Anemia is common and is associated with significant morbidity and mortality.1 In the past, transfusion practice in the perioperative period focused on the use of allogeneic blood to treat and correct anemia which was culturally embedded as default therapy. It has become increasingly clear however that allogeneic blood transfusion (ABT) itself is an independent risk factor for poor clinical outcomes.2 Moreover, the cost of transfusion continues to escalate and the gap between supply and demand of this scarce resource is ever widening.3 In response to these drivers, there has been a paradigm shift from a product focus to a patient focus in transfusion medicine.
Patient blood management (PBM), defined by the Society for the Advancement of Blood Management, is the timely application of evidence-based medical and surgical concepts designed to maintain hemoglobin (Hb) concentration, optimize hemostasis, and minimize blood loss in an effort to improve patient outcomes. It rejects the standard dogma which considers red blood cell (RBC) transfusion to be the primary solution in the correction of anemia and views the patient’s own blood as a resource that should be conserved and managed appropriately as a standard of care. PBM can be seen as consisting of 3 pillars, the optimization of RBC mass, reduction of blood loss and bleeding, and optimization of the patient’s physiological tolerance toward anemia.4 Patient-centered decision-making is crucial when determining an individualized management plan and involves the communication of the risks and benefits of the various potential interventions to decide on the right course of action.
In 2010, PBM was adopted by the World Health Organization (WHO) and it is supported by the National Health Service Blood and Transplant (NHSBT) and the National Blood Transfusion Committee in the United Kingdom. Started at the earliest opportunity before surgery and continued into the postoperative period, PBM addresses the triad of independent risk factors that can affect outcome in surgical patients, namely anemia, blood loss, and transfusion. It is in the setting of elective surgery where the most evidence for benefit of PBM has been demonstrated in reducing exposure to ABT and improving patient outcomes.5
In this article, we will review the outcomes associated with anemia and ABT and consider how the 3 pillars of PBM can provide a structure for multidisciplinary and multimodal care bundles and strategies that can be instituted into perioperative pathways with the aim of improving patient outcome.
Anemia: Definition, Causes, and Outcomes
Since 1968, the WHO has defined anemia as an insufficient circulating red cell mass with a Hb level <13 g/dL in males and <12 g/dL in menstruating females.6 More than 30% of the world’s population is anemic but the incidence varies with age and comorbidity. In the US National Surgery Quality Improvement Program (NSQIP), the prevalence of anemia in patients undergoing surgery was 30.4%,1 while in Europe, it was found to be 28.7%.7 Estimates of anemia in surgical patients range widely as the underlying surgical condition can predispose the patient to anemia, from 5% in elderly females with hip fracture to 75.8% in Dukes stage D colon cancer.8 Postoperative anemia is more common than preoperative anemia and can be present in up to 90% of patients after major surgery.8
Anemia has multiple different causes such as hemoglobinopathy, nutritional deficiencies, and renal failure. One of the most prominent causes is iron deficiency9 and can be either absolute or functional. In a 70-kg male, total body iron is about 3500 mg, of which most (65%) is found in Hb within the RBC and much of the remainder is stored in the liver, macrophages, and bone marrow.10
In absolute iron deficiency, there is a reduction in the total body iron which can either be present in isolation, when the level of erythroid iron is still sufficient for erythropoiesis, or in conjunction with anemia. In functional iron deficiency, in contrast, there is iron-restricted erythropoiesis despite normal or even increased total body iron. Inflammation, whether caused by autoimmune mechanisms, infection, or malignant cells, can result in functional iron deficiency secondary to its activation of hepcidin and thus functional iron deficiency is the most common cause of anemia of chronic disease.11 Hepcidin is an amino acid glycoprotein produced in the liver whose normal role is to act on ferroportin, a transmembrane iron transporter found in duodenal enterocytes and macrophages. Degradation of ferroportin by activated hepcidin prevents enteral iron absorption and transport of iron from the liver, where it is stored as ferritin, and macrophages to the plasma. Consequent to this, binding of transferrin, the plasma iron transport protein, to iron is reduced and less iron is delivered to the bone marrow affecting effective erythropoiesis.12
Of concern, anemia is an independent risk factor for perioperative morbidity and mortality in cardiac13–16 and noncardiac surgery17–19 and is not just a laboratory value but also a disease in itself. Mild anemia leads to impaired functional capacity and performance and a reduced quality of life.20
In a retrospective cohort study, which used data from the American College of Surgeons’ NSQIP, the effect of mild and moderate–severe anemia was evaluated in 227,425 patients undergoing elective major noncardiac surgery.1 Preoperative anemia was associated with a 35% increased odds ratio of composite postoperative morbidity and a 42% increased odds ratio of mortality at 30 days. Of note, this relationship was present for mild anemia as well. Data from NSQIP were used again to study the effect of anemia in 23,348 patients who underwent elective open and laparoscopic colectomies.21 Preoperative anemia, even if mild, was found to be a risk factor for a composite outcome consisting of myocardial infarction, stroke, progressive renal insufficiency, or death within 30 days of operation and to correlate with a longer hospital length of stay (LOS). Further studies have continued to use NSQIP data to demonstrate the association between anemia and adverse outcomes.22,23 More recently, a secondary analysis of noncardiac and nonneurological surgery in 39,309 patients which included elective and nonelective cases showed that moderate and severe anemia resulted in increased postoperative admission to intensive care, hospital LOS, and in-hospital mortality.7
Compared to comorbidities and severity of illness, anemia is a strong predictor of the likelihood of ABT.24 ABT has been traditionally used to correct anemia with insufficient consideration of the underlying cause or the associated risks and benefits. If the cause is not addressed, which in most cases is chronic and ongoing in nature, the correction is likely to be transient and the anemia may recur. Considerable variations in transfusion practice have underlined the need for appropriate transfusion use. In orthopedic surgery, for example, the ABT rate varies from 1.5% to 78% for total hip replacement.25 Indication for ABT should take into consideration patient-specific factors, laboratory values, physiological factors, and the presence or absence of bleeding. In the emergency setting of acute hemorrhage, ABT could however be the treatment of choice.
In the most recent report from the Serious Hazards of Transfusion, 166 patients suffered major morbidity and 26 died, 2 of which were definitely related, 9 probably related, and 15 possibly related to transfusion.26 Complications from transfusion included acute and hemolytic transfusion reactions, circulatory overload, dyspnea, transfusion-transmitted infection, and transfusion-related acute lung injury.
