Author: Brit Long, MD (@long_brit, EM Staff Physician at SAUSHEC, USAF) and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) // Edited by Erica Simon, DO, MHA (@E_M_Simon, EM Chief Resident at SAUSHEC, USAF)
Numerous studies have identified anemia, defined as a hemoglobin (Hgb) less than 12g/dL in females and less than 13g/dL in males, as associated with a poor prognosis in trauma patients, post-operative patients, the elderly, and the critically ill.1-9 Today anemia affects nearly 90% of ICU patients, with approximately 30% possessing a Hgb less than 9 g/dL, and 70% a Hgb less than 12 g/dL upon admission.10-12 For more than one hundred years, the transfusion of red blood cells (RBCs) has been a standard of care for the management of anemia. Approximately 14.5 million units of RBCs are transfused annually in the U.S., with 40% of critically ill patients receiving an average of 2-5 units per hospitalization.13-15
There are multiple etiologies of anemia in the setting of trauma, chronic disease, and critical illness: active hemorrhage, blunted erythropoietin production, inflammatory cytokine production, increased hepcidin levels (resulting in hepatocyte and macrophage iron trapping), iron deficiency, and anemia secondary to underlying disease processes.17
What threshold is used for transfusion?
The question for emergency medicine providers ultimately revolves around the threshold for transfusion. RBC transfusion can increase oxygen delivery and address symptoms related to anemia; however, transfusion may result in fluid overload, transfusion reaction, immunomodulation, multiple organ dysfunction, hypothermia, and coagulopathy.17
Previously, the accepted indications for transfusion were a Hgb ≤ 10 g/dL or hematocrit (Hct) < 30%.15,17-19 Given this publicized metric, transfusions were historically administered to asymptomatic patients in an effort to target the aforementioned Hgb goal (a liberal transfusion strategy). However, recent studies have questioned this liberal transfusion threshold in the setting of sepsis, gastrointestinal (GI) bleeding, ACS (acute coronary syndrome), and trauma, touting the adverse events/reactions associated with transfusions as detailed above.
Today there is little debate regarding the necessity for blood product transfusion in the hemodynamically unstable, critically ill patient with a low Hgb and Hct. In alternative clinical scenarios, however, we often times operate within a gray area. The goals of this post are to provide a summary of the physiologic effects of RBC transfusions, detail inherent properties of donor RBCs, describe RBC products available for transfusion in the U.S., review notable adverse reactions associated with transfusions, and provide evidence-based indications for RBC transfusions in a number of clinical scenarios.
Physiologic Effects of RBC Transfusion
Oxygenation is dependent on Hgb concentration, Hgb saturation, oxygen supply, cardiac output, and pulmonary ventilation and perfusion.
Peripheral oxygen delivery occurs predominantly through attachment to Hgb. 20,21 In a healthy adult, the daily production of RBCs is 0.25/kg, with an average RBC lifespan of 120 days.22 While there exists a significant oxygen reservoir (the rate of oxygen delivery exceeds that of oxygen consumption by a factor of four), decreases in Hgb level may manifest as symptoms ranging from shortness of breath to chest pain to syncope.
In the setting of anemia, the body demonstrates a number of physiologic compensatory methods:
- Increased cardiac output improves end organ perfusion and increases the circulation of intravascular vasodilators which in turn results in increased time for oxygen off-loading. 20,21,23
- Alterations in gene transcription and expression lead to increased levels of 2,3-diphosphoglycerate (2,3-DPG) thereby improving peripheral oxygen off-loading.20,21,2
Transfusion of RBCs serves as a mechanism of improving peripheral oxygen delivery.
