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Newly Designed CRRT Membranes for Sepsis and SIRS—A Pragmatic Approach for Bedside Intensivists Summarizing the More Recent Advances: A Systematic Structured Review

Honore, Patrick M.*; Jacobs, Rita*; Joannes-Boyau, Olivier; De Regt, Jouke*; De Waele, Elisabeth*; van Gorp, Viola*; Boer, Willem; Verfaillie, Lies; Spapen, Herbert D.

doi: 10.1097/MAT.0b013e3182816a75
Review

In recent years, after all the attention has been focused on the dose for continuous renal replacement therapy (CRRT) in sepsis and systemic inflammation response syndrome (SIRS), the relatively negative results of all those studies did urge our expectations on new approaches regarding CRRT in sepsis and SIRS. So far, after the failure of the major randomized studies on dose, attention is now drawn to new membranes that could better eliminate massive amounts of unbound mediators in wider spectrum and also in greater magnitude Nevertheless, for septic acute kidney injury, the recommended dose will remain 35 ml/kg/h until the IVOIRE (hIgh VOlume in Intensive Care) study will be published. In this new armamentarium, we have distinguished the first tools that can still be called membranes ranging from AN69 Surface Treated (ST), SEPTEX, polymethylmetacrylate, to Oxiris that can still run with a CRRT device. Polymyxin B is still a kind of membrane although it has a larger surface, but it can run in a hemoperfusion system and is also much more selective. Adsorptive columns and sorbents are not anymore membranes but are seen as cartridges as the surface is extremely huge when compared with that of membranes (more than 500 m2). They can still run in a hemoperfusion device. At the very end, we do have apheresis or selective plasma exchange (also very close to sorbents and columns) but we have very few data up to now regarding sepsis. Regarding spectrum, CytoSorb seems to be very promising although it is not able to capture endotoxin and IL-10. Oxiris is also promising as it can capture endotoxin and cytokines. AN69 ST is very powerful to capture numerous cytokines and especially high-mobility group box 1 protein (a very upstream cytokine). Polymethylmetacrylate has also the power to capture endotoxin and numerous other cytokines probably with a larger magnitude than Oxiris although this is not proven. Lastly, high-porosity membranes (Septex) may play a role especially when used in continuous venovenous hemodialysis mode. At the end, if we look for a more enlarged spectrum and a higher magnitude, CytoSorb might be seen as the most promising although not having the ability to fix endotoxin. Future studies will tell us which membrane or sorbent will be most useful in the adjunctive treatment for sepsis.

From the *Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium; Haut Leveque University Hospital of Bordeaux, University of Bordeaux 2, Pessac, France; and Department of Anaesthesiology and Critical Care Medicine, Ziekenhuis Oost-Limburg, Genk, Belgium.

Disclosure: The authors have no conflicts of interest to report.

Reprint Requests: Patrick Honoré, MD, PhD, Intensivist-Nephrologist, Head of Clinics, ICU Department, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, 101 Laarbeeklaan, 1090 Jette, Belgium. Email: Patrick.Honore@uzbrussel.be or Pathonor@skynet.be.

In recent years, after all the attention has been focused on the dose of continuous renal replacement therapy (CRRT) in sepsis and systemic inflammation response syndrome (SIRS), the relatively negative results of all those studies did urge the expectations on new approaches regarding CRRT in sepsis and SIRS.1,2 So, the manufacturers launched different types of new membranes. The first type was dedicated to sepsis and SIRS and do comprise high cutoff (HCO) membranes,3 high nonselective adsorptive membranes,4 and high semiselective membranes5 (especially those capturing endotoxin). Although these membranes were orientated to fight the issue of inflammation, they can also be used in pure CRRT. Another direction was also given recently whereby a modified membrane coated with antibiotics (polymyxin B [PMX])6 can adsorb endotoxin almost selectively using the hemoperfusion technique but cannot anymore run in a pure CRRT device. This therapy is called PMX therapy. In this systematic review, we explore the literature from 1997 up to 2012 using PubMed database by using appropriate keywords. Also, in this review, we will touch on heparin-soaking membranes whereas the heparin is passively or actively adsorbed onto the membranes after manufacturing.7 Although this type of membranes can adsorb better mediators, their role seems more devoted to the use of these membranes under conditions when no anticoagulation can be given. This review will better address new types of membranes structured in a cartridge that are called sorbents nowadays that can be unselective or also quite selective.7

