Introduction
Blood transfusions are common. In 2009, approximately 15 million units of red blood cells were transfused in the United States. Between 60% and 70% of all red blood cell units are transfused in the perioperative setting. Surgical patients are frequently anemic from the underlying disease, from the injury leading to the need for surgery, and from the blood loss associated with the surgical procedure.
Over the past 25 years, the trend has been to use a lower hemoglobin concentration as a transfusion trigger. The main motivation has been concern about blood safety prompted by the human immunodeficiency virus (HIV) epidemic in the 1980s. Fortunately, the risks of transmitting viral infections have become extremely low. The most recent estimates of the risk of residual units of infected blood donated by repeat donors were 1 per 1,149,000 for hepatitis C virus and 1 per 1,467,000 for HIV.
New risks from infections, however, may emerge, such as West Nile virus. Concerns about the rare transmission of variant Creutzfeldt-Jakob disease have led to the increasing use of leukocyte-depleted blood and, in the United States, the elimination of donors who lived in the United Kingdom and Europe. The result of new testing and donor policies is a blood supply that is so safe that it is difficult to measure changes in markers of disease after policy changes. However, noninfectious risks such as transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload may be even more common than previously appreciated.
With the improvement in safety and recently published clinical trials, it is timely to evaluate the evidence that documents when blood transfusion should be administered in the perioperative time period.
Options/Therapies
The indications for red blood cell transfusion are controversial. Most recommendations suggest that the decision to transfuse should be based on individual assessment of signs and symptoms of anemia. However, in practice, most clinicians transfuse at a specific hemoglobin concentration, such as 8 g/dL. Opinions on the indications for transfusion of predeposit autologous blood also vary. Some clinicians argue that the indications should be the same as for allogeneic blood cells, whereas others suggest that because the risk of transfusion is less, autologous blood should be given at higher transfusion thresholds. However, predeposit autologous donation is generally not recommended because it does not reduce the overall exposure to transfusion.
Evidence
Several critical lines of evidence are needed to guide transfusion decisions. First, it is necessary to understand the risks associated with different levels of anemia in the perioperative period. Second, randomized clinical trials are needed to document that transfusion improves outcome. Third, as previously described, the risks of allogeneic and autologous transfusion must also be taken into account. The current data suggest that allogeneic blood transfusion is extremely safe. To determine the efficacy of transfusion, we need to know at what point the risks of anemia increase and whether transfusions will eliminate or reduce the risks.
Risks Associated with Anemia
Studies in patients who refuse blood transfusion for religious reasons provide insights into the risks of anemia during the perioperative period. The largest study included 1958 patients undergoing surgery in the operating room. Mortality rates rose as the preoperative hemoglobin levels fell. Patients with underlying cardiovascular disease, who had a hemoglobin level of 10 g/dL or less, had a higher risk of death than patients without underlying cardiovascular disease ( Figure 22-1 ). An analysis of patients from the same cohort with postoperative hemoglobin levels lower than 8 g/dL found that mortality rates rose when the postoperative hemoglobin level was less than 7 g/dL and became extremely high with postoperative hemoglobin levels below 5 g/dL. These results are consistent with an analysis of mortality and morbidity rates from case reports in Jehovah’s Witness patients.
Studies in volunteers who underwent isovolemic reduction of hemoglobin levels to 5 g/dL also provide insight into the risks of anemia. Two studies found that most transient and asymptomatic electrocardiogram changes occurred in 5 of 87 volunteers when their heart rates were faster and their hemoglobin level was between 5 and 7 g/dL. Other studies in young, healthy volunteers younger than 35 years have identified subtle and reversible cognitive changes at hemoglobin levels between 5 and 7 g/dL and increased fatigue at hemoglobin levels below 7 g/dL. It is uncertain how to apply these results to older patients, although one can surmise that these changes might occur at higher hemoglobin levels.
Large cohort studies have found anemia to be associated with increased mortality and morbidity. In a study of 310,000 veterans 65 years or older undergoing major noncardiac surgery, the 30-day mortality rate rose 1.6% for each percentage point in hematocrit below 39% and above 51%. Similar findings were present in a study of hospitalized patients with community-acquired pneumonia.
