Endotoxin Adsorption Research Articles

Polymyxin B-Immobilized Fiber Column Hemoperfusion Therapy for Septic Shock

Endotoxin, an outer membrane component of gram-negative bacteria, plays an important role in the pathogenesis of septic shock. Endotoxin adsorption therapy by polymyxin B-immobilized fiber column hemoperfusion (PMX) has been used for the treatment of septic shock patients in Japan since 1994. The covalent binding of polymyxin B onto the surface of the polystyrene-based carrier fiber in PMX inactivates the endotoxin in the blood without exerting toxicity. This study was performed as a systematic review to evaluate the efficacy and mechanism of PMX treatment in patients with septic shock. The PubMed database and references from identified articles were used to search and review the literature relating to the efficacy and mechanism of PMX treatment in patients with septic shock. Polymyxin B-immobilized fiber column hemoperfusion adsorbed monocytes, activated neutrophils, and anandamide, as well as endotoxin through direct covalent bond, hydrophobic and ionic interactions, and hydrodynamics, and reduced the blood concentrations of inflammatory cytokines, plasminogen activator inhibitor 1 and adhesion molecules. Polymyxin B-immobilized fiber column hemoperfusion increased blood pressure and reduced the dosage requirements for vasopressive/inotropic agents. The meta-analysis showed that PMX treatment had beneficial effects on the hemodynamics, pulmonary oxygenation, and mortality. These beneficial effects may be attributable to the direct adsorption of endotoxin, monocytes, activated neutrophils, and anandamide, as well as indirect decrease in inflammatory cytokines and other mediators. Polymyxin B-immobilized fiber column hemoperfusion treatment has additional effects on reducing endothelial damage, proapoptotic activity, and immunosuppression. Further studies will be needed to confirm the efficacy and mechanism of PMX treatment in septic shock.

Changes in Serum S100A12 and sRAGE Associated with Improvement of the PaO2/FiO2 Ratio following PMX-DHP Therapy for Postoperative Septic Shock

Background: Endotoxin (Et) adsorption therapy with a column of polymyxin B-immobilized fibers (PMX) is effective in improving the partial pressure of arterial oxygen/fraction of inspired oxygen ratio (PaO₂/FiO₂ ratio) and increasing mean arterial blood pressure (MAP) in sepsis. S100A12 and soluble receptor for advanced glycation end product (sRAGE) are useful as early markers of acute lung injury. Purpose: To investigate the effect of improving the PaO₂/FiO₂ ratio by PMX-direct hemoperfusion (PMX-DHP) on production of S100A12 and sRAGE. Subjects and Methods: Sepsis patients after surgery for perforation of the lower gastrointestinal tract were adopted as the subjects. We retrospectively reviewed the cases of 20 patients on mechanical ventilation and continuous administration of norepinephrine. We recorded PaO₂/FiO₂ ratio, MAP, and norepinephrine doses. S100A12, sRAGE, and Et levels were measured before and after PMX-DHP. Results: The PaO₂/FiO₂ ratio and MAP improved significantly after PMX-DHP (p < 0.05). S100A12 and Et decreased significantly after PMX-DHP (p < 0.05). No differences were observed in sRAGE. Conclusion: S100A12 is useful as a marker that reflected improvement in the PaO₂/FiO₂ ratio after PMX-DHP. We consider PMX-DHP to be useful as adjunctive therapy for sepsis that reduces the Et and corrects the pathology in the early stage.

Efficacy of a novel endotoxin adsorber polyvinylidene fluoride fiber immobilized with L-serine ligand on septic pigs

A novel adsorber, polyvinylidene fluoride matrix immobilized with L-serine ligand (PVDF-Ser), was developed in the present study to evaluate its safety and therapeutic efficacy in septic pigs by extracorporeal hemoperfusion. Endotoxin adsorption efficiency (EAE) of the adsorber was firstly measured in vitro. The biocompatibility and hemodynamic changes during extracorporeal circulation were then evaluated. One half of 16 pigs receiving lipopolysaccharide (Escherichia coli O111:B4, 5 μg/kg) intravenously in 1 h were consecutively treated by hemoperfusion with the new adsorber for 2 h. The changes of circulating endotoxin and certain cytokines and respiratory function were analyzed. The 72 h-survival rate was assessed eventually. EAE reached 46.3% (100 EU/ml in 80 ml calf serum) after 2 h-circulation. No deleterious effect was observed within the process. The plasma endotoxin, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) levels were decreased during the hemoperfusion. Arterial oxygenation was also improved during and after the process. Furthermore, the survival time was significantly extended (>72 h vs. 47.5 h for median survival time). The novel product PVDF-Ser could adsorb endotoxin with high safety and efficacy. Early use of extracorporeal hemoperfusion with the new adsorber could reduce the levels of circulating endotoxin, IL-6, and TNF-α, besides improve respiratory function and consequent 72 h-survival rate of the septic pigs. Endotoxin removal strategy with blood purification using the new adsorber renders a potential promising future in sepsis therapy.

