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INTRODUCTION — For many decades, the decision to transfuse red blood cells (RBCs) was based upon the "10/30 rule": transfusion was used to maintain a blood hemoglobin concentration above 10 g/dL (100 g/L) and a hematocrit above 30 percent . However, concern regarding transmission of blood-borne pathogens and efforts at cost containment caused a re-examination of transfusion practices in the 1980s. The 1988 National Institutes of Health Consensus Conference on Perioperative Red Blood Cell Transfusions suggested that no single criterion should be used as an indication for red cell component therapy, and that multiple factors related to the patient's clinical status and oxygen delivery needs should be considered . During the subsequent 30 years, a large body of clinical evidence was generated, resulting in the publication of many guidelines for RBC transfusion in different settings [3-17]. A common theme of these guidelines is the need to balance the benefit of treating anemia with the desire to avoid unnecessary transfusion, with its associated costs and potential harms. This requires considerable diagnostic skill and acumen on the part of physicians ordering transfusions.
As blood transfusion practices are evaluated in randomized trials, we are increasingly able to emphasize clinical trial data, since these data provide the best evidence to guide transfusion decisions.
The indications and thresholds for RBC transfusion in adults will be reviewed here. General aspects of RBC collection, storage, safety, and administration, as well as practices for some special populations, are presented separately.
●Pretransfusion testing – (see "Pretransfusion testing for red blood cell transfusion")
●Practical aspects of administration – (see "Red blood cell transfusion in adults: Storage, specialized modifications, and infusion parameters")
●Pediatric indications – (see "Red blood cell transfusion in infants and children: Indications")
●Surgery/anesthesia issues – (see "Surgical blood conservation: Preoperative autologous blood donation" and "Surgical blood conservation: Blood salvage")
●Trauma/massive transfusion – (see "Massive blood transfusion" and "Initial management of moderate to severe hemorrhage in the adult trauma patient")
●Hematologic disorders – (see "Red blood cell transfusion in sickle cell disease" and "Management and prognosis of the thalassemias")
RATIONALE FOR TRANSFUSION
Role of blood in oxygen delivery — Blood delivers oxygen to the tissues, and the vast majority of oxygen delivered is bound to hemoglobin in RBCs. Thus, anemia has the potential to reduce oxygen delivery. However, most patients are able to increase tissue oxygen delivery by increasing cardiac output over a range of hemoglobin concentrations. The major physiologic considerations relevant to anemic patients are the degree to which oxygen delivery to the tissues is adequate and whether compensatory mechanisms for maintaining oxygen delivery will become overwhelmed or deleterious . (See "Oxygen delivery and consumption".)
Oxygen delivery (DO2) is determined by the formula:
DO2 = cardiac output x arterial oxygen content
In healthy patients, DO2 can be raised by increasing cardiac output (increased heart rate in conscious patients and increased stroke volume in anesthetized patients). In critically ill patients, DO2 may become more dependent on arterial oxygen content, and oxygen utilization may become pathologically dependent upon DO2. This pathologic dependence may be due to elevated arterial lactate concentrations and a change in the slope of the oxygen extraction ratio. Determining what hemoglobin level is adequate in individual clinical scenarios has been the goal of a large number of clinical studies and randomized trials. (See 'Asymptomatic hospitalized patient' below.)
At rest, there is a large reserve in oxygen delivery, since the rate of delivery normally exceeds consumption by a factor of four. Thus, if intravascular volume is maintained during bleeding and cardiovascular status is not impaired, oxygen delivery theoretically will be adequate until the hematocrit falls below 10 percent because greater cardiac output, rightward shift of the oxygen-hemoglobin dissociation curve, and increased oxygen extraction can compensate for the decrease in arterial oxygen content (table 1).
These predictions were confirmed in a study in which healthy resting individuals underwent acute isovolemic reduction of their hemoglobin to 5 g/dL (equivalent to a hematocrit of approximately 15 percent) . Though some individuals did develop electrocardiogram (ECG) changes consistent with myocardial ischemia, there was little evidence of inadequate oxygen delivery, and the fall in hemoglobin was associated with progressive increases in stroke volume and heart rate (and therefore cardiac output), and a progressive reduction in the systemic vascular resistance. Heart rate was found to increase linearly in response to the acute isovolemic anemia . Of note, cognitive function measured by reaction time and immediate memory was impaired when the hemoglobin concentration was reduced to 5 to 6 g/dL .
The oxygen-carrying capacity of blood does not directly reflect the delivery of oxygen to tissues. Although techniques to measure tissue oxygenation are under development, they are not yet ready for clinical use .
The preceding considerations represent the optimal clinical response in healthy adults. However, blood transfusion is usually administered to patients who are ill with underlying comorbidities, and there is concern that compensatory mechanisms may be impaired in critically ill patients, particularly in patients with underlying cardiovascular disease. It has been argued in the past that this might justify prophylactic transfusion to maintain a hemoglobin of 10 g/dL. However, data in favor of this hemoglobin target level are lacking. To the contrary, multicenter randomized controlled trials indicate that compared with a target hemoglobin of 10 g/dL, target hemoglobin values of 7 to 8 g/dL are associated with equivalent or better outcomes in most patient populations. (See 'Transfusion thresholds' below.)
Impact of anemia on morbidity and mortality — While numerous observational studies have shown an association between anemia and increased mortality, it is not clear that correction of anemia will improve mortality. The following studies illustrate the deleterious effect of severe postoperative anemia:
●In a study of 1958 patients who declined blood transfusion for religious reasons, the odds of death rose as the preoperative hemoglobin fell, and the odds of death were much greater in patients with underlying cardiovascular disease .