Clinical Trials Evaluating Transfusion in Adults
A total of 6264 patients have entered trials evaluating transfusion thresholds, although only two are adequately powered to detect important differences in outcomes. The first large trial is the Transfusion Requirement in Critical Care (TRICC) trial. In this study, 838 volume-resuscitated intensive care unit (ICU) patients were randomly assigned to either a “restrictive” or “liberal” transfusion strategy. The “restrictive” group received allogeneic red blood cell transfusions at hemoglobin levels of 7 g/dL (and levels were maintained between 7 and 9 g/dL), and the “liberal” group received red blood cells at 10 g/dL (and levels were maintained between 10 and 12 g/dL). The restrictive group had lower average hemoglobin levels (8.5 versus 10.7 g/dL) and fewer transfusions (2.6 versus 5.6) compared with the liberal group. The 30-day mortality rate was slightly lower in the restrictive transfusion group (18.7% versus 23.3%), although the finding was not statistically significant ( p = 0.11). The risk of clinically recognized myocardial infarction (0.07% versus 2.9%; p = 0.02) and congestive heart failure (5.3% versus 10.7%; p < 0.001) also occurred less frequently in the restrictive transfusion group. In two subanalyses, patients randomly assigned to the restrictive transfusion group who were younger than 50 years and less ill as defined by Acute Physiology and Chronic Health Evaluation (APACHE) score had a significantly lower mortality rate than patients in the liberal group. In another subanalysis of patients with cardiovascular disease, there were no significant differences in mortality rate, although the confidence intervals were wide (adjusted odds ratio, 1.26; 95% confidence interval, 0.70-2.24). This trial contributed 47% of the patients and 82% of the recorded deaths among all the patients entered into all the trials.
The second trial is Transfusion Trigger Trial for Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair (FOCUS). A total of 2016 patients with a history of cardiovascular disease or risk factors were randomly allocated to liberal transfusion strategy (maintain hemoglobin concentration greater than 10 g/dL) or restrictive transfusion strategy (transfuse if hemoglobin concentration was less than 8 g/dL or if symptoms of anemia developed). The restrictive group received transfusions at a hemoglobin concentration of 7.9 g/dL and the liberal group at 9.2 g/dL. The liberal group received about three times the number of transfusions as the restrictive group. There was no difference between the liberal (35.2%) and restrictive-strategy group (34.7%) for the primary outcome of walking 10 feet or across the room without human assistance at 60 days, and the results were similar at 30 days. In-hospital acute coronary syndrome or death occurred in 4.3% in the liberal and 5.2% in the restrictive groups (absolute risk difference, –0.9%; 99% CI, –3.3 to 1.6), and rates of death on 60-day follow-up were 7.6% and 6.6%, respectively (absolute risk difference, 1.0%; 99% CI, –1.9 to 4.0). The rates of other complications were similar in the two groups. This trial and the pilot study were the only trials to include patient assessment for symptoms of anemia.
Twelve other randomized clinical trials have evaluated the effects of different transfusion thresholds ( Table 22-1 ). The clinical settings and outcomes were different among the studies. The transfusion thresholds varied and overlapped among the “restrictive” or “liberal” strategy.
| Study (Year) | Setting | Subjects: Eligibility and Comparability | Transfusion Strategy | Blood Usage Units/pt Mean (SD)/Median (IQR) | Proportion Transfused (%) ( n ) | Hb/Hct Levels Mean (SD) |
|---|---|---|---|---|---|---|
| Topley (1956) | Trauma ( n = 22) | <1 L blood loss; considered to be at no clinical risk in raising blood volume ≥100% of normal, or allowing it to reach 30% below normal | Liberal: to achieve RBC volume ≥100% of normal Restrictive: maintain RBC volume 70%-80% of normal | Total mean: 11.3 (6.9) Total mean: 4.8 (6.7) | 100 (10) 67 (8) | Lowest Hb: (15.6 ± 2.0) g/dL Lowest Hb: (11.3 ± 0.7) g/dL |
