Since the 17th century, blood transfusions have been

attempted to offset blood loss from trauma and child birth, or for therapeutic uses. Until the identification of iso-agglutinating antibodies, however, transfusions were undesirable with significant early complications. These early complications sparked interest in using haemoglobin as an oxygen carrier in plasma. Early trials of these solutions proved disastrous as well, with significant immediate complications resulting from infusions of stroma-free human haemoglobin solutions These complications were most often acute renal failure thought to be the result of direct haemoglobin nephro toxicity.

 Blood is a specialized body fluid that delivers

necessary substances to the body's cells (in animals) such as nutrients and oxygen and transports waste products away from those same cells. It is composed of blood cells suspended in a liquid called blood plasma. Plasma, which constitutes 55% of blood fluid, is mostly water (92% by volume), and contains proteins, glucose, mineral ions, hormones, carbon dioxide(plasma being the main medium for excretory product transportation), platelets and blood cells themselves. The most abundant cells in vertebrate blood are red blood cells. These contain haemoglobin, an ironcontaining protein, which facilitates transportation of oxygen by reversibly binding to this respiratory gas and greatly increasing its solubility in blood. In contrast, carbon dioxide is almost entirely transported extracellularly dissolved in plasma as bicarbonate ion.

 Blood is circulated around the body through blood

vessels by the pumping action of the heart. In animals with lungs, arterial blood carries oxygen from inhaled air to the tissues of the body, and venous blood carries carbon dioxide, a waste product of metabolism produced by cells, from the tissues to the lungs to be exhaled.

 The history of blood transfusion can be regarded as

the history of blood substitute as infusion of any material other than autologous blood, is actually infusion of blood substitute.
Substances like milk, casein derivatives, starch,

saline and Ringers solution had been tried prior to the first successful human to human transfusion.
Development of a haemoglobin-based blood

substitute was pursued vigorously by the military as a means to have an oxygen-carrying plasma expander available for battlefield use. Despite research throughout the Vietnam War, a clinically effective blood substitute was unable to be developed.

 During the era of blood substitute research in the

1960s, Dr. Leland Clark began experimenting with a class of compounds known as per-fluorocarbons. Oxygen has approximately 100 times greater solubility in per-fluorocarbon solutions than in plasma. As a result, the amount of oxygen dissolved in plasma may be sufficient to sustain life, without the need for RBC-contained haemoglobin to provide additional oxygen. The functions of each blood component and the substitution of each are quite familiar, excepting that of oxygen carrying capacity. There has been considerable progress in two major classes of substitutes ,i.e. haemoglobin solutions and perfluorocarbon (PFC) emulsions.

Working of haemoglobulin molecules

 Oxygen transport is primarily a function of

erythrocyte-contained haemoglobin. Von Stark (1898) was the first to use haemoglobin (Hb) solution in the treatment of a patient suffering from anaemia. A lot of research has subsequently modified Hb solution to form purified Hb solutions.
Initial trials of free haemoglobin solutions

demonstrated little benefit to patients with unmodified haemoglobin molecules. Presently, HBOCs represent an interesting class of blood substitutes, which are undergoing advanced clinical trials. The therapeutic goal of these compounds is to avoid or reduce blood transfusion in different surgical and medical situations of acute Hb

 The main advantages include availability in large

volumes, storage for prolonged periods, rapid administrationand sterilisation by pasteurisation.

Poly-haemoglobin preparations will increase in

plasma half-life as their size is enlarged; a limit to the size is the viscosity and oncotic effects of the larger haemoglobin molecules. Most preparations will be retained in the plasma for half-lives of 8-30 hours

 Haemoglobin-based oxygen carriers have some

advantages over allogeneic red blood cell transfusions. The lack of iso-agglutinating antigens, due to the absence of a red cell membrane, obviates blood typing and screening and eliminates the most common morbidity and mortality of allogeneic and autologous transfusions, mismatching of blood units and the transfusion recipient. The lack of cross-matching requirements also allows virtually immediate availability of an oxygen carrier in critical periods of trauma or haemorrhage. However, there may be issues with administration of free haemoglobin in potentially septic situations.

 Plasma haemoglobin is not a true blood substitute;

haemoglobin can replace only the oxygen transport capacity of whole blood, without the coagulation or immunologic aspects which are normally present in blood.
Haemoglobin-based oxygen carriers will not replace

blood, allogeneic whole blood, or allogeneic red blood cells completely. Thus, use of these products may be limited to specific applications or with specialized techniques, such as cardiopulmonary bypass.

