Use of adsorptive mechanisms in continuous renal replacement therapies in the critically ill

Abstract

Use of adsorptive mechanisms in continuous renal replacement therapies in the critically ill. The pathophysiology of sepsis is becoming a more complicated scenario. In sepsis, endotoxin or other gram-positive derived products induce a complex and dynamic cellular response giving rise to several mediators known to be relevant in the pathogenesis of septic shock, such as specific mediators, substances responsible for up- or down-regulation of cytokine receptors and cytokine antagonists, inactivators of nuclear factor B or signal transduction pathways, and precursor molecules. In this article, we delve into some new concepts stemming from the use of sorbents in continuous plasma filtration. The rationale is based on the assumption that the nonspecific removal of several mediators of the inflammatory cascade and cytokine network may improve outcome in a rabbit model of septic shock and hemodynamics in a pilot clinical study. The importance of looking for innovative treatments specifically targeted for the special needs of the critically ill patients rather than using concepts and technology applied to the treatment of chronic renal failure is underlined. Use of adsorptive mechanisms in continuous renal replacement therapies in the critically ill. The pathophysiology of sepsis is becoming a more complicated scenario. In sepsis, endotoxin or other gram-positive derived products induce a complex and dynamic cellular response giving rise to several mediators known to be relevant in the pathogenesis of septic shock, such as specific mediators, substances responsible for up- or down-regulation of cytokine receptors and cytokine antagonists, inactivators of nuclear factor B or signal transduction pathways, and precursor molecules. In this article, we delve into some new concepts stemming from the use of sorbents in continuous plasma filtration. The rationale is based on the assumption that the nonspecific removal of several mediators of the inflammatory cascade and cytokine network may improve outcome in a rabbit model of septic shock and hemodynamics in a pilot clinical study. The importance of looking for innovative treatments specifically targeted for the special needs of the critically ill patients rather than using concepts and technology applied to the treatment of chronic renal failure is underlined. Sepsis develops as a result of the host response to infection1Morrison D.C. Ulevitch R.Y. The effects of bacterial endotoxin on host mediator system.Am J Pathol. 1987; 93: 527-617Google Scholar. Bacterial components such as the lipid A-containing lipopolysaccharide (LPS) in the cell wall of gram-negative bacteria trigger a global response that involves both cellular and humoral systems with the generation of both proinflammatory and anti-inflammatory activities2Glauser M.P. Zanetti G. Baumgartner J.D. Cohen J. 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Continuous renal replacement therapies (CRRT) also have made extracorporeal treatment possible in hemodynamically unstable patients in order to balance hypercatabolism and hyperhydration. In addition to removing excess fluid and sodium in septic patients, the removal of LPS and other mediators by CRRTs has introduced the new concept of blood purification6Silvester W. Bellomo R. Ronco C. Continuous versus intermittent renal replacement therapy in the critically ill.Critical Care Nephrology. edited by Ronco C, Bellomo R. 1998: 1225-1238Crossref Google Scholar, 7Canaud B. Mion C. Extracorporeal treatment of acute renal failure: Methods, indications, quantified and personalized therapeutic approach.Adv Nephrol. 1995; 24: 271-281PubMed Google Scholar, 8Bellomo R. Tipping P. Boyce N. Continuous veno-venous hemofiltration with dialysis cytokines from the circulation of septic patients.Crit Care Med. 1993; 21: 522-526Crossref PubMed Scopus (327) Google Scholar, 9Schetz M. Ferdinande P. 