RBC Transfusion in the Emergency Department

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

So…age matters?

 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

 

Transfusion Guidelines

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

  1. Adhere to a restrictive transfusion strategy: 7 to 8 g/dL transfusion threshold in hospitalized, stable patients (Grade: strong recommendation; high-quality evidence).
  2. 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).
  3. No current recommendation for hemodynamically stable patients with ACS (Grade: uncertain recommendation; very low-quality evidence).
  4. 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

Sepsis/Critically Ill

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

GI Bleeding

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.

Trauma

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).

 

Future Directions

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

 

Conclusions

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.

Summary

– 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.

 

References/Further Reading:

  1. Emmanuel JE, McClelland B, Page R, editors. The Clinical use of Blood in Medicine, Pediatrics, Surgery, Anesthesia, Trauma & Burns. World Health Organization. 1997. p.337.
  2. Balducci L. Anemia, fatigue and aging. Transfus Clin Biol 2010;17:375–81.
  3. Terekeci HM, Kucukardali Y, Onem Y, Erikci AA, Kucukardali B, Sahan B, et al. Relationship between anaemia and cognitive functions in elderly people. Eur J Intern Med 2010;21:87–90.
  4. Chaves PH, Xue QL, Guralnik JM, Ferrucci L, Volpato S, Fried LP. What constitutes normal hemoglobin concentration in community dwelling disabled older women? J Am Ger Soc 2004;52:1811–6.
  5. Musallam KM, Tamim HM, Richards T, Spahn DR, Rosendaal FR, Habbal A, Khreiss M, Dahdaleh FS, Khavandi K, Sfeir PM, et al. Preoperative anaemia and postoperative outcomes in non-cardiac surgery: a retrospective cohort study. Lancet 2011;378:1396–1407.
  6. Sabatine MS, Morrow DA, Giugliano RP, Burton PB, Murphy SA, McCabe CH, Gibson CM, Braunwald E. Association of hemoglobin levels with clinical outcomes in acute coronary syndromes. Circulation 2005;111:2042–2049.
  7. Ripollés Melchor J, Casans Francés R, Espinosa A, Martínez Hurtado E, Navarro Pérez R, Abad Gurumeta A, Basora M, Calvo Vecino JM. Restrictive versus liberal transfusion strategy for red blood cell transfusion in critically ill patients and in patients with acute coronary syndrome: a systematic review, meta-analysis and trial sequential analysis. Minerva Anestesiol. 2015 Jul 22. [Epub ahead of print].
  8. Hebert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, Tweeddale M, Schweitzer I, Yetisir E. 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.
  9. Marik PE, Corwin HL. Efficacy of red blood cell transfusion in the critically ill: a systematic review of the literature. Crit Care Med 2008;36:2667–2674.
  10. Corwin HL, Surgenor SD, Gettinger A. Transfusion practice in the critically ill. Crit Care Med 2003;31:S668–S671.
  11. Corwin HL, Gettinger A, Pearl RG, Fink MP, Levy MM, Abraham E, MacIntyre NR, Shabot MM, Duh MS, Shapiro MJ. The CRIT Study: Anemia and blood transfusion in the critically ill–current clinical practice in the United States. Crit Care Med 2004;32:39–52.
  12. Walsh TS and Saleh E. Anaemia during critical illnessBr. J. Anaesth 2006;97(3):278-291.
  13. U.S. Department of Health and Human Services. The 2009 national blood collection and utilization survey report. Washington, DC: U.S. Department of Health and Human Services, Office of the Assistant Secretary for Health; 2011.
