The hemodynamic and metabolic aspects of early-onset clinical septic shock are not yet fully understood; as a result, more than 50 percent of affected infants die. Moreover, little research has been done on gram-positive sepsis, even though gram-positive organisms are the principal cause of septic shock in newborns. We have developed a replicable Group B beta hemolytic streptococcal (GBS) early-onset sepsis newborn rat model, and, using this model, have shown that two prostaglandin inhibitors - Indomethacin and Ibuprofen - significantly reduced mortality rates. We now propose a two-phase study to continue and expand our research, using the newborn pig. In Year I, we plan to develop a reliable newborn pig GBS early-onset sepsis model, with a mortality rate of 50 percent, comparable to the rate in humans. This larger model will allow hemodynamic and metabolic testing impossible in the newborn rat. We then will inject bacteria intraperitoneally, and will evaluate the cardiovascular and metabolic changes that occur in septic shock. In Year 2, we will use this model to study the role of the prostaglandin system in septic shock and to evaluate further the value of prostaglandin inhibitors in improving survival rates. This research should further substantiate the value of prostaglandin inhibitors to treat septic shock. In addition, because the newborn pig is similar to the human newborn, this study should help determine whether prostaglandin inhibitors might be effective in reducing early-onset septic shock mortality in human newborns, and whether clinical trials are warranted at this time.
