Despite advances in resuscitation at the scene of the accident, a large number of trauma patients subsequently die of sepsis and multiple organ failure. Our hypothesis is that the various microcirculatory alterations, generation of toxic substances, and metabolic disturbances produced after severe blood loss are not adequately corrected by resuscitation with conventional fluids alone, and that such alterations eventually lead to multiple organ failure. We have recently developed: 1) a unique non- heparinized, unrestrained rat model of trauma-hemorrhagic shock/resuscitation which is associated with multiple organ dysfunction and late mortality; 2) techniques of repeated measurement of organ function in such a model. Our results indicate that microvascular patency is dramatically decreased after hemorrhage and is not restored despite adequate resuscitation. Administration of non-anticoagulant heparin (NACH) before hemorrhage or during resuscitation, maintained the microvascular patency (Preliminary studies). Even regular heparin given before hemorrhage (as in most models), or during resuscitation, maintained the microvascular patency. The increase in plasma TNF and IL-6 (inflammatory cytokines) during hemorrhage, which were even more pronounced after resuscitation, suggests that heparinization or resuscitation does not eliminate the stimulus for cytokine release. Studies are proposed to determine: 1) the mechanism of organ dysfunction after hemorrhage/resuscitation, 2) whether NACH or heparanoids as an adjuvant during resuscitation restores microcirculation and organ function, 3) whether inflammatory cytokine release can be blocked by NACH when combined with chloroquine (an agent which blocks such cytokine release) and if this improves cell/organ function. Post-hemorrhage resuscitation will comprise Ringer's lactate and NACH or heparanoids (to restore microvasculature) with/without chloroquine and, to further improve blood flow and provide additional metabolic support, dopamine, and/or diltiazem, or ATP-MgCl2, will be administered. We will evaluate the action of each these agents, individually and their interaction with each other, on cell and organ (cardiac, renal, hepatic, and gut (absorptive)) function after resuscitation. Such an approach should yield an optimal combination for: 1) restoring microvascular patency, thus improving the delivery of substrates; 2) decreasing the release of toxic substances (TNF, IL-6,K endotoxin); 3) producing synergistic beneficial effects on cell/organ function following injury; and 4) providing increased resistance to subsequent sepsis.
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