Testing an Automatic Drug Delivery System in a Rat Sepsis Model

在测试新疗法时，开发模拟临床条件的动物模型非常重要。在这方面，脓毒症的动物模型应该包括患者接受的相同类型的标准血流动力学支持。这种标准疗法包括血管加压药滴定到平均动脉血。然而，提供这种类型的治疗是非常劳动密集型的，因为血管加压药通常每10到15分钟由床边的护士滴定一次。然而，由于滴定血管加压药物是临床败血症治疗中不可或缺的一部分，我们的实验室现在已经适应了一种自动给药系统（添加）（哈佛仪器，剑桥，马萨诸塞州），可能应用于大鼠败血症模型ASP CCM 1108。该系统根据连续监测的血压给药不同剂量的血管加压剂（0、低或高剂量），并可同时对多达12只动物进行单独测量和治疗。

Developing animal models that simulate conditions encountered clinically is important when testing new therapies. In this regard, animal models of sepsis should include the same types of standard hemodynamic support patients receive. Such standard therapy would include vasopressors titrated to mean arterial blood. Providing this type of therapy however is very labor intensive since vasopressors are typically titrated every 10 to 15 minutes by a nurse at the bedside. However, because titrated vasopressors are such an integral part of sepsis care clinically, our laboratory has now adapted an automated drug delivery system (ADDS) (Harvard Instruments, Cambridge, MA) for possible application in a rat sepsis model ASP CCM 1108. This system administers differing doses of vasopressor (0, low or high dose) based on continuously monitored blood pressure and can perform individual measurements and treatments in up to 12 animals simultaneously. The purpose of the present protocol is to determine whether administration of a three dose norepinephrine (NE) regimen titrated with the ADDS improves outcome in animals challenged with intratracheal (IT) E. coli and treated with a 24 hour normal saline (NS) infusion previously shown to increase survival in the model. From that prior study, in animals receiving NS, MAP (mean+se) was lower in nonsurvivors compared to survivors (91.0 +/- 2.9, n=15 vs. 107.0 +/- 1.9, n=9; measured at 12 and 24 hours after challenge). Experiments performed thus far for this protocol have demonstrated that administration of NE with the ADDS is capable of reliably and consistently increasing blood pressure in animals developing shock related to challenge with intra-bronchial E. coli. The doses of NE necessary to produce these changes are significantly less than the doses administered with a much less sensitive fixed infusion system. Studies continue to determine how the ADDS can be employed to improve survival in this model. Work from this study was presented in the International Conference of the American Thoracic Society 2013.