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Removal of pro-inflammatory cytokines with renal replacement therapy: Sense or nonsense?.Intensive Care Med. 1995; 21: 169-176Crossref PubMed Scopus (110) Google Scholar, 10van Bommel E.F.H. Hesse C.J. Jutte N.H. Zietse R. Bruining H.A. Weimer W. Cytokine kinetics (TNF, IL1β, IL6) during continuous hemofiltration: A laboratory and clinical study.Contrib Nephrol. 1995; 116: 62-75Crossref PubMed Google Scholar, 11Bellomo R. Tipping P. Boyce N. Interleukin-6 and interleukin-8 extraction during continuous venovenous-hemodiafiltration in septic acute renal failure.Renal Fail. 1995; 17: 457-466Crossref PubMed Scopus (63) Google Scholar, 12Millar A.B. Armstrong L. van der Linden J. Moat N. Ekroth R. Westwick J. Scallan M. Lincoln C. Cytokine production and hemofiltration in children undergoing cardiopulmonary bypass.Ann Thorac Surg. 1993; 56: 1499-1502Abstract Full Text PDF PubMed Scopus (164) Google Scholar, 13Journois D. Pouard P. Greely W.J. Mauriat P. Vouhe P. Safran D. Hemofiltration during cardiopulmonary bypass in pediatric cardiac surgery.Anesthesiology. 1994; 81: 1181-1189Crossref PubMed Scopus (231) Google Scholar, 14Goldfarb S. Golper T.A. Proinflammatory cytokines and hemofiltration membranes.J Am Soc Nephrol. 1994; 5: 228-232PubMed Google Scholar, 15Ronco C. Tetta C. Lupi A. Galloni E. Bettini M.C. Sereni L. Mariano F. De Martino A. Montrucchio G. Camussi G. La Greco G. Removal for platelet-activating factor in experimental continuous arteriovenous hemofiltration.Crit Care Med. 1995; 23: 99-107Crossref PubMed Scopus (78) Google Scholar, 16Hoffmann J.N. Hartl W.H. Deppisch R. Faist E. Jochum M. Inthorn D. Hemofiltration in human sepsis: Evidence for elimination of immunomodulatory substances.Kidney Int. 1995; 48: 1563-1570Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 17Lonnemann G. Schindler R. Dinarello C.A. Removal of circulating cytokines by hemodialysis membranes in vitro.Host Defense Dysfunction in Trauma: Shock and Sepsis. edited by Faist E, Markewitz A, Schildber C. 1993Crossref Google Scholar. For this reason, the fulfillment and even the very rationale of blood purification in CRRT have been disputed. The concept of a continuous therapy in critically ill patients is self-evident. These are patients who, aside from their quite unstable hemodynamics, are in need of a high calorie intake and an intravenous drug administration that must be in balance with poorly functioning kidneys. Conventional CRRTs have gained increased popularity for their ability to ensure the removal of excess fluid and sodium in septic patients. In order to enhance the removal of septic-associated mediators, two approaches have been taken under consideration. In their original proposal, Grootendorst et al suggested that high-volume (100 liter/day) hemodiafiltration could remove cardiac depressant activity and other sepsis mediators in the ultrafiltrate in a pig model of septic shock18Grootendorst A.F. van Bommel E.F. van der Hoven B. van Leengoed L.A. van Osta A.L. High-volume hemofiltration improves right ventricular function in endotoxin-induced shock in the pig.Intensive Care Med. 1992; 18: 235-240Crossref PubMed Scopus (224) Google Scholar. In a subsequent clinical study, Bellomo et al further implicated this possibility, as evidenced by a significant reduction in norepinephrine administration19Bellomo R. Baldwin I. Cole L. Ronco C. Preliminary experience with high-volume hemofiltration in human septic shock.Kidney Int. 1998; 53: S182-S185Google Scholar. The other approach has been to use larger pore membranes than those currently used in hemofiltration. Lee et al suggested an increased survival in a porcine model of septic shock and related it to an enhanced overall blood purification20Lee Pa Matson J.R. Pryor R.W. Hinshaw L.B. Continuous arteriovenous hemofiltration therapy for Staphylococcus aureus-induced septicemia in immature swine.Crit Care Med. 1993; 21: 914-924Crossref PubMed Scopus (97) Google Scholar. Other authors have reported the benefits in survival when using plasmapheresis in both animal21Lonergan J.M. Orlowski J.P. Sato T. Mchugh M.J. Zborowski M. Extracorporeal endotoxin removal in a canine model of septic shock.ASAIO J. 1994; 40: M654-M657Crossref PubMed Scopus (12) Google Scholar and human22Berlot G. Tomasini A. Silvestri L. Gullo A. Plasmapheresis in the