| Blair (1986) | GI bleeding ( n = 50) | Acute severe upper gastrointestinal hemorrhage | Liberal: patients received at least 2 units of PRBCs immediately on admission to hospital Restrictive: patients were not transfused PRBCs during the first 24 hr unless Hb <8.0 g/dL or shock persisted after initial resuscitation with colloid | Total mean: 4.6 (1.5) Total mean: 2.6 (3.1) | 100 (24) 19.2 (5) | Admission Hct: 28 (5.9%) Discharge Hct: 37.0 (7.8%) Admission Hct: 29 (8.2%) Discharge Hct: 37.0 (7.1%) |
| Fortune (1987) | Trauma/acute hemorrhage ( n = 25) | Patients who had sustained a Class III or Class IV hemorrhage and had clinical signs of shock | Liberal: Hct was brought up to 40% slowly over a period of several hours by infusion of PRBCs Restrictive: Hct was kept close to 30% by administration of PRBCs | Not available | Not available | Average Hct for 3-day period: 38.4 (2.1%) Average Hct for 3-day period: 29.7 (1.9%) |
| Johnson (1992) | Cardiac surgery ( n = 38) | Patients undergoing elective coronary revascularization and able to donate at least three units of packed cells preoperatively | Liberal: patients received blood transfusion to achieve Hct value of 32% as long as autologous blood was available Restrictive: patients received transfusion only if Hct value fell below 25% | Total mean: 2.05 (0.93) Total mean: 1.0 (0.86) | 100 (18) 75 (15) | Hct at 4 hr postoperative: 31.3% Hct at 4 hr postoperative: 28.7% |
| Hebert (1995) | Critical care ( n = 69) | Critically ill patients admitted to one of five tertiary-level ICUs with normovolemia after initial treatment who had Hb concentrations < 9.0 g/dL within 72 hr | Liberal: patients were transfused PRBCs if their Hb concentration maintained at 10.0-12.0 g/dL Restrictive: patients were transfused PRBCs only if their Hb was 7.0-7.5 g/dL; Hb concentration maintained at 7.0-9.0 g/dL | Total mean: 4.8 (SD not available) Total mean: 2.5 (SD not available) | Not available | Admission Hb: 9.3 (1.3) g/dL Average daily Hb: 10.9 g/dL Admission Hb: 9.7 (1.4) g/dL Average daily Hb: 9.0 g/dL |
| Bush (1997) | Vascular surgery ( n = 99) | Patients undergoing elective aortic and infrainguinal arterial reconstruction surgery | Liberal: transfused with PRBCs to maintain Hb >10.0 g/dL Restrictive: transfused only if Hb level fell below 9.0 g/dL | Total mean: 3.7 (3.5) Total mean: 2.8 (3.1) | 88 (43) 80 (40) | Hb during 48-hr postoperative period (g/dL): 11.0 (1.2) Hb during 48-hr postoperative period (g/dL): 9.8 (1.3) |
| Carson (1998) | Orthopedic surgery ( n = 84) | Hip fracture patients undergoing surgical repair who had postoperative Hb levels less than 10.0 g/dL | Liberal: patients received one unit PRBCs at the time of random assignment and then as needed to maintain Hb >10.0 g/dL Restrictive: transfusion was delayed until patient developed symptoms or consequences of anemia, or Hb value <8.0 g/dL in absence of symptoms | Total median: 2 (1-2) Total median: 0 (0-2) | 98 (41) 45 (19) | Lowest Hb (g/dL): 9.4 (1.0) Last Hb (g/dL): 10.7 (0.9) Lowest Hb (g/dL): 8.8 (1.2) Last Hb (g/dL): 9.7 (0.9) |
| Hebert (1999) | Critical care ( n = 838) | Critically ill patients admitted to 1 of 22 tertiary-level and 3 community ICUs with normovolemia after initial treatment who had Hb concentrations <9.0 g/dL within 72 hr | Liberal: patients were transfused with PRBCs to maintain Hb concentration at 10.0-12.0 g/dL Restrictive: patients were transfused to maintain Hb concentration at 7.0-9.0 g/dL | Total mean: 5.6 (5.3) Total mean: 2.6 (4.1) | 100 (420) 67 (280) | Mean daily Hb (g/dL): 10.7 (0.7) Mean daily Hb (g/dL): 8.5 (0.7) |
| Bracey (1999) | Cardiac surgery ( n = 428) | Patients undergoing first-time elective coronary revascularization | Liberal: received PRBC transfusions per individual physicians, who considered clinical assessment of patient and institutional guidelines, which propose Hb level <9.0 g/dL as postoperative threshold for PRBC transfusion Restrictive: received PRBC transfusion in postoperative period for Hb level <8.0 g/dL, unless patient experienced blood loss >750 mL since last transfusion; hypovolemia with hemodynamic instability, and excessive acute blood loss, acute respiratory failure, or inadequate cardiac output and oxygenation; or hemodynamic instability requiring vasopressors | Postoperative: 1.4 (1.8) Total: 2.5 (2.6) Postoperative: 0.9 (1.5) Total: 2.0 (2.2) | 48 (104) 35 (74) | Mean net reduction in Hb (admission to discharge): 4.2 (1.9) g/dL Mean net reduction in Hb (admission to discharge): 4.2 (1.7) g/dL |
