Endotoxin Adsorption Therapy Research Articles

Up-to-date information on polymyxin B-immobilized fiber column direct hemoperfusion for septic shock.

Endotoxin adsorption therapy by polymyxin B-immobilized fiber column direct hemoperfusion (PMX-DHP) has been used for the treatment of septic shock patients. Endotoxin, an outer membrane component of Gram-negative bacteria, plays an important role in the pathogenesis of septic shock. Endotoxin triggers a signaling cascade for leukocytes, macrophage, and endothelial cells to secrete various mediators including cytokines and nitric oxide, leading to septic shock and multiple organ dysfunction syndrome. PMX-DHP directly adsorbed not only endotoxin but also monocytes and anandamide. It reduced blood levels of inflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor-alpha and IL-17A, adhesion molecules, plasminogen activator inhibitor 1, and high mobility group box-1. As a result, PMX-DHP increased blood pressure and reduced the dose of vasoactive-inotropic agents. PMX-DHP improved monocyte human leukocyte antigen-DR expression in patients with severe sepsis and septic shock. A post hoc analysis of EUPHRATES (Evaluating the Use of Polymyxin B Hemoperfusion in Randomized Controlled Trial of Adults Treated for Endotoxemia and Septic Shock) trial has shown that PMX-DHP significantly reduced 28-day mortality compared with the control group in septic shock patients with endotoxin activity assay level between 0.60 and 0.89. Longer duration of PMX-DHP may be another strategy to bring out the beneficial effects of PMX-DHP. Further studies are needed to confirm the efficacy of PMX-DHP treatment for septic shock.

Kawasaki disease with acute myocarditis in an adolescent.

A previously healthy 16-year-old adolescent was admitted to our hospital with fever, sore throat, diarrhoea, strawberry tongue, rashes on lower extremities, and pain in the neck, abdomen and joints. He was initially diagnosed with IgA vasculitis triggered by acute pharyngitis. Despite antibiotic treatment, he gradually developed multiorgan failure and cardiac shock. Cardiac catheterisation did not show any signs of coronary artery disease. Subsequently, he developed serious rhabdomyolysis and peripheral extremity necrosis, suggesting peripheral arteritis. Although blood culture results were negative, he received endotoxin adsorption therapy, but it was ineffective. Hence, we suspected Kawasaki disease (KD). We administered high-dose intravenous immunoglobulin therapy (2 g/kg), which was effective. He gradually recovered without major complications and was given ambulatory discharge 43 days after admission. Early diagnosis and administration of intensive care in adolescents with KD with acute myocarditis are critical but challenging.

History and future in endotoxin adsorption therapy

History and future in endotoxin adsorption therapy

Progress of endotoxin adsorption therapy with polymyxin B fixed fiber column

Progress of endotoxin adsorption therapy with polymyxin B fixed fiber column

A case of neonatal sepsis treated with low-dose endotoxin adsorption therapy

A case of neonatal sepsis treated with low-dose endotoxin adsorption therapy

O7-4 - A Case of Left Ventricular Pseudoaneurysm Developed from Myocardial Abscess

The patient was a 57-year-old woman who had undergone maintenance hemodialysis due to diabetic nephropathy. She suddenly developed high fever of 40°C, lumbago and epigastralgia with hypotension and was diagnosed as having septic shock requiring vasopressors and endotoxin adsorption therapy. Laboratory test demonstrated severe inflammation and methicillin sensitive Staphylococcus aureus was cultured from blood samples, but clear source of infection was not detected. After the administration of specific intravenous antibiotics, inflammatory data gradually declined, but 10 days later, she developed high fever and pericarditis. Echocardiogram disclosed pericardial effusion and calcification of the posterior mitral leaflet but vegetation was not detected. Although the aspiration was negative for bacterial growth, we diagnosed her as bacterial pericarditis and continued the administration of antibiotics for four weeks. Thereafter she got well and discharge. One month later, she visited our hospital with anorexia and computed tomography revealed a large pseudoaneurysm of the posterior left ventricular wall just below the posterior mitral valve leaflet. She underwent emergent surgery. The left ventricular aneurysm orifice was closed. If patients on hemodialysis become complicated by long term fever, we need to pay attention to the onset of infective endocarditis.

