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Blood purification therapy for sepsis
Transfusion and Apheresis Science 35 (2006) 245–251 intl.elsevierhealth.com/journals/tras
Blood puriWcation therapy for sepsis Hiromi Sakata, Motoki Yonekawa, Akio Kawamura
¤
Department of Surgery, Sapporo Hokuyu Hospital, Research Institute for ArtiWcial Organs, Transplantation and Gene Therapy, 6-6-5-1, Higashi Sapporo, Shiroishi-Ku, Sapporo, Hokkaido 003-0006, Japan Received 26 May 2006; accepted 14 June 2006
Abstract Accumulating evidences of underlining pathogenesis of sepsis have contributed to the therapeutic strategy for sepsis. Not only endotoxin and cytokine, but also signal transduction through Toll-like receptors could be a strategic target for the management of sepsis. Blood puriWcation therapy including polymyxin B-immobilized hemoperfusion cartridge and continuous hemodiaWltration has shown the beneWcial eVect on patients with sepsis in Japan. Although they were initially designed to remove endotoxin and cytokines respectively, they might eliminate unexpected mediators responsible for sepsis. Further elucidation of mechanism and randomized controlled studies are needed to establish the role of blood puriWcation therapy in sepsis. © 2006 Elsevier Ltd. All rights reserved.
1. Introduction Sepsis remains the leading cause of death in critically ill patients in worldwide despite the extensive research. It passed 15 years since sepsis and systemic inXammatory response syndrome (SIRS) were deWned in consensus conference [1]. Improved understanding of the pathogenesis of sepsis has facilitated the development of multiple strategies to cope with sepsis. It is generally accepted that sepsis is triggered by endotoxin or lipopolysaccharide (LPS), resulting in the overproduction of inXammatory mediators including tumor necrosis factor- (TNF-), interleukin-6 (IL-6) and IL-1. However, most clinical trials targeting blockade of LPS and speciWc inXamma* Corresponding author. Tel.: +81 11 865 0111; fax: +81 11 865 9719. E-mail address: [email protected] (A. Kawamura).
1473-0502/$ - see front matter © 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.transci.2006.06.003
tory mediators have not been successful [2–5]. Later, molecules such as bacterial LPS, microbial lipopeptides, microbial DNA, peptidoglycans, lipoteochoic acid, and heparan sulfate (HS) all turned out to interact with the Toll-like receptors (TLRs), the principal sensors of the innate immunity [6,7]. Stimulation of TLRs induces activation of innate immunity and distinct patterns of gene expression, leading production of inXammatory cytokines [8]. This signiWcant paradigm shift of our understanding of sepsis has changed our strategies to treat sepsis. Unfortunately, no deWnitive study exists that can successfully treat sepsis and its associated complications at this stage. Blood puriWcation therapy (BPT) including polymyxin B-immobilized hemoperfusion cartridge (Toraymyxin®, PMX) and continuous hemodiaWltration (CHDF) has been applied to treat patients with sepsis in Japan. In this review, we will describe some recent advances in the pathogenesis of sepsis and focus on
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BPT using PMX and CHDF, which are extensively used in clinical settings in Japan. 2. The pathogenesis of sepsis The word “sepsis” originated from the Greek word ‘sepsios’ which denotes decay and implies rotting tissues [7]. Sepsis is a symptom as the host response to infection, a syndrome associated with the release of many cytokines and other mediators in response to an infectious process. These factors play roles in defending the host against an invading organism, while the septic response become harmful to the host, resulting in tissue damage, organ failure, and ultimately death. A consensus conference deWned sepsis as “the systemic inXammatory response syndrome (SIRS)” that occurs during infection [1]. The diagnosis of sepsis required conWrmation of bacterial growth in blood cultures as well as the presence of the following symptoms: hypothermia or hyperthermia, tachycardia, tachypnea and leukocytopenia or leukocytosis. SIRS is a clinically identical to sepsis seen on human with burns, acute pancreatitis, trauma and reperfusion injury in the absence of infection (Fig. 1). The Wrst insight into the molecular pathogenesis of sepsis attributed to the discovery of endotoxin and LPS on gram-negative bacteria. Once such causative agents enter the body, the inXammatory system becomes hyperactive, resulting in production of pro-inXammatory mediators, especially TNF-, IL6, IL-1, IL-8, as well as activation of the coagulation and complement systems early in the onset of sepsis. In the late phase of sepsis, anti-inXammatory mediators, such as IL-10, transforming growth factor- and IL-13, are produced to abolish the activity of
pro-inXammatory mediators. To describe the excessive production of anti-inXammatory cytokines, Bone et al. deWned it as compensated anti-inXammatory response syndrome (CARS) [9]. As a result of CARS, tissue damage and organ failure occur, leading to immunoparalysis. The novel role of innate immunity in the immunology against microorganisms facilitated our understanding of the molecular mechanisms of the sepsis [8]. The immune system can be classiWed into two groups: innate and acquired immunity. The innate immunity is considered as the Wrst line of defense against pathogens with a relatively nonspeciWc system. In contrast, acquired immunity is mediated through T and B cells with highly speciWc and diverse antigen receptors generated by DNA rearrangement. Recent studies have revealed that the innate immunity senses the pathogenic microorganisms through the TLRs, which recognize speciWc molecular patterns on microbial components [10]. Further, the TLRs signaling not only induce the activation of innate immunity but also instruct the development of acquired immunity [6]. Based on this pathogenesis of sepsis, most therapeutic strategies used to focus on LPS and pro-inXammatory mediators. Unfortunately, anti-cytokines strategies did not improve survival even in large and multicenter randomized clinical trials. The failure of the anti-endotoxin monoclonal antibody trials raised the controversy about endotoxin as the therapeutic target. Johnson et al. proposed the hypothesis of the alternative pathway of TLR4 [7]. They found that HS could bind and activate TLR4, resulting in sepsis (Fig. 2). HS normally exists as an extra-cellular and matrix macromolecule similar to heparin. The protein components of HS are highly susceptible to cleavage by proteases that are abundant in the Anti-LPS
Infection BACTEREMIA
INFECTION
SIRS
TLR4
Proteases
HS
Cytokines
TRAUMA
SEPSIS
FUNGEMIA
LPS
OTHER
BURNS
Trauma Pancreatitis Reperfusion
Sepsis SIRS
PARASITEMIA VIREMIA OTHER
PANCREATITIS
Fig. 1. Correlation between SIRS, sepsis, and infection. Adapted from Bone et al. [1].
