Patient blood management as the standard of care

A 64-year-old female is referred to the Department of Orthopedic Surgery with chronic infection of a hip replacement that requires revision surgery. The patient is otherwise fit and well but has a history of myocardial infarction 3 years ago.

A full blood count is performed as soon as the patient is listed for surgery, maximizing the available time for preoptimization. Hemoglobin (Hb) concentration is 9.8 g/dL, and therefore hematinics are measured. These reveal a transferrin saturation of 9% (normal, 16%-50%), ferritin of 475 μg/L (normal, 12-150 μg/L), and C-reactive protein of 34 mg/L (normal, <10 mg/L). These results are compatible with a diagnosis of functional iron deficiency. Vitamin B12 and folate levels are within normal range, and a referral is made to gastroenterology to exclude gastrointestinal malignancy.

An IV iron infusion of 1 g ferric carboxymaltose is administered 6 weeks before surgery, which increases the Hb to 10.8 g/dL by the day of surgery.

Pretransfusion compatibility testing reveals multiple red blood cell (RBC) antibodies. It is not possible to accurately estimate the number of donor blood units that will be required for surgery; however, blood loss >1 L is anticipated. Four compatible RBC units are identified and transported to the blood bank in advance of surgery.

Surgery is performed under spinal anesthesia; 1 g IV tranexamic acid is administered at the start of the procedure, and 1 g is administered topically to the surgical field at the end of the procedure. Intraoperative cell salvage produces 256 mL (hematocrit 60%) that are reinfused during the procedure. No drains are used postoperatively.

During the postoperative period, the Hb is 7.7 g/dL, and a single unit of donor RBCs is transfused. The Hb transfusion threshold was 8.0 g/dL, in line with the findings of the Transfusion Trigger Trial for Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair (FOCUS) trial,¹  which found that a liberal RBC transfusion policy (Hb transfusion threshold of 10.0 g/dL) did not reduce rates of death, inability to walk independently on 60-day follow-up, or in-hospital morbidity in elderly patients at high cardiovascular risk in comparison with a restrictive policy (Hb transfusion threshold of 8.0 g/dL). The Hb increased to 8.8 g/dL. The decision to transfuse donor blood is guided by an electronic decision support tool within the electronic patient record. No additional donor blood is required.

Blood transfusion is one of the most common hospital procedures in developed countries, such as the United States and the United Kingdom.²  Over 11.3 million units of RBCs, 1.9 million units of platelets, and 2.7 million units of plasma were transfused to patients in the United States in 2015,³  and there were nearly 3 million blood donations in the United Kingdom in 2017.⁴  Unnecessary use of blood transfusion is common worldwide; national audits of blood transfusion in England and elsewhere suggest that there is substantial inappropriate use of transfusions of all types of blood components.^5,6  Recent evidence indicates that strategies for the restrictive use of RBC transfusions reduce transfusions but are associated with similar patient outcomes to liberal transfusion strategies.^1,7-11  A systematic review of 31 randomized, controlled trials involving >12 000 patients found that transfusing at an Hb concentration between 7 and 8 g/dL decreased the proportion of participants exposed to RBC transfusion by 43% across a broad range of clinical specialties, but there was no difference in mortality or morbidity, such as cardiac events, stroke, pneumonia, thromboembolism, or infection, compared with a liberal transfusion strategy (pretransfusion Hb, 9-10 g/dL).¹⁰  These data from randomized, controlled trials are of considerable importance, because they repudiate data from retrospective and observational studies indicating a variety of adverse outcomes associated with transfusion.¹²  However, transfusions are costly, and they are well known to be associated with adverse events. The inclusion of the evidence for restrictive RBC transfusion in practice guidelines for transfusion^13,14  has resulted in a worldwide reduction in the use of RBC transfusions; some hospitals are using strategies, such as electronic decision support, to support the implementation of restrictive RBC transfusion.¹⁵  In recent years, there has also been a focus on patient blood management (PBM), which recognizes the importance of conserving the patient’s own blood alongside the judicious use of transfusion. PBM is relevant to each stage of the patient journey (see the case study above).

An early driver of exploring measures for blood conservation and the avoidance of blood transfusion was the need to provide modern medical and surgical care for those individuals objecting to transfusion because of their religious beliefs.¹⁵  Additional interest derived from other events, such as the recognition of transfusion-transmitted hepatitis C virus and HIV, concerns about the transmission by transfusion of variant Creutzfeldt–Jakob disease particularly in the United Kingdom, and evidence for the safety of restrictive transfusion practice beginning with the Transfusion Requirements in Critical Care trial published in 1999.⁷  These efforts became organized through the formation of bodies, such as the National Association of Bloodless Medicine and Surgery (1996), The Network for the Advancement of Transfusion Alternatives (1998; now the Network for the Advancement of Patient Blood Management, Haemostasis and Thrombosis), and the Society for the Advancement of Blood Management (2000).

