INVESTIGATIONS OF NEW THERAPIES IN SEPTIC SHOCK

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Septic shock and related sequelae of infection (e.g., multiple organ system failure) are the most common cause of death in intensive care units. Deaths due to sepsis can occur in previously healthy individuals, in all age groups, and in a variety of common clinical settings. Some common predisposing conditions are: premature neonates, previously healthy children with acquired infections (e.g., meningitis, pneumonia, upper respiratory infections), teenagers and young adults with trauma or cancer, and elderly patients with pneumonia or gall bladder disease. Half of all children and adults who acquire septic shock die from the syndrome. Thus, septic shock, which affects young children and the elderly alike (even those without predisposing illness), is a common and important clinical problem with substantial mortality and produces a great financial burden on society. Surprisingly, little is known about the pathophysiology of this disease. Available data indicate that septic shock is caused by a highly complex interaction of factors related to the infection (organism virulence factors and toxins) and factors related to the host response (endogenous molecules that affect and modulate the inflammatory response). Thus, successful treatment of the septic shock syndrome which reduces morbidity and mortality will result from curing the infection and interrupting the effects of these organism and host mediators. Using purpose-bred beagles, the canine model of septic shock has successfully provided information on the pathophysiology and treatment of the human disease. This model, of acute and chronic infection, simulates the course and cardiovascular changes seen routinely in children and adults with septic shock. Prior experiments using the model have established the role of specific bacteria (gram positive and gram negative), bacterial toxins (endotoxin), and host mediators (TNF) to produce septic shock. Thus, the canine model has been highly successful in simulating the human disease and guiding therapy for humans. There are several therapies under investigation that might be effective in human septic shock. As these therapies are potentially toxic and might worsen a patient's condition, they must be tested in an animal model that closely simulates the human disease. The canine model, which simulates the cardiovascular changes seen in children and adult humans with septic shock, is ideally suited for pre-clinical trials of these new therapies. The canine model allows properly controlled trials to evaluate therapeutic mechanisms and adverse effects of therapies, that is not always possible in human studies. We are evaluating or have planned to evaluate the following therapies of septic shock in the canine model; Lipid X; Plasmapheresis, Ibuprofen; Monoclonal Antibodies to Endotoxin; Antibody to Tumor Necrosis Factor; Pentoxyphylline; Granulocyte Stimulating Factor; Antibodies to Platelet Activating Factor; Antibodies to Protein C; Antibodies to Receptors on White Blood Cells.