Recommendations From the International Consensus Conference on Anemia Management in Surgical Patients (ICCAMS).

BACKGROUND: Perioperative anemia has been associated with increased risk of red blood cell transfusion and increased morbidity and mortality after surgery. The optimal approach to the diagnosis and management of perioperative anemia is not fully established. OBJECTIVE: To develop consensus recommendations for anemia management in surgical patients. METHODS: An international expert panel reviewed the current evidence and developed recommendations using modified RAND Delphi methodology. RESULTS: The panel recommends that all patients except those undergoing minor procedures be screened for anemia before surgery. Appropriate therapy for anemia should be guided by an accurate diagnosis of the etiology. The need to proceed with surgery in some patients with anemia is expected to persist. However, early identification and effective treatment of anemia has the potential to reduce the risks associated with surgery and improve clinical outcomes. As with preoperative anemia, postoperative anemia should be treated in the perioperative period. CONCLUSIONS: Early identification and effective treatment of anemia has the potential to improve clinical outcomes in surgical patients.

Patients' Choice, Consent, and Ethics in Patient Blood Management.

The goal of patient blood management (PBM) is to optimize clinical outcomes for individual patients by managing their blood as a precious and unique resource to be safeguarded and managed judiciously. A corollary to successful PBM is the minimization or avoidance of blood transfusion and stewardship of donated blood. The first is achieved by a multidisciplinary approach with personalized management plans shared and decided on with the patient or their substitute. It follows that the physician-patient relationship is an integral component of medical practice and the fundamental link between patient and doctor based on trust and honest communication. Central to PBM is accurate and timely diagnosis based on sound physiology and pathophysiology as the bedrock on which scientifically based medicine is founded. PBM in all disease contexts starts with the questions, "What is the status of the patient's blood?" "If there are specific abnormalities in the blood, how should they be managed?" and "If allogeneic blood transfusion is considered, is there no reasonable alternative therapy?" There are compelling scientific reasons to implement a nontransfusion default position when there is clinical uncertainty and questionable evidence of clinical efficacy for allogeneic blood transfusion due to known potential hazards. Patients must be informed of their diagnosis, the nature, severity and prognosis of the disease, and treatment options along with risks and benefits. They should be involved in decision-making regarding their management. However, as part of this process, there are multifaceted medical, legal, ethical, and economic issues, encompassing shared decision-making, patient choice, and informed consent. Furthermore, variability in patient circumstances and preferences, the complexity of medical science, and the workings of health care systems in which consent takes place can be bewildering, not only for the patient but also for clinicians obtaining consent. Adding "patient" to the concept of blood management differentiates it from "donor" blood management to avoid confusion and the perception that PBM is a specific medical intervention. Personalized PBM is tailoring the PBM to the specific characteristics of each patient. With this approach, there should be no difficulty addressing the informed consent and ethical aspects of PBM. Patients can usually be reassured that there is nothing out of order with their blood, in which case the focus of PBM is to keep it that way. In some circumstances, a hematologist may be involved as a patient's blood advocate when abnormalities require expert involvement while the primary disease is being managed.

A Global Definition of Patient Blood Management.

While patient blood management (PBM) initiatives are increasingly adopted across the globe as part of standard of care, there is need for a clear and widely accepted definition of PBM. To address this, an expert group representing PBM organizations from the International Foundation for Patient Blood Management (IFPBM), the Network for the Advancement of Patient Blood Management, Haemostasis and Thrombosis (NATA), the Society for the Advancement of Patient Blood Management (SABM), the Western Australia Patient Blood Management (WAPBM) Group, and OnTrac (Ontario Nurse Transfusion Coordinators) convened and developed this definition: "Patient blood management is a patient-centered, systematic, evidence-based approach to improve patient outcomes by managing and preserving a patient's own blood, while promoting patient safety and empowerment." The definition emphasizes the critical role of informed choice. PBM involves the timely, multidisciplinary application of evidence-based medical and surgical concepts aimed at (1) screening for, diagnosing, and appropriately treating anemia; (2) minimizing surgical, procedural, and iatrogenic blood losses and managing coagulopathic bleeding throughout the care; and (3) supporting the patient while appropriate treatment is initiated. We believe that having a common definition for PBM will assist all those involved including PBM organizations, hospital administrators, individual clinicians, and policy makers to focus on the appropriate issues when discussing and implementing PBM. The proposed definition is expected to continue to evolve, making this endeavor a work in progress.

Associations of a Preoperative Anemia and Suboptimal Iron Stores Screening and Management Clinic in Colorectal Surgery With Hospital Cost, Reimbursement, and Length of Stay: A Net Cost Analysis.

