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Maintenance of Tissue Metabolism for at Least 3 Hours between 20-28oC with an Asanguinous Fluid

Description:

TECHNOLOGY AREAS: Biomedical

ACQUISITION PROGRAM: Office of the Principal Assistant for Acquisition

OBJECTIVE: To determine if fluids such as transplantation solutions or tissue culture medium have potential as resuscitation fluids with the goal of better preservation of physiological function in the traumatically injured patient in an austere environment as compared to the currently used saline or Hextend®.

DESCRIPTION: Hemorrhage, or rapid loss of blood, is the single greatest cause of morbidity and mortality during combat (9) as well in civilian trauma (13). When more than half of the circulating blood is removed, death quickly ensues if bleeding is not stopped and blood or blood substitutes are not provided. Even after return of oxygen-carrying capacity to near normal, the poor oxygenation and/or nutrient delivery to tissues result in organ damage to the injured.  Several reports have indicated some benefit by the addition of single components such as glutamine (21) arginine (4) glycine (22) or estrogen (3). The benefits of hypothermia as protective against hemorrhagic shock are well-known (11, 14, 20), and it has been demonstrated that blood can be replaced in animal models with fluids designed for low temperature preservation of organs (1, 2, 10, 16).  However, carrying out hypothermic resuscitation in an austere environment without means to rapidly reduce body temperature is not possible at the present time.

Recently, organ transplant medicine has sought to improve the methods and techniques of organ preservation.  Some of these improvements may be applicable to resuscitation medicine.  The current approved transplantation fluids have minimal nutrients and rely on low temperature for their hypo-metabolic effect. However, demand for organs for use in transplantation has stimulated new technologies for preserving organs. Examination of recent literature in the area of transplantion surgery indicates that experimental transplantation fluids have been developed. These fluids have shown increases in time-to-transplant, as well as increases in the storage temperature, therefore, reducing the need for cold storage (5-8, 12, 15, 18, 19). The described fluids provide both nutrients and oxygen, which may be the reason for their success. These results indicate that a fluid more complex than saline solutions, yet simpler than blood or plasma, and relatively free of protein and therefore less labile, could legitimately maintain metabolism and tissue perfusion These solutions are asanguinous, i.e. are not derived from blood; therefore any oxygen carrying capacity must be related to its delivery by constituents not based on hemoglobin.  In prior research, solutions based on oxygen delivery by hemoglobin were shown not to be efficacious (17); therefore, the solutions of interest should not use hemoglobin as the oxygen transport mechanism.

Desired Capability:  The goal of this SBIR initiative is to determine if the advancement in the capabilities of transplantation fluids or other physiologic solutions may lead to their additional use as a resuscitation fluid to extend survivability of the traumatically injured until definitive care can be provided.  This is not a solicitation for the development of a fluid, rather it is meant to be an evaluation of fluids designed for organ preservation at ambient temperature as a possible resuscitation fluid. The commercial potential for a resuscitation fluid would increase the usefulness ten-fold both for the military and the general public.  The fluid should be shelf-ready without the need for mixing.  The end product should not require refrigeration during storage, nor should there be the requirement for cold infusion, reducing the logistical footprint necessary to send the product far-forward into extreme environments.  The unit size for the fluid should be of comparable size with current resuscitation fluids so that no revisions will be needed to incorporate this into the current supply chain. 

PHASE I: The selected contractor will report on the feasibility of their proprietary asanguinous solution being used to maintain the kidney or heart of a mammal prior to transplantation. Due to the requirement of a second level Animal Use review there will not be time in Phase I (6 months) to get approvals in place to demonstrate the feasibility.  Therefore, the PI will also need to include data from in vitro tissue culture studies demonstrating the viability of mammalian cells in their fluid. 

PHASE II: If selected for Phase II, the deliverable will be the validation of the fluid in a large animal model (swine) by completely replacing the blood with the fluid and determining for how long at a temperature between 20-28oC the animal can be maintained before death is certain. If the animal remains alive for three hours, it should be resuscitated with its blood and remain alive for 48 hours with no evidence of physiological decrements.  If the fluid performs as expected, the US Army Institute of Surgical Research would like to evaluate the fluid in their validated hemorrhage model through a Materials Transfer Agreement. 

PHASE III: Since this fluid would be used in patients, FDA approval would be sought in this phase.  It is anticipated during the approval process that the fluid would be tested in surgical patients for safety and efficacy as a blood supplement or replacement.  Fluid production would follow close behind the approval due to the need for a more effective resuscitation fluid.  The resultant fluid would be of great value to the military, however, civilian populations would also benefit significantly from the development of this fluid.  The technology would provide a means to resuscitate and save lives and reduce morbidity by preventing the progression to more serious complications including multiple organ failure. The so-called “golden hour” might be extended allowing the treatment of the traumatically injured en route prior definitive care in a combat support hospital or civilian trauma center.  Additionally, there would also be practical applications to blood loss during both emergency and routine surgeries.  The potential usefulness of the fluid is an indication of the likely market for the product.

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