Alkaline Phosphatase for the Prevention of Intestinal and Renal Injury in a Rat Model of Cardiopulmonary Bypass with Deep Hypothermic Circulatory Arrest
Abstract
Fiscal Year Peer Reviewed Medical Research Program Topic Area: Congenital Heart Disease. Background: Today children born with heart defects are more likely to live than ever before. Surgeons are able to improve even difficult-to-treat heart defects due to better open heart surgery techniques. Unfortunately, children who do live with heart defects often suffer serious problems including heart failure, strokes, kidney failure, and difficulty eating requiring a permanent feeding tube. There are very few treatments for these problems, and research is desperately needed to improve the health of children living with heart defects. In order to operate on the heart, the surgeon often must drain the blood from the heart and stop the heart from beating. This is done using a heart-lung machine that pumps the blood to the rest of the body while the heart is stopped. Some surgeries are so difficult that the surgeon needs to cool the child s body and stop all blood flow for a period of time (circulatory arrest) or stop flow to the lower body while continuing flow to the brain (selective cerebral perfusion). Although these methods are necessary to perform life-saving surgeries, they are not natural for the body and can cause significant harm. The abdominal organs, especially the intestines and kidneys, need a good supply of blood and may be injured during this process. Injury to the intestines and kidneys can cause children to struggle with recovery from surgery and may have long-term effects. Currently, doctors have no way of preventing or treating injury to the intestines or kidneys during open heart surgery. We are interested in studying a naturally occurring protein called alkaline phosphatase that helps protect the intestines and kidneys from some kinds of injury in both animals and grown-ups. It has never been studied in children having open heart surgery, but we do know that children may have less of this protein after surgery than they should. We hope that giving children more of this protein before or during surgery will help protect their intestines, and possibly other organs, from harm. However, before we treat children with it, we want to learn more about how well it works and how safe it is. So we are planning to test it in animals that will be placed on the heart-lung machine and then have their blood flow stopped for a period of time. Our Theory: Giving alkaline phosphatase to rats before or during the heart-lung machine and prior to stopping all blood flow will help protect the intestines and kidneys from injury. What We Plan to Do: We will place a total of 80 rats on a small version of the heart-lung machine, cool their bodies halfway to freezing, and then stop blood flow for 45 minutes. We will then restart blood flow, warm the rats up to normal temperature, and take them off the heart-lung machine. Four hours after we take them off the heart-lung machine, we will humanely kill the rats and examine their intestines and other organs for injury. We will also test their blood and tissues for how much alkaline phosphatase is present. Ten rats will receive no additional treatment, while 20 will be given medicine to prevent alkaline phosphatase from working and 30 will be given extra alkaline phosphatase to try to protect them from injury. In the last 20 rats, we will test one of the biochemical pathways we think helps alkaline phosphatase create its protective effects. What Specific Questions Do We Hope to Answer? (1) If we give medicine to stop alkaline phosphatase from working, do the rats have more injury to their intestines and kidneys, showing that their own alkaline phosphatase is important for their protection? (2) If we treat with extra alkaline phosphatase, do the rats have less injury to their intestines and kidneys? (3) What dose of alkaline phosphatase is necessary to protect the abdominal organs? (4) Does alkaline phosphatase work by increasing a molecule called adenosine?
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610090
Entities
People
- Jesse Davidson
Organizations
- United States Army
- University of Colorado Denver