Blood/Blood transfusion
Introduction:
Blood Transfusion of red cells is a lifesaving measure in the management of a variety of medical and surgical conditions. The AIDS epidemic has raised the level of apprehension regarding the transmission of infectious disease by transfusion. This has stimulated a reexamination of the benefit-to-risk relationship for transfusion therapy. For many patients, homologous red cell transfusion carries great benefits, permitting surgical procedures that would not otherwise be possible and allowing medical therapies for patients who are or may become anemic. Blood Transfusions were once believed to be relatively safe, but recently many physicians and patients have come to regard them as potentially dangerous. As with all potent and effective therapies, homologous blood transfusion carries risks along with benefits.
About two-thirds of all red cell transfusions are given in the perioperative period. Newer knowledge of physiology and of the effects of anemia during and after surgery permits reevaluation of the indications for red cell transfusion in the perioperative period. Translation of this new information into clinical practice is appropriate. Autologous transfusion is increasingly used as an alternative to homologous red cell transfusion, especially in the perioperative period. There are other strategies that need to be considered.
To assess these issues, the National Heart, Lung, and Blood Institute, the Office of Medical Applications of Research, the Warren Grant Magnuson Clinical Center of the National Institutes of Health (NIH), and the Food and Drug Administration (FDA) convened the Consensus Development Conference on Perioperative Red Cell Transfusion on June 27- 29, 1988. After a day-and-a-half of presentations by experts in the field, a consensus panel drawn from the medical professions, blood banking organizations, and the general public considered the evidence. The focus of the presentations and of the panel was on adults and older children. Red cell transfusion in the neonatal period and early childhood were not addressed by this conference. The panel responded to the following questions:
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What should the criteria be for perioperative red blood cell transfusion?
What is the morbidity of anemia in the perioperative period?
What are the risks of red cell transfusion--both immediate and long term?
What are the alternatives to red cell transfusion?
What are the directions for future research?
What Should the Criteria Be for Perioperative Red Blood Cell Transfusion?
Modern surgical and anesthetic practice has been guided by the belief that a hemoglobin value of less than 10 g/dL or a hematocrit value of less than 30 percent indicates a need for perioperative red cell transfusion. This guideline is widely applied in surgical patients, except those with chronic renal failure, although firm evidence to support the practice is difficult to identify. This guideline had been based on calculations that suggested that oxygen availability to tissues and organs might be impaired when the hemoglobin value decreased to less than 10 g/dL. However, these calculations rarely included appropriate corrections for cardiac output, oxygen extraction, or alterations in the hemoglobin affinity for oxygen.
The guideline was first challenged in the early 1960s, as surgical and anesthetic experience accumulated with patients who had severe anemia complicating chronic renal failure and other conditions. Subsequently, clinical experience suggested that those with severe anemia could tolerate anesthesia and surgery without evidence of major morbidity or mortality resulting from the anemia.
Evidence that hemoglobin values of less than 10 g/dL are tolerated during surgery is provided both by clinical and physiologic studies. Reports of several series of patients who refuse blood transfusions demonstrate that a variety of major operations are tolerated without apparent major morbidity or mortality. The available evidence does not support the necessity for the "10/30" rule. However, the literature is remarkable for the absence of carefully controlled, randomized trials that would permit definitive conclusions regarding perioperative transfusion practice.
Other data suggest that cardiac output does not increase dramatically in healthy humans until the hemoglobin value decreases to approximately 7 g/dL. Anesthetized, paralyzed, and ventilated animals may survive acute isovolemic anemia until the hematocrit decreases to approximately 5 percent. However, significant functional deterioration occurs well before that point.
The decision to transfuse a specific patient should take into consideration the duration of anemia, the intravascular volume, the extent of the operation, the probability for massive blood loss, and the presence of coexisting conditions such as impaired pulmonary function, inadequate cardiac output, myocardial ischemia, or cerebrovascular or peripheral circulatory disease. These factors are representative of the universe of considerations that comprise clinical judgment.
No single measure can replace good clinical judgment as the basis for decisions regarding perioperative transfusion. However, current experience would suggest that otherwise healthy patients with hemoglobin values of 10 g/dL or greater rarely require perioperative transfusion, whereas those with acute anemia with resulting hemoglobin values of less than 7 g/dL will frequently require red cell transfusions. It appears that some patients with chronic anemia such as those with chronic renal failure tolerate hemoglobin values of less than 7 g/dL. The decision to transfuse red cells will depend on clinical assessment aided by laboratory data such as arterial oxygenation, mixed venous oxygen tension, cardiac output, the oxygen extraction ratio and blood volume, when indicated.
It is essential to recognize that the combination of hypovolemia and anemia may lead to severe morbidity and/or mortality and that there is a minimum hemoglobin value for each individual below which severe morbidity and/or mortality due to inadequate oxygen delivery is likely to occur.
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What Is the Morbidity of Anemia in the Perioperative Period?
