Sepsis, a condition characterized by a systemic response to infection, can result in remote organ dysfunction through a variety of mechanisms (1). When sepsis results in organ failure, the term severe sepsis is used and this condition affects more than 750,000 people annually in the United States with mortality rates ranging from 28% to 50% (2, 3). However, clinical manifestations of severe sepsis are not homogenous with some patients exhibiting different degrees of organ dysfunction compared with others. For example, some patients exhibit profound shock requiring vasopressors while others are hemodynamically stable yet may still manifest other forms of organ dysfunction. Similarly, there is marked variation in the manifestation of various pathophysiologic processes in patients with sepsis. In a large observational study of community acquired pneumonia expression of inflammation (by circulating cytokines for example) was highly variable (4). For example, interleukin (IL)-6 concentrations in the plasma ranged from normal (<5.9 pg/mL) to markedly elevated (>105 pg/mL). While mean cytokine levels were significantly higher for patients with severe sepsis compared with those without, there was considerable overlap.
Importantly, sepsis involves complex interactions between endothelial cells, platelets, leukocytes, and the coagulation system, as well as inflammatory mediators. Similar variation exists in the expression of coagulation abnormalities as that seen with inflammation and even the least ill patient with sepsis frequently demonstrates at least some abnormalities (5). Since high concentrations of circulating mediators tend to correlate with mortality and mortality is highest when both pro- and anti-inflammatory cytokine levels are high (4), extracorporeal blood purification is used by some centers in order to modulate the immune response. Unlike drugs targeting specific mediators, blood purification can influence a wide range of molecules. While source control and antibiotics remain the mainstays of therapy for infection (6), no specific treatment for sepsis is available. Observations over more than 20 years have suggested a role for extracorporeal blood purification, but no definitive trials have been published to date (7). Indeed while a meta-analysis of multiple small trials (Fig. 1) has shown potential for blood purification to be effective in sepsis, two of the largest trials to date do not support its use (8, 9). First, Payen et al. (8) conducted a prospective, randomized, multicenter trial in 12 ICUs in France. They enrolled 80 patients within 24 h of development of the first sepsis-related organ failure and randomized them to receive either hemofiltration (25 mL/kg/h) for a 96-h period, or conventional management. The trial was discontinued after an interim analysis and while there was no difference in survival, the number and severity of organ failures (the primary endpoints) were significantly higher in the hemofiltration group (P < 0.05). Importantly, despite recovery of cytokines in the ultrafiltrate, no changes in plasma cytokine levels were detected. Given that the primary target of the blood purification, plasma cytokines, was not impacted, it is perhaps not surprising that the therapy was not effective. The authors concluded that while standard dose hemofiltration (25 mL/kg/h) was not beneficial, higher doses might be. Next, Joannes-Boyau et al. tested this hypothesis in a multicenter clinical trial in 18 ICUs in France, Belgium, and The Netherlands (9). They enrolled 140 critically ill patients with septic shock and acute kidney injury for less than 24 h and randomized them to either high-volume hemofiltration (HVHF) at 70 mL/kg/h or standard-volume hemofiltration (SVHF) at 35 mL/kg/h, for a 96-h period. This trial was also stopped prematurely after enrolment of 140 patients because of slow patient accrual. The primary study endpoint was mortality at 28 days which was not different between groups (HVHF 37.9 % vs. SVHF 40.8 %, log-rank test P = 0.94). Unfortunately, this trial did not measure cytokine or any other markers so we do not know if the therapy was ineffective because it failed to modulate the immune response or whether immune modulation itself was ineffective. The two trials shared important features including early initiation, enrollment based on a clinical diagnosis of sepsis (regardless of the source) rather than driven by molecular targets.