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New Membranes Designated for Sepsis and SIRS: High Cutoff CRRT Membranes

Although numerous animal trials did show the potential of HCO membranes, everything really starts after the realization of this important trial.3 Indeed, this pilot trial studied the performance of HCO membranes in septic patients with acute kidney injury (AKI). Thirty patients were randomized to treatment with either an HCO membrane (60 kDa/P2SH Gambro) or with a classic cutoff membrane (35 kDa/Polyflux 11S). Although 20 patients were initially randomized in the treated group, two patients died early on during the therapy and only 18 patients could be really assessed in the analysis. In the HCO group, a significant reduction in noradrenaline dose (p = 0.0002) and a 10-fold increase (p = 0.0001) in clearance of interleukin (IL)-6 and IL-Ra were observed when compared with the classic membrane group. The preliminary results of the recently completed High Cut-Off Sepsis (HICOSS) study were presented at the 10th World Federation of Societies of Intensive and Critical Care Meeting in Florence (2009). These results were encouraging in safety but not in efficiency.8,9 Indeed, this study randomized 120 patients with septic shock and AKI to either a conventional membrane or an HCO membrane (cutoff of 60 kDa). Patients were treated for five consecutive days in a continuous venovenous hemodialysis (CVVHD) mode. The study was stopped prematurely after enrolment of only 81 patients because of a lack of difference in the 28 day mortality (31% for the HCO group and 33% for the conventional group). No difference was seen in vasopressor need, duration of mechanical ventilation, or duration of ICU stay. No difference in albumin levels was founded between the two groups, suggesting that the HCO membrane is safe for clinical use. It should be emphasized that the study was performed using CVVHD, thus precluding the observation of synergy between high-volume hemofiltration (HVHF) and high-permeability hemofiltration (HPHF) as shown by other trials.10 The CVVH mode, however, seems to be efficient for removal of mediators and cytokines. Indeed, in an ex vivo study,11 blood from healthy volunteers was spiked with endotoxin and then exposed to a 100 kDa HCO filter at a dose of 16.6 ml/kg/h or to the same filter at a dose of 80 ml/kg/h. Clearance of cytokines was nearly 10-fold higher (statistically significant) in the mixed HCO and HVHF group demonstrating synergy between HVHF and HPHF. The future of HCO membranes in sepsis, despite the recent negative study (HICOSS), could still be of interest as potential synergies could be founded by mixing HVHF and HPHF together, and also by combining HCO with highly adsorptive membranes. (Currently, a new protocol is being put together to start a new study in the near future. Of course, this study will not run anymore in CVVHDF mode but in CVVH mode this time. [Among investigators, we can find previous investigators from the HICOSS study, some members of the steering committee, and several senior scientists and experts in the field.]) Therefore, studies should go on with combinations of techniques that can be called today as hybrid therapies.12 Very recent reports have been encouraging especially in nontraumatic and traumatic rhabdomyolysis in ICU patients where HCO membranes showed the ability to eliminate myoglobin and derivatives more effectively.12–15 Those preliminary results need to be confirmed by large randomized trials. So, the take home message for the clinician should be that HCO membranes are still in the experimental phase but could represent a major revolutionary step in nontraumatic and traumatic rhabdomyolysis, not only in ICU patients but also in patients with septic shock perhaps in synergy with a CVVH mode with a minimal dose of 35 ml/kg/h. Most of the generated data up to date have been realized using the septex membrane which has a cutoff of approximately 60,000 Da and is quiet homogenous. This high homogeneity can explain why this membrane is safe in albumin losses.8,9 These preliminary conclusions should be confirmed or infirmed in more sophisticated studies in design in the near future.

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New Membranes Designated for Sepsis and SIRS: High Nonselective Adsorptive CRRT Membranes

