Septic shock has a high mortality risk despite the availability of various treatments. Endotoxin, an outer membrane component of gram-negative bacteria, plays an important role in the pathogenesis of septic shock. Endotoxin (LPS) and LPS-binding protein bind together to membrane receptor CD14 on the surfaces of monocytes/macrophages and an accessory protein, myeloid differentiation factor 2. This, in turn, activates the signaling molecule complex of Toll-like receptor 4 (TLR-4) to create a signaling complex that activates downstream signaling. This downstream signaling induces an excessive generation of cytokines, which in turn increases systemic inflammatory response and sets the stage for endothelial dysfunction, cellular damage, and organ dysfunction (1).
Polymyxin B, a cationic polypeptide antibiotic, has a strong affinity to endotoxin and is able to bind the lipid A portion of endotoxin through ionic and hydrophobic interactions. Intravenous administration of polymyxin B has significant nephrotoxic and neurotoxic effects. However, the covalent binding of polymyxin B onto the surface of the polystyrene-based carrier fiber inactivates the endotoxin in the blood without exerting toxicity. Polymyxin B-immobilized fiber column hemoperfusion (PMX) is a method performed with a clinically applied adsorbent column (Toraymyxin 20-R; Toray Industries, Inc, Tokyo, Japan) containing 5 mg of polymyxin B per gram of polystyrene fiber with a priming volume of 135 mL (2, 3). Polymyxin B-immobilized fiber column hemoperfusion has been used for the treatment of septic shock since 1994 in Japan and since 2002 in Italy. Its use continues to widen worldwide year by year. This review evaluates the efficacy and mechanism of PMX treatment in patients with septic shock.
A PubMed search was performed to find articles containing the following terms up to February 2011: "PMX" (and/or "polymyxin B hemoperfusion") and "septic shock." The PubMed database and references from identified article were used to search and review the literature relating to PMX treatment in adult patients with septic shock. The quality of each article was assessed. The effects of PMX on hemodynamic status, doses of vasopressive/inotoropic agents, blood concentrations of endotoxin and mediators, pulmonary oxygenations, and mortality in patients with septic shock were evaluated. To provide tabular data, articles that used the sepsis definitions from the American College of Chest Physicians/Society of Critical Care Medicine consensus conference were selected (4).
Concerning meta-analysis, we calculated weighted difference in means and 95% confidence intervals (CIs) between PMX treatment and conventional therapy for increase in mean arterial pressure and PaO2/FiO2 ratio, where it is assumed that 95% confidence level is generally approximated by 2 SDs, or 2 sigmas. We also calculated odds ratio and 95% CI between PMX treatment and conventional therapy for mortality. Difference in means, odds ratio, and 95% CI of total were calculated by general variance-based method.
The PMX treatment is administered by the following method. Toraymyxin 20-R is washed by perfusion with 4 L of physiological saline. After inserting a double-lumen catheter into a central vein of patients, blood is drawn from the proximal port, perfused through Toraymyxin 20-R, and returned to the vein through the distal port of the catheter (V-V method). The blood is perfused at a rate of 80 to 100 mL/min using protease inhibitor nafamostat mesilate (Torii Pharmaceuticals, Co, Ltd, Tokyo, Japan), unfractionated heparin, or low-molecular-weight heparin as an anticoagulant. A 2- to 27-h PMX treatment is administered either once or in some patients up to two, three, or four times, depending on the clinical response.
Hemodynamics and dose of vasopressive/inotoropic agents
As shown in Tables 1 and 2, PMX treatment increased blood pressure in almost all studies (5-7, 9, 10, 12, 13-15, 17, 19, 21). Mean arterial pressure significantly increased in PMX treatment compared with conventional therapy (Fig. 1). In a pilot study in Europe, PMX was found to significantly increase the cardiac index, left ventricular stroke work index, and oxygen delivery index, compared with control (9). The doses of dopamine, dobutamine, and norepinephrine were consistently reported to decrease after PMX treatment (5, 10, 12, 14, 17).