●In a subset analysis of 300 postoperative patients, a hemoglobin between 7 and 8 g/dL appeared to have no immediate adverse effect on mortality, whereas there was a clear risk of postoperative death when the hemoglobin fell below 7 g/dL . Similar results were observed in a 2014 analysis in 293 patients . The combined 30-day in-hospital mortality for patients with various postoperative hemoglobin levels were :
•7.1 to 8.0 (n = 232) – 0.9 percent
•5.1 to 7.0 (n = 217) – 9.2 percent
•3.1 to 5.0 (n = 101) – 26.7 percent
•≤3.0 (n = 37) – 62.1 percent
●A retrospective database review of 310,311 veterans >65 years of age undergoing non-cardiac surgery evaluated the association of preoperative anemia with mortality or cardiac events . The adjusted odds of death or cardiac events correlated inversely with the preoperative hematocrit. Even mild anemia (HCT 36.0 to 38.9) was associated with a 10 percent increase in events; this rose to a 52 percent increased risk with more severe anemia (HCT 18.0 to 20.9).
While these and other studies suggest that severe anemia is associated with poor outcome, data from randomized trials have shown that more aggressive correction of anemia does not necessarily improve these outcomes [26,27]. Clinical trials are needed to establish whether anemia is merely a marker for more severe underlying disease or a direct cause of poor outcomes.
RISKS AND COMPLICATIONS OF TRANSFUSION — The risks and potential long term complications of RBC transfusion, and strategies to minimize these risks and complications, are discussed separately. These include the following:
●Infection is a risk of transfusion since transfusion-transmitted pathogens (eg, viruses, bacteria, and parasites) can be transmitted if they are present in donor blood and if they escape detection by screening assays. In addition, some studies have reported that transfusion-mediated immunosuppression may lead to increased risk of postoperative bacterial infection, although a 2016 meta-analysis of randomized trials did not find an increased risk of infection . (See "Transfusion-transmitted bacterial infection" and "Risk of HIV from blood transfusion" and "Epidemiology and transmission of hepatitis C virus infection", section on 'Blood transfusion' and "Epidemiology, transmission, and prevention of hepatitis B virus infection", section on 'Transfusion' and "Leukoreduction to prevent complications of blood transfusion", section on 'Complications for which leukoreduction is shown to be beneficial'.)
●Allergic and immune transfusion reactions can occur in any patient, and are more common in multiply-transfused patients. (See "Immunologic transfusion reactions" and "Hemolytic transfusion reactions" and "Transfusion-related acute lung injury (TRALI)".)
●Volume overload is typically a concern in the elderly, small children, and those with compromised cardiac function. (See "Transfusion-associated circulatory overload (TACO)".)
●Hyperkalemia from potassium released from RBCs during blood bank storage is primarily a concern in massive transfusion, impaired renal function, and infants/newborns. (See "Red blood cell transfusion in adults: Storage, specialized modifications, and infusion parameters", section on 'Potassium leakage'.)
●Iron overload becomes a concern after a large number of transfusions for chronic anemia . (See 'Ambulatory patient' below and "Approach to the patient with suspected iron overload", section on 'Transfusional iron overload'.)
Society guidelines — Since 2012, transfusion guidelines have been published by the following societies:
●AABB (formerly the American Association of Blood Banks), 2016 
●United Kingdom National Clinical Guideline Centre, 2016 
●American Society of Anesthesiologists (perioperative blood management), 2015 
●British Committee for Standards in Haematology, 2014 (myelodysplastic syndromes [MDS] management) 
●National Comprehensive Cancer Network (chemotherapy-induced anemia), 2014 
●American College of Physicians (anemia in heart disease), 2013 
●Surviving Sepsis Campaign Guidelines Committee including the pediatric subgroup (sepsis and shock), 2013 
●British Committee for Standards in Haematology (critically ill adults), 2012 
●Patient Blood Management Guidelines: Modules 1-4. National Blood Authority Canberra Australia, 2012 
●Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Anemia in Chronic Kidney Disease, 2012 
Links to some of these guidelines are presented below. (See 'Society guideline links' below.)
In general, the different guidelines have recommended use of a restrictive transfusion threshold of 7 to 8 g/dL. As an example, the 2016 AABB guidelines (which we co-authored) include the following recommendations for hemodynamically stable patients without active bleeding :
●Hemoglobin <6 g/dL – Transfusion recommended except in exceptional circumstances.
●Hemoglobin 6 to 7 g/dL – Transfusion generally likely to be indicated.
●Hemoglobin 7 to 8 g/dL – Transfusion may be appropriate in patients undergoing orthopedic surgery or cardiac surgery, and in those with stable cardiovascular disease, after evaluating the patient’s clinical status.
●Hemoglobin 8 to 10 g/dL – Transfusion generally not indicated, but should be considered for some populations (eg, those with symptomatic anemia, ongoing bleeding, acute coronary syndrome with ischemia, and hematology/oncology patients with severe thrombocytopenia who are at risk of bleeding).
●Hemoglobin >10 g/dL – Transfusion generally not indicated except in exceptional circumstances.
The guidelines also emphasize that the decision to transfuse should not be based only on hemoglobin level but should incorporate individual patient characteristics and symptoms. Clinical judgment is critical in the decision to transfuse; therefore, transfusing RBCs above or below the specified hemoglobin threshold may be dictated by the clinical context. Similarly, the decision not to transfuse RBCs to a patient with a hemoglobin concentration below the recommended thresholds is also a matter of clinical judgment.
A brief comparison of recommendations from 10 clinical guidelines published between 2012 and 2017 is available .
Overview of our approach — Optimal transfusion practice should provide enough RBCs to maximize clinical outcomes while avoiding unnecessary transfusions.
We consider many factors in deciding whether to transfuse patients with anemia, rather than basing the decision solely on the presence or absence of symptoms or on a specified hemoglobin level. The final decision to transfuse should incorporate the clinical status, co-morbidity, and the individual wishes of the patient. The hemoglobin level chosen is based on the results from clinical trials, but clinical judgment is required. It is also important to recognize that lower hemoglobin thresholds have not been tested in most clinical settings and may be tolerated by many patients. This approach is most consistent with the AABB Guidelines, which we coauthored . (See 'Society guidelines' above.)