Fig. 2. Pathways to sepsis and SIRS through TLR4. Lipopolysaccharide (LPS) can bind and activate Toll-like receptor (TLR) 4, resulting in cytokines production, leading to sepsis and SIRS. The proteases release heparan sulfate (HS) also can activate TLR4 as an alternative pathway of TLR4. Adapted from Johnson et al. [7].
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course of sepsis and SIRS. Recent study also revealed that decay of tissues, resulting in production of other possible candidate stimulating TLR4 such as fragment of hyaluronic acid and heat-shock proteins, might cause sepsis and SIRS [11]. These evidences have changed our concept regarding the pathogenesis and treatment of sepsis. All of these molecules could be a potential target option for sepsis therapy. 3. Extracorporeal blood puriWcation therapy to sepsis as an alternative therapy The role of extracorporeal BPT in the management of sepsis remains controversial for several years. BPT is deWned as techniques in which blood is removed from the body, circulated in an extracorporeal circuit, treated with a variety of devices and returned to the patient. Initially, the concept of blood puriWcation therapies derived from the assumption that nonspeciWc elimination of various inXammatory mediators would improve outcome in sepsis. Various kinds of BPT, including plasma exchange, continuous hemoWltration (CHF), CHDF, and PMX, have been applied to treat sepsis. Advancement of the current pathogenesis of sepsis may reveal the putative harmful mediators. In the following paragraph, we will discuss the role of PMX and CHDF on the management of sepsis. 3.1. Polymyxin B-immobilized hemoperfusion cartridge, Toraymyxin® (PMX) Polymyxin-B is a cationic peptide antibiotic that is known to bind to endotoxin speciWcally and neutralize its toxicity. It has been considered as a logical approach to devise extracorporeal systems that could remove promptly endotoxin. Based on this principle, polymyxin-B was chemically immobilized in polystyrene-derived Wbers, creating a hemoperfusion column, Toraymyxin® (Fig. 3) (PMX, Toray Industries Inc., Tokyo, Japan) that aims to remove endotoxin [12]. PMX is approved to use in patients with sepsis under the Japanese National Health Insurance system in 1994 and is now widely used in Japan. Patients should fulWll the following criteria to be covered by health insurance in Japan: 1. Patients with endotoxisemia or suspected gram-negative infection. 2. Patients who fulWll two or more of the SIRS criteria. 3. Septic shock patients who require inotropic and/or vasoactive agents. PMX treatment is typically performed for 2 h at a blood Xow rate of
Fig. 3. Polymyxin B-immobilized hemoperfusion cartridge, Toraymyxin (PMX).
80–100 ml min¡1 by direct hemoperfusion with nafamostat mesilate as the anticoagulant. The Wrst multicenter clinical study, though in open-label and non-randomized clinical study, was performed in 42 patients with sepsis by the PMX Clinical Study Group [13]. They showed the signiWcance decrease of endotoxin concentration from 83.7 § 26.7 pg ml¡1 to 56.4 § 27.9 pg ml¡1 after PMX in 37 patients with detectable endotoxin. Twenty patients survived and 17 patients died. Although mean endotoxin level did not diVer between the survivors and non-survivors before PMX, they reported that the endotoxin level was signiWcantly lower in the survivors after PMX. The second multicenter clinical study was conducted in 88 patients with sepsis at 15 diVerent centers [14]. They investigated the correlation between inXammatory cytokines and endotoxin activity in 88 sepsis patients. In the survival group (N D 45), the plasma level of TNF-, IL-6, IL-10 and plasminogen activator inhibitor-1 (PAI-1) was all decreased coincident with endotoxin removal after PMX. In contrast, in the non-survival group, only TNF- was decreased after PMX. They concluded
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that plasma endotoxin was the major cause of sepsis, and that the reduction of endotoxin contributed to an elimination of inXammatory mediators. However, these studies are designed as open-labeled, non-randomized clinical studies. Multi-center randomized clinical trials now need to be conducted to conWrm the eVects of PMX treatment in patients with sepsis. Recently, a Wrst pilot-controlled study of PMX in patients with severe sepsis was reported in Europe [15]. Thirty-six post-surgical patients with severe sepsis were randomized to PMX treatment or conventional therapy. Surprisingly there was no statistically diVerence in the change in endotoxin and IL-6 levels after PMX treatment. While, PMX treatment demonstrated signiWcant improvement of hemodynamic status and cardiac function compared with the controls. This study indicated the possibility that PMX removed unknown substances responsible for improvement of hemodynamic status. One possible candidate is endogenous cannabinoids, such as anandamide and 2-arachidonyl glyceride (2-AG), have been reported as mediators inducing hypotension at the early stage of septic shock [16]. Anandamide is generated by macrophages in response to LPS during gram-negative bacterial sepsis. Endogenous anandamide has an important role in the pathogenesis of septic shock, especially hypotension [17]. 2-AG is one of the endogenous cannabinoids (eCBs), secreted from platelets [16]. They demonstrated that PMX could adsorb not only endotoxin, but also anandamide [18] and 2-AG [19], and removed the increased anandamide and 2-AG in the blood of septic shock patients, resulting in a quick recovery from hypotension. These results suggested that endogenous cannabinoids other than endotoxin might be a promising target for PMX. Further clinical studies are needed to investigate the mechanisms of beneWcial hemodynamic eVects in PMX treatment. Another unexpected beneWcial eVect of PMX on recovery from immunoparalysis was reported [20]. They evaluated the expression of human leukocyte antigen-DR on monocytes and CD16 on granulocytes in patients with sepsis treated with PMX. They found that the down-regulation of both cell surface antigens was correlated to the severity of sepsis, suggesting immunosuppressive status, and PMX treatment exhibited their beneWcial up-regulation of these antigens. These results suggested that PMX might induce the beneWcial immunomodulation in patients with sepsis.