Polyacrylonitrile and AN69 Surface Treated

The process of adsorption has been already widely used in chronic dialysis especially with beta-2 microglobulin.16 Indeed, adsorption is another physicochemical principle allowing the so called catching of some molecules (mediators, cytokines, antibiotics, and proteins) in the CRRT membrane itself after the interaction with variable polarity ionic charges. Continuous renal replacement therapy membranes do exhibit variable adsorption properties depending on the composition of the membrane. Membranes getting important adsorption properties would be able to remove not only additional molecules from blood circulation but also molecules with molecular weight beyond the membrane cutoff, and this is the most important effect that we are looking for.17,18 This property can be particularly attractive knowing the large scale of pro- and anti-inflammatory mediators’ molecular weights, ranging from 0.5 to 60 kDa. Concerning the CRRT membrane composition, the experimental study of Rogiers and coworkers,19 conducted in an acute canine endotoxic shock model, has mentioned a transient hemodynamic superiority effect of polyacrylonitrile compared with polysulfone, which was explained by a more effective adsorption of inflammatory mediators. Recently, manufacturers of polyacrylonitrile have launched a new more adsorptive membrane called AN69 ST (ST for surface treatment).5 This surface treatment consists of the grafting of a second layer with polyethyleneimine and a third layer consisting of heparin coated during manufacturing. This membrane AN69 ST is very different from the AN69 Oxiris. Indeed, the surface treatment does consist of the grafting of a second layer with polyethyleneimine but this time at a concentration three times lower (this low concentration of polyethyleneimine does not allow the surface adsorption of endotoxin). The second layer allows the construction of a third layer consisting of heparin coated during membrane soaking. Therefore, the heparin is present at a concentration 10 times lesser (than AN69 Oxiris) and is not biologically active. This new membrane also has a greater bulk adsorption capacity when compared with older polyacrylonitrile membranes.5 The adsorption properties of the polyacrylonitrile membrane have been enhanced by a surface treatment modifying the membrane surface polarity. This new design permits to adsorb not only antibiotics such as aminoglycosides, vancomycin, and several others but also lactate. An additional effect of this AN69 ST is to very effectively adsorb high-mobility group box 1 protein (HMGB-1) as shown by recent studies in Japan.4 High-mobility group box 1 protein is a very upstream mediator stimulated by endotoxin and liberated by macrophages. It can then activate the production of a bunch of cytokines. The molecular weight is around 30 kDa and therefore is not eliminated through filtration and even not by HCO CRRT as shown by this recent Japanese study.4 This finding might be seen as a crucial one in the ability of CRRT to interact with sepsis and SIRS more upstream as before. Nevertheless, this preliminary report is looking at ex vivo data and we should remain prudent. Anyhow, a very recent prospective randomized study on clinical sepsis was able to elicit some relationship between the elimination of HMGB-1 and clinical improvements.20 Nonetheless, future large randomized trials will be eagerly needed to confirm this relationship. So far, relatively small clinical trials are underway mostly in Japan (also in Europe) evaluating in a randomized fashion, the ability to fix HMGB-1 and the related clinical improvements between AN69 ST and a control membrane. The control membrane is polymethylmetacrylate (PMMA) in Japan and polyethersulphone (PAES) in Europe. These studies are essentially mechanistic by nature and do not have the power to detect mortality or surrogate. One study shall be done by our group which shall randomize 40 septic patients with AKI requiring CRRT into two groups. One group will be running CRRT with the AN69 ST and the other one, the control group, will be with PAES. The primary end-point shall be hemodynamics during the first 96 hours (duration of the experimental therapy). Secondary end-points shall include ICU length of stay, free dialysis days when reaching 28 and 90 days, free ventilatory days when reaching 28 and 90 days, and free pressors days also when reaching 28 and 90 days. Results are awaited in around 18 months time. Finally, knowing that adsorption is a very short-term way for inflammatory mediators removal because of rapid membrane saturation, it seems to be very important to optimize this mechanism as best as possible. Because the smaller the membrane, the faster the saturation occurs, the membrane surface area needs to be as important as possible (at least 1.5 m2).21,22 Nevertheless, as this membrane can also adsorb in the bulk and not only via the surface, saturation will occur more lately and perhaps only for some mediators after 12 hours. In addition, to take advantage of the adsorption properties of a CRRT membrane, it is recommended to regularly change the membrane because of relatively rapid membrane saturation. These frequent membrane changes can be a source of difficulties in medical clinical practice by significantly increasing the cost and the nursing workload of the CRRT sessions.23 On the contrary, frequent changes allow us to avoid processes of deadsorption, which can occur when devices with adsorption properties are used continuously. More experimental and clinical work has to be done to determine how long this treated membrane should be used in clinical practice without any change and to find the best arrangement between frequently changing the membrane and financial considerations. For example, one of the possible answers could be the consideration of those frequent changes only for the very early phase of septic shock, when serum endotoxin and cytokine levels are very important. Nevertheless, again with bulk adsorption, the risk of deadsorption is much more limited as well.

