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，对液体和血管加压剂常规治疗的休克抵抗在非幸存者中很常见。在先前的研究中，虽然致死性脂多糖（LPS）和炭疽芽孢杆菌致死毒素（LeTx）刺激血压类似地降低，但血浆细胞因子和一氧化氮水平，虽然LPS升高，但LeTx却没有。本研究的目的是确定流体支撑是否会对这两种挑战产生不同的影响。spague - dawley大鼠留置中心静脉和全身动脉导管，24小时注射LPS或LeTx。在攻毒开始时，动物随机接受24小时的生理盐水（NS）输注（2.5、5、10、20或40 ml/kg/h）或不输注（对照组）。在此大鼠模型中，类似的液体方案已被证明可以提高大肠杆菌攻击的存活率。观察动物168小时。对于LPS，与没有液体的存活率相比（研究的8只动物中有1只存活，13%），增加液体剂量可以提高生存率或不使其恶化（7,38%的3只；8,50%的4只；8,25%的2只；6,17%的1只；7,14%的1只）。然而，与无液体的存活率相比，增加液体剂量的LeTx患者的存活率均下降（5例为16.31%；3例为16.19%；1例为15.7%；3例为15.20%；3例为15.20%）。在所有剂量下，这些液体方案增加了LPS的存活率，但使LeTx的存活率恶化，其模式显著不同（液体与这两种挑战的效果比较p=0.05）。为了探索延迟启动LeTx攻击的液体治疗是否会改变这种治疗的效果，另外的实验测试了LeTx攻击开始6小时后液体输注的开始。对这些数据的初步分析并没有表明液体的功效有任何明显的增加。因此，在该大鼠模型中，LPS和LeTx刺激不仅炎症介质的产生不同，而且对液体支持的反应也不同。根据临床推断，这些发现表明，更好地定义液体复苏对炭疽杆菌感染期间LeTx相关休克的疗效可能是必要的。研究计划中，儿茶酚胺管理的影响将与LeTx和LPS挑战进行比较。

Shock resistant to conventional treatment with fluid and vasopressor 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. The purpose of the present study was to determine whether fluid support would have different effects comparing these two challenges. Sprague-Dawley rats with indwelling central venous and systemic arterial catheters received 24 hour infusions of LPS or LeTx. At the initiation of challenge, animals were randomized to also receive 24 hour infusions with increasing doses of normal saline (NS) (2.5, 5, 10, 20 or 40 ml/kg/h) or no NS (control). Similar regimens of fluid had been shown previously to increase survival rates with E. coli challenge in this rat model. Animals were observed for 168 hours. With LPS, compared to survival rates with no fluid (1 survivor of 8 animals studied, 13%) increasing fluid doses either increased survival or did not worsen it (3 of 7, 38%; 4 of 8, 50%; 2 of 8, 25%; 1 of 6, 17%; and 1 of 7, 14%). With LeTx however, compared to survival rates with no fluid (7 of 15, 47%) increasing fluid doses all worsened survival (5 of 16, 31%; 3 of 16, 19%; 1 of 15, 7%; 3 of 15, 20%; and 3 of 15, 20%). Across all doses, these fluid regimens increased survival rates with LPS but worsened it with LeTx in patterns that were significantly different (p=0.05 comparing the effects of fluid with these two challenges). To explore whether delaying the initiation of fluid treatment with LeTx challenge would alter this treatment's effects, additional experiments tested the initiation of fluid infusions 6 hours after the initation of LeTx challenge. Preliminary analysis of this data does not demonstrate any clear increase in the efficacy of fluids. Thus, not only does the production of inflammatory mediators differ comparing LPS and LeTx challenge in this rat model, but the response to fluid support does also. Extrapolated clinically, these findings suggest that better defining the efficacy of fluid resuscitation for shock related to LeTx during B. anthracis infection may be necessary. Studies are planned in which the effects of catecholamine administration will be compared with LeTx and LPS challenges.