In summary, PMX treatment is safe and eVective in patients with sepsis associated with an improved homodynamic status. Nevertheless, no large, multicenter controlled clinical studies exist to support the eVectiveness of PMX. Further study needs to clarify the novel mechanisms of PMX. 3.2. Continuous hemodiaWltration in sepsis The classical indication for renal replacement therapy is intermittent hemodialysis (IHD). While, CHF and CHDF techniques have recently emerged as alternative modalities to critically ill patients. CHDF, also known as continuous renal replacement therapy (CRRT), is performed continuously for 24 h in the intensive care unit. CHDF allows extracorporeal treatment in patients with gradual correction of Xuid balance, electrolytes, and osmotic pressure, as well as enough nutrition. In addition to the advantage of CHDF, it may eliminate middle- to high-molecular weight substances including bacterial LPS and inXammatory cytokines through mechanisms of convection and adsorption by the Wltrating membrane. Thus, CHDF has been extensively investigated to apply sepsis as a cytokine removal technology in Japan [21]. Kramer Wrst reported CHF as continuous arteriovenous hemoWltration (CAVH) in 1977 [22]. Thereafter, continuous venovenous hemoWltration (CVVH) with a peristaltic pump was developed [23]. To improve the eYcacy of substance removal, CHDF has been applied to multiple organ failure in sepsis [24]. The advantages of CRRT over the intermittent therapies are clearly demonstrated in critically ill patients. One of the most signiWcant advantages is that blood puriWcation is feasible in septic patients who have hemodynamic instability [25]. CRRT permits strict Xuid balance allowing optimization of nutritional support without the concern of Xuid overload. A further beneWt is the elimination of various mediators of diVerent molecular weights generated by sepsis. However, which modality of blood puriWcation therapy such as intermittent and continuous should be used for patients with critically illness remains controversial. Van der Schueren, G. et al. studied the inXuence of IHD on systemic and regional oxygen transport in critically ill patients [26]. As a result, IHD induced an increase in calculated systemic oxygen consumption (p < 0.01) and needed signiWcantly higher inotropic support (p < 0.05) to maintain arterial blood pressure, suggesting the inferiority of IHD. In contrast, three
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independent studies reported that there was no signiWcant diVerence between IHD and CHDF for the treatment of acute renal failure (ARF). Firstly, Mehta et al. compared CRRT with IHD in the treatment of ARF in a multicenter randomized controlled trial [27]. Despite the potential advantage of continuous techniques, they showed no evidence of a survival beneWt of CHDF compared with IHD. Secondly, Kellum et al. performed a meta-analysis of all prior randomized and observational studies that compared CRRT with IHD through a MEDLINE search [28]. The evidence was insuYcient to draw strong conclusions regarding the mode of replacement therapy for ARF. While, the life-saving potential with CRRT suggested that further investigation by a large, randomized trial would be reasonable to consider. Thirdly, Guerin et al. tried to estimate the impact of hemodialysis modality such as IHD versus CRRT on patient outcome in ARF [29]. Accordingly, the type of renal replacement therapy was not signiWcantly associated with outcome. These results suggested that there was no deWnitive evidence to support the superiority of CRRT over IHD especially in ARF. However, in the case of sepsis in the absence of ARF, CHDF may contribute to improve clinical outcome by means of removing unknown mediators. Although, many cytokines with pro- and antiinXammatory action play roles in sepsis, blocking any one cytokine has not led to a positive outcome in patients with sepsis [3–5]. Since CHDF is considered as the BPT derived from the assumption that nonspeciWc and nonselective elimination of various inXammatory mediators [30]. CHDF has been applied to patients with sepsis. However, the capability of CHDF to remove inXammatory cytokines has remained controversial for several years. Numerous studies have demonstrated that hemoWltration can eliminate nearly every substance involved in sepsis to a certain degree [31]. CHF was Wrst applied to patients with sepsis in 1993 with a polyacrylonitrile (AN69) membrane which is thought to removed cytokines such as TNF- and IL-1 by convection [32]. Subsequently, Oda et al. reported that 3 consecutive days of CHDF with polymethylmethacrylate (PMMA) membrane can remove cytokines, including TNF-, IL-6 and IL-8, eYciently compared to an ethylene vinyl alcohol copolymers membrane by mainly adsorption rather than convection. While, even after 3 days of CHDF treatment, blood cytokine levels only showed 20– 25% of reduction [33].
