Despite advances in resuscitation of trauma victims, a large number of such patients subsequently die of sepsis and multiple organ failure. Improvement in survival of such victims should, however, be possible. Our hypothesis is that the generation of toxic substances and the various metabolic and microcirculatory alterations produced after severe injury are not adequately corrected by resuscitation with conventional fluids alone, and that such alterations eventually lead to organ failure. Although numerous attempts at overcoming these problems have been made, including the use of hypertonic solutions, substrates, inotropes and other agents, there has not been a systematic investigation of the specific needs and interdependance between the heart, liver, and kidney following low flow states. Low flow produces an ischemic environment resulting in depletion of tissue energy stores, cellular electrolyte imbalance, generation of toxic substances, cell swelling and eventually microcirculatory and organ failure. Our plans are to determine the specific needs of the organs which are not met with volume resuscitation alone, and to then correct those abnormalities by pharmacologic means. Organ blood flow and function following injury may be better maintained by providing osmotic and oncotic agents along with metabolic support and agents that improve microcirculatory flow and inhibit the generation of toxic substances. We plan to develop a pharmacologic solution (i.e., composite of pharmacologic agents which will act synergistically) which, together with appropriate volume replacement, will maintain cell and organ function and host defense mechanisms after injury better than conventional solutions alone, and thus prevent subsequent multiple systems failure. Such a solution (osmolarity approximately 600 mOsm) will initially contain dextrose, albumin and electrolytes. To this solution we will systematically add dopamine, diltiazem, imidazole and ATP-MgC12 individually and in various combinations. In this manner, we will evaluate the action of each of the above agents individually and their interaction with each other. Such an approach should yield an optimal combination to produce synergistic beneficial effects on cell and organ function following injury, and produce resistance to a subsequent septic challenge. If these studies uncover a lack of improvement in any cell, organ or system function, the constituents of the pharmacologic solution will be modified to specifically address that problem. To accomplish these goals we will utilize a rat hemorrhage model.
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