For most patients, we prefer using a restrictive transfusion strategy (ie, giving less blood; transfusing at a lower hemoglobin level; and aiming for a lower target hemoglobin level) rather than a liberal transfusion strategy (ie, giving more blood; transfusing at a higher hemoglobin level). For most hemodynamically stable medical and surgical patients, we suggest considering transfusion at a hemoglobin of 7 to 8 g/dL, with the threshold based on the value established as safe in the clinical trial with the population that most closely resembles the patient. Some patients may tolerate a lower hemoglobin level (table 2).
Assessment of the post-transfusion hemoglobin level can be performed as early as 15 minutes following transfusion, as long as the patient is not actively bleeding. This practice is based on studies showing a high degree of concordance between values measured 15 minutes after completion of the transfusion versus longer intervals [30,31].
Major exceptions to the use of a threshold of 7 to 8 g/dL, where evidence is insufficient to guide therapy, include the following:
●Symptomatic patients may be transfused at higher hemoglobin levels to treat symptoms. (See 'Symptomatic patient' below.)
●Patients with acute coronary syndromes have not been adequately evaluated in clinical trials and may require higher thresholds for transfusion. (See 'Acute coronary syndrome' below.)
●Threshold-based transfusion is not appropriate for patients requiring massive transfusion, such as in the setting of trauma or serious gastrointestinal bleeding. Rather, estimated blood loss and hemodynamic status should guide transfusion given the delay for hemoglobin to equilibrate and time waiting for hemoglobin levels to be reported. (See "Massive blood transfusion" and "Initial management of moderate to severe hemorrhage in the adult trauma patient".)
●Severe thrombocytopenia in hematology/oncology patients at risk of bleeding.
●Chronic transfusion-dependent anemia.
Our goal of avoiding unnecessary transfusion also guides our practice of transfusing one unit of RBCs at a time, rather than requesting multiple units, for a hemodynamically stable patient who is not actively bleeding [32,33]. Whenever possible, we also initiate or continue treatment of the underlying condition responsible for the anemia.
Our approach of considering a threshold hemoglobin of 7 or 8 g/dL for most patients is supported by a 2016 Cochrane systematic review and meta-analysis of 31 randomized clinical trials comparing higher versus lower transfusion thresholds in 12,587 medical and surgical patients (adults and children) . Trials were included if transfusion was administered on the basis a transfusion trigger, defined as a hemoglobin or hematocrit level below which a blood transfusion was to be given. Most trials compared outcomes in patients transfused at hemoglobin thresholds between 7 and 10 g/dL; specific thresholds differed for each trial. Compared with liberal transfusion strategies (higher thresholds), restrictive strategies (lower thresholds) resulted in the following :
●Decreased probability of receiving a transfusion (43 percent decrease; relative risk [RR] 0.57; 95% CI 0.49-0.65)
●Fewer units transfused per patient (1.30 fewer)
●No difference in 30-day mortality (RR 0.97; 95% CI 0.81 to -1.16) (figure 1)
●No difference in pneumonia rate (RR 0.94; 95% CI 0.80-1.11)
●No difference in functional recovery, or hospital or intensive care length of stay
●No increased risk of myocardial infarction (RR 1.08; 95% CI 0.74-1.60)
Evidence from one real-world practice setting also shows that mortality is not adversely affected by the use of restrictive transfusion. An integrated health care system of 21 community hospitals conducted a review of electronic medical records in 218,056 patients with hemoglobin less than 10 g/dL who were hospitalized before or after institution of restrictive transfusion guidelines [34,35]. The 30-day mortality rate was unaffected by adoption of a restrictive practice (7.8 versus 7.8 percent) despite reduction in the number of units transfused (from 42 to 31 units per 100 patients).
Based on these results, we use a restrictive strategy with a threshold hemoglobin of 7 to 8 g/dL for most hemodynamically stable medical and surgical patients except those with acute coronary syndromes. (See 'Acute coronary syndrome' below.)
In deciding which restrictive threshold to use, we favor applying specific thresholds as closely as possible to the patient population in which they were established in randomized trials, rather than applying a single threshold to all patients (table 2) . This view is based on our recognition that different patient populations may have different clinical features that could potentially affect transfusion outcomes . As an example, a hemoglobin threshold of 7 g/dL may be safer for patients with gastrointestinal bleeding because it reduces portal pressure and decreases the chance of rebleeding, whereas a threshold of 8 g/dL for patients with pre-existing coronary disease may provide better oxygen delivery to a vulnerable myocardium. Similarly, the distinction between using a threshold of 7 g/dL for hemodynamically stable patients in the intensive care unit (ICU) and 8 g/dL for hemodynamically stable medical and surgical patients is based solely on the values used in randomized trials; we do not know if these two populations (ICU and medical/surgical) are biologically distinct and truly have different Hbg requirements.
Symptomatic patient — In some randomized trials of transfusion thresholds, symptoms of anemia were an indication for transfusion regardless of whether the hemoglobin was above the prescribed threshold [38,39]. We agree with the premise that symptomatic anemia should be treated with transfusion in all patients with hemoglobin <10 g/dL, regardless of the hemoglobin level, provided that the symptoms are severe enough and are clearly related to the anemia rather than the underlying condition.
Symptoms of anemia include symptoms of myocardial ischemia, orthostatic hypotension or tachycardia unresponsive to fluid replacement. While exertional symptoms can be helpful in alerting the clinician to the presence of anemia, they are generally not considered indications for red cell transfusion. (See "Approach to the adult patient with anemia", section on 'Signs and symptoms of anemia'.)
Chronic anemia can present with symptoms such as irritability, weakness, and exercise intolerance. These symptoms of anemia are nonspecific and often not considered sufficient indications for transfusion. Decisions on whether to transfuse RBCs to treat fatigue are covered separately. (See "Approach to the adult patient with anemia", section on 'Signs and symptoms of anemia' and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Clinical manifestations'.)