Inherent Properties of Donor RBCs
Unlike native RBCs, transfused RBCs have a lifespan of approximately 60 days.22 Transfusion of one unit of RBCs increases Hgb by 1 g/dL and Hct by 3%, however, these levels may not be reached in the setting of occult bleeding, repeated laboratory draws, fever, hypersplenism, immunologic disease, or hemolysis.22-26
Effect of Product Age
While the majority of documented transfusions occur within 16-21 days of processing/storage, regulations allow the storage/utilization of PRBC products for up to 42 days. 11,12 As a consequence of the preservation process, RBCs experience changes in cell wall integrity, and exhibit decreased 2,3-DPG. In fact, levels of 2,3-DPG are depleted within 2 weeks of storage, thereby reducing the aforementioned ability of releasing oxygen to peripheral tissues (decreased 2,3-DPG shifts the oxygen binding-dissociation curve to the left).27-36
A 2008 study in the New England Journal of Medicine demonstrated that in patients undergoing cardiac procedures, administration of products stored for a prolonged period vs. short duration (20 days vs. 11 days) was associated with increased mortality (2.8% vs. 1.7%, P=0.004), increased rate of intubation beyond 72 hours (9.7% vs. 5.6%, P<0.001), increased incidence of renal failure (2.7% vs. 1.6%, P=0.003), and increased incidence of sepsis/septicemia (4.0% vs. 2.8%, P=0.01).37 Another study, published by Shimmer et al., followed 492 single center cardiology patients receiving RBCs transfusions (stored for 14 days to 42 days) and noted higher rates of sepsis (4.0% vs. 2.8%, P=0.01), increased requirement for intubation beyond 72 hours (9.7% vs. 5.6%, P<0.001), increased incidence of renal failure (2.7% vs. 1.6%, P=0.003), and increased in-hospital mortality (2.8% vs. 1.7%, P=0.004).38
While the P values are convincing, this literature conflicts with current research demonstrating no effect of product age on patient outcomes, in particular mortality. A 2015 New England Journal of Medicine article, published by Steiner et al., focused again on cardiac patients receiving transfusions (multi-center RCT, n = 1096), and compared transfusion with products less than 10 days post donation versus those greater than 21 days. Mortality was not statistically significant between groups (p=0.57).39 A second 2015 study, evaluating the age of products transfused in critically ill patients admitted to an ICU (n = 2430), demonstrated that products stored for a mean (±SD) of 6.1±4.9 days as compared with 22.0±8.4 days in the standard-blood group (P<0.001) had no clinically significant effect on mortality, major illness, duration of hospital stay, critical care requirement, or transfusion reaction.40
Where do we go from here?
The most recent Cochrane review notes insufficient literature for the provision of transfusion product age recommendations in patients with acute coronary syndrome, critical illness, trauma, or in the peri-operative state.41 According to the authors, existing studies suffer from extensive heterogeneity, differing definitions of “old” versus “fresh” products, and significant study bias.41
Currently, there is insufficient evidence to suggest that the transfusion of older blood products is associated with adverse patient outcomes.42,43 Several randomized trials are underway with preliminary results indicating no adverse outcomes associated with transfusion of products age <21 days.
Types of Products
There are several types of RBC products. Leukoreduced or leukodepleted RBCs are employed to prevent febrile non-hemolytic reactions (induced by the presence of antibodies to white blood cells), to reduce the risk of CMV transmission (especially important in bone marrow transplant patients, pregnant women, and those with HIV/AIDS), and to decrease the risk of transplant rejection.44,45 Washed RBCs are used to prevent allergic reactions, specifically in patients with IgA deficiency, as well as in patients with recurrent severe transfusion reactions not prevented by pre-treatment with antihistamines and corticosteroids.44,45 Irradiated products prevent Transfusion Associated Graft-Versus Host Disease (TAGVHD) through gamma irradiation of blood products.46-49
Transfusion Reactions and Infections
Transfusion of RBCs functions as an allogeneic tissue transplantation. Host response to transfusion varies as gene transcription and expression lead to modifications in intrinsic T cell, natural killer cell, and phagocyte function, and alterations in lymphocyte response and cytokine production. This effect is known as transfusion-related immunomodulation (TRIM), which may be associated with increased blood viscosity and decreased cardiac output. 2,3,10,21,24,25,31,48
Additional transfusion reactions include: febrile non-hemolytic transfusion reaction, allergic reaction, acute hemolytic reaction, anaphylactic reaction, transfusion-associated circulatory overload (TACO), transfusion-associated acute lung injury (TRALI), iron overload, delayed hemolytic reaction, and transfusion-associated graft vs. host disease (GVHD). For further discussion, please see references 47-49.