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Even if CHDF can remove cytokines from blood circulation of septic patients, the blood level of cytokines is not always low. In a randomized controlled trial (RCT) using CVVH in early sepsis, Cole et al. demonstrated that the early use of CVVH at 2 L h¡1 did not reduce circulating cytokine concentrations. In contrast, Matsuda et al. showed the signiWcant decrease of various cytokines levels when basal levels of cytokines were high before CHDF with PMMA membrane. Taken together, these results suggested that there was no consensus on correlation between cytokine level and eYcacy of CHDF. On the contrary, it has been hypothesized that the peak concentration of inXammatory cytokines in plasma are responsible for the severity of sepsis. This concept is called “peak concentration hypothesis” [34]. The peak concentration hypothesis is the concept of cutting peaks of soluble mediators through continuous hemoWltration. Thus, CRRT could be able to reduce the peaks of the pro- and anti-inXammatory substances circulating during sepsis, leading to a less severe degree of inXammation and immunodepression. The removal of cytokines by CRRT remains to be proven as a method for improving survival in patients with sepsis. Several studies have found correlation between circulating levels of inXammatory cytokines and outcome of patients with sepsis. However, it remains unclear whether circulating cytokines contribute to the inXammatory reactions taking place locally in aVected organs during sepsis, or whether they are merely indirect markers of the severity of sepsis. Hirasawa et al. performed CHDF on patients with multiple organ failure (MOF) and observed strong improvement of the respiratory index, tissue oxygen metabolism, and cellular injury score in accordance with the decreased cytokine levels [21,35]. Further, they showed that CHDF improved the survival of MOF patients with APACHE H score of 25–34 in retrospective study [21]. RCT is needed to determine the eVect of CHDF on survival in MOF patients. Recently, 2 RCTs of CRRT for sepsis have been conducted. The Wrst was a small multicenter RCT to determine the eVect of plasmaWltration for 34 h [36]. This study showed no diVerence in mortality. The second study was also a small single-center RCT of septic patients using CVVH at 2 L h¡1 of ultraWltration [37]. This study also showed no eVects of CVVH on survival. These studies suggested that neither plasmaWltration for 34 h nor 2 L h¡1 of CVVH might be suYcient to treat sepsis in the absence of ARF.
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In spite of encouraging results as mentioned, outcome of conventional CRRT in sepsis has been still disappointing. Consequently, high-volume-hemoWltration (HVHF) has been developed to improve removal of mediators of sepsis by increasing ultraWltration rate. Ronco et al. randomized 425 patients with an ultraWltration dose of 20 ml kg¡1 h¡1, 35 ml kg¡1 h¡1, and 45 ml kg¡1 h¡1, demonstrating signiWcantly improved survival in septic patients with an ultraWltration dose of 35 ml kg¡1 h¡1 [38]. They recommended that ultraWltration should be prescribed according to patient’s bodyweight and should reach at least 35 ml kg¡1 h¡1. These results reinforced the clinical signiWcance of ultraWltration rate in CHDF. Enlarging pore size of membranes could be other approaches to achieve higher mediator clearance in sepsis. Experimental and clinical data proved that more open membrane exhibited superior removal capability of cytokines [36,39,40] . 4. Conclusion Most clinical studies were performed with a nonrandomized uncontrolled design treating small series of patients especially in Japan. Obviously, well-designed randomized clinical trials are needed to evaluate the eVect of BPT on survival in sepsis. However, there are many restrictions to conduct RCT. First, sepsis and SIRS are clinical entity including heterogeneous group of patients. Patients have a wide spectrum of disease with diVerent causative microorganisms and diVerent source of infection. Thus, better understanding of the immune status and practical biological markers of sepsis are required. Second, the timing of treatment is also critical. The status of hospitalized patients with sepsis may vary whether they are early or late stage of sepsis. In addition, prophylactic treatment may be beneWcial in some cases. Third, we have to determine what kind of BPT will bring favorable results in sepsis, including plasmaWltration, high volume hemoWltration, hemoWltration with higher porosity of membrane, combination of PMX and CHDF, and frequent change of adsorption membrane. Accordingly, due to these unavoidable circumstances, PMX and CHDF have gained popularity in Japan as a prospective or uncontrolled clinical study. Historically, conventional treatments of sepsis have targeted to endotoxin and various cytokines. However, the failure of blocking LPS or cytokine in RCT and understanding of innate immunity through Toll-like receptors caused a paradigm shift
in strategy for treatment of sepsis. PMX was originally developed to aim elimination of endotoxin. While, unexpected beneWcial eVects including improvement of hemodynamic instability and immunosuppression, revealed that PMX might remove other mediators than endotoxin. Although the clinical eYcacy of BPT in sepsis, as represented by CHDF, has been extensively studied in Japan under the Japanese National Health Insurance system, most of these studies have not been published due to lack of RCT. CHDF is initially considered as the blood puriWcation therapy derived from the assumption that nonspeciWc and nonselective elimination of various inXammatory mediators. However, accumulating evidences suggested that clinical beneWt of CHDF stemmed from the elimination of not only various cytokines but also undetermined mediators responsible for improvement of survival. Recent study also revealed that decay of tissues resulted in production of possible candidate stimulating TLR, such as HS, proteases, fragment of hyaluronic acid, and heat-shock proteins [11]. These substances as well as signal transduction molecules of TLRs pathway [8] could become promising targets for treatment of sepsis. Further understanding of underlining mechanisms of sepsis may shed light on the novel mechanisms of blood puriWcation therapy. References [1] Bone RC, Sibbald CL, Sprung WJ. The ACCP–SCCM consensus conference on sepsis and organ failure. Chest 1992;101:1481–3. [2] Ziegler EJ, Fisher Jr CJ, Sprung CL, Straube RC, SadoV JC, Foulke GE, et al. Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebocontrolled trial. The HA-1A Sepsis Study Group. N Engl J Med 1991;324:429–36. [3] Fisher Jr CJ, Slotman GJ, Opal SM, Pribble JP, Bone RC, Emmanuel G, et al. Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. Crit Care Med 1994;22:12–21. [4] Fisher Jr CJ, Agosti JM, Opal SM, Lowry SF, Balk RA, SadoV JC, et al. Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med 1996;334:1697– 702. [5] Abraham E, Wunderink R, Silverman H, Perl TM, Nasraway S, Levy H, et al. EYcacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, doubleblind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. Jama 1995;273:934–41.