Various forms of extracorporeal blood purification, from apheresis to hemofiltration, are standard of care for management of specific forms of sepsis around the world. However, there is currently no consensus on how these therapies should be applied or studied in clinical trials (10). One major stumbling block has been the lack of clear descriptions of sepsis phenotypes—tied to specific mechanisms that would permit the identification of molecular targets. The purpose of the fourteenth international consensus conference of acute dialysis quality initiative (ADQI) was to develop consensus for a conceptual model of sepsis-induced organ failure that can be treated by extracorporeal blood purification and possibly also with drugs or other therapies. Current evidence suggests that sepsis-related morbidity and mortality involve widely different clinical phenotypes that variably include mitochondrial dysfunction, abnormalities of vascular biology including endothelial dysfunction and coagulopathy, epithelial dysfunction, and immune suppression and dysregulation (1). While most cases of sepsis involve some element of all of these pathobiologic processes, the magnitude of each varies greatly from patient to patient in part as a result of the pathogen and in part related to host-specific factors.
ADQI methodology combines both “expert panel” and “evidence appraisal” and was chosen to achieve the best of both methods. We recognize that the expert panel in the absence of the literature can lead to statements at odds with high-quality research and that evidence appraisal without expert input to question the framework can lead to erroneous interpretation. Furthermore, this combined approach has led to important practice guidelines with wide acceptance and adoption into clinical practice (11). We further recognize that additional research will be needed and that the development of a research agenda will also be fostered by this approach (12). The specific methods for ADQI conferences have been developed and refined over several years and have been reported in detail elsewhere (13). Briefly, our methods comprise (a) a systematic search for evidence with review and evaluation of the available literature, (b) the establishment of clinical and physiologic outcomes as well as measures to be used for comparison of different treatments, (c) the description of the current practice and the rationale for the use of current techniques, and (d) the analysis of areas in which evidence is lacking and future research is required to obtain new information. The topics chosen for each conference are selected on the basis of the following criteria: (a) prevalence of the clinical problem, (b) estimate of variation in clinical practice, (c) potential influence on outcome, (d) potential for development of evidence-based guidelines, and (e) availability of scientific evidence.
The activities for each ADQI conference are divided into three phases: preconference, conference, and post-conference. In the preconference phase, the topics are selected and the work groups are assembled and assigned to specific topics. Each group identifies a list of key questions, conducts a systematic literature search, and generates a bibliography of key studies. Studies are identified via Medline search, bibliographies of review articles, and participants’ files. Searches are generally limited to English-language articles. However, articles written in other languages are used when identified and presented by members of the group. The next step, the conference itself, is divided into breakout sessions, where work groups address the issues in their assigned topic area, and plenary sessions, where the findings and deliberations are presented, debated, and refined. Each work group is composed of four to six members (Table 1). Conference directors circulate between the breakout groups and also serve as facilitators and moderators for plenary sessions. A series of summary statements are then developed through a series of breakout sessions where individual work group members are required to identify key issues for which recommendations are needed, classify the current state of consensus, and identify supporting evidence for each issue. Work group members are then required to present their findings to the entire group, revising each statement as needed until a final version is agreed upon. The responsibility for presenting the findings of the work group to the rest of the participants is typically shared by each member on a rotating basis. Group facilitators revise work group findings as needed after each plenary session. Directives for future research are also sought and when possible, pertinent study design issues are also considered. Finally, a writing committee assembles the individual reports from the work groups. Each report is edited to conform to a uniform style and for length. The final reports are then circulated to each participant for comment and revision.
The ADQI XIV consensus conference took place in Bogota, Colombia, from Oct 13–15, 2014 and focused on sepsis phenotypes and targets for blood purification as well as other therapies and diagnostics. The conference was jointly organized by ADQI and the Academia Colombiana de Medicina Crítica (ACOMEC) and sponsored by unrestricted educational grants from numerous industry partners. As many of the most representative groups that have worked on this topic come from Europe, Australia, and North America, we have intended to provide this conference with an unbiased, neutral ground for sound discussion, as well as inclusion of other regions in the world interested in sepsis.
