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Jan B. Wade · #1 (**permalink**) 05-15-2004, 07:33 AM

From - American Association of Critical Care Nurses

The Transfusion Trigger
The primary function of blood is to transport oxygen to the cells of the body. In the presence of massive hemorrhage, the question arises of how much blood a patient needs to ensure adequate oxygenation of the tissues. The theoretical â€œtransfusion trigger,â€ or the critical point at which a physician decides to transfuse a patient, has been generously debated in journals. The argument centers around whether the decision to transfuse blood should be based on absolute numbers, or on parameters that relate to the clinical picture.¹³ An overview of various transfusion triggers is contained in Table 1.

Table 1. Transfusion Trigger
	*RBC Infusion*	*Platelet Infusion*	*FFP Infusion*	*Cyro Infusion*
American Society of Anesthesiologists Guidelines for Blood Component Therapy¹³	Rarely for Hgb>10g/dL Usually for Hgb <6g/dL Decision based on risk for complications related to inadequate oxygenation	Rarely for PLT>100,000 Usually for PLT<50,000 For PLT between 50,000 and 100,000 decision based on assessment of risk	Microvascular bleeding present and PT or PTT is 1.5 times normal In the absence of lab results: After transfusion of 1 total blood volume Condemns use for volume replacement	Consider for fibrinogen levels<80 mg/dL to 100 mg/dL or when levels can not be rapidly obtained
Coffland & Shelton1⁸	Symptoms, not Hgb and Hct, should dictate transfusion Symptomatic anemia	PLT < 50,000	Condemns use for volume replacement	Minimum therapeutic fibrinogen 50-100 mg/dL
Crosson⁵	-	PLT < 100,000	Only if PT and PTT >1.5 times normal After 10u of RBCs	Fibrinogen < 150mg/dL
Dennis (1992)³	-	Condemns prophylactic use Bleeding times usu abnormal after 5u RBCs; little value in determination PLT < 100,000	After 10u of RBCs	-
Faringer et al (1993)⁷	HCT < 30%	Penetrating trauma with low PLT: delayed until microvascular bleeding is identified Blunt trauma with low PLT: replace promptly	Only monitor PT For PT > 1.5 times normal	Fibrinogen < 100 mg/dL
Hurley Medical Center⁶	-	Oozing and PLT < 50,000	Initial: 2u FFP after10u RBCs Followed by: 1u FFP after each additional 5u RBC Consider coagulation	-
Spence¹⁴	Hgb alone should not dictate transfusion Must understand physiologic anemia	-	-	-

Hgb = hemoglobin; Hct = hematocrit; PLT = platelets; PT = prothrombin time; PTT = partial thromboplastin time; FFP = fresh frozen plasma; RBCs = red blood cells; Cryo = cryoprecipitate.

In 1994, the American Society of Anesthesiologists created a task force to investigate and make recommendations on blood component therapy. The task force reviewed 1,417 articles and surveyed expert opinion groups in an effort to create evidenced-based guidelines on the proper indications for blood transfusion in perioperative and peripartum settings.¹³ In 1996 they published their report, Practice Guidelines for Blood Component Therapy. Among the groupâ€™s recommendations is the qualifying parameter that blood is rarely indicated with hemoglobin levels more than 10 g/dL and is almost always indicated with hemoglobin levels less than 6 g/dL.

They also suggest that the decision to transfuse should be based on the patientâ€™s risk for development of complications related to inadequate oxygenation. Specifically, this includes the patientâ€™s cardiopulmonary reserve, the rate and severity of the blood loss, oxygen consumption, and atherosclerotic risk. The task force denounces the use of a single hemoglobin trigger, such as the outdated â€œ10/30 rule,â€ which translates to automatic transfusion when hemoglobin is less than 10 g/dL and hematocrit is less than 30%. They urge physicians to consider the physiologic and surgical factors that affect the patientâ€™s oxygenation and to base the decision to transfuse on these factors in combination with lab values.

