Abstract
Increasing concerns over the widespread use of blood transfusions have prompted interest in blood conservation strategies, including various pharmacologic agents, as well as numerous devices and techniques. Blood conservation strategies including pharmacologic agents, numerous techniques and devices have reduced the need for blood transfusion. This article details currently available blood conservation strategies and evidence supporting their efficacy in acute clinical settings. These strategies include antifibrinolytic agents, desmopressin, erythropoiesis stimulating agents, parenteral iron, vitamin K, recombinant activated factor VII.  Other strategies which have been used in surgical and trauma settings are acute normovolemic haemodilution, cell salvage, reduction of blood loss during diagnostic testing, use of potentially red cell substitutes and restrictive blood transfusion. This article includes areas of controversy and need for development of blood conservation strategies.
Introduction
A lot of literature mentions potential hazards of blood transfusion.  Although it can be life- saving but associated adverse effects limits its use. Hence, several blood conservation strategies have been used to avoid or reduce blood transfusion.
Benefits and risks of blood transfusion
Transfused RBCs increase oxygen delivery and reduce tissue ischaemia; however, ability of RBC transfusions to increase oxygen consumption has not been clearly demonstrated1.
Allogenic RBC transfusion carries risk factors like viral, bacterial, parasitic or prion transmission. Non-infectious risks include febrile, allergic, anaphylactic and haemolytic transfusion reactions, transfusion related acute lung injury (TRALI) and transfusion related circulatory overload (TRCO) are more common than infectious risks which can lead to greater morbidity and mortality2.
Pharmacologic strategies to reduce blood transfusion  
Pharmacologic agents used in blood conservation either reduce or stop bleeding and decrease likelihood of transfusion by raising haemoglobin. These agents are antifibrinolytic agents, desmopressin (DDAVP), erythropoiesis-stimulating agents (ESAs), parenteral iron, vitamin K, and recombinant activated factor VII.

Antifibrinolytic agents
These agents (tranexamic acid, epsilon amonocaproic acid and aprotinin)    inhibit breakdown of blood clots. EACA inhibits fibrinolysis by inhibition of plasminogen inhibitors and to certain extent through antiplasmin activity. Tranexamic acid is similar to EACA but 10 times more potent. Aprotinin also limits action of plasmin but has different mode of action. Perioperative use of antifibrinolytics has been shown to reduce the need for blood transfusion and reoperation3.

 
DDAVP
Desmopressin acetate (1-desamino-8-D-arginine vaspressin [DDAVP]) is a synthetic analogue of arginine vasopressin that induces release of stored factor VIII and von Willebrand factor from endothelial cells. A dose of 0.3mcg/kg subcutaneously results in 3 to 5 fold increase in levels of factor VIII and von Willebrand factor. DDAVP is effective in controlling and preventing bleeding in patients who have congenital platelet disorders and in those who have platelet dysfunction due to associated renal failure. A meta-analysis of DDAVP in the treatment of perioperative bleeding showed a nonsignificant reduction in blood loss without evidence of a reduction in transfusion need; DDAVP may not be effective in improving haemostasis or in reducing acute blood loss in critically ill patients who do not have specific bleeding disorders4.

Recombinant activated factor VII
rFVIIa is approved mainly for patients with factor deficiencies (haemophilia) but it has been used in many clinical situations to stop bleeding because of its ability to enhance thrombin generation. It is currently used as off-label in various bleeding causes5.

ESAs
The currently US Food and Drug Administation approved ESAs, epoetin alfa and darbepoetin alfa share similar mechanism of action, which involves stimulation of erythropoiesis via binding to the erythropoietin receptor on erythroid progenitors. It is commonly used in patients with chronic renal failure or cancer with bone marrow suppression to increase haemoglobin levels and avoid the need for blood transfusions. Erythropoietin used in critically ill patients has shown reduced incidence of blood transfusion. Erythropoietin does not reduce mortality and has potential risk for thrombotic events6.

Artificial oxygen carriers
Haemoglobin substitutes may delay or reduce the exposure to allogenic blood transfusion in trauma patients with acute blood loss. These products can replace the use of blood products during acute blood loss. When combined with acute normovolemic haemodilution in perioperative setting, or in critically ill patients they could reduce the need for blood transfusion. There are 2 classes of haemoglobin substitutes: modified haemoglobins and perfluorocarbons.  The artificial haemglobin solutions are either recombinant products or are derived from outdated human RBCs (Polyheme) or bovine haemoglobin (Haemopure). Their use is advantageous as they can be given without cross matching, have a long shelf life, ability to store products at room temperature and a reduced risk of disease transmission. The disadvantages include their relatively short half-life after administration (24-48hrs), their interference with laboratory measurements, renal toxic effects, and adverse effect on vascular tone and blood pressure. The most recent generation of haemoglobin-based oxygen carriers have been modified to prevent rapid dissociation and short half- life, to avoid renal toxic effects and reduce vasoconstriction by decreasing nitric oxide scavenging. These products reduce the need for blood transfusion in acute trauma and surgical patients without systemic or pulmonary artery hypertension6.
Perfluorocarbons are another class of haemoglobin substitutes that are attractive because they transport both oxygen and carbon dioxide and can release oxygen to the tissues at a rate of about twice that of haemoglobin.  Perfluorocarbons have longer shelf life and no risk of transmission of blood-borne infections.  However, they need high inspired oxygen concentration which can cause acute lung injury. To date, perfluorocarbons have been tried with acute normovolemic haemoilution which showed decrease in amount of allogenic blood transfusion6.
BLOOD CONSERVATION DEVICES/TECHNIQUES
Many devices and techniques have been used in many clinical scenarios to diminish blood loss and to minimize reliance on blood transfusion.
Acute Normovolemic Haemodilution (ANH)
As a blood conservation method in surgery, acute normovolemic  haemodilution (ANH)  was re-introduced in 1970 in response to growing awareness of transfusion related risks and religious objections to transfusion. This strategy involves removing a portion of a patient’s blood immediately prior to surgery and simultaneously replacing it with an acellular (crystalloid or colloid) fluid to maintain normovolemia. With this technique amount of loss of plasma and RBCs is reduced. In the mean time collected blood is properly stored and reinfused into the patient after cessation of major blood loss or when transfusion is needed. As ANH does not require testing and involves collection and storage at patient’s bedside, it is more advantageous than preoperative blood donation (PABD).  PABD requires patient to make preoperative visits to hospital and donate his/her own blood, has testing requirements, and because units are not stored in operating room , it can lead to potential errors leading to ABO-incompatible blood transfusion and risk of bacterial contamination7.   

