How to comprehend the pathophysiology of sepsis and treat the patients with endotoxemia?

In the pathophysiology of sepsis leading to multiple organ dysfunction syndrome (MODS), uncontrolled hyper-inflammatory responses to infected microorganism play a pivotal role. However, the concept that MODS and death from sepsis was attributable to overstimulated immune response, which based on basic studies in which large doses of endotoxin or bacteria were administered and the animal died from “cytokine storm”, and does not reflect the clinical pictures of sepsis. The outcome of sepsis depends mainly on delayed organ failure, which cannot be explained by the concept. We can discuss the pathophysiology of sepsis as mentioned below to comprehend this condition.<BR>1) The duration of overstimulated inflammatory response to infection is short-lasting than it was originally thought to be. Immunosuppression may occur earlier phase of sepsis. Characteristic finding from autopsy of septic patients is apoptotic immune cell death, such as lymphocytes and intestinal epithelial cells, which may contribute to the impaired immune response of sepsis.<BR>2) Organ dysfunction of sepsis cannot be explained by histological evidence of cell death. The concept of sepsis-induced mitochondrial dysfunction is supported as cytopathic hypoxia to understand the pathogenesis of organ dysfunction.<BR>A considerable body of evidence has accumulated the implication of endotoxin in pathophysiology of sepsis. Although 25g of endotoxin is reserved in gut of healthy humans, full clinical manifestations of sepsis can be developed by administration small dose of endotoxin. However, antiendotoxin strategy, such as monoclonal antibody, have not provided survival benefits in clinical trials. EUPHAS trial is a trial to determine whether polymixin B hemoperfusion (PMX-DHP) added to conventional therapy improves outcome, 1) hemodynamic parameters, 2) respiratory parameters, SOFA score, and 28-day mortality compared with conventional therapy. PMX-DHP improved significantly those parameters and mortality. The analysis triggered the stopping rule based on a statistically significant reduction in mortality. We reviewed several points regarding this study.<BR>1) Although circulating endotoxin levels was not determined, does the clinical efficacy of PMX-DHP depend on removal of endotoxin?<BR>2) Severe leukocytopenic/thrombocytopenic patients, those are important target of this treatment, have been excluded.<BR>3) Why did not improve hemodynamic parameters in conventional therapy?<BR>4) Is the 28-day mortality 53% in conventional therapy group too high?<BR>5) Is it important full removal of endotoxin? Does PMX-DHP improve immunosuppressive state of sepsis?<BR>6) Is early termination of the study justified?<BR>This trial realized the importance of PMX-DHP in the management of abdominal sepsis in our country again, and also may provide the influence to the world.