Spence¹⁴ corroborates the findings of the task force and believes that hemoglobin level alone should not be used as the transfusion trigger. He states that it is necessary to understand the physiologic response to anemia when making transfusion decisions. Farion and McLellan¹⁵ have reported the abolishment or lowering of the hemoglobin transfusion trigger, evidenced by the significantly decreased number of trauma patients undergoing transfusion and the decreased number of total units transfused. They found that patients have lower hemoglobin concentrations during their hospital stays, and that there is a trend toward more aggressive transfusion practice during the early stages of the resuscitation period. There is also a trend toward more complete crossmatching of transfused blood. They conclude that these findings are a result of the lower or abandoned hemoglobin transfusion trigger in combination with increased awareness of transfusion-related complications.

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Transfusion-Related Complications
Numerous adverse effects of blood transfusions can cause a myriad of difficulties. Adverse reactions occur in 20% of all transfusions.²² Given the sheer volume of blood and number of donors that the patient receiving massive transfusion is exposed to, the risk of complication is great. In one study⁷ the trauma patient who received an average of 25 units of blood was exposed to an average of 80 different donors. Complications can be caused by the preservation process of blood, an adverse reaction to the transfusion, or the infectious quality of blood. Crosson⁵ suggests that the clinical complications that arise from massive transfusion are most often a result of the biologic effects of blood preservation or the physiologic changes that occur during the storage period.

These alterations include increased acidity, elevated plasma potassium, and a decrease in 2,3-diphosphoglycerate (DPG) levels and half-saturation (P₅₀) values that affect the bloodâ€™s ability to transport oxygen to the cells. In addition to changes affecting the quality of erythrocytes, platelet function decreases with storage, and levels of factor V and VIII decline in the plasma.⁵

Transfusion reactions can be immediate and life-threatening, or delayed and insidious. Acute hemolytic transfusion reaction is a severe, life-threatening condition that occurs once in every 25,000 units of infused erythrocytes²³ and is usually caused by an antigen-antibody reaction to ABO-incompatible blood.¹⁸ Most incidents occur as a result of errors in patient identification and administration of incompatible blood. Primary symptoms of fever and hypotension can occur with infusion of as little as 0.7-mL, and death has occurred after infusion of only 30 mL.²³ Treatment includes immediate discontinuation of the blood, hemodynamic and renal support with vasopressors and diuretic agents, and avoidance of future incompatibility by obtaining an updated blood sample for crossmatching.

Delayed hemolytic transfusion reaction occurs once in every 2,500 units of erythrocytes¹⁸ and often goes unnoticed.²³ The reaction typically occurs 2 to 14 days after transfusion and results in fever, jaundice, and anemia. It is a result of the clearance of the antibody-coated erythrocyte by the reticuloendothelial system. Therapy includes treating the anemia symptomatically and transfusion of antigen-negative blood if needed in the future.

Treatment-related acute lung injury or noncardiogenic pulmonary edema is a reaction caused by antibodies in the donor blood that react against the leukocytes of the recipient.²³ The estimated rate of occurrence is once in 10,000 units.²³ The onset of symptoms, which include bronchospasm, hypoxia, fever, and diffuse bilateral pulmonary infiltrates, occurs less than 6 hours after transfusion and usually results in pulmonary failure. The condition is treated with supplemental oxygen and mechanical support.²⁴Full recovery occurs within 2 to 4 days, but occasionally takes as long as 7 days. Chest radiograph is a definitive diagnostic tool, in that the signs and symptoms are sometimes confused with those of congestive heart failure.

Anaphylactic reactions to blood transfusions are rare, occurring only once in 150,000 units,²³ and often the exact allergen is never identified. Clinical signs generally occur shortly after the transfusion is begun and include swelling of the throat and hypertension followed by chills, flushing, bronchospasm, and gastrointestinal distress. Treatment includes immediate discontinuation of the blood, administration of epinephrine and corticosteroids, avoidance of FFP in the future, and infusion of only washed blood to decrease the allergen potential.

Several transfusion reactions are not likely to cause significant difficulties for the patients and are of limited clinical significance. Febrile nonhemolytic transfusion reaction occurs once in five transfusions of platelets and once in 100 units of erythrocytes.^18,23 The patient experiences fever within 2 hours of transfusion, which is managed with antipyretic drugs. The transfusion is usually discontinued, and it is recommended that in the future the patient receive leukocyte-reduced products and be premedicated with an antipyretic agent to prevent future reactions.¹⁸ Urticarial reactions are actually incomplete anaphylactic reactions, and patients must be monitored closely for further development of signs of anaphylaxis.²³ This reaction happens once in 1,000 units transfused and is usually accompanied by pruritus.²³ If a patient shows the described signs, the infusion should be stopped immediately and antihistamines administered. Patients with a history of allergic reaction to transfusion can be premedicated with an antipyretic and antihistamine to help prevent a reaction.¹⁸

