Effects of Fluid Treatment in a B. Anthracis Lethal Toxi

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Shock resistant to conventional treatment with fluid and vasopressors was common in nonsurvivors in the recent outbreak of B. anthracis infection in the US. In prior studies, although blood pressure was reduced similarly with lethal lipopolysaccharide (LPS) and Bacillus anthracis lethal toxin (LeTx) challenges, plasma cytokine and nitric oxide levels, while increased with LPS were not with LeTx. This and other data suggests that the pathogenesis of shock with LeTx may differ from the types of bacterial toxin commonly encountered in patients with sepsis and septic shock. Whether the response of LeTx shock to conventional hemodynamic support differs as well should be considered. The purpose of the present study has been to compare the effects of conventional hemodynamic support in rats challenged with LeTx, LPS or E. coli bacteria. In one phase of this study now completed, we showed that fluid support, while increasing blood pressure and improving survival with LPS and E. coli, worsened these with LeTx in patterns that differed significantly. Furthermore, fluid support negated the beneficial effects of LeTx directed monoclonal antibodies. Worsened hypoxemia with fluids during LeTx challenge provide one basis for the detrimental effects of this treatment. We have now extended these studies and are presently comparing the effects vasopressor treatment with norepinephrine in animals challenged with LeTx versus LPS. In these studies we found that while norepinephrine does increase blood pressure with both LPS and LeTx, it improves survival with the former but not thelatter toxin. Once again therefore, a conventional hemodynamic treatment which has the expected beneficial effects with LPS challenge, does not with LeTx. Further studies are underway determining whether differences in the endogenous catecholamine response during LeTx and LPS challenge provide a basis for the differing effects of norepinephrine on outcome. Overall however the present findings raise questions regarding the effectiveness of conventional hemodynamic support for LeTx associated shock. Since this toxin plays a key role in shock during B. anthracis better defining the role of these treatments during live bacterial infection may be important. A paper has been submitted for publication describing the fluid experiments outlined above. Vasopressor studies are being submitted in abstract form.