocompatibility, have allowed the development of adsorptive techniques to obtain clearances and total removal rates of target compound that would be unthinkable with conventional hemodialysis or hemofiltration. Despite several adsorptive techniques already being available commercially for treatment of sepsis/septic shock and acute liver failure, controlled studies with clinical end points are still lacking. In the near future it is expected that a final answer to the question in this article's title will be provided.

Extracorporeal blood purification techniques such as hemofiltration or albumin dialysis can exert a significant, but not easily predictable influence on plasma pharmacokinetics of antimicrobial agents. The effect of albumin dialysis on the pharmacokinetics of liposomal amphotericin B (AMB) and other lipid-formulated drugs has not been investigated so far. Therefore, plasma concentrations of liberated and liposomal AMB were measured in a patient, who obtained liposomal AMB for suspected invasive mycosis and required albumin dialysis because of cholestatic liver failure caused by graft versus host disease after bone marrow transplantation. Liberated and liposomal AMB were separated by solid phase extraction and measured by high performance liquid chromatography. No excessive AMB elimination took place during albumin dialysis. Plasma levels of liposomal AMB exceeded those of liberated AMB. Pharmacokinetic data were comparable to those obtained previously in patients on hemofiltration and in critically ill patients without extracorporeal blood purification.

Mortality in sepsis remains high. Various techniques for extracorporeal cytokine removal have been investigated as additional therapeutic measures in sepsis and septic shock. To summarize a selection of extracorporeal blood purification techniques, with a special focus on therapeutic plasma exchange, and their current evidence in clinical use. Non-systematic literature review. Various extracorporeal blood purification techniques with different levels of evidence regarding cytokine removal, vasopressor sparing effects and reduction of mortality are currently in clinical use. Most extensively studied modalities include high-volume hemofiltration/dialysis with and without high cut-off filters a well as hemoadsorption techniques (including CytoSorb, and polymyxin-B filters). Despite partly encouraging observations regarding removal of inflammatory cytokines and hemodynamic stabilization, results from randomized studies did not show an effect on survival. Due to use of donor plasma as substitution fluid, therapeutic plasma exchange represents the only modality able to additionally replace protective and consumed factors. The use of extracorporeal blood purification methods cannot be recommended for sepsis patients outside of clinical trials given the current lack of evidence of their efficacy. Future investigations should aim to homogenize the studied patient collective in respect to clinical sepsis severity, time point of intervention and different inflammatory (sub-)phenotypes.

Introduction: Extracorporeal blood purification techniques have become a well-established part of routine practice in intensive therapy units. Ensuring appropriate anticoagulation to prevent the clotting of the circuit is the major concern while applying these techniques. Aim: The aim of this paper is to present methods of systemic anticoagulation which are currently used in continuous extracorporeal blood purification techniques. Ma t e r i a l and me thods : This work is based on the available literature and the experience of the authors. Re sul t s and di s cus s ion: The prevention of clotting in the extracorporeal circuit may be achieved through regional or systemic anticoagulation. Systemic anticoagulation is usually achieved by administration of unfractionated heparin. The most common complications include bleeding; additionally, there is a risk of type II thrombocytopenia occurring. Systemic anticoagulation may also be provided through administration of low molecular weight heparins. Some research papers have discussed the use of thrombin antagonists (argatroban, bivalirudin) and heparinoids (danaparoid, fondaparinux), as well as platelet inhibitors as systemic anticoagulants. It is also possible to conduct extracorporeal blood purification without anticoagulation. C o n c l u s i o n s : The introduction of continuous extracorporeal blood purification techniques into everyday practice of intensive care units has brought many unquestioned benefits to the patients treated in this setting. On the other hand, it means that doctors need to show an in-depth knowledge of the anticoagulation methods. Despite the wider use of regional anticoagulation during continuous renal replacement therapy, systemic anticoagulation is still important. This is especially when therapies with high blood flow are performed and contraindications to citrate use are present.

Sepsis is a life-threatening organ failure exacerbated by a maladaptive infection response from the host, and is one of the major causes of mortality in the intensive care unit. In recent decades, several extracorporeal blood purification techniques have been developed to manage sepsis by acting on both the infectious agents themselves and the host immune response. This research aims to summarize recent progress on extracorporeal blood purification technologies applied for sepsis, discuss unanswered questions on renal replacement therapy for septic patients, and present a decision-making strategy for practitioners.