There has been a significant decline in the number of reactions to bacterially contaminated blood because of the improved processing available in the sterilization of the blood. Bacterial reactions are most commonly associated with platelets, which must be stored at room temperature to maintain function.^22,25 The cause is presumed to be related to inadequate preparation and sterilization of the donorâ€™s venipuncture site.²³ It could also be undiagnosed bacteremia of the donor at the time of donation, a leak in the collection system, or contamination in the processing.²³ Most commonly, Gram-negative organisms such as Pseudomonas, Citrobacter freundii, Escherichia coli, and Yersinia enterocolitica are the cause of bacterial contamination.Symptoms, which generally occur within 4 hours after transfusion, are signs of shock and high fever.²³ Treatment includes hemodynamic support, antibiotics, and steroids.¹⁸

Transmission of infectious diseases is a continual risk with blood transfusion. Diseases such as human immunodeficiency virus (HIV), hepatitis, malaria, babesiosis, Chagasâ€™ disease, yersinia, and cytomegalovirus can be transmitted through blood products.²⁴Screening of donor blood is reliable in detecting hepatitis A and B, HIV, and bacteria; however, newer types of hepatitis C and E are less detectable.²⁴ The risk of transfusion-transmitted HIV is 1 in 450,000 to 660,000 cases.²⁶ The transmission of CMV through blood is of particular concern in immunosuppressed patients, because it can cause life-threatening pneumonia and colitis.²⁴ Cytomegalovirus seronegative blood, which is approximately 20% to 25% of the donated blood supply, must be provided to these high-risk patients.²⁴

Alloimmunization, or the development of antibodies after transfusion, occurs in approximately 1% of all erythrocyte transfusions.²⁷ Although it is rarely clinically significant, it increases the time required for crossmatching and may delay treatment.²⁷ If transfused, alloantibodies can be fatal, resulting in death in 1 of 600,000 cases.²⁷ Alloimmunization to platelet-related antigens occurs in 30% of patients who undergo long-term platelet therapy, causing patients to become refractory to further platelet therapy.²⁷ Alloimmunization to plasma proteins can cause a fatal anaphylactic reaction.²⁷

Transfusion of massive quantities of blood does not come without a price. Blood transfusion is an early risk factor for multiple organ failure.²⁸ Risk of death in patients who have undergone massive blood replacement is directly related to the volume of blood transfused.³ Massive transfusion of the severely injured trauma patient causes several potential complications that must be anticipated and monitored closely. Because erythrocytes are stored at 1Â°C to 6Â°C, rapid blood product administration can lead to hypothermia.³ Resuscitation fluids should be warmed and the blood diluted with equal parts of warmed saline.⁹ Hypothermia can cause the release of potassium from the cell and increase the affinity of hemoglobin for oxygen, making it less available for the cells.³ It can also result in decreased production of clotting factors and decreased hepatic clearance of citrate.³

Citrate, an additive used in stored blood, is normally rapidly excreted by the liver at a rate of up to 150 mL per 70 kg per minute without toxicity.⁹However, when a patient receives more than 1 unit of erythrocytes every 5 minutes, the capacity of the liver to metabolize citrate effectively is exceeded, and levels begin to build in the blood.⁵ This effect can occur more rapidly in patients with impaired hepatic function. Because of the affinity of citrate for calcium, hypocalcemia is often associated with elevated citrate levels. Independent elevation of citrate levels does not cause harm to the patient; however, the associated hypocalcemia can cause depressed ventricular contractility and decreased peripheral vascular resistance, increasing hypotension.³

Once the rate of transfusion has slowed, citrate levels decrease rapidly, and there is a rebound of serum calcium levels. Other factors that affect calcium levels include pH, hypothermia, calcium stores, and liver function. In addition to calcium, citrate binds to magnesium,⁵ which can result in hypomagnesemia in the patient undergoing massive transfusion. Such patients require judicious monitoring for calcium and magnesium deficiency and swift replacement therapy.

