INVESTIGATIONS OF NEW THERAPIES IN SEPTIC SHOCK

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Septic shock and related sequalae 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 pre- disposing conditions are premature neonates, previously healthy children with acquired infections (e.g., meningitis, pneumonia, upper respiratory infections), teenagers or young adults with trauma or cancer, and elderly patients with pneumonia or gall bladder disease. Half of all children or adults who acquire this 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 substan- tial mortality and produces an great financial burden on society. Surprisingly little is known about the pathophysiology of this disease 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 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 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. The canine model, which simulates the cardiovascular changes seen in children and adult humans with septic shock is ideally suited for preclinical 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 for septic shock in the canine model: Tyrosine kinase inhibitors, endotoxin precursors, brady- kinin antagonists, dantrolene, soluble tumor necrosis factor receptor, antibodies to CD-18 receptors on white blood cells; ibuprofen; antibody to human tumor necrosis factor receptor, granulocyte stimu- lating factor; antibodies to platelet activating factor; antibodies to protein C; continuous artiovenous hemofiltration; high density lipoproteins; platelet activating factor inhibitor.