We showed previously that anti-inflammatory agents have differing effects in sepsis related to the underlying severity of infection. These agents were highly beneficial with severe sepsis when the risk of death was high, but they were less beneficial and potentially harmful with less severe infection. In these experiments, severity of infection was altered by varying the dose of infecting bacteria. However, the severity of infection in patients may relate not only to the number of bacteria they are initially exposed to but also to the time at which they present and begin antibiotic and supportive fluid treatment. In the present set of experiments, the influence of severity of infection on the anti-inflammatory agent tumor necrosis factor antibody (TNF Ab) will be studied. In these studies however, severity of infection will be altered by varying the time at which animals receive antibiotic and fluid treatment following inoculation with similar doses of bacteria. Prior to the actual study of TNF Ab however, a clinically relevant mouse model of sepsis required development showing that the addition of fluid and antibiotic treatment would have beneficial effects as they are believed to have clinically. Experiments have been completed comparing the effects of antibiotics alone, fluids alone, antibiotics plus fluids or no treatment in animals randomized to receive one of several increasing doses of intraperitoneal E. coli designed to produce low or high lethality rates. In a surprising finding which likely has clinical relevance we have found that although fluid therapy alone has little beneficial effect, it synergistically increases the beneficial effects of antibiotics. In contrast to our prior experiments with anti-inflammatory agents, either antibiotics with or without fluids increased survival rates independent of the lethality of infectious challenge. Furthermore, delaying treatment with antibiotics and fluids resulted in time ordered decreases in survival rates despite inoculation with similar doses of bacteria. This model will now allow us to evaluate the effects of varying treatment time with conventional sepsis therapies on the effects of anti-inflammatory agents like TNF Ab.
| Eichacker, Peter Q; Parent, Chantal; Kalil, Andre et al. (2002) Risk and the efficacy of antiinflammatory agents: retrospective and confirmatory studies of sepsis. Am J Respir Crit Care Med 166:1197-205 |