Although hyperkalemia is often discussed in treatment with massive transfusion, it is rarely observed clinically.⁹ Large amounts of potassium leak out of the erythrocytes during storage, with reported concentrations as high as 70 mEq/mL.²⁹ This potassium leakage is related to shelf life, and blood bank personnel are therefore instrumental in identifying potential high-risk situations. Fortunately, most of this potassium is reabsorbed by healthy erythrocytes when it is transfused into a patient.⁹

Additionally, several factors including aldosterone, antidiuretic hormone, corticosteroids, and catecholamines help to counteract the high potassium levels.³ Rapid massive transfusion in the presence of renal dysfunction places the patient at higher risk for this complication. In fact, as many patients have hypokalemia as have hyperkalemia.³ Evaluation of these patients has shown no correlation between the number of units of blood transfused to the development of increased or decreased potassium levels, and there is no predictor to identify patients who may experience alterations in potassium metabolism.⁵ Close monitoring of potassium levels and immediate appropriate therapy is warranted.

Patients who undergo massive transfusion are at risk for development of an acid-base imbalance. Stored blood has a pH level of 6.6 to 7.0 relative to its citrate, lactate, and carbon dioxide content. Stored blood becomes more acidic with time, especially blood stored more than 3 weeks. Acidosis is likely to develop in patients with severe refractory shock because of inadequate resuscitation and the inability to reinstate tissue perfusion.³ Often this persistent acidosis is thought to be a cause of the shock state, rather than the acidic blood replacement.⁵ Normally, in the adequately resuscitated patient, citrate and lactate can be rapidly processed into a bicarbonate resulting in an alkalotic state, which is the more common acid-base imbalance in transfusion therapy.

Coagulation abnormalities in patients treated with massive transfusion have a multitude of causes. After the replacement of 1.5 to 2 total blood volumes, significant thrombocytopenia can be observed.⁵ Dilutional thrombocytopenia is usually the earliest and most severe coagulation abnormality noted. Thrombocytopenia is complicated by hypothermia which causes platelet dysfunction. Treatment includes elevating the body temperature and judicious platelet transfusion.

Cosgriff et al.³⁰ investigated coagulopathy in the patients treated with massive transfusion and found that life-threatening coagulopathy developed in 47%. The group identified four significant risk factors for the development of coagulopathy: pH less than 7.1, temperature less than 34Â°C, injury severity score higher than 25, and systolic blood pressure less than 70 mmHg. Patients with an injury severity scores higher than 25 and systolic blood pressure less than 70 mmHg had a 39% likelihood of coagulopathy. Patients with hypothermia and an injury severity score higher than 25 had a 49% probability of coagulopathy.

Occurrence in acidic patients with an injury severity score higher than 25 was also 49%. The presence of all four risk factors increased the incidence of coagulopathy to 98%. Researchers have concluded that serious coagulopathy in massive transfusion can be predicted in the presence of persistent acidosis and hypothermia.

The suppressive effect of transfusion on the immune system was substantiated in organ transplant medicine when it was discovered that renal transplant recipients who underwent transfusion had longer survival time than renal transplant recipients who did not.⁵ In patients receiving massive transfusion, Cue et al.³¹ identified the predisposing factor for immunosuppression as hypovolemia, rather than the resultant transfusion. Their observations revealed no correlation between transfusion and immunosuppression.

Autotransfusion
Intraoperative blood salvage is a treatment method that has been used for years in cardiothoracic surgical procedures and trauma patients with massive hemorrhage. In early attempts at salvage and autotransfusion, a primitive approach was used that resulted in many complications including renal dysfunction, hemolysis, pulmonary dysfunction, and disseminated intravascular coagulopathy. The availability of more advanced processes and equipment that require the skills of specialized technicians have led to fewer adverse events and more successful outcomes. An adequate amount of blood must be collected to salvage, wash, centrifuge, and produce a specimen of good quality for reinfusion.³²

The minimum recoverable amount varies among sources from 500 mL³² to 1,500 mL.³³ Complications associated with autotransfused blood have raised concerns over the quality of the salvaged blood in plasma, residual heparin, and free hemoglobin released from damaged cells. Researchers recently assessed the quality of salvaged blood in 1,593 patients during a 6-year period.³² They found that free hemoglobin levels varied with the operative procedure. Overall, the quality assessment revealed very low levels of heparin, minimal plasma, and acceptable hematocrit levels. Investigators concluded that the reinfused intraoperative salvaged blood was of high quality.³²