Similar to anemia, ABT is an independent risk factor for perioperative morbidity and mortality.27–29 In a prospective study that used NSQIP to collect data from 6301 patients undergoing noncardiac surgery, ABT was associated with increased postoperative pneumonia, hospital LOS, and mortality.18 Multiple subsequent studies included an increasing number of patients and confirmed the dose-dependent relationship between ABT and a composite outcome of myocardial infarction or stroke, pulmonary, renal, septic, thromboembolic and wound complications, and increased hospital LOS.30–33 Consistent with the results of previous studies, a systematic review of observational studies concluded that ABT does have an adverse effect on mortality but could not exclude the possibility that confounding secondary to unknown and hence unadjusted factors still played a role.32
Concerns have also been raised about the influence of ABT on immunomodulation and postoperative infection, metastasis, and the recurrence of cancer.34–42 Immunomodulation of the innate and adaptive immune system occurs after exposure of the recipient to the many cell bound and soluble antigens expressed on viable and decaying cells in the transfusion.43 In particular, contaminant leukocytes are thought to have a significant role. ABT has been associated with infectious complications after operations for gastrointestinal and pancreatic cancer, hip replacement, and spinal fusion.34–37 Moreover, a systematic review demonstrated that the odds ratio of postoperative bacterial infection was 3.45 subsequent to ABT.38 It has been widely reported that perioperative blood transfusions increase the risk of colorectal cancer recurrence.39–41 A Cochrane meta-analysis examined this association in 12,127 patients from 36 trials.42 It showed that blood transfusion was related to a 42% increase in the odds ratio for cancer recurrence in a dose-related manner and thus recommended that ABT should be restricted in its use in patients with curable colorectal cancer. Similar trends in recurrence have been found with the use of blood transfusion in surgical patients with various other cancers.44–47
Importantly, transfusion is costly and the cost of transfusing a RBC unit, including consumables and labor, is approximately 4 times higher than to purchase the product.48,49 In the United Kingdom, after including derived costs such as hospital stay, the mean cost for a transfusion of 2 units in hematology and oncology patients was determined to be £546.12.50 Evaluation of the cost of blood in a surgical population at 2 European and 2 US hospitals found each RBC unit to cost between $522 and $1183.49 Annual expenditures on blood and transfusion-related activities, limited to surgical patients, ranged from $1.62 to $6.03 million per hospital and were largely related to the transfusion rate.
First Pillar: Optimization of RBC Mass
In the preoperative period, laboratory investigations should be performed as soon as possible if moderate to high blood loss, defined as more than 500 mL is likely, or there is a ≥10% probability for ABT.51 They should include a full blood count, serum ferritin, transferrin saturation, a marker of inflammation, such as C-reactive protein and a surrogate of renal function. Guidelines from the Network for Advancement of Transfusion Alternatives (NATA) advocate that the level of Hb should be measured 28 days before elective orthopedic surgery,52 while those from the European Society of Anaesthesiology recommend that patients at risk of bleeding be assessed for anemia 4–8 weeks before surgery.53 In our view, females should be optimized to the same level of Hb as males to 13 g/dL despite the WHO definition of anemia. Both sexes lose comparable amounts of blood in similar surgical procedures but females have a relatively lower circulating volume which means they lose proportionally more. Females could therefore be at otherwise increased risk of ABT which has been corroborated by the results of previous studies.54,55
Treatment of anemia should be directed at the cause. In the case of iron deficiency anemia, either oral or intravenous (IV) iron can be used. Oral iron is low cost and a recent meta-analysis demonstrated that it increases the Hb and decreases the proportion of patients who require ABT.56 Notably however, the bioavailability of ferrous iron is only 10%–15% and this may be reduced further by the stimulation of hepcidin in inflammatory conditions. Enteral iron is absorbed at a rate of 2–16 mg per day and if the iron deficit which needs to be replaced is significant, it could take too long for oral iron to effectively replenish stores. Compliance can be a problem as well because of gastrointestinal side effects, such as abdominal pain, constipation, and diarrhea.57 Interestingly, high doses of oral iron sulphate in iron deficient but nonanemic females stimulate hepcidin and result in lower iron absorption from the next daily dose. Administration of low-dose oral iron on alternate days may increase fractional iron absorption, maximize dosage efficacy, reduce gastrointestinal exposure to unabsorbed iron, and improve adherence to treatment.58 Once oral iron has been commenced, the Hb should be measured again, at least 4 weeks before surgery.
If there has not been an increment in the Hb with oral iron, the patient is intolerant of it or surgery is scheduled in <6 weeks time, IV iron is preferred. Compared to oral iron, IV iron is more effective in raising the level of Hb.56 In the context of hepcidin upregulation, IV iron may be more likely to work as it is taken up by macrophages and degraded leading to an increase in intracellular iron.59 Intracellular iron increases ferroportin expression, partly overcoming hepcidin blockade and allowing iron to be transported by transferrin in the plasma to the bone marrow for erythropoiesis. In multiple studies, IV iron has been associated with a decrease in the need for ABT, a fall in the incidence of acute kidney injury and infections, and a reduction in the hospital LOS.60–62
Currently, 6 different formulations of IV iron are available in Europe and the United States (Table). Depending on the preparation, the dose can be administered in as little as 15 minutes which is more acceptable to the patient as it incurs shorter and fewer hospital visits. A recent meta-analysis demonstrated that IV iron, when compared to oral or intramuscular iron, no iron or placebo, was not associated with an increase in the risk of infection or serious adverse events but did reduce the risk of adverse gastrointestinal events.63 Serious adverse reactions and death are very rare, occurring in 38/106 and 0.4/106 administrations, respectively.64 In a comparison of the cost of IV iron versus ABT, which included consideration of acquisition, administration, and transport costs, IV iron was found to be more cost effective.65
Use of recombinant erythropoietin (rEPO) to act on progenitors in the bone marrow and stimulate erythropoiesis first became widespread in dialysis patients.66 A meta-analysis of an overall small sample size evaluated the effect of rEPO in colorectal cancer surgery and demonstrated no significant change in the level of Hb nor the number of units transfused per patient.67 Subsequent meta-analyses in patients undergoing cardiac or orthopedic surgery have found that rEPO increased the level of Hb55 and reduced the risk of ABT.68–71 Guidelines from the NATA recommend that, in the setting of orthopedic surgery, rEPO should be used for anemic patients in whom nutritional deficiencies have been corrected or excluded.52 In 1 systematic review, subgroup analysis showed that variation in the dose and route of administration of rEPO had no effect on the risk of ABT.68 Definitive conclusions however about the optimal dose, duration of treatment, and route of administration of rEPO cannot be reached because of the significant heterogeneity in the scheduling pattern of rEPO in the individual clinical trials in these meta-analyses. Of note, rEPO has been associated with hypertension and ischemic and thrombotic events, possibly secondary to the rapidity of rise and potential overshoot in Hb concentration as well as the the trophic effect of rEPO on other cells.72
Second Pillar: Reduction of Blood Loss and Bleeding
A standardized history to assess the risk of bleeding should be taken. It should ascertain as to whether there is a history of bleeding after surgery or trauma, menorrhagia in females, drug history related to anticoagulant and antiplatelet medication, and a family history of bleeding diathesis. Increasingly, anticoagulant and antiplatelet medication is being continued into the perioperative period. An individualized assessment of the thrombotic risk of discontinuing these medications should be balanced against the risk of perioperative bleeding.