Some patients will not manifest typical anemia symptoms for a variety of reasons (eg, altered mental status, diabetic neuropathy, analgesic therapy). Thus, surrogate measures (eg, ECG changes) may be useful in some situations. When transfusion is used in a symptomatic patient, it is important to determine whether symptoms have improved following the transfusion, because this may guide further decision-making. (See "Red blood cell transfusion in adults: Storage, specialized modifications, and infusion parameters".)
Acute coronary syndrome — The optimal transfusion threshold in the setting of acute coronary syndromes (ACS; ie, acute myocardial infarction [MI], unstable angina) remains unresolved [40,41]. Our practice in patients with ACS is to transfuse when hemoglobin is <8 g/dL and to consider transfusion when the hemoglobin is between 8 and 10 g/dL. If the patient has ongoing ischemia or other symptoms, we maintain the hemoglobin ≥10 g/dL. In a stable, asymptomatic patient, it is unknown when to transfuse, although we tend to maintain a higher hemoglobin level using clinical judgment based on evaluating the patient's symptoms and underlying condition.
Our opinion is based on a lack of clinical trial data that support a lower threshold, and a suggestion from a pilot trial of 110 patients with ACS that a threshold of 10 g/dL is safer in patients with ACS . This trial found that compared with transfusion for a hemoglobin <8 g/dL (restrictive strategy), transfusion to raise the hemoglobin ≥10 (liberal strategy) was associated with greater survival at 30 days (98 versus 87 percent). Other experts, including other authors for UpToDate, prefer to give transfusions only when the hemoglobin is at a slightly lower threshold than is used for some patients in our practice . Evaluation of the transfusion thresholds in this population is ongoing. (See "Overview of the non-acute management of unstable angina and non-ST elevation myocardial infarction", section on 'Red cell transfusion' and "Overview of the non-acute management of ST elevation myocardial infarction", section on 'Red cell transfusion'.)
There is variation in transfusion practice in patients undergoing percutaneous coronary intervention (PCI) . A discussion of transfusion in patients undergoing PCI complicated by periprocedural bleeding is presented separately. (See "Periprocedural bleeding in patients undergoing percutaneous coronary intervention", section on 'Blood transfusion'.)
Asymptomatic hospitalized patient — As described above, for most hemodynamically stable medical and surgical patients, we suggest considering transfusion at a hemoglobin of 7 to 8 g/dL. Some patients will remain asymptomatic from anemia at lower hemoglobin levels; conversely transfusion at higher hemoglobin levels is often appropriate for symptomatic patients and in the setting of an ACS. In addition, threshold-based transfusion may not be appropriate for patients requiring massive transfusion. Discussions surrounding specific clinical scenarios are presented separately. The final decision regarding transfusion must take into account the patient’s wishes and clinical status.
Cardiovascular disease — The decision of whether to transfuse patients with cardiovascular disease should consider the nature of the cardiovascular disorder. As an example, it is possible that patients with ACS require different thresholds for transfusion than do patients with stable coronary artery disease or patients with congestive heart failure .
Pre-existing coronary artery disease — A transfusion threshold of 8 g/dL is supported by subgroup analysis of two randomized transfusion trials that included patients with coronary artery disease; however, use of this threshold is somewhat challenged by a 2016 meta-analysis .
●Patients with pre-existing coronary artery disease were included in the Transfusion Trigger Trial for Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair (FOCUS) trial, which found that compared with a threshold of 10 g/dL, a restrictive transfusion strategy (transfusion at a threshold of 8 g/dL or for symptoms) was not associated with worse outcomes, with the exception of an increase in MI that was marginally statistically significant. (See 'Non-cardiac surgery' below.)
●Patients with coronary artery disease were also included in the Transfusion Requirements in Critical Care (TRICC) trial, which found that compared with a threshold of 10 g/dL, a restrictive strategy (transfusion at a threshold of 7 g/dL) was associated with lower mortality. (See 'Intensive care unit/septic shock' below.)
●A 2016 meta-analysis of selected trials found a higher risk of acute coronary syndrome but not 30-day mortality among patients with cardiovascular disease who received a restrictive transfusion strategy compared with a liberal transfusion strategy . However, the meta-analysis did not include all the relevant trials, and the trials that were included contained patients with acute myocardial infarction and as well as pre-existing cardiovascular disease.
●Another 2016 meta-analysis performed a "context-specific" evaluation, stratifying by patient characteristics and clinical settings. The authors concluded that, with restrictive transfusion, there was an increased risk of a composite outcome in patients undergoing cardiac/vascular procedures and in older adult orthopedic patients . In a second 2017 meta-analysis, older patients were benefited by liberal transfusion . However, both of these analyses predated publication of Transfusion Requirements in Cardiac Surgery III (TRICS III) trial data  (see 'Cardiac surgery' below), which found that restrictive transfusion was safe in cardiac surgery and that older cardiac surgery patients appeared to benefit even more from restrictive transfusion. Thus, the two meta-analyses may be incomplete, and their results should be cautiously interpreted unless confirmed by subsequent meta-analyses.
Based on our evaluation of these data, we consider the threshold of 8 g/dL safe for asymptomatic medical patients with stable coronary artery disease .
Transfusion of symptomatic patients with coronary artery disease is guided by the symptoms and clinical judgment, and the optimal threshold for patients with acute coronary syndromes is unresolved. (See 'Symptomatic patient' above and 'Acute coronary syndrome' above and "Overview of the non-acute management of ST elevation myocardial infarction", section on 'Red cell transfusion'.)
Heart failure — Anemia and heart failure (HF) often coexist for a variety of reasons (eg, cytokine changes, dilutional anemia, medical therapy for HF). Many experts consider anemia to be a surrogate marker for poor prognosis in individuals with HF, rather than a therapeutic target. This idea was supported by a randomized controlled trial of 2278 patients with systolic heart failure and anemia, in which increasing the hemoglobin concentration from 9-12 g/dL to 13 g/dL using erythropoietin did not improve outcomes .
