Blood Purification Techniques for Sepsis and Septic AKI

Blood Purification Techniques for Sepsis and Septic AKI Thibaut Girardot, MD *,† Antoine Schneider, MD, PhD ‡ and Thomas Rimmele
, MD, PhD*,† Summary: Sepsis is the primary cause of acute kidney injury in critically ill patients. During the past decades, several extracorporeal blood purification techniques have been developed for sepsis and sepsis-induced acute kidney injury management. These therapies could act on both the infectious agent itself and the host immune response. In this article, we review the available literature discussing the different extracorporeal blood purification techniques, including high-volume hemofiltration, cascade hemofiltration, hemoperfusion, coupled plasma filtration adsorption, plasma exchange, and specific optimized renal replacement therapy membranes. Semin Nephrol 39:505−514 Ó 2019 Published by Elsevier Inc. Keywords: Acute kidney injury, adsorption, blood purification, hemoperfusion, renal replacement therapy, sepsis

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eptic shock represents approximatively 15% of intensive care unit (ICU) admissions and its incidence is increasing.1 It is the leading cause of death in the ICU.2 Despite recent advances in intensive care and the release of international recommendations, mortality related to sepsis is still very high, reaching 40% at day 28 in case of septic shock.1,3 Septic shock management combines symptomatic support of organ dysfunction, early and adapted antimicrobial therapy, and source control whenever possible. Severe inflammatory conditions, such as septic shock, are characterized by marked immune alterations. The host systemic inflammatory response to sepsis, although necessary, can become deleterious if excessive or unbalanced. The new definition of sepsis, a dysregulated host response to an infectious process, is in line with this concept.4 Intense anti-inflammatory cytokine production, namely interleukin (IL)10,5 endotoxin tolerance (ie, incapacity to produce tumor necrosis factor-a [TNF-a] after a new exposure to *Anesthesiology and Intensive Care Medicine, Edouard Herriot Hospital, Lyon, France yEA 7426 PI3 (Pathophysiology of Injury‑Induced Immunosuppression), Claude Bernard University Lyon 1, Biom
erieux, Hospices Civils de Lyon, Lyon, France zIntensive Care Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland Financial support: none. Conflict of interest statement: Thomas Rimmel
e has received speaker and consulting honoraria from Fresenius Medical Care, Baxter Healthcare Corp, Biom
erieux, Medtronic, Nikkiso, and B. Braun, and is the principal investigator of the Endotoxin and Cytokines Removal during continuous hemofiltration with oXiris trial (NCT 03426943); and Antoine Schneider has received a grant from the Leenaards Foundation, speaker honoraria from Fresenius Medical Care and Baxter Healthcare Corp, and consulting honoraria from B. Braun Melsungen AG, and is the principal investigator of the Cytokine Clearance With Cytoabsorbant Device During Cardiac Bypass trial (NCT02775123). Address reprint requests to Thomas Rimmel
e, MD, PhD, Service eanimation, H^ opital Edouard Herriot, 5 Place d’Anesth
esie‑R
d’Arsonval, 69003 Lyon, France. E-mail: [email protected] 0270-9295/ - see front matter © 2019 Published by Elsevier Inc. https://doi.org/10.1016/j.semnephrol.2019.06.010

Seminars in Nephrology, Vol 39, No 5, September 2019, pp 505−514

endotoxin),6 and, finally, immunoparalysis resulting from prolonged release of inflammatory mediators, are some examples of these immune alterations.7 Most sepsisinduced deaths occur during this secondary phase of immune incompetence, mainly owing to health care −associated infections or viral reactivations.8 Adjuvant therapies have been developed to modulate the complex immuno-inflammatory process triggered by sepsis. The effect of hydrocortisone on survival from septic shock still is debated.9,10 The most promising molecules to date seem to be recombinant human IL7 and granulocyte-macrophage colony-stimulating factor.11-14 These therapies could limit sepsis-induced immunoparalysis, thus avoiding secondary infectious complications, which are responsible for an important part of sepsisassociated mortality.8,15 Thanks to technological advances on membranes and extracorporeal circuits, some therapies also have been developed to induce nonspecific modulation of the uncontrolled immunoinflammatory process observed during septic shock. Some have been well studied, however, others currently are under investigation. These techniques rely on the concept of “blood purification.”16 They could interfere with proinflammatory and antiinflammatory mediators, with the infectious agent itself or its components, or both.17,18 This review presents the pathophysiological theories underlying the blood purification concept and discusses the available literature assessing these therapies.

EXTRACORPOREAL BLOOD PURIFICATION TECHNIQUES: RATIONALE Several theories have been proposed to explain the potential positive effects of blood purification techniques. First, Ronco et al19 proposed the “cytokine peak hypothesis”: blood purification decreases proinflammatory and anti-inflammatory molecules’ plasmatic concentrations during early sepsis, avoiding a “toxic threshold” to be reached, and thus limiting organ dysfunctions (Fig. 1). Blood purification also could involve 505

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Figure 1. Cytokine peaks model hypothesis.

the pathogen agent itself, or one of its components such as the endotoxin.18 Indeed, infusion of ultrafiltrate obtained from infected animals to healthy ones led to death, suggesting the transmission of either the infectious agent itself or some cytokines that induced fatal organ dysfunctions.20 Later, Honor
e and Matson21 suggested that cytokine removal from the blood compartment would mobilize cytokines from the tissues via concentration equalization. Cytokine removal from tissues could limit their local deleterious effects. This theory was named the “threshold immunomodulation hypothesis”. More recently, the “cytokinetic model” proposed that decreasing cytokine blood concentration would restore an appropriate cytokine gradient between blood and infected tissues, thus promoting leukocyte chemotaxis16 (Fig. 2). Finally, a cellular theory suggested that complex interactions could occur between the adsorbing material or the hemofilter and immune

cells. For example, expression of surface molecules, involved in leukocyte adhesion and migration, antigen presentation, and apoptosis, may be modulated by various blood purification techniques.22-24 Some immune cells (namely monocytes and neutrophils) also can be adsorbed on the blood purification device, thus participating in the immune modulation.25 Hence, blood purification mechanisms of action are not completely understood yet, justifying further experimental research. Moreover, the optimal initiation timing and duration of extracorporeal blood purification for septic shock have not been determined to date. Recent advances in ICU patient immune monitoring probably will help to answer those questions within the next decade. The best biomarker(s) to describe sepsis-associated immune alterations, to choose a therapeutic strategy, and monitor its efficacy still are unknown.26 Our team recently conducted the REAnimation Low Immune

Figure 2. Cytokinetic model hypothesis.