BACKGROUND: In 2016, a preoperative clinic was implemented to screen, evaluate, and manage anemia and suboptimal iron stores at a major tertiary care medical center in Western Australia. Few studies compare the costs and reimbursements associated with preoperative anemia and suboptimal iron stores management. The objective of our study was to conduct a net cost analysis associated with the implementation of this clinic. METHODS: We designed a retrospective cohort study involving elective colorectal surgical admissions over a 3-year period. The baseline year selected was the 2015-2016 financial year, with outcomes in the 2016-2017 and 2017-2018 year compared to baseline. The study perspective was the Western Australian Health System. Hospital costs were extracted from the health service clinical costing system, which captures costs at the admission level. The primary outcome was net cost, defined as gross cost minus reimbursement (or funding) received. RESULTS: Our 3-year study included 544 admissions for elective colorectal surgery. After the implementation of the preoperative clinic, 73.4% (n = 257) of admissions were screened for anemia and suboptimal iron stores, and 31.4% (n = 110) received intravenous iron. In our adjusted analysis, when comparing the final year (2017-2018) with baseline (2015-2016), the units of red blood cells transfused per admission decreased 53% (142 vs 303 units per 1000 discharges; P = .006), and mean hospital length of stay decreased 15% (7.7 vs 9.1 days; P = .008). When comparing the final year with baseline, rectal resection admissions were associated with a mean decrease in the net cost of Australian dollar (A$) 7619 (95% confidence interval, 4230-11,008; P < .001) between 2015-2016 and 2017-2018. For small and large bowel procedures, there was a mean decrease of A$6744 (95% confidence interval, 2430-11,057; P = .002). CONCLUSIONS: The implementation of a preoperative anemia and suboptimal iron stores screening and management clinic in elective colorectal surgery was associated with reductions in red cell transfusions, length of stay, and net costs.

Systematic reviews and meta-analyses comparing mortality in restrictive and liberal haemoglobin thresholds for red cell transfusion: an overview of systematic reviews.

BACKGROUND: There are no overviews of systematic reviews investigating haemoglobin thresholds for transfusion. This is important as the literature on transfusion thresholds has grown considerably in recent years. Our aim was to synthesise evidence from systematic reviews and meta-analyses of the effects of restrictive and liberal transfusion strategies on mortality. METHODS: This was a systematic review of systematic reviews (overview). We searched MEDLINE, Embase, Web of Science Core Collection, PubMed, Google Scholar, and the Joanna Briggs Institute EBP Database, from 2008 to 2018. We included systematic reviews and meta-analyses of randomised controlled trials comparing mortality in patients assigned to red cell transfusion strategies based on haemoglobin thresholds. Two independent reviewers extracted data and assessed methodological quality. We assessed the methodological quality of included reviews using AMSTAR 2 and the quality of evidence pooled using an algorithm to assign GRADE levels. RESULTS: We included 19 systematic reviews reporting 33 meta-analyses of mortality outcomes from 53 unique randomised controlled trials. Of the 33 meta-analyses, one was graded as high quality, 15 were moderate, and 17 were low. Of the meta-analyses presenting high- to moderate-quality evidence, 12 (75.0%) reported no statistically significant difference in mortality between restrictive and liberal transfusion groups and four (25.0%) reported significantly lower mortality for patients assigned to a restrictive transfusion strategy. We found few systematic reviews addressed clinical differences between included studies: variation was observed in haemoglobin threshold concentrations, the absolute between group difference in haemoglobin threshold concentration, time to randomisation (resulting in transfusions administered prior to randomisation), and transfusion dosing regimens. CONCLUSIONS: Meta-analyses graded as high to moderate quality indicate that in most patient populations no difference in mortality exists between patients assigned to a restrictive or liberal transfusion strategy. TRIAL REGISTRATION: PROSPERO CRD42019120503.

Anemia in hospitalized patients: an overlooked risk in medical care.

BACKGROUND: This study investigated the association between nadir anemia and mortality and length of stay (LOS) in a general population of hospitalized patients. STUDY DESIGN AND METHODS: A retrospective cohort study of tertiary hospital admissions in Western Australia between July 2010 and June 2015. Outcome measures were in-hospital mortality and LOS. RESULTS: Of 80,765 inpatients, 45,675 (56.55%) had anemia during admission. Mild and moderate/severe anemia were independently associated with increased in-hospital mortality (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.36-1.86, p = 0.001; OR 2.77, 95% CI 2.32-3.30, p < 0.001, respectively). Anemia was also associated with increased LOS, demonstrating a larger effect in emergency (mild anemia-incident rate ratio [IRR] 1.52, 95% CI 1.48-1.56, p < 0.001; moderate/severe anemia-IRR 2.18, 95% CI 2.11-2.26, p < 0.001) compared to elective admissions (mild anemia-IRR 1.30, 95% CI 1.21-1.41, p < 0.001; moderate/severe anemia-IRR 1.69, 95% CI 1.55-1.83, p < 0.001). LOS was longer in patients who developed anemia during admission compared to those who had anemia on admission (IRR 1.13, 95% CI 1.10-1.17, p < 0.001). Red cell transfusion was independently associated with 2.23 times higher odds of in-hospital mortality (95% CI 1.89-2.64, p < 0.001) and 1.31 times longer LOS (95% CI 1.25-1.37, p < 0.001). CONCLUSION: More than one-third of patients not anemic on admission developed anemia during admission. Even mild anemia is independently associated with increased mortality and LOS; however, transfusion to treat anemia is an independent and additive risk factor.