The approach to transfusion (including more restrictive thresholds for asymptomatic individuals and transfusion for symptoms if hemoglobin is <10 g/dL) and other management strategies in patients with heart failure (eg, attention to the volume load from the transfusion) is discussed in detail separately. (See "Approach to anemia in adults with heart failure", section on 'Transfusion'.)
Trauma/massive transfusion — Use of massive transfusion in the critically ill, hemodynamically unstable patient cannot be guided by hemoglobin levels alone and often cannot await interval measurements of hemoglobin. This issue is discussed separately. (See "Massive blood transfusion" and "Initial management of moderate to severe hemorrhage in the adult trauma patient".)
Intensive care unit/septic shock — Restrictive transfusion appears to be safe in medical patients in an intensive care unit (ICU), with the possible exception of patients with ischemic heart disease/acute coronary syndrome.
The use of a threshold of 7 g/dL in hemodynamically stable patients in the ICU is supported by data from the Transfusion Requirements in Critical Care (TRICC) trial . This trial randomly assigned 838 critically ill, euvolemic patients with a hemoglobin less than 9 g/dL within 72 hours of admission to an intensive care unit to a restrictive transfusion strategy (RBCs transfused for hemoglobin concentration <7 g/dL and hemoglobin maintained at 7 to 9 g/dL) or a liberal strategy (RBCs transfused for hemoglobin <10 g/dL and hemoglobin maintained at 10 to 12 g/dL). The mean age was 58, and 82 percent were on mechanical ventilation.
Compared with liberal transfusion, 30-day mortality favored the restrictive strategy but was not statistically significant (23 percent in the liberal group versus 19 percent in the restrictive group). However, 30-day mortality rates were lower with the restrictive strategy in two predefined subgroups:
●Patients who were less severely ill (APACHE II score ≤20; mortality 9 versus 16 percent)
●Patients <55 years of age (mortality 6 versus 13 percent)
In contrast, in patients with ischemic heart disease, there was a reversal in the trend in 30-day mortality, with 30-day mortality in the restrictive strategy arm slightly higher than in the liberal strategy group (26 versus 21 percent) .
Important morbidities were also lower in the restrictive transfusion strategy group as a whole. As examples, rates of myocardial infarction and pulmonary edema were lower in the restrictive group than the liberal strategy group (0.7 versus 2.9 percent and 5.3 versus 10.7 percent, respectively).
The use of a threshold of 7 g/dL was also shown to be safe in patients with septic shock. The Transfusion Requirements in Septic Shock (TRISS) trial randomly assigned 998 patients with septic shock and a hemoglobin level less than 9 g/dL to a restrictive or a liberal transfusion strategy (transfusion at a hemoglobin ≤7g/dL or ≤9 g/dL, respectively) . Consensus criteria for sepsis were used (eg, infection, systemic inflammatory response, hypotension). Transfusions were given as single units of prestorage leukoreduced RBCs. Mortality at 90 days was similar in those transfused with the restrictive and the liberal strategy (43 versus 45 percent; relative risk, 0.94, 95% CI 0.78-1.09). Other outcomes (eg, ischemic events, transfusion reactions, use of vasopressor or inotropic therapy, need for mechanical ventilation) were also similar between the two groups. (See "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Additional therapies'.)
These results demonstrate that a restrictive strategy of RBC transfusion is at least as effective as a liberal transfusion strategy in critically ill patients in the ICU, with the possible exception of patients with underlying ischemic heart disease . (See 'Acute coronary syndrome' above and "Use of blood products in the critically ill", section on 'RBC indications'.)
A trial that randomly assigned 198 patients in the ICU following major abdominal surgery for cancer to transfusion at a hemoglobin threshold of 7 versus 9 g/dL favored the higher threshold . A composite outcome at 30 days composed of all-cause mortality, stroke, myocardial infarction, pulmonary embolism, heart failure, cardiac arrest, septic shock, acute kidney injury, respiratory distress, mesenteric ischemia, and septic shock was less frequent in the liberal group (19 versus 36 patients; 20 versus 36 percent). However, the larger TRICC and TRISS trials in patients in the ICU, and the FOCUS trial in patients undergoing non-cardiac surgery, all favor restrictive transfusion. (See 'Non-cardiac surgery' below.)
Acute bleeding — Acute bleeding is an especially challenging clinical setting in which to evaluate RBC transfusion thresholds. For patients with massive bleeding or who are hemodynamically unstable, transfusion should be guided by hemodynamic parameters (eg, pulse and blood pressure), the pace of the bleeding, and the ability to stop the bleeding, rather than by the hemoglobin. Therefore, the use of transfusion in acutely hemorrhaging patients cannot be based on thresholds. (See "Use of blood products in the critically ill", section on 'Red blood cells' and "Massive blood transfusion" and "Initial management of moderate to severe hemorrhage in the adult trauma patient".)
For patients who are bleeding but hemodynamically stable, some guidance is provided by two randomized trials in patients with upper gastrointestinal bleeding, which have suggested that a restrictive transfusion strategy is safe when there is access to rapid endoscopic treatment. (See "Approach to acute upper gastrointestinal bleeding in adults", section on 'Blood product transfusions'.)
