After initial tentative steps with bioincompatible sorbents, hemoadsorption is making a comeback. This has been fueled by improved coating technology and improved sorbent technology. Both have markedly increased the safety, biocompatibility, and efficiency of hemoadsorption. Despite such development and an emerging body of evidence, the research agenda for hemoadsorption is substantial and, in most ways, unfulfilled. In this chapter, we highlight the need for more extensive and sophisticated work to understand the biological effect of hemoadsorption in key areas (especially sepsis). We also explain why more technical research needs to be conducted ex vivo and in large animals to understand the performance characteristics of hemoadsorption sorbent cartridge, including optimal blood flow, optimal anticoagulation, and optimal duration of application. Finally, we focus on the need to develop registries of the use of this technique so that more extensive information can be obtained about current use and real-world performance.
Acute liver failure and acute-on-chronic liver failure are conditions in which the loss of metabolic function of the liver leads to the accumulation of several toxins such as bilirubin. Patients with sepsis or multiple organ dysfunction syndrome have a greater risk of developing liver failure, and hyperbilirubinemia is associated with poor prognosis. Bilirubin removal may not only alleviate signs and symptoms of liver dysfunction but also act as an index of removal of albumin-bound toxins. Conjugated and unconjugated bilirubin, due to their molecular weight and albumin-binding capacity, respectively, cannot be removed by classic dialysis; therefore, different extracorporeal techniques have been developed to remove bilirubin from the blood. Plasma adsorption perfusion is an extracorporeal liver support technique in which bilirubin is removed from the plasma through a specific adsorbing cartridge. Double plasma molecular adsorption system adds a broad-spectrum adsorption column for the removal of inflammatory mediators and antibodies and other medium toxins. Their use in the treatment of hyperbilirubinemia has been established with several emerging data indicating their efficacy when compared to other extracorporeal techniques. However, bilirubin adsorption kinetics has not been sufficiently elucidated, and more studies are needed to improve the quality of treatment in terms of timing and prescriptions.
The history of sorbents is about 2 centuries long. It is important to analyze and report the progress of science in this field, understand how modern hemoadsorption takes place, and appreciate how new devices have been designed and manufactured. It is also important to describe the nature, the structure, and the composition of sorbent materials and characterize the mechanisms of the adsorption process. Progressive improvements have been obtained from the original aluminosilicates and porous carbons with the use of new synthetic polymeric materials. New developments now allow the safe and effective application of sorbents in extracorporeal blood purification techniques and in specific clinical syndromes.
Hemoperfusion (HP) is an extracorporeal blood purification therapy that is used to remove poisons or drugs from the body. This chapter provides a brief overview of the technical aspects and the potential indications and limitations of HP, with the focus being on the use of HP for acute poisoning cases reported from January 1, 2000, to April 30, 2022.
A strong rationale supports the development of adsorption-based extracorporeal blood purification in conditions such as sepsis, acute kidney disease, uremia, and acute liver failure. The retention of compounds as a consequence of acute or chronic organ dysfunction might have detrimental effects. When a causative effect of an accumulated compound in a pathogenic condition is demonstrated, a rationale for the removal of this solute is also established. Adsorption is a mass transfer mechanism in which a solute chemically interacts with the surface of a solid structure (sorbent) and is removed from its solvent (i.e., blood or plasma). Traditional extracorporeal blood purification techniques utilize semipermeable membranes and depend mainly on diffusion and convection as mechanisms of mass transfer. Protein-bound solutes and water-soluble compounds with molecular weight above 25 kDa are scantly removed by either diffusive or convective clearances. In contrast, recently developed resins have demonstrated safety aligned with notable adsorptive capability, which enables the extraction of endotoxins, inflammatory mediators, and uremic toxins. The understanding of the kinetics of these elements and the improvement in patient selection are key factors to propel exploratory and confirmatory trials that ultimately will lead to the expected changes in clinical practice.