Blood use in patients receiving intensive chemotherapy for acute leukemia or hematopoietic stem cell transplantation: the impact of a health system-wide patient blood management program.

BACKGROUND: Little is published on patient blood management (PBM) programs in hematology. In 2008 Western Australia announced a health system-wide PBM program with PBM staff appointments commencing in November 2009. Our aim was to assess the impact this program had on blood utilization and patient outcomes in intensive chemotherapy for acute leukemia or hematopoietic stem cell transplantation. STUDY DESIGN AND METHODS: A retrospective study of 695 admissions at two tertiary hospitals receiving intensive chemotherapy for acute leukemia or undergoing hematopoietic stem cell transplantation between July 2010 and December 2014 was conducted. Main outcomes included pre-red blood cell (RBC) transfusion hemoglobin (Hb) levels, single-unit RBC transfusions, number of RBC and platelet (PLT) units transfused per admission, subsequent day case transfusions, length of stay, serious bleeding, and in-hospital mortality. RESULTS: Over the study period, the mean RBC units transfused per admission decreased 39% from 6.1 to 3.7 (p < 0.001), and the mean PLT units transfused decreased 35% from 6.3 to 4.1 (p < 0.001), with mean RBC and PLT units transfused for follow-up day cases decreasing from 0.6 to 0.4 units (p < 0.001). Mean pre-RBC transfusion Hb level decreased from 8.0 to 6.8 g/dL (p < 0.001), and single-unit RBC transfusions increased 39% to 67% (p < 0.001). This reduction represents blood product cost savings of AU$694,886 (US$654,007). There were no significant changes in unadjusted or adjusted length of stay, serious bleeding events, or in-hospital mortality over the study. CONCLUSION: The health system-wide PBM program had a significant impact, reducing blood product use and costs without increased morbidity or mortality in patients receiving intensive chemotherapy for acute leukemia or hematopoietic stem cell transplantation.

Improved outcomes and reduced costs associated with a health-system-wide patient blood management program: a retrospective observational study in four major adult tertiary-care hospitals.

BACKGROUND: Patient blood management (PBM) programs are associated with improved patient outcomes, reduced transfusions and costs. In 2008, the Western Australia Department of Health initiated a comprehensive health-system-wide PBM program. This study assesses program outcomes. STUDY DESIGN AND METHODS: This was a retrospective study of 605,046 patients admitted to four major adult tertiary-care hospitals between July 2008 and June 2014. Outcome measures were red blood cell (RBC), fresh-frozen plasma (FFP), and platelet units transfused; single-unit RBC transfusions; pretransfusion hemoglobin levels; elective surgery patients anemic at admission; product and activity-based costs of transfusion; in-hospital mortality; length of stay; 28-day all-cause emergency readmissions; and hospital-acquired complications. RESULTS: Comparing final year with baseline, units of RBCs, FFP, and platelets transfused per admission decreased 41% (p < 0.001), representing a saving of AU$18,507,092 (US$18,078,258) and between AU$80 million and AU$100 million (US$78 million and US$97 million) estimated activity-based savings. Mean pretransfusion hemoglobin levels decreased 7.9 g/dL to 7.3 g/dL (p < 0.001), and anemic elective surgery admissions decreased 20.8% to 14.4% (p = 0.001). Single-unit RBC transfusions increased from 33.3% to 63.7% (p < 0.001). There were risk-adjusted reductions in hospital mortality (odds ratio [OR], 0.72; 95% confidence interval [CI], 0.67-0.77; p < 0.001), length of stay (incidence rate ratio, 0.85; 95% CI, 0.84-0.87; p < 0.001), hospital-acquired infections (OR, 0.79; 95% CI, 0.73-0.86; p < 0.001), and acute myocardial infarction-stroke (OR, 0.69; 95% CI, 0.58-0.82; p < 0.001). All-cause emergency readmissions increased (OR, 1.06; 95% CI, 1.02-1.10; p = 0.001). CONCLUSION: Implementation of a unique, jurisdiction-wide PBM program was associated with improved patient outcomes, reduced blood product utilization, and product-related cost savings.

