Guidelines for red blood cell and plasma transfusion for adults and children
Allogeneic red blood cell transfusion
The standard unit of whole blood collected consists of approximately 450 mL of blood taken into 63 mL of anticoagulant.17 Red blood cells are prepared by removing supernatant plasma from a whole blood donation after centrifugation. The characteristics of this component vary depending on the anticoagulantpreservative solution used (Table 1). In the average adult, each unit of blood should raise hemoglobin by 1015 g/L.17
Oxygen transport and the physiologic responses to anemia
The simplest method of reducing the frequency of allogeneic blood transfusion is to withhold transfusion until more severe levels of anemia are reached. However, the optimum threshold for the initiation of transfusion therapy is not yet defined and, clearly, the level of anemia permitted cannot be such that tissue oxygen delivery (DO2) or consumption are compromised. The oxygen carrying capacity of blood is measured either indirectly by measurement of the red blood cell concentration (the hematocrit) or directly by determining hemoglobin concentration ([Hb]). Although both measures are employed in research reports, [Hb] is more commonly used in the context of clinical medicine. (In this document, where authors report hematocrit, the original value is given and an approximate [Hb] provided.)
DO2 is the product of tissue blood flow and arterial oxygen content; at the whole body level these factors are represented by the product of cardiac output (CO) and the arterial oxygen content (CaO2).
DO2 = CO × CaO2
CaO2 depends on [Hb] and the percentage of Hb saturated with oxygen. CO is affected by both preload (venous return) and afterload. Blood flow is determined by resistance to flow in the vascular bed and the perfusion pressure driving flow through the bed. Blood is more viscous (inherently resistant to flow) at lower flow rates. Thus, viscosity is highest in venules and lowest in the aorta. Viscosity, independent of flow rate, is primarily a function of red blood cell concentration. Reduction in the red blood cell concentration lowers blood viscosity and reduces the resistance to flow. With progressive reduction there is an incremental rise in CO.18 There is some inconsistency in reports as to the [Hb] at which CO begins to rise. In adults, the higher CO is initially a result of enhanced preload and a decreased afterload. The augmented venous return is a result of the profound reduction in viscosity and a passive increase in blood flow in the postcapillary venules. The decrease in afterload is produced by the reduction in the viscosity component of the systemic vascular resistance. In children, the increase in CO is more dependent on increased heart rate and less on enhanced stroke volume than in adults.
Blood with a low [Hb] has decreased oxygen carrying capacity. To compensate for this and to maintain oxygen delivery, tissues may augment blood flow, either by recruiting capillaries or by increasing flow through the existing capillary network. Tissues may also increase oxygen extraction ratios (ER). Enhanced oxygen extraction may occur particularly in tissue beds that normally consume a small proportion of the available oxygen. In supply-dependent beds, such as in the heart, higher ERs occur under normal conditions.19,20 In these beds, to preserve oxygen consumption and aerobic metabolism, regional blood flow must increase proportionally more than the increment in CO. As [Hb] decreases to 50 g/L (hematocrit 0.15), there is evidence of decreased myocardial oxygen consumption, which may be due to impairment in myocardial oxygen extraction.21 In animals, the onset of coronary lactate production (anaerobic metabolism) occurs at a [Hb] below 35 g/L (hematocrit 0.10).22 In a model of coronary stenosis, this anaerobic state occurs at a [Hb] of 6070 g/L.2325 These values also coincide with the onset of ventricular wall motion abnormalities.25
Tissue oxygenation may be improved with a shift to the right of the Hb-oxygen dissociation curve (to a higher P50). This can be achieved through increased red blood cell levels of 2,3-diphosphoglycerate (2,3-DPG) and decreased pH, both of which facilitate oxygen unloading in the tissues. Changes in the Hb-oxygen dissociation curve resulting from changes in red blood cell 2,3-DPG levels take 1236 hours to occur and increase with decreasing [Hb]. Because of these adaptations, in chronic anemia a 50% decrease in oxygen carrying capacity is accompanied by only a 25% decrease in oxygen availability.26
The physiologic compensations for a decreased [Hb] must be sufficient to balance the lower oxygen carrying capacity and maintain tissue oxygen delivery. The optimum [Hb] is the level that allows for the greatest oxygen delivery at the lowest energy cost to the organism. In terms of whole-body oxygen delivery, Messmer concluded that the optimum [Hb] was 100 g/L (hematocrit 0.30).27,28 As [Hb] was decreased from 150 g/L to 100 g/L, while maintaining normal circulating blood volume, reduction in viscosity was sufficient to allow increased blood flow such that systemic oxygen transport capacity increased. With further reduction in [Hb], oxygen delivery declined so that, at [Hb] about 90 g/L, tissue oxygen delivery was at or below preanemic levels.29 Because oxygen delivery remained relatively constant between [Hb] 90 g/L and 150 g/L, there appeared to be little rationale for transfusing red blood cells to patients with [Hb] already in this range to increase oxygen delivery. Messmer's conclusion that systemic oxygen transport was optimum at [Hb] of 100 g/L was supported by whole-body physiologic measurements and cannot be extrapolated to support conclusions regarding regional circulations. Furthermore, although Messmer's assertions are widely acknowledged and help form the basis for current transfusion strategies, they disagree with the work of other investigators. Le Merre and co-workers30 reported that systemic oxygen transport capacity decreased with even moderate hemodilution and argued that increased tissue extraction of oxygen was the major compensating factor.