Despite recent technical advances in dialysis care over the past decades, the mortality rate of critically ill patients with acute kidney injury (AKI) requiring dialysis and of chronic kidney disease (CKD) remains unacceptably high. Several preclinical studies have increased our knowledge of the principal mechanisms involved in the pathophysiology of AKI and CKD. Additionally, the development of efficient and specific compensatory sorbent systems in renal replacement therapy to remove unwanted compounds has created the possibility to treat renal diseases and their underlying pathological triggers. Recently, several biomedical blood purification materials have been developed to improve the removal of waste and inflammatory compounds, improve the quality of treatment, and reduce the duration of treatment. This chapter is focused on the principal mechanisms involved in AKI and CKD and the current state of the art for blood purification strategies to identify the most feasible solution to reduce immunological dysfunction and waste compound clearance. In this regard, the current literature underlines the high efficacy of polymethyl methacrylate membrane hemofilters to overcome the shortcomings in the efficiency of current methodologies in removing the excess of metabolic waste and inflammatory mediators from blood. The purpose of this chapter is therefore to enhance physicians' knowledge about PMMA.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global emergency outbreak disease that devastatingly affected world public health and the economy. The pathogenesis of severe SARS-CoV-2 infection in humans has been linked to a strong immunological response that leads to a hyperinflammatory state, or "cytokine storm," which is a sepsis-like state resulting in capillary leakage, microvascular and macrovascular thrombosis, and multiple organ destruction. In recent years, there have been several case series and few randomized controlled trials studying the effectiveness and risk of various hemoperfusion techniques in the context of severe SARS-CoV-2 infection including HA330, CytoSorb, Polymyxin, oXiris, and Seraph 100 cartridges. Because inconsistencies exist between studies, there is currently no consensus regarding the use of hemoperfusion in patients with SARS-CoV-2 infection. Further well-designed research is needed to validate its potential clinical benefits and identify the timing and characteristics of patients who might benefit the most.
Sepsis and multiple organ failure (MOF) are characterized by multiple hemodynamic changes and imbalanced immune response of the patient. Oxiris is a highly adsorptive membrane with the ability to remove cytokines and endotoxins, as well as to perform renal replacement therapy. Here we describe the evolution from previous AN69 to the 3-in-1 Oxiris membrane, and review its characteristics and performance. In clinical practice, Oxiris showed consistent effects in mean arterial pressure recovery, a decrease in vasopressor needs, and reduction of the Sequential Organ Failure Assessment score. These results have been reproduced by several independent studies addressing both sepsis and, to a lesser extent, COVID-19 patients. In addition, more recent studies in sepsis showed improvements in MOF duration and the length of stay in the ICU, as well as some promising results regarding mortality. Finally, we review ongoing clinical trials and discuss its potential significance to clinical practice improvement and to further reinforce knowledge on the use of blood purification in sepsis and acute kidney injury.
Liver failure in the intensive care unit (ICU), whether acute or acute-on-chronic, remains a serious condition with reduced functions, various metabolite and toxin accumulation in the systemic circulation, and a high mortality rate. While transplantation remains the treatment of choice, the lack of organ transplants necessitates finding alternative solutions. Within the last years, several therapies aiming to support liver function have been developed in order to serve as a bridge to liver transplantation or as replacement therapy, allowing regeneration of the injured liver. In those therapies, nonbiological extracorporeal liver support devices are the most widely used, mainly based on detoxification by eliminating accumulated toxins notably by adsorption on specific membranes and/or with plasmapheresis. One of the most recent techniques is the double plasma molecular adsorption system combining plasma filtration and two specific adsorption membranes, which is largely described and studied in this chapter. This technique seems promising to remove deleterious toxins, cytokines and bilirubin in particular, is fairly simple to use, does not require a specific machine (it works on continuous renal replacement therapy machines), and has given encouraging results in the pilot studies published recently, in association with plasmapheresis or alone. However, further studies and evaluations are needed before this technique can be used routinely in ICU.