In most of the Japanese studies, endotoxin concentrations were measured by endotoxin-specific assay (endospecy; limit of normal is 9.8 pg/mL; Seikagaku Corporation, Tokyo Japan). In one European study (9), endotoxin concentrations were measured by the modified limulus amebocyte lysate assay kit (COATEST; DiaPharma Group, Inc, Westchester, Ohio). This kit is sensitive up to 0.05 endotoxin units/mL in serum or plasma. In studies by our group and another group (17, 22), endotoxin concentrations were measured by kinetic turbidimetric limulus assay using a toxinometer (MT-251 or MT-358; Wako Pure Chemicals Industries, Ltd, Osaka, Japan) (22, 23), a device theoretically capable of measuring with an accuracy up to 0.01 pg/mL. This limulus assay test is specific to endotoxin and has no cross-reaction to β-glucan, as previously described (24). As shown in Tables 1 and 2, endotoxin concentrations decreased after PMX treatment in most of the studies (5-8, 11-14, 17, 19, 21) but did not significantly change in the European randomized controlled study (9).
The PaO2/FiO2 ratio increased after PMX treatment in most of the studies (7, 10, 13, 14, 16, 17, 19) (Tables 1 and 2). Polymyxin B-immobilized fiber column hemoperfusion treatment significantly increased the PaO2/FiO2 ratio compared with conventional therapy (Fig. 1).
As shown in Tables 1 and 2, PMX decreased blood concentrations of IL-6 (7, 12, 13, 15, 18, 21), IL-8 (16), IL-10 (13, 15), TNF-α (7, 13), plasminogen activator inhibitor 1 (PAI-1) (13, 14, 16), neutrophil elastase (16, 25), platelet factor 4 (5, 7), β-thromboglobulin (5), soluble P selectin (5), soluble endothelial leukocyte adhesion molecule 1 (ELAM-1), and soluble intercellular adhesion molecule 1 (ICAM-1) (17), erythropoietin (26), metalloproteinase 9 (27), anandamide (28), high-mobility group box 1 (HMGB-1), and soluble receptor for advanced glycation end products (RAGE) (21). The changes in endotoxin obtained by PMX treatment were significantly correlated with those in HMGB-1, soluble RAGE, and IL-6 (21). However, the other study has reported that HMGB-1 concentrations remained unchanged after PMX treatment (18). In a subset of patients with liver failure (18), HMGB-1 concentrations reduced after PMX treatment in survivors, but HMGB-1 concentrations increased after PMX treatment in nonsurvivors.
Organ dysfunction and mortality
Polymyxin B-immobilized fiber column hemoperfusion treatment decreased Sequential Organ Failure Assessment (SOFA) scores (10, 17, 19). Polymyxin B-immobilized fiber column hemoperfusion treatment significantly reduced 28-day mortality compared with conventional therapy (Fig. 2).
Polymyxin B-immobilized fiber column hemoperfusion treament shows beneficial effects compared with conventional therapy in patients with septic shock. Polymyxin B-immobilized fiber column hemoperfusion treatment increases blood pressure while reducing the dosage requirements for vasopressive/inotropic agents. In one study, the treatment increased the cardiac index (9). In another, it reduced the concentration of cardiac troponin T (11), a potential marker of septic myocardial injury (29). Furthermore, a significant relationship was found between the concentrations of endotoxin and cardiac troponin T in the study in which both were significantly decreased after the treatment (11). On this basis, we speculate that PMX treatment may be effective in reducing myocardial damage by reducing blood endotoxin concentrations. Overall, these findings suggest that PMX treatment improves hemodynamic status.
