PI Mitchell P. Fink, MD
Co-PI(s) Marina V. Kameneva, PhD and Alan J. Russell, PhD
Title Next Steps in the Development of Drag Reducing Polymers for Treatment of Life-Threatening Hemmorrhagic Shock in Combat Casualties Using Small Volumes of Resuscitation Fluid
Summary Early deaths due to battlefield injuries are secondary to exsanguinations or overwhelming central nervous system trauma, whereas late deaths are secondary to sepsis and multiple organ system dysfunction syndrome. Currently, the primary strategy for treating hemorrhagic shock is to control ongoing bleeding and restore intravascular volume by infusing an asanguineous fluid (e.g., Ringer’s lactate solution) and packed red blood cells. However, conventional approaches toward resuscitation require administration of large volumes of fluids that are intrinsically heavy and bulky (e.g., normal saline solution or various colloidal solutions) and/or difficult to store (packed red blood cells). Interestingly, if intravascular volume expansion successfully restores cardiac output and arterial blood pressure before definitive hemostasis has been achieved, then, paradoxically, resuscitation can promote bleeding and shorten survival. Thus, logistical considerations limit the capacity of first responders to provide adequate conventional resuscitation on the battlefield and even in some cases of civilian trauma. In view of these considerations, an ideal initial resuscitation fluid for the initial management of hemorrhagic shock would require administration of just a small volume to improve tissue perfusion and oxygen utilization without increasing blood pressure to such an extent that endogenous hemostatic mechanisms (soft platelet-fibrin plugs) are disrupted.
Polymers with a molecular mass >10 exp 6 Da and a relatively linear structure are drag-reducing polymers (DRPs) that have been shown to reduce resistance to turbulent flow in pipes, thereby increasing flow rate at constant pressure (Toms effect). The flow conditions associated with the Toms effect probably do not occur when blood flows through arteries, arterioles, capillaries, venules and veins. Nevertheless, a number of studies have shown that intravenous administration of DRPs to experimental animals increases blood flow rate and decreases blood pressure and calculated peripheral vascular resistance without affecting blood viscosity or vascular smooth muscle tone. Furthermore, in a preliminary series of experiments, Kameneva et al. reported that survival was markedly improved when rats were resuscitated from hemorrhagic shock with a DRP-containing fluid. Prompted by these observations, we used seed-grant funding from DARPA to carry out a study to test the hypothesis that intravenous administration of very small volumes of an aloe vera-based DRP might improve oxygen consumption and extend survival time in rats subjected to otherwise lethal hemorrhage. The aloe vera-derived DRP used for these studies was a mixture of polysaccharides with an average molecular mass of ~4×10 exp 6 Da. Treatment of the rats with 7 ml/kg of the aloe vera-derived DRP (i.e., ~20% of the shed blood volume) significantly prolonged survival relative to treatment with a similar volume of the normal saline vehicle.
While these results are exciting and have created considerable “buzz” in both the scientific and lay press, there clearly is much to be done before the DRP concept can be tested clinically and developed commercially for the treatment of combat casualties or other indications. The aloe vera extract is a complex mixture of polysaccharides, and the natural product has not been optimized with respect to a number of chemical parameters (e.g., charge, molecular mass, hydrophobicity, and chain-branching) that might affect its ability to augment oxygen delivery and improve perfusion in vivo. Accordingly, the present proposal seeks to extend our preliminary DARPA-supported studies by using modern chemical methods to create a manageable library of biocompatible blood-soluble polymers. The polymers will be synthesized and modified using a statistically designed approach. These compounds will be evaluated both in vitro and in vivo for DRP-like properties, and the most promising compounds will be evaluated in a rat model of lethal hemorrhagic shock. A key aspect of the first phase of the research will be to determine to what degree the in vitro tests are effective predictors of in vitro utility. A “lead compound” will be identified, and this agent will be extensively evaluated in a clinically relevant rodent model of lethal hemorrhagic shock.
Term Year 2: 03/01/06 – 02/28/07