Any adverse effect that occurs immediately preceding, during, or after the operation is considered to be perioperative morbidity. Morbid events include wound infection, delayed wound healing, bleeding, and impaired recovery. Many physicians and patients are concerned that anemia may increase perioperative morbidity.
In adults, anemia is usually considered as hemoglobin <11.5 g/dL or hematocrit <36 percent in females and hemoglobin <12.5 g/dL or hematocrit <40 percent in males. Anemia may be mild or severe, acute or chronic. The cause of the anemia may be more important in adversely affecting the perioperative course than the severity of the anemia. Significant disease may be a determinant of morbidity. Mild anemia itself is not associated with perioperative morbidity. The principal concern is whether more severe anemia is related to morbid events. It is important to separate the effects of hypovolemia and decreased perfusion from the effects of anemia. If there is normal intravascular volume and normal tissue perfusion, there is no adverse effect on cardiovascular function until anemia is profound.
Healing of a surgical wound depends on angiogenesis, collagen deposition, and epithelialization. Oxygen tension and adequate perfusion are critically important for wound healing. However, healing is not compromised by normovolemic anemia unless it is extreme. Animal experiments suggest that wound healing is impaired below a hematocrit of 15 percent. There is no support for transfusion to a certain level of hematocrit or hemoglobin to promote wound healing. Likewise, there is no clear evidence that anemia increases the frequency or severity of postoperative infections. There are also no data to suggest that transfusion of red cells has a salutory effect on infection.
In patients with renal failure, associated metabolic abnormalities, and anemia, there may be a prolonged bleeding time that appears to be corrected by increasing the hematocrit. Some animal experiments also suggest that decreased hematocrit is associated with prolonged bleeding time. However, in nonuremic humans, no relationship has been demonstrated between anemia and an increased bleeding time. Moreover, there is no clinical evidence that anemic patients have increased bleeding during or following surgery. Phlebotomy has been demonstrated to decrease exercise tolerance in healthy people; however, there are no controlled studies of the relationship of anemia to delayed recuperation or increased hospital stay.
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What Are the Risks of Red Cell Transfusion -- Both Immediate and Long Term?
In deciding whether to use red cell transfusion in the perioperative period, the need for possibly improved oxygenation must be weighed against the risks of adverse consequences, both short term and long term. The disadvantages are of two general types: transmission of infection and adverse effects attributable to immune mechanisms.
Any infectious agent that is present in the blood of a donor at the time of donation is potentially transmissible to a susceptible recipient. The consequence may be seen as clinical morbidity and mortality after an incubation period characteristic of the agent or recognized only by serologic or other types of laboratory testing. If the agent produces chronic infection, clinical morbidity and mortality may not be seen until years after the transfusion.
In modern blood banking practice, bacterial contamination of red cell units is rare. For practical purposes, the transmissible agents of greatest concern are viruses.
Human hepatitis viruses are the most frequently transmitted infectious agents. The incidence of non-A, non-B infection after recent changes in criteria for donor acceptance and the introduction of nonspecific laboratory tests (antibody to hepatitis B core antigen and alanine aminotransferase) is not precisely known, but it may be 1:100 or less per unit. Hepatitis B virus infection, for which a specific screening procedure has been in use since 1971, still occurs, and prior to recent changes in donor populations was in the range of 1:200 to 1:300 per unit.
Human immunodeficiency virus(es), about which there is the greatest public concern, presently pose only a remote hazard because of donor selection and laboratory screening procedures. It is variously estimated that the risk of HIV transmission by transfusion is 1:40,000 to 1:1,000,000. That level of risk is unlikely to be appreciably decreased in the foreseeable future even if additional screening tests are added. The consequences of HIV infection are rarely seen until 2 or many more years have elapsed, but ultimately morbidity and mortality are extremely high.
Cytomegalovirus infection occurs with moderate frequency among those recipients without prior infection. Most of these infections are asymptomatic except among immunocompromised people.
Human T-cell lymphotropic viruses (HTLV-I/II) occur with low but not negligible frequency among donor populations in the United States. It is not known whether transfusion-transmitted infection with these viruses among adults results in T-cell leukemia/lymphoma and/or neurologic disease several to many years later.
On rare occasions, other microbial agents, including parvoviruses, plasmodia, Epstein-Barr virus, and babesia, cause infection and disease.
It is known for the human hepatitis viruses that the incidence of infection in recipients increases with the number of donor exposures. This relationship is probably true for other transfusion-transmitted infections. If homologous transfusion is to be used, therefore, the number of units administered should be kept to a minimum.
Immunologic consequences also complicate homologous red cell transfusion. Hemolytic and nonhemolytic reactions are largely caused by alloimmunization to red cell and leukocyte antigens. Compatibility testing has virtually eliminated immediate hemolytic transfusion reactions; when they occur, they are largely due to human error. Nonhemolytic febrile reactions occur in 1 to 2 percent of recipients due to sensitization to leukocyte antigens. This may be minimized by the use of leukocyte-poor blood products.
