Long Term Objective: To elucidate the link between hemorrhagic and septic shock and to determine better methods of prevention and treatment. We have developed a model of treated, maintained, hemorrhagic shock in the rat in which post shock treatment purely by manipulating the maintenance infusion results in 24 hour survival in most of the experimental animals despite shock levels of a severity never before employed. All of these animals eventually die but this occurs on the second or third day after shock. We claim that the pattern of mortality in the treated maintained shock model much more closely mimics the clinical situation. We have recently found that there is a bacterial invasion of portal and systemic blood in most of these rats by 24 hours after shock. Using this model we propose to address the following specific aims: (1) What are the characteristics of bacterial invasion in the rat during and after treated shock? When does it begin and what is the type and number of bacteria involved? (2) Is the bacterial invasion directly related to the death of the animals? (3) Does initiation of the complement cascade and other phenomena of the immune system precede, follow or coincide with bacterial invasions? (4) Is the source of bacterial invasion the gastrointestinal tract? (5) Can the bacterial invasion be treated by antibiotics and will this improve the long term survival of the animals? In pursuing these aims we will:
Aim 1) Extend our pilot observations of bacterial invasion in this model to include colony counts in tissue as well as increasing the number of animals observed.
Aim 2) We will observe survival when this model is used in germfree compared to conventional animals.
Aim 3) We will determine the time and amount of anaphylatoxins appearing in the model both in conventional and germfree animals.
Aim 4) We will use various techniques to label internal bacteria in rats used in this model and observe if labeled bacteria appear in the blood or organs.
Aim 5) We will determine the effect of the most potent currently available antibiotic combinations on survival in this model.