Surgical blood loss is decreased with neuraxial techniques relative to general anesthesia, probably secondary to a fall in blood pressure and venous tone resulting from sympathetic blockade.73 Compared to open and invasive surgery, laparoscopic and minimally invasive surgical techniques, such as robotic gastrectomy, are associated with reduced surgery-related blood loss.74,75 Judicious use of diathermy dissection and meticulous hemostasis are crucial. The patient should be positioned in such a way that venous return is not obstructed which could otherwise increase venous pressure and therefore bleeding at the operative site. Cardiovascular physiology should be manipulated as appropriate to limit bleeding. In hepatic resection, for example, the central venous pressure can be lowered. Maintenance of normothermia and avoidance of acidosis and hypocalcemia are key in the optimization of hemostatic conditions.76
Conventional coagulation tests can in certain circumstances be misleading and have an unacceptably long response time in dynamic situations.77,78 Viscoelastic tests (VET), in contrast, are performed at the point of care and can direct the perioperative management of coagulopathy. Both thromboelastography and thromboelastometry measure changes in clot tensile strength over time and provide information on the kinetics of clot formation and dissolution within 10–20 minutes.79 Specific patterns of VET measurements can guide the administration of fresh frozen plasma, platelets, cryoprecipitate, factor concentrates, and antifibrinolytics. Use of VET has been advocated in cardiac surgery by the National Institute for Health and Care Excellence (NICE) in the United Kingdom,80 where a meta-analysis found it to decrease the need for transfusion in those patients at risk of coagulopathic bleeding.81 It did not however decrease mortality, reoperation for bleeding, stroke, ventilation time, or hospital LOS. In other meta-analyses, where most included studies were undertaken in the setting of cardiac surgery, transfusion requirements were also similarly reduced,82,83 but in 1, the use of VET was associated with a reduction in overall mortality.83
Pharmacological treatments have demonstrated benefit in reducing perioperative blood loss. Epsilon aminocaproic acid (EACA) and tranexamic acid (TXA) are analogs of the amino acid lysine and reversibly inhibit fibrinolysis by binding the lysine-binding sites on plasminogen, limiting the activation of plasmin which degrades fibrin.84 A meta-analysis of EACA and TXA in the setting of elective surgery found that the evidence was stronger for TXA than for EACA with a relative risk reduction of 39% and 25%, respectively, in the need for ABT.85 Early use of TXA in trauma has been associated with a reduction in mortality due to bleeding and all-cause mortality.86 Because the hemostatic responses to surgery and trauma are similar, TXA might reduce mortality due to bleeding in surgical patients.87 TXA can also be used in topical form where a systematic review showed that it reduced blood loss by 29% and the relative risk of receiving a blood transfusion by 45% in cardiothoracic, oral, orthopedic, otorhinolarnygeal, spinal, and urological surgery.88
Other topical hemostatic agents include fibrin sealants which contain fibrinogen (with or without factor XIII) and thrombin (with calcium) and mimic the final phase of the coagulation cascade.89 Previously, a meta-analysis demonstrated that fibrin sealant decreased relative exposure to ABT by 54%90 and a more recent systematic review showed a reduced ABT and blood loss in orthopedic surgery.91
Cell salvage is an established technique in cardiac, orthopedic, and major vascular surgery92,93 and should be considered where the anticipated blood loss is >1000 mL.94 It is performed with the use of a double lumen suction device to collect blood. Blood is stored within a reservoir with added anticoagulant and once enough blood is collected, the RBCs are washed, filtered, and suspended in saline to be returned to the patient. Retransfused RBCs from cell salvage have no clotting factors, platelets, or plasma and so additional hemostatic therapies may be required. Use of cell salvage reduces the relative rate of ABT by 38%, saving an average of 0.68 of allogeneic RBCs per patient,91 and it is cost effective compared with transfusion.95 Though there have been concerns about the harmful effects of bacteria and malignant cells aspirated from the surgical field, studies have shown that there is no increase in positive culture or postoperative infection despite the aspiration of blood contaminated with microorganisms which the washing process is unable to eliminate completely.96,97
Acute normovolemic hemodilution (ANH) is the practice of preoperative withdrawal of whole blood with concurrent infusion of fluids to maintain normovolemia. Potential benefits of ANH include improvement in tissue oxygenation because of decreased blood viscosity, dilution of circulating components reducing the red cell mass lost due to surgical bleeding and the availability of whole blood for retransfusion at the conclusion of surgery. ANH may be more cost effective than cell salvage95 and though a recent meta-analysis has suggested that ANH is effective in reducing ABT, these conclusions were limited by the significant identified heterogeneity and publication bias.98
In the postoperative period, efforts to avoid coagulopathy and reduce bleeding should be continued. Cell salvage can be used after the operation94 but surgical drains can increase the rate of ABT in orthopedic surgery99 though its use is declining with the establishment of enhanced recovery programs. Repeated blood sampling can result in iatrogenic blood loss, contribute to postoperative anemia and should be minimized. In cardiac surgery, cumulative median phlebotomy volume for the hospital stay was 454 mL and increased with LOS.100 Patients with similar risk factors for mortality in the intensive care environment were subjected to more blood tests if they had an indwelling arterial catheter.101 Because of this, noninvasive monitoring should be considered where appropriate. Blood tests should be performed only when indicated and when taken, the smallest collection tube size that is practical for the required analysis should be used. In a study, replacement of adult blood tubes with pediatric ones reduced blood loss associated with diagnostic testing by 47%.102 Transition to the use of pediatric blood tubes is not however simple as the patient identification labels are often larger than the tube, process costs are higher and the analysis can be delayed. Discard volume should be as low as possible and blood waste minimized by the use of closed in-line flush blood sampling devices for arterial and central venous devices.103
Third Pillar: Optimization of the Patient’s Physiological Tolerance Toward Anemia
Oxygen uptake, transport, delivery, and utilization are complex biological processes and deficiency in any link in this chain, such as anemia, can be compensated for by other links.104 Adaptive responses include increased minute ventilation and cardiac output, improved ventilation–perfusion in the lungs, preferential oxygen delivery to vital organs, and higher tissue oxygen extraction. A patient’s physiological tolerance of anemia can be harnessed in several ways.105 Oxygenation can be optimized by increasing the inspired fraction of oxygen and hemodynamics can be manipulated with the use of vasopressors to maintain organ perfusion. Consumption of oxygen can be decreased by ensuring adequate analgesia and minimizing infection.