  14. Vincent JL, Baron JF, Reinhart K, Gattinoni L, Thijs L, Webb A, Meier-Hellmann A, Nollet G, Peres-Bota D. Anemia and blood transfusion in critically ill patients. JAMA 2002;288:1499–1507.
  15. Blood Observational Study Investigators of ANZICS-Clinical Trials Group, Westbrook A, Pettilä V, Nichol A, Bailey MJ, Syres G, Murray L, Bellomo R, Wood E, Phillips LE, Street A, French C, Orford N, Santamaria J, Cooper DJ. Transfusion practice and guidelines in Australian and New Zealand intensive care units. Intensive Care Med 2010;36:1138–1146.
  16. Napolitano LM, Kurek S, Luchette FA, Corwin HL, Barie PS, Tisherman SA, Hebert PC, Anderson GL, Bard MR, Bromberg W, Chiu WC, Cipolle MD, Clancy KD, Diebel L, Hoff WS, Hughes KM, Munshi I, Nayduch D, Sandhu R, Yelon JA; American College of Critical Care Medicine of the Society of Critical Care Medicine; Eastern Association for the Surgery of Trauma Practice Management Workgroup. Clinical practice guideline: red blood cell transfusion in adult trauma and critical care. Crit Care Med 2009 Dec;37(12):3124-57.
  17. Blair SD, Janvrin SB, McCollum CN, Greenhalgh RM. Effect of early blood transfusion on gastrointestinal haemorrhage. Br J Surg 1986;73:783-785.
  18. McIntyre L, Hebert PC, Wells G, et al. Is a restrictive transfusion strategy safe for resuscitated and critically ill trauma patients? J Trauma 2004;57:563-568.
  19. Bracey AW, Radovancevic R, Riggs SA, et al. Lowering the hemoglobin threshold for transfusion in coronary artery bypass procedures: effect on patient outcome. Transfusion 1999;39:1070-1077.
  20. Finch CA, Lenfant C. Oxygen transport in man. N Engl J Med 1972;286:407–415.
  21. Hameed SM, Aird WC. Oxygen delivery. Crit Care Med 2003;31:S658-67.
  22. Liumbruno G, Bennardello F, Lattanzio A, Piccolli P, Roseetti G. Recommendations for the transfusion of red blood cells. Blood Transfus 2009;7:49-64.
  23. Hebert PC, Van der Linden P, Biro G, Hu LQ. Physiologic aspects of anemia. Crit Care Clin 2004;20:187-212.
  24. Clinical practice guidelines on the use of blood components (red blood cells, platelets, fresh frozen plasma, cryoprecipitate). Endorsed September 2001. National Health and Medical Research Council, Australasian Society of Blood Transfusion Inc. Available at: http://www.nhmrc.gov.au/publications/ synopses/_files/cp78.pdf.
  25. Practice guidelines for blood transfusion: a compilation from recent peer-reviewed literature. American Red Cross 2002. Available at: http://chapters.redcross.org/ br/indianaoh/hospitals/transfusion guidelines.htm.re.
  26. Elzik ME, Dirschl DR, Dahners LE. Correlation of transfusion volume to change in hematocrit. Am J Hematol 2006;81:145-6.
  27. Zou S, Dorsey KA, Notari EP, Foster GA, Krysztof DE, Musavi F, et al. Prevalence, incidence, and residual risk of human immunodeficiency virus and hepatitis C virus infections among United States blood donors since the introduction of nucleic acid testing. Transfusion 2010;50(7):1495–504
  28. Chin-Yee I, Arya N, d’Almeida MS. The red cell storage lesion and its implication for transfusion. Transfus Sci 1997;18:447–458.
  29. Card RT, Mohandas N, Perkins HA, Shohet SB. Deformability of stored red blood cells. Relationship to degree of packing. Transfusion 1982;22:96–101.
  30. Karam O, Tucci M, Toledano BJ, Robitaille N, Cousineau J, Thibault L, Lacroix J, Le Deist F. Length of storage and in vitro immunomodulation induced by prestorage leukoreduced red blood cells. Transfusion 2009;49:26–2334.
  31. Rana R, Fernandez-Perez ER, Kahn SA, et al. Transfusion-related acute lung injury and pulmonary edema in critically ill patients: A retrospective study. Transfusion 2006;46:1478–1483