Give the aforementioned list of transfusion complications, the decision to transfuse should not be taken lightly. The risk of infection occurring secondary to transfusion is also concerning: One meta-analysis found an absolute pooled risk of serious transfusion related infection of 11.8% with a restrictive transfusion strategy versus 16.9% with a liberal strategy.43 The number needed to treat with a restrictive strategy in order to prevent one serious infection was 38.43 In a study focusing on critically ill patients, the nosocomial infection rate in patients receiving RBC transfusion was 24.3%, while amongst the control group not requiring transfusion, nosocomial infections occurred in 10.2%.37
In developed nations with well-regulated supplies, safety of transfusion has drastically improved due to changes in blood screening measures and quality control. In the U.S., the risk of HIV transmission is 1 per 1.5 million and HBV 1 in 357,000 donations.38 Unfortunately, in developing nations the story is different. With 39 countries lacking systems to test donated units, the prevalence of HIV in low-income nations is 2.3% of the blood products obtained.50-53
While multiple guidelines for transfusion exist, the most commonly referenced is the American Association of Blood Banks’ (AABB). Other guidelines from the American Society of Anesthesiology, British Committee for Standards in Hematology, European Society of Cardiology, Australian and New Zealand Society of Blood Transfusion, and American College of Physicians offer similar recommendations.54-57 The AABB’s guidelines include the following:58
- Adhere to a restrictive transfusion strategy: 7 to 8 g/dL transfusion threshold in hospitalized, stable patients (Grade: strong recommendation; high-quality evidence).
- Adhere to a restrictive strategy in hospitalized patients with preexisting cardiovascular disease; consider transfusion for symptomatic patients or those with a hemoglobin level of 8 g/dL or less (Grade: weak recommendation; moderate-quality evidence).
- No current recommendation for hemodynamically stable patients with ACS (Grade: uncertain recommendation; very low-quality evidence).
- Transfusion decisions should be influenced by symptoms as well as hemoglobin concentration (Grade: weak recommendation; low-quality evidence).
Restrictive versus Liberal Transfusion Threshold: The Studies
If you’re questioning the origin of the 7-8g/dl margin, look no further: AABB recommendations originate in several large clinical trials evaluating transfusion thresholds in various populations including critically ill patients admitted to ICU, those having undergone cardiac surgery, or orthopedic surgery, those experiencing trauma, and those suffering from sepsis, with primary hypotheses that restrictive transfusion strategies were as safe, if not safer, than liberal thresholds.10,15,16,54-58
Perhaps the most commonly cited AABB utilized study is the landmark 1999 Transfusion Requirements in Critical Care (TRICC) trial, completed in euvolemic ICU patients with a Hgb < 9 g/dL within 72 hours of admission. Patients were randomized to a restrictive (7 g/dL) or liberal transfusion (10 g/dL) strategy. The TRICC trial revealed no significant difference in all-cause mortality at 30 days (Restrictive 18.7%, Liberal 23.3% (95% CI -0.84 – 10.2%, p = 0.11)), however as a secondary outcome, mortality during hospitalization was found to be lower in the restrictive transfusion group.10
A second study cited by the AABB, The Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair (FOCUS) trial included 2,016 patients > 50 years of age having undergone hip arthroplasty, and found no mortality benefit or improvement in return to ambulation with a restrictive (8 g/dL) versus liberal (10g/dL) transfusion threshold.59 Finally, The CRIT study (2004) conducted in intensive care units, demonstrated increased mortality with increasing number of RBC transfusions.11
What do other sources have to say about liberal vs. restrictive transfusion strategies?
