Transfusion Therapy

According to a survey conducted by the Committee on Blood and Blood Products of the American Society of Anesthesiologists,much of all blood given to patients is during the perioperative period. The anesthesiologist should be an expert on the implications and the complications associated with blood transfusions and should be a leader of acute transfusion medicine in the hospital setting.

Blood transfusions are given to increase oxygen-carrying capacity and intravascular volume.

FactorsClass IClass IIClass IIIClass IV Blood loss (mL) or more Blood loss (% blood volume) or more Pulse (beats/min) or higher Blood pressureNormal Decreased Pulse pressure (mm Hg)Normal or increasedDecreased Capillary refill testNormalPositive Respirations per minute Urine output (mL/hr) Negligible Central nervous system: mental status Slightly anxiousMildly anxiousAnxious, confusedConfused, lethargic Fluid replacement (3-1 rule)Crystalloid Crystalloid + blood American College of Surgeons' Classes of Acute Hemorrhage

In 2006, the American Society of Anesthesiologists Practice Guidelines offered these recommendations: 1. Transfusion is rarely indicated when the hemoglobin concentration is greater than 10 g/dL and is almost always indicated when it is less than 6 g/dL, especially when the anemia is acute. 2. The determination of whether intermediate hemoglobin concentrations (6 to 10 g/dL) justify or require RBC transfusion should be based on the patient's risk for complications of inadequate oxygenation. 3. The use of a single hemoglobin “trigger” for all patients and other approaches that fail to consider all important physiologic and surgical factors affecting oxygenation is not recommended. 4. When appropriate, preoperative autologous blood donation, intraoperative and postoperative blood recovery, acute normovolemic hemodilution, and measures to decrease blood loss (i.e., deliberate hypotension and pharmacologic agents) may be beneficial. 5. The indications for transfusion of autologous RBCs may be more liberal than those for allogeneic RBCs because of less frequent (but still significant) risks associated with the former.

The following indications were recommended in the 6th edition of Anesthesia with the rule of thumb that administration of 1 unit of packed RBCs will increase hematocrit value by 3% to 5%: 1. Blood loss greater than 20% of blood volume 2. Hemoglobin level less than 8 g/dL 3. Hemoglobin level less than 10 g/dL with major disease (e.g., emphysema, ischemic heart disease) 4. Hemoglobin level of less than 10 g/dL with autologous blood 5. Hemoglobin level less than 12 g/dL and ventilator dependent

In view of the aforementioned considerations, the following steps are recommended for patients who are hypovolemic and require blood transfusion: 1. Infuse crystalloids or colloids. 2. Draw a blood sample for typing and crossmatching. 3. If crossmatched blood is not ready to give, use type-specific or type O Rh-negative cells or type O Rh- positive cells for males or postmenopausal females without a history of transfusions; type-specific, partially crossmatched blood; or type-specific, crossmatched blood.

During emergency transfusion of more than two units of type O Rh-negative, uncrossmatched whole blood, the patient probably cannot be switched to his or her blood type (A, B, or AB) as soon as the blood bank determines the correct blood type.

Switching could cause major intravascular hemolysis of donor RBCs by increasing titers of transfused anti-A and anti-B. Continued use of O Rh-negative whole blood results only in minor hemolysis of recipient RBCs, with hyperbilirubinemia as the only complication. The patient must not be transfused with his or her correct blood type until the blood bank determines that the transfused anti-A and anti-B has decreased to levels that permit safe transfusion of type-specific blood.

Complications Changes in Oxygen Transport Coagulopathy Dilutional Thrombocytopenia Low Levels of Factors V and VIII Disseminated Intravascular Coagulation-like Syndrome (DIC) Hemolytic Transfusion Reaction

coagulopathy This coagulopathy is caused by a combination of factors, of which the most important are the volume of blood given and the duration of hypotension or hypoperfusion.

Patients who are well perfused and are not hypotensive for a long period (e.g., 1 hour) can tolerate multiple units of blood without developing a coagulopathy.