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Polymethylmethacrylate and Other Related Types

Other types of membranes such as PMMA and indeed, Nakada et al.24 found that PMMA CVVH exhibited a higher capacity to remove cytokines than using a hemofilter made of a different material. This high capacity of PMMA CVVH for cytokine removal was principally ascribable to the adsorption of cytokines to the hemofilter membrane.25 Some studies (as for AN69 ST) also described a significant decrease in blood lactate level during PMMA CVVH.24 It has been shown that PMMA has a larger potential to adsorb mediators up to 65,000 Da.24 On the contrary, the PMMA membrane had half of the adsorption capacity of the AN69 ST membrane regarding HMGB-1.4 Indeed, among the four membranes studied, surface-treated polyacrylonitrile (AN69 ST) showed the highest capacity to adsorb HMGB-1. It adsorbed nearly 100 µg of HMGB-1 in the initial 60 min and showed a markedly high clearance rate (60.8 ± 5.0 ml/min) at 15 min.4 The take home message for the clinician should be that new high nonselective adsorptive membranes such as AN69 ST, PMMA, and some others could potentially revolutionize our approach of septic shock because indeed, these membranes can adsorb not only large mediators but also new key upstream mediators and in a much larger quantity because bulk adsorption is also a major mechanism that comes into play. Saturation will occur much slowly and deadsorption is nearly negligible. With these new membranes, adsorption of excess mediators during septic shock is not a theoretical possibility anymore but looks as a plausible therapeutic approach as an adjunctive treatment in patients with septic shock, however, we are awaiting for large randomized studies to occur.

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New Membranes Dedicated for Sepsis and SIRS: High Selective Adsorptive CRRT Membranes

Polyacrylonitrile and AN69 Oxiris

Recent development of AN69 Oxiris membranes this time with three layers has led to the capability of this membrane to selectively adsorb endotoxin. Indeed, a full scale of new-generation membranes has emerged that focuses on endotoxin adsorption (Toraymyxin [Toray] or Oxiris [Gambro]) or on specific immunoadsorption (Prosorba [Fresenius]). Preliminary results are promising,26 and future large randomized controlled trials are being prepared.27 Toramyxin is obviously not a CRRT membrane but a membrane that can be used in hemoperfusion, and this will be described in another paragraph. Prosorba is a kind of sorbent used in apheresis, and this will also be discussed in another paragraph.28 Regarding AN69 Oxiris when compared with AN69 ST, the surface treatment does consist of the grafting of a second layer with polyethyleneimine but this time at a concentration three times higher (and thus biologically active and able to adsorb onto the surface endotoxin). This second layer allows for the construction of a third layer consisting of heparin grafted during manufacturing. Therefore, the heparin is present at a concentration 10 times greater (as opposed to AN69 ST) and is biologically active. This new feature does allow the selective binding of endotoxin via the polyethyleneimine layer.29 This new membrane also has a greater bulk adsorption capacity when compared with older polyacrylonitrile membranes in the same line of AN69 ST. In a recent investigation, Rimmelé et al.29 showed that indeed, adsorption properties of AN69 Oxiris have been enhanced by a surface treatment modifying the membrane surface polarity (addition of a polycation which is a positive charge allowing the catching via surface adsorption of endotoxins that are considered as negative charges). Therefore, this membrane can strongly adsorb endotoxins and inflammatory mediators in vitro. In a porcine model of septic shock, the use of the AN69 Oxiris membrane during a 6 hour HVHF session decreased the clinical and biological severity of the shock obtained compared with the use of a standard hemofiltration membrane (AN69). This was objectivized by a reduction in the amount of clinical intervention necessary to sustain the desired MAP and PCWP levels. Fluid expansion requirement, lactic acidosis, and pulmonary arterial hypertension were less pronounced in the treated membrane group than in the AN69 group at the end of the experiment. So far, we have not had comparable studies on human septic shock regarding this AN69 Oxiris membrane. Semantically, membrane selectivity has to be defined with regard to a specific membrane layer. Indeed, surface adsorption is purely selective on endotoxin because of the specific configuration of the membrane. Conversely, the bulk adsorption is nonselective and can adsorb numerous mediators unselectively.

