To Transfuse or Not Transfuse
SPECIAL FEATURE
By Eric C. Walter, MD, MSc
Pulmonary and Critical Care Medicine, Northwest Permanente and Kaiser Sunnyside Medical Center, Portland
Dr. Walter reports no financial relationships relevant to this field of study.
BACKGROUND
In 1818, James Blundell performed the first successful human blood transfusion in a woman with postpartum hemorrhage.1 Nearly 200 years later, about 15 million red blood cell (RBC) units are transfused annually in the United States.2 Many of these transfusions occur in the intensive care unit (ICU), where up to 30-50% of patients are transfused.3-5 Despite the frequency of RBC transfusions, there is little evidence that transfusions benefit patients. There have been no randomized, controlled trials demonstrating that RBC transfusions save lives. The expected benefits from transfusions have largely been extrapolated from very early successes treating massive hemorrhage in obstetric and trauma patients, where transfusions were truly lifesaving.6 Today, most patients are transfused for anemia, not hemorrhage, and assuming patients today will have the same benefit is overly optimistic.5
The primary argument for RBC transfusion is to improve oxygen delivery (DO2). When oxygen consumption (VO2) exceeds DO2, tissue ischemia will develop. DO2 is the product of cardiac output (CO) and arterial oxygen content (CaO2):
DO2 = CO × CaO2
CaO2 is comprised of oxygen bound to hemoglobin (Hb) and oxygen dissolved in plasma:
CaO2 = (SaO2 × Hb × constant)
+ (PaO2 × constant)
Where SaO2 is the hemoglobin oxygen saturation, Hb is the hemoglobin concentration, and PaO2 is the partial pressure of oxygen in arterial blood.6 Under most circumstances, the amount of oxygen bound to Hb far exceeds the amount of oxygen dissolved in plasma. Therefore, it makes intuitive sense that by increasing a patient's Hb concentration, CaO2 will increase and in turn DO2 will increase. However, evidence that improving DO2 leads to better tissue perfusion and less ischemia is lacking. This is in part because under normal conditions about 4-5 times more oxygen is delivered than consumed, providing a wide margin of safety.6,7 Even in anemic patients, DO2 is so much greater than VO2 that most patients are not at risk for tissue ischemia and may not experience benefit from the additional oxygen carrying capacity provided by additional RBCs.6
In addition to a potential lack of benefit, RBC transfusions are costly and have both known and unknown risks. Since the first reports of HIV transmission in 1982, the fear of infection has dominated the discussion of transfusion risks. The first question many patients will ask prior to consenting for a transfusion is what is their risk of contracting HIV or hepatitis. Physicians will often assuage patients' fears by accurately informing them that given today's screening protocols, the risk of viral infection transmitted via RBC transfusion is quite rare. Estimated risks of transfusion-related infection are currently < 1 in 1 million for HIV and hepatitis C and approximately 1 in 350,000 for hepatitis B, on par with the risk of dying in an airplane crash or being killed by lightning.2 Often not discussed are more common and at times serious transfusion-associated risks. Fever and transfusion-associated cardiac overload occur in about 1-8 out of every 100 transfusions. The risk of transfusion-related acute lung injury is about 1 in 10,000 and life-threatening reactions occur in about 1 in 140,000 transfusions.2
Given unproven benefits and potential risks, a number of recent studies have compared "restrictive" and "liberal" transfusion strategies. A restrictive strategy delays transfusion until a lower Hb threshold is reached (usually a Hb of < 7 g/dL). A liberal strategy permits transfusion at a higher Hb threshold (usually a Hb of 9 or 10 g/dL). Several of the more notable transfusion strategy studies will be reviewed here and are summarized in the Table.