Although the mechanisms for compensation remain to be clarified, clinical experience supports Messmer's conclusions; that is, there seems to be little clinical gain in transfusing most patients whose [Hb] is in the range 90150 g/L.3133 The lack of measured benefit of transfusion is supported by the work of Hébert and colleagues,34 who in a multicentred, randomized, controlled clinical trial, evaluated the effects of a restrictive transfusion threshold ([Hb] 7090 g/L) compared with a more liberal one (100120 g/L) in critically ill patients developing a [Hb] of less than 90 g/L in the first 72 hours after admission to an intensive care unit (ICU). The study groups were demographically similar. The number of units of blood administered was significantly smaller for the patients with the restrictive threshold; yet there was no difference noted in ICU 30-day and 120-day mortality. Although the findings are encouraging, this was a small study and confirmation following evaluation of larger groups is required.
Messmer's work provides a basis for estimating the optimum [Hb], but the experience of Jehovah's Witness patients provides data on the lowest tolerable concentration, perhaps a more appropriate marker to justify transfusion. Viele and Weiskopf35 reviewed 54 publications involving 134 patients with moderate to severe anemia. The overall case fatality rate was 37%, and all patients whose deaths were attributed to anemia died with [Hb] less than 50 g/L. Considering only anemia-related deaths, the case fatality rate was 27% for patients who were under 50 years of age and 53% for patients over 50 years. No patients with a [Hb] of 5080 g/L) died because of their anemia. Although these findings may reassure clinicians that very low [Hb] is tolerated in many younger patients and some older ones, there is a selection bias in these reports. Obviously, severely anemic survivors are more frequently reported than nonsurvivors, and the risk of severe anemia may thus be understated. Furthermore, mortality is not the only endpoint to be avoided with blood transfusion; these papers provide little information about morbidity-avoidance with transfusion.
Although there is little direct clinical evidence, much of the risk posed to the patient by a low [Hb] probably relates to the ability of the heart to tolerate anemia. Carson and co-workers36 reported a retrospective cohort study of 1958 adults (over 18 yrs of age) who underwent surgery and refused blood transfusion between 1981 and 1994. There was an increase in the risk of death associated with a lower preoperative [Hb], and this risk was enhanced by the presence of cardiovascular disease. Mortality within 30 days was 1.3% in patients with [Hb] of 120g/L and increased in a roughly linear fashion to 33.3% in patients with [Hb] less than 60 g/L. In addition, the effect of blood loss on mortality was greater in patients with a lower preoperative [Hb]. The authors concluded that a low preoperative [Hb] or substantial blood loss during surgery increases the risk of death or perioperative morbidity and that this effect is larger in patients with cardiovascular disease.
Many physiologic mechanisms compensate for acute anemia and preserve tissue oxygen delivery. However, if these compensatory mechanisms are not intact, oxygen delivery may not be preserved and organ dysfunction may result. Older patients are less tolerant of low [Hb] levels; they are less able to increase heart rate and stroke volume (and hence CO) in response to exercise.37 In elderly patients with low [Hb] but normal blood volume, oxygen delivery is decreased as a result of failure to increase CO. Oxygen consumption is maintained by increased extraction. This finding has been reported in healthy patients, patients with medical disease excluding patients with heart disease and patients with recognized coronary artery disease.3840 Although chronologic age does not necessarily parallel physiologic age, and there are wide individual differences in functional capability in a population, the compensatory mechanisms that preserve oxygen delivery generally are reduced in the elderly.