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Status Markers study with the goal to help answer these questions, not only during sepsis but also in case of other severe inflammatory states such as severe trauma, burns, and major surgeries.27 Results will be available in the upcoming years.

AVAILABLE EXTRACORPOREAL BLOOD PURIFICATION TECHNIQUES High-Volume Hemofiltration High-volume hemofiltration (HVHF) is a modification of continuous renal replacement therapy (RRT) in hemofiltration mode. In HVHF, ultrafiltration flow is set to a much higher value (ie, >50 mL/kg/h) than that recommended for standard renal support for acute kidney injury (AKI).28 High ultrafiltration flow enhances middle molecular weight (500 Da to 60 kDa) hydrophilic molecule clearance.29 The first encouraging results were obtained in the 1990s when studying cardiac function of septic pigs.30 Later, in an experimental porcine model of acute pancreatitis complicated with sepsis, HVHF improved hemodynamic parameters, 60-hour survival, and immunoparalysis. The magnitude of these beneficial effects correlated with higher ultrafiltration flow and frequent hemofilter changes.31,32 In human beings, numerous studies have shown hemodynamic33,34 and respiratory35 improvement, as well as lower-than-expected mortality.35-38 However, the hIgh VOlume in Intensive care randomized controlled (IVOIRE) trial compared ultrafiltration flow rates of 35 and 70 mL/kg/h during a 96-hour period in 140 early septic shock patients with AKI and did not show any difference on mortality at days 28, 60, or 90. HVHF also failed to improve secondary outcomes (ventilator-, RRT-, and vasopressor-free days; length of stay; hemodynamic and standard biologic parameters; severity score evolution).39 A recent meta-analysis did not report any 28-day survival benefit of HVHF compared with conventional continuous venovenous hemofiltration (CVVH) in septic AKI.40 The Cochrane collaboration meta-analysis on this subject recently was updated. It did not conclude in any beneficial effect of HVHF during sepsis compared with usual renal support techniques.41 It also is worth noting important HVHF drawbacks. Of those, removal of little molecular weight molecules must be taken into account (nutrients, vitamins, trace elements, and medications such as antibiotics). Treatment cost and nursing workload are increased owing to the frequent change of substitution fluid containers.42 Cascade Hemofiltration Cascade hemofiltration has been proposed to avoid these limitations while conserving theoretical HVHF advantages —namely high clearance of middle-weight molecules.43

The primary idea is to selectively remove middle molecules, while retaining little ones (trace elements, vitamins, medications) by combining two hemofilters with distinct cut-off values. The first hemofilter, with a relatively high cut-off value, generates a first ultrafiltrate containing lowand middle-weight molecules and directs it toward a second filter. This latter is characterized by a much lower cut-off value. Only middle molecules then will be cleared in the final effluent, while little ones will be re-injected as a predilution before the first hemofilter, finally to be infused back to the patient. Infused volumes are much lower than those required for HVHF.44 Cascade hemofiltration lowered epinephrine requirements in a porcine septic shock model.44 In human beings, however, a recent study comparing adjunction of cascade HVHF with standard care in 60 septic shock patients did not show any beneficial effect, neither on inflammatory cytokines nor on clinical endpoints, except the number of RRT-free days.45 Hemoperfusion Hemoperfusion is a technique in which patient’s blood is in contact with adsorbing materials. Some molecules therefore can adhere to such materials, thanks to van der Waals, electrostatic, and/or hydrophobic interactions.46 Removal of high-molecular-weight molecules then is allowed, with no particular cut-off consideration. Biocompatibility issues with these adsorbing materials have been resolved. Importantly, hemoperfusion is not a renal replacement therapy technique, but can be added to one. Polymyxin B

Polymyxin B (Toraymyxin; Toray Industries, Tokyo, Japan) is the most commonly used adsorbing material worldwide, particularly in Japan, where it routinely is provided to patients with gram-negative bacilli (GNB)induced severe septic conditions. Indeed, this therapy targets bacterial endotoxin, which largely triggers inflammation in septic shock. Interestingly, the beneficial effects of blood purification techniques, suggested by a recent meta-analysis, primarily were owing to results from Japanese cohorts assessing polymyxin B hemoperfusion.47 Several retrospective Japanese cohorts triggered conflicting results on mortality.48-50 Two other propensity-matched cohorts recently were published. The first cohort included nearly 2,000 septic shock patients requiring RRT, and concluded there was a 6% decrease in absolute mortality.51 The second study confirmed this positive result, with an 8% decrease in absolute hospital mortality among 500 septic shock Japanese patients.52 The analysis of a registry recording data from septic shock patients treated with polymyxin B hemoadsorption in Asia (n = 60) and in Europe (n = 297) showed an improvement in Sequential Organ Failure Assessment