Evidence suggests that transfusion with RBCs fails to improve tissue oxygenation within the first 24 hours and might in fact decrease it.106,107 In the seminal Transfusion Requirements in Critical Care (TRICC) trial, a restrictive strategy with a transfusion threshold of <7 g/dL was as effective as a liberal strategy with a transfusion threshold of <10 g/dL in 838 critically ill patients.108 Further studies have supported these findings and a restrictive threshold of <8 g/dL was compared to a liberal transfusion threshold of <10 g/dL in patients with a history of or risk factors for cardiovascular disease who were undergoing hip fracture surgery.109,110 A restrictive transfusion strategy did not reduce functional capacity or increase 60-day and long-term mortality. Multiple meta-analyses have shown that the use of a restrictive transfusion threshold across a broad range of specialties does not impact adversely on morbidity and mortality compared to a liberal transfusion threshold.111–113
In recognition that restrictive transfusion thresholds are noninferior to liberal ones, NICE advocates that RBC transfusion should be considered at a Hb threshold of 7 g/dL in patients who do not have acute coronary syndrome or major hemorrhage, aiming for a target concentration of 7–9 g/dL after transfusion.114 After each single unit of RBC transfusion, a clinical reassessment should be made and the level of Hb checked to evaluate the appropriateness of further transfusion. Such practice could improve RBC utilization and decrease patient exposure to ABT.115
Patients with cardiovascular disease could represent a specific high-risk group at the limits of their physiological reserve for which liberal transfusion thresholds should be recommended. In a feasibility study of transfusion thresholds in 110 patients with acute coronary syndrome or stable angina undergoing cardiac catheterization, a liberal transfusion strategy of 10 g/dL was associated with a decreased risk of death compared to a restrictive transfusion strategy of 8 g/dL.116 Evidence from randomized controlled trials in cardiac surgery refutes findings from observational studies that liberal thresholds for RBC transfusion are related to a substantially increased risk of morbidity and mortality.117 In the Transfusion Indication Threshold Reduction (TITRe2) trial, 2007 patients with a postoperative Hb level of <9 g/dL after cardiac surgery were randomized to either a restrictive transfusion strategy of <7.5 g/dL or a liberal transfusion strategy of <9 g/dL.118 No difference in a composite outcome of serious infection or ischemic events was found but it did show that restrictive transfusion resulted in more deaths. NICE, as it stands, recommends that RBC transfusion should be considered at a Hb threshold of 8 g/dL in patients with acute coronary syndrome, aiming for a concentration target of 8–10 g/dL after transfusion.114
Challenges and Practicalities in the Implementation of PBM
In view of its demonstrable benefits, there is an increasing awareness of the need to integrate the pillars of PBM into routine surgical care. In the United States, PBM has been successfully introduced in some centers,119 while in Western Australia, it has become the standard of care.120 PBM initiatives in Europe however have been variable and inconsistent, reflecting the difficulties that can be met with its implementation.121 Multiple barriers, including lack of knowledge, interdisciplinary commitment, resources, and concerns limit the translation of PBM guidelines into clinical practice.122–125
National health care quality change initiatives set the agenda for change,114 but the patient-centered approach to PBM must be delivered in a way that is also hospital centered so it is practical, feasible, and socially acceptable within each institution. To evaluate the cost effectiveness of the introduction of PBM, registries for systematic data collection should be considered. Incentives for the adoption of newer measures and disincentives against older practices are needed. Individual hospitals may otherwise be discouraged from setting up a PBM program because of the assumed initial costs.
Clinical champions and strong leadership are needed to establish PBM and overcome clinical inertia. In the United Kingdom, the NHSBT has been responsible for the development and support of Hospital Transfusion Committees (HTC) which offer a multidisciplinary leadership role, providing effective hospital governance that caters for all transfusion-related issues within the institution. The HTC oversees the implementation of national policies on blood transfusion and guidelines on the clinical use of blood. One discipline cannot manage the shift in the paradigm alone and hence communication and understanding the motivational frameworks and principles of various disciplines is critical to success. Consensus among anesthesiologists, cardiologists, critical care specialists, gastroenterologists, hematologists, and surgeons on the bundles of diagnostic and therapeutic interventions is required.126 Cooperation and engagement of the main stakeholders, such as health authorities, administrative, finance, information technology and quality management personnel, blood services, transfusion committee, practitioners and nurses, can harmonize their different backgrounds and philosophies and pave the foundation for the effective institution of PBM. To this end, a PBM coordinator can be instrumental to success.
Characterization of the current practice of PBM at each hospital is needed and benchmarking of performance should be instituted to identify areas of need. The NHSBT in the United Kingdom, for example, continues to undertake the National Comparative Audit of Blood Transfusion to assess the current practice of PBM.127 Information can then be shared with stakeholders to enable the planning of appropriate interventions which should be put in place under the precondition of applied change management principles after the identification of drivers for change. Constructive criticism and suggestions from the multidisciplinary field are crucial to adjust and improve the program and should be welcomed.
Individualized multimodal PBM care bundles, defined by the Institute for Healthcare Improvement as a straightforward set of evidence-based interventions that when implemented together will result in significantly better, more penetrating, and sustainable outcomes than when implemented individually,128 could provide a clinical and pragmatic template for hospitals to follow.129 Outside PBM, such care bundles have improved compliance with guidelines and resulted in a beneficial impact on care processes and outcomes.130–132
Barriers to effective PBM implementation need be recognized and acted on. Before practice guidelines can affect patient outcome, doctors of all specialties must have a shared understanding of the evidence and principles driving the paradigm shift toward the practice of PBM. Doctors, familiar with the ease and established use of ABT, may not appreciate the risks associated with transfusion and the benefits related to PBM. Education and training should be considered to increase awareness of the clinical implications of anemia and the need for alternatives to transfusion. Once any deficiencies in underlying knowledge have been addressed, their attitude and finally behavior should change.133 All recommendations and standard operating procedures must be easily accessible and the use of checklists and visual aids as aide memoires are important. Electronic real-time clinical decision support systems are valuable and can, for instance, increase the appropriateness of RBC utilization.134
Practice needs to be continuously audited at ward, specialty, divisional, and hospital level135 and progress monitored to achieve sustainability. Focus should be shifted to the reporting of data on transfusion rates and patient outcomes which can provide iterative feedback to reinforce the attitudes and motivations of the main stakeholders. Institutions must collaborate and learn from centers of excellence in PBM to accelerate their own success in the implementation of PBM.
It is clear that the establishment of PBM offers the prospect of reduced risk and improved patient outcomes in perioperative pathways. All 3 pillars of PBM are equally important and can structure the decisions and interventions relating to anemia and blood transfusion. A more considered approach to blood transfusion, acknowledging its risks, preventatives, and alternatives should be adopted. Collaborative and continuous efforts to translate PBM guidelines into clinical practice, if done in an engaged, multidisciplinary, organized and structured way, could make PBM the norm.
Name: Neel Desai, FRCA.
Contribution: This author helped prepare, write, and revise the manuscript.
Name: Nick Schofield, FRCA.
Contribution: This author helped revise the manuscript.
Name: Toby Richards, FRCS.
Contribution: This author helped revise the manuscript.
This manuscript was handled by: Marisa B. Marques, MD.