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Blood puriWcation therapy for sepsis Hiromi Sakata, Motoki Yonekawa, Akio Kawamura
¤
Department of Surgery, Sapporo Hokuyu Hospital, Research Institute for ArtiWcial Organs, Transplantation and Gene Therapy, 6-6-5-1, Higashi Sapporo, Shiroishi-Ku, Sapporo, Hokkaido 003-0006, Japan Received 26 May 2006; accepted 14 June 2006
Abstract Accumulating evidences of underlining pathogenesis of sepsis have contributed to the therapeutic strategy for sepsis. Not only endotoxin and cytokine, but also signal transduction through Toll-like receptors could be a strategic target for the management of sepsis. Blood puriWcation therapy including polymyxin B-immobilized hemoperfusion cartridge and continuous hemodiaWltration has shown the beneWcial eVect on patients with sepsis in Japan. Although they were initially designed to remove endotoxin and cytokines respectively, they might eliminate unexpected mediators responsible for sepsis. Further elucidation of mechanism and randomized controlled studies are needed to establish the role of blood puriWcation therapy in sepsis. © 2006 Elsevier Ltd. All rights reserved.
1. Introduction Sepsis remains the leading cause of death in critically ill patients in worldwide despite the extensive research. It passed 15 years since sepsis and systemic inXammatory response syndrome (SIRS) were deWned in consensus conference [1]. Improved understanding of the pathogenesis of sepsis has facilitated the development of multiple strategies to cope with sepsis. It is generally accepted that sepsis is triggered by endotoxin or lipopolysaccharide (LPS), resulting in the overproduction of inXammatory mediators including tumor necrosis factor- (TNF-), interleukin-6 (IL-6) and IL-1. However, most clinical trials targeting blockade of LPS and speciWc inXamma* Corresponding author. Tel.: +81 11 865 0111; fax: +81 11 865 9719. E-mail address: [email protected] (A. Kawamura).
1473-0502/$ - see front matter © 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.transci.2006.06.003
tory mediators have not been successful [2–5]. Later, molecules such as bacterial LPS, microbial lipopeptides, microbial DNA, peptidoglycans, lipoteochoic acid, and heparan sulfate (HS) all turned out to interact with the Toll-like receptors (TLRs), the principal sensors of the innate immunity [6,7]. Stimulation of TLRs induces activation of innate immunity and distinct patterns of gene expression, leading production of inXammatory cytokines [8]. This signiWcant paradigm shift of our understanding of sepsis has changed our strategies to treat sepsis. Unfortunately, no deWnitive study exists that can successfully treat sepsis and its associated complications at this stage. Blood puriWcation therapy (BPT) including polymyxin B-immobilized hemoperfusion cartridge (Toraymyxin®, PMX) and continuous hemodiaWltration (CHDF) has been applied to treat patients with sepsis in Japan. In this review, we will describe some recent advances in the pathogenesis of sepsis and focus on
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BPT using PMX and CHDF, which are extensively used in clinical settings in Japan. 2. The pathogenesis of sepsis The word “sepsis” originated from the Greek word ‘sepsios’ which denotes decay and implies rotting tissues [7]. Sepsis is a symptom as the host response to infection, a syndrome associated with the release of many cytokines and other mediators in response to an infectious process. These factors play roles in defending the host against an invading organism, while the septic response become harmful to the host, resulting in tissue damage, organ failure, and ultimately death. A consensus conference deWned sepsis as “the systemic inXammatory response syndrome (SIRS)” that occurs during infection [1]. The diagnosis of sepsis required conWrmation of bacterial growth in blood cultures as well as the presence of the following symptoms: hypothermia or hyperthermia, tachycardia, tachypnea and leukocytopenia or leukocytosis. SIRS is a clinically identical to sepsis seen on human with burns, acute pancreatitis, trauma and reperfusion injury in the absence of infection (Fig. 1). The Wrst insight into the molecular pathogenesis of sepsis attributed to the discovery of endotoxin and LPS on gram-negative bacteria. Once such causative agents enter the body, the inXammatory system becomes hyperactive, resulting in production of pro-inXammatory mediators, especially TNF-, IL6, IL-1, IL-8, as well as activation of the coagulation and complement systems early in the onset of sepsis. In the late phase of sepsis, anti-inXammatory mediators, such as IL-10, transforming growth factor- and IL-13, are produced to abolish the activity of
pro-inXammatory mediators. To describe the excessive production of anti-inXammatory cytokines, Bone et al. deWned it as compensated anti-inXammatory response syndrome (CARS) [9]. As a result of CARS, tissue damage and organ failure occur, leading to immunoparalysis. The novel role of innate immunity in the immunology against microorganisms facilitated our understanding of the molecular mechanisms of the sepsis [8]. The immune system can be classiWed into two groups: innate and acquired immunity. The innate immunity is considered as the Wrst line of defense against pathogens with a relatively nonspeciWc system. In contrast, acquired immunity is mediated through T and B cells with highly speciWc and diverse antigen receptors generated by DNA rearrangement. Recent studies have revealed that the innate immunity senses the pathogenic microorganisms through the TLRs, which recognize speciWc molecular patterns on microbial components [10]. Further, the TLRs signaling not only induce the activation of innate immunity but also instruct the development of acquired immunity [6]. Based on this pathogenesis of sepsis, most therapeutic strategies used to focus on LPS and pro-inXammatory mediators. Unfortunately, anti-cytokines strategies did not improve survival even in large and multicenter randomized clinical trials. The failure of the anti-endotoxin monoclonal antibody trials raised the controversy about endotoxin as the therapeutic target. Johnson et al. proposed the hypothesis of the alternative pathway of TLR4 [7]. They found that HS could bind and activate TLR4, resulting in sepsis (Fig. 2). HS normally exists as an extra-cellular and matrix macromolecule similar to heparin. The protein components of HS are highly susceptible to cleavage by proteases that are abundant in the Anti-LPS
Infection BACTEREMIA
INFECTION
SIRS
TLR4
Proteases
HS
Cytokines
TRAUMA
SEPSIS
FUNGEMIA
LPS
OTHER
BURNS
Trauma Pancreatitis Reperfusion
Sepsis SIRS
PARASITEMIA VIREMIA OTHER
PANCREATITIS
Fig. 1. Correlation between SIRS, sepsis, and infection. Adapted from Bone et al. [1].
