Our progress to date has yielded a reproducible and well- characterized isobaric model of hypovolemic shock. A recent refinement of our model involving normalization of the data to the maximal shed blood volume has resulted in a decrease in the inter- animal variability allowing us to study blood loss-related changes with a much greater sensitivity than is possible using a time-based analysis. We propose to use the advantages of this approach to evaluate substrate turnover and its relationship to the maintenance of homeostasis and potential contribution to the onset of decompensation of homeostasis in hemorrhagic shock. Our working hypotheses are: 1) The loss of tolerance and ultimately death from persisting hypovolemic shock are related to deterioration of energy dependent mechanisms supportive of homeostasis. 2) When hypovolemia persists, glucose becomes the important substrate for aerobic as well as anaerobic energy production due to decreased availability of alternative substrates. 3) A critical event leading to loss of tolerance for hypovolemia is the failure of hepatic glucose production (gluconeogenesis and glycogenolysis) and lactate clearance. 4) The level of plasma lactate, a result of the balance between aerobic and anaerobic production and clearance by gluconeogenic and oxidizing organs does not necessarily reflect anaerobic energy metabolism of ischemic tissue during all phases of shock. Our goals are to: 1) Measure the turnover and recycling of glucose and lactate during the compensatory and decompensatory stages of hemorrhagic shock in fed and fasted animals in order to correlate the changes in these parameters with changes in organ flow and shock phase; 2) Determine whether the prolonged survival during hypovolemic shock induced by glucose is unique to glucose by infusing alternative aerobically utilized substrates; acetoacetate, beta-hydroxybutyrate or octanoate; 3) Evaluate the contribution of individual organ beds to the substrate turnover during successive phases of hemorrhagic shock; 4) Study the mechanism of the compromise of gluconeogenesis observed in isolated perfused livers taken from animals in the decompensatory phase of hemorrhagic shock; and 5) Extend our studies of changes in energy stores and blood flow in skeletal muscle to include white muscle to determine whether there is evidence for muscle ischemia during any phase of shock. The proposed studies will provide a better understanding of the inter-organ substrate interactions and their role in sustaining homeostasis during hemorrhagic shock. This insight should add to the rational therapy of profound or persisting hypovolemic shock.
| Pearce, F J; Drucker, W R (1987) Glucose infusion arrests the decompensatory phase of hemorrhagic shock. J Trauma 27:1213-20 |
| Connett, R J; Pearce, F J; Drucker, W R (1986) Scaling of physiological responses: a new approach for hemorrhagic shock. Am J Physiol 250:R951-9 |
| McEnroe, C S; Pearce, F J; Ricotta, J J et al. (1986) Failure of oxygen-free radical scavengers to improve postischemic liver function. J Trauma 26:892-6 |
| Pearce, F J; Connett, R J; Drucker, W R (1985) Phase-related changes in tissue energy reserves during hemorrhagic shock. J Surg Res 39:390-8 |
| Chadwick, C D; Pearce, F J; Drucker, W R (1985) Influences of fasting and water intake on plasma refill during hemorrhagic shock. J Trauma 25:608-14 |