The patient who is hypotensive and has received many units of blood probably has a coagulopathy from a condition that resembles disseminated intravascular coagulation (DIC) and dilution of coagulation factors from stored bank blood

When such bleeding occurs, the differential diagnosis for a patient who did not have a pretransfusion coagulopathy (e.g., hemophilia) is dilutional thrombocytopenia, low factors V and VIII, a DIC-like syndrome, or hemolytic transfusion reaction. Clinical manifestations include oozing into the surgical field, hematuria, gingival bleeding, petechial bleeding from venipuncture sites, and ecchymoses.

Dilutional Thrombocytopenia When the platelet count is less than 50,000 to 75,000/mm, a bleeding problem is likely and is probably a combination of dilutional thrombocytopenia and DIC. Platelet therapy would be appropriate in this situation. For unexplained reasons, patients with an acutely induced thrombocytopenia (e.g., from blood transfusions) develop a hemorrhagic diathesis at a much higher platelet count than do patients with a chronically induced thrombocytopenia (e.g., idiopathic thrombocytopeniac purpura). A higher platelet count is required to maintain adequate hemostasis with a surgical incision or trauma because damaged capillaries require platelets to plug the holes.

Low Levels of Factors V and VIII Most of the factors are stable in stored blood, with two exceptions: factors V and VIII.These factors gradually decrease to 15% and 50% of normal, respectively, in whole blood after 21 days of storage. Packed RBCs even have fewer coagulation factors. Consequently, administration of fresh frozen plasma (FFP), which contains all the factors except platelets, has been recommended on a therapeutic or a prophylactic basis. However, this practice is of questionable benefit because only 5% to 20% of factor V and 30% of factor VIII are needed for adequate hemostasis during surgery. Although low factors V and VIII appear to be an unlikely primary cause of bleeding during massive blood transfusion, such deficiencies may intensify bleeding from other causes, usually dilutional thrombocytopenia in the case of blood transfusion.

Disseminated Intravascular Coagulation-like Syndrome (DIC) DIC is likely with thrombocytopenia, hypofibrinogenemia, and lysis of a clot within 2 hours.

Drugs Used to Improve Hemostasis desmopressin (1-deamino-8- D -arginine vasopressin [DDAVP]), a synthetic analog of the antidiuretic hormone vasopressin. It increases the levels of factor VIII and von Willebrand factor and is a well- established therapy for hemophilia and von Willebrand disease. It also reduces blood loss and transfusion requirement in patients with normal preoperative coagulation status who are undergoing spinal or cardiac surgery. However, the ultimate role of desmopressin remains to be determined.It can cause hypotension, hyponatremia, and increased platelet adhesion.

aprotinin, a serine protease inhibitor that inhibits fibrinolysis and improves platelet function. It has been used to decrease blood loss in multiple surgical procedures, including cardiopulmonary bypass. However, its ultimate place in the treatment of coagulopathies has not been established.

tranexamic acid, is also an antifibrinolytic drug. Two studies found a decreased blood loss from total-knee arthroplasty. Presumably, release of the pneumatic tourniquet releases fibrinolytic material, which is inhibited by tranexamic acid.

Citrate Intoxication Citrate intoxication is not caused by the citrate ion per se; it occurs because citrate binds calcium. The signs of citrate intoxication are those of hypocalcemia: hypotension, narrow pulse pressure, and increased intraventricular end-diastolic pressure and central venous pressure. However, citrate intoxication is very rare. Having hypothermia, liver disease, liver transplantation, or hyperventilation or being a pediatric patient increases the possibility of citrate intoxication. infusion of more than 1 unit of blood every 10 minutes is necessary for ionized calcium levels to begin to decrease.

Hyperkalemia For significant hyperkalemia to occur clinically, bank blood must be given at a rate of 120 mL/min or more. As with citrate intoxication, hyperkalemia is rare and this also rules against the routine administration of calcium. Calcium may cause cardiac arrhythmias, particularly in patients anesthetized with halothane. Calcium administration should be based on diagnostic signs of hyperkalemia (i.e., peak T wave).

Temperature Perhaps the safest and most common method of warming blood is to pass it through plastic coils or plastic cassettes in a warm water (37° to 38°C) bath or warming plates. These heat exchangers should have upper (e.g., 43°C) and lower (e.g., 33°C) temperature limits.

