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). The present study will be done in 2 parts. Part 1 will define an E. coli dose for challenge in the study. Part 2 will itself include 2 parts, Part 2A and Part 2B. Part 2A will define a regimen of NE that achieves a targeted blood pressure in E. coli challenged animals. Part 2B will address the primary purpose of the protocol and will compare three treatment groups: no treatment; NS alone; or NS plus a regimen of NE titrated with the ADDS to maintain MAP close to 110 mmHg (NS + NE group). Continuous measures of blood pressure and heart rate will be made in all animals. The standard battery of tests employed in the model (i.e. complete blood count, arterial blood gas, blood cultures, cytokines, and nitric oxide levels) will also be collected.