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(SOFA) score after polymyxin B hemoperfusion, although there was no control group in this cohort.53 Considering randomized controlled trials, the Early Use of Polymyxin B Hemoperfusion in Abdominal Sepsis (EUPHAS) study, enrolling patients with abdominal severe sepsis or septic shock, showed hemodynamic and respiratory enhancement. A positive effect on 28-day survival also was observed, although it was not the primary outcome.54 Polymyxin B hemoperfusion also was evaluated in peritonitis-induced early septic shock in the ABDOMIX trial (effects of hemoperfusion with a polymyxin B membrane in peritonitis with septic shock). Approximatively 140 patients were randomized to receive either standard care or standard care plus two hemoperfusion sessions (>90 minutes with a 24-hour interval between sessions). The intervention was not associated with different SOFA score evolution. However, it was associated with a trend toward higher mortality (34% versus 24%; P = .11).55 Cytokine plasmatic concentrations were not different between groups after the second hemoperfusion session, even when restricting analysis to patients with GNB-proven peritonitis.56 Finally, the EUPHRATES (safety and efficacy of polymyxin B hemoperfusion for septic shock) trial was a double-blinded (sham circuit in the control group) randomized controlled trial conducted in North America. In this study, 450 septic shock patients with a shown increase in plasma endotoxin level (endotoxin activity assay [EAA] >0.6) were randomized to either standard of care or standard of care plus hemoperfusion (two sessions of 90-120 minutes within 24 hours). In this trial, day 28 mortality was not different between groups, including in a per-protocol analysis of the subgroup of patients with a high organ dysfunction score and who effectively received the two polymyxin hemoperfusion sessions (n = 244).57 However, an exploratory post hoc analysis suggested a beneficial effect on hemodynamic parameters, ventilator-free days, and survival in the subgroup of patients with an EAA between 0.6 and 0.9 (n = 194).58 To summarize, it seems that the potential beneficial effect of polymyxin B hemoperfusion on survival can be observed only when the control group mortality is higher than 30% to 40%.59 However, the level of evidence for the effect of polymyxin B hemoperfusion on mortality remains quite low. Future research should focus on patients with very high expected mortality and/or EAA between 0.6 and 0.9. Finally, considering the numerous positive results obtained in Japan, one also could hypothesize that a patient’s genetic and enzymatic profile could play a role in the patient’s response to this therapy. CytoSorb

Other adsorbing materials are available such as divinylbenzene (CytoSorb; CytoSorbents Corp, Monmouth Junction, NJ). CytoSorb is designed and marketed to

remove proinflammatory and anti-inflammatory cytokines from the blood. An ex vivo study showed that this adsorbing cartridge can remove activated leukocytes and monocytes from blood and modulate cytokine (TNF-a, IL8) expression.23 This cartridge also decreases plasma concentrations of several damage- or pathogen-associated molecular patterns, as well as mycotoxins, in an in vitro model of bovine blood with added inflammatory mediators.60 In another in vitro study with human blood, CytoSorb efficiently removed numerous proinflammatory and anti-inflammatory cytokines, complement factors, serine protease, and growth factors, with removal rates higher than 90% to 95% for almost all of these molecules at 120 minutes. Importantly, endotoxin is not removed by CytoSorb.61 In a murine septic shock model, treatment with CytoSorb decreased IL6 and IL10, and also decreased mortality.62 In human beings, evidence is scarce. Almost all publications are case reports or case series.63 A proof of concept, pilot randomized controlled trial in 20 septic shock patients without the need for renal replacement therapy, concluded that vasopressor needs and procalcitonin levels were more reduced in the CytoSorb than in the control group.64 In a randomized controlled trial comparing standard care and adjunction of hemoperfusion with CytoSorb (6-hour sessions during 7 consecutive days) in septic shock patients with respiratory failure, hemoperfusion with CytoSorb was not associated with a decrease in IL6 plasma levels (primary endpoint). The intervention was associated with a modest crossadsorber IL6 clearance.65 Intermittent and short sessions of hemoperfusion were used, and IL6 levels were quite low for septic shock patients, potentially explaining these results. To date, the level of evidence supporting the use of CytoSorb in septic shock remains low. However, further studies are required to establish its safety and efficacy in patients with a very high inflammatory response. Indeed, CytoSorb also can be used in other conditions generating inflammation, such as severe burns or cardiopulmonary bypass. It also removes many drugs and medications, and myoglobin, bilirubin, and bile acids.66 Plasma Exchange Techniques derived from plasmapheresis also have been evaluated in septic shock. Only a limited number of studies are available, with interesting results, especially in GNB-induced sepsis. Early initiation seems to be associated with better efficacy.67 A randomized trial first suggested a decrease in early sepsis inflammatory markers and a trend toward less organ dysfunction in plasmapheresis-treated patients.68 Another trial involving 100 severe sepsis or septic shock patients even suggested a survival benefit when plasma exchange was added to conventional care.69 This study, however, presented several limitations. Groups were not strictly comparable

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before treatment, with patients older and more likely to have respiratory failure in the control group. Moreover, this positive result was driven mainly by the subgroup of patients with intra-abdominal sepsis. In other types of infection, plasmapheresis did not appear to confer any advantage over standard care. In children, another study, although underpowered, did not show any beneficial effect of plasma filtration.70 A meta-analysis focusing on adult septic shock patients concluded that plasma exchange could be beneficial on survival, but the methodologic quality of included studies—conducted 20 years ago—is questionable.71 A recent pilot nonrandomized trial (n = 20) showed a rapid reduction of vasopressor requirements and plasmatic cytokine decrease, along with a reduction of endothelial hyperpermeability, after plasma exchange during early septic shock.72 However, the level of evidence of such trials cannot support the routine use of this technique to date in sepsis.

adhesion. Purified plasma then is returned to the main circuit. Blood then undergoes conventional hemofiltration, allowing for kidney support in addition to blood purification for sepsis (Fig. 3). CPFA has shown similar positive results to HVHF on hemodynamics73,74 and immune function modulation, reflected for instance by monocyte HLA-DR expression.75 In the COMbining Plasma-filtration and Adsorption Clinical Trial (COMPACT)-1 randomized trial, patients who received the highest dose of CPFA seemed to benefit from this therapy on the mortality criterion, compared with controls.76 Therefore, the COMPACT-2 trial (NCT 01639664) evaluated the effect of high doses of CPFA in septic shock. This study was stopped prematurely because CPFA was associated with an increase in early mortality compared with the control group. Before publication of the final results, the manufacturer released a safety report recommending that CPFA should not be used in septic shock. Definitive results should be available soon.

Coupled Plasma Filtration and Adsorption Coupled plasma filtration and adsorption (CPFA) is an extracorporeal therapy in which plasma is separated from blood at the beginning of the extracorporeal circuit, and then runs slowly through an adsorbing cartridge. The slow plasma flow enables a prolonged contact time with the adsorbing material, thus optimizing molecule

Hemofiltration With Highly Adsorbing Membranes The potential synergistic effect of the various blood purification techniques may represent an interesting strategy.77 Several associations have been tested ex vivo or in animal models.78 For example, a standard polyacrilonytrile hemofiltration membrane was modified with the

Figure 3. Coupled plasma filtration and adsorption (CPFA) circuit.