The beneficial effects of PMX may be attributable to decrease in the concentrations of endotoxin and/or inflammatory cytokines. If this is so, the effect in reducing endotoxins may be capable of modulating the cascade of events in sepsis. Cytokines play an important role in the pathological condition of sepsis. Endotoxin removal by PMX might indirectly inhibit the release of inflammatory cytokines. In fact, PMX treatment decreases plasma concentrations of IL-6 (7, 12, 13, 15, 18), IL-8 (16), IL-10 (13, 15), and TNF-α (7, 13). Elevated nitric oxide (NO) production is a well-known phenomenon in septic shock, one that results from the activation of the inducible NO synthase pathway via infection and inflammation (30). Polymyxin B-immobilized fiber column hemoperfusion treatment decreases NO breakdown products (NOx) in urine (8). As such, the inhibition of NO production by PMX could prevent vasodilation and increase blood pressure. Another potential source of the hemodynamic may be the adsorption of anandamide. Anandamide, an endogenous cannabinoid, is generated by macrophages during endotoxin shock and is thought to contribute to hypotension in a paracrine fashion. Polymyxin B-immobilized fiber column hemoperfusion has been found to directly bind to anandamide and to be neutralized by bioactivity effects conferred by anandamide such as vasodilation and cytotoxicity (28).
Plasminogen activator inhibitor 1, a marker of vascular endothelial cell activation, is elevated by endotoxin and cytokines. The PMX-induced decrease in cytokine release might lower the PAI-1 concentration by reducing the stimulation of vascular endothelial cells (13, 14, 16). Plasminogen activator inhibitor 1, one of the fibrinolysis inhibitory factors, plays an important role in regulating fibrinolysis by blocking unnecessary fibrinolysis via its actions as an inhibitor of tissue plasminogen activator. Polymyxin B-immobilized fiber column hemoperfusion treatment reduces PAI-1 concentration and may thereby inhibit the development of ischemic organ dysfunction in sepsis.
Several studies showed PMX-confirmed improvements in pulmonary oxygenation (7, 10, 13, 14, 16, 17, 19), a condition associated with decreased adhesion molecule in patients with septic shock. A longer-duration PMX treatment in our study improved pulmonary oxygenation associated with decreased adhesion molecule in patients with septic shock (17). We do not know whether PMX treatment removes adhesion molecules directly or weakens their concentration by reducing the stimulation of endothelial cells via its effect in adsorbing pathogenic toxins. One study reported significant negative correlations between the PaO2/FiO2 ratio and the concentrations of IL-8 and neutrophil elastase in patients with septic shock (16). Another study showed PMX-induced decreases of metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 concentrations in patients with acute respiratory distress syndrome (27). The improved PaO2/FiO2 ratio conferred by PMX treatment may therefore be attributable to decreases in adhesion molecules, IL-8, neutrophil elastase, metalloproteinase 9, or the tissue inhibitor of metalloproteinase 1.
The monocyte-macrophage system is involved in acute inflammatory response and plays an important role in host defense. Three of the main functions of monocytes, namely, phagocytosis, antigen expression, and cytokine production, are mediated by surface molecules such as CD14 and human leukocyte antigen (HLA) DR. CD14 binds LPS and induces cellular activation. Neutrophil receptor CD16 also plays an important role in phagocytosis, cell-mediated cytotoxity, and free radical release. One study revealed decreased expression of surface antigens such as HLA-DR on monocytes and CD16 on granulocytes in patients with septic shock, but PMX increased the expression of these surface antigens on leukocytes in the same patients (15). This suggests that PMX treatment may help septic shock patients recover from immunoparalytic conditions. Polymyxin B-immobilized fiber column hemoperfusion was also reported to reduce the number of CD16+CD14+ monocytes and decrease the monocyte expression of TLR-4 in patients with septic shock (31). CD16+CD14+ monocytes exhibit the features of activated cells and might contribute, in their activated state, to the immunosuppression associated with severe infections. Meanwhile, the adsorption of CD16+CD14+ monocytes may be the mechanism by which PMX treatment improves the clinical outcome in patients with septic shock. In recent experiments using immunocytochemical and electron microscopic techniques to analyze the cells bound by the PMX column, the column was confirmed to specifically bind monocytes from the peripheral blood leukocytes of septic patients (32). The specific removal of monocytes from septic patients may produce beneficial effects by reducing the interaction between monocytes and functionally associated cells, including vascular endothelial cells. Although the true mechanism still remains unclear, PMX may remove monocytes by removing the LPS-monocyte complex.