As a rule, blood salvage and autotransfusion were not performed in patients with blood grossly contaminated from the involvement of abdominal hollow organs and viscera. However, autotransfusion with blood contaminated with enteric contents is under investigation as a potentially lifesaving measure in trauma patients with massive hemorrhage. In two studies^34,35 investigators have shown successful autotransfusion of enterically contaminated salvaged blood in trauma patients. They monitored infection rates and found that bacteremia, urinary tract infection, and pulmonary infection, were not attributable to the bacteria identified in the salvaged blood. They concluded that washed salvaged blood from the abdominal cavity is a viable alternative method of treatment for the patient with massive bleeding.^34,35

Blood Substitutes
The search for an ideal blood substitute has been ongoing for decades with only small advances. However, clinical trials using blood substitutes are presently under way in hospitals throughout the United States and Europe. Blood is not an easy product to replicate because of its unique properties of transporting nutrients, wastes, and hormones; fighting off infection; and preventing clots and blood loss. Undoubtedly, the most important function of blood is the transport of oxygen and carbon dioxide. The ideal blood substitute must possess excellent oxygen-carrying capacity. It should also be stable in temperature, readily available, universally compatible with all blood types, and possess a longer storage life than blood. The solution must have good intravascular persistence to support circulation and be effective at carrying oxygen at room temperature. Additionally, the compound should be free from any undesirable side effects and should present no risk of transmitting infection.

Historically, there have been two major approaches in the search for a blood substitute: perfluorochemicals and stroma-free hemoglobins. Perfluorochemicals (PFCs) are natural compounds in which hydrogen atoms are replaced with fluorine. Fluorine is highly soluble to oxygen and carbon dioxide, allowing for easy transport to the cells. Oxygen moves from the lungs to the PFC and diffuses into the capillaries by passive transport. One PFC compound first used in the 1980s is Fluosol DA (Green Cross Corp., Osaka, Japan). It is approved for use in Jehovah Witness patients and those who object to the use of blood and blood products. Because of difficult complications connected with storage, undesirable side effects, and limited efficacy, it has not gained widespread acceptance in the medical field. A newer PFC-based product called Oxygent (Alliance Pharmaceutical Corp., San Diego, CA) has a shelf life of 2 years and may not cause the same problems associated with the earlier PFCs.³⁶

A more intense approach in the race to find a blood substitute has been the manipulation of the hemoglobin molecule, natureâ€™s perfect design for oxygen transportation. Hemoglobin is the best carrier of oxygen known to scientists. Stroma-free hemoglobin solutions, not associated with the erythrocyte, are prepared from donated human cells that have died. The challenge in using the natural hemoglobin molecule is that it cannot be used without modification. A molecule normally found in the erythrocyte, 2,3-DPG is required to allow hemoglobin to release adequate oxygen.

When the erythrocyte is lysed, 2,3-DPG is released and loses its stability outside the cell membrane. In the absence of 2,3-DPG, the affinity of hemoglobin for oxygen becomes too high, and oxygen is not released to the cells. Researchers have attempted to modify the hemoglobin molecule to improve stability while encouraging the release of oxygen to the cells.

Currently, there are five hemoglobin-based oxygen carrier solutions in human clinical trials.³⁶ Optro (Somatogen; Colorado) is a recombinant hemoglobin in which human hemoglobin is produced by E. coli.³⁶ Genetically engineered from bacteria, the source material is unlimited; however, processing procedures are costly. Two other scientific efforts involving bovine blood have produced Hemopure (Biopure, Cambridge, MA) and Enzon (Piscataway, NJ). The appeal of animal hemoglobin is the limitless supply and lower costs; however, animal-borne viruses complicate the effort.

By far the most promising advances have been made with two stroma-free hemoglobin therapeutics, Polyheme and HemAssist. Polyheme (Northfield Laboratories; Illinois) is a polymerized human hemoglobin product that contains 50 g hemoglobin in 500 mL of solution, comparable with the physiologic hemoglobin available in 1 unit of erythrocytes.³⁷ Gould et al.³⁷ have demonstrated the safety and efficacy of the infusion of up to 6 units of Polyheme in bleeding trauma patients. Fifty-nine percent of the study population avoided allogenic blood transfusions during the first 24 hours after acute blood loss with the administration of Polyheme, and researchers reported no side effects with use of the product.³⁷ Clinical trials involving Polyheme continue, and researchers are encouraged by the preliminary data.