Transient left ventricular dysfunction associated with severe Legionella infection

Legionella infection, although commonly seen as pneumonia, can also manifest systemic involvement. Here, we describe a case of sporadic Legionella infection coinciding with pneumonia, rhabdomyolysis, renal failure, and severe left ventricular dysfunction, which subsequently developed refractory septic shock. An endomyocardial biopsy revealed no findings of interstitial inflammatory infiltrates. After 3 days of intensive care, including percutaneous cardiopulmonary support, intraaortic balloon pumping, and continuous hemodialysis with endotoxin adsorption therapy, left ventricular wall motion improved spontaneously in accordance with a decrease in the concentration of inflammatory cytokines. Cardiac complications are rare but Legionella infection should be considered as a possible etiology of left ventricular dysfunction in patients with sepsis.

Intraoperative direct hemoperfusion with a polymyxin-B immobilized fiber column for treatment of infective endocarditis

Endotoxin adsorption treatment (direct hemoperfusion using a polymyxin-B immobilized fiber column, or PMX-DHP) is now considered a useful option for treating severe sepsis. However, the efficacy of PMX-DHP for infective endocarditis (IE), in which the causative microorganisms are usually gram-positive cocci, remains unclear. In the present study, we investigated the impact of intraoperative PMX-DHP on clinical parameters during the treatment of IE. From November 2006 to December 2009, a total of 11 patients with active IE underwent emergent surgery using intraoperative PMX-DHP. The perioperative courses of these patients were compared with those of seven patients who underwent emergent surgery for active IE with the conventional method from January 2003 to October 2006. PMX-DHP was associated with a significant decrease in the postoperative catecholamine dose and duration. Intubation time and intensive care unit length of stay for the PMX-DHP group was significantly shorter than that for the conventional therapy group. There was also a significant difference in the number of failed organs postoperatively between the two groups. Intraoperative PMX-DHP demonstrated several positive effects, such as a drastic decrease in the doses of inotropic agents and shortening of the duration of mechanical ventilation, in patients who underwent emergent surgery for active IE. Intraoperative PMX-DHP can be a useful option for the treatment of critically ill patients with IE.

Extended duration of direct hemoperfusion with polymyxin B-immobilized fiber column improves hemodynamics in patients with septic shock

Endotoxin adsorption therapy by direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) has been widely used in patients with septic shock in Japan. Many Japanese doctors use each PMX cartridge only for 2 hours; however, the mechanisms and optimal duration of PMX treatment remain unclear. We have performed PMX-DHP for longer than 2 hours to confirm that an extended duration of PMX-DHP for patients with septic shock would give significant improvements of hemodynamics.

A 6-year-old child with idiopathic gastric rupture leading to septic shock, who responded well to PMX (endotoxin adsorption using polymyxin-B immobilized fiber) and CHDF (continuous hemodiafiltration)

症例は6歳，男児．平成19年6月26日，昼食後から上腹部痛と嘔吐が出現．翌27日には腹部膨満も現れたため近医を受診後，当院小児科を紹介となり精査・加療目的に入院となった．高熱と頻呼吸を伴うショック状態であったためICUへ入室となった．腹部CTにおいて多量のfree airと腹水，胃・十二指腸・小腸の拡張を認めたため上部消化管の穿孔と考え緊急開腹手術となった．胃上部大彎後壁側の破裂と食物残渣を伴った腹水が認められたため胃破裂による腹膜炎と診断し，破裂部を含む部分胃切除を行った．術後はdopamine（DOA）8μg/kg/min投与下でも収縮期血圧が60mmHg台と敗血症性ショックの状態であったことからエンドトキシン吸着（PMX）を施行した．PMX開始後より血圧は速やかに上昇し2時間後には136/70mmHgまで改善した．PMX終了後，持続的血液透析濾過（CHDF）に移行し十分な利尿も得られるようになり，3日後にはDOA，CHDFともに離脱．7月27日にはICUを退室し，12月22日に退院となった．特発性胃破裂の学童期での発症は稀であり，さらに敗血症性ショックに至り血液浄化を行った症例はわれわれが検索した限り本邦では3例目であった．小児例であっても重篤な敗血症性ショックからの早期離脱・全身状態の早期改善をはかるためにPMXを含めた血液浄化療法の施行を検討すべきであると考えられた．