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Figure 4. oXiris membrane layers.

adjunction of a positively charged polyethyleneimine polymer (oXiris, Baxter, Meyzieu, France) to enhance its endotoxin and cytokine adsorption capacities (Fig. 4). The oXiris membrane was compared with a standard hemofiltration membrane in a porcine model of septic shock. After 6 hours of HVHF, the volume of fluids infused was reduced, as well as hyperlactatemic acidosis, in the oXiris group.79 An industry-sponsored in vitro study showed that the oXiris membrane presented similar endotoxin adsorption properties as polymyxin B, whereas CytoSorb does not adsorb endotoxin. Regarding proinflammatory and anti-inflammatory cytokines, removal rates were similar with oXiris and CytoSorb (>90% at 120 min for most cytokines studied), but polymyxin B was less efficient.61 Moreover, oXiris is a continuous RRT membrane, whereas neither CytoSorb nor polymyxin B are. However, clinical evidence remains scarce and often limited to case series. One of them compared six patients with sepsis-induced AKI treated with oXiris with 24 historical severity-matched controls and concluded that the SOFA score was reduced after 48 hours in the oXiris group.80 We recently launched the multicenter randomized controlled trial Endotoxin and Cytokines Removal during continuous hemofiltration with oXiris (ECRO), comparing a standard membrane and the oXiris filter in peritonitis-induced septic shock with indication for RRT (NCT 03426943). A comparable Swedish study recently was completed in GNBdocumented or suspected septic shock, but results have not been published yet (NCT 02600312). Other highly adsorbing membranes are commercialized, for example, AN69 ST81 (Baxter, Meyzieu, France) or

polymethylmethacrylate membranes,82 for which the thrombogenicity issues seem to have been solved.83 High Cut-Off Membranes To enlarge the spectrum of middle molecular weight molecule removal, the membrane cut-off value can be increased. These filters, first used with hemofiltration techniques, were associated with hemodynamic improvement in experimental20 and human sepsis.84 The major drawback was the massive albumin leakage into the effluent, which could increase up to 15 g in 4 hours.85 Nevertheless, when used with diffusive rather than convective modalities, albumin loss is clearly and logically reduced.86 Cut-off values and other membrane parameter optimization (eg, surface or pore size homogeneity) represent another solution to such difficulties.82 Such modified high cut-off (HCO) membranes show similar properties, but their slightly lower cut-off value limits albumin loss while still removing inflammatory mediators.86,87 HCO membranes have shown promising properties on inflammation mediator removal, although the level of evidence still is low. When assessing the single-pass effect and compared with standard CVVH, HCO-CVVH resulted in decreasing one of the apoptosis indices in a pilot study of AKI patients.88 On the other hand, it did not modify the nucleosome concentration of levels of Toll-like receptor 2 and Toll-like receptor 4 expression.89 Sieving coefficients of many cytokines were higher with HCO-CVVH than with standard CVVH, but this did not result in a lower plasma cytokine

Technique

Animal Studies 31

Human Non-RCTs 35

HVHF

Yekebas et al # mortality, # immunosuppression

Tapia et al Respiratory improvement, mortality lower than expected

Cascade


et al44 Rimmele # epinephrine requirements

NA

Hemoperfusion with polymyxin B

Iba et al94 # organ damage, # proinflammatory cytokines, # mortality Mitaka et al95 Hemodynamic and acid-base balance maintained, # lactate, # creatinine, # IL6 and IL10

Iwagami et al51 # 6% absolute mortality

Hemoperfusion with CytoSorb

Gruda et al60 # DAMPs and PAMPs Peng et al62 # IL6 and IL10 # mortality

Malard et al61 Removal rates >90%-95% for numerous proinflammatory and anti-inflammatory cytokines, complement factors, serine protease, and growth factors

Plasma exchange

Toft et al96 Temporary # activated cell-mediated immunity

Hjorth and Stenlund67 Mortality < expected by APACHE

Natanson et al97 # survival, worsened hemodynamics

Knaup et al72 # vasopressors requirement, # plasma cytokines, # endothelial permeability Ronco et al73 # vasopressors requirements # immunosuppression markers

CPFA

Tetta et al98 # mortality Sykora et al99 No beneficial effect

Highly-adsorptive membranes


et al Rimmele # fluid requirements, # hyperlactatemic acidosis Lee et al20 Hemodynamic improvement

High cut-off membranes

79

Nakamura et al52 # 8% absolute hospital mortality

80

Shum et al # SOFA score Villa et al92 # IL6 and TNF-a Chelazzi et al93 # ICU length of stay, # ICU mortality

Human RCTs Joannes-Boyau et al,39 IVOIRE No difference in mortality No difference in ventilator-, RRT-, and vasopressor-free days, length of stay, hemodynamic and standard biologic parameters, severity score evolution Quenot et al45 No difference in mortality No difference in vasopressor- or ventilator-free days More RRT-free days Payen et al,55 ABDO-MIX No difference on mortality No difference on SOFA evolution or cytokines concentration Dellinger et al,57 EUPHRATES No difference in mortality Post hoc analysis: " hemodynamic parameters, "ventilatorfree days, and " survival, in patients with EAA 0.6-0.9 €dler et al65 Scha No decrease in plasmatic IL6 level Modest cross-adsorber IL6 clearance Hawchar et al64 # norepinephrine needs # procalcitonin Reeves et al68 # early sepsis inflammatory markers, trend toward less organ dysfunctions Busund et al69 # mortality (result still debated)

Blood purification techniques

Table 1. Major Publications for Each Blood Purification Technique

Livigni et al,76 COMPACT-1 # mortality in patients receiving the higher dose of CPFA? COMPACT-2 (not published yet) " early mortality (72 hours) NA NA

Abbreviations: ABDO-MIX, Effects of Hemoperfusion With a Polymyxin B Membrane in Peritonitis With Septic Shock; APACHE, Acute Physiologic Assessment and Chronic Health Evaluation; CPFA, coupled plasma filtration and adsorption; COMPACT, Combining Plasma-filtration and Adsorption Clinical Trial; DAMP, damage-associated molecular pattern; EAA, endotoxin activity assay; EUPHRATES, Safety and Efficacy of Polymyxin B Hemoperfusion for Septic Shock; HVHF, high-volume hemofiltration; ICU, intensive care unit; IL, interleukin; IVOIRE, hIgh VOlume in Intensive care; NA, not applicable; PAMP, pathogen-associated molecular patterns; RCT, randomized controlled trial; SOFA, sequential organ failure assessment; TNF, tumor necrosis factor.

