Testing an Automatic Drug Delivery System in a Rat Sepsis Model

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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.