Recent evidence suggests that mortality from severe sepsis (14) or even septic shock (15) has decreased dramatically over the last decade. However, although considerable advances in the understanding of the pathogenesis of sepsis have been made, there have been no new treatments to account for the improvement in survival. As such, the explanation for this apparent improvement is more likely to be found in improved recognition. Improved recognition of sepsis affects overall survival in two ways. First, more patients receive early effective antibiotics and source control and fewer go unrecognized with inadequate resuscitation. Second, more patients are included in epidemiologic studies of sepsis and these new patients have less severe disease and hence better overall outcomes. Thus, the apparent improvement in survival for sepsis is both real and artificial. Unfortunately, there remains a subpopulation of patients with sepsis whose mortality has not changed. For example, the composite mortality at 90 days in the 6S trial (a trial of fluid therapy in patients with severe sepsis) was 47% (16). Thus, the quest for effective therapies for the most severe patients with sepsis remains.
Extracorporeal blood purification as an adjunctive therapy for sepsis has been used for several years, but its efficacy is still unknown. In recent years, there has also been considerable progress in our understanding of the technical capabilities and the rationale for its use. Although data from large-scale randomized clinical trials are lacking, some technologies seem promising in animal studies and small-scale clinical observations. However, over the last decade important new insights have been gained as to sepsis pathophysiology. It is time for us to re-evaluate blood purification in light of these new findings (17).
Pathophysiology of sepsis: new insights
Probably, the most critical advance in our understanding of sepsis over the past three decades is the discovery that pattern recognition receptors on the surface of many cells can respond to a number of different molecules derived from both pathogen and host (18). Thus, the host response to sepsis is not different, at a molecular level, from the response to massive tissue injury from trauma for example. Furthermore, although it remains generally accepted that systemic inflammation in response to pathogen or tissue damage is in large part responsible for the development of shock and the occurrence of organ injury (19), it is becoming increasingly apparent that this host response also induces severe immune suppression (20) and this defect plays a major role in mortality (21). Failure to address both the cytotoxic and immune suppressive components of sepsis may help explain the lack of success in developing effective treatments for sepsis. Unfortunately, the two phenomena produce a conundrum: how can innate immunity be simultaneously curtailed to limit tissue damage and augmented to improve bacterial clearance? The answer, at least in part, appears to come from the multicompartmental aspects of systemic infection and the role of chemokines and cytokines in directing leukocyte traffic (22, 23).
A useful model of immune response and dysfunction is immunosenescence. Older animals and humans exhibit greater cytokine response yet worse bacterial clearance and increased mortality (21). Indeed, older individuals are also much more susceptible to sepsis. Recent evidence points to the critical role of chemokine gradients between the nidus of infection and the systemic circulation (24, 25). Systemic activation of inflammation recruits immune effector cells into the circulation and into tissues away from the pathogen, simultaneously impairing pathogen clearance and increasing remote organ injury. Thus, an important goal of treatment would be to reduce systemic inflammation without reducing inflammation at the local site of infection.
A third stumbling block that may have limited the development of targeted, effective therapies is the lack of recognition that various phenotypes, possibly linked to diverse, specific mechanistic pathways, coalesce within the current broad definition of the septic syndrome. This has been evident by the failed overall results of multiple clinical trials that have consistently targeted therapeutic interventions to populations selected on the sole basis of clinical severity framed by the current broad definition; and by the demonstration by these same trials that despite discouraging average results, subpopulations of patients still respond dramatically to various interventions. The recognition of such diversity may be fundamental to the future research agenda, to trial design and ultimately to succeed in identifying targeted therapies that will ameliorate not only the overall mortality of the syndrome, but also, the morbid consequences that many of the survivors have to deal with long after discharge.