The World Health Organization defines PBM as “a patient-focused, evidence-based and systematic approach to optimize the management of patients and transfusion of blood products for quality and effective patient care. It is designed to improve patient outcomes through the safe and rationale use of blood and blood products and by minimizing unnecessary exposure to blood products.”¹⁶ 

An alternative definition takes the focus away from transfusion and puts it on improving patient outcomes: “PBM is the timely application of evidence-based medical and surgical concepts designed to maintain Hb concentration, optimize hemostasis and minimize blood loss in an effort to improve patient outcome.”¹⁷  These are sometimes termed the “3 pillars” of PBM, and each pillar is illustrated by our case study.

Anemia is very common in hospitalized patients. The main causes are blood loss, poor RBC production, and hemolysis. A study by the American College of Surgeons National Surgical Quality Improvement Program involving 211 hospitals worldwide and 277 425 patients found that 30% of noncardiac surgery patients had anemia on admission.¹⁸  There was an increased risk of 30-day mortality and 30-day morbidity in anemic compared with nonanemic patients in both those with mild anemia and those with moderate severe anemia. Similar results have been found in other studies^19,20  and a meta-analysis of 24 observational studies, which found that preoperative anemia was associated with an increased risk of adverse outcomes, including mortality.²¹ 

A recent retrospective study of 445 371 patients who survived after hospitalization in an integrated network of 21 hospitals found that the prevalence of moderate anemia (Hb, 7-10 g/dL) at discharge from the hospital increased from 20% to 25% and that RBC transfusions decreased by 28% in the same period from 2010 to 2014. The increase in anemia at hospital discharge was not associated with a rise in rehospitalization, subsequent RBC transfusion, or mortality within 6 months of discharge.²²  The authors concluded that their data supported the safety of efforts to limit RBC transfusion and tolerate anemia during and after hospitalization. In an accompanying editorial, Shander and Goodnough²³  emphasized the harms caused by anemia and questioned the false choice between transfusion and tolerance of anemia. They argued that the mindset of “transfusion or anemia” risks calls for even more restrictive transfusion trials rather than focusing on the needs of the patient, which are the judicious use of transfusion, with its known risks and costs, as a short-term measure to prevent tissue hypoxia and ischemia followed by specific treatments for anemia.²³ 

The change in Hb concentration may be more important than absolute values. A difference in Hb of ≥50% after gastrointestinal surgery was associated with complications, especially ischemic adverse events, even if the absolute nadir level of Hb remained greater than the transfusion threshold of 70 g/L.²⁴ 

Over the last 10 years, there have been many publications indicating that PBM implemented in various ways reduces the use of transfusions, but less convincing are data on improvement in clinical outcomes as already described above.^25-28 

An example of such a PBM study is the one conducted in Western Australia, which initiated a comprehensive health system–wide PBM program in 2008.²⁷  It was a retrospective study of 605 046 patients admitted to 4 major adult tertiary care hospitals between July 2008 and June 2014. Comparing final year with baseline, units of RBCs, fresh frozen plasma, and platelets transfused per admission decreased by 41%, representing a saving of over US$18 million. Mean pretransfusion Hb decreased from 7.9 to 7.3 g/dL, and the proportion of elective surgery admissions admitted anemic decreased from 20.8% to 14.4%. Single-unit RBC transfusions increased from 33.3% to 63.7%. There were risk-adjusted reductions in hospital mortality (odds ratio [OR], 0.72; 95% confidence interval [95% CI], 0.67-0.77; P < .001), length of stay (incidence rate ratio, 0.85; 95% CI, 0.84-0.87; P < .001), hospital-acquired infections (OR, 0.79; 95% CI, 0.73-0.86; P < .001), and acute myocardial infarction/stroke (OR, 0.69; 95% CI, 0.58-0.82; P < .001).

Several national bodies and international groups of experts have produced recommendations for PBM.^29-33  The most ambitious of these initiatives was the Consensus Conference held in Frankfurt in April 2018.³⁴ 

The Consensus Conference was held in Frankfurt in April 2018, and it was based on a considerable amount of preparatory work in conducting systematic reviews before the conference and the presentations and discussion at the conference focusing on 17 population/intervention/comparison/outcome (PICO) questions on RBC transfusion in adult patients (Table 1). The questions encompassed preoperative anemia (3 questions), RBC transfusion thresholds (11 questions), and implementation of PBM programs (3 questions). MEDLINE, EMBASE, Cochrane Library, and the Transfusion Evidence Library were searched for relevant literature through January 2018. Meta-analyses were conducted by 3 panels, including clinical and scientific experts, nurses, patient representatives, and methodologists using the GRADE (Grades of Recommendation Assessment, Development, and Evaluation) methodology³⁵  and the Evidence-to-Decision framework,³⁶  to develop clinical recommendations.