The perception that the elderly are at greater risk than younger cohorts if they become anemic presumably is related, not only to their reduced physiologic compensatory mechanisms, but also to the higher incidence of coronary artery disease and the resultant reduced capacity to increase coronary artery blood flow and, perhaps, CO.41 This may limit the degree of hemodilution that will be tolerated by these patients because increased flow is an essential compensatory mechanism. Relatively modest hemodilution plus depleted or exhausted coronary vasodilator reserve may compromise ventricular metabolism and function.41 Electrocardiographic evidence of ischemia was observed in 22% of patients with pre-existing impaired left ventricular function who were hemodiluted, but was not seen in patients with normal left ventricular function.41 This report suggests that, in the presence of moderate coronary artery stenosis, flow may not increase sufficiently to offset the loss of oxygen carrying capacity caused by hemodilution, and ischemic cardiac dysfunction may result from even a modest reduction in [Hb]. Patients with critical vessel stenosis or pre-existing left ventricular dysfunction may not tolerate hemodilution to any degree. An association has been reported between low perioperative [Hb] levels and the occurrence of myocardial ischemia and infarction.42 Finally, Carson and co-workers36 concluded that patients with cardiovascular disease had a much greater risk of perioperative death than patients without cardiovascular disease when their preoperative [Hb] was 100 g/L or less. Coronary artery disease likely constitutes an important factor in determining a patient's tolerance of low [Hb].
Much of the information on tolerable levels of anemia comes from research in which anemia is the predominant physiologic stressor. In clinical medicine, the concurrent presence of underlying disease states, both acute and chronic, metabolic derangements or disturbances in oxygen transport may alter the patient's tolerance of anemia. However, there is insufficient explicit information to justify conclusions and meaningful comment in these specific situations.
For clinically stable patients who are not at risk for coronary artery disease, transfusion is more likely to be beneficial when [Hb] is less than 60 g/L, but not when [Hb] is greater than 80 g/L, as long as normal blood volume is maintained and patient assessment is ongoing. Critically ill patients and those at risk for coronary artery disease are less likely to be as tolerant of low [Hb] and will likely benefit from maintenance of a higher range of [Hb] than patients not at risk.
Indices of oxygen delivery and tissue oxygenation may accurately indicate the need to transfuse red blood cells; however invasive monitoring is required to generate these indices. Thus, decisions about transfusion must often be made on the basis of available but less informative data, including patient characteristics (i.e., age, presence of heart disease), the clinical context (i.e., stable with no ongoing bleeding versus ongoing blood loss), measured vital signs and the patient's tolerance of the situation. In some situations, particularly in the perioperative period and also in critically ill, sedated and ventilated patients, medications may further mask the expected hemodynamic indices, and patient characteristics and the clinical context may have a greater role in the decision to transfuse red blood cells.
In some situations, transfusion of multiple units is appropriate -- typically during resuscitation from a major hemorrhage. However, the routine transfusion of multiple units in less urgent situations appears to be common and should be re-evaluated. Instead, physicians should consider transfusing one unit at a time with assessment after each unit to avoid unnecessary exposure.
Principles specific to acute blood loss
When blood loss is acute, initial reductions in total arterial oxygen content are usually well tolerated because of compensatory increases in CO. Although determined by the rate of blood loss, the lower limit of human tolerance to acute anemia has not been established, but oxygen delivery will probably be adequate in most people with a [Hb] above 70 g/L,2,43 assuming that oxygen delivery is not compromised by other physiologic disturbances. However this is not always a valid assumption. The effects of medications, pre-existing disease and hypothermia have been described well and must be considered when assessing an individual patient's response to acute blood loss.4345 Barring such other factors, tissue oxygenation appears to be maintained and anemia well tolerated at a hematocrit as low as 0.180.25 ([Hb] of 6080 g/L).46
Measured [Hb] will frequently be misleading during acute blood loss because it depends on the rapidity and degree of blood loss and the effects of fluid resuscitation (acute hemodilution). With ongoing blood loss, by the time a [Hb] is reported (from a sample drawn earlier), the actual oxygen carrying capacity may have changed.