A potential role for blood purification
Considering the complexity of the host response, effective modulation would require influencing multiple domains from inflammation to coagulation. Furthermore, any effective treatment must promote pathogen clearance or at least not reduce it. Such a therapy would need to influence a variety of cells and mediators given the enormous redundancy of inflammatory signaling networks. Most of the immune mediators in sepsis are water-soluble and fall into the “middle molecular-weight” category and hence can theoretically be removed by a blood purification system designed for renal support (e.g., hemofiltration). These mediators include eicosanoids, leukotrienes, complement, cytokines, chemokines, and other potentially important small peptides and vasogenic substances. Available blood purification technologies can remove these inflammatory mediators via convection, diffusion, and adsorption. The effects of blood purification are broad-spectrum and autoregulating. These advantages provide a powerful rationale for blood purification used in sepsis. However, existing renal replacement technology is quite limited in its ability to achieve biologically relevant reductions in mediators of inflammation and apoptosis (26).
Fortunately, extracorporeal therapies have been improved considerable over the last two decades (27). To augment convective clearance, hemofiltration rates were increased and high-volume hemofiltration (HVHF) was developed. To improve convective or diffusive clearances of large molecules membranes with increased permeability, large surface area and a nominal cutoff of 60 to 150 kD have been developed. However as filter permeability is increased, albumin loss becomes inevitable. More importantly, HVHF has not been shown to be more effective than standard hemofiltration for management of patients with severe sepsis and AKI (9). However, trials have not phenotyped patients beyond crude clinical criteria and thus it remains unknown whether HVHF might have a role in select patients.
Sorbents have been shown to increase the removal of inflammatory mediators markedly with improved survival in animals (28). Therefore, an alternative strategy for the reduction of soluble immune mediators and modulation of cellular immunity is provided by adsorption technologies. Sorbents bind molecules as a result of hydrophobic interactions, electrostatic attraction, hydrogen bonding, and van der Waals forces. Adsorptive materials include activated charcoal, polymyxin B-immobilized sepharose, amino-acid-immobilized adsorbents, polyamine-immobilized adsorbents, adsorbents having hydrophobic alkali chain ligand, and adsorbents with special antibodies. The present technology for appropriately modifying several intrinsic characteristics of the adsorbents has helped fine-tune extracorporeal devices for more defined clinical applications. These properties, together with improved biocompatibility, have allowed the development of sorbent techniques to obtain clearances and total removal rates of target compounds that would be unthinkable with conventional hemodialysis or hemofiltration.
In order to remove mediators with high efficacy hybrid techniques have been produced comprising the combination of advantages of different purification methods. Coupled plasma filtration-adsorption (CPFA) is one such technique (29, 30). CPFA involves plasma separation followed by an adsorptive step-over sorbent allowing nonspecific removal of mediators. After return of the cleaned plasma to the circuit, standard hemofiltration is applied. As a low flow of plasma is used, it allows a longer contact time of mediators with the sorbent. Two small studies have shown that CPFA improves hemodynamic status and immune function in patients with severe sepsis and multiorgan dysfunction (29, 30). Interestingly, changes in monocyte function and hemodynamics were achieved without any measurable effect on plasma levels of TNF and IL-10. In the future, the optimal blood purification strategy could be to combine physicochemical principles in one single technique. For example, a new hemofiltration membrane having enhanced adsorption properties was recently developed, allowing combination of high convective exchanges with endotoxin adsorption (30).