Intraoperative endotoxin adsorption for visceral malperfusion complicating acute type A aortic dissection

A 65-year-old man presenting with visceral malperfusion complicating acute type A aortic dissection underwent emergent surgery. Bypass grafting from the right common iliac artery to the superior mesenteric artery was performed prior to central aortic repair because intestinal ischemia caused hemodynamic instability. Subsequently, the ascending aorta was replaced with a Dacron graft under a condition of circulatory arrest with selective cerebral perfusion. Endotoxin adsorption was carried out intraoperatively in parallel with cardiopulmonary bypass to prevent postoperative end-organ failure. The patient recovered uneventfully and was discharged from our hospital 31 days after surgery.

A LONGER DURATION OF POLYMYXIN B-IMMOBILIZED FIBER COLUMN HEMOPERFUSION IMPROVES PULMONARY OXYGENATION IN PATIENTS WITH SEPTIC SHOCK

Endotoxin plays an important role in the pathogenesis of septic shock. Exposure of endothelial cells to endotoxin activates endothelial cells and increases the surface expression of adhesion molecules, markers of endothelial damage in organ dysfunction. Endotoxin adsorption therapy by polymyxin B-immobilized fiber column (PMX) hemoperfusion has been used for the treatment of septic shock patients. In this study, we measured plasma concentrations of endotoxin and soluble adhesion molecules in septic shock patients before and after the PMX treatment then observed on the relationships between actual duration of use and various outcomes. Sixteen patients with septic shock were studied. The 28-day mortality rate was 50%. The elevated plasma concentrations of endotoxin decreased after the PMX treatment in the survivors but not in the nonsurvivors. The norepinephrine dose and plasma concentrations of soluble endothelial leukocyte adhesion molecule 1 and soluble intercellular adhesion molecule 1 significantly (P < 0.05) decreased in the PMX greater-than-2-h (prolonged) group than in the PMX 2-h (conventional) group (-17.8 +/- 14.6 vs. -1.8 +/- 2.7 microg/min, -143.0 +/- 111.0 vs. 0 +/- 2.8 ng/mL, and -126.2 +/- 144.9 vs. 16.5 +/- 108.1 ng/mL, respectively). Changes in the PaO2-FiO2 ratio and the Sequential Organ Failure Assessment score were significantly (P < 0.05) more improved in the PMX greater-than-2-h group than in the PMX 2-h group (75.4 +/- 80.7 vs. 1.2 +/- 49.2 and -0.8 +/- 1.8 vs. 2.2 +/- 1.9 torr, respectively). We thus suggest that a longer duration of PMX treatment may improve the pulmonary oxygenation associated with decreased adhesion molecules in septic shock.

Preliminary Report regarding the Use of Selective Sorbents in Complex Cardiac Surgery Patients with Extensive Sepsis and Prolonged Intensive Care Stay

Aims: The purpose of this publication is to evaluate the first experiences with the supplemental use of selective endotoxin adsorption cartridges in the treatment of critically ill patients complicated by severe sepsis after cardiac surgery. Methods: Thirteen patients with Gram-negative sepsis underwent the procedure of selective lipopolysaccharide (LPS) adsorption using Alteco adsorber (group I) or Toraymyxin™ columns (polymyxin-B-immobilized fiber) (group II). Results: This therapy positively influenced the course of sepsis. After the second procedure, levels of serum endotoxin and procalcitonin markedly decreased in both groups. We also discovered a positive effect on leukocytosis levels and a trend towards normalization of body temperature, improvement of hemodynamic indices and increase of the lung’s oxygenating function. Blood cultures taken several days after the procedure were negative. Conclusion: Our experience with LPS adsorption shows some evidence for the potential efficacy of this method in the treatment of critically ill patients with sepsis. Further investigations are required.