1. Musallam KM, Tamim HM, Richards T, et al. Preoperative anaemia and postoperative outcomes in non-cardiac surgery: a retrospective cohort study. Lancet. 2011;378:1396–1407.
2. Ferraris VA, Davenport DL, Saha SP, Austin PC, Zwischenberger JB. Surgical outcomes and transfusion of minimal amounts of blood in the operating room. Arch Surg. 2012;147:49–55.
3. Hofmann A, Farmer S, Shander A. Five drivers shifting the paradigm from product-focused transfusion practice to patient blood management. Oncologist. 2011;16Suppl 33–11.
4. Goodnough LT, Shander A. Patient blood management. Anesthesiology. 2012;116:1367–1376.
5. Farmer SL, Trentino K, Hofmann A, et al. A programmatic approach to patient blood management – reducing transfusions and improving patient outcomes. Open Anesthesiol J. 2015;9:1–11.
6. WHO. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin and Mineral Nutrition Information System. 2011 Geneva, Switzerland: World Health Organization, (WHO/NMH/NHD/MNM/11.1). Available at: http://www.who.int/vmnis/indicators/haemoglobin.pdf
. Accessed August 6, 2017.
7. Baron DM, Hochrieser H, Posch M, et al.; European Surgical Outcomes Study (EuSOS) group for Trials Groups of European Society of Intensive Care Medicine; European Society of Anaesthesiology. Preoperative anaemia is associated with poor clinical outcome in non-cardiac surgery patients. Br J Anaesth. 2014;113:416–423.
8. Shander A, Knight K, Thurer R, Adamson J, Spence R. Prevalence and outcomes of anemia in surgery: a systematic review of the literature. Am J Med. 2004;116Suppl 7A58S–69S.
9. Kassebaum NJ, Jasrasaria R, Naghavi M, et al. A systematic analysis of global anemia burden from 1990 to 2010. Blood. 2014;123:615–624.
10. Muñoz M, García-Erce JA, Remacha ÁF. Disorders of iron metabolism. Part II: iron deficiency and iron overload. J Clin Pathol. 2011;64:287–296.
11. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352:1011–1023.
12. Ganz T. Hepcidin and iron regulation, 10 years later. Blood. 2011;117:4425–4433.
13. Kulier A, Levin J, Moser R, et al.; Investigators of the Multicenter Study of Perioperative Ischemia Research Group; Ischemia Research and Education Foundation. Impact of preoperative anemia on outcome in patients undergoing coronary artery bypass graft surgery. Circulation. 2007;116:471–479.
14. Karkouti K, Wijeysundera DN, Beattie WS; Reducing Bleeding in Cardiac Surgery (RBC) Investigators. Risk associated with preoperative anemia in cardiac surgery: a multicenter cohort study. Circulation. 2008;117:478–484.
15. van Straten AH, Hamad MA, van Zundert AJ, Martens EJ, Schönberger JP, de Wolf AM. Preoperative hemoglobin level as a predictor of survival after coronary artery bypass grafting: a comparison with the matched general population. Circulation. 2009;120:118–125.
16. Ranucci M, Di Dedda U, Castelvecchio S, Menicanti L, Frigiola A, Pelissero G; Surgical and Clinical Outcome Research (SCORE) Group. Impact of preoperative anemia on outcome in adult cardiac surgery: a propensity-matched analysis. Ann Thorac Surg. 2012;94:1134–1141.
17. Carson JL, Poses RM, Spence RK, Bonavita G. Severity of anaemia and operative mortality and morbidity. Lancet. 1988;1:727–729.
18. Dunne JR, Malone D, Tracy JK, Gannon C, Napolitano LM. Perioperative anemia: an independent risk factor for infection, mortality, and resource utilization in surgery. J Surg Res. 2002;102:237–244.
19. Beattie WS, Karkouti K, Wijeysundera DN, Tait G. Risk associated with preoperative anemia in noncardiac surgery: a single-center cohort study. Anesthesiology. 2009;110:574–581.
20. Geisel T, Martin J, Schulze B, et al. An etiologic profile of anemia in 405 geriatric patients. Anemia. 2014;2014:932486.
21. Leichtle SW, Mouawad NJ, Lampman R, Singal B, Cleary RK. Does preoperative anemia adversely affect colon and rectal surgery outcomes? J Am Coll Surg. 2011;212:187–194.
22. Gupta PK, Sundaram A, Mactaggart JN, et al. Preoperative anemia is an independent predictor of postoperative mortality and adverse cardiac events in elderly patients undergoing elective vascular operations. Ann Surg. 2013;258:1096–1102.
23. Saager L, Turan A, Reynolds LF, Dalton JE, Mascha EJ, Kurz A. The association between preoperative anemia and 30-day mortality and morbidity in noncardiac surgical patients. Anesth Analg. 2013;117:909–915.
24. Roubinian NH, Murphy EL, Swain BE, Gardner MN, Liu V, Escobar GJ; NHLBI Recipient Epidemiology and Donor Evaluation Study-III (REDS-III); Northern California Kaiser Permanente DOR Systems Research Initiative. Predicting red blood cell transfusion in hospitalized patients: role of hemoglobin level, comorbidities, and illness severity. BMC Health Serv Res. 2014;14:213.
25. Qian F, Osler TM, Eaton MP, et al. Variation of blood transfusion in patients undergoing major noncardiac surgery. Ann Surg. 2013;257:266–278.
26. Bolton-Maggs P, Thomas D, Watt A, et al.; on behalf of the SHOT Steering Group. Annual Shot Report 2015. Available at: https://www.shotuk.org/wp-content/uploads/SHOT-2015-Annual-Report-Web-Edition-Final-bookmarked.pdf
. Accessed August 6, 2017.
27. Engoren MC, Habib RH, Zacharias A, Schwann TA, Riordan CJ, Durham SJ. Effect of blood transfusion on long-term survival after cardiac operation. Ann Thorac Surg. 2002;74:1180–1186.
28. Murphy GJ, Reeves BC, Rogers CA, Rizvi SI, Culliford L, Angelini GD. Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery. Circulation. 2007;116:2544–2552.
29. 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.
30. Bernard AC, Davenport DL, Chang PK, Vaughan TB, Zwischenberger JB. Intraoperative transfusion of 1 U to 2 U packed red blood cells is associated with increased 30-day mortality, surgical-site infection, pneumonia, and sepsis in general surgery patients. J Am Coll Surg. 2009;208:931–937, 937.e1.
31. Glance LG, Dick AW, Mukamel DB, et al. Association between intraoperative blood transfusion and mortality and morbidity in patients undergoing noncardiac surgery. Anesthesiology. 2011;114:283–292.
32. Hopewell S, Omar O, Hyde C, Yu LM, Doree C, Murphy MF. A systematic review of the effect of red blood cell transfusion on mortality: evidence from large-scale observational studies published between 2006 and 2010. BMJ Open. 2015;3:e002154.