Evidence and perspectives of endotoxin adsorption therapy

Evidence and perspectives of endotoxin adsorption therapy

Effectiveness of polymyxin b immobilized fiber hemoperfusion in patients with septic shock due to Gram-negative bacillus infection: the PMXHP study

Mortality from septic shock in the ICU remains high, ranging from 30 to 50%. In particular, Gram-negative bacilli (GNB) account for 40% of the causative bacteria of severe sepsis, which progresses to multiorgan failure due to significant inflammation. Hemoperfusion with polymyxin B-immobilized fiber (PMX) adsorbs endotoxin and can reduce the inflammatory cascade of sepsis due to GNB. However, the clinical efficacy of this treatment has not been demonstrated. We aimed to verify the efficacy of endotoxin adsorption therapy by using PMX.

A case of fatal interstitial pneumonia during treatment of radiotherapy plus cetuximab for patient with head and neck carcinoma

We report a case of fatal interstitial pneumonia in a patient treated with radiotherapy plus cetuximab for head and neck carcinoma. The patient was an 86-year-old man with laryngeal squamous cell carcinoma (T2N0M0). Cetuximab was given in combination with radiotherapy; however, the patient developed dyspnea on day 30 and computed tomography findings confirmed a diagnosis of interstitial pneumonia. Noninvasive positive pressure ventilation was immediately started in conjunction with steroid pulse and endotoxin adsorption therapy. This led to temporary relief of symptoms. However, a subsequent relapse was resistant to steroid pulse therapy, and the patient died from interstitial pneumonia on day 47.

Erratum to: Endotoxin adsorption therapy using polymyxin B-immobilized fiber as a treatment for septic shock-associated severe acute cholangitis.

The application of endotoxin adsorption therapy for severe acute cholangitis is controversial. We present a survival case of septic shock and multiple organ failure due to severe acute cholangitis. The patient was treated by endotoxin adsorption therapy using polymyxin B-immobilized fiber because he continued to remain in shock even after successful endoscopic nasobiliary drainage. The patient was an 84-year-old male diagnosed with acute cholangitis and acute pancreatitis who was transferred to our department because of shock and severe dyspnea. The patient had already developed acute respiratory failure, acute renal failure, and disseminated intravascular coagulation. We performed endoscopic nasobiliary drainage immediately, but the patient continued to remain in shock and plasma endotoxin level was markedly elevated at 133.6 pg/mL. Therefore, we performed direct hemoperfusion with polymyxin B-immobilized fiber. On starting the hemoperfusion, blood pressure and urine volume increased, and the plasma endotoxin level reduced considerably. On the basis of our experience in this case, we think that direct hemoperfusion with polymyxin B-immobilized fiber may be a useful modality in the management of severe acute cholangitis.

