Throughout centuries and across civilizations and cultures, a mysterious and often magical link was frequently envisioned between life and blood. According to Greek mythology, blood taken from the right side of the Gorgons—hideous monsters with hair of snakes—could revive and bring the dead back to life. On the contrary, blood from their left side was a lethal poison that killed instantly. Quite interestingly, this ambivalent nature may find some reflections in the real world. Blood transfusions have undoubtedly saved the lives of thousands at risk of bleeding out, whereas others have suffered from the complications of transfusions. It has become apparent that the risks associated with allogeneic blood transfusions may not be outweighed by the potential benefits in many patients who are routinely transfused. Advancements in blood processing and blood banking have resulted in decreasing risks of transmitting blood-borne infections and transfusion errors.1 Although the risks still persist and are unlikely ever to be completely eliminated (after all, to err is human), the incidence of these severe complications is relatively low.2 On the other hand, allogeneic transfusion is emerging as a potent risk factor for many other complications commonly seen in hospitalized patients, such as lung injury and nosocomial infections, and as an independent predictor of, and contributor to, worse patient outcomes (eg, higher risk of morbidity and mortality). On the other hand, studies have shown that clinical outcomes of patients who are treated without (or with less) allogeneic blood transfusion are often similar to or better than the outcomes of patients who are transfused or receive more blood.3 These risks, in addition to the associated increasing direct and indirect costs of allogeneic blood, as well as the ongoing challenges of maintaining a safe and adequate blood supply, have been the main driving force behind initiatives to limit the use of allogeneic blood transfusions. Additionally, the increased demand of an aging population and a diminished donor pool have further impacted the imperative to adopt a more judicious, evidence-based approach when considering transfusions in patient care.3–7 The era of thinking of blood transfusion as a vitalizing treatment to improve patients' conditions and accelerate their recovery has now been superseded by judicious consideration of allogeneic blood transfusions when other, less-risky modalities are not available.
Allogeneic transfusion is emerging as a potent risk factor for many complications commonly seen in hospitalized patients, such as lung injury and nosocomial infections, and as an independent predictor of, and contributor to, worse patient outcomes. Consequently, the era of thinking of blood transfusion as a vitalizing treatment to improve patients' conditions and accelerate their recovery has now been superseded by judicious consideration of allogeneic blood transfusions when other, less-risky modalities are not available.
WHAT IS PATIENT BLOOD MANAGEMENT?
Bloodless Surgery and Medicine
Invaluable experience has been gained from the care of the severely anemic or bleeding patients who refuse blood transfusions for religious or other personal or medical reasons.8 Particularly, patients belonging to the Jehovah's Witness faith should be acknowledged and credited for their contributions to the field. The believers interpret Bible passages that proscribe consumption of blood (eg, Genesis 9:4) as a ban on receiving blood transfusions, and this is a core value of their faith.9 As a result, care for these patients could pose a tough challenge to clinicians, especially under conditions that are often associated with excessive blood loss and/or severe anemia and thus may call for blood transfusions.
Although the end results occasionally ranged from grave clinical consequences, including increased mortality,10 to resorting to the courts to order the treatment against patients' (or guardians') will, a more constructive approach should be pursued, with the collaboration of the patients and the clinicians to explore and establish care strategies that would improve the outcome of these patients without violating their religious convictions. It should be noted that refusal of allogeneic blood transfusion by Jehovah's Witness patients does not mean that these patients refuse medical treatment. Additionally, the pattern of acceptance of minor blood fractions and factors and other related modalities varies among these patients, allowing and requiring individualized planning based on the preferences of the patients. To improve the care and outcome of these patients, several approaches have been developed—dubbed collectively as bloodless medicine and surgery—to optimize patients' hemoglobin levels, maximize hematopoiesis, minimize blood loss, and maximize oxygen delivery to tissues.11 Using such methods, patients with extremely low hemoglobin levels, not conducive to survival under ordinary conditions, have survived and recovered without receiving allogeneic transfusions.12,13
From Bloodless Medicine and Surgery to Patient Blood Management
As previously discussed, minimizing and avoiding unnecessary allogeneic transfusions appears to be beneficial for most patients. Subsequently, many techniques and approaches used in the management of patients for whom allogeneic transfusions are not an option have been successfully used to care for other patients, under a discipline termed patient blood management (PBM). Here, the goal is not merely to avoid or withhold transfusions, but to apply evidence-based medical and surgical approaches to manage anemia, optimize hemostasis, and minimize blood loss and blood transfusion in order to improve patient outcomes. As such, all patients—regardless of their preference or acceptance of blood products—can be considered as candidates for PBM.