33. Whitlock EL, Kim H, Auerbach AD. Harms associated with single unit perioperative transfusion: retrospective population based analysis. BMJ. 2015;350:h3037.
34. Tartter PI, Quintero S, Barron DM. Perioperative blood transfusion associated with infectious complications after colorectal cancer operations. Am J Surg. 1986;152:479–482.
35. Murphy P, Heal JM, Blumberg N. Infection or suspected infection after hip replacement surgery with autologous or homologous blood transfusions. Transfusion. 1991;31:212–217.
36. Braga M, Vignali A, Radaelli G, Gianotti L, Di Carlo V. Association between perioperative blood transfusion and postoperative infection in patients having elective operations for gastrointestinal cancer. Eur J Surg. 1992;158:531–536.
37. Triulzi DJ, Vanek K, Ryan DH, Blumberg N. A clinical and immunologic study of blood transfusion and postoperative bacterial infection in spinal surgery. Transfusion. 1992;32:517–524.
38. Hill GE, Frawley WH, Griffith KE, Forestner JE, Minei JP. Allogeneic blood transfusion increases the risk of postoperative bacterial infection: a meta-analysis. J Trauma. 2003;54:908–914.
39. Francis DM, Shenton BK. Blood transfusion and tumour growth: evidence from laboratory animals. Lancet. 1981;2:871.
40. Burrows L, Tartter P. Effect of blood transfusions on colonic malignancy recurrent rate. Lancet. 1982;2:662.
41. Acheson AG, Brookes MJ, Spahn DR. Effects of allogeneic red blood cell transfusions on clinical outcomes in patients undergoing colorectal cancer surgery: a systematic review and meta-analysis. Ann Surg. 2012;256:235–244.
42. Amato A, Pescatori M. Perioperative blood transfusions for the recurrence of colorectal cancer. Cochrane Database Syst Rev. 2006;1:CD005033.
43. Waanders M, van de Watering L, Brand A. Immunomodulation and allogeneic blood transfusion. Transfus Altern Transfus Med. 2008;10:127–138.
44. Luan H, Ye F, Wu L, Zhou Y, Jiang J. Perioperative blood transfusion adversely affects prognosis after resection of lung cancer: a systematic review and a meta-analysis. BMC Surg. 2014;14:34.
45. Sun C, Wang Y, Yao HS, Hu ZQ. Allogeneic blood transfusion and the prognosis of gastric cancer patients: systematic review and meta-analysis. Int J Surg. 2015;13:102–110.
46. Cata JP, Lasala J, Pratt G, Feng L, Shah JB. Association between perioperative blood transfusions and clinical outcomes in patients undergoing bladder cancer surgery: a systematic review and meta-analysis study. J Blood Transfus. 2016;2016:9876394.
47. Poorman CE, Postlewait LM, Ethun CG, et al. Blood transfusion and survival for resected adrenocortical carcinoma: a study from the United States Adrenocortical Carcinoma Group. Am Surg. 2017;83:761–768.
48. Shander A, Hofmann A, Gombotz H, Theusinger OM, Spahn DR. Estimating the cost of blood: past, present, and future directions. Best Pract Res Clin Anaesthesiol. 2007;21:271–289.
49. Shander A, Hofmann A, Ozawa S, Theusinger OM, Gombotz H, Spahn DR. Activity-based costs of blood transfusions in surgical patients at four hospitals. Transfusion. 2010;50:753–765.
50. Agrawal S, Davidson N, Walker M, et al. Assessing the total costs of blood delivery to hospital oncology and haematology patients. Curr Med Res Opin. 2006;22:1903–1909.
51. Muñoz M, Acheson AG, Auerbach M, et al. International consensus statement on the peri-operative management of anaemia and iron deficiency. Anaesthesia. 2017;72:233–247.
52. Goodnough LT, Maniatis A, Earnshaw P, et al. Detection, evaluation, and management of preoperative anaemia in the elective orthopaedic surgical patient: NATA guidelines. Br J Anaesth. 2011;106:13–22.
53. Kozek-Langenecker SA, Ahmed AB, Afshari A, et al. Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology: first update 2016. Eur J Anaesthesiol. 2017;34:332–395.
54. Rosencher N, Kerkkamp HE, Macheras G, et al.; OSTHEO Investigation. Orthopedic Surgery Transfusion Hemoglobin European Overview (OSTHEO) study: blood management in elective knee and hip arthroplasty in Europe. Transfusion. 2003;43:459–469.
55. Gombotz H, Rehak PH, Shander A, Hofmann A. Blood use in elective surgery: the Austrian benchmark study. Transfusion. 2007;47:1468–1480.
56. Clevenger B, Gurusamy K, Klein AA, Murphy GJ, Anker SD, Richards T. Systematic review and meta-analysis of iron therapy in anaemic adults without chronic kidney disease: updated and abridged Cochrane review. Eur J Heart Fail. 2016;18:774–785.
57. Tolkien Z, Stecher L, Mander AP, Pereira DI, Powell JJ. Ferrous sulfate supplementation causes significant gastrointestinal side-effects in adults: a systematic review and meta-analysis. PLoS One. 2015;10:e0117383.
58. Moretti D, Goede JS, Zeder C, et al. Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood. 2015;126:1981–1989.
59. Muñoz M, Auerbach M. Postoperative intravenous iron: a simple strategy to improve outcomes. Lancet Haematol. 2016;3:e401–e402.
60. Yoo YC, Shim JK, Kim JC, Jo YY, Lee JH, Kwak YL. Effect of single recombinant human erythropoietin injection on transfusion requirements in preoperatively anemic patients undergoing valvular heart surgery. Anesthesiology. 2011;115:929–937.
61. Muñoz M, Gómez-Ramírez S, Cuenca J, et al. Very-short-term perioperative intravenous iron administration and postoperative outcome in major orthopedic surgery: a pooled analysis of observational data from 2547 patients. Transfusion. 2014;54:289–299.
62. Froessler B, Palm P, Weber I, Hodyl NA, Singh R, Murphy EM. The important role for intravenous iron in perioperative patient blood management in major abdominal surgery: a randomized controlled trial. Ann Surg. 2016;264:41–46.
63. Avni T, Bieber A, Grossman A, Green H, Leibovici L, Gafter-Gvili A. The safety of intravenous iron preparations: systematic review and meta-analysis. Mayo Clin Proc. 2015;90:12–23.
64. Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmén J. Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant. 2006;21:378–382.
65. Bhandari S. Update of a comparative analysis of cost minimization following the introduction of newly available intravenous iron therapies in hospital practice. Ther Clin Risk Manag. 2011;7:501–509.
66. Winearls CG, Oliver DO, Pippard MJ, Reid C, Downing MR, Cotes PM. Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet. 1986;2:1175–1178.
67. Devon KM, McLeod RS. Pre and peri-operative erythropoietin for reducing allogeneic blood transfusions in colorectal cancer surgery. Cochrane Database Sys Rev. 2009;1:CD007148.