Sepsis is a life-threatening syndrome initiated by a dysregulated host response to infection. Maladaptive inflammatory burst damages host tissues and causes organ dysfunction, the burden of which has been demonstrated as the paramount predictor of worse clinical outcomes. In this setting, septic shock represents the most lethal complication of sepsis and implies profound alterations of both the cardiovascular system and cellular metabolism with consequent high mortality rate. Although an increasing amount of evidence attempts to characterize this clinical condition, the complexity of multiple interconnections between underlying pathophysiological pathways requires further investigations. Accordingly, most therapeutic interventions remain purely supportive and should be integrated in light of the continuous organ cross-talk, in order to match a patient's specific needs. In this context, different organ supports may be combined to replace multiple organ dysfunctions through the application of sequential extracorporeal therapy in sepsis (SETS). In this chapter, we provide an overview of sepsis-induced organ dysfunction, focusing on the pathophysiological pathways that are triggered by endotoxin. Based on the need to apply specific blood purification techniques in specific time windows with different targets, we suggest a sequence of extracorporeal therapies. Accordingly, we reported the hypothesis that sepsis-induced organ dysfunction may benefit the most from SETS. Finally, we point out basic principles of this innovative approach and describe a multifunctional platform that allows SETS, in order to make clinicians aware of this new therapeutic frontier for critically ill patients.
The mechanism of adsorption is regulated by various factors including the nature of the sorbent and the molecules involved in the adsorption process. The design of a device for adsorption therapies must fulfil specific requirements. The device should allow the use of the minimum amount of sorbent material sufficient to achieve safe and effective blood purification therapy. Each component of the device must respond to criteria of safety and function in order to maximize the efficiency of the cartridge. The design should be optimized to enable utilization of all the sorbent surface available for adsorption. The structure and packing of the sorbent particles should allow the even distribution of flow inside the cartridge and the avoidance of channeling phenomena and excessive resistance to flow. All these factors depend on specific governing laws such as the Kozeny-Carman equation and Darcy's law. The system must also consider blood viscosity and possible turbulent flows (Reynolds number). The final manufacturing process of a sorbent unit must also consider the dimensions and the cost, and the final performance after sterilization and storage.
Direct hemoperfusion with the CytoSorb® adsorbent has experienced widespread use in several critical care settings including sepsis and multiorgan failure. The reported conditions of clinical usage and resulting outcomes vary considerably. The aim of the study was to provide an overview on current treatment recommendations based on the available clinical evidence. We performed a literature analysis using PubMed/MEDLINE and ClinicalTrials.gov to identify clinical data describing parameters of clinical usage of CytoSorb® in patients with septic shock (inclusion and exclusion criteria, starting, and dosing of treatment) and their impact on outcome. The literature search terms yielded 146 entries in September 2022, including clinical case reports, case series, and controlled and uncontrolled clinical trials. Five recommendations were identified linking usage parameters with improved outcome. These were (a) early start of treatment within 12-24 h after onset of septic shock, (b) individualized patient selection (preferably with higher severity scores, procalcitonin >3 ng/mL, serum interleukin 6 >500 pg/mL), (c) exclusion of patients with lactate ≥6 mmol/L or platelets <100 GPT/L, (d) intense treatment (>6 L of blood/kg body weight), and (e) early change of the adsorbent (e.g., every 12 h). Moreover, there is a rationale suggesting therapeutic drug monitoring when possible, avoidance of drug application at the beginning of treatment, and/or usage of increased dosages of antibiotics. However, for the later recommendations, no links to clinical outcome were reported yet. All recommendations are based on the best available knowledge. They need confirmation in future clinical investigations. Currently available clinical data on the use of CytoSorb® in septic patients suggest that early and intense treatment in carefully chosen patients increases the chance of survival. The analysis can inform current clinical practice and future clinical trials.