A single center trial randomly assigned 921 patients with acute upper gastrointestinal bleeding to a restrictive or a liberal transfusion strategy (transfusion threshold of 7 g/dL versus 9 g/dL) and determined all-cause mortality at 45 days . Patients with massive bleeding, acute coronary syndrome, history of peripheral vascular disease or stroke, and hemoglobin >12 g/dL were excluded. All patients underwent emergent upper endoscopy within six hours and were treated with endoscopic therapy as needed. When compared with the liberal transfusion threshold, the restrictive transfusion threshold in these bleeding patients resulted in the following:
●A lower percent of patients undergoing transfusion (49 versus 86 percent) and fewer transfusions (mean 1.5 versus 3.7 units)
●Fewer complications (40 versus 48 percent)
●Less subsequent (further) bleeding (10 versus 16 percent; hazard ratio [HR] 0.62; 95% CI 0.43-0.91)
●Fewer deaths due to uncontrolled bleeding (0.7 versus 3.1 percent)
●Fewer deaths from any cause (5 versus 9 percent; HR 0.55; 95% CI 0.33-0.92)
A multicenter cluster trial that randomly assigned 936 patients with acute upper gastrointestinal bleeding to a restrictive or liberal threshold (8 g/dL versus 10 g/dL) found no significant differences in clinical outcomes; fewer transfusions were given in the restrictive group (33 versus 16 percent) .
These studies suggest that in patients with bleeding from other sites (eg, gynecologic, trauma) who are hemodynamically stable; who are not at increased risk for complications (eg, from unstable coronary artery disease); and who have access to rapid surgical intervention, a restrictive transfusion strategy may be safe and might be associated with improved outcomes. Randomized trials to guide transfusion practice in patients with bleeding from other sites are awaited. (See "Management of hemorrhage in gynecologic surgery".)
Non-cardiac surgery — Results of a randomized trial in patients undergoing hip surgery suggest that it is reasonable to use a lower threshold restrictive strategy of 8 g/dL for patients who have undergone surgery, in the absence of symptoms of anemia, even in elderly patients with underlying cardiovascular disease or cardiovascular risk factors.
The optimal transfusion threshold for perioperative transfusion was examined in the Transfusion Trigger Trial for Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair (FOCUS) trial . This trial randomized 2016 patients with preexisting cardiovascular disease or cardiovascular risk factors, to liberal versus restrictive postoperative transfusion after hip repair surgery. All patients were ≥50 years (mean, 82 years) with a postoperative hemoglobin <10 g/dL. The liberal transfusion group received immediate transfusion of one unit of packed RBCs plus subsequent transfusions to raise the hemoglobin level to >10 g/dL whenever it fell below this level. The restrictive transfusion group received single unit transfusions only if they developed symptoms of anemia (defined as chest pain, orthostatic hypotension, tachycardia unresponsive to fluid resuscitation, or congestive heart failure) or, in the absence of symptoms, when the hemoglobin level fell below 8 g/dL.
The primary outcome of the study was death or an inability to walk 10 feet or across a room without assistance at the 60-day evaluation. Secondary outcomes included a combined outcome of in-hospital myocardial infarction, unstable angina, or death; and later death for any reason. Results included the following [38,55]:
●The liberal and restrictive groups had similar rates of death or inability to walk 10-feet unassisted at the 60-day evaluation (35.2 versus 34.7 percent, respectively; OR 1.01; 95% CI 0.84-1.22). Similar results were found at 30-day follow-up.
●The liberal and restrictive groups had similar rates of the composite endpoint of in-hospital acute coronary syndrome or death (4.3 versus 5.2 percent, respectively; OR 0.82; 99% CI 0.48-1.42). Separately, the endpoint of MI was lower in the liberal group (2.3 versus 3.8 percent, OR 0.60; 99% CI 0.30-1.19), while the endpoint of in-hospital death was higher in the liberal group (2.0 versus 1.4 percent, OR 1.44; 99% CI 0.58-3.56).
●Mortality was similar for the liberal and restrictive groups.
•At 60 days, rates of death were 7.6 and 6.6 percent, respectively (OR 1.17; 99% CI 0.75-1.83).
•At approximately three years, rates of death were 43 and 41 percent, respectively (HR 1.09; 95% CI 0.75-1.25).
The causes of death, and the proportion of deaths due to cardiovascular disease, cancer, and infection were comparable between the liberal and restrictive groups.
A systematic review that included this trial and five others in patients with hip fracture came to similar conclusions regarding the safety of a restrictive transfusion strategy in this setting .
Major intraabdominal cancer surgery resulting in a requirement for care in the intensive care unit is a possible exception; however, we do not use liberal transfusion in these patients and await additional trials. (See 'Intensive care unit/septic shock' above.)
Issues related to autologous blood salvage and reinfusion during surgery are discussed separately. (See "Surgical blood conservation: Blood salvage".)
Cardiac surgery — Transfusion thresholds in cardiac surgery have been evaluated in several randomized trials. Together, data from these trials suggest that a restrictive transfusion strategy with a hemoglobin threshold of 7.5 to 8 g/dL appears to be reasonable in patients undergoing cardiac surgery with cardiopulmonary bypass.
●The largest clinical trial conducted is the Transfusion Requirements in Cardiac Surgery III (TRICS III) trial, which randomly assigned 5243 patients undergoing cardiac surgery with cardiopulmonary bypass to transfusion for a hemoglobin of <7.5 g/dL versus a higher level (<8.5 g/dL if on the non-ICU ward or <9.5 g/dL if in the operating room or ICU) . Approximately 60 percent had good left ventricular function; the procedures included coronary artery bypass grafting (CABG), valve surgery, or both. The incidence of a composite endpoint of death, non-fatal myocardial infarction, stroke, or renal failure with dialysis was similar in the restrictive and liberal groups (12.3 versus 12.9 percent; odds ratio [OR] 0.95; 95% CI -2.38-1.27). Mortality was also similar (3.0 versus 3.6 percent; OR 0.85; 95% CI 0.62-1.16). Fewer people in the restrictive group received transfusions (52 versus 73 percent) and people who were transfused received fewer units of blood (2 versus 3 units).