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concentration.90 In a retrospective analysis of 28 septic shock patients treated with HCO-CVVHD (with no control group), effective removal of interferon-a, IL1b, IL2, IL6, IL10, and IL12 was observed.91 In a prospective observational cohort of 38 patients with septic shock −associated AKI treated with HCO-CVVHD, a significant reduction in circulating IL6 and TNF-a levels was observed.92 One retrospective study focused on clinical outcome. HCO-CVVHD was compared with high-flux continuous veno-venous hemodiafiltration in 16 versus 8 septic patients with AKI. In the HCO group, ICU length of stay and mortality were reduced, but hospital mortality was not different between groups.93

CONCLUSIONS Will extracorporeal blood purification someday be part of standard sepsis management? Data published to date from animal and human studies are too conflicting to firmly answer this question (Table 1). Although hemodynamic and respiratory improvements, along with inflammation mediator removal, have been observed when using such techniques, a clear clinical positive effect on patient survival has not been proven yet. Although some blood purification techniques did not show any clear benefit in randomized controlled trials, membrane optimization (highly adsorptive, high cut-off value) seems to be a promising field for future development and research. Patient selection based on biomarkers such as endotoxin levels also could allow identification of those patients who will benefit from such therapies.

REFERENCES 1. Quenot J-P, Binquet C, Kara F, Martinet O, Ganster F, Navellou JC, et al. The epidemiology of septic shock in French intensive care units: the prospective multicenter cohort EPISS study. Crit Care. 2013;17:R65. 2. Bossi P, Grimaldi D, Caille V, Vieillard-Baron A. [Diagnosis of sepsis, severe sepsis and septic shock]. Presse Med. 2004;33:2624. discussion 269. 3. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43:304-77. 4. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315:801-10. 5. Kasten KR, Muenzer JT, Caldwell CC. Neutrophils are significant producers of IL-10 during sepsis. Biochem Biophys Res Commun. 2010;393:28-31. 6. Astiz M, Saha D, Lustbader D, Lin R, Rackow E. Monocyte response to bacterial toxins, expression of cell surface receptors, and release of anti-inflammatory cytokines during sepsis. J Lab Clin Med. 1996;128:594-600. 7. Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13:862-74. 8. Venet F, Lukaszewicz A-C, Payen D, Hotchkiss R, Monneret G. Monitoring the immune response in sepsis: a rational approach

9.

10.

11. 12.

13.

14.

15.

16. 17. 18. 19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

to administration of immunoadjuvant therapies. Curr Opin Immunol. 2013;25:477-83. Venkatesh B, Finfer S, Cohen J, Rajbhandari D, Arabi Y, Bellomo R, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med. 2018;378:797-808. Annane D, Renault A, Brun-Buisson C, Megarbane B, Quenot J-P, Siami S, et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med. 2018;378:809-18. Venet F, Rimmel
e T, Monneret G. Management of sepsis-induced immunosuppression. Crit Care Clin. 2018;34:97-106. Shindo Y, Fuchs AG, Davis CG, Eitas T, Unsinger J, Burnham CAD, et al. Interleukin 7 immunotherapy improves host immunity and survival in a two-hit model of Pseudomonas aeruginosa pneumonia. J Leukoc Biol. 2017;101:543-54. Francois B, Jeannet R, Daix T, Walton AH, Shotwell MS, Unsinger J, et al. Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial. JCI Insight. 2018;3. Shindo Y, Unsinger J, Burnham C-A, Green JM, Hotchkiss RS. Interleukin-7 and anti-programmed cell death 1 antibody have differing effects to reverse sepsis-induced immunosuppression. Shock. 2015;43:334-43. Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis. 2013;13:260-8. Rimmel
e T, Kellum JA. Clinical review: blood purification for sepsis. Crit Care. 2011;15:205. Lukaszewicz AC, Payen D. Purification methods: a way to treat severe acute inflammation related to sepsis? Crit Care. 2013;17:159. Ronco C. Endotoxin removal: history of a mission. Blood Purif. 2014;37(Suppl 1):5-8. Ronco C, Tetta C, Mariano F, Wratten ML, Bonello M, Bordoni V, et al. Interpreting the mechanisms of continuous renal replacement therapy in sepsis: the peak concentration hypothesis. Artif Organs. 2003;27:792-801. Lee PA, Matson JR, Pryor RW, Hinshaw LB. Continuous arteriovenous hemofiltration therapy for Staphylococcus aureusinduced septicemia in immature swine. Crit Care Med. 1993;21:914-24. Honor
e PM, Matson JR. Extracorporeal removal for sepsis: acting at the tissue level−the beginning of a new era for this treatment modality in septic shock. Crit Care Med. 2004;32:896-7. Peng Z, Singbartl K, Simon P, Rimmel
e T, Bishop J, Clermont G, et al. Blood purification in sepsis: a new paradigm. Contrib Nephrol. 2010;165:322-8. Rimmel
e T, Kaynar AM, McLaughlin JN, Bishop JV, Fedorchak MV, Chuasuwan A, et al. Leukocyte capture and modulation of cell-mediated immunity during human sepsis: an ex vivo study. Crit Care. 2013;17:R59. Srisawat N, Tungsanga S, Lumlertgul N, Komaenthammasophon C, Peerapornratana S, Thamrongsat N, et al. The effect of polymyxin B hemoperfusion on modulation of human leukocyte antigen DR in severe sepsis patients. Crit Care. 2018;22:279. Ma S, Xu Q, Deng B, Zheng Y, Tian H, Wang L, et al. Granulocyte and monocyte adsorptive apheresis ameliorates sepsis in rats. Intensive Care Med Exp. 2017;5:18. Rouget C, Girardot T, Textoris J, Monneret G, Rimmel
e T, Venet F. Biological markers of injury-induced immunosuppression. Minerva Anestesiol. 2017;83:302-14. Rol M-L, Venet F, Rimmele T, Moucadel V, Cortez P, Quemeneur L, et al. The REAnimation Low Immune Status Markers (REALISM) project: a protocol for broad characterisation and follow-up of injury-induced immunosuppression in intensive care unit (ICU) critically ill patients. BMJ Open. 2017;7:e015734. Rimmel
e T, Kellum JA. High-volume hemofiltration in the intensive care unit: a blood purification therapy. Anesthesiology. 2012;116:1377-87.