Fig. 2. Pathways to sepsis and SIRS through TLR4. Lipopolysaccharide (LPS) can bind and activate Toll-like receptor (TLR) 4, resulting in cytokines production, leading to sepsis and SIRS. The proteases release heparan sulfate (HS) also can activate TLR4 as an alternative pathway of TLR4. Adapted from Johnson et al. [7].
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course of sepsis and SIRS. Recent study also revealed that decay of tissues, resulting in production of other possible candidate stimulating TLR4 such as fragment of hyaluronic acid and heat-shock proteins, might cause sepsis and SIRS [11]. These evidences have changed our concept regarding the pathogenesis and treatment of sepsis. All of these molecules could be a potential target option for sepsis therapy. 3. Extracorporeal blood puriWcation therapy to sepsis as an alternative therapy The role of extracorporeal BPT in the management of sepsis remains controversial for several years. BPT is deWned as techniques in which blood is removed from the body, circulated in an extracorporeal circuit, treated with a variety of devices and returned to the patient. Initially, the concept of blood puriWcation therapies derived from the assumption that nonspeciWc elimination of various inXammatory mediators would improve outcome in sepsis. Various kinds of BPT, including plasma exchange, continuous hemoWltration (CHF), CHDF, and PMX, have been applied to treat sepsis. Advancement of the current pathogenesis of sepsis may reveal the putative harmful mediators. In the following paragraph, we will discuss the role of PMX and CHDF on the management of sepsis. 3.1. Polymyxin B-immobilized hemoperfusion cartridge, Toraymyxin® (PMX) Polymyxin-B is a cationic peptide antibiotic that is known to bind to endotoxin speciWcally and neutralize its toxicity. It has been considered as a logical approach to devise extracorporeal systems that could remove promptly endotoxin. Based on this principle, polymyxin-B was chemically immobilized in polystyrene-derived Wbers, creating a hemoperfusion column, Toraymyxin® (Fig. 3) (PMX, Toray Industries Inc., Tokyo, Japan) that aims to remove endotoxin [12]. PMX is approved to use in patients with sepsis under the Japanese National Health Insurance system in 1994 and is now widely used in Japan. Patients should fulWll the following criteria to be covered by health insurance in Japan: 1. Patients with endotoxisemia or suspected gram-negative infection. 2. Patients who fulWll two or more of the SIRS criteria. 3. Septic shock patients who require inotropic and/or vasoactive agents. PMX treatment is typically performed for 2 h at a blood Xow rate of
Fig. 3. Polymyxin B-immobilized hemoperfusion cartridge, Toraymyxin (PMX).
80–100 ml min¡1 by direct hemoperfusion with nafamostat mesilate as the anticoagulant. The Wrst multicenter clinical study, though in open-label and non-randomized clinical study, was performed in 42 patients with sepsis by the PMX Clinical Study Group [13]. They showed the signiWcance decrease of endotoxin concentration from 83.7 § 26.7 pg ml¡1 to 56.4 § 27.9 pg ml¡1 after PMX in 37 patients with detectable endotoxin. Twenty patients survived and 17 patients died. Although mean endotoxin level did not diVer between the survivors and non-survivors before PMX, they reported that the endotoxin level was signiWcantly lower in the survivors after PMX. The second multicenter clinical study was conducted in 88 patients with sepsis at 15 diVerent centers [14]. They investigated the correlation between inXammatory cytokines and endotoxin activity in 88 sepsis patients. In the survival group (N D 45), the plasma level of TNF-, IL-6, IL-10 and plasminogen activator inhibitor-1 (PAI-1) was all decreased coincident with endotoxin removal after PMX. In contrast, in the non-survival group, only TNF- was decreased after PMX. They concluded
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that plasma endotoxin was the major cause of sepsis, and that the reduction of endotoxin contributed to an elimination of inXammatory mediators. However, these studies are designed as open-labeled, non-randomized clinical studies. Multi-center randomized clinical trials now need to be conducted to conWrm the eVects of PMX treatment in patients with sepsis. Recently, a Wrst pilot-controlled study of PMX in patients with severe sepsis was reported in Europe [15]. Thirty-six post-surgical patients with severe sepsis were randomized to PMX treatment or conventional therapy. Surprisingly there was no statistically diVerence in the change in endotoxin and IL-6 levels after PMX treatment. While, PMX treatment demonstrated signiWcant improvement of hemodynamic status and cardiac function compared with the controls. This study indicated the possibility that PMX removed unknown substances responsible for improvement of hemodynamic status. One possible candidate is endogenous cannabinoids, such as anandamide and 2-arachidonyl glyceride (2-AG), have been reported as mediators inducing hypotension at the early stage of septic shock [16]. Anandamide is generated by macrophages in response to LPS during gram-negative bacterial sepsis. Endogenous anandamide has an important role in the pathogenesis of septic shock, especially hypotension [17]. 2-AG is one of the endogenous cannabinoids (eCBs), secreted from platelets [16]. They demonstrated that PMX could adsorb not only endotoxin, but also anandamide [18] and 2-AG [19], and removed the increased anandamide and 2-AG in the blood of septic shock patients, resulting in a quick recovery from hypotension. These results suggested that endogenous cannabinoids other than endotoxin might be a promising target for PMX. Further clinical studies are needed to investigate the mechanisms of beneWcial hemodynamic eVects in PMX treatment. Another unexpected beneWcial eVect of PMX on recovery from immunoparalysis was reported [20]. They evaluated the expression of human leukocyte antigen-DR on monocytes and CD16 on granulocytes in patients with sepsis treated with PMX. They found that the down-regulation of both cell surface antigens was correlated to the severity of sepsis, suggesting immunosuppressive status, and PMX treatment exhibited their beneWcial up-regulation of these antigens. These results suggested that PMX might induce the beneWcial immunomodulation in patients with sepsis.