●The Transfusion Indication Threshold Reduction (TITRe2) trial randomly assigned 2007 patients who underwent cardiac surgery to postoperative transfusion for a hemoglobin threshold of <7.5 g/dL versus <9 g/dL . Approximately two-thirds of the patients had underlying coronary artery disease, and the procedures included CABG, valve surgery, or both. The incidence of a composite endpoint of infection or an ischemic event was similar in the restrictive and liberal groups (35 versus 33 percent). In secondary analyses, there were more deaths at 90 days in the restrictive group (4.2 versus 2.6 percent); however, the 30 day mortality was similar (2.6 versus 1.9 percent) as was the incidence of pulmonary complications (13 versus 12 percent). Transfusions were significantly reduced with the restrictive strategy (median 1 versus 2 units per patient; transfusion avoided in 36 versus 5 percent); and transfusion costs were lower with restrictive transfusion (median savings, approximately £140 [USD $200]).
●Another trial randomly assigned 428 consecutive patients undergoing CABG to postoperative transfusion at a hemoglobin <8 g/dL versus <9 g/dL . There was no difference in morbidity, mortality, or self-assessment for fatigue or anemia between the two groups. Postoperative transfusion rates were significantly lower for the group with the lower transfusion threshold (0.9 versus 1.4 RBC units/patient), amounting to a savings of 500 RBC units per 1000 CABG procedures.
●A fourth trial randomly assigned 502 consecutive patients who underwent cardiac surgery with cardiopulmonary bypass to a liberal or restrictive transfusion strategy (to maintain hematocrit at 30 or 24 percent respectively) throughout surgery and the postoperative period (Transfusion Requirements After Cardiac Surgery; TRACS) . The primary outcome was a composite endpoint of 30-day all-cause mortality, cardiogenic shock, acute respiratory distress syndrome, or acute renal injury requiring dialysis or hemofiltration. There was no difference in this composite endpoint between the groups (10 percent liberal versus 11 percent restrictive). Independent of transfusion strategy, the number of transfusions correlated with clinical complications and death (HR 1.2 for each unit transfused).
●A fifth trial randomly assigned 722 cardiac surgery patients to liberal or restrictive transfusion threshold (hematocrit of 28 or 24 percent) and found no differences in a composite endpoint of postoperative in-hospital morbidity and mortality .
Based on these trials, a restrictive transfusion threshold (ie, to maintain the hemoglobin above 7.5 or 8 g/dL or the hematocrit above 21 or 24 percent) appears to be reasonable in this population. This issue is discussed in more detail separately. (See "Early noncardiac complications of coronary artery bypass graft surgery", section on 'Blood transfusion'.)
Chronic kidney disease — Management of anemia in patients with chronic kidney disease is complex. Discussion of transfusion and alternatives to transfusion (eg, erythropoietin, iron) in this setting are presented separately. (See "Treatment of anemia in hemodialysis patients" and "Anemia and the renal transplant recipient", section on 'Therapy' and "Treatment of iron deficiency in nondialysis chronic kidney disease (CKD) patients".)
Ambulatory patient — Symptoms from chronic anemia in ambulatory (ie, non-hospitalized) patients differ from those caused by acute decreases in hemoglobin concentration in hospitalized patients, because there is time for compensatory mechanisms to occur. The optimal transfusion threshold in ambulatory patients has not been studied.
Some patients with chronic anemia (eg, from bone marrow failure syndromes) may be dependent upon RBC replacement over a period of months or years, which can lead to iron overload. Approximately 200 mg of iron are delivered per unit of RBC; this iron is released when hemoglobin from the transfused RBCs is metabolized after red cell death. Chelating therapy is recommended after transfer of approximately 10 to 20 red cell units in patients who are anticipated to require ongoing red cell transfusion support . (See "Approach to the patient with suspected iron overload", section on 'Transfusional iron overload'.)
RBC transfusion in patients with acquired or congenital hemolytic anemia is more complex, because transfusion also suppresses erythropoiesis. This issue is discussed separately. (See "Warm autoimmune hemolytic anemia: Treatment", section on 'Red blood cell transfusion' and "Red blood cell transfusion in sickle cell disease".)
Erythropoietin treatment may be an alternative to chronic transfusion for some ambulatory patients. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer" and "Treatment of anemia in nondialysis chronic kidney disease" and "Hyporesponse to erythropoiesis-stimulating agents (ESAs) in chronic kidney disease" and "Surgical blood conservation: Preoperative autologous blood donation", section on 'Role of erythropoietin'.)
Oncology patient — There are two major groups of oncology patients for whom transfusion may be indicated:
●Patients undergoing myelosuppressive chemotherapy
●Patients with terminal cancer receiving palliative care
The approach to blood transfusion may differ for these groups depending on the goals of therapy.
In treatment — There are no randomized trials comparing transfusion thresholds in patients undergoing cancer therapy (eg, with chemotherapy-induced anemia). Pending such trials, patients undergoing cancer therapy with curative intent should be transfused similarly to other medical patients, with transfusion for symptoms and consideration of a threshold hemoglobin of 7 to 8 g/dL in the absence of symptoms. (See 'Asymptomatic hospitalized patient' above and 'Ambulatory patient' above.)
Palliative care — Small observational studies have shown that transfusion offers symptom relief to patients with advanced cancer [61,62]. A Cochrane Database review found no randomized trials of transfusion in patients with advanced cancer, and 12 observational studies that included 653 patients . These studies showed that anemic individuals had subjective responses in symptoms that ranged from 31 to 70 percent. However, receiving unnecessary transfusions takes time away from other activities. Thus, we believe the use of transfusion in oncology patients should be made on a case-by-case basis. (See "Overview of managing common non-pain symptoms in palliative care", section on 'Fatigue'.)
Patients under hospice care continue to receive treatments that improve their comfort and quality of life. Contrary to popular misconceptions, hospice care does not exclude the use of RBC transfusion to alleviate symptoms. However, the hospice model of care in the United States addresses the costs associated with transfusion differently from other benefits. Thus, patients who are benefitting from transfusion near the end of life should determine which specific benefits are available from their hospice provider. (See "Hospice: Philosophy of care and appropriate utilization in the United States", section on 'Common questions and misperceptions about hospice' and "Hospice: Philosophy of care and appropriate utilization in the United States", section on 'Limitations'.)