Blood purification techniques

29. Kellum JA, Johnson JP, Kramer D, Palevsky P, Brady JJ, Pinsky MR. Diffusive vs. convective therapy: effects on mediators of inflammation in patient with severe systemic inflammatory response syndrome. Crit Care Med. 1998;26:1995-2000. 30. Grootendorst AF, van Bommel EF, van der Hoven B, van Leengoed LA, van Osta AL. High volume hemofiltration improves right ventricular function in endotoxin-induced shock in the pig. Intensive Care Med. 1992;18:235-40. 31. Yekebas EF, Eisenberger CF, Ohnesorge H, Saalm€ uller A, Elsner HA, Engelhardt M, et al. Attenuation of sepsis-related immunoparalysis by continuous veno-venous hemofiltration in experimental porcine pancreatitis. Crit Care Med. 2001;29:1423-30. 32. Wang H, Zhang Z-H, Yan X-W, Li W-Q, Ji D-X, Quan Z-F, et al. Amelioration of hemodynamics and oxygen metabolism by continuous venovenous hemofiltration in experimental porcine pancreatitis. World J Gastroenterol. 2005;11:127-31. 33. Cole L, Bellomo R, Journois D, Davenport P, Baldwin I, Tipping P. High-volume haemofiltration in human septic shock. Intensive Care Med. 2001;27:978-86. 34. Boussekey N, Chiche A, Faure K, Devos P, Guery B, d’Escrivan T, et al. A pilot randomized study comparing high and low volume hemofiltration on vasopressor use in septic shock. Intensive Care Med. 2008;34:1646-53. 35. Tapia P, Chinch
on E, Morales D, Stehberg J, Simon F. Effectiveness of short-term 6-hour high-volume hemofiltration during refractory severe septic shock. J Trauma Acute Care Surg. 2012;72:1228-37. 36. Honore PM, Jamez J, Wauthier M, Lee PA, Dugernier T, Pirenne B, et al. Prospective evaluation of short-term, high-volume isovolemic hemofiltration on the hemodynamic course and outcome in patients with intractable circulatory failure resulting from septic shock. Crit Care Med. 2000;28:3581-7. 37. Joannes-Boyau O, Rapaport S, Bazin R, Fleureau C, Janvier G. Impact of high volume hemofiltration on hemodynamic disturbance and outcome during septic shock. ASAIO J. 2004;50:102-9. 38. Ratanarat R, Brendolan A, Piccinni P, Dan M, Salvatori G, Ricci Z, et al. Pulse high-volume haemofiltration for treatment of severe sepsis: effects on hemodynamics and survival. Crit Care. 2005;9: R294-302. 39. Joannes-Boyau O, Honor
e PM, Perez P, Bagshaw SM, Grand H, Canivet J-L, et al. High-volume versus standard-volume haemofiltration for septic shock patients with acute kidney injury (IVOIRE study): a multicentre randomized controlled trial. Intensive Care Med. 2013;39:1535-46. 40. Clark E, Molnar AO, Joannes-Boyau O, Honor
e PM, Sikora L, Bagshaw SM. High-volume hemofiltration for septic acute kidney injury: a systematic review and meta-analysis. Crit Care. 2014; 18:R7. 41. Borthwick EM, Hill CJ, Rabindranath KS, Maxwell AP, McAuley DF, Blackwood B. High-volume haemofiltration for sepsis in adults. Cochrane Database Syst Rev. 2017;1. CD008075. 42. Srisawat N, Lawsin L, Uchino S, Bellomo R, Kellum JA, BEST Kidney Investigators. Cost of acute renal replacement therapy in the intensive care unit: results from The Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) study. Crit Care. 2010;14:R46. 43. Rimmel
e T, Wey P-F, Bernard N, Monchi M, Semenzato N, Benatir F, et al. Hemofiltration with the Cascade system in an experimental porcine model of septic shock. Ther Apher Dial. 2009;13:63-70. 44. Rimmel
e T, Hayi-Slayman D, Page M, Rada H, Monchi M, Allaouchiche B. [Cascade hemofiltration: principle, first experimental data]. Ann Fr Anesth Reanim. 2009;28:249-52. 45. Quenot J-P, Binquet C, Vinsonneau C, Barbar S-D, Vinault S, Deckert V, et al. Very high volume hemofiltration with the Cascade system in septic shock patients. Intensive Care Med. 2015;41:2111-20.