The concept of PBM is evolving. Earlier definitions involved the appropriate provision and use of blood, its components and derivatives, and strategies to reduce or avoid the need for a blood transfusion, with the ultimate goal of improved patient outcome.14 The newer concept places more emphasis on preventive measures that will obviate the need for transfusions (ie, by relying on the patient's own blood rather than a donor's blood). Given the negative outcomes of inappropriate transfusions, blood transfusion has been proposed as a quality indicator in surgery.15,16 Considering the promising benefits of PBM strategies for patients and the healthcare system, it is hoped that PBM is increasingly viewed and adopted as a standard of care for all patients who may be at risk of being transfused at any time during their care.
Principles of Patient Blood Management
Studies have shown that the vast majority of transfusions (as many as 94%) in surgical patients can be attributed to one or a combination of the following factors: low preoperative hemoglobin levels, excessive surgical blood loss, and inappropriate transfusion practices.14 To this end, PBM relies on 3 corresponding aspects, the pillars of PBM (Figure 1)17,18: (1) optimizing hematopoiesis, (2) minimizing bleeding and blood loss, and (3) harnessing and optimizing physiological tolerance of anemia through application of all available modalities, leaving transfusion as the last resort. The broad nature of the approaches employed in PBM calls for multidisciplinary teamwork to achieve the best results. It requires using a combination of various interventions, involving every step of patient care.
Studies have shown that the vast majority of transfusions (as many as 94%) in surgical patients can be attributed to low preoperative hemoglobin levels, excessive surgical blood loss, and/or inappropriate transfusion practices, in consideration of which patient blood management relies on 3 pillars: (1) optimizing hematopoiesis, (2) minimizing bleeding and blood loss, and (3) harnessing and optimizing physiological tolerance of anemia.
The treating clinician should assume a proactive role in applying PBM to the individual patient's care and anticipate and be prepared to address complications; consultation with specialists experienced in PBM should be sought as soon as possible in case of complications or deterioration of the patient's condition. If required and permissible, transfer of the patient to a center capable of proving more advanced care should be considered.17
Whenever possible, adequate preparation is needed in advance to optimize the patient's condition (eg, treatment of anemia, adjustment of the dose of anticoagulant and antiplatelet agents). Similarly, astute planning of procedures can result in more efficient management of the patient's condition and less blood loss. The plan of care for each patient should ideally be tailored to the individual patient's condition and procedures to be performed. For emergent and urgent cases, it is recommended that a general management plan for rapid control of bleeding and possibly transferring to an appropriate center is established in advance. Finally, integration of the PBM strategies as part of a hospital-wide program and establishment of effective data collection and monitoring systems for continuous evaluation and improvement of practices (at institutional, regional, national, and international levels, depending on resources available) should be considered.8
OVERVIEW OF PATIENT BLOOD MANAGEMENT STRATEGIES
Strategies utilized in PBM generally revolve around the 3 pillars discussed previously (Figure 1). The rapidly evolving nature of medicine and development of various medications and devices mean that any review of PBM strategies is bound to be outdated soon. However, certain general strategies and approaches of PBM can be considered universal and unlikely to undergo any major changes.17 Examples of the suggested perioperative PBM strategies are depicted in Figure 2. It should be emphasized that many of these strategies are not limited to surgical cases and can be used in all patients who are at risk of being transfused.
Indication of Transfusion
Judicious use of allogeneic blood products, in accordance with current guidelines, has been included as part of early definitions of PBM. Unlike most modern medical treatments, the safety and efficacy of allogeneic blood transfusions have never been established through randomized controlled trials; and hence, formulation of evidence-based indications for blood transfusion has remained a challenge.19 Transfusion guidelines for various patient populations are available, and they all emphasize that blood products should be transfused when clear physiologic need exists, rather than blindly based on arbitrary hemoglobin or hematocrit triggers. The goal should be treating the patient, rather than attaining a certain hemoglobin level.17,20–23 Nonetheless, it can be concluded from the current guidelines that blood transfusions are generally not indicated in management of patients with hemoglobin levels >10 g/dL, and they are often needed in patients with hemoglobin levels <6 g/dL, and although not substantiated, possibly <8 g/dL in patients with ischemic heart disease. In light of available evidence, a consensus multidisciplinary panel has concluded that allogeneic red blood cell transfusions are unlikely (or uncertain) to improve patients' outcomes in the vast majority of clinical scenarios in which transfusions are commonly used, when patients' hemoglobin level is ≥8 g/dL.24
Whenever possible, physiologic indicators of tissue oxygen delivery and ischemia should be used in guiding transfusion decisions.17,25 This is a field of ongoing research, and new devices for (preferably noninvasive) continuous monitoring of hemoglobin levels, oxygen delivery, oxygen consumption, and ischemia are being developed for routine clinical use. Similarly, guidelines for transfusion of other blood products are available and should be considered in making objective transfusion decisions.