Incidence of Transfusion Reaction Per Unit
Fever, Chills, Urticaria 1:100
Hemolytic Transfusion Reactions 1:6,000
Fatal Hemolytic Transfusion Reactions 1:100,000
Components of red cell transfusions, possibly leukocytes, may induce immunosuppression. The clinical significance of the phenomenon is unclear and is presently under investigation in a number of areas.
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What Are the Alternatives to Red Cell Transfusion?
Although homologous red cell transfusion is becoming continuously safer and is a major therapy, it should not be considered a substitute for good surgical and anesthetic technique. Progress in anesthesia has allowed more time for the surgeon to be fastidious about hemostasis, and new surgical techniques have improved the surgeon's ability to control bleeding.
A variety of alternatives to homologous transfusions exist. The available literature does not permit a definitive recommendation concerning the cost/benefit or the risk/benefit ratio of any of them. In most cases, the expected blood loss with the surgical procedure can be predicted from clinical evaluation. This prediction should be used in the selection of a strategy to minimize use of homologous red cells.
Autologous transfusion programs eliminate the viral transmission and immunologic risks previously discussed. The practice appears useful for selected patients and is most valuable when major blood loss is anticipated. However, the risks of the procedure have not been fully evaluated. There are a number of complicated issues that deserve further investigation. These include the logistics of the process and concerns about unnecessary transfusions, errors in distribution, testing, and the disposition of unused units. Current experience with autologous transfusion is limited to about 2 percent of transfusions in the United States.
Intraoperative blood salvage appears to be safe in some applications and reduces the requirement for homologous transfusion. Although current technology is costly because of disposable supplies, equipment, and personnel, it may eliminate the need for homologous blood in some patients.
Selection of patients for intraoperative isovolemic hemodilution is based upon still-emerging criteria. Appropriate limits have not yet been established for its general use. Many of the criteria applicable to the use of autologous transfusion are comparable to those for use of intraoperative hemodilution. Some patients can be treated in this way and may avoid homologous transfusion.
Maintenance of perfusion is still the primary problem in dealing with blood loss. There are a number of cost-effective substitutes for treatment of reduced plasma volume and total blood volume. By contrast, there is at present no suitable available material to support oxygen transport. Modified hemoglobin solutions and improved perfluorochemical emulsions are under development but may serve only limited clinical purposes. Thus, no recommendation can be made for use of any such materials.
Pharmacologic approaches to reducing surgical blood loss are promising. Hemostasis may be improved with the use of desmopressin. Intraoperative deliberately induced hypotension may also reduce surgical blood loss in some procedures.
Recombinant erythropoietin (r-HuEPO) may be useful in avoiding homologous transfusion by increasing the amount of blood available in programs of autologous transfusion. Studies in uremic patients as well as animal experiments suggest that some anemic patients can have useful increase in hemoglobin levels by treatment with r-HuEPO preoperatively or postoperatively, which would reduce their transfusion requirements. This approach also should be developed further.
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What Are the Directions for Future Research?
Future research should adhere to appropriate standards of research design, including adequate sample sizes, controls, multiple sites, and randomization, where feasible. The panel identified the following research areas worthy of emphasis:
The effect of anemia on rate of recovery and length of hospital stay.
The determination of the risk of transfusion-transmitted infection with contemporary donor screening procedures and evaluation of new measures to identify infected donors.
The determination of immune changes induced by transfusions and their clinical consequences, if any.
The identification of organs that are specifically at risk during acute anemia and the development of clinical monitors that measure directly or indirectly the state of perfusion and the presence of cellular hypoxia in those organs that are specifically sensitive to low hemoglobin values.
The development of predictors that better define the need for perioperative transfusion.
The development of appropriate blood substitutes.
The performance of prospective controlled trials to evaluate the effects of increasing the hematocrit in anemic patients in the perioperative period.
The evaluation and improvement of the safety and efficacy of autologous transfusion and intraoperative blood salvage procedures and the definition of criteria for selection of patients.
The development of measures for the improvement of the safety of homologous blood transfusion.
The evaluation of the risks and benefits of directed donations. The existing data are inconclusive
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Conclusions:
Available evidence does not support the use of a single criterion for transfusion such as a hemoglobin concentration of <10 g/dL. No single measure can replace good clinical judgment as the basis for decision making regarding perioperative transfusion.
There is no evidence that mild-to-moderate anemia contributes to perioperative morbidity.
Perioperative transfusion of homologous red cells carries documented risks of infection and immune changes. Therefore, the number of homologous transfusions should be kept to a minimum.
There are being developed a variety of promising alternatives to homologous transfusion. These alternatives will reduce the use of homologous transfusion to some extent and their development should be encouraged. However, in the foreseeable future, homologous blood will continue to be the therapeutic mainstay. Therefore, primary attention should be devoted to the promotion of safe and effective transfusions from carefully selected volunteer donors.
Future research is necessary to define the best indications for red cell transfusion and the safest methods of blood conservation and delivery.
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