Patient population
Hb threshold (g/dL)
Patients transfused (%)
Notable inclusion criteria
Notable exclusion criteria
Primary outcome
Additional information
Intensive care (TRICC)8
7 vs 10
67 vs 99
ICU patients age ≥ 16 years who were considered to have euvolemia
Active blood loss or post-op from cardiac surgery
No difference in 30-day all-cause mortality (18.7% vs 23.3%)
30-day all-cause mortality was lower for the subgroups of patients with APACHE II score ≤ 20 and patients < 55 years
Cardiothoracic surgery (TRACS)9
8 vs 10
47 vs 78
Patients ≥ 18 years undergoing elective CABG or valve replacement surgery
Aortic procedures, preoperative Hb < 10 g/dL
No difference in composite outcome of 30-day all-cause mortality or severe comorbidity (11% vs 10%)
Number of transfused RBC units was an independent risk factor for clinical complications
Post hip fracture repair (FOCUS)10
8 vs 10
41 vs 97
Age ≥ 50 years undergoing hip fracture repair with clinical evidence or risk factors for cardiovascular disease
Acute MI within 30 days, symptoms of anemia, or active bleeding
No difference in composite outcome of death or inability to walk without human assistance at day 60 (34.7% vs 35.2%)
No difference in 60-day all-cause mortality (6.6% vs 7.6%)
Acute upper GI bleeding11
7 vs 9
49 vs 86
Age > 18 years with hematemesis, melena,
or both
Massive exsanguinating bleeding, acute coronary syndrome, stroke, lower GI bleeding
45-day all-cause mortality was significantly lower in the restrictive strategy group (5% vs 9%)
Risk of death was reduced among both patients with and without portal hypertension
Abbreviations: ICU = intensive care unit; APACHE = Acute physiology and chronic health evaluation; CABG = coronary artery bypass grafting; Hb = hemoglobin; RBC = red blood cell; MI = myocardial infarction; GI = gastrointestinalTRANSFUSION STRATEGY TRIALS
Of most relevance to ICU physicians was the landmark Transfusion Requirements in Critical Care (TRICC) trial, published in 1999.8 Hebert and colleagues randomized more than 800 euvolemic ICU patients with a Hb ≤ 9.0 g/dL to a restrictive or liberal transfusion strategy. Patients randomized to the restrictive strategy were transfused only if the Hb was < 7 g/dL, with a goal between 7-9 g/dL. Patients randomized to the liberal strategy were transfused for a Hb < 10 g/dL, with a goal of 10-12 g/dL. Notable exclusions were active blood loss or admission following a routine cardiac surgical procedure. Patients in the restrictive group were transfused on average three red-cell units per patient less than those in the liberal group. Furthermore, 33% of patients in the restrictive group were never transfused compared to 0% of patients in the liberal group.
Death from all causes at 30 days was the primary outcome and occurred less frequently among patients in the restrictive compared to the liberal group (18.7% vs 23.3%, respectively; 95% confidence interval [CI], -0.84 to 10.2%; P = 0.11). While this primary outcome did not quite reach statistical significance demonstrating increased mortality with a liberal transfusion strategy, the results strongly suggested no benefit to a liberal transfusion strategy. Furthermore, a restrictive transfusion strategy did significantly reduce the rate of death in two a priori-defined subgroups: younger patients (age < 55 years) and patients with lower illness severity (APACHE II score ≤ 20). For patients < 55 years old, mortality was 5.7% in the restrictive group compared to 13% in the liberal group (95% CI, 1.1-13.5%; P = 0.028). For patients with lower illness severity, mortality was 8.7% vs 16.1% for the restrictive and liberal groups, respectively (95% CI, 1.0-13.5%; P = 0.03). The authors also looked at a third a priori subgroup; patients with cardiac disease. Even among patients with cardiac disease, there was no measurable benefit for a more liberal transfusion strategy (30-day mortality was 20.5% in the restrictive group vs 22.9% in the liberal group). The authors concluded that among critically ill patients, a threshold for RBC transfusion of 7 g/dL was as effective, and possibly superior, to a threshold of 10 g/dL.
Criticisms of this trial have been that transfused blood was not leukocyte reduced, as is now commonplace. The presence of leukocytes may have led to a more inflammatory reaction in transfused patients and may have explained some differences in outcomes. Additionally, despite the fact that no differences in outcome were seen among patients with cardiac disease, there may have been selection bias as few patients with cardiac disease were enrolled. Finally, only patients who were euvolemic and not actively bleeding were enrolled.
Following the TRICC trial, two subsequent trials addressed the lingering question of transfusion strategies in patients with cardiac disease. The Transfusion Requirements After Cardiac Surgery (TRACS) trial was published in 2010.9 The trial enrolled 502 consecutive patients following coronary artery bypass grafting or cardiac valve surgery with cardiopulmonary bypass. Patients were randomized to either a restrictive (to maintain a hematocrit of ≥ 24%) or liberal (hematocrit ≥ 30%) transfusion strategy. Similar to the TRICC trial, patients in the restrictive group received fewer blood transfusions. There was no difference in the composite endpoint of 30-day mortality and severe comorbidity (cardiogenic shock, acute respiratory distress syndrome, or acute renal failure requiring dialysis or hemofiltration) between groups (11% restrictive vs 10% liberal; P = 0.85).
The following year, the FOCUS trial was published.10 FOCUS compared a restrictive and liberal transfusion strategy in just over 2000 patients age ≥ 50 years with clinical evidence or risk factors for cardiovascular disease who had undergone surgery to repair a hip fracture. Patients were not critically ill, but they were a high-risk population with a mean age of 81 years. The transfusion trigger for the restrictive group was "symptoms of anemia or at physician discretion for a Hb < 8 g/dL" vs a Hb < 10 g/dL for the liberal group. Once again, a restrictive transfusion strategy was equivalent to a liberal strategy with no difference in the primary outcome of death or mobility at 60 days (35.2% restrictive vs 34.7% liberal; P = 0.90).