Interestingly, while broad-spectrum immunomodulation may be desirable for some patients, a class of small molecules appears to be of critical importance in simultaneously promoting pathogen clearance and remote organ injury. Recruitment of leukocytes to the location of pathogens is a critical step in the innate immune response to infection (31). However, leukocyte trafficking during sepsis is altered (32) and widespread activation of neutrophils and monocytes leads to multiple organ injury and failure (33–35). Directing leukocyte recruitment to the site of infection and away from healthy tissue can therefore be seen as a fundamental strategy to treat sepsis (23). Numerous studies have suggested that leukocyte recruitment is dramatically influenced by the relative proportions of chemokines such as (C-X-C motif ligand 1 (CXCL1), and ligand 2 (CXCL2), between tissue and plasma (25, 36, 37). Within a physiologic range, as the gradient between infected tissue and plasma increases, leukocyte recruitment is enhanced and pathogen clearance is improved. Conversely, as the gradient between noninfected tissue and plasma increases, inflammation and injury to these tissues are worsened. Recently, Craciun et al. (22) demonstrated that local injection of CXCL1 and CXCL2 into the peritoneum following cecal ligation and puncture (CLP) resulted in enhanced neutrophil localization, decreased bacterial growth, and improved survival in mice. However, translation of these findings into clinical practice would be challenging. Alternatively, it is possible to change the chemokine gradients by reducing the plasma concentrations using apheresis. Using CytoSorb beads, Peng et al. (23) recently studied rats with CLP-induced sepsis. In these experiments apheresis significantly removed plasma cytokines and chemokines, increased peritoneal fluid to blood chemokine (CXCL1, CXCL2, and C-C motif ligand 2) ratios, and decreased bronchoalveolar lavage fluid to blood chemokine ratios resulting in enhanced leukocyte recruitment into the peritoneal cavity and improved bacterial clearance, but decreased recruitment into the lung. Apheresis also reduced myeloperoxidase activity and histological injury in the lung, liver, and kidney. Labeled donor neutrophils exhibited decreased localization in the lung when infused into apheresis treated animals. Thus, these results support the concept of chemokine gradient control of leukocyte trafficking and demonstrate efficacy of apheresis to target this mechanism and reduce leukocyte infiltration in the lung.
Blood purification has also been reported to restore immune function through the regulation of monocytes and neutrophils (29, 38). Oxidative burst and phagocytosis capacity have been shown to be impaired in septic patients. In an experimental porcine sepsis model, high-volume hemofiltration (HVHF; 100 mL/kg/h) improved oxidative burst and phagocytosis in polymorphonuclear leukocytes, which suggested that neutrophil function was stabilized by HVHF (38). HVHF significantly reduced bacterial translocation and endotoxemia and improved long-term survival (>60 h), 67 vs. 33% with low-volume hemofiltration versus 0% in controls. Improvement in MHC II and CD14 expression on monocytes (markers of monocyte function) was also observed with HVHF in this study (38). Finally, in a clinical study, CPFA increased HLA-DR expression in monocytes of septic patients and also improved leukocyte responsiveness after LPS stimulus (in vitro) in septic patients (29).
In conclusion, blood purification offers many potential advantages over alternative therapies for sepsis and other forms of systemic inflammation. However, progress has been slow due to inadequate understanding of potential targets and failure to phenotype patients enrolled in trials. ADQI is an iterative process that produces evidence-based statements on different issues concerning the interface between nephrology and critical care medicine. Our efforts aim at distilling the evidence and presenting it with perspective and interpretation and at developing a research agenda dedicated to improving patient care in this field. We hope this ADQI on sepsis and blood purification will further the interest of those already investigating this lethal disease, and will ignite curiosity in others. We seek to advance an ongoing dialogue that will continue to move closer to the goal of improving knowledge and practice in the management of these complex patients.
APPENDIX 1. ADQI XIV WORKGROUP
Lakhmir S. Chawla
Daniel de Backer
Clifford S. Deutschman
Mitchell P. Fink
Stuart L. Goldstein
John A. Kellum
John C. Marshall
Philip R. Mayeux
Trung C. Nguyen
Steven M. Opal
Michael R. Pinksy
Paul T. Schumacker
Brian S. Zuckerbraun
Appendix 2. Search Terms
Sepsis, inflammation, ADQI, dialysis, renal replacement therapy, blood purification, organ dysfunction, phenotype, molecular targets, epithelium, endothelium, immune cells, mitochondria.
1. Angus DC, van der Poll T. Severe sepsis
and septic shock. N Engl J Med
2013; 369 9:840–851.
2. Angus DC, Lidicker J, Linde-Zwirble WT, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis
in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med
3. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis
in the United States from 1979 through 2000. N Engl J Med
2003; 348 16:1546–1554.
4. Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky MR, Fine J, Krichevsky A, Delude RL, Angus DC, et al. Understanding the inflammatory cytokine response in pneumonia and sepsis
: results of the Genetic and Inflammatory Markers of Sepsis
(GenIMS) Study. Arch Intern Med
2007; 167 15:1655–1663.
5. Milbrandt EB, Reade MC, Lee M, Shook SL, Angus DC, Kong L, Carter M, Yealy DM, Kellum JA. GenIMS Investigators. Prevalence and significance of coagulation abnormalities in community-acquired pneumonia. Mol Med
2009; 15 (11–12):438–445.
6. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, et al. Surviving sepsis
campaign: international guidelines for management of severe sepsis
and septic shock: 2012. Crit Care Med
2013; 41 2:580–637.
7. 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 9:2209–2220.
8. Payen D, Mateo J, Cavaillon JM, Fraisse F, Floriot C, Vicaut E. Hemofilration and Sepsis
Group of the Collége National de Réanimation et de Médecine d’Urgence des Hôpitaux extra-Universitaires. Impact of continuous venovenous hemofiltration on organ failure during the early phase of severe sepsis
: a randomized controlled trial. Crit Care Med
2009; 37 3:803–810.
9. Joannes-Boyau O, Honore PM, Perez P, Bagshaw SM, Grand H, Canivet JL, Dewitte A, Flamens C, Pujol W, Grandoulier AS, 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 9:1535–1546.
10. Kellum JA, Uchino S. International differences in the treatment
: are they justified? JAMA
2009; 301 23:2496–2497.
11. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute Dialysis Quality Initiative workgroup. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care
2004; 8 4:R204–R212.
12. Vella K, Goldfrad C, Rowan K, Bion J, Black N. Use of consensus development to establish national research priorities in critical care. BMJ
2000; 320 7240:976–980.
13. Kellum JA, Bellomo R, Ronco C. Acute dialysis quality initiative (ADQI): methodology. Int J Artif Organs
2008; 31 2:90–93.
14. Kaukonen K-M, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe sepsis
and septic shock among critically ill patients in Australia and New Zealand, 2000–2012. JAMA
2014; 311 13:1308–1316.
15. Yealy DM, Kellum JA, Huang DT, Barnato AE, WEissfeld LA, Pike F, Terndrup T, Wang HE, Hou PC, et al. ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. ProCESS InvestigatorsN Engl J Med
2014; 370 18:1683–1693.
16. Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Åneman A, Madsen KR, Møller MH, Elkjaer JM, Poulsen LM, et al. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis
. N Engl J Med
2012; 367 2:124–134.
17. Peng Z, Singbartl K, Simon P, Rimmelé T, Bishop J, Clermont G, Kellum JA. Blood purification
: a new paradigm. Contrib Nephrol
18. Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards DR, McDonald-Smith GP, Gao H, Hennessy L, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci USA
2013; 110 9:3507–3512.
19. Bone RC. The pathogenesis of sepsis
. Ann Intern Med
1991; 115 6:457–469.
20. Hotchkiss RS, Coopersmith CM, McDunn JE, Ferguson TA. The sepsis
seesaw: tilting toward immunosuppression. Nat Med
2009; 15 5:496–497.
21. Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards DR, McDonald-Smith GP, Gao H, Hennessy L, et al. Effects of aging on the immunopathologic response to sepsis
. Crit Care Med
2009; 37 3:1018–1023.
22. Craciun FL, Schuller ER, Remick DG. Early enhanced local neutrophil recruitment in peritonitis-induced sepsis
improves bacterial clearance and survival. J Immunol
2010; 185 11:6930–6938.
23. Peng Z-Y, Bishop JV, Wen X-Y, Elder M, Zhou F, Chuasuwan A, Carter MJ, Devlin JE, Kaynar AM, Singbartl K, et al. Modulation of chemokine gradients by apheresis redirects leukocyte trafficking to different compartments during sepsis
, studies in a rat model. Crit Care
2014; 18 4:1–13.