| Lotke (1999) | Orthopedic surgery ( n = 127) | Patients undergoing primary total knee arthroplasty who were able to donate two units autologous blood preoperatively | Liberal: received their autologous blood immediately after surgery: the first unit in recovery room and the second unit delivered on return to the ward Restrictive: received all autologous blood if Hb level had fallen below 9.0 g/dL | Not available | 100 (65) 26 (16) | Mean postoperative Hb (g/dL): Day 1: 11.4 Day 3: 10.7 Mean postoperative Hb (g/dL): Day 1: 10.6 Day 3: 10.0 |
| Grover (2005) | Orthopedic surgery ( n = 260) | Patients undergoing elective hip and knee replacement surgery | Liberal: received PRBC transfusion when Hb < 10.0 g/dL and to maintain Hb concentration at 10.0-12.0 g/dL Restrictive: received PRBC transfusion when Hb < 8.0 g/dL and to maintain Hb concentration 8.0-9.5 g/dL | Total median: 0 (0-10) Total median: 0 (0-5) | 42.2 (46) 33.9 (37) | Mean postoperative Hb Day 5 (g/dL): 11.1 (0.9) Mean postoperative Hb Day 5 (g/dL): 9.8 (1.2) |
| Colomo (2009) | GI bleeding ( n = 214) | Patients with cirrhosis and acute gastrointestinal bleeding | Liberal: received PRBC when Hb < 9.0 g/dL, to maintain Hb concentration at 9.0-10.0 g/dL Restrictive: received PRBC when Hb < 7.0 g/dL, to maintain Hb concentration at 7.0-8.0 g/dL | Not available | 90.5 (95) 62.4 (68) | Mean Hb (g/dL) at discharge: 10.1 (0.9) Mean Hb (g/dL) at discharge: 9.2 (1.3) |
| Webert (2008) | Oncology ( n = 60) | Patients with acute leukemia receiving induction chemotherapy or undergoing stem cell transplantation | Liberal: received two units PRBC when Hb < 12.0 g/dL Restrictive: received two units PRBC when Hb < 8.0 g/dL | Not available | 93.5 (29) 89.7 (26) | Not available |
| Foss (2009) | Orthopedic surgery ( n = 120) | Patients > 65 years of age admitted for hip fracture | Liberal: received PRBC when Hb < 10.0 g/dL Restrictive: received PRBC when Hb < 8.0 g/dL | Total median: 2 (1-2) Total median: 1 (1-2) | 73.3 (44) 36.7 (22) | Not available |
| Zygun (2009) | Critical care ( n = 30) | Patients admitted to critical care unit with severe traumatic brain injury | Liberal group 1: received two units PRBC when Hb < 9.0 g/dL Liberal group 2: received two units PRBC when Hb < 10.0 g/dL Restrictive: received two units PRBC when Hb < 8.0 g/dL | Not available | Not available | Not available |
| Hajjar (2010) | Cardiac surgery ( n = 502) | Patients admitted to ICU for elective cardiac surgery with cardiopulmonary bypass | Liberal: received PRBC when HCT < 30% at any time from start of surgery to discharge from ICU Restrictive: received PRBC when HCT < 24% | Total median: 2 (1-3) Total median: 0 (0-2) | 78.3 (198) 47.4 (118) | Mean Hb at postoperative day 7 (g/dL): 10.8 (8.9) Mean Hb at postoperative day 7 (g/dL): 9.4 (10.5) |
| So-Osman (2010) | Orthopedic surgery ( n = 619) | Patients undergoing elective hip and knee replacement surgery | Liberal: received PRBC according to “Standard Care,” which differed between hospital sites Restrictive: received PRBC using a “New Transfusion Policy,” that risk-stratified patients according to age and comorbidities | Total mean: 0.86 (1.6) Total mean: 0.78 (1.4) | 39.1 (119) 36.5 (109) | Mean Hb at discharge (g/dL): 11.4 (1.1) Mean Hb at discharge (g/dL): 11.4 (1.1) |
| Carson (2011) | Orthopedic surgery ( n = 2016) | Patients > 50 years of age with cardiovascular disease or cardiovascular disease risk factors who were undergoing surgery for hip fracture and have postoperative Hg < 10.0 g/dL | Liberal: received PRBC when Hb < 10.0 g/dL Restrictive: received PRBC when Hb < 8.0 g/dL or if developed symptoms of anemia | Total median: 2 (1-2) Total median: 0 (0-1) | 96.7 (974) 41.1 (415) | Mean Hb (g/dL): 10.9 (0.9) Mean Hb (g/dL): 9.6 (1.1) |
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