513

46. Winchester JF, Kellum JA, Ronco C, Brady JA, Quartararo PJ, Salsberg JA, et al. Sorbents in acute renal failure and the systemic inflammatory response syndrome. Blood Purif. 2003;21:79-84. 47. Zhou F, Peng Z, Murugan R, Kellum JA. Blood purification and mortality in sepsis: a meta-analysis of randomized trials. Crit Care Med. 2013;41:2209-20. 48. Iwagami M, Yasunaga H, Doi K, Horiguchi H, Fushimi K, Matsubara T, et al. Postoperative polymyxin B hemoperfusion and mortality in patients with abdominal septic shock: a propensitymatched analysis. Crit Care Med. 2014;42:1187-93. 49. Lee C-T, Tu Y-K, Yeh Y-C, Chang T, Shih P-Y, Chao A, et al. Effects of polymyxin B hemoperfusion on hemodynamics and prognosis in septic shock patients. J Crit Care. 2018;43:202-6. 50. Saito N, Sugiyama K, Ohnuma T, Kanemura T, Nasu M, Yoshidomi Y, et al. Efficacy of polymyxin B-immobilized fiber hemoperfusion for patients with septic shock caused by Gram-negative bacillus infection. PLoS One. 2017;12:e0173633. 51. Iwagami M, Yasunaga H, Noiri E, Horiguchi H, Fushimi K, Matsubara T, et al. Potential survival benefit of polymyxin B hemoperfusion in septic shock patients on continuous renal replacement therapy: a propensity-matched analysis. Blood Purif. 2016;42:9-17. 52. Nakamura Y, Kitamura T, Kiyomi F, Hayakawa M, Hoshino K, Kawano Y, et al. Potential survival benefit of polymyxin B hemoperfusion in patients with septic shock: a propensity-matched cohort study. Crit Care. 2017;21:134. 53. Cutuli SL, Artigas A, Fumagalli R, Monti G, Ranieri VM, Ronco C, et al. Polymyxin-B hemoperfusion in septic patients: analysis of a multicenter registry. Ann Intensive Care. 2016;6:77. 54. Cruz DN, Antonelli M, Fumagalli R, Foltran F, Brienza N, Donati A, et al. Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. JAMA. 2009;301:2445-52. 55. Payen DM, Guilhot J, Launey Y, Lukaszewicz AC, Kaaki M, Veber B, et al. Early use of polymyxin B hemoperfusion in patients with septic shock due to peritonitis: a multicenter randomized control trial. Intensive Care Med. 2015;41:975-84. 56. Coudroy R, Payen D, Launey Y, Lukaszewicz A-C, Kaaki M, Veber B, et al. Modulation by polymyxin-B hemoperfusion of inflammatory response related to severe peritonitis. Shock. 2017;47:93-9. 57. Dellinger RP, Bagshaw SM, Antonelli M, Foster DM, Klein DJ, Marshall JC, et al. Effect of targeted polymyxin B hemoperfusion on 28-day mortality in patients with septic shock and elevated endotoxin level: the EUPHRATES randomized clinical trial. JAMA. 2018;320:1455-63. 58. Klein DJ, Foster D, Walker PM, Bagshaw SM, Mekonnen H, Antonelli M. Polymyxin B hemoperfusion in endotoxemic septic shock patients without extreme endotoxemia: a post hoc analysis of the EUPHRATES trial. Intensive Care Med. 2018;44:2205-12. 59. Chang T, Tu Y-K, Lee C-T, Chao A, Huang C-H, Wang M-J, et al. Effects of polymyxin B hemoperfusion on mortality in patients with severe sepsis and septic shock: a systemic review, meta-analysis update, and disease severity subgroup meta-analysis. Crit Care Med. 2017;45:e858-64. 60. Gruda MC, Ruggeberg K-G, O’Sullivan P, Guliashvili T, Scheirer AR, Golobish TD, et al. Broad adsorption of sepsis-related PAMP and DAMP molecules, mycotoxins, and cytokines from whole blood using CytoSorbÒ sorbent porous polymer beads. PLoS One. 2018;13:e0191676. 61. Malard B, Lambert C, Kellum JA. In vitro comparison of the adsorption of inflammatory mediators by blood purification devices. Intensive Care Med Exp. 2018;6:12. 62. Peng Z-Y, Carter MJ, Kellum JA. Effects of hemoadsorption on cytokine removal and short-term survival in septic rats. Crit Care Med. 2008;36:1573-7. 63. Houschyar KS, Pyles MN, Rein S, Nietzschmann I, Duscher D, Maan ZN, et al. Continuous hemoadsorption with a cytokine

T. Girardot et al.

514

64.

65.

66. 67. 68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

adsorber during sepsis - a review of the literature. Int J Artif Organs. 2017;40:205-11. € Hawchar F, L
aszl
o I, Oveges N, Tr
asy D, Ondrik Z, Molnar Z. Extracorporeal cytokine adsorption in septic shock: A proof of concept randomized, controlled pilot study. J Crit Care. 2019;49:172-8. Sch€adler D, Pausch C, Heise D, Meier-Hellmann A, Brederlau J, Weiler N, et al. The effect of a novel extracorporeal cytokine hemoadsorption device on IL-6 elimination in septic patients: a randomized controlled trial. PLoS One. 2017;12:e0187015. Poli EC, Rimmel
e T, Schneider AG. Hemoadsorption with CytoSorbÒ . Intensive Care Med. 2019;45:236-9. Hjorth V, Stenlund G. Plasmapheresis as part of the treatment for septic shock. Scand J Infect Dis. 2000;32:511-4. Reeves JH, Butt WW, Shann F, Layton JE, Stewart A, Waring PM, et al. Continuous plasmafiltration in sepsis syndrome. Plasmafiltration in Sepsis Study Group. Crit Care Med. 1999;27:2096-104. Busund R, Koukline V, Utrobin U, Nedashkovsky E. Plasmapheresis in severe sepsis and septic shock: a prospective, randomised, controlled trial. Intensive Care Med. 2002;28:1434-9. Long EJ, Shann F, Pearson G, Buckley D, Butt W. A randomised controlled trial of plasma filtration in severe paediatric sepsis. Crit Care Resusc. 2013;15:198-204. Rimmer E, Houston BL, Kumar A, Abou-Setta AM, Friesen C, Marshall JC, et al. The efficacy and safety of plasma exchange in patients with sepsis and septic shock: a systematic review and meta-analysis. Crit Care. 2014;18:699. Knaup H, Stahl K, Schmidt BMW, Idowu TO, Busch M, Wiesner O, et al. Early therapeutic plasma exchange in septic shock: a prospective open-label nonrandomized pilot study focusing on safety, hemodynamics, vascular barrier function, and biologic markers. Crit Care. 2018;22:285. Ronco C, Brendolan A, Lonnemann G, Bellomo R, Piccinni P, Digito A, et al. A pilot study of coupled plasma filtration with adsorption in septic shock. Crit Care Med. 2002;30:1250-5. Formica M, Olivieri C, Livigni S, Cesano G, Vallero A, Maio M, et al. Hemodynamic response to coupled plasmafiltration-adsorption in human septic shock. Intensive Care Med. 2003;29:703-8. Mao H-J, Yu S, Yu X-B, Zhang B, Zhang L, Xu X-R, et al. Effects of coupled plasma filtration adsorption on immune function of patients with multiple organ dysfunction syndrome. Int J Artif Organs. 2009;32:31-8. Livigni S, Bertolini G, Rossi C, Ferrari F, Giardino M, Pozzato M, et al. Efficacy of coupled plasma filtration adsorption (CPFA) in patients with septic shock: a multicenter randomised controlled clinical trial. BMJ Open. 2014;4:e003536. Joannes-Boyau O, Honore PM, Boer W, Collin V. Are the synergistic effects of high-volume haemofiltration and enhanced adsorption the missing key in sepsis modulation? Nephrol Dial Transplant. 2009;24:354-7. Uchino S, Bellomo R, Goldsmith D, Davenport P, Cole L, Baldwin I, et al. Super high flux hemofiltration: a new technique for cytokine removal. Intensive Care Med. 2002;28:651-5. Rimmel
e T, Assadi A, Cattenoz M, Desebbe O, Lambert C, Boselli E, et al. High-volume haemofiltration with a new haemofiltration membrane having enhanced adsorption properties in septic pigs. Nephrol Dial Transplant. 2009;24:421-7. Shum HP, Chan KC, Kwan MC, Yan WW. Application of endotoxin and cytokine adsorption haemofilter in septic acute kidney injury due to Gram-negative bacterial infection. Hong Kong Med J. 2013;19:491-7. Shiga H, Hirasawa H, Nishida O, Oda S, Nakamura M, Mashiko K, et al. Continuous hemodiafiltration with a cytokine-adsorbing hemofilter in patients with septic shock: a preliminary report. Blood Purif. 2014;38:211-8. Honore PM, Jacobs R, Joannes-Boyau O, De Regt J, De Waele E, van Gorp V, et al. Newly designed CRRT membranes for sepsis

