An oxygen-carrying blood substitute (sometimes called Artificial hemoglobin) is an artificially made blood substitute whose main function is to carry oxygen, as does natural hemoglobin. The use of oxygen-carrying blood substitutes is often called oxygen therapeutics. 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 (one 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:
- perfluorocarbons (PFCs), chemical compounds which can carry and release oxygen. The specific PFC usually used is perfluorodecalin.
- haemoglobin derived from humans, animals, or artificially via recombinant technology
History
The first approved HBOC 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 Because of limited success, complexity of use and side effects, it was withdrawn in 1994.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 the 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 haemoglobin-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 haemoglobin-based oxygen therapeutic, PolyHeme, began field tests in a Phase III trial on emergency patients (in trauma settings) in the U.S. PolyHeme was 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 studyconclude in mid-2006 with final enrollment of 720 patients. Wired news reported that the trial failed when 47 of the 350 people given PolyHeme died compared to 35 deaths out of 363 in the control group. Debate exists as to whether or not the difference in the mortality rate is attributable to the small sample size. The fact that the experimental subjects did not give consent is a significant factor.
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 take up less room, weigh less and can be used much longer than blood plasma. Saline 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:
- Donations are increasing by about 2-3% annually in the United States, but demand is climbing by between 6-8% as an aging population requires more operations that often involve blood transfusion.
- Although the blood supply in the US is very safe, this is not the case for all regions of the world. Blood transfusion is the second largest source of new HIV infections in Nigeria. In certain regions of southern Africa, it is believed that as much as 40% of the population has HIV/AIDS, although testing is not financially feasible. A disease-free source of blood substitutes would be incredibly beneficial in these regions.
- In battlefield scenarios, it is often impossible to administer rapid blood transfusions. Medical care in the armed services would benefit from a safe, easy way to manage blood supply.
- Great benefit could be derived from the rapid treatment of patients in trauma situations. Because these blood substitutes do not contain any of the antigens that determine blood type, they can be used across all types without immunologic reactions.
- While it is true that receiving a unit of transfused blood in the US does not carry many risks, with only 10 to 20 deaths per million units, blood substitutes could eventually improve on this. There is no practical way to test for prion-transmitted diseases in donated blood, such as Mad Cow and Creutzfeld-Jacob disease, and other disease could emerge as problems for the blood supply, including smallpox and SARS.
- Transfused blood is currently more cost effective, but there are reasons to believe this may change. For example, the cost of blood substitutes may fall as manufacturing becomes refined.
- Blood substitutes can be stored for much longer than transfusable blood, and can be kept at room temperature. Most haemoglobin-based oxygen carriers in trials today carry a shelf life of between 1 and 3 years, compared to 42 days for donated blood, which needs to be kept refrigerated.
- Blood substitutes allow for immediate full capacity oxygen transport, as opposed to transfused blood which can require about 24 hours to reach full oxygen transport capacity due to 2,3-diphosphoglycerate depletion.
Haemoglobin-based blood substitutes may increase the odds of deaths and heart attacks.
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 1/40 the size of 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.
Perfluorocarbon-based blood substitutes are completely man-made; this provides advantages over blood substitutes that rely on modified haemoglobin, such as unlimited manufacturing capabilities, ability to be heat-sterilized, and PFCs’ efficient oxygen delivery and carbon dioxide removal. PFCs in solution act as an intravascular oxygen carrier to temporarily augment oxygen delivery to tissues. PFCs are removed from the bloodstream within 48 hours by the body's normal clearance procedure for particles in the blood - exhalation. PFC particles in solution can carry several times more oxygen per cc than blood, while being 40x-50x smaller than haemoglobin.
Haemoglobin based
Haemoglobin is the main component of red blood cells, comprising about 33% of the cell mass. Haemoglobin-based products are called haemoglobin-based oxygen carriers (HBOCs). However, pure haemoglobin 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 haemoglobin 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 haemoglobin, but a complex entity with many biomolecular features.
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