Whenever possible, physiologic indicators of tissue oxygen delivery and ischemia should be used in guiding transfusion decisions.
Detailed history-taking and physical examination is the first step in PBM. Close attention should be given to family and past history of anemia and bleeding disorders, as well as medications that affect coagulation, to identify patients who are at higher risk of anemia and bleeding and plan accordingly (eg, dose adjustment or discontinuation of oral anticoagulants before the surgery). Whenever possible and indicated, less-invasive procedures such as laparoscopic and radiologic interventions should be considered in lieu of open surgeries. Other measures such as preoperative embolization can be effective to decrease blood flow and reduce blood loss during the operation.26,27
Management of Anemia
Anemia is not only a major risk factor for transfusion, but it is also an independent predictor of morbidity and mortality, and patients should be monitored for anemia throughout their course of care.28,29 Recently, a multidisciplinary panel convened by the Network for Advancement of Transfusion Alternatives (NATA) has recommended that hemoglobin level be measured 28 days (4 weeks) before the scheduled procedures in elective orthopaedic surgery patients. These patients should be treated to achieve a target hemoglobin level within the normal range by the time of surgery. Laboratory testing should be used to determine the etiology of the anemia and guide the treatment options.30 Although these recommendations addressed orthopaedic surgeries, most also apply to patients undergoing other major procedures.
Anemia is not only a major risk factor for transfusion, but it is also an independent predictor of morbidity and mortality, and patients should be monitored for anemia throughout their course of care.
Management of anemia consists of treating the underlying cause and use of hematinic agents to rapidly restore hemoglobin levels to normal. Choice of agents should be guided by the etiology of the anemia as well as the patient's condition and available time prior to surgery; commonly used agents include iron (oral or intravenous preparations), folic acid, vitamin B12, and erythropoiesis-stimulating agents (ESAs). Erythropoiesis-stimulating agents are highly effective in increasing hemoglobin levels, and they can produce the equivalent of 1 unit of blood per week of treatment.31 On the other hand, they have been linked with increased risk of cardiovascular and thromboembolic events, increased mortality, and possibly promoting growth of existing tumor cells. Their use should be closely monitored and adjusted to ensure that potential benefits outweigh the risks.32 The US Food and Drug Administration has recently placed ESAs under a risk-mitigation program to ensure their safe use and has reduced its recommended target hemoglobin level for ESA therapy, with emphasis on lowering the dose of these agents to avoid the potential side effects.
Iron supplementation is an effective therapy to increase hemoglobin level in patients with iron-deficiency anemia (or increased iron demand), and possibly even in patients without iron deficiency who are at risk of anemia, although more evidence is needed for the latter indication.33 Several studies have indicated that intravenous iron acts faster and more effectively and is better tolerated compared with oral iron in various populations.34,35 Intravenous iron preparations are available with various formulations (ie, iron dextran, iron sucrose, iron gluconate, and recently approved ferumoxytol), each with specific characteristics to treat iron-deficiency anemia.36 Given the concerns associated with ESAs, the role of intravenous iron has become even more important as the primary therapy for anemia, and as an adjuvant to ESA therapy, to improve efficiency and decrease the ESA dose. Additionally, evidence indicates that intravenous iron with or without ESA therapy can reduce blood transfusions in surgical patients.37 Adverse events associated with intravenous iron are usually mild. Anaphylaxis is the most feared complication of intravenous iron, but it is not an issue with newer intravenous iron supplements such as iron sucrose and iron gluconate, to the point that a test dose may not be required for some of the formulations.35,38
In elective procedures with expected high risk of significant blood loss and need for transfusion, preoperative autologous donation (PAD) can be considered. In this procedure, a few units of the patient's blood are collected and stored during the weeks preceding the procedure and reinfused back to the patient perioperatively if needed.17 This approach can be an appealing option for some patients who prefer to avoid allogeneic blood transfusions, although it is usually not accepted by those of Jehovah's Witness faith (because the circulation of predonated blood with the body is broken).