critically ill patient.Kidney Int. 1998; 53: S178-S181Google Scholar studies. In vitro studies showed that plasma filtration allowed the removal of higher amounts of proinflammatory cytokines (such as TNF-α, IL-1β, IL-8). Clearances and sieving coefficients of these cytokines were greatly and significantly increased with “open” plasma filtration membranes rather than with high permeability membranes Figure 123Tetta C. Cavaillon J.M. Schulze M. Ronco C. Ghezzi P.M. Camussi G. Serra A.M. Curti F. Lonnemann G. Removal of cytokines and activated complement components in an experimental model of continuous plasmafiltration coupled with sorbent adsorption.Nephrol Dial Transplant. 1998; 13: 1458-1464Crossref PubMed Scopus (95) Google Scholar. However, plasmapheresis is hardly as considerable or effective as a CRRT. The combination of the two requirements, that is, higher sieving coefficient and continuous therapy, has led to the implication of sorbents in affecting the experimental or clinical outcome. The use of sorbents in extracorporeal therapies is not new. Classically, hemoperfusion and more recently apheresis have witnessed intensive research in this area. Sorbents may be of a natural origin, such as charcoal (mineral or vegetable) or synthetic (different resins with covalently bound groups reactive with specific ligands). Treatment modalities have been either hemoperfusion, double-chamber hemodiafiltration, or plasma separation with sorbent adsorption. Although hemoperfusion has the advantage of a much simpler circuit, it may require the sorbents to be rendered biocompatible for the direct contact with blood and with blood cells particularly. In the case of charcoals, which exhibit a high adsorbent capacity, especially for low molecular weight waste products that accumulate during kidney or liver failure, their use in hemoperfusion requires them to be used in “coated” forms. However, coated charcoals, albeit biocompatible, have a remarkably reduced adsorptive capacity. The alternative has been the use of sorbents in an “uncoated” form on the ultrafiltrate or the plasma filtrate [reviewed in24La Greca G. Brendolan A. Ghezzi P.M. De Smet R. Tetta C. Gervasio R. Ronco C. The concept of sorbents in hemodialysis.Int J Artif Organs. 1998; 21 (editorial): 303-308PubMed Google Scholar]. In the field of hemoperfusion, besides the widely-used coated charcoal (Detoxyl, Sorin), new applications such as heparin removal devices (HRD)s, using plasma separation and poly-L-lysine affinity adsorption have been shown to be an effective alternative to protamine after cardiopulmonary bypass25Tao W. Deyo D.J. Alpard S.K. Vertrees R.A. Hoang V. Zwischenberger J.B. Significant reduction in circuit pressure with modified plasma separation chamber for a heparin removal device.ASAIO J. 1999; 45: 50-52Crossref PubMed Scopus (2) Google Scholar. Different commercially available sorbents for specific target molecules in human disease, when they are considered of pathogenetic relevance, such as low-density lipoproteins [DALI (Fresenius, Bad Homburg, Germany), Liposorber (LA-15; Kaneka), LDL-Therasorb (Baxter, McGaw Park, IL, USA)], immune complexes, antibodies, or activated complement components [Therasorb (Baxter), Prosorba® or MIRO (Fresenius)], or anti-DNA antibodies (Immunosorba PH-350 and TR-350; Asahi Medical Co., Ltd., Tokyo, Japan; Selesorb, Kaneka Co., Osaka, Japan). In apheresis, there has been a widespread tendency to remove “bad factors” rather than to attempt to bring about a restoration of balance of physiological factors. Often, too much emphasis is on individual markers, and treatments need to focus on a “balancing hypothesis” such as immunological suppression versus activation. This becomes particularly true when the converging concepts of plasma filtration coupled with sorbent adsorption are to be applied to the very complex scenario of severe sepsis evolving in septic shock. The rationale for sorbent adsorption in a plasma filtration system is to reinfuse endogenous plasma after nonselective simultaneous removal of different sepsis-associated mediators without the need of donor plasma. This rationale was based on a series of studies in vitro, animal and a preliminary, ethical committee-approved clinical trial according to the European legislation for unregistered biomedical devices (EN 540; Figure 2). In vitro studies demonstrated that removal rates were different according to varying sorbents tested23Tetta C. Cavaillon J.M. Schulze M. Ronco C. Ghezzi P.M. Camussi G. Serra A.M. Curti F. Lonnemann G. Removal of cytokines and activated complement components in an experimental model of continuous plasmafiltration coupled with sorbent adsorption.Nephrol Dial Transplant. 