In this chapter, anticoagulation treatments for adsorption techniques in continuous renal replacement therapy (CKRT) will be reviewed. Anticoagulation used with adsorption techniques is quite different than anticoagulation in classical CKRT with nonadsorptive therapies. Regional citrate anticoagulation (RCA) and unfractionated heparin (UFH) are the most common anticoagulation modalities for both nonselective adsorptive membranes - such as surface-treated acrylonitrile 69 membranes (AN69ST) and polymethylmethacrylate membranes - and selective adsorptive membranes such as AN69-oXiris. For these techniques, the efficacy of RCA seems to be superior to UFH. Regardless of the lack of large comparative studies in comparison to ones conducted for adsorptive filter techniques in CKRT, RCA and UFH will also be discussed for nonselective adsorptive sorbents like CytoSorb and Jafron HA. For selective adsorptive sorbents, such as polymyxin-B hemoperfusion, UFH and RCA seems to be the appropriate techniques; however, randomized controlled trials confirming this are yet to be conducted. Lastly, anticoagulation prophylaxis for more specific techniques like coupled plasma filtration adsorption and double plasma molecular adsorption system will be discussed.
Sorbents have been utilized in the past for intoxication and poisoning, but their spectrum of clinical application is now expanding. Hemoadsorption (HA) is still indicated for toxin and poison removal, but other molecules are considered appropriate targets for this blood purification modality. HA combined with hemodialysis (HA + HD) has been proposed for end-stage kidney disease patients to remove molecules that are not easily removed by classic HD or hemodiafiltration. More recently, a rationale for the use of sorbents in critical illness, sepsis, and acute kidney injury has emerged due to the proposed humoral theory behind these disorders. Pathogenetic circulating molecules in critical illness (damage- and pathogen-associated molecular patterns) cannot be sufficiently removed by classic continuous renal replacement therapies. New sorbent-based extracorporeal therapies have therefore been designed to remove these molecules, offering potential biological and clinical benefits. There is also the possibility of employing selective sorbents to target specific molecules or to perform nonspecific HA for a wide spectrum of molecules. Moreover, there is the possibility of separating plasma from blood and then applying adsorption to plasma or of combining HA with other extracorporeal therapies. Here, we describe a complete appraisal of current available techniques utilizing adsorption.
Major trauma care has seen significant improvements in early mortality, reflecting improvements in prehospital techniques for hemorrhage control and speed of access to specialized trauma centers. However, many patients then go on to die in the intensive care unit (ICU), and improvements in immediate trauma care are presenting intensivists with greater numbers of severely injured patients who might previously have died shortly after injury. It is theorized that, despite initial survival, these patients deteriorate due to massive release of damage associated molecular patterns (DAMPs) after traumatic and ischemic tissue injury. These trigger a vicious cycle of overactive pro- and anti-inflammatory pathways, leading to organ dysfunction and immunoparesis. Extracorporeal hemoperfusion, with its ability to adsorb both DAMPs and inflammatory mediators from the bloodstream, has the potential to break this cycle and could, in theory, then prevent early death or organ dysfunction in the ICU. However, currently, there has been little research around the indications for, and efficacy of, this therapy in the setting of polytrauma. Here we outline potential molecular targets, summarize existing exploratory studies, and suggest areas for future research required to establish the benefits of hemoperfusion as an adjunct therapy in major polytrauma.
Recent advances in the development of sorbent materials have enabled the development of hemoperfusion (HP). However, HP dose and prescription are not standardized and there is no consensus in clinical practice guidelines. Adequate prescription and modality are of utmost importance to ensure HP effectiveness. Although the main indication of CytoSorb®, HA330/380, polymyxin B, and Seraph® is sepsis, these devices may be beneficial in many other situations such as liver failure, rhabdomyolysis, pancreatitis, cardiopulmonary bypass, extensive burns, and trauma or to ensure antiplatelet therapy drug removal. They can be applied as stand-alone therapies or combined with renal replacement therapy. The usual prescribed blood flow varies between 100 and 700 mL/min. CytoSorb® sessions usually last 24 h and may be repeated up to 7 days, whereas HA330/380, polymyxin B, and Seraph® sessions usually last between 2 and 4 h and are repeated up to 3 days. Current clinical data are lacking to establish the optimal operating conditions of HP and studies focusing on defining the optimal timing, dose, and duration of these therapies could help define future clinical applications.