A 2012 Cochrane review found restrictive transfusion strategies to be associated with reduced in-hospital mortality, (RR 0.77, 95% CI 0.62-0.95) but not 30 day mortality (RR 0.85, 95% CI 0.70 to 1.03). The strategy did not affect patient length of stay or functional recovery, and ultimately, although the authors recommend use of a restrictive strategy, the review cautions readers regarding the use of a restrictive strategy for patients with acute coronary syndrome.60 A second Cochrane review identified restrictive strategies as reducing infection (RR 0.76; 95% CI 0.60 to 0.97), but not affecting mortality, rates of cardiac events or stroke, or lengths of stay.61
A recently published meta-analysis found a restrictive threshold of 7 g/dL associated with reduced in-hospital mortality (risk ratio [RR], 0.74; confidence interval [CI], 0.60-0.92), total mortality (RR, 0.80; CI, 0.65-0.98), re-bleeding (RR, 0.64; CI, 0.45-0.90), acute coronary syndrome (RR, 0.44; CI, 0.22-0.89), pulmonary edema (RR, 0.48; CI, 0.33-0.72), and bacterial infections (RR, 0.86; CI, 0.73-1.00), with a NNT of 33 to prevent one death.62
A British Medical Journal meta-analysis evaluated 31 trials with 9813 patients. Similar to the Cochrane reviews, no difference in morbidity, mortality, and myocardial infarction was found when comparing liberal and restrictive transfusion strategies. However, they did find reduced incidence of infection with a restrictive transfusion strategy.63
Ultimately it would seem that a restrictive transfusion strategy is correlated with decreased in-hospital mortality and decreased rates of infection. But does this translate to all populations?
Transfusion in Special Populations: The Studies
The care of patients with sepsis underwent a revolution with Early Goal Directed Therapy (EGDT) in 2001, in which blood transfusion became a central component. The Surviving Sepsis Guidelines advised transfusion to Hgb of 10 g/dL or Hct of 30% during the first 6 hours of resuscitation if hypoperfusion persisted despite fluid resuscitation and pressor support.64
This threshold has subsequently been questioned due to its basis in weak observational evidence. Enter the TRISS trial: The TRISS trial enrolled approximately 1000 patients with septic shock with a Hgb < 9 g/dL. Participants underwent randomization to one of two groups: one with a transfusion threshold of 7 g/dL and the other with a threshold of 9 g/dL. If patients met the threshold, 1 unit of leukoreduced RBCs was transfused. The investigators found that the primary outcome of death up to 90 days post transfusion did not differ between the groups (43% and 45%, RR 0.94 with 95% CI 0.78-1.09). Secodary outcomes including the use of life support, mechanical ventilation, vasopressor support, and renal replacement therapy were also equivalent between groups. As the restrictive group ultimately received fewer total PRBC units, the authors suggested that avoiding unnecessary transfusions conserved resources, and reduced the risk of infection or immune reaction secondary to tranfusion.70
More recent ground breaking studies, The ProCESS trial (2014) and ARISE study both revealed no difference in clinical outcomes according to threshold transfusion levels:
The ProCESS trial compared original EGDT to a group with a less invasive protocol that required transfusion for Hgb < 7.5 g/dL, and a group with treatment left at discretion of the treating physician. The EGDT group underwent transfusion at a rate of 14.4%, approximately double that of the other groups. As mentioned above, no difference in clinical outcomes was discovered.66 The ARISE study compared EGDT with usual care. Again, the EGDT group underwent double the transfusion frequency when compared to the group undergoing usual care, with no difference in outcomes.67
With the support from these studies, a transfusion threshold of 7 g/dL in patients with septic shock is advised.58,65