HOSPITAL-WIDE OVERSIGHT PROGRAMS — Many hospitals have developed general guidelines for the appropriate use of blood transfusion, and an "implementation blueprint" for establishing a patient blood management program has been published by members of the High Value Practice Academic Alliance . A patient blood management program uses "an evidence-based multidisciplinary approach to optimizing the care of patients who might need transfusion." Patient blood management programs "include interventions taken early in the preparation of medical and surgical patients for treatment, as well as techniques and strategies in the preoperative, operative, and postoperative periods or completion of treatment" . Three pillars of this type of program include optimizing hematopoiesis, minimizing blood loss and bleeding, and harnessing and optimizing tolerance of anemia .
Two components of patient blood management offer the greatest opportunity to reduce blood use:
●Since preoperative anemia is strongly associated with increased risk of transfusion in surgical patients, it is important to screen for anemia early enough prior to surgery to have time to evaluate the cause of anemia and treat it if possible .
●Use of a restrictive transfusion approach reduces blood transfusion for those who do not need it.
In addition to these approaches, some other techniques that may reduce blood use include stopping drugs that impair hemostasis (ie, aspirin) when possible, and using meticulous surgical technique.
We are in favor of such programs, because they attempt to reduce unnecessary transfusion (and may reduce costs) . However, such programs and broad guidelines should not supersede clinical judgment in decisions regarding transfusion, especially by clinicians who are familiar with the individual patient. As an example, if a patient is experiencing symptoms that are known to reflect cardiac ischemia in that individual, transfusion may be appropriate. Alternatively, if a patient is known to tolerate a lower hemoglobin than that specified in the guideline, then it may be possible for that patient to avoid transfusion.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anemia in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Blood donation and transfusion (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Anemia is associated with adverse clinical outcomes. However, randomized clinical trials are required to establish if transfusion is beneficial or harmful in anemic patients. (See 'Rationale for transfusion' above.)
●There is excellent clinical trial evidence that suggests that a restrictive policy of transfusion at a hemoglobin concentration of 7 to 8 g/dL should guide transfusion decisions in most patients. The use of transfusion thresholds that restrict transfusion to this hemoglobin concentration are safe in most patient populations, may improve clinical outcomes, and will reduce unnecessary transfusion (table 2). (See 'Rationale for transfusion' above and 'Overview of our approach' above and 'Society guidelines' above.)
●All patients should be assessed clinically when transfusion is considered. If the patient is stable, transfusion may not be needed even when the hemoglobin level is 7 to 8 g/dL. (See 'Symptomatic patient' above.)
●For most medical and surgical hospitalized hemodynamically stable patients, including those in the intensive care unit or with septic shock, we recommend transfusion to maintain the hemoglobin at >7 g/dL rather than a higher threshold (Grade 1B); however there may be cases in which the patient is asymptomatic at a hemoglobin of 7 g/dL, and clinician judgment may support not administering a transfusion. (See 'Overview of our approach' above and 'Intensive care unit/septic shock' above.)
●For patients with underlying cardiovascular disease, undergoing orthopedic surgery, or cardiac surgery, as well as ambulatory patients, we recommend blood transfusion to maintain the hemoglobin at ≥7 to 8 g/dL rather than 10 g/dL, with the threshold based on the value established as safe in the clinical trial that most closely resembles the patient (Grade 1B); however, there may be cases in which the patient is asymptomatic at a hemoglobin <8 g/dL, and clinician judgment may support not administering a transfusion. (See 'Overview of our approach' above and 'Asymptomatic hospitalized patient' above and 'Ambulatory patient' above.)
Exceptions include the following:
•Symptomatic patients with hemoglobin <10 g/dL should be transfused to improve hemodynamic instability and symptoms of myocardial ischemia. (See 'Symptomatic patient' above.)
•For patients with acute coronary syndromes, we use an individualized approach. We transfuse when the hemoglobin is <8 g/dL; we consider transfusion when the hemoglobin is between 8 and 10 g/dL; and we maintain the hemoglobin ≥10 g/dL in the patient with symptoms or ongoing ischemia. In a stable, asymptomatic patient, it is unknown when to transfuse, although we tend to maintain a higher hemoglobin level based on evaluating the patient's symptoms and underlying condition. Other experts, including other authors for UpToDate, prefer a slightly lower hemoglobin threshold for transfusion in this population. (See 'Acute coronary syndrome' above and "Overview of the non-acute management of ST elevation myocardial infarction", section on 'Red cell transfusion' and "Overview of the non-acute management of unstable angina and non-ST elevation myocardial infarction", section on 'Red cell transfusion'.)
•Patients requiring massive transfusion (eg, from trauma or ongoing bleeding) often cannot be managed using hemoglobin thresholds. This issue is discussed separately. (See "Massive blood transfusion" and "Initial management of moderate to severe hemorrhage in the adult trauma patient".)
•Severe thrombocytopenia in hematology/oncology patients at risk of bleeding
•Chronic transfusion-dependent anemia
●Transfusion may be appropriate in the palliative setting. Some hospice programs provide blood transfusion for comfort and symptom relief. (See 'Palliative care' above.)
●Transfusion of one unit of red blood cells (RBCs) at a time is reasonable for hemodynamically stable patients, with assessment of symptoms immediately after transfusion and post-transfusion hemoglobin levels, which can be done as early as 15 minutes and as late as 24 hours after transfusion. (See 'Overview of our approach' above.)
●Hospital-wide patient blood management programs may be helpful in guiding transfusion practices and reducing unnecessary transfusions, but they should not supersede clinical judgment. (See 'Hospital-wide oversight programs' above.)
●Risks and complications of transfusion are discussed separately. (See 'Risks and complications of transfusion' above.)
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