 Their main known disadvantages are, reduced

circulation half-life, haemodynamic and gastrointestinal perturbations, probably related to nitric oxide (NO) scavenging, free radical induction, and alterations of biochemical and haematological parameters (increase in liver enzyme levels, platelet aggregation).

 For per-fluorocarbon emulsions, newer molecules,

coupled with advances in emulsification technology, has produced solutions with great potential for clinical applications. Novel methods of cross linking and chemical modification have made haemoglobin solutions a viable alternative as temporary oxygen carriers.
After the initial excitement regarding Fluosol,

subsequent small studies demonstrated no benefit from Fluosol infusions in patients with profound anemia.With colloid solutions as a comparator, Fluosol did not improve indirect measures of oxygenation. However, Fluosol continued to be available for infusion as an oxygen carrier during

 New emulsions have been developed which utilize

emulsifying agents similar to the primary compound. In particular, perflubron (perfluorooctyl bromide) has been developed as a stable emulsion safe for intravenous infusion by the addition of small amounts of perfluorodecyl bromide as an emulsifying agent; the emulsion is then buffered with egg yolk phospholipids. The resulting emulsion has a calculated oxygen carrying capacity which is approximately three fold the amount of oxygen carrying capacity of the earlier Fluosol solutions.

 As Perflubron oxygen carrying capacity is directly

related to the oxygen partial pressure. Therefore perflubron oxygen delivery is predictable; direct diffusion of oxygen is the mechanism by which oxygen is off-loaded to peripheral tissues.

 Transport of oxygen as soluble gas in plasma is

radically different from hemoglobin-based oxygen transport.

Administration of perflubron can increase

dissolved oxygen to approximately 10-15% of the total arterial oxygen content, an increase from the norm of two to three fold, depending on the partial pressure of oxygen inspired. This can also be understood by considering the figure.:

 Per-fluorocarbons are inert biologically. The retention of

per-fluorocarbons does pose an additional problem with respect to dosage. Per-fluorocarbons relatively disappear in the plasma, with a half life of approximately 3-4 hours in the plasma phase. clinical data exist to distinguish whether per-fluorocarbon re-dosing results in serious adverse effects; future studies and newer generation emulsions will address this issue and lead to newer results.

At present, this limitation of dosing is theoretical, as no

 Current blood substitutes have been demonstrated

to be safe when administered in small quantities to volunteers. Both perfluorocarbon and hemoglobin based oxygen carriers have undergone clinical trials designed to determine the safety of these compounds when given to otherwise healthy patients. These preliminary studies have shown that a clinically useful dose of a blood substitute can be infused to patients. The short plasma half-life of these compounds limits the usefulness of blood substitutes to short periods of time. Ultimately, the blood substitute will be removed or metabolized, and decreased oxygen carrying capacity will reappear as the plasma oxygen carrying capacity diminishes.

 Thus, if no longer acting agents are available, it is

likely that these blood substitutes will merely delay an allogeneic transfusion, rather than avoiding exposure, when used in place of conventional allogeneic red blood cell transfusions.
In order to effectively use these compounds, special

techniques should be considered. One technique which theoretically should optimize blood substitute utility is acute normovolemic hemodilution. Aggressive harvesting of potentially several units of autologous fresh whole blood is possible when the solution to replace the harvested blood is capable of transporting oxygen.

 Coupling of blood substitutes with acute

normovolemic hemodilution has been successful in small clinical trials; whether this mode of using blood substitutes will result in substantial clinical and economic benefits await larger clinical trials.

 The final goal of any transfusion service is to create

a transfusion system with no side effects and with more effective medical care. The current system of homologous blood, although is marked by many problems, like allosensitisation and transfusion transmittable diseases, is working well with low cost, acceptable efficacy and relatively less sideeffects. Even so, the technologies of the future promise to generate an effective blood substitute, which will definitely have an impact on transfusion medicine and the transfusion services. Presently, the prospect of using artificial blood is difficult to envision owing to problems of short half life, prolonged tissue retention, potential toxicity, and issues of

 This may cause a temporary shift of focus from

completely replacing blood cells, to that of using this as a supplement to homologous transfusion. However, in prehospital or battlefield emergencies , or in countries where supply of safe blood is affected by potential threat of HIV infection, the role of blood substitutes will undoubtedly be of immense value. And it is absolutely certain that a new system of blood service with synthetic blood and blood substitutes, including artificial oxygen carriers and recombinant plasma components, will be developed in the near future, which will define a new dimension to transfusion medicine.