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Blood substitutes, often called artificial blood, are used to fill fluid volume and/or carry oxygen and other gases in the cardiovascular system. Although commonly used, the term is not accurate since human blood performs many important functions. Red blood cells transport oxygen, white blood cells defend against disease, platelets promote clotting, and plasma proteins provide various functions. The preferred and more accurate terms are volume expanders for inert products, and oxygen therapeutics for oxygen-carrying products. Examples of these two "blood substitute" categories:
Oxygen therapeutics are in turn broken into two categories based on transport mechanism: perfluorocarbon based, and hemoglobin based.
Volume expanders are widely available and are used in both hospitals and first response situations by paramedics and emergency medical technicians. Oxygen therapeutics are in clinical trials in the U.S. and Europe, however Hemopure is more widely available in South Africa.
When blood is lost, the greatest immediate need is to stop blood loss. The second greatest need is replacing the lost volume. This way remaining red blood cells can still oxygenate body tissue. Normal human blood has a significant excess oxygen transport capability, only used in cases of great physical exertion. Provided blood volume is maintained by volume expanders, a quiescent patient can safely tolerate very low hemoglobin levels, less than 1/3rd of a healthy person.
The body automatically detects the lower hemoglobin level and compensatory mechanisms start up. The heart pumps more blood with each beat. Since the lost blood was replaced with a suitable fluid, the now diluted blood flows more easily, even in the small vessels. As a result of chemical changes, more oxygen is released to the tissues. These adaptations are so effective that if only half of the red cells remain, oxygen delivery may still be about 75 percent of normal. A patient at rest uses only 25 percent of the oxygen available in his blood. In extreme cases, patients have survived with a hemoglobin level of 2 g/dl, about 1/7th of normal, although levels this low are very dangerous.
With enough blood loss, ultimately red cell levels drop too low for adequate tissue oxygenation, even if volume expanders maintain circulatory volume. In these situations the only alternatives are blood transfusions, packed red cells, or oxygen therapeutics (if available). However in some circumstances hyperbaric oxygen therapy can maintain adequate tissue oxygenation even if red cell levels are below normal life sustaining levels.
Artificial blood is supposed to fulfill some functions of biological blood, especially in humans. The term oxygen therapeutic is more accurate, as human blood performs other functions besides carrying oxygen. For example white blood cells defend against infectious disease, and platelets are involved in blood clotting.
The initial goal of oxygen carrying blood substitutes is merely to mimic blood's oxygen transport capacity. There is additional longer range research on true artificial red and white blood cells which could theoretically compose a blood substitute with higher fidelity to human blood.
Unfortunately, oxygen transport (the function that distinguishes real blood from other volume expanders) has been very difficult to reproduce. There are two basic approaches to constructing an oxygen therapeutic:
Perfluorochemicals will not mix with blood, therefore emulsions must be made by dispersing small drops of PFC in water. This liquid is then mixed with antibiotics, vitamins, nutrients and salts, producing a mixture that contains about 80 different components, and performs many of the vital functions of natural blood. PFC particles are about 40 times smaller than the diameter of a red blood cell (RBC). This small size can enable PFC particles to traverse capillaries through which no RBCs are flowing. In theory this can benefit damaged, blood-starved tissue, which conventional red cells cannot reach. PFC solutions can carry oxygen so well that mammals and humans can survive breathing liquid PFC solution, called liquid breathing.
Hemoglobin is the main component of red blood cells, comprising about 33% of the cell mass. Hemoglobin-based products are called HBOCs (Hemoglobin Based Oxygen Carriers). However pure hemoglobin separated from red cells cannot be used since it causes renal toxicity. It can be treated to avoid this, but it still has incorrect oxygen transport characteristics when separated from red cells. Various other steps are needed to form hemoglobin into a useful and safe oxygen therapeutic. These may include cross-linking, polymerization, and encapsulation. These are needed because the red cell is not a simple container for hemoglobin, but a complex entity with many biomolecular features.
