Effects of Fluid Treatment in a B. Anthracis Lethal Toxi

在美国最近爆发的炭疽杆菌感染中，对液体和血管升压剂的常规治疗耐受休克在死亡患者中很常见。在以往的研究中，尽管致死性脂多糖(LPS)和炭疽芽孢杆菌致死毒素(LeTx)对血压有相似的降压作用，但血浆细胞因子和一氧化氮水平与LeTx无关。这一数据和其他数据表明，LeTx休克的发病机制可能不同于败血症和感染性休克患者常见的细菌毒素类型。应考虑LeTx休克对常规血流动力学支持的反应是否也不同。 本研究的目的是比较常规血流动力学支持在用LeTx、内毒素或大肠杆菌攻击的大鼠中的效果。在这项现已完成的研究的一个阶段中，我们表明，液体支持在提高血压并改善脂多糖和大肠杆菌的存活率的同时，以显著不同的模式恶化了使用LeTx的这些情况。此外，液体支持否定了LeTx导向的单抗的有益效果。在LeTx挑战期间，液体引起的低氧血症的恶化为这种治疗的不利影响提供了一个基础。 我们现在已经扩展了这些研究，目前正在比较血管升压剂治疗和去甲肾上腺素在用LeTx和脂多糖挑战的动物中的效果。在这些研究中，我们发现，尽管去甲肾上腺素确实在脂多糖和LeTx中都会增加血压，但它可以提高前者的存活率，但不能提高后者的存活率。因此，传统的血流动力学治疗在挑战脂多糖的情况下具有预期的有益效果，但与LeTx并非如此。进一步的研究正在进行中，以确定在LeTx和脂多糖刺激期间内源性儿茶酚胺反应的差异是否为去甲肾上腺素对结果的不同影响提供了基础。 然而，总体而言，目前的发现对常规血流动力学支持治疗LeTx相关性休克的有效性提出了质疑。由于这种毒素在炭疽杆菌感染期间的休克中起着关键作用，因此更好地确定这些治疗方法在活体细菌感染期间的作用可能是重要的。已经提交了一篇描述上述流体实验的论文供出版。血管加压药研究正在以抽象的形式提交。

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.