Recently, Kumagai et al. (20) found that activated neutrophils with increased expression of CD11b/CD64 and low expression of C-X-C chemokine receptor 1 (CXCR1)/CXCR2 preferentially adhered to PMX filters. In addition, neutrophils obtained after ex vivo perfusion through PMX filters showed less endothelial damage without affecting neutrophil phagocytic function. Therefore, PMX selectively removes activated neutrophils and reduces the ability of circulating cells to cause endothelial damage.
Polymyxin B-immobilized fiber column hemoperfusion treatment reduced acute kidney injury and the proapoptotic activity of the plasma of septic patients on cultured renal cells (33). Apoptosis contributes to organ dysfunction during septic shock and is activated via endotoxin-initiated signaling pathways. The protective effects of PMX against acute kidney injury may thus be attributable to a reduced systemic proapoptotic activity. Polymyxin B-immobilized fiber column hemoperfusion treatment seems to decrease mortality. High-mobility group box 1 is a late mediator of endotoxin lethality in mice (34), and RAGE is involved in HMGB-1 signaling (35). Polymyxin B-immobilized fiber column hemoperfusion treatment decreased concentrations of HMGB-1 and soluble RAGE in patients with septic shock (21). Therefore, suppression of HMGB-1 and RAGE may be useful in the treatment for septic shock. These effects of PMX treatment may protect patients from multiple organ dysfunction syndrome. In fact, PMX treatment decreased SOFA score (10, 17, 19) and mortality (5-7, 10, 12). The reduction in mortality demonstrated in the EUPHAS trial was especially prominent (10). Yet this beneficial effect of PMX on mortality may depend on the severity of the sepsis. Whereas PMX improved outcome in patients with an APACHE II score less than 30, it failed to improve survival in patients with an APACHE II score of greater than 30 (6). Unlike the EUPHAS trial, the European pilot study on PMX treatment in sepsis with abdominal infection showed no SOFA score improvement (9). The PMX treatment was administered only once in that study. It may be that a single column hemoperfusion is insufficient to remove endotoxin in septic shock patients under some conditions.
Polymyxin B has both antibacterial and antiendotoxin capability, and it destroys the bacterial outer membrane and selectively binds the lipid A portion of endotoxin, thus neutralizing its adverse effects on cells. Concerning multiscale analysis of the Toraymyxin column, two studies have been published. Vesentini et al. (36) have investigated the interaction energies of polymyxin B-endotoxin complexes and clarified the mechanisms of complex formation. In the short range, the fatty acid chain stabilizes the complex, and the resulting binding is about 2nN due to both ionic and hydrophobic effects; in the long range, ionic forces become prevalent, and the binding force decreases. Fiore et al. (37) have investigated fluid dynamics inside the Toraymyxin column using a computational multiscale analysis. In macroscale study, the velocity distribution was quite uniform within the sorbent region, and peak velocity spots were located immediately below the impact surface. In mesoscale study, wall shear stresses ranged from homogeneous pattern to uneven pattern, depending on the alignment of fiber layers. In microscale study, the fate of an endotoxin particle depends both on its initial distance from the fiber wall and on wall shear stress. They demonstrated that the fiber-grafted polymyxin B was able to capture endotoxin molecules up to distances far beyond the short-range interval. This finding suggests that hydrodynamics strongly affect the adsorption potential.