1998; 13: 1458-1464Crossref PubMed Scopus (95) Google Scholar. More importantly, when tested at different linear velocities, their efficiencies in removing cytokines, albeit reduced, were far away above the mass of individual cytokines calculated on the basis of the highest levels detected in the plasma of septic patients23Tetta C. Cavaillon J.M. Schulze M. Ronco C. Ghezzi P.M. Camussi G. Serra A.M. Curti F. Lonnemann G. Removal of cytokines and activated complement components in an experimental model of continuous plasmafiltration coupled with sorbent adsorption.Nephrol Dial Transplant. 1998; 13: 1458-1464Crossref PubMed Scopus (95) Google Scholar. Animal studies were performed in a model of septic shock in the rabbit (abstract; Tetta et al, J Am Soc Nephrol 9:A3008, 1998). The model consisted on a single intravenous injection of LPS at a dose that was experimentally assessed to determine a mortality of 80% at 72 hours. Coupled plasma-filtration adsorption resulted in a significant survival (P = 0.0041; 85%) at 72 hours with respect to rabbits injected with LPS, but not treated with coupled plasma-filtration adsorption. In the pathogenesis of gram-negative infections, the complex and dynamic host interaction involves the inflammatory cascade, complement activation, coagulation, and hemodynamic and physiological parameters26Parillo J.E. Pathogenetic mechanisms of septic shock.N Engl J Med. 1993; 328: 1471-1477Crossref PubMed Scopus (1502) Google Scholar, 27Bone R.C. Sepsis and its complications: The clinical problem.Crit Care Med. 1994; 22: S8-S11PubMed Google Scholar, 28Moldawer L.L. Biology of proinflammatory cytokines and their antagonists.Crit Care Med. 1994; 22: S3-S7Crossref PubMed Scopus (4) Google Scholar. In fact, improved survival was negatively correlated with the severity score that included plasma LPS, bioactive TNF as well as mean arterial protein (MAP), base excess (BE), and white blood cells (WBC). However, cumulative survival was not correlated with the levels of circulating TNF. It must be emphasized that the overall net effect on survival could be due to the removal not only of the mediators that we measured, but also to many other mediators not monitored in our study. Finally, we cannot rule out that the simultaneous removal of different mediators could possibly prevent the formation of other biologically active substances such as prostaglandins/leukotrienes, other cytokines, molecules that up- or down-regulate membrane receptors, selectins, and adhesion molecules. Many new therapeutic strategies have targeted single molecules but thus far have failed to lower the mortality rates [reviewed in5Zeni F. Freeman B. Nathanson C. Anti-inflammatory therapies to treat sepsis and septic shock: A reassessment.Crit Care Med. 1997; 25: 1095-1100Crossref PubMed Scopus (589) Google Scholar]. Whether the simultaneous removal of different mediators was linked in a cause–effect relationship with improved survival in our experimental model was strongly suggested, and may provide the rationale for blood purification to CRRT [reviewed in29Silvester W. Mediator removal with CRRT: Complement and cytokines.Am J Kidney Dis. 1997; 30: S38-S43Abstract Full Text PDF PubMed Scopus (84) Google Scholar]. A clinical trial, which was a prospective, randomized cross-over trial aimed at comparing the clinical and biological effects of coupled plasma-filtration adsorption (CPFA; Figure 3) versus continuous venovenous hemofiltration (CVVH) in critically ill septic patients, has recently been concluded, and preliminary data were presented in abstract form (abstract; Brendolan et al, J Am Soc Nephrol 9:A0655, 1998) Figure 