In total, 17 607 literature citations were identified to be associated with the 17 PICO questions, including 145 studies, of which 63 were randomized clinical trials with 23 143 patients and 82 were observational studies with >4 million patients. The recommendations are shown in Table 2. For preoperative anemia, 4 clinical and 3 research recommendations were developed, including the strong recommendation to detect and manage anemia sufficiently early before major elective surgery. For RBC transfusion thresholds, 4 clinical and 6 research recommendations were developed, including 2 strong clinical recommendations for critically ill but clinically stable intensive care patients with or without septic shock (recommended threshold for RBC transfusion: Hb < 7 g/dL) as well as patients undergoing cardiac surgery (recommended threshold for RBC transfusion: Hb < 7.5 g/dL). For the implementation of PBM programs, 2 clinical and 3 research recommendations were developed, including recommendations to implement comprehensive PBM programs and use electronic decision support systems to improve appropriate RBC utilization. These recommendations should be adopted for current clinical practice (see the case study).

The quality of evidence for the majority of questions considered at the Consensus Conference apart from RBC transfusion thresholds was moderate to very low. This limited the number of strong recommendations for many of the key questions for PBM and supports the need for additional research and a consensus for clinically meaningful end points for multicenter trials. Research recommendations were made for priority questions in areas with limited evidence (Table 3).

The vast majority of clinical PBM implementation trials were observational and only focused on the number of units of RBCs transfused rather than clinical outcomes, such as patient survival and adverse events. There was concern about bias owing to concurrent interventions or practice evolution that might have occurred during the study period in the reports of these studies as well as the lack of information about how well the PBM interventions of interest were actually implemented in practice. The assessment of reduction in “inappropriate transfusion” (ie, transfusions given outside current guidelines) was often not addressed. Health economic evaluations were lacking to provide robust data on the cost savings, which were primarily in reduced blood usage, compared with the costs of the interventions. Although there was evidence for reduction in RBC use resulting from PBM implementation, there was inadequate evidence for reduction of platelet and plasma usage.

As already indicated in this review, several national bodies and international groups of experts have produced recommendations for PBM.^29-33  A different challenge is to develop “standards” for PBM to encourage the measurement of key parameters and facilitate the identification of opportunities for improvement. The Joint Commission developed performance measures for PBM in collaboration with the University of Pittsburgh (Table 4).³⁷  The American Association of Blood Banks (AABB) followed this by developing Standards for PBM in 2014, updating them in 2018,³⁸  and establishing PBM certification in partnership with The Joint Commission. At the time of writing, 6 centers have achieved PBM certification, and it is expected that 30 centers will have done so by the end of 2020.

The AABB standards cover all aspects of PBM, including the optimization of erythropoiesis, minimization of blood loss, and management of anemia, including the appropriate indications for transfusion. Organizational issues are also encompassed, including management oversight and support, adequate staffing, equipment and information systems, policies and procedures for clinical care, documentation, and responding to nonconformance and adverse events.³⁸ 

Despite the worldwide recognition of the value of PBM, there is still some way to go in terms of its widespread adoption to become “the standard of care.” A recent survey of hospitals in England found poor compliance with PBM standards developed by the National Institute for Health and Care Excellence (NICE) (Table 5).³⁹  Comprehensive PBM implementation is challenging, because it encompasses patients with a wide range of clinical conditions undergoing many different procedures and therapies and involves many clinical settings and many types of health care professionals.

PBM activities require coordination, arguably but not necessarily best led by a transfusion medicine specialist. The support of hospital managers is essential to ensure that sufficient resources are made available and that any organizational problems that might interfere with a comprehensive PBM program are overcome. PBM requires input from multiple medical specialties that may include hematology, anesthesiology, surgery, and gastroenterology as illustrated by the case study. Efforts to raise awareness about PBM include the “Choosing Wisely” campaigns of the AABB⁴⁰  and the American Society of Hematology,⁴¹  which are intended to encourage clinicians to rethink their ingrained culture of liberal transfusion practice and prompt patients to question why they are being prescribed blood.

Our case study illustrates the implementation of PBM. Preoperative anemia is diagnosed and treated at the earliest opportunity before elective surgery. Intraoperatively, antifibrinolytic medication is administered to reduce blood loss, and cell salvage allows a unit of autologous RBCs to be reinfused. There is evidence that spinal anesthesia may reduce blood loss. Conventional suction drains are avoided, because these may increase blood loss. Postoperatively, the recommended transfusion threshold of 8.0 g/dL is followed, and only a single unit of donor RBCs is required supported by an electronic decision support tool.

It is recognized that additional studies are needed to provide better evidence for the whole range of PBM interventions, including evidence for improved patient outcomes and lower hospital costs as well as for reductions in blood utilization. More research also needs to be undertaken to understand how best to use educational efforts and other methods, such as electronic clinical decision support systems,⁴²  to support the implementation of PBM interventions. However, while these studies are being conducted, it is of utmost importance to translate PBM guidelines into practical day-to-day recommendations and encourage their use. The output in terms of practice and research recommendations from the recent PBM Consensus Conference in Frankfurt is another step on the path to making PBM the standard of care.

Michael F. Murphy, National Health Service Blood and Transplant, John Radcliffe Hospital, Oxford OX3 9BQ, United Kingdom; e-mail: mike.murphy@nhsbt.nhs.uk.