68. Laupacis A, Fergusson D. Erythropoietin to minimize perioperative blood transfusion: a systematic review of randomized trials. The International Study of Peri-operative Transfusion (ISPOT) Investigators. Transfus Med. 1998;8:309–317.
69. Alghamdi AA, Albanna MJ, Guru V, Brister SJ. Does the use of erythropoietin reduce the risk of exposure to allogeneic blood transfusion in cardiac surgery? A systematic review and meta-analysis. J Card Surg. 2006;21:320–326.
70. Alsaleh K, Alotaibi GS, Almodaimegh HS, Aleem AA, Kouroukis CT. The use of preoperative erythropoiesis-stimulating agents (ESAs) in patients who underwent knee or hip arthroplasty: a meta-analysis of randomized clinical trials. J Arthroplasty. 2013;28:1463–1472.
71. Voorn VM, van der Hout A, So-Osman C, et al. Erythropoietin to reduce allogeneic red blood cell transfusion in patients undergoing total hip or knee arthroplasty. Vox Sang. 2016;111:219–225.
72. Unger EF, Thompson AM, Blank MJ, Temple R. Erythropoiesis-stimulating agents–time for a reevaluation. N Engl J Med. 2010;362:189–192.
73. Richman JM, Rowlingson AJ, Maine DN, Courpas GE, Weller JF, Wu CL. Does neuraxial anesthesia reduce intraoperative blood loss? A meta-analysis. J Clin Anesth. 2006;18:427–435.
74. Lier H, Krep H, Schroeder S, Stuber F. Preconditions of hemostasis in trauma: a review. The influence of acidosis, hypocalcemia, anemia, and hypothermia on functional hemostasis in trauma. J Trauma. 2008;65:951–960.
75. Kostakis ID, Alexandrou A, Armeni E, et al. Comparison between minimally invasive and open gastrectomy for gastric cancer in Europe: a systematic review and meta-analysis. Hepatobiliary Surg Nutr. 2016;5:300–310.
76. Hallet J, Beyfuss K, Memeo R, Karanicolas PJ, Marescaux J, Pessaux P. Short and long-term outcomes of laparoscopic compared to open liver resection for colorectal liver metastases. Scand J Surg. 2017;106:3–20.
77. Mallett SV. Clinical Utility of Viscoelastic Tests of Coagulation (TEG/ROTEM) in patients with liver disease and during liver transplantation. Semin Thromb Hemost. 2015;41:527–537.
78. Haas T, Fries D, Tanaka KA, Asmis L, Curry NS, Schöchl H. Usefulness of standard plasma coagulation tests in the management of perioperative coagulopathic bleeding: is there any evidence? Br J Anaesth. 2015;114:217–224.
79. Whiting D, DiNardo JA. TEG and ROTEM: technology and clinical applications. Am J Hematol. 2014;89:228–232.
80. Detecting, managing and monitoring haemostasis: viscoelastometric point-of-care testing (ROTEM, TEG and Sonoclot systems). National Institute for Health and Care Excellence website. Available at: https://www.nice.org.uk/guidance/dg13
. Published 2014. Accessed August 9, 2017.
81. Serraino GF, Murphy GJ. Routine use of viscoelastic blood tests for diagnosis and treatment of coagulopathic bleeding in cardiac surgery: updated systematic review and meta-analysis. Br J Anaesth. 2017;118:823–833.
82. Whiting P, Al M, Westwood M, et al. Viscoelastic point-of-care testing to assist with the diagnosis, management and monitoring of haemostasis: a systematic review and cost-effectiveness analysis. Health Technol Assess. 2015;19:1–228, v.
83. Wikkelso A, Wetterslev J, Moller AM, Afshari A. Thromboelastography (TEG) or thromboelastometry (ROTEM) to monitor haemostatic treatment versus usual care in adults or children with bleeding. Cochrane Database Syst Rev. 2016;8:CD007871.
84. Okamoto S, Hijikata-Okunomiya A, Wanaka K, Okada Y, Okamoto U. Enzyme-controlling medicines: introduction. Semin Thromb Hemost. 1997;23:493–501.
85. Henry DA, Carless PA, Moxey AJ. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2007;4:CD001886.
86. Shakur H, Roberts I, Bautista R, et al. Effects of tranexamic acid on death, vascular occlusive events and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376:23–32.
87. Lawson JH, Murphy MP. Challenges for providing effective hemostasis in surgery and trauma. Semin Hematol. 2004;41:55–64.
88. Ker K, Beecer D, Roberts I. Topical application of tranexamic acid for the reduction of bleeding. Cochrane Database Syst Rev. 2013;7:CD010562.
89. Radosevich M, Goubran HI, Burnouf T. Fibrin sealant: scientific rationale, production methods, properties, and current clinical use. Vox Sang. 1997;72:133–143.
90. Carless PA, Henry DA, Anthony DM. Fibrin sealant use for minimising peri-operative allogeneic blood transfusion. Cochrane Database Syst Rev. 2013;2:CD004171.
91. Li J, Li HB, Zhai XC, Qin-Lei, Jiang XQ, Zhang ZH. Topical use of topical fibrin sealant can reduce the need for transfusion, total blood loss and the volume of drainage in total knee and hip arthroplasty: a systematic review and meta-analysis of 1489 patients. Int J Surg. 2016;36:127–137.
92. Carless PA, Henry DA, Moxey AJ, O’Connell D, Brown T, Fergusson DA. Cell salvage for minimising perioperative allogeneic blood transfusions. Cochrane Database Syst Rev. 2010;17:CD001888.
93. Shantikumar S, Patel S, Handa A. The role of cell salvage autotransfusion in abdominal aortic aneurysm surgery. Eur J Vasc Endovasc Surg. 2011;42:577–584.
94. Ashworth A, Klein AA. Cell salvage as part of a blood conservation strategy in anaesthesia. Br J Anaesth. 2010;105:401–416.
95. Davies L, Brown TJ, Haynes S, Payne K, Elliott RA, McCollum C. Cost-effectiveness of cell salvage and alternative methods of minimising perioperative allogeneic blood transfusion: a systematic review and economic model. Health Technol Assess. 2006;10:iii–iv, ix.
96. Bowley DM, Barker P, Boffard KD. Intraoperative blood salvage in penetrating abdominal trauma: a randomised, controlled trial. World J Surg. 2006;30:1074–1080.
97. Feltracco P, Michieletto E, Barbieri S, et al. Microbiologic contamination of intraoperative blood salvaged during liver transplantation. Transplant Proc. 2007;39:1889–1891.
98. Zhou X, Zhang C, Wang Y, Yu L, Yan M. Preoperative acute normovolemic hemodilution for minimizing allogeneic blood transfusion: a meta-analysis. Anesth Analg. 2015;121:1443–1455.