4. The major findings can be summarized as follows. Despite the fact that all patients had relatively low plasma concentrations of cytokines (TNF-α, IL-1β), the sorbent adsorbed almost 100% of the cytokines in the plasma filtrate. In all patients starting the treatment, the in vitro TNF production of circulating monocytes to exogenous LPS was remarkably impaired compared to the monocytes from healthy subjects. When the same patient was studied after five hours of treatment with CPFA, the ability of monocytes to produce TNF-α was restored in the range seen for normal monocytes. Coincubation experiments with a monoclonal antibody directed against IL-10 could abrogate (60%) the monocyte unresponsiveness. In CVVH, abrogation of monocyte unresponsivess was only partial as compared with CPFA, and was significantly delayed (after 10 hr of treatment). At the hemodynamic level, all patients (APACHE score> 20) showed increased peripheral vascular resistances that allowed a significant reduction in the dose of vasopressor drugs at five hours and remained steadily low after 10 hours of treatment. The reduction of vasopressor drugs was not observed during CVVH. These data suggest the possibility that CPFA may ensure better hemodynamics in highly unstable patients than CVVH. Because the CPFA may be modular to conventional CVVH, the system may ensure a fluid and salt balance together with an enhanced blood purification. A prospective, randomized clinical trial involving a large cohort of patients is anticipated and should verify the clinical significance of restoring monocyte responsiveness. Beside CPFA, other systems are now in the process of being evaluated in clinical trials. The detoxification plasma filtration (DTPF) system (HemoCleanse, Inc., West Lafayette, IN, USA) combines the DT hemodiabsorption system in series with a push-pull pheresis plasma-filtration system (a suspension of powdered sorbents surrounding 0.5 micron plasma filter membranes). Bidirectional plasma flow (at 80 to 100 ml/min) across the plasma filtration membranes provides direct contact between plasma proteins and powdered sorbents, as well as clearance of cytokines (TNF-α, IL-1β, and IL-6) at a rate of 15 to 25 ml/min, without evidence of saturation for 90 minutes. In a U.S. Food and Drug Administration-approved study, eight patients with systemic inflammatory response syndrome (SIRS) and organ failure underwent a single DTPF treatment, using powdered charcoal as sorbent in four patients and powdered charcoal and silica in four patients30Levy H. Ash Sr, Knab W. Steczko J. Carr D.J. Blake D.E. Systemic inflammatory response syndrome treatment by powdered sorbent pheresis: Biologic-detoxification plasma filtration system.ASAIO J. 1998; 44: M659-M665Crossref PubMed Scopus (25) Google Scholar. Treatment proceeded for six hours. All patients improved during the treatment, and each had increased blood pressure and decreased need for pressor agents. Plasma cytokine levels stabilized or decreased during treatment and were significantly lower the morning after treatment. Multiple organ dysfunction (MOD) and Acute Physiology Chronic Health Evaluation II scores and organ function gradually improved in most patients, and two patients survived for more than 28 days and two for more than 14 days.Figure 4Criteria used to assess the efficiency of innovative techniques to treat sepsis.View Large Image Figure ViewerDownload (PPT) In conclusion, these new approaches stem from emerging concepts on how to assess innovative techniques for the critically ill patients. Efficiency and adequacy of treatment, known milestones in the extracorporeal treatment for chronic renal failure, are now being reconsidered in critical care nephrology. The complex scenario of sepsis must not be underestimated. Notwithstanding, 20 years or so after the first descriptions, we all face a disease with an ever increasing incidence and unrestrained mortality. The more nephrologists and intensivists will work side by side for a common understanding and a concerted strategy, the more we are going to assist in the development of dedicated and hopefully successful systems for treating critically ill patients.