Application of Combined Cardioprotective Agents to Preserve Organ Function and Improve Survival during Experimental Hemorrhagic Shock
Abstract
The Fiscal Year 2015 Peer Reviewed Medical Research Program Topic Area addressed in this proposal is Cardiovascular Health: Risk assessment, prevention, and treatment of trauma-induced cardiac arrest secondary to hemorrhage and polytrauma. Our focus is on developing novel therapies for treating hemorrhagic shock. The majority of Soldiers who die during combat do so before reaching the hospital, and hemorrhage (bleeding) remains the leading cause of death. Of those Soldiers that do make it to a hospital, over 21% are in hemorrhagic shock, a condition where there has been so much blood loss that there is a lack of perfusion of oxygen and nutrients to vital organs. If the problem is not reversed in a timely manner, the organs become irreversibly injured. Therapy for this deadly condition currently involves administering fluids and blood products. However, there have been no substantial new breakthroughs in treatment. A new approach might be to protect the organs so that they are more resilient to a lack of oxygen. There are proven therapies that reduce the death of heart cells after a heart attack, as well as improve the function of the heart long term after a heart attack. We propose to test these same therapies for the condition of hemorrhagic shock. Some of these therapies can be given prior to a Soldier going into a high-risk situation, almost like giving a vaccination. We have studied three of these therapies extensively in our experimental laboratories. One, remote ischemic preconditioning, is based on the discovery that a brief reduction in blood flow to a body limb protects heart cells during a heart attack. We were the first to show this phenomenon experimentally, and this therapy, induced by brief inflations and deflations of a blood pressure cuff around the arm, has now been shown to reduce the size of heart attacks in patients. A second therapy that has been shown to improve heart function after a heart attack, as well as in models of heart failure, is the drug SS31, which specifically protects the mitochondria of cells. Mitochondria are the energy-producing factories of cells and when protected allow the heart to work better, even when under stress. A third therapy, therapeutic hypothermia, uses the concept that cooling the body in the setting of injury causes the organs to enter a state similar to suspended animation, making them much more resistant to a loss of blood and oxygen. We have shown that inducing therapeutic hypothermia during the acute phase of injury (such as a heart attack) reduces heart cell death and preserves blood flow into the wall of the heart. These therapies could revolutionize the way in which an injured Soldier is treated for hemorrhagic shock. They have the potential to greatly improve survival and protect vital organs from damage. However, before these therapies are used in Soldiers, they must be rigorously tested in experimental models, meaning that long-term survival, function, and structure of the major vital organs must be assessed, as well as the safety of these therapies. The purpose of our proposal is to test these three therapies, known to protect the heart during a heart attack, in a model of hemorrhagic shock. Anesthetized rats are bled to the point that their blood pressure is reduced, mimicking the situation of hemorrhagic shock in the Soldier. Low blood pressure is maintained for a period and then the blood is returned. Long-term survival and the function and structure of major organs will be assessed. If these agents improve survival and protect organ structure and function, the therapies will be combined to determine whether combination therapy is superior to single therapy. If the results of these studies are positive, they could improve survival and reduce morbidity in combat Soldiers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610606
Entities
People
- Robert A Kloner
Organizations
- Huntington Medical Research Institutes
- United States Army