In summary, PMX treatment is safe and eVective in patients with sepsis associated with an improved homodynamic status. Nevertheless, no large, multicenter controlled clinical studies exist to support the eVectiveness of PMX. Further study needs to clarify the novel mechanisms of PMX. 3.2. Continuous hemodiaWltration in sepsis The classical indication for renal replacement therapy is intermittent hemodialysis (IHD). While, CHF and CHDF techniques have recently emerged as alternative modalities to critically ill patients. CHDF, also known as continuous renal replacement therapy (CRRT), is performed continuously for 24 h in the intensive care unit. CHDF allows extracorporeal treatment in patients with gradual correction of Xuid balance, electrolytes, and osmotic pressure, as well as enough nutrition. In addition to the advantage of CHDF, it may eliminate middle- to high-molecular weight substances including bacterial LPS and inXammatory cytokines through mechanisms of convection and adsorption by the Wltrating membrane. Thus, CHDF has been extensively investigated to apply sepsis as a cytokine removal technology in Japan [21]. Kramer Wrst reported CHF as continuous arteriovenous hemoWltration (CAVH) in 1977 [22]. Thereafter, continuous venovenous hemoWltration (CVVH) with a peristaltic pump was developed [23]. To improve the eYcacy of substance removal, CHDF has been applied to multiple organ failure in sepsis [24]. The advantages of CRRT over the intermittent therapies are clearly demonstrated in critically ill patients. One of the most signiWcant advantages is that blood puriWcation is feasible in septic patients who have hemodynamic instability [25]. CRRT permits strict Xuid balance allowing optimization of nutritional support without the concern of Xuid overload. A further beneWt is the elimination of various mediators of diVerent molecular weights generated by sepsis. However, which modality of blood puriWcation therapy such as intermittent and continuous should be used for patients with critically illness remains controversial. Van der Schueren, G. et al. studied the inXuence of IHD on systemic and regional oxygen transport in critically ill patients [26]. As a result, IHD induced an increase in calculated systemic oxygen consumption (p < 0.01) and needed signiWcantly higher inotropic support (p < 0.05) to maintain arterial blood pressure, suggesting the inferiority of IHD. In contrast, three
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independent studies reported that there was no signiWcant diVerence between IHD and CHDF for the treatment of acute renal failure (ARF). Firstly, Mehta et al. compared CRRT with IHD in the treatment of ARF in a multicenter randomized controlled trial [27]. Despite the potential advantage of continuous techniques, they showed no evidence of a survival beneWt of CHDF compared with IHD. Secondly, Kellum et al. performed a meta-analysis of all prior randomized and observational studies that compared CRRT with IHD through a MEDLINE search [28]. The evidence was insuYcient to draw strong conclusions regarding the mode of replacement therapy for ARF. While, the life-saving potential with CRRT suggested that further investigation by a large, randomized trial would be reasonable to consider. Thirdly, Guerin et al. tried to estimate the impact of hemodialysis modality such as IHD versus CRRT on patient outcome in ARF [29]. Accordingly, the type of renal replacement therapy was not signiWcantly associated with outcome. These results suggested that there was no deWnitive evidence to support the superiority of CRRT over IHD especially in ARF. However, in the case of sepsis in the absence of ARF, CHDF may contribute to improve clinical outcome by means of removing unknown mediators. Although, many cytokines with pro- and antiinXammatory action play roles in sepsis, blocking any one cytokine has not led to a positive outcome in patients with sepsis [3–5]. Since CHDF is considered as the BPT derived from the assumption that nonspeciWc and nonselective elimination of various inXammatory mediators [30]. CHDF has been applied to patients with sepsis. However, the capability of CHDF to remove inXammatory cytokines has remained controversial for several years. Numerous studies have demonstrated that hemoWltration can eliminate nearly every substance involved in sepsis to a certain degree [31]. CHF was Wrst applied to patients with sepsis in 1993 with a polyacrylonitrile (AN69) membrane which is thought to removed cytokines such as TNF- and IL-1 by convection [32]. Subsequently, Oda et al. reported that 3 consecutive days of CHDF with polymethylmethacrylate (PMMA) membrane can remove cytokines, including TNF-, IL-6 and IL-8, eYciently compared to an ethylene vinyl alcohol copolymers membrane by mainly adsorption rather than convection. While, even after 3 days of CHDF treatment, blood cytokine levels only showed 20– 25% of reduction [33].