A few studies suggest that PAD can be a safe and effective modality to reduce allogeneic blood transfusions in selected (often high-blood-loss) procedures.39 However, patients undergoing PAD often need hematinic agents to avoid developing anemia and may face the increased risk of transfusions as a result of the blood draws. The procedure must be timed appropriately to ensure that the patients are not anemic due to PAD at the time of surgery. Additionally, predonated blood units are stored similar to allogeneic blood units and hence may suffer from the same deleterious effects of storage (storage lesion),40 and face the same risk of transfusion errors. Finally, a substantial percentage of the predonated blood (as much as half of it) is never transfused and is wasted.41–43 These and other limitations, in addition to availability of more effective and practical measures (eg, blood cell salvage; see below) have led to a decline in use of PAD in favor of other blood-management modalities.17,41
Surgical planning and rehearsal in complicated procedures can be effective in improving the pace and efficiency of the procedure, minimizing length of surgery and blood loss. Patient blood management strategies during surgery generally focus on minimizing blood loss, collecting and reinfusing shed blood, and improving tolerance of anemia. Vital signs should be closely monitored, and unnecessary hypovolemia and tachycardia should be avoided.17,26
Various options are available to limit the blood flow to the site of surgery, thereby limiting the blood loss. Examples include patient positioning to elevate the site of blood loss, use of tourniquet, and infusion of local vasoconstrictive agents. Hypotensive anesthesia is the other approach to limit blood loss, although hypotension must be closely monitored and controlled to ensure adequate perfusion of vital organs.44 Other approaches revolve around improving hemostasis at the site of bleeding. Electrocautery and argon-beam coagulation provide cleaner cuts and more effective hemostasis at the site of incisions.26,31 Topical hemostatic agents contain active ingredients such as thrombin, fibrinogen, collagen, gelatin, and cellulose and act by promoting coagulation at the site of application and/or physical blockade and tamponade of bleeding vessels.45 Alternatively, systemic agents to promote hemostasis are available. Lysine analogues (tranexamic acid and epsilon aminocaproic acid) are the most commonly used antifibrinolytic agents, which act by inhibiting plasmin and preserving blood clots formed at sites of bleeding. Several studies and meta-analyses have indicated that these agents are safe and effective in reducing bleeding, transfusions, and mortality in various patient populations.46–48 Systemic infusion of certain coagulation factors (eg, activated factor VII, prothrombin complex, factor XIII, and fibrinogen) has also been investigated as means to reduce blood loss (occasionally used in conjunction with point-of-care coagulation tests), and the verdict on the safety and efficacy of these agents for this indication is still unclear.46 Particularly, recent meta-analyses of clinical trials have questioned the efficacy of off-label recombinant activated factor VII in reducing bleeding49 and concluded that the off-label use at high doses increases the risk of thromboembolic events.50 Another systemic approach to minimize blood loss is avoiding hypothermia (if not otherwise indicated), as hypothermia can adversely affect platelet function and result in increased blood loss.17 Even mild perioperative hypothermia has been reported to be associated with increased blood loss and risk of transfusion.51
Certain perfusion strategies are available to reduce surgical blood loss. One option is to collect (or salvage) the blood lost during the surgery, wash and/or filter it, and reinfuse it into the patient when transfusion is needed. This technique is known as autologous blood cell salvage and it has been shown to be effective in reducing allogeneic transfusion.52,53 The technique is generally safe, although concerns have been raised regarding the possibility of reintroducing unwanted cells or materials (eg, tumor cells, fat droplets, amniotic fluid, bacteria, or pharmaceutical agents present in the surgical field) into the blood circulation during the procedure.54,55 However, published case reports and studies have not indicated a significant risk with the use of currently available cell salvage systems.41,56–60 Notably, several studies have indicated that leukocyte depletion filters are able to substantially reduce and remove unwanted cells and particulate materials from the salvaged blood.61,62 Overall, intraoperative cell salvage remains a safe and effective technique in reducing allogeneic transfusions and improving patient outcomes.17,53
On the other hand, acute normovolemic hemodilution relies on removing a part of the blood volume from the circulation and replacing it with other fluids (crystalloids or colloids) before bleeding takes place. Therefore, the blood lost during the surgery is diluted, and the total amount of blood loss from the surgical wound is reduced. The collected blood is kept in the operating room and is reinfused back to the patient at wound closure or whenever transfusion is needed. Despite a reasonable theoretical basis, the safety and efficacy of acute normovolemic hemodilution in clinical practice is still debated. Although some studies show its efficacy in reducing allogeneic blood transfusions and complications,63,64 other studies fail to demonstrate significant benefits.65,66 Acute normovolemic hemodilution is more likely to be beneficial in patients undergoing high-blood-loss procedures, in whom most of the collected blood is expected to be reinfused and waste will be minimal.8,63,67,68 Depending on the specific type of procedure performed, other PBM strategies such as the use of smaller prime volume and smaller circuits in patients undergoing cardiopulmonary bypass can be considered.31