99. Parker MJ, Roberts CP, Hay D. Closed suction drainage for hip and knee arthroplasty. A meta-analysis. J Bone Joint Surg Am. 2004;86-A:1146–1152.
100. Koch CG, Reineks EZ, Tang AS, et al. Contemporary bloodletting in cardiac surgical care. Ann Thorac Surg. 2015;99:779–784.
101. Low LL, Harrington GR, Stoltzfus DP. The effect of arterial lines on blood-drawing practices and costs in intensive care units. Chest. 1995;108:216–219.
102. Smoller BR, Kruskall MS, Horowitz GL. Reducing adult phlebotomy blood loss with the use of pediatric-sized blood collection tubes. Am J Clin Pathol. 1989;91:701–703.
103. Fischer DP, Zacharowski KD, Meybohm P. Savoring every drop—vampire or mosquito? Crit Care. 2014;18:306.
104. Hare GM, Tsui AK, Ozawa S, Shander A. Anaemia: can we define haemoglobin thresholds for impaired oxygen homeostasis and suggest new strategies for treatment? Best Pract Res Clin Anaesthesiol. 2013;27:85–98.
105. Meier J, Gombotz H. Pillar III—optimisation of anaemia tolerance. Best Pract Res Clin Anaesthesiol. 2013;27:111–119.
106. Gramm J, Smith S, Gamelli RL, Dries DJ. Effect of transfusion on oxygen transport in critically ill patients. Shock. 1996;5:190–193.
107. Tsai AG, Cabrales P, Intaglietta M. Microvascular perfusion upon exchange transfusion with stored red blood cells in normovolemic anemic conditions. Transfusion. 2004;44:1626–1634.
108. Hébert PC, Wells G, Blajchman MA, 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.
109. Carson JL, Terrin ML, Noveck H, et al.; FOCUS Investigators. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med. 2011;365:2453–2462.
110. Carson JL, Sieber F, Cook DR, et al. Liberal versus restrictive blood transfusion strategy: 3-year survival and cause of death results from the FOCUS randomised controlled trial. Lancet. 2015;385:1183–1189.
111. Curley GF, Shehata N, Mazer CD, Hare GM, Friedrich JO. Transfusion triggers for guiding RBC transfusion for cardiovascular surgery: a systematic review and meta-analysis*. Crit Care Med. 2014;42:2611–2624.
112. 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. 2015;350:h1354.
113. Carson JL, Stanworth SJ, Roubinian N, et al. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev. 2016;10:CD002042.
114. Padhi S, Kemmis-Betty S, Rajesh S, Hill J, Murphy MF; Guideline Development Group. Blood transfusion: summary of NICE guidance. BMJ. 2015;351:h5832.
115. Ma M, Eckert K, Ralley F, Chin-Yee I. A retrospective study evaluating single-unit red blood cell transfusions in reducing allogeneic blood exposure. Transfus Med. 2005;15:307–312.
116. Carson JL, Brooks MM, Abbott JD, et al. Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease. Am Heart J. 2013;165:964–971.e1.
117. Patel NN, Avlonitis VS, Jones HE, Reeves BC, Sterne JA, Murphy GJ. Indications for red blood cell transfusion in cardiac surgery: a systematic review and meta-analysis. Lancet Haematol. 2015;2:e543–e553.
118. Murphy GJ, Pike K, Rogers CA, et al.; TITRe2 Investigators. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med. 2015;372:997–1008.
119. Shander A, Goodnough LT. Objectives and limitations of bloodless medical care. Curr Opin Hematol. 2006;13:462–470.
120. Farmer SL, Towler SC, Leahy MF, Hofmann A. Drivers for change: Western Australia Patient Blood Management Program (WA PBMP), World Health Assembly (WHA) and Advisory Committee on Blood Safety and Availability (ACBSA). Best Pract Res Clin Anaesthesiol. 2013;27:43–58.
121. Shander A, Van Aken H, Colomina MJ, et al. Patient blood management in Europe. Br J Anaesth. 2012;109:55–68.
122. Mbanya D. Barriers and enablers to introducing comprehensive patient blood management in the hospital. Biologicals. 2012;40:205–208.
123. Fischer DP, Zacharowski KD, Müller MM, et al. Patient blood management implementation strategies and their effect on physicians’ risk perception, clinical knowledge and perioperative practice—the Frankfurt experience. Transfus Med Hemother. 2015;42:91–97.
124. Muñoz M, Gómez-Ramírez S, Kozek-Langeneker S, et al. ‘Fit to fly’: overcoming barriers to preoperative haemoglobin optimization in surgical patients. Br J Anaesth. 2015;115:15–24.
125. Baron DM, Metnitz PG, Fellinger T, Metnitz B, Rhodes A, Kozek-Langenecker SA. Evaluation of clinical practice in perioperative patient blood management. Br J Anaesth. 2016;117:610–616.
126. Kozek-Langenecker S, Bettelheim P, Guirea A, et al. Interdiscplinary recommendations for the management of anaemia (patient blood management). Available at: http://www.oegari.at/web_files/dateiarchiv/editor/interdisciplinary_recommendations_for_the_management_of_anaemia_2013.pdf
. Accessed August 24, 2017.
127. NHS Blood and Transplant. National comparative audit of blood transfusion. 2015 audit of patient blood management in adults undergoing elective, scheduled surgery. Available at: http://hospital.blood.co.uk/media/28123/2015-pbm-in-scheduled-surgery-audit-report.pdf
. Accessed August 31, 2017.
128. Resar R, Griffin F, Haraden C, Nolan T. Using care bundles to improve health care quality. IHI innovation series white paper. 2012.Cambridge, MA: Institute for Healthcare Improvement.
129. Meybohm P, Richards T, Isbister J, et al. Patient blood management bundles to facilitate implementation. Transfus Med Rev. 2017;31:62–71.
130. Black MD, Vigorito MC, Curtis JR, et al. A multifaceted intervention to improve compliance with process measures for ICU clinician communication with ICU patients and families. Crit Care Med. 2013;41:2275–2283.
131. Levy MM, Rhodes A, Phillips GS, et al. Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study. Crit Care Med. 2015;43:3–12.
132. Lim WS, Rodrigo C, Turner AM, Welham S, Calvert JM; British Thoracic Society. British Thoracic Society community-acquired pneumonia care bundle: results of a national implementation project. Thorax. 2016;71:288–290.
133. Cabana MD, Rand CS, Powe NR, et al. Why don’t physicians follow clinical practice guidelines? A framework for improvement. JAMA. 1999;282:1458–1465.
134. Goodnough LT, Shieh L, Hadhazy E, Cheng N, Khari P, Maggio P. Improved blood utilization using real-time clinical decision support. Transfusion. 2014;54:1358–1365.
135. Meybohm P, Froessler B, Goodnough LT, et al. “Simplified International Recommendations for the Implementation of Patient Blood Management” (SIR4PBM). Perioper Med (Lond). 2017;6:5.