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Polymethylmethacrylate and Other Related Types

Although not promoted as such (by Toray) because of a concurrent product (Toraymycin), PMMA has been shown to adsorb endotoxin very effectively perhaps as much as AN69 Oxiris.30 This membrane is also well-known for a series of serendipity. Among those, long-term follow-up of patients dialyzed using the membrane revealed that plasma BMG (beta-2 microglobulin) levels were significantly low and that the occurrence ratio of carpal tunnel syndrome was suppressed.31 These results were obtained by the adsorptive removal of BMG onto a PMMA membrane. Recently, new aspects in succession mainly based on clinical experiences that were not aimed at a development stage, that is, they were kinds of serendipity. For the membrane with the largest pore size, this includes removal of furancarboxylic acid, homocysteine, pentosidine, and soluble CD40.31 CD40 is a cell surface protein belonging to the tumor necrosis factor (TNF) receptor family. For the membrane with a slightly anionic component, this includes the removal of free immunoglobulin light chains.31 As one can see, PMMA is able to tackle the sepsis cascade upstream (lipopolysaccharide) and further down (soluble CD40 and various cytokines). This ability will be evaluated at some stage to see whether this membrane can be able to fight the sepsis network effectively.30,31

Lack of human data remains a major issue for AN69 Oxiris, whereas we do have human data for PMMA. Indeed, so far we have used ex vivo and animal data and we are eagerly awaiting human data. Before embarking on large randomized trials, mechanistic studies are urgently needed. Therefore, a small randomized study has been put together evaluating 30 patients with septic shock randomly assigned into two groups. One group will be treated with CRRT together with the AN69 Oxiris membrane and the control group will be treated with CRRT and a classical AN69. The results of this study will be available in around 18 months. Investigators will be Europeans (from France, Belgium, Switzerland, Italy, and Spain) who are very well used to measure endotoxin at the bedside on a daily basis. The target population shall be patients with septic shock after surgery for peritonitis who exhibit a higher likelihood of liberating high levels of endotoxin, that is, those patients in an early phase of septic shock before entering into AKI. Thus, the technique shall be used as a true blood purification technique and not a classical CRRT approach. As opposed to both newly developed AN69 ST and AN69 Oxiris, regarding PMMA membranes, human data have been largely accumulated over the recent years. In a recent cohort study, evaluating 43 patients with septic shock exhibiting hypercytokinemia (via IL-6 monitoring), the early initiation of CRRT using PMMA membranes was associated with improvement of hemodynamics and reduction of organ failure. It was concluded from this study that CRRT using PMMA could improve hypercytokinemia, dysoxia, and the level of organ failure.24,32 Taking all together and especially in view of the weak design (cohort study), those preliminary findings have to be further challenged in large randomized studies. A tentative table (Table 1) has been put together to summarize the ongoing trials, recently completed, and projects that are close to be launched but not yet. We want to emphasize that this tentative table is not based on published data and may therefore carry some imprecisions linked to this type of exercise. The table is obviously incomplete because not all the scientists who were contacted replied to our specific demand. We did try our best in contacting most of the physicians and manufacturers that we knew about to start with this type of investigation. This type of extensive contact is obviously required when doing a systematic review. We might have also missed to include some investigators especially with lack of time.

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New Membranes Dedicated for Sepsis and SIRS: High Selective Adsorptive Hemoperfusion Membranes Including PMX Therapy

Numerous studies on PMX therapy have confirmed the preliminary results also underlined in the recent meta-analysis33 regarding positive effects on hemodynamics during the course of septic shock. Cantaluppi et al.34 investigated in 2007, the effects of PMX therapy on the prevention of AKI during septic shock. In this study, 16 patients with gram-negative sepsis were randomly divided into two groups having standard treatment versus standard treatment plus PMX therapy. The plasma was collected in both groups and then incubated with renal tubular cells and glomerular podocytes.34 Cantaluppi et al.34 demonstrated that the use of PMX therapy was able to reduce the proapoptotic activity of septic plasma on renal tubular cells and glomerular podocytes. Sepsis can directly induce AKI without the need of hemodynamic instability. This effect was mainly modulated by Fas upregulation and caspases cascade modulation.34 The Early Use of Polymyxin B Hemoperfusion in Abdominal Sepsis (EUPHAS) study was recently published and was relatively unique as it was targeting a population that was likely to exhibit high circulating levels of endotoxin and in whom the source of sepsis was definitely cured by initial surgery.6 Sixty-four patients with surgical sepsis were randomly assigned to receive either standard treatment or standard treatment plus two sessions of PMX therapy. Aside from beneficial hemodynamic effects, this study was able to show a significant improvement in the Sequential Organ Failure Assessment (SOFA) score and in 28 day mortality as well with a significant p value when the level of sickness was adjusted to initial SOFA score which further adds fuel to the ongoing debate on the statistical evaluation of mortality in this specific study.35 New larger ongoing multicentric studies will tell us whether those preliminary findings could be confirmed or not. It is interesting enough that the population targeted by this therapy exhibited high levels of endotoxin and therefore tackled sepsis before the occurrence of AKI thus rendering the use of CRRT as support therapy, which is useful in blood purification techniques, such as PMX therapy. Nonetheless, there should be some overlap and therefore, the use of this therapy in early stage of AKI does still make sense. Solid organ transplants in patients with sepsis were also studied using this technique but this time using three sessions and this technique did show positive hemodynamic improvements.36 Mortality was not assessed.