Patient blood management strategies continue after the surgery into the postoperative care unit and beyond. Red-cell salvage can be performed postoperatively and any blood lost in the drains can be washed, filtered, and reinfused if needed. During the first few hours following the surgery, close attention must be given to continued blood loss. If the bleeding persists, the patient should be returned to the operating room for re-exploration without further delay. Vital signs should be closely monitored, and hypothermia (unless otherwise indicated) should be avoided, as previously explained. Cardiac output and ventilation/oxygenation should be optimized. Close attention should be paid to medications and drug interactions that could result in or exacerbate anemia. Prophylaxis of upper gastrointestinal bleeding is recommended in specific cases. Any blood draws for laboratory investigations should be limited to the lowest blood volume needed to successfully carry out the required tests. Additionally, standing laboratory orders (eg, daily complete blood counts for all postsurgical patients) should be avoided, and laboratory tests should only be ordered when a clear indication exists and the result is likely to change the management of the case.26,31
If anemia is present, treatment with hematinics should be considered and additional diagnostic work-up should be performed if other possible causes are suspected. Anemia in the postoperative period is usually due to surgical blood loss (iron-restricted hematopoiesis) and can take weeks to correct if left untreated. Treatment with iron in this period can be highly effective and hasten recovery.69 However, some levels of functional iron deficiency due to the inflammatory inhibition of hematopoiesis may also be present and treatment with ESAs may also be needed, although limited evidence is available in surgical patients.70 Throughout the care, particularly in the postoperative recovery period, allogeneic blood products should only be transfused when clear indication exists and according to the current transfusion guidelines. Transfusions for vague reasons (eg, to speed up recovery or because of fatigue) should be avoided as the associated risks are likely to outweigh any potential benefits.17
The clinical outcome of patients is the ultimate endpoint of interest and all treatments should be evaluated for their effect on improving patients' outcomes. Despite widespread use, allogeneic blood products have not undergone such scrutiny, and the balance between their established risks and questionable benefits is often obscured by a quest to meet and surpass arbitrary laboratory thresholds. The result is a transfusion practice that is highly variable, costly, and likely to do more harm than good to the patients.15 Patient blood management emphasizes the appropriate use of blood components with the ultimate goal of improving patient outcomes using multimodality approaches. Strategies utilized in PBM usually revolve around optimizing patient blood mass and coagulation status, minimizing blood loss, and evidence-based transfusion practices (often considered restrictive compared with common practices). To be most effective, PBM requires multidisciplinary teamwork in the context of a pre-established hospital-wide program. For individual patients, the plan of care should be tailored to their specific condition and planned procedure. Patient blood management modalities span every step in the care of patients and they include various pharmacologic, anesthetic, and surgical interventions, many of which are under active research and development. Figure 2 depicts just a number of options to consider as part of a PBM strategy, yet it can be seen that several tools and modalities are available at every step of care that can be effective in reducing allogeneic transfusions and improving patient outcome. Importantly, the attitude of the clinicians toward the role of allogeneic blood components in the management of their patients is a central component of PBM throughout care. When considering the use of any blood products, the physiologic need and expected benefit, as well as the potential adverse effect on the outcome of the patients should be considered, rather than arbitrary threshold values of hemoglobin or hematocrit. Rather than rushing to order blood, efforts should be made to harness and optimize physiologic adaptations to anemia through application of other available modalities. Although the safety and efficacy of various modalities used in PBM should be evaluated individually, and available options are constantly and continuously evolving, emerging data support that PBM is safe and effective in providing better care and improving patients' outcomes while reducing transfusion of allogeneic blood components.71
Potential conflict of interest: Aryeh Shander has been a consultant for Bayer, Luitpold, Masimo, Novartis, Novo Nordisk, OrthoBiotech, and Zymogenetics; has received research and grant support from U.S. Department of Defense, Bayer, Novartis, Novo Nordisk, OrthoBiotech, Pfizer, and ZymoGenetics; and has been a speaker with honorarium for Bayer, Novartis, OrthoBioetch, Zymogenetics, Masimo. He is a founding member of SABM where he currently serves as the President Elect. Mazyar Javidroozi has received grant and research support from SABM.