Adjunctive therapy of severe sepsis and septic shock in adults

Summary Sepsis continues to be a major unresolved medical challenge of the present. Despite earlier diagnosis and treatment initiation, source control, improvements in the standard of care and attempts at standardization of treatment and resuscitation protocols intensive care unit mortality rates for severe sepsis is 32.2% and 54.1% for septic shock. Further reduction in mortality may be achievable through knowledge and use of the expanding field of adjunctive therapy: a supplement to optimal, supportive, intensive therapy and antibiotic treatment. Numerous and unsuccessful trials targeted at inhibiting various essential inflammatory mediators and receptors involved in the sepsis syndrome have failed to show a reduction in mortality, raising the question whether mortality in sepsis actually derives from an uncontrolled pro-inflammatory response. Thus, more broad based attempts at modulating the inflammatory response to infection like corticosteroids and drotrecogin alfa (activated) are to date the only drugs to have demonstrated mortality benefits in large randomized controlled trials. Advances in understanding the pathophysiology of sepsis as a heterogeneous, dynamic syndrome caused by imbalances in the inflammatory network have provided newer hemofiltration techniques with a strong treatment rationale. Furthermore, endotoxin adsorption, if effective, has the potential to prevent further progression of the biological cascade of gram-negative sepsis.

Efficacy of an Extracorporeal Endotoxin Adsorber System during Hyperdynamic Porcine Endotoxemia

Background: Endotoxemia is a crucial factor in the pathogenesis of sepsis. Elimination of endotoxin is aimed at the reduction of sepsis-related morbidity and lethality. The objective of this study was to examine the impact of an endotoxin adsorber on hemodynamics, O₂ exchange and metabolism during resuscitated porcine endotoxemia. Methods: Twenty pigs were randomized into 2 intervention groups (n = 7 each) and 1 control group (n = 6). Endotoxemia was induced by continuous intravenous application of lipopolysaccharide for 8 h. Adsorber therapy was started at the same time as the induction of endotoxemia or 2 h later. An extracorporeal hemoperfusion device using immobilized human serum albumin for endotoxin adsorption was used. Results: Hemodynamic, metabolic and acid-base parameters, as well as the kinetics of interleukin (IL)-6, IL-8, IL-10 and tumor necrosis factor-α, were characteristic for endotoxic shock. Endotoxin plasma levels were low (arterial, hepatic and portal vein). None of the parameters were significantly influenced by the adsorber system. Conclusion: Despite typical clinical signs of endotoxemia, the adsorber system had no significant effect on hemodynamic, metabolic and acid-base parameters during endotoxic shock. The reasons for the absence of an effect are elusive; however, failure of the method per se or exceeded capacity of the adsorber cannot be excluded.

Effects of Polymyxin B-Immobilized Fiber Using a Rat Cecal Ligation and Perforation Model

We evaluated the efficacy of polymyxin B-immobilized fiber (PMX-F) on organ dysfunction using a rat cecal ligation and perforation (CLP) model. Fifteen-week-old Sprague-Dawley rats (n = 21) were divided into three groups. For a PMX group, n = 7, peritonitis was induced by CLP. After 24 hours from CLP, endotoxin adsorption was performed for 1 hour with a PMX-F column. A sham group, n = 7, external circulation was performed with nonimmobilized fiber column. A control group, n = 7, were sacrificed 25 hours after CLP (no hemoperfusion performed). The changes in interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-alpha and plasminogen activator inhibitor (PAI)-1 were measured. The lungs, liver, and kidneys were stained with hematoxylin and eosin and anti-PAI-1 antibodies. Terminal uridine-triphosphate nick-end labeling assay was performed to evaluate apoptosis. The PMX group showed a tendency to decrease in blood levels of IL-6 and PAI-1 compared with the sham group. Anti-PAI-1 antibody staining was seen in the lungs of the control and sham groups. The PMX group showed significantly decreased apoptotic cells in renal tubule cells compared with sham and control groups. We conclude that PMX-F may have inhibited PAI-1 expression in the lungs and decreased apoptosis of renal tubule cells.