24. Alves-Filho JC, Freitas A, Souto FO, Spiller F, Paula-Neto H, Silva JS, Gazzinelli RT, Teixeira MM, Ferreira SH, Cunha FQ. Regulation of chemokine receptor by Toll-like receptor 2 is critical to neutrophil migration and resistance to polymicrobial sepsis
. Proc Natl Acad Sci USA
2009; 106 10:4018–4023.
25. Call DR, Nemzek JA, Ebong SJ, Bolgos GL, Newcomb DE, Remick DG. Ratio of local to systemic chemokine concentrations regulates neutrophil recruitment. Am J Pathol
2001; 158 2:715–721.
26. Murugan R, Wen X, Shah N, Lee M, Kong L, Pike F, Keener C, Unruh M, Finkel K, Vijayan A, et al. Plasma inflammatory and apoptosis markers are associated with dialysis dependence and death among critically ill patients receiving renal replacement therapy. Nephrol Dial Transplant
27. Rimmele T, Kellum JA. High-volume hemofiltration in the intensive care unit: a blood purification
2012; 116 6:1377–1387.
28. 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 5:1573–1577.
29. Ronco C, Brendolan A, Lonnemann G, Bellomo R, Piccinni P, Digito A, Dan M, Irone M, La Greca G, Inguaggiato P, et al. A pilot study of coupled plasma filtration with adsorption in septic shock. Crit Care Med
2002; 30 6:1250–1255.
30. Rimméle T, Assadi A, Cattenoz M, Desebbe O, Lambert C, Boselli E, Goudable J, Etienne J, Chassard D, Bricca G, et al. High-volume haemofiltration with a new haemofiltration membrane having enhanced adsorption properties in septic pigs. Nephrol Dial Transplant
2009; 24 2:421–427.
31. Alves-Filho JC, Sônego F, Souto FO, Freitas A, Verri WA Jr, Auxiliadora-Martins M, Basile-Filho A, McKenzie AN, Xu D, Cunha FQ, et al. Interleukin-33 attenuates sepsis
by enhancing neutrophil influx to the site of infection. Nat Med
2010; 16 6:708–712.
32. Guo R-F, Riedemann NC, Laudes IJ, Sarma VJ, Kunkel RG, Dilley KA, Paulauskis JD, Ward PA. Altered neutrophil trafficking during sepsis
. J Immunol
2002; 169 1:307–314.
33. Brown KA, Brain SD, Pearson JD, Edgeworth JD, Lewis SM, Treacher DF. Neutrophils in development of multiple organ failure in sepsis
2006; 368 9530:157–169.
34. Souto FO, Alves-Filho JC, Turato WM, Auxiliadora-Martins M, Basile-Filho A, Cunha FQ. Essential role of CCR2 in neutrophil tissue infiltration and multiple organ dysfunction in sepsis
. Am J Respir Crit Care Med
2011; 183 2:234–242.
35. Rittirsch D, Flierl MA, Ward PA. Harmful molecular mechanisms in sepsis
. Nat Rev Immunol
2008; 8 10:776–787.
36. Remick DG, Green LB, Newcomb DE, Garg SJ, Bolgos GL, Call DR. CXC chemokine redundancy ensures local neutrophil recruitment during acute inflammation. Am J Pathol
2001; 159 3:1149–1157.
37. Cavčić A, Tešović G, Gorenec L, Grgić I, Benić B, Lepej SŽ. Concentration gradient of CXCL10 and CXCL11 between the cerebrospinal fluid and plasma in children with enteroviral aseptic meningitis. Eur J Paediatr Neurol
2011; 15 6:502–507.
38. Yekebas EF, Eisenberger CF, Ohnesorge H, Saalmüller, Elsner HA, Englehardt M, Gillesen A, Meins J, Strate T, et al. Attenuation of sepsis
-related immunoparalysis by continuous veno-venous hemofiltration in experimental porcine pancreatitis. Crit Care Med
2001; 29 7:1423–1430.