The studies evaluating transfusion threshold in patients with GI bleeding provide important information, as investigations were performed in patients with active hemorrhage. The TRICC and TRISS trials did not evaluate this subset of patients.10,65 Villanueva et al. evaluated adults with hematemesis or melena randomized to a restrictive strategy (7 g/dL) versus 9 g/dL. This trial excluded patients with minor bleeding or massive bleeding (defined by exsanguination), and patients with concern for acute coronary syndrome. All patients underwent endoscopy within six hours of presentation. Patients in the restrictive group demonstrated lower mortality versus the liberal group (5% and 9%, P=0.02). The rate of bleeding was also lower in the restrictive group (10% and 16%, P=0.01), with less products transfused.68 In the setting of nonvariceal bleeding, re-bleeding was found to occur at increased rates in patients receiving transfusion (23.6% versus 11.3%, P < 0.01).69 In this same group, 30 day mortality was notably higher (6.8% versus 3.7%, P = 0.005).69
A second study in the UK enrolled patients 18 years and older with upper GI bleeding, randomizing patients to restrictive (8 g/dL) and liberal (10 g/dL) thresholds, with no difference in clinical outcomes.70
Outcomes of these trials are supported by a meta-analysis evaluating studies with restrictive versus liberal transfusions for upper GI bleeding. This meta-analysis found restrictive transfusion groups had decreased death rates (OR 0.26, 95% CI: 0.03-2.10, P = 0.21), shorter hospital stays, (standard mean difference: -0.17, 95% CI: -0.30–0.04, P = 0.009).71
Why do transfusions potentially worsen outcomes in GI bleeding? It is hypothesized that transfusion counteracts the splanchnic vasoconstriction occurring in hypovolemia, thereby increasing pressure in the splanchnic circulation, and impairing clot formation. Transfusion itself is also known to alter coagulation properties. The concept of hemostatic resuscitation is paramount in these patients. Restrictive transfusion strategies decrease the number of transfusions and may directly impact mortality.67,69,70
Restrictive transfusion in the setting of GI bleeding is recommended, with a transfusion threshold of 7 g/dL.
Acute Myocardial Ischemia (AMI)
Data regarding transfusion paramaters in the setting of myocardial ischemia is significantly limited. What we do know is that myocardial oxygen demands are high in the setting of ischemia, and during anemic states, oxygen delivery increases through stroke volume and heart rate, potentially worsening ischemia.72 While this may seem a clear indication for transfusion, the transfusion associated risks of circulatory overload and increased thrombogenicity must also be considered.57,58
As previously cited, the AABB does not identify a transfusion threshold in myocardial ischemia.58
A randomized trial (n = 110) comparing transfusion triggers in patients with AMIs identified increased rates of unscheduled revascularization, death, and recurrent MIs within 30 days of transfusion in patients having been assigned a restrictive transfusion protocol (10.9% in the liberal group and 25.5% in the restrictive group; risk difference 15%, 95%; CI 0.7% to 29.3%), leading the authors to hypothesize that a liberal transfusion strategy in this population is associated with decreased cardiac events and death.72,74
However, these results conflict with numerous current studies. A review of 24,000 patients in the GUSTO IIb, PURSUIT, and PARAGON B trials found an increased risk of death 30 days post transfusion (adjusted hazard ratio, 3.94; 95% CI, 3.26 to 4.75) in patients transfused in the setting of cardiac disease/ischemia.74 A meta-analysis performed by Chatterjee et al. (JAMA, 2013; n = 200,000) revealed increased all-cause mortality with a strategy of product transfusion (18.2%) as compared to no transfusion (10.2%), risk ratio 2.91 (95% ICI 2.46-3.44, P < 0.001). A number needed to harm of 8 identified. Transfusion was associated with higher mortality independent of baseline Hgb, nadir Hgb, and change in Hgb during the hospitalization.75
Current studies conducted in patients experiencing myocardia ischemia suffer from a number of isssues: confounding factors such as anti-platelet agents, varying transfusion thresholds, and differing primary outcomes. As stated previously, the AABB has not published recommendations for this population in regards to transfusion thresholds.63 The meta-analysis detailed above has provided the best data to date, with suggestions of risk with transfusion. Further trials are needed in this population, but a restrictive threshold of 7 g/dL is likely safe if the patient is hemodynamically stable.