The first approved was a perfluorocarbon-based product called Fluosol-DA-20, manufactured by Green Cross of Japan. It was approved by the Food and Drug Administration (FDA) in 1989. Because of limited success, complexity of use and side effects, it was withdrawn in 1994. However Fluosol-DA remains the only oxygen therapeutic ever fully approved by the FDA.
In 1990s because of the risk of undetected blood bank contamination from AIDS, hepatitis C and other emergent diseases such as Creutzfeldt-Jakob disease, there was additional motivation to pursue oxygen therapeutics. Significant progress was achieved, and a hemoglobin-based oxygen therapeutic called Hemopure was approved for Phase III trial (in elective orthopedic surgery) in the U.S., and more widely approved for human use in South Africa.
In December 2003 a new hemoglobin-based oxygen therapeutic, PolyHeme, began field tests in a Phase III trial on emergency patients (in trauma settings) in the U.S. PolyHeme is the 15th experiment to be approved by the Food and Drug Administration since 1996. Patient consent is not necessary under the special category created by the FDA for these experiments. In late 2005, an independent panel verified, after the fourth and final review of 500 trauma patients enrolled in this study by that date, that no statistical evidence of safety concerns had arisen so far in the study. This pivotal study is expected to conclude in mid-2006 with final enrollment of 720 patients. If successful, this trial could lead to Food and Drug Administration approval of PolyHeme for use for severely bleeding trauma victims as early as sometime in 2007.
The U. S. Military is one of the greatest proponents of oxygen therapeutics, mainly because of the vital need and benefits in a combat scenario. Since oxygen therapeutics are not yet widely available, the United States Army is experimenting with varieties of dried blood, which takes up less room, weigh less and can be used much longer than blood plasma. Water has to be added prior to use. These properties make it better for first aid during combat than whole blood or packed red cells.
Oxygen therapeutics even if widely available would not eliminate the use of human blood, which performs various functions besides oxygen transport. However oxygen therapeutics have major advantages over human blood in various situations, especially trauma.
Blood substitutes are useful for the following reasons:
Oxygent is a solution used as an intravascular oxygen carrier to temporarily augment oxygen delivery to tissues and is currently being developed by Alliance Pharmaceutical Corp. Right now, the goal of the development of Oxygent is simply to reduce the need for donor blood during surgery, but this product clearly has the potential for additional future uses. Perfluorocarbons surrounded by a surfactant called lecithin and suspended in a water based solution give Oxygent its oxygen carrying capacity. The Oxygent particles are removed from the bloodstream within 48 hours by the body's normal clearance procedure for particles in the blood. Namely, the lecithin is digested intracellularly and the PFC's are exhaled through the lungs. The fact that this blood substitute is completely man-made gives it certain distinct advantages over blood substitutes that rely on modified hemoglobin, such as unlimited manufacturing capabilities, ability to be heat-sterilized, and the PFCs’ efficient oxygen delivery. Oxygent has done well in most clinical trials, but recently ran into some trouble, with participants in a cardiac surgery study slightly more likely to suffer a stroke if treated with Oxygent rather than the standard care.
Recently, Northfield Laboratories has come under scrutiny for a Phase III trial they are conducting in over 20 level 1 trauma centers across the country. The controversy arises from the fact that the participants in this study are incapable of giving their consent due to the nature of their injuries. Even though this practice is sanctioned by the FDA as necessary emergency research, patients’ rights groups have begun to protest the study.
Dextran-Hemoglobin is currently undergoing trials in dogs in Thailand, and the company hopes to begin human trials by the end of the year.
The major obstacle with this method of producing red blood cells is cost. At the moment, the complex three step method of producing the cells would make a unit of these red blood cells too expensive. However, the study is the first of its kind to demonstrate the possibility of producing red blood cells which closely resemble native red blood cells on a large scale.