  32. Li G, Daniels CE, Kojicic M, et al. The accuracy of natriuretic peptides in the differentiation between transfusion-related acute lung injury and transfusion-related circulatory overload in the critically ill. Transfusion 2009;49:13–20.
  33. Skeate RC, Easlung T. Distinguishing between transfusion-related acute lung injury and transfusion-associated circulatory overload. Curr Opin Hematol 2007;14:682– 687.
  34. Ho J, Sibbald WJ, Chin-Yee IH. Effects of storage on efficacy of red cell transfusion: When is it not safe? Crit Care Med 2003;31(12 Suppl):S687–S697.
  35. Almac E, Ince C. The impact of storage of red cell function in blood transfusion. Best Pract Res Clin Anaesthesiol 2007;21:195–208.
  36. Offner PJ. Age of blood: Does it make a difference? Crit Care 2004;8(Suppl 2):S24 –S26.
  37. Koch CG, Li L, Sessler DI, Figueroa P, Hoeltge GA, Mihaljevic T, Blackstone EH. Duration of red-cell storage and complications after cardiac surgery. N Engl J Med 2008 Mar 20;358(12):1229-39.
  38. Shimmer C, Hamouda K, Özkur M, et al. Influence of storage time and amount of red blood cell transfusion on postoperative renal function: an observational cohort study. Heart, Lung and Vessels 2013;5(3):148-157.
  39. Steiner ME, Ness PM, Assmann SF, Triulzi DJ, Sloan SR, Delaney M, Granger S. Effects of red-cell storage duration on patients undergoing cardiac surgery. N Engl J Med 2015 Apr 9;372(15):1419-29.
  40. Lacroix J, Hébert PC, Fergusson DA, Tinmouth A, Cook DJ, Marshall JC, Clayton L, McIntyre L, Callum J, Turgeon AF, Blajchman MA, Walsh TS, Stanworth SJ, Campbell H, Capellier G, Tiberghien P, Bardiaux L, van de Watering L, van der Meer NJ, Sabri E, Vo D; ABLE Investigators; Canadian Critical Care Trials Group. Age of transfused blood in critically ill adults. N Engl J Med 2015 Apr 9;372(15):1410-8.
  41. Brunskill SJ, Wilkinson KL, Doree C, Trivella M, Stanworth S. Transfusion of fresher versus older red blood cells for all conditions. Cochrane Database of Systematic Reviews 2015, Issue 5. Art. No.: CD010801. DOI: 10.1002/14651858.CD010801.pub2.
  42. Aubron C, Nichol A, Cooper DJ, Bellomo R. Age of red blood cells and transfusion in critically ill patients. Annals of Intensive Care 2013;3:2.
  43. Rohde JM, Dimcheff DE, Blumberg N, et al. Health Care–Associated Infection After Red Blood Cell Transfusion: A Systematic Review and Meta-analysis. JAMA 2014;311(13):1317-1326.Elzik ME, Dirschl DR, Dahners LE. Correlation of transfusion volume to change in hematocrit. Am J Hematol 2006;81:145-6.
  44. Topics in transfusion medicine. Guidelines. Irradiated blood products. Leucocyte depletion of blood and blood components. Australasian Society of Blood Transfusion Inc. October 1996. Available at: http:// www.anzsbt.org.au/publications/documents/1996_Vol3_2.pdf
  45. Council of Europe. Guide to the Preparation, Use and Quality Assurance of Blood Components. Recommendation No R (95) 15 on the Preparation, Use and Quality Assurance of Blood Components, 14th ed, Strasbourg, Council of Europe Press; 2008.
  46. Guidelines for gamma irradiation of blood components. Revised 2003. Australian & New Zealand Society of Blood Transfusion Inc. Australian Red Cross Blood Service, New Zealand Blood Service. Available at: http://www.anzsbt.org.au/ publications/documents/ANZSBTguide_May03.pdf.
  47. Gorlin JB, Minz PD. Transfusion-associated graft-vs- host disease. In: Mintz PD editor. Transfusion Therapy: Clinical Principles and Practice, Bethesda, MD: AABB; 2005. p.579-96.
  48. Vamvakas EC, Blajchman MA. Transfusion-related immunomodulation (TRIM): an update. Blood Rev 2007 Nov;21(6):327-48.