HemAssist (Baxter International; Illinois), also known as diaspirin cross-linked hemoglobin (DCLHb), was the first hemoglobin-based oxygen carrier to be used in comparative trials in the United States. HemAssist is a modified stroma-free hemoglobin solution compound that is prepared from outdated human erythrocytes. During the production process, the cells are lysed to release the hemoglobin from the erythrocyte. The hemoglobin is then cross-linked with an aspirin derivative, diaspirin, to increase stability and prevent rapid renal filtration of the molecule.³⁸The molecule then undergoes viral deactivation and heat treatment before it is concentrated into an electrolyte solution containing 10 g hemoglobin in 100 mL of solution.³⁹ The effect of the cross-linking process also increases the half-life and allows for the off-loading of oxygen without 2,3 DPG.³⁸ In addition to its excellent oxygen carrying capacity, HemAssist also induces a vasopressor effect that increases perfusion to tissues.⁴⁰

In March 1998, clinical trials involving HemAssist in hemorrhagic shock were terminated in the United States on recommendation of an independent safety committee. Data indicated higher than expected mortality rates in the experimental group.⁴¹ In addition, European trauma studies involving HemAssist have been indefinitely suspended based on inefficacy. Studies involving HemAssist in the elective perioperative setting including orthopedic surgery, abdominal aneurysm repair, and uncomplicated abdominal surgery, have also been temporarily halted in the United States while the manufacturer and an independent safety committee evaluate the interim data.

Researchers are concerned about the long-term effects of these blood substitute products, because they are known to cause some degree of hypertension, renal dysfunction, tachycardia, and gastrointestinal distress.^1,39,42 Despite this concern, investigators concede that the benefits of the substitutes outweigh the risk of side effects, because they are expected to be used in short-term, life-threatening situations.³⁶ The cost of the products will be much higher than blood, as high as $240 per unit, as the pharmaceutical companies attempt to reclaim the exorbitant costs they have incurred in the development of the products and to cover the processing charges. According to Nucci³⁶ the blood substitute market in the United States alone has an estimated worth of $5 billion a year.

Nursing Considerations
Management of a critically injured trauma patient requiring massive transfusion requires the advanced skills of an experienced, expert clinician (Table 3). Established MTPs are essential in facilitating optimal care of the patient. Advanced nurse practitioners have a role in the development and implementation of these protocols. Identifying patients at risk for severe hemorrhage and anticipating transfusion needs can help predict treatment strategies. Maintenance of effective communication between the patient care team and the blood bank technicians is at the core of the partnership and is essential to a successful process.

The experienced trauma nurse demonstrates leadership and acts as a role model for others in the trauma suite through coordination of procedures, with attention to hospital policy. Technical administration of blood products requires accuracy and proficiency. Areas to be monitored include vital signs and the effectiveness of blood component therapy through clinical evidence and laboratory data. Prompt intervention in response to abnormal laboratory findings and transfusion-related complications are imperative. The goal of treatment for the patient with massive hemorrhage is to stay one step ahead, always anticipating the next move. Recipe for success = 90% anticipation + 10% basic instinct.

Conclusion
Blood is a limited resource that has the capacity to save lives. Treating a patient requiring massive transfusion is complex and challenging for even the most experienced trauma staff. Early identification of patients at increased risk for severe hemorrhage and anticipation of blood needs can be used to assess resource use strategies. Implementation of an established massive transfusion protocol facilitates more effective communication among personnel and assists in predicting necessary actions. Complications of massive transfusion can be severe, and clinical management must be prompt and decisive. Alternative therapies for the exsanguinating patient such as, administration of uncrossmatched blood and salvage and autotransfusion of contaminated blood should be considered for optimal patient outcomes.

Self-imposed blood bank limits and established protocols help define termination points to futile transfusions, preserving the most precious of scarce resources. As the medical community awaits the arrival of the secret wonder solution in emergency departments, critical care units, and operating rooms, clinical research into the ideal blood substitute continues. The near future holds promising new technologies that may significantly affect outcomes in patients who undergo massive transfusion.

References
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Transfusion Trigger?