With the growing prevalence of acute liver failure or acute-on-chronic liver failure, on the one hand, and the limited supply of liver organs for transplantation, on the other hand, it is critical to the design, validate, and implement devices that can provide extracorporeal liver support (ECLS) as the bridge to transplantation or potentially destination therapies. The number of attempts to generate ECLS devices has resulted in several options with various levels of impact on clinical outcomes. The described ECLS tools could be as simple as devices used for kidney replacement therapies (e.g., continuous kidney replacement therapy) to tools that employ albumin (e.g., Prometheus, single-pass albumin dialysis, or molecular adsorbent recirculating system), fresh frozen plasma (e.g., high-volume plasmapheresis), or hepatocytes (e.g., extracorporeal liver assist device with hepatocytes) to support failing liver functions, that is, metabolic or synthetic functions. This chapter describes the current landscape of ECLS devices and their associated evidence-based data.
Application of extracorporeal blood purification in children is increasing with the improvement of technology and the broadening of indications in critically ill patients. Furthermore, novel devices are being made available with a miniaturized design to be applicable to pediatric machines and circuits. Current literature in the pediatric setting is essentially based on case series and observational studies. Novel prospective uncontrolled databases are underway, and the interest is growing in children, since the potential indications for pediatric sepsis and other inflammatory conditions might rely on the enhanced mediator clearance warranted by these techniques. This review will describe the application of hemadsorption in children, the available cartridges, the clinical results available in the pediatric setting, and the potential future uses.
Leptospirosis is the most common zoonosis frequently seen in the tropics and subtropics especially during the rainy season when humans wade in floods contaminated by the urine of infected rats in urban areas. Aside from direct toxicity of the leptospires, the role of an exuberant immune response to the pathogen leading to secondary organ damage has been recognized. Thus, our treatment protocol for patients with severe leptospirosis characterized by renal failure, acute liver injury, and lung hemorrhage now includes a short course of methylprednisolone and intravenous cyclophosphamide. In some patients, however, hemodynamic collapse and acute respiratory distress syndrome ensue, which may be due to the release of cytokines resulting from the dysregulated immune response. Blood purification in the form of hemoperfusion (HP) with neutral macroporous resin-adsorbing beads adsorbs cytokines and other inflammatory mediators leading to cardiovascular stability and stabilization of endothelial membranes. HP may be considered part of a multiorgan system therapeutic approach in diseases with reversible multiorgan failure that can lead to an improvement in patient survival.
The Jafron series of sorbent cartridges provides a comprehensive array of coated, highly biocompatible sorbent beads made of styrene-divinylbenzene copolymers. Such beads carry a mean diameter of 0.8 mm with a range from 0.60 to 1.18 mm. The maximal pore size of these coated beads and the volume of the cartridge vary according to the type of cartridge ranging between 50 Da and 60 kDa. The sorbents, the size of the cartridge, the volume of sorbent, and the pore size (which reaches 60 kDa with the HA330 cartridge) aim to take advantage of the principles of molecular adsorption in a variety of diseases from uremic toxin retention to poisoning and drug overdose, from kidney disease to liver failure, from acute respiratory distress syndrome to sepsis, from toxic skin injury to COVID-19. The preliminary data from ex vivo studies, animal investigations, and human pilot work look promising and justify a program of systematic investigation of these products to advance our understanding of how they may be incorporated into our therapeutic arsenal.
