It was said...

"PTEI-funded projects allowed obtaining critical information for my work on the mechanisms of blood-soluble, drag-reducing polymer effects on hemodynamics and further progress in the development of novel small-volume resuscitation fluids."

Marina V. Kameneva, PhD
Research Professor of Surgery and Bioengineering and Director, Hemorheology, Hemodynamics and Artificial Blood Research Laboratory, University of Pittsburgh

Development of Blood-Soluble Drag-Reducing Polymers as Innovative Therapy for Hemorrhagic Shock

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Marina Kameneva, PhD

University of Pittsburgh

Dr. Kameneva is developing a new concept for treatment of insufficient blood circulation and for improvement of resuscitation outcomes from severe blood loss based on an ability of special blood soluble drag-reducing polymers (DRPs), as soluble components/additives to a resuscitation fluid, to improve microvascular blood flow characteristics impaired by hemorrhagic shock. Dr. Kameneva has accrued an extensive body of work on the hemodynamic and hemorheological effects of the DRPs in animals subjected to severe hemorrhage and hypoxia and have identified DRP preparations that may serve as an innovative approach to modulate and enhance microcirculatory blood flow and improve oxygen delivery in hypovolemic shock and potentially delay/prevent transition to an irreversible state.

Historically, 20% of all injured combatants die on the battlefield before they can be evacuated to a field hospital. Many others who survive long enough to receive hospital care suffer multiple organ failure with 50-70% mortality (33). Almost 50% of the battlefield casualties died of exsanguinations. According to National Vital Statistics Reports, about 150,000 civilians die annually due to trauma. Accidents are the fifth leading cause of death in the U.S., exceeding diabetes and kidney and liver diseases. Accidents continue to be the first leading cause of death for people younger than 40 years old. Hemorrhage is the major cause of these deaths, acutely due to blood loss itself, or later in the course of a subsequent metabolic and immunologic depression favoring development of sepsis and/or multiple organ failure. Severe bleeding may also occur during elective surgery or childbirth.

Current conventional treatments for hemorrhagic shock are essentially based on hemorrhage control and volume expansion including intravenous infusion of large volumes of crystalloid- and/or colloid-based fluids as well as packed red blood cells and other blood products. If refractory shock began to ensue, then additional therapies aimed at improving already compromised tissue hypoperfusion include administration of simpathomimetic vasopressive agents (to enhance coronary perfusion pressure); administering inotropic agents (to enhance myocardial contractility); administering chronotropic agents (to alter cardiac periodicity); and the use of vasoactive drugs. While adequately addressing the problem of insufficient circulating volume and oxygen-carrying capacity, the current strategies fail to address at all the issue of impaired microvascular perfusion.

However, fluid resuscitation is the only supportive therapy, and currently there are no specific resuscitation strategies for casualties or patients with severe bleeding that may be predisposed to develop irreversible shock, which is the final pathway of severe irreversible hypoperfusion and consequent irremediable organ damage that results from the combined effects of impaired microcirculation and impaired oxygen delivery. Furthermore battlefield casualties and some civilian trauma victims cannot receive immediate surgical control of hemorrhage.  Thus, development of novel resuscitation fluids, which would only require administration of 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, would be extremely beneficial.

The combined effects of ischemia induced endothelial swelling and circulating granulocyte activation play an important role in capillary stasis and tissue injury. Impaired microcirculation is evidenced by obstruction of capillaries, a major characteristic of the no-reflow phenomenon, and a significant decrease in the density of functioning capillaries. The endothelium is the primary target and its dysfunction augments ischemic injury by activating platelets and leukocytes. The proinflammatory cytokines in concert with migrating activated leukocytes cause direct tissue damage. We hypothesize that impaired microcirculation is a major component of the acute hemodynamic decompensation following severe hemorrhagic shock.

If the hemodynamic and rheological changes seen in the microcirculation in the presence of nanomolar concentrations of DRPs (as low as 1-10 mg/ml) translate into improved tissue perfusion and end organ oxygen uptake, then it is likely that the use of DRPs as a rescue therapy may delay or even prevent the onset of irreversibility of hemorrhagic shock. Based on our preliminary data, we also hypothesize that the use of the DRPs will allow a substantial reduction in the amount of fluid needed for acute resuscitation. Although exact mechanisms of the DRP beneficial effects on the animal survival after severe hemorrhage remain to be identified, based on our preliminary studies, we hypothesize that DRPs attenuate the “plasma-skimming” effect in microvessels and increase intracapillary hematocrit and density of functioning capillaries.