Reply

Reply We thank Koga and colleagues for referring to our article (1) and reporting the successful use of endotoxin adsorption therapy for pediatric endotoxin shock, in their letter to the editor. We would like to make a few comments regarding this case report. Sepsis remains a major cause of morbidity and mortality among children despite the availability of various treatments using antibiotics, fluids, or vasopressive/inotropic approaches. Children with severe sepsis have hospital mortality rates of 10.3% in the United States (2) and 17% in the United Kingdom (3). Several factors, including age and immune status, influence the defense mechanisms against infection in children. Susceptibility to infection in some children is linked to immaturity of the immune system or the immunocompromising effects of chemotherapy. In these children, bacteria and virulence such as endotoxin in the blood stimulate the systemic inflammatory response. Even under intensive care, these processes can rapidly progress to multiple organ dysfunction syndrome and death. Endotoxin, an outer membrane component of gram-negative bacteria, plays an important role in the pathogenesis of severe sepsis and septic shock. Endotoxemia is common in children admitted to pediatric intensive care units and may be associated with increased severity of illness (4). The international guidelines for the management of severe sepsis and septic shock recommend fluid resuscitation, antibiotics, source control, inotropes/vasopressors, and corticosteroids, if needed, for the treatment for pediatric septic shock (5). When these treatments are ineffective and the plasma endotoxin concentration or endotoxin activity assay is increased, endotoxin adsorption therapy by polymyxin B–immobilized fiber column direct hemoperfusion (PMX-DHP) can be used as an optional treatment in Japan. In their letter to the editor, Koga and colleagues reported the effective use of PMX-DHP therapy for endotoxin shock in an immunocompromised child. Polymyxin B–immobilized fiber column direct hemoperfusion therapy has been widely used in adult patients with septic shock in Japan. We have shown in the meta-analysis that PMX therapy for adult patients with septic shock had beneficial effects on the hemodynamics, pulmonary oxygenation, and mortality (1). 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. Children with septic shock have also received PMX-DHP therapy, but the pediatric use of the therapy has only been reported in English once, in a letter to the editor in Digestive Diseases and Sciences (6). The Japan Society for Premature and Newborn Medicine issued a guideline for PMX-DHP therapy for infants/neonates in Japanese in 2010. Polymyxin B–immobilized fiber column direct hemoperfusion therapy is indicated for pediatric patients with septic shock when the patients manifest endotoxemia associated with the criteria for pediatric sepsis (7). The criterion for excluding PMX-DHP therapy for pediatric patients with septic shock is intracranial bleeding or a tendency to bleed in general. The following are important points for PMX-DHP performance in children: (1) an appropriately sized catheter should be inserted for vascular access; (2) an appropriately sized PMX column should be used; (3) the blood flow rate should be gradually increased to 2 to 5mL/kg per minute to prevent circulatory collapse; (4) nafamostat mesilate should be infused at a rate of 0.5 to 1.0 mg/kg per hour for anticoagulant and thereafter maintained at the rate necessary to sustain activated clotting time for 150 to 200 s. When the priming volume is greater than 10% of the patient’s body weight, a mixture of a red blood cell suspension and physiological saline is needed to prevent anemia. The PMX-05R column or PMX-01R column is usually used for children with endotoxin shock, because circulating blood volumes are low. The former, the PMX-05R column, has a low priming volume (40 mL) and is used for children with body weights of 10 kg or over. The PMX-01R column, which has a lower priming volume (8 mL), has been used for smaller children (body weights <10 kg) since its introduction in Japan in April 2012. When administering PMX-DHP for children, physicians should be mindful of their lower circulating blood volumes. Electrocardiogram and blood pressure must be monitored during this therapy. Severe arrhythmia such as ventricular tachycardia or ventricular fibrillation may occur as a consequence of low circulating volumes several minutes after the initiation of extracorporeal circulation. Hence, the safety and efficacy of PMX-DHP therapy for high-risk children with septic shock have not yet to be confirmed. Nevertheless, we believe that PMX-DHP is a useful therapy for severe pediatric endotoxin shock. Chieko Mitaka Department of Critical Care Medicine Tokyo Medical and Dental University Graduate School Tokyo, Japan Makoto Tomita Clinical Research Center Tokyo Medical and Dental University Hospital of Medicine Tokyo, Japan

Endotoxin adsorption therapy using polymyxin B-immobilized fiber as a treatment for septic shock-associated severe acute cholangitis

The application of endotoxin adsorption therapy for severe acute cholangitis is controversial. We present a survival case of septic shock and multiple organ failure due to severe acute cholangitis. The patient was treated by endotoxin adsorption therapy using polymyxin B-immobilized fiber because he continued to remain in shock even after successful endoscopic nasobiliary drainage. The patient was an 84-year-old male diagnosed with acute cholangitis and acute pancreatitis who was transferred to our department because of shock and severe dyspnea. The patient had already developed acute respiratory failure, acute renal failure, and disseminated intravascular coagulation. We performed endoscopic nasobiliary drainage immediately, but the patient continued to remain in shock and plasma endotoxin level was markedly elevated at 133.6pg/mL. Therefore, we performed direct hemoperfusion with polymyxin B-immobilized fiber. On starting the hemoperfusion, blood pressure and urine volume increased, and the plasma endotoxin level reduced considerably. On the basis of our experience in this case, we think that direct hemoperfusion with polymyxin B-immobilized fiber may be a useful modality in the management of severe acute cholangitis.

Polymyxin B-immobilized fiber column hemoperfusion has the ability of endotoxin removal during 24 hours

Endotoxin plays an important role in the pathogenesis of septic shock. Endotoxin adsorption therapy by Polymyxin B-immobilized fiber column (PMX) hemoperfusion has been used for the treatment of septic shock patients in Japan. According to the company's recommendation, the standard duration of PMX treatment for patients with septic shock is 2 hours. However, we have shown that greater than 2 hours duration of PMX treatment significantly improved hemodynamics and significantly decreased administration of norepinephrine than 2 hours duration of PMX treatment. Our hypothesis was that PMX treatment had the ability of endotoxin removal during 24 hours. Therefore, the purpose of this study was to evaluate the endotoxin adsorption ability of 24 hours duration of PMX treatment.

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.

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.

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 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.

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.

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.