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New Sorbents Dedicated for Sepsis and SIRS: Cytokine-Adsorbing Columns

Cytokine-Adsorbing Columns Such as CytoSorb and Related Using Columns

Cytokine-adsorbing columns, such as CytoSorb, CYT-860-DHP, Lixelle, CTR-001, and MPCF-X, the structures of which vary significantly, have excellent adsorption rates for inflammatory cytokines, such as TNF-alpha, IL-1 beta, IL-6, and IL-8.37 Many studies have demonstrated that treatment with cytokine-adsorbing columns has beneficial effects on the survival rate and inflammatory responses in animal septic models. Moreover, several cases have been reported in which treatment with cytokine-adsorbing columns is very effective in hemodynamics and organ failures in critically ill patients. Although further investigations and clinical trials are needed, in the future, cytokine-adsorbing columns may play a major role in the treatment of hypercytokinemia, such as multiple organ failure and acute respiratory distress syndrome. So far, the most interesting part of these cytokine-adsorbing columns is the enormous surface (8,500 m2) when compared with that of classical CRRT membranes (1.5 m2).38 For instance, the most known CytoSorbs comprises porous, adsorbent polymer beads that target molecules up to 50,000 Da, such as pro- and anti-inflammatory cytokines, that is, IL-1, IL-6, TNF, and IL-10, which are associated with sepsis. These cytokines are believed to be largely untouched by current blood purification techniques, including state-of-the-art hemofiltration technology. This adsorbent polymer bead technology has a porous surface and uses size selectivity for filtering toxins from blood and physiologic fluids. These polymer beads are slightly larger than a grain of salt and are highly compatible with blood. The beads contain pores that are large enough to allow toxins to enter the beads and adhere to the bead through hydrophobic interactions with the neutral lipophilic surface of the polymer while allowing large essential blood proteins to pass around the beads through the filter, back into the patient. CytoSorb cartridge contains 10 g of polystyrene divinylbenzene copolymer beads with a biocompatible polyvinylpyrrolidone coating. Each bed is 300–800 μm in size, and each gram of material has a surface of 850 m2.38 In this small table modified from Taniguchi,37 we have summarized the most important differences between the various cytokine-adsorbing columns (Table 2).

The most studied is obviously the CytoSorb which was initially mostly studied in animals and which showed enormous capacities of reducing within 2 hours 50% of the cytokines37–39 and in some cases, even nearly 80% of the circulating cytokines. This is obviously almost impossible to reach with HCO or even high adsorptive membranes.37–39 So far, the only known human study evaluating CytoSorb has been completed in Germany this year.40 In this study, 43 patients were electronically randomized to either standard treatment or to on-top CytoSorb therapy for a 6 hour period for 7 days. The results show significant reduction of IL-1, MCP-1, IL-1ra, and IL-8. So far, no IL-10 was significantly reduced. Twenty-eight day mortality was also significantly reduced with a p value of 0.03. This is obviously a pilot study, and we should remain very prudent.40 One of the biggest disadvantage is obviously the fact that CytoSorb cannot adsorb endotoxin.39 CYT-860-DHP has the possibility to adsorb endotoxin and exotoxins.41

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Other Sorbents Using an Apheresis System Such as Prosorba