RBC Salvage
RBC salvage has been in practice over the last 2 decades and is based on the concept of collecting patient’s own blood and retransfusion to a later stage.  This form of autologous transfusion involves aspiration of shed blood from surgical field into a closed suction device, filtration, and transfer into anticoagulant reservoir. This unprocessed blood can be given in case of emergency. However, this collected blood may be centrifugally washed to remove debris and contaminants before reinfusion. The cell saver technique is quite useful in cardiothoracic or vascular surgeries8.  

Reducing Blood Loss during Diagnostic Testing
Diagnostic testing is an important cause of blood loss in critically ill patients. Blood samples for diagnostic testing are commonly taken up to 24 times per day depending on patient illness acuity, ease of sampling and institutional practice. Studies from 1980s reported a mean blood loss per patient per day of 377mls in cardiothoracic ICUs, 240mls in general surgical ICUs and 41.5mls in medical-surgical ICUs. A recent European study in ICUs found blood loss of 41.1ml/day/patient. One study mentioned about 17% blood loss towards sampling in patients who are admitted to ICU for more than 3 days6.  
Approaches to reduce iatrogenic blood loss in critically ill patients included the use of small collection tubes, elimination or reduction of discarded blood when collecting blood from indwelling catheters, altering test ordering behavior, use of sterile syringe for sampling and reinfusing same blood to the patient and use of automated closed arterial systems. These strategies can reduce blood loss amount by 50%6. However, these techniques do not necessarily avoid blood transfusion.
AREAS OF CONTROVERSY
The common concern with major pharmacological agents used in blood conservation is the risk of thrombosis including acute cerebrovascular thrombosis and AMI, most commonly in patients with hypercoagulable states. A large observational study in patients with CABG has suggested that the antifibrinolytic agent, aprotinin is associated with increased risk of thrombosis, cardiac complications, renal toxicity and death. ESAs are known to cause thrombotic complications.
The major risks of cell salvage include air embolism, induction of inflammatory state, sepsis, haemolysis and coagulopathy. Use of cell salvage in oncosurgery is becoming useful in recent years.  
Most of the controversy in ANH is due to limitations in trial design including lack of blinding and widely accepted standards for ANH procedure, as well as too many variables.   
AREAS OF DEVELPOMENT
In recent years there has been increasing interest in the development of red cell substitutes including cell free haemoglobin solutions and perfluorocarbons. Some of the newer products like diaspirin cross-linked Hb  have longer half-lives and appear to be less toxic and vasoconstricting, but some studies have shown increased mortality in trauma patients.
Perfluorocarbons appear promising because they can transport oxygen and carbondioxide and have longer half life but require delivery of 100% oxygen which may not be applicable in prehospital situations.
CONCLUSION
Blood transfusions in critically ill patients are commonly associated with adverse events. Reducing blood loss and the need for transfusion and improving the appropriateness of blood transfusion are important quality of care issues for critically ill patients. Various blood conservation strategies include use of haemostatic drugs, erythropoietin and artificial blood substitutes. However, the most effective blood conservation strategies remain the simplest and least costly. The reduction of blood loss associated with diagnostic testing seems to be logical, may reduce anaemia in critically ill patients. The adoption of low haemoglobin threshold as a restrictive transfusion practice is the only intervention that has reduced transfusion requirements. Simple interventions like audits, surveys can be effective in changing transfusion practice. Additional pharmacological and mechanical therapies to reduce blood loss and transfusion are yet to prove to be beneficial.  The effectiveness and safety of these measures still need to be proven.
REFERENCES
1. Herbert PC et al. Review of physiologic mechanisms in response to anemia. CMAJ 1997; 156:S27-40.
2. Kleinman S et al. Risks associated with transfusion of cellular blood components in Canada. Transfus Med Rev 2003;17:83-9.
3. Ferraris A et al. Perioperative blood transfusion and blood conservation in cardiac surgery: the society of Thoracic surgeons andand the society of cardiovascular anaesthesiologists clinical practice guideline. ATS 2007;83:S27-S86.
4. Jubelirer ST. Coronary artery bypass in two patients with immune thrombocytic purpura without preoperative splenectomy. WV Med J 1992;88:510-511.
5. Aryeh Shander. John Hopkins Advanced studies in Medicine. Vol 8, No10 September 2008.
6. Alan T Tinmouth et al. Blood conservation strategies to reduce the need for RBC transfusion in critically ill patients. CMAJ 2008;178(I):49-57
7. Goodnough LT et al. Transfusion Medicine: blood conservation. New Engl J Medicine. 1999;340:525-533.
8. Mackenzie CF et al. What to do if no blood is available but patient is bleeding? South Afr J Anaes Anag. 2008:14(1).