Various neutralization of endotoxin strategies such as HA-1A human monoclonal antibody against endotoxin, E5 murine monoclonal antiendotoxin antibody, and phospholipid emulsion (GR270773) has been investigated (38-40). However, none of these therapies have been shown to reduce mortality of septic shock. Recently, phase 2 trial of eritotan (E5564), a TLR-4 antagonist, in patients with severe sepsis has shown that mortality was not statistically significant (41). These results are probably due to nonspecific and weak bond achieved in the complex with the lipid A of endotoxin (42). The lack of clinical success with these therapies has led to an interest in extracorporeal therapies to decrease the mediators in septic shock. Suzuki et al. (12) compared cytokine levels, endotoxin levels, and mortality of septic shock patients between PMX plus continuous hemodiafiltration (CHDF) group and CHDF group. Continuous hemodiafiltration was performed using a PMMA dialyzer (Toray Industries, Inc). Although CHDF decreased IL-1β and IL-6 levels a little, CHDF alone could not reduce endotoxin levels. In addition, 28-day mortality was 25% in the PMX plus CHDF group and 75% in the CHDF group. These findings show that PMX treatment has more beneficial effects than CHDF. Polymyxin B-immobilized fiber column hemoperfusion treatment has additional effects on reducing monocytes activity (31, 32); abolishing the diverse negative effects of anandamide such as hypotension, immunosuppression, and cytotoxity (28); reducing endothelial damage by removal of activated neutrophils (20) and proapoptotic activity (33); and recovering patients from immunosuppression (15, 31). These actions of PMX treatment may be superior to previous neutralization of endotoxin strategies.
A fairly stable concentration after peaks of endotoxin has been removed by PMX treatment. Although endotoxin removal from the blood by PMX treatment might promote a dynamic equilibrium between the tissue and blood compartments, thus enabling a continuous withdrawal of endotoxin from the tissues during extracorporeal therapies (43), plasma endotoxin levels would be continuously derived from the lysis of bacteria present in sites other than blood. Because, septic shock patients are treated with antimicrobial agents, which induce lysis of bacterial cells and release endotoxin (44). On the other hand, endotoxin is also bound to circulating monocytes (45), to erythrocyte (46), and to platelets (47) during sepsis. Endotoxin-monocyte complex has been shown to be removed by PMX treatment (32). Because lipid A portion of endotoxin binds to the membrane of platelets (48) and erythrocytes (46), PMX theoretically cannot remove the endotoxin that is bound to platelets and erythrocytes. Plasma endotoxin levels have been shown to be significantly higher in platelet-rich plasma than those in platelet-poor plasma (47). Accordingly, endotoxin binding to platelet is present in blood after PMX treatment. Taken together, PMX treatment may not end to a total removal of endotoxin.
All endotoxins from different bacterial origin are biochemically different (49) and thus do not interact similarly with polymyxin B. Examples are provided by the polymyxin B-resistant strains. The main mechanism of polymyxin resistance is the modification of the bacterial outer membrane, which is mainly mediated by two-component regulatory systems PhoP-PhoQ and PmrA-PmrB. Polymyxin resistance is encoded by the PmrA-PmrB regulon, the products of which modify the LPS core and lipid A portions with ethanolamine and add aminoarabinose to the 4′ phosphate of lipid A (50). Therefore, PMX column may not have a similar efficiency, depending on the nature of the infectious agent.
These findings suggest that PMX treatment has beneficial effects on hemodynamics, pulmonary oxygenation, and mortality in patients with septic shock. These beneficial effects may be attributable to direct adsorption of endotoxin, monocytes, activated neutrophils, and anandamide and indirect decreases in inflammatory cytokines and other mediators. Polymyxin B-immobilized fiber column hemoperfusion treatment has additional effects on reducing endothelial damage, apoptotic activity, and immunosuppression. Further studies will be needed to confirm the efficacy and mechanism of PMX treatment in septic shock.
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