There is currently no evidence to support a threshold value for initiating blood transfusion in the case of acute blood loss. All recent reviews have refuted the concept of a transfusion threshold, most concluding that insufficient evidence exists to support a single hemoglobin requirement.46,47 The decision to administer red blood cell transfusions should be determined by evaluating the rate of ongoing blood loss, evidence of end-organ compromise and the risk or presence of coronary artery disease.
Acute blood loss may occur in a variety of clinical situations. The most important clinical features are the amount of blood loss and the likelihood of continuing losses. The primary treatment goals in this setting are to restore intravascular volume, to ensure sufficient oxygen carrying capacity and to stop the blood loss as soon as possible. Management of a patient with acute blood loss should also include other measures to maximize the oxygenation of circulating blood (such as airway management, administration of oxygen and treatment of pulmonary injuries). The principles of management of hypovolemic shock are reviewed in the manual for the American College of Surgeons' advanced trauma life support course.43
In cases of acute hemorrhage related to elective surgery, the availability of predeposited autologous blood units and measures to decrease blood loss (intra-operative and postoperative blood salvage, acute normovolemic hemodilution) may reduce the requirement for allogeneic blood cell transfusion (Andreas Laupacis et al. See citation on page S3).
Principles specific to chronic anemia
In determining the need for red blood cell transfusion, it is important to consider the differences between acute and chronic anemia. Acute anemia is often accompanied by hypovolemia which, at least initially, is often the major physiologic problem. The patient with chronic anemia is normovolemic or even hypervolemic. Also, in the case of chronic anemia, decisions usually need not be made rapidly; there is time to consider and discuss the role of transfusion therapy, and its benefits and risks with the patient. It is an ideal situation for involving a competent patient in the treatment plan.
Evaluating the symptoms of chronic anemia is not a simple process. In a study48 of adult patients with iron-deficiency anemia and [Hb] of 80120 g/L, there was no correlation between the degree of anemia and the intensity of any of the symptoms of fatigue, irritability, palpitations, dizziness, breathlessness and headache. Furthermore, treatment with iron in amounts sufficient to increase [Hb] an average of 23 g/L resulted in no greater improvement in any of the symptoms than did treatment with a placebo.
The relationship between the degree of anemia and functional status in patients with chronic renal failure was studied by the Canadian Erythropoietin Study Group.49 In a randomized, placebo-controlled study of 118 dialysis patients, investigators examined the effect on quality of life and exercise capacity of 3 levels of anemia: mean [Hb] of 70 g/L (placebo group); mean [Hb] of 100 g/L (low-dose erythropoietin group); and mean [Hb] of 120 g/L (high-dose erythropoietin group). Quality of life, in global terms, was similar in all 3 groups. However, treated patients experienced significant improvement in symptoms (fatigue, depression, physical symptoms), although no difference was noted between the low- and high-dose treatment groups.
In general, otherwise healthy people display few symptoms or signs of anemia at rest when [Hb] is greater than 7080 g/L, although they often show dyspnea with exertion; at 60 g/L most patients will complain of some weakness; at 30 g/L patients will complain of dyspnea at rest; and at [Hb] of 2025 g/L congestive heart failure frequently occurs.50 Children are amazingly tolerant of chronic anemia and may remain asymptomatic even when [Hb] is less than 50 g/L.
Before considering transfusion of red blood cells for the treatment of chronic anemia, it is essential to determine the cause of the anemia so that, where appropriate, treatment other than red blood cell transfusion may be used. Classic examples of anemias that may be severe but correctable by alternative therapies are iron-deficiency anemia in childhood and pernicious anemia in adults.
If red blood cell transfusion is considered necessary for the immediate treatment of a chronic anemia, the goal need not be to attain a normal [Hb] but rather to attain a [Hb] that will avert the danger of inadequate tissue oxygenation or cardiac failure. When red blood cell transfusion is considered for the long-term treatment of chronic anemia, treatment goals (other than to maintain a certain [Hb]) should be determined in advance and assessment of success should be done at an interval (or intervals) appropriate to the underlying condition. In this setting, the physician and the patient must consider such questions as: What symptoms and signs are caused or aggravated by the anemia? Can these symptoms and signs be alleviated by red blood cell transfusions? What is the minimum level of hemoglobin at which the patient can function satisfactorily? Do the potential benefits of red blood cell transfusion outweigh the risks (and possibly the inconveniences) for this patient? In determining the riskbenefit ratio for a given patient, such factors as lifestyle, the presence of other medical disorders, the likely duration of the anemia and the patient's overall prognosis must be considered. For example, a patient may be willing to tolerate a very limited capacity for exertion if the anemia is likely to be temporary, but not if the anemia will be permanent.