Most physicians would agree that transfusion is required in the setting of life-threatening trauma with massive hemorrhage. Hgb levels in active hemorrhage do not accurately predict RBC mass, and anemia is often only discovered when non-RBC fluid replacement is provided. The PROPPR trial evaluated the ratio of blood products in massive transfusion. A ratio of 1:1:1 platelet to plasma to RBC transfusion strategy was associated with decreased death by exsanguination in the first 24 hours and increased chance of hemostasis on post-hoc analysis when compared to a ratio of 1:1:2, though the primary outcome of 24 hour and 30 day mortality did not differ.76
In major trauma victims not undergoing massive transfusion, RBC transfusion has been associated with increased mortality, lung injury, infection rates, multiple organ failure, and renal injury.77,78 Brakenridge et al. found an association between increased RBC transfusion ( >9.5 units) with multiple organ dysfunction (OR of 1.91).77
A 2008 study evaluated the relationship between transfusion and patient outcomes including mortality, infection rate, ICU admission, and length of mechanical ventilation: Patients receiving transfusion had higher rates of infection (34% versus 9.4%), inpatient mortality (21.4% versus 6.5%), ICU admission (74% versus 26%), and duration of mechanical ventilation. Patients requiring transfusion had higher injury severity scales, lower GCS scores, and were more advanced in age. When adjustments were made for these variables, infection was found to increase as the number of units transfused increased (OR 2.8).79 Of note: Fresh frozen plasma transfusion has been associated with greater risk of multiple organ failure, as compared to RBCs, potentially confounding study results.78
One trial, published by McIntyre et al. in the Journal of Trauma (2004; n = 203) evaluated transfusion strategies for critically ill trauma patients utilizing restrictive and liberal thresholds of 7g/dL and 10g/dL respectively.18 Utilizing these parameters, McIntyre and his team discovered that mortality, multiple organ dysfunction, and length of stay were similar between the two groups.18
At this time, resuscitation of the trauma patient with hemorrhage should be based upon clinical status, not laboratory values. Transfusion is warranted in the setting of acute hemorrhagic shock. Once the patient is hemodynamically stable, transfusion should be considered in the setting of symptomatic anemia (chest pain, shortness of breath, poor distal perfusion).
As the brain and spinal cord have little anaerobic reserve and are not able to compensate for decreased oxygen delivery, the central nervous system relies on a consistent metabolic supply of oxygen.79 Studies in traumatic brain injury and subarachnoid hemorrhage have suggested utilizing a transfusion threshold of Hgb 8-9 g/dL, but further information is needed to develop true transfusion recommendations.78,79
A subgroup analysis of the TRICC trial analyzed patients with moderate and severe head injury, with transfusion thresholds of 7 g/dL and 10 g/dL. Similar to previous findings and suggestions, no difference in mortality, multiple organ dysfunction, and hospital length of stay were found in this retrospective subgroup analysis.83 A 2016 meta-analysis evaluating RBC transfusion in patients with traumatic brain injury, found no difference in mortality with transfusion threshold varying from Hgb 6-10 g/dL.84
As the AABB guidelines are ambiguous, emergency physicians should consider transfusion thresholds and weigh the risks and benefits of transfusion. If the patient is hemodynamically stable and asymptomatic, a Hgb of 7 g/dL is safe. If the patient is hemodynamically unstable and anemic, transfusion may assist the provider in stabilizing the patient.
– The transfusion threshold of 10 g/dL has recently been questioned, as RBC transfusion is not without risks (transfusion reaction, infection, and potentially increased mortality).
– The AABB currently recommends a transfusion threshold of 7 g/dL Hgb, though studies evaluating transfusion are small in sample size, retrospective, and observational in nature, affecting their applicability.
– Age of products transfused likely has no effect on products administered prior to 21 days of storage, though further study is required.
– A hemoglobin level of 7 g/dL is safe in the setting of critical illness, sepsis, gastrointestinal bleeding, and trauma.
– The clinician at the bedside should evaluate the patient for symptoms associated with anemia and transfuse based on risks and benefits.
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