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Even if CHDF can remove cytokines from blood circulation of septic patients, the blood level of cytokines is not always low. In a randomized controlled trial (RCT) using CVVH in early sepsis, Cole et al. demonstrated that the early use of CVVH at 2 L h¡1 did not reduce circulating cytokine concentrations. In contrast, Matsuda et al. showed the signiWcant decrease of various cytokines levels when basal levels of cytokines were high before CHDF with PMMA membrane. Taken together, these results suggested that there was no consensus on correlation between cytokine level and eYcacy of CHDF. On the contrary, it has been hypothesized that the peak concentration of inXammatory cytokines in plasma are responsible for the severity of sepsis. This concept is called “peak concentration hypothesis” [34]. The peak concentration hypothesis is the concept of cutting peaks of soluble mediators through continuous hemoWltration. Thus, CRRT could be able to reduce the peaks of the pro- and anti-inXammatory substances circulating during sepsis, leading to a less severe degree of inXammation and immunodepression. The removal of cytokines by CRRT remains to be proven as a method for improving survival in patients with sepsis. Several studies have found correlation between circulating levels of inXammatory cytokines and outcome of patients with sepsis. However, it remains unclear whether circulating cytokines contribute to the inXammatory reactions taking place locally in aVected organs during sepsis, or whether they are merely indirect markers of the severity of sepsis. Hirasawa et al. performed CHDF on patients with multiple organ failure (MOF) and observed strong improvement of the respiratory index, tissue oxygen metabolism, and cellular injury score in accordance with the decreased cytokine levels [21,35]. Further, they showed that CHDF improved the survival of MOF patients with APACHE H score of 25–34 in retrospective study [21]. RCT is needed to determine the eVect of CHDF on survival in MOF patients. Recently, 2 RCTs of CRRT for sepsis have been conducted. The Wrst was a small multicenter RCT to determine the eVect of plasmaWltration for 34 h [36]. This study showed no diVerence in mortality. The second study was also a small single-center RCT of septic patients using CVVH at 2 L h¡1 of ultraWltration [37]. This study also showed no eVects of CVVH on survival. These studies suggested that neither plasmaWltration for 34 h nor 2 L h¡1 of CVVH might be suYcient to treat sepsis in the absence of ARF.
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In spite of encouraging results as mentioned, outcome of conventional CRRT in sepsis has been still disappointing. Consequently, high-volume-hemoWltration (HVHF) has been developed to improve removal of mediators of sepsis by increasing ultraWltration rate. Ronco et al. randomized 425 patients with an ultraWltration dose of 20 ml kg¡1 h¡1, 35 ml kg¡1 h¡1, and 45 ml kg¡1 h¡1, demonstrating signiWcantly improved survival in septic patients with an ultraWltration dose of 35 ml kg¡1 h¡1 [38]. They recommended that ultraWltration should be prescribed according to patient’s bodyweight and should reach at least 35 ml kg¡1 h¡1. These results reinforced the clinical signiWcance of ultraWltration rate in CHDF. Enlarging pore size of membranes could be other approaches to achieve higher mediator clearance in sepsis. Experimental and clinical data proved that more open membrane exhibited superior removal capability of cytokines [36,39,40] . 4. Conclusion Most clinical studies were performed with a nonrandomized uncontrolled design treating small series of patients especially in Japan. Obviously, well-designed randomized clinical trials are needed to evaluate the eVect of BPT on survival in sepsis. However, there are many restrictions to conduct RCT. First, sepsis and SIRS are clinical entity including heterogeneous group of patients. Patients have a wide spectrum of disease with diVerent causative microorganisms and diVerent source of infection. Thus, better understanding of the immune status and practical biological markers of sepsis are required. Second, the timing of treatment is also critical. The status of hospitalized patients with sepsis may vary whether they are early or late stage of sepsis. In addition, prophylactic treatment may be beneWcial in some cases. Third, we have to determine what kind of BPT will bring favorable results in sepsis, including plasmaWltration, high volume hemoWltration, hemoWltration with higher porosity of membrane, combination of PMX and CHDF, and frequent change of adsorption membrane. Accordingly, due to these unavoidable circumstances, PMX and CHDF have gained popularity in Japan as a prospective or uncontrolled clinical study. Historically, conventional treatments of sepsis have targeted to endotoxin and various cytokines. However, the failure of blocking LPS or cytokine in RCT and understanding of innate immunity through Toll-like receptors caused a paradigm shift
in strategy for treatment of sepsis. PMX was originally developed to aim elimination of endotoxin. While, unexpected beneWcial eVects including improvement of hemodynamic instability and immunosuppression, revealed that PMX might remove other mediators than endotoxin. Although the clinical eYcacy of BPT in sepsis, as represented by CHDF, has been extensively studied in Japan under the Japanese National Health Insurance system, most of these studies have not been published due to lack of RCT. CHDF is initially considered as the blood puriWcation therapy derived from the assumption that nonspeciWc and nonselective elimination of various inXammatory mediators. However, accumulating evidences suggested that clinical beneWt of CHDF stemmed from the elimination of not only various cytokines but also undetermined mediators responsible for improvement of survival. Recent study also revealed that decay of tissues resulted in production of possible candidate stimulating TLR, such as HS, proteases, fragment of hyaluronic acid, and heat-shock proteins [11]. These substances as well as signal transduction molecules of TLRs pathway [8] could become promising targets for treatment of sepsis. Further understanding of underlining mechanisms of sepsis may shed light on the novel mechanisms of blood puriWcation therapy. References [1] Bone RC, Sibbald CL, Sprung WJ. The ACCP–SCCM consensus conference on sepsis and organ failure. Chest 1992;101:1481–3. [2] Ziegler EJ, Fisher Jr CJ, Sprung CL, Straube RC, SadoV JC, Foulke GE, et al. Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebocontrolled trial. The HA-1A Sepsis Study Group. N Engl J Med 1991;324:429–36. [3] Fisher Jr CJ, Slotman GJ, Opal SM, Pribble JP, Bone RC, Emmanuel G, et al. Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. Crit Care Med 1994;22:12–21. [4] Fisher Jr CJ, Agosti JM, Opal SM, Lowry SF, Balk RA, SadoV JC, et al. Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med 1996;334:1697– 702. [5] Abraham E, Wunderink R, Silverman H, Perl TM, Nasraway S, Levy H, et al. EYcacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, doubleblind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. Jama 1995;273:934–41.
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