Testing an Automatic Drug Delivery System in a Rat Sepsis Model

在测试新疗法时，开发模拟临床遇到的条件的动物模型很重要。在这一点上，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。这种标准疗法将包括滴定到平均动脉血的血管升压剂。然而，提供这种类型的治疗是非常劳动密集型的，因为血管升压剂通常每10到15分钟由床边的护士滴定一次。然而，由于滴定的血管升压剂在临床上是败血症护理中不可或缺的一部分，我们的实验室现在已经采用了自动给药系统(ADDS)(哈佛仪器，剑桥，马萨诸塞州)，可能应用于大鼠脓毒症模型ASP CCM 1108。该系统可根据持续监测的血压给药不同剂量的血管升压剂(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。 本方案的目的是确定用ADDS滴定的三剂量去甲肾上腺素(NE)方案是否能改善气管内感染大肠杆菌(IT)并经24小时生理盐水(NS)输注治疗的动物的预后，此前已有证据表明，该方案可提高模型中的存活率。在先前的研究中，在接受生理盐水的动物中，死亡的动物的MAP(均值+Se)低于幸存者(91.0+/-2.9，n=15比107.0+/-1.9，n=9；在挑战后12和24小时测量)。 到目前为止为该方案进行的实验已经证明，NE与ADS一起使用能够可靠和持续地提高因挑战支气管内大肠杆菌而发生休克的动物的血压。产生这些变化所需的去甲肾上腺素剂量明显少于使用敏感性低得多的固定输液系统的剂量。研究继续确定如何利用ADDS来提高这种模型的存活率。这项研究的成果发表在2013年美国胸科学会国际会议上。

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.