Hemodynamic and anti-Toxin Treatments in Anthrax Lethal Toxin Challenged Canines

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Abstract

Although shock resistant to conventional hemodynamic support with fluids and vasopressors contributed to death in all five non-survivors in the 2001 United States anthrax outbreak, its mechanisms and optimal management remain unclear. Lethal (LeTx) and edema (ETx) toxin are major contributors to the pathogenesis of anthrax. Both LeTx and ETx consist of protective antigen (PA), which is necessary for cellular uptake of the toxic moities; lethal factor (LF) for LeTx and edema factor (EF) for ETx. Lethal factor is a zinc metalloproteinase that inhibits mitogen activated protein kinase kinases (MAPKK1-4, 6 and 7) while EF is a calmodulin dependent adenyl cyclase. Recent research has shown that LeTx and ETx produce cellular changes different from those associated with more commonly encountered bacterial toxins such as lipopolysaccharide (LPS) or the exotoxins of gram-positive organisms like S. aureus. Despite this research, there has been limited in vivo work defining these toxins cardiovascular effects. Furthermore, although there have been major efforts to develop and test new toxin directed agents, little attention has been paid to the efficacy of conventional fluid, vasopressor and inotrope support during anthrax toxin associated shock. Work done largely in our laboratory suggests these responses may be difficult to predict. In a rat model, 24 h LeTx infusion produced lethality and shock, but it did not alter circulating inflammatory cytokines, nitric oxide or catecholamines. In this model, while PA directed monoclonal antibody (PA-mAb, 5H3 or Raxibacumab) (HGS, Rockville, MD) was protective, regimens of fluid or norepinephrine support beneficial with LPS or E. coli, were not with LeTx (4 - 6). In fact fluids not only worsened survival with LeTx but also negated the effects of PA-mAb. Although informative, the rat model did not permit the duration (i.e. > 24h) or type of hemodynamic monitoring (i.e. systemic and pulmonary arterial catheter measures and serial cardiac imaging) necessary to fully characterize the cardiovascular effects of LeTx and ETx. Therefore a canine model was developed with support from the Trans-NIH/FDA Biodefense Program. In initial studies, LeTx challenge in the canine produced many of the same changes noted in the rat. LeTx was also associated with myocardial depression in the canine. The purpose of present study is to use the now developed canine anthrax LeTx model to comprehensively investigate the effects of fluid and vasopressor treatment alone and in combination with a toxin directed treatment. An advantage of this model not possible in smaller animal models is the ability to titrate hemodynamic support based on measures of preload and perfusion pressure just as it is done in critically ill patients. Specifically, this study will address whether a standard regimen (fluid and norepinephrine infusion) or a toxin directed therapy (i.e. 5H3-mAb or Raxibacumab) are beneficial when used alone or together in canines challenged with 24 h infusions of LeTx. Based on earlier studies with this canine model, treatment algorithms have been developed for the sequential administration of fluid and norepinephrine titrated using preload measures. Studies examining the effects of hemodynamic support and Raxibacumab with LeTx challenge are complete. Addition of Raxibacumab to hemodynamic support improved hemodynamics, reduced vasopressor needs and fluid retention and increased survival following LeTx challenge. This data was presented at the International Conference of the American Thoracic Society 2011 and has now been published. (Barochia et al. Protective antigen antibody augments hemodynamic support in anthrax lethal toxin shock in canines. J Infect Dis. 2012; 205: 818-829.) Studies are completed examining the effects of Raxibacumab and hemodynamic support alone or together with ETx challenge alone and with ETx and LeTx in combination inthis same canine model. Raxibacumab augmented hemodynamic support and improved survival with ETx alone and with ETx and LeTx together. These findings were presented at the International Conference of the American Thoracic Society in 2013 and 2014. Additional agents are now under consideration for study in this model.