Acid-Base Abnormalities As a result of accumulation of lactic and pyruvic acids by RBC metabolism and glycolysis, the pH of bank blood continues to decrease to about 6.9 after 21 days of storage. A large portion of the acidosis can be accounted for by the P CO 2 of 150 to 220 mm Hg. the metabolic acid-base response to blood transfusion was variable. Blood transfusions provide a substrate, namely, citrate, in large quantities for the endogenous generation of bicarbonate, and this accounts for the significant incidence of metabolic alkalosis after blood transfusions.

Transfusion Reactions

Hemolytic Transfusion Reaction From 2004 to 2006, three of the four most common causes of transfusion-related deaths were hemolytic transfusion reactions, septic transfusions (e.g., bacterial contamination), and transfusion-related acute lung injury (TRALI). Intravascular hemolysis occurs when there is a direct attack on transfused donor cells by recipient antibody and complement. Such a reaction can occur from infusion of as little as 10 mL of blood. If properly treated, death is rare.

The classic signs and symptoms of a hemolytic transfusion reaction chills, fever, chest and flank pain, and nausea—are masked by anesthesia. Under general anesthesia, the only signs may be hemoglobinuria, bleeding diathesis, or hypotension. The presenting sign is usually hemoglobinuria.

Laboratory tests that should be performed if hemolytic transfusion reaction is suspected include serum haptoglobin, plasma and urine hemoglobin, bilirubin, and direct antiglobulin determinations. The direct antiglobulin test can confirm the presence of hemolytic transfusion reaction because it shows that there is antibody attached to transfused donor RBCs.

Treatment If a hemolytic reaction is suspected, blood and urine samples should be sent to the laboratory for examination. The blood bank should check all paperwork to ensure that the correct blood component was transfused to the patient. Laboratory tests should be performed to determine the presence of hemoglobinemia: a direct antiglobulin test, repeat compatibility testing, repeat other serologic tests (i.e., ABO and Rh), and analysis of urine for hemoglobinuria.

Although there are several consequences of intravascular hemolysis, mainly the renal and coagulation systems are affected. The exact cause of acute renal failure from intravascular hemolysis is controversial, but the most common hypothesis is that hemoglobin in the form of acid hematin precipitates in the distal tubule and causes mechanical tubular blockage.

The magnitude of the precipitation probably is inversely related to the volume of urine flow and its pH. The primary emphasis of therapy should be directed toward maintaining urinary output in excess of 75 mL/hr by generous administration of intravenous fluids and diuretics. One approach is the administration of lactated Ringer's solution to maintain the central venous pressure between 10 and 15 cm H 2 O while initially administering 12.5 to 50 g of mannitol. If this is ineffective, the dose of mannitol may be increased or the use of more potent diuretics, such as furosemide, which increases blood flow to the renal cortex, may be required to maintain adequate urinary output. Alkalinization of the urine to prevent precipitation of acid hematin in the distal tubules is of questionable value but is easy and therefore recommended

DIC commonly occurs with hemolytic transfusion reactions, probably because RBC stroma is severed, releasing erythrocytin, which activates the intrinsic system of coagulation. This activated coagulation leads to fibrin formation. Subsequently, platelets and factors I, II, V, and VII are consumed. As soon as a hemolytic transfusion reaction is recognized, platelet count, prothrombin time, and partial thromboplastin time should be determined to provide baseline values with which subsequent laboratory values can be compared.

Hypotension during a hemolytic transfusion reaction may result from activation of the kallikrein system.After a series of reactions, plasma kininogen is converted to bradykinin, a potent vasodilator that can cause hypotension.

Steps in the Treatment of a Hemolytic Transfusion Reaction 1. STOP THE TRANSFUSION. 2. Maintain the urine output at a minimum of 75 to 100 mL/hr by the following methods: a. Generously administer fluids intravenously and possibly mannitol (12.5 to 50 g, given over 5 to 15 minutes). b. If intravenously administered fluids and mannitol are ineffective, administer furosemide (20 to 40 mg) intravenously. 3. Alkalinize the urine; because bicarbonate is preferentially excreted in the urine, only 40 to 70 mEq of sodium bicarbonate per 70 kg of body weight is usually required to raise the urine pH to 8, whereupon repeat urine pH determinations indicate the need for additional bicarbonate. 4. Assay urine and plasma hemoglobin concentrations. 5. Determine platelet count, partial thromboplastin time, and serum fibrinogen level. 6. Return unused blood to blood bank for repeat crossmatch. 7. Send patient's blood and urine sample to blood bank for examination. 8. Prevent hypotension to ensure adequate renal blood flow.