  49. Pineda AA, Taswell HF. Transfusion reactions associated with anti-IgA antibodies: report of four cases and review of the literature. Transfusion Jan-Feb 1975;15(1):10-5
  50. Goodnough LT, Shander A. Risks and complications of blood transfusions: optimizing outcomes for patients with chemotherapy-induced anemia. Advanced Studies in Medicine 2008;8(10):357–62.
  51. Kitchen AD, Barbara JAJ. Current information on the infectious risks of allogeneic blood transfusion. Transfusion Alternative in Transfusion Medicine 2008;10:102–11.
  52. Klein HG, Spahn DR, Carson JL. Red blood cell transfusion in clinical practice. Lancet 2007;370(9585):415–26.
  53. Zou S, Stramer SL, Notari EP, Kuhns MC, Krysztof D, Musavi F, et al. Current incidence and residual risk of hepatitis B infection among blood donors in the United States. Transfusion 2009;49(8):1609–20.
  54. Practice guidelines for blood component therapy: a report by the American Society of Anesthesiologists Task Force on Blood Component Therapy. Anesthesiology 1996;84:732-47.
  55. Murphy MF, Wallington TB, Kelsey P, Boulton F, Bruce M, Cohen H, et al; British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the clinical use of red cell transfusions. Br J Haematol 2001;113:24-31.
  56. National Health and Medical Research Council/Australasian Society of Blood Transfusion. Clinical Practice Guidelines: Appropriate Use of Red Blood Cells. Sydney, Australia: National Health and Medical Research Council/Australasian Society of Blood Transfusion; 2001.
  57. Bassand JP, Hamm CW, Ardissino D, Boersma E, Budaj A, Fernandez-Aviles F, et al; Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European Society of Cardiology. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007;28:1598-660.
  58. Carson JL, Terrin ML, Noveck H, Sanders DW, Chaitman BR, Rhoads GG, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med 2011;365:2453–62.
  59. Carson JL, Terrin ML, Noveck H, Sanders DW, Chaitman BR, Rhoads GG, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med 2011;365:2453–62.
  60. Carson JL, Carless PA, Herbert PC. Transfusion thresholds and other strategies for guiding allogenic red blood cell transfusion. The Cochrane database of systematic reviews. 2012;4:CD002042. doi:10.1002/12651858.CD002042.pub3.
  61. Carless PA, Henry DA, Carson JL, Herbert PPC, McClellandB, Ker K. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database of Systematic Reviews 2010, Issue 10. Art. No.:CD002042. do:10.1002/14651858.CD002042.pub2.
  62. Salpeter SR, Buckley JS, Chatterjee S. Impact of more restrictive blood transfusion strategies on clinical outcomes: a meta-analysis and systematic review. Am J Med. 2014 Feb; 127 (2):124-131.e3.
  63. Holst LB, Petersen MW, Haase N, Perner A, Wetterslev J. Restrictive versus liberal transfusion strategy for red blood cell transfusion: systematic review of randomised trials with meta-analysis and trial sequential analysis. BMJ: British Medical Journal 2015;350:h1354.
  64. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77.
  65. Holst LB, Haase N, Wetterslev J, et al. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med 2014;371:1381-91.
  66. The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014;370:1683-93.
  67. The ARISE Investigators and the ANZICS Clinical Trials Group. Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014 Oct 16;371(16):1496-506.
  68. Villanueva C, Colomo A, Bosch A, Concepcion M, Hernandez-Gea V, Aracil C, Graupera I, Poca M, Alvarez-Urturi C, Gordillo J, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 2013; 368:11-21.
