Blood substitutes

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(Redirected from Artificial blood)

Blood substitutes 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:

  • Volume expanders: inert and merely increase blood volume. These may be crystalloid-based (Ringer's lactate, normal saline, D5W (dextrose 5% in water)) or colloid-based (Haemaccel, Gelofusin).

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 reponse 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.


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Volume expanders

When blood is lost, the greatest immediate need is replacing the lost volume. This way remaining red 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.

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Towards artificial blood

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:

  • perfluorocarbons (PFCs), a chemical compound which can carry and release oxygen. The specific PFC usually used is perflubron.
  • hemoglobin derived from humans, animals, or artificially via recombinant technology

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 "blood substitute" approved was a perfluorocarbon-based product called Flourasol-DA-20, manufactured by Green Cross of Japan. It was approved by the FDA in 1989. Because of limited success, complexity of use and side effects, it was withdrawn in 1994. However Flourasol-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 trials 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 on emergency patients 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.

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Advantages

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:

  • Long shelf life, vs 40 days for human whole blood
  • Immediate full capacity oxygen transport, vs transfused human blood which can require about 24 hr to reach full oxygen transport capacity because of 2,3-diphosphoglycerate depletion
  • Can be stored at room temperature, vs refrigerated storage for human blood
  • Avoids disease transmission, unlike human blood which can transport various diseases despite testing
  • No blood typing required, hence can be used for all patients and avoids administration errors of wrong blood type
  • Can be deployed for use by first responders: paramedics, military medics on front lines. This would give much more rapid response to major blood loss, and would improve chance of survival

True artificial blood which fulfills all functions of human blood is much further off. There are no companies close to clinical trials for true artificial blood. However the most pressing immediate need is for the blood's oxygen transport, and oxygen carrying products are much closer to wide availability.

In addition to attempts to create oxygen therapeutics by genetic engineering, work is being conducted on nanotechnology-based oxygen carriers.

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Current oxygen therapeutics under development

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Perfluorocarbon based

  • Oxygent, by Alliance Pharmaceutical. Status: U.S. phase II trials, European phase III trials
  • Oxycyte, by Synthetic Blood International. Status: U.S. phase II trials
  • PHER-02, by Sanguine Corp. Status: In research
  • Perftoran (Russian). Status: approved for Russian clinical trials in 1996
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Hemoglobin based

  • Hemopure, by Biopure Corp. Status: U.S. phase III trials, more widely approved in South Africa. Biopure makes a similar veninary product called Oxyglobin
  • Hemolink, by Hemosol, Inc. Status: U.S. phase II trials
  • PolyHeme, by Northfield Laboratories. Status: U.S. phase III trials
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Withdrawn oxygen therapeutics

  • Flourasol-DA, by Green Cross. Status: withdrawn in 1994 due to usage complexity, limited clinical benefit and complications
  • HemAssist, by Baxter International. Status: withdrawn in 1998 due to higher than expected mortality
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See also

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External links

de:Künstliches Blut

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