Delayed Hemolytic Transfusion Reaction (Immune Extravascular Reaction) the level of antibody at the time of transfusion is too low to be detected or too low to cause RBC destruction. RBC destruction occurs only when the level of antibody is increased after a secondary stimulus (i.e., anamnestic response).

These delayed reactions are often manifested only by a decrease in the post-transfusion hematocrit value. However, jaundice and hemoglobinuria can occur in these patients and can cause some impairment in renal function but only rarely do they lead to death. Unlike immediate reactions, antibodies most commonly involved in delayed hemolytic reactions are those in the Rh and Kidd systems rather than the ABO system.

Although improved blood-banking procedures have decreased the incidence of immediate hemolytic transfusion reactions, the delayed hemolytic reaction may not be preventable, because pretransfusion testing is unable to detect very low levels of antibody present in potential blood recipients.

Nonhemolytic Transfusion Reactions Nonhemolytic reactions to blood transfusions usually are not serious and are febrile or allergic in nature. The most common adverse reactions to blood transfusions are the less serious febrile reactions. The symptoms consist of chills, fever, headache, myalgia, nausea, and nonproductive cough occurring shortly after blood transfusion caused by pyrogenic cytokines and intracellular contents released by donor leukocytes.

A direct antiglobulin test readily differentiates a hemolytic reaction from a febrile reaction because this test rules out the attachment of an RBC antibody to transfused donor RBCs. There is no clear consensus on whether the transfusion should be terminated when a febrile reaction occurs.

Allergic reactions can be minor, anaphylactoid, or anaphylactic. Anaphylactoid is similar to anaphylaxis clinically but are not mediated by IgE. Most allergic transfusion reactions are minor and are thought to be caused by the presence of foreign protein in the transfused blood. The most common symptom is urticaria associated with itching. Occasionally, the patient has facial swelling. When these reactions are clearly not a serious hemolytic reaction, the transfusion does not need to be discontinued. Antihistamines are used to relieve the symptoms of the allergic reaction.

These are anaphylactic reactions caused by the transfusion of IgA to patients who are IgA deficient and have formed anti-IgA. This type of reaction does not involve red cell destruction and it occurs very rapidly, usually after the transfusion of only a few milliliters of blood or plasma.

Infectivity of Blood Ninety percent of post-transfusion hepatitis is caused by the hepatitis C virus. Many blood components, such as FFP and platelet concentrates, also transmit hepatitis at an incidence equal to that of whole blood and packed RBCs. Certainly the HCV nucleic acid technology testing represents a dramatic increase in blood safety, although HCV RNA can be below detection by this process, which probably represents the occasional ongoing transmission risk. It is a major health care advance or even a miracle that HIV is only rarely transmitted by blood transfusions except in some developing countries

Transfusion-Related Acute Lung Injury Transfusion-related acute lung injury (TRALI) is now the leading cause of transfusion-related mortality, although it probably is underdiagnosed and underreported.This injury manifests as noncardiogenic pulmonary edema. Clinically, symptoms and signs appear 1 to 2 hours after transfusion and are in force within 6 hours. Fever, dyspnea, fluid in the endotracheal tube, and severe hypoxia are typical. During anesthesia, a persistent decrease in blood oxygen saturation can be the presenting sign. Although the chest radiograph is characteristic of pulmonary edema, circulatory overload (i.e., left atrial hypertension) is not present.

All blood components, especially FFP, are implicated as caustic factors. There is no specific therapy other than stopping the transfusion and instituting critical care supportive measures. However, the transfusion should be immediately stopped and the blood bank notified for a different donor and quarantining all units from that donor. Most patients recover in 96 hours, although TRALI remains the leading cause of transfusion-related death.