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

and SIRS−a pragmatic approach for bedside intensivists summarizing the more recent advances: a systematic structured review. ASAIO J. 2013;59:99-106. Oshihara W, Fujieda H, Ueno Y. A new poly(methyl methacrylate) membrane dialyzer, NF, with adsorptive and antithrombotic properties. Contrib Nephrol. 2017;189:230-6. Morgera S, Haase M, Kuss T, Vargas-Hein O, ZuckermannBecker H, Melzer C, et al. Pilot study on the effects of high cutoff hemofiltration on the need for norepinephrine in septic patients with acute renal failure. Crit Care Med. 2006;34:2099-104. Morgera S, Rockt€aschel J, Haase M, Lehmann C, von Heymann C, Ziemer S, et al. Intermittent high permeability hemofiltration in septic patients with acute renal failure. Intensive Care Med. 2003;29:1989-95. Haase M, Bellomo R, Baldwin I, Haase-Fielitz A, Fealy N, Davenport P, et al. Hemodialysis membrane with a high-molecularweight cutoff and cytokine levels in sepsis complicated by acute renal failure: a phase 1 randomized trial. Am J Kidney Dis. 2007;50:296-304. Naka T, Haase M, Bellomo R. “Super high-flux” or “high cut-off” hemofiltration and hemodialysis. Contrib Nephrol. 2010;166: 181-9. Atan R, Virzi GM, Peck L, Ramadas A, Brocca A, Eastwood G, et al. High cut-off hemofiltration versus standard hemofiltration: a pilot assessment of effects on indices of apoptosis. Blood Purif. 2014;37:296-303. Atan R, May C, Bailey SR, Tanudji M, Visvanathan K, Skinner N, et al. Nucleosome levels and toll-like receptor expression during high cut-off haemofiltration: a pilot assessment. Crit Care Resusc. 2015;17:239-43. Atan R, Peck L, Visvanathan K, Skinner N, Eastwood G, Bellomo R, et al. High cut-off hemofiltration versus standard hemofiltration: effect on plasma cytokines. Int J Artif Organs. 2016;39:479-86. Kade G, Lubas A, Rzeszotarska A, Korsak J, Niemczyk S. Effectiveness of high cut-off hemofilters in the removal of selected cytokines in patients during septic shock accompanied by acute kidney injury-preliminary study. Med Sci Monit. 2016;22:4338-44. Villa G, Chelazzi C, Morettini E, Zamidei L, Valente S, Caldini AL, et al. Organ dysfunction during continuous venovenous high cut-off hemodialysis in patients with septic acute kidney injury: a prospective observational study. PLoS One. 2017;12:e0172039. Chelazzi C, Villa G, D’Alfonso MG, Mancinelli P, Consales G, Berardi M, et al. Hemodialysis with high cut-off hemodialyzers in patients with multi-drug resistant gram-negative sepsis and acute kidney injury: a retrospective, case-control study. Blood Purif. 2016;42:186-93. Iba T, Okamoto K, Kawasaki S, Nakarai E, Miyasho T. Effect of hemoperfusion using polymyxin B-immobilized fibers on nonshock rat sepsis model. J Surg Res. 2011;171:755-61. Mitaka C, Masuda T, Kido K, et al. Polymyxin B hemoperfusion prevents acute kidney injury in sepsis model. J Surg Res. 2016;201:59-68. Toft P, Schmidt R, Broechner AC, Nielsen BU, Bollen P, Olsen KE. Effect of plasmapheresis on the immune system in endotoxin-induced sepsis. Blood Purif. 2008;26:145-50. Natanson C, Hoffman WD, Koev LA, et al. Plasma exchange does not improve survival in a canine model of human septic shock. Transfusion. 1993;33:243-8. Tetta C, Gianotti L, Cavaillon JM, et al. Coupled plasma filtrationadsorption in a rabbit model of endotoxic shock. Crit Care Med. 2000;28:1526-33. Sykora R, Chvojka J, Krouzecky A, et al. Coupled plasma filtration adsorption in experimental peritonitis-induced septic shock. Shock. 2009;31:473-80.