Adsorption of Endotoxin from Aqueous Solution Using Bone Char

The aim of this study is the removal of endotoxin from aqueous solution using bone char (BC) as an adsorbent material. The BC was prepared from cattle animal bone by pyrolysis in a furnace at 850 degrees C. The morphology and physico-chemical characteristics of the adsorbent were investigated. Kinetic studies revealed that the adsorption of endotoxin is rapid. The adsorption mechanisms in the endotoxin-BC had a significant contribution from film diffusion. The maximum adsorption efficiency achieved is 98% at an adsorbent dose of 40 g L(-1) with an initial endotoxin concentration of 80 Eu mL(-1). The results show that the Langmuir isotherm adsorption equation model describe the experimental adsorption isotherm with good accuracy. A survey of the regeneration capabilities showed that the BC could be regenerated and rendered endotoxin free by heating at 350 degrees C for 30 min. The results suggest that BC could be used as effective adsorbent for endotoxin removal.

Specific Removal of Monocytes from Peripheral Blood of Septic Patients by Polymyxin B-immobilized Filter Column.

Lipopolysaccharide (LPS) is one of the major causes of septic shock. The polymyxin B-immobilized filter column (PMX) was developed for the adsorption of endotoxin by direct hemoperfusion and has been used for the treatment of LPS-induced septic shock. In this study, we demonstrated that PMX also specifically bound monocytes from the peripheral blood leukocytes of septic patients by mean of an analysis of bound cells using immunocytochemical and electron microscopic techniques. 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.

Experience with the use of selective sorbents in complex intensive care of sepsis in patients after cardiac surgery

The aim of the study was to evaluate the first experience with endotoxin adsorption in complex intensive care of critically ill patients with sepsis after heart surgery.

Successful Treatment of Necrotizing Fasciitis and Toxic Shock Syndrome by Hip Amputation and Endotoxin Hemoadsorption

Background: Necrotizing fasciitis is a rare but severe condition associated with high mortality. We encountered a patient with severe and rapidly progressing necrotizing fasciitis. Patient: A 40-year-old male was hit by a tractor and received a wide laceration wound spanning the length of his posterior thigh. Soon after the accident, the wound was washed and debridement was performed. Two days postoperatively, we observed septic changes in the wound and diagnosed this condition as necrotizing fasciitis. Consequently, the patient's leg was amputated at the thigh. The patient, however, developed toxic shock syndrome after the amputation. Endotoxin adsorption using a polymyxin B-immobilized fiber column was performed for 2 days. Finally, a hip joint amputation was performed after 11 days, following which the patient's general condition gradually improved. Discussion: Treatment for necrotizing fasciitis should be initiated promptly. Early debridement is associated with a significant decrease in mortality. In severe conditions, endotoxin and cytokine removal by blood purification is one of the most effective treatments. Although group A streptococci are widely known as flesh-eating bacteria, we should also consider a wide variety of pathogenic organisms to be the probable cause of severe necrotizing fasciitis. Conclusion: Management of necrotizing fasciitis requires careful investigation as well as an aggressive therapeutic approach, which may include urgent surgical intervention. In addition to surgery, endotoxin adsorption therapy should be considered.

Study of Prognostic Factors for Colorectal Perforation and application of Endotoxin Adsorption Therapy

Study of Prognostic Factors for Colorectal Perforation and application of Endotoxin Adsorption Therapy

Clinical effects of polymyxin B immobilised fiber with direct hemoperfusion for the patients of severe sepsis or septic shock caused by intra-abdominal infections

The endotoxin adsorption method polymyxin B immobilised fiber with direct hemoperfusion (PMX-DHP) has been used for treatment of patients with severe sepsis and septic shock primarily caused by Gram-negative infections in Japan [1]. One hundred and twenty-six septic patients who had severe sepsis or septic shock due to intra-abdominal infections were treated with PMX-DHP.

Fulminant amoebic colitis during chemotherapy for advanced gastric cancer

A 52-year-old man had bloody stools during chemotherapy for gastric cancer. A colonoscopy revealed necrotizing ulcer-like changes. A biopsy confirmed the presence of amoebic trophozoites. Subsequently, peritonitis with intestinal perforation developed, and emergency peritoneal lavage and colostomy were performed. After surgery, endotoxin adsorption therapy was performed and metronidazole was given. Symptoms of peritonitis and colonitis resolved. However, the patient's general condition worsened with the progression of gastric cancer. The patient died 50 d after surgery. Fulminant amoebic colitis is very rarely associated with chemotherapy. Amoebic colitis should be considered in the differential diagnosis of patients who have bloody stools during chemotherapy.