Prosorba column works as a selective plasma exchange and is thus very different from a classical unselective plasma exchange.42 Protein A, a major cell wall component of Staphylococcus aureus, binds human immunoglobulin G (Ig) with high affinity. In Prosorba columns, protein A is covalently bound to a silica matrix and is used to purify the patient’s plasma. Cells and plasma are separated with a continuous cell separator; a total of 1,250 ml of plasma is passed through a Prosorba column. Treated plasma is then reconstituted with cells and returned to the patient. This procedure, initially approved to treat idiopathic thrombocytopenic purpura, was then tried to treat rheumatoid arthritis (RA).43 On the basis of this study, in March 1999 the FDA approved Prosorba immunoadsorption columns for the treatment of moderate to severe RA. There are a few reports in the literature regarding the use of apheresis in sepsis.44 How Prosorba column adsorption may cause improvement in patients with RA and sepsis is still unknown. It unlikely results from the direct removal of IgG because no significant modifications of Ig, rheumatoid factor, or CIC levels were observed throughout the 12 weekly treatments.43 The column removes at most 1.5% of circulating Ig.43 Additional factors, such as complement activation or production of anti-idiotype antibodies, may contribute to clinical improvement.45 Recently, Suda and coworkers46 were able to develop a new sorbent type that could specifically adsorb HMGB-1.

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Current Status and Recent Advances Regarding Blood–Membrane Interactions

Biocompatibilities during blood purification therapy remain a complex issue. Indeed, biocompatibilities are often associated with not only materials to be used but also sterilization method, eluted substance, medical agents such as anticoagulant, and in some cases, even contamination. It has effects on cellular pathways such as leukocyte and platelet and on humoral pathways such as complement system, coagulation and fibrinolysis system, kallikrein-kinin system, and cytokines.18 Regarding intermittent hemodialysis, biocompatibilities during blood purification therapy are not just a prognostic factor for patients on dialysis but also a contributory factor for long-term complications, such as immunodeficiency, cardiovascular disease, and dialysis-related amyloidosis.18,47 For critically ill patients, this effect is not so well described but has merely been evaluated during bypass surgery and was clearly associated with postpump syndrome, including remote organ damages with acute respiratory distress syndrome and AKI.48 The material of the dialyzer is roughly classified into cellulose type such as cellulose triacetate and synthetic type, including polyethersulfone (PES), polyacrylonitrile (PAN/AN69), PMMA, and ethylene vinyl alcohol membrane. The use of highly biocompatible membranes (PES, PMMA, and PAN) has surely decreased the risk of membrane interaction leading to the activation of many humoral pathways. Recently, new forms of AN69 (AN69 ST and AN69 Oxiris) do not anymore induce a bradykinin syndrome when in the presence of angiotensin-converting enzyme inhibitors.49 Nevertheless, we are lacking large randomized studies looking at this issue as it has been already done in chronic dialysis patients.18,47

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Conclusions

So far, after the failure of the major randomized studies on dose, attention is now drawn to new membranes that could better in wide spectrum and also could eliminate massive amounts of unbound mediators in great magnitude.1,2,50 Nevertheless, for septic AKI, the recommended dose will remain 35 ml/kg/h until the IVOIRE (hIgh VOlume in Intensive Care) study will be published.51,52 In this new armamentarium, we have distinguished the first tools that can still be called membranes, ranging from AN69 ST, SEPTEX, PMMA, to Oxiris that can still run with a CRRT device.53 Polymyxin B is still a kind of membrane although it has a large surface, but it can run in a hemoperfusion system and is also much more selective.54 Adsorptive columns and sorbents are not anymore membranes but are seen as cartridges because the surface is extremely huge when compared with membranes (more than 500 m2).55 They can still run with an hemoperfusion device. At the very end, we do have apheresis or selective plasma exchange (also closer to sorbents and columns) but we do have very few data up to now regarding sepsis. Regarding spectrum, CytoSorb seems to be very promising although it is not able to capture endotoxin and IL-10.39 Oxiris is also promising as it can capture endotoxin and cytokines. AN69 ST is very powerful to capture numerous cytokines and especially HMGB-1 (a very upstream cytokine).4 Polymethylmetacrylate also has the power to capture endotoxin and numerous other cytokines probably with a larger magnitude than Oxiris although this is not proven.56 Lastly, high-porosity membranes (Septex) may play a role especially when used in CVVH mode.11 At the end, if we look for the more enlarged spectrum and the higher magnitude, CytoSorb might be seen as the most promising although not having the ability to fix endotoxin. The future will tell us which membrane or which sorbent will be the most useful in adjunctive treatment in patients with sepsis.

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References

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sepsis; acute kidney injury; hemofiltration; SIRS; septic shock; sepsis; membranes; ICU; dialysis; adsorption; sorbents; review

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