A trial published in early 2013 addressed transfusion strategies in patients with severe acute upper gastrointestinal bleeding.11 Patients were randomized to either a transfusion trigger of Hb < 7 g/dL (restrictive) or Hb < 9 g/dL (liberal). Nearly half of the patients (49%) had peptic ulcer bleeding, 31% had cirrhosis, and 21% had esophageal varices. Thirty percent of patients had signs of hypovolemic shock (systolic blood pressure < 100 and heart rate > 100). All patients were transfused leukocyte-reduced RBCs. Remarkably, a restrictive transfusion strategy was associated with a 45% relative-risk reduction in death at 45 days (95% CI, 0.33-0.92; P = 0.02). Patients in the restrictive-strategy group also had less rebleeding, transfusion reactions, pulmonary edema, and a shorter hospital length of stay. The decrease in risk of death was primarily due to a decrease in deaths from bleeding that could not be successfully controlled.
The authors suggested that transfusions may counteract normal hypovolemia-induced splanchnic vasoconstriction leading to an increase in blood flow that may impair clot formation.11 Transfusion may also cause abnormalities in coagulation properties. These results are compelling and coupled with previous trials, strongly argue for a restrictive RBC transfusion strategy in most patients, even in the setting of acute bleeding. However, it is important to note some limitations of this study. Patients with "massive exsanguinating bleeding" were excluded. Moreover, all patients had emergency gastrostomy within 6 hours. In settings where this is not possible, bleeding control may take longer to obtain and results could be different. Furthermore, outcomes among patients with more severe shock were not described. The accompanying editorial recommended that while most patients with upper gastrointestinal bleeding, with or without portal hypertension, should only be transfused for a Hb < 7 g/dL, it is probably reasonable to transfuse patients with marked hypotension at higher Hb levels.12
CONCLUSION
Too often, critical care practitioners have been faced with apparent practice-changing studies only to find that results are not replicated in subsequent studies — stress-dose steroids and tight insulin control come to mind. In contrast, with respect to transfusion strategies, repeated studies in different populations have consistently shown the same direction of effect and conclusions: restrictive transfusion strategies are either no worse, and probably superior, to liberal strategies. In addition to the studies reviewed here, similar results have been seen in patients with moderate-to-severe head injury13 and in several pediatric populations.14 These data have been accepted by numerous professional societies worldwide, and a restrictive RBC transfusion strategy is supported by many published clinical guidelines worldwide.2,3,6,7 While there are slight variations, most guidelines recommend a transfusion threshold of Hb of 7 g/dL for most critically ill patients. A threshold of 7 g/dL should also be used in most patients presenting with acute upper gastrointestinal bleeding. In patients with cardiac disease, a threshold of Hb of 8 g/dL may be reasonable, especially if there are signs of anemia.
Of course, clinical decision making needs to be applied whenever RBC transfusions are being considered. A Hb concentration by itself should never be used as the sole determinant of when to transfuse. However, when clinicians are considering transfusion, the benefits of a restrictive transfusion strategy should not be overlooked. Fewer transfusions equate to less cost, fewer patients exposed to the potential harms of RBC transfusion, and potentially decreased morbidity and mortality.
REFERENCES
- American Red Cross; 2013. http://www.redcrossblood.org/learn-about-blood/history-blood-transfusion. Accessed November 24, 2013.
- Carson JL, et al. Red blood cell transfusion: A clinical practice guideline from the AABB. Ann Intern Med 2012;157:49-58.
- Retter A, et al. Guidelines on the management of anaemia and red cell transfusion in adult critically ill patients. Br J Haematol 2013;160:445-464.
- Corwin HL, Carson JL. Blood transfusion when is more really less? N Engl J Med 2007;356:1667-1669.
- Vincent JL, et al. Anemia and blood transfusion in critically ill patients. JAMA 2002;288:1499-1507.
- Shander A, et al. A new perspective on best transfusion practices. Blood Transfus 2013;11:193-202.
- Goodnough LT, et al. Concepts of blood transfusion in adults. Lancet 2013;381:1845-1854.
- Hebert PC, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999;340:409-417.
- Hajjar LA, et al. Transfusion requirements after cardiac surgery: The TRACS randomized controlled trial. JAMA 2010;304:1559-1567.
- Carson JL, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med 2011;365:2453-2462.
- Villanueva C, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 2013;368:11-21.
- Laine L. Blood transfusion for gastrointestinal bleeding. N Engl J Med 2013;368:75-76.
- McIntyre LA, et al. Effect of a liberal versus restrictive transfusion strategy on mortality in patients with moderate to severe head injury. Neurocrit Care 2006;5:4-9.
- Secher EL, et al. Transfusion in critically ill children: An ongoing dilemma. Acta Anaesthesiol Scand 2013;57:684-691.
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