Although shock resistant to conventional cardiopulmonary support contributed to death in all five nonsurvivors from the recent US outbreak of inhalational B. anthracis, its mechanisms and management have received little study. Absence of a large animal model that simulates B. anthracis shock and permits continuous invasive cardiopulmonary monitoring and serial cardiac and pulmonary imaging has hampered such study. Much of the pathogenesis of B. anthracis is thought to be associated with its production of lethal toxin (LeTx). We previously developed a rat model LeTx induced sepsis that employed 24 h toxin infusions. This model prolonged the time to death in nonsurvivors and showed that in comparison to lipopolysaccharide, the mechanisms and the responses to conventional treatment with sepsis due to LeTx differed from those typically encountered in critically ill patients. However, while LeTx is closely associated with the pathogenesis of B. anthracis, new evidence suggests that edema toxin (ETx) may have an equally important role. Using a rat model we have shown that ETx is only 10 times less lethal than LeTx. Furthermore similar weight doses or similar lethal doses of ETx produce greater hypotension than LeTx and increase rather than decrease heart rate. Finally, ETx and LeTx work additively in this model. Based on these studies, a canine model employing lethal doses of ETx and LeTx administered in combination as prolonged infusions is under development. This model which will permit continuous invasive hemodynamic monitoring and serial cardiac and pulmonary imaging for up to 120 h will be used to determine the contributions of mycocardial, pulmonary and peripheral vasculature dysfunction to the lethal shock associated with these two toxins. In future studies, the model will be employed to investigate the response of shock related to these ETx and LeTx to conventional and new therapies.