In general, the risks per unit of red blood cell transfusion are the same in any setting. However, with the presence of severe chronic anemia, transfusion may lead to congestive heart failure, particularly in the elderly. In such cases, red blood cell transfusions must be administered very slowly and, in some patients, partial exchange transfusion may be performed. The administration of many red blood cell transfusions over a prolonged period will eventually lead to iron overload.
Issues specific to red blood cell transfusion in children
Principles guiding the decision to administer red blood cell transfusions to infants over 4 months of age and children are for the most part the same as for adults. Young children have lower [Hb] than adults -- from 95115 g/L at 6 months of age to 115125 g/L at 2 years. These lower levels are thought to be due to the higher intra-erythrocyte levels of 2,3-DPG found in children.51
The physiologic responses to anemia in childhood and the [Hb] at which transfusion becomes necessary have not been well studied. Two studies in Africa attempted to identify when transfusions should be given to prevent death in children with anemia and malaria. One52 involved 116 children under 5 years of age with mean hematocrit on admission of 0.14 ([Hb] of 47 g/L). Children were randomly chosen to receive or not receive a transfusion of whole blood. There was no difference in hospital admissions and deaths in the "no transfusion" group versus the "transfusion" group. The second was a surveillance study53 in which data were collected over about 12 months on all children under 12 years of age (n = 2433) admitted to the pediatric ward of a Kenyan hospital. Transfusions (with whole blood) were administered according to routine practice and availability. Based on laboratory and clinical criteria, children with clinical signs of respiratory distress and [Hb] of less than 47 g/L who were transfused had a lower fatality rate than those who were not. Among children without respiratory distress there was no association between receipt of blood transfusion and death, irrespective of [Hb] on admission. Although these studies are not definitive, they do support the clinical impression that asymptomatic children without underlying cardiorespiratory disease are able to tolerate very low [Hb] (4050 g/L) provided the anemia has developed slowly.
There are reports of successful outcomes of surgical procedures without the use of blood transfusion in the children of Jehovah's Witnesses. These procedures include open heart surgery in selected patients weighing less than 20 kg.54,55
For acute nonsurgical bleeding, the principles of resuscitation of a child are generally the same as for an adult. However, young infants are less able to tolerate rapid blood loss because of their limited ability to increase myocardial contractility in response to hypovolemia. Young infants rely primarily on increases in heart rate rather than contractility to increase CO. In addition, an apparently small amount of lost blood may be significant in a small child, because it may represent an important fraction of total blood volume (80
90 mL/kg). Therefore, young infants, particularly those under 6 months of age, require earlier and more vigorous volume replacement and possibly earlier red blood cell replacement (e.g., after losses of 2025% of total blood volume versus 3035% in the older infant and child).56
Pediatric patients are more likely than many adults to be long-term survivors; thus, in determining the balance between benefits and risks of transfusion, greater consideration must be given to long-term complications. For example, the transmission of viruses with long incubation periods (e.g., hepatitis C virus) and, for girls, the potential for hemolytic disease of the newborn in future pregnancies should they become alloimmunized to red blood cell antigens are considerations. Nevertheless, untreated chronic and severe anemia can lead to growth retardation in childhood.
Recommendations regarding the transfusion of red blood cells
- A physician prescribing transfusion of red blood cells or plasma should be familiar with the indications for and the benefits and risk from the use of these fractions.
Level of evidence: N/A
- Documentation that supports the administration of the red blood cells or plasma should be found in the patient's chart.
Level of evidence: N/A
- Red blood cell transfusions should be administered primarily to prevent or alleviate symptoms, signs or morbidity due to inadequate tissue oxygen delivery (resulting from a low red blood cell mass).
Level of evidence: II
- There is no single value of hemoglobin concentration that justifies or requires transfusion; an evaluation of the patient's clinical situation should also be a factor in the decision.
Level of evidence: II
- In the setting of acute blood loss, red blood cell transfusion should not be used to expand vascular volume when oxygen carrying capacity is adequate.
Level of evidence II
- Anemia should not be treated with red blood cell transfusions if alternative therapies with fewer potential risks are available and appropriate.
Level of evidence: II