  69. Restellini S, Kherad O, Jairath V, Martel M, Barkun N. Red blood cell transfusion is associated with increased rebleeding in patients with nonvariceal upper gastrointestinal bleeding. Aliment Pharmacy There 2-13;37:316-22.
  70. Jairath V, Kahan BC, Gray A, Doré CJ, Mora A, James MW, Stanley AJ. Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (TRIGGER): a pragmatic, open-label, cluster randomised feasibility trial. Lancet 2015 Jul 11;386(9989):137-44.
  71. Wang J, Bao Y-X, Bai M, Zhang Y-G, Xu W-d, et al. A meta-analysis of randomized controlled trials. World Journal of Gastroenterology; WJG 2013;19(40):6919-6927.
  72. Levy PS, Kim SJ, Eckel PK, Chavez R, Ismail EF, Gould SA, et al. Limit to cardiac compensation during acute isovolemic hemodilution: influence of coronary stenosis. Am J Physiol 1993;265:H340–9.
  73. Cooper HA, Rao SV, Greenberg MD, et al. Conservative vs liberal red cell transfusion in acute myocardial infarction (the CRIT Randomized Pilot Study). Am J Cardiol 2011;108(8):1108–1111.
  74. Rao SV, Jollis JG, Harrington RA, Granger CB, Newby LK, Armstrong PW, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 2004;292:1555–62.
  75. Chatterjee S, Wetterslev J, Sharma A, Lichstein E, Mukherjee D. Association of Blood Transfusion with increased mortality in myocardial infarction: A meta-analysis and diversity adjusted study sequential analysis. JAMA Intern Med 2013;173(2):132-139.
  76. Baraniuk S, Tilley BC, del Junco DJ, Fox EE, van Belle G, Wade CE, Podbielski JM, Beeler AM, Hess JR, Bulger EM, Schreiber MA, Inaba K, Fabian TC, Kerby JD, Cohen MJ, Miller CN, Rizoli S, Scalea TM, O’Keeffe T, Brasel KJ, Cotton BA, Muskat P, Holcomb JB; PROPPR Study Group. Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial: design, rationale and implementation. Injury 2014 Sep;45(9):1287-95.
  77. Brakenridge SC, Phelan HA, Henley SS, Golden RM, Kashner TM, Eastman AE, Sperry JL, Harbrecht BG, Moore EE, Cuschieri J, Maier RV, Minei JP. Inflammation and the Host Response to Injury Investigators. Early blood product and crystalloid volume resuscitation: risk association with multiple organ dysfunction after severe blunt traumatic injury. J Trauma 2011 Aug;71(2):299-305.
  78. Johnson JL, Moore EE, Kashuk JL, et al. Effect of Blood Products Transfusion on the Development of Postinjury Multiple Organ Failure. Arch Surg 2010;145(10):973-977.
  79. Bochicchio GV, Napolitano L, Joshi M, et al. Outcome analysis of blood product transfusion in trauma patients: a prospective, risk-adjusted study. World J Surg 2008;32:2185–2189.
  80. LeRoux P. Haemoglobin management in acute brain injury. Curr Opin Crit Care 2013;19:83–91.
  81. Diedler J, Sykora M, Hahn P, Heerlein K, Schölzke MN, Kellert L, et al. Low hemoglobin is associated with poor functional outcome after non-traumatic, supratentorial intracerebral hemorrhage. Crit Care 2010;14:R63.
  82. Oddo M, Milby A, Chen I, Frangos S, MacMurtrie E, Maloney-Wilensky E, et al. Hemoglobin concentration and cerebral metabolism in patients with aneurysmal subarachnoid hemorrhage. Stroke 2009;40:1275–81.
  83. McIntyre LA, Fergusson DA, Hutchison JS, Pagliarello G, Marshall JC, Yetisir E, Hare GM, Hébert PC. Effect of a liberal versus restrictive transfusion strategy on mortality in patients with moderate to severe head injury. Neurocrit Care 2006;5(1):4-9.
  84. Boutin A, Chassé M, Shemilt M, Lauzier F, Moore L, Zarychanski R, Griesdale D, et al. Red Blood Cell Transfusion in Patients With Traumatic Brain Injury: A Systematic Review and Meta-Analysis. Transfus Med Rev 2016 Jan;30(1):15-24.

 

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