Increased hospital costs associated with red blood cell transfusion.

BACKGROUND: Red blood cell (RBC) transfusion is independently associated in a dose-dependent manner with increased intensive care unit stay, total hospital length of stay, and hospital-acquired complications. Since little is known of the cost of these transfusion-associated adverse outcomes our aim was to determine the total hospital cost associated with RBC transfusion and to assess any dose-dependent relationship. STUDY DESIGN AND METHODS: A retrospective cohort study of all multiday acute care inpatients discharged from a five hospital health service in Western Australia between July 2011 and June 2012 was conducted. Main outcome measures were incidence of RBC transfusion and mean inpatient hospital costs. RESULTS: Of 89,996 multiday, acute care inpatient discharges, 4805 (5.3%) were transfused at least 1 unit of RBCs. After potential confounders were adjusted for, the mean inpatient cost was 1.83 times higher in the transfused group compared with the nontransfused group (95% confidence interval, 1.78-1.89; p < 0.001). The estimated total hospital-associated cost of RBC transfusion in this study was AUD $77 million (US $72 million), representing 7.8% of total hospital expenditure on acute care inpatients. There was a significant dose-dependent association between the number of RBC units transfused and increased costs after adjusting for confounders. CONCLUSION: RBC transfusions were independently associated with significantly higher hospital costs. The financial implication to hospital budgets will assist in prioritizing areas to reduce the rate of RBC transfusions and in implementing patient blood management programs.

Transfusion strategy trials excluding patients transfused outside the trial study period are more likely to report a trend favouring restrictive strategies: a meta-analysis.

OBJECTIVE: Some large, randomized trials investigating red cell transfusion strategies have significant numbers of transfusions administered outside the trial study period. We sought to investigate the potential impact of this methodological issue. STUDY DESIGN AND SETTING: Meta-analysis of randomized controlled trials comparing liberal versus restrictive transfusion strategies in cardiac surgery and acute myocardial infarction patients. The outcome of interest was 30-day or in-hospital mortality. RESULTS: In cardiac surgery, the pooled risk ratio for mortality was 0.83 (95% CI 0.62-1.12, P=0.22) times lower in the restrictive group when compared to the liberal group in trials applying a transfusion strategy throughout the patient's entire perioperative period, and 1.33 (95% CI 0.84-2.11, P=0.22) times higher in the restrictive group in trials not applying transfusion strategies throughout the entire perioperative period. When combined, the risk ratio for mortality was 0.98 (95% CI 0.73-1.32, P=0.89). In patients with acute myocardial infarction, the risk ratio for mortality was 0.72 (95%CI 0.40-1.28, P=0.26) times lower in the restrictive group when compared to the liberal group in one trial excluding patients administered the intervention pre-randomization and 1.19 (95% CI 0.96-1.47, P=0.11) times higher in the restrictive group in one trial including patients receiving the intervention pre-randomization. When combined the risk ratio for mortality was 1.00 (0.62-1.59, P=0.99). CONCLUSION: Though not statistically significant, there was a consistent difference in trends between randomized controlled trials administering significant numbers of transfusion outside the trial study period compared to those that did not. The implications of our results may extend to randomized controlled trials in other settings that ignore if and how frequently an investigated therapy is administered outside the trial window.

Multivariable statistical models to predict red cell transfusion in elective surgery.

BACKGROUND: Predicting red cell transfusion may assist in identifying those most likely to benefit from patient blood management strategies. Our objective was to identify a simple statistical model to predict transfusion in elective surgery from routinely available data. MATERIALS AND METHODS: Our final multicentre cohort consisted of 42,546 patients and contained the following potential predictors of red cell transfusion known prior to admission: patient age, sex, pre-admission hemoglobin, surgical procedure, and comorbidities. Missing data were handled by multiple imputation methods. The outcome measure of interest was administration of a red cell transfusion. We used multivariable logistic regression models to predict transfusion, and evaluated the performance by applying a 10-fold cross-validation. Model accuracy was assessed by comparing the area under the receiver operating characteristics curve. After applying an optimal probability cut-off we measured model accuracy, sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS: 7.0% (n=2,993) of the study population received a red cell transfusion. Our most simple model predicted red cell transfusion based on admission hemoglobin and surgical procedure with a multiply imputed estimated area under the curve of 0.862 (0.856, 0.864). The estimated accuracy, sensitivity, specificity, positive predictive, and negative predictive values at the probability cut-off of 0.4 were 0.934, 0.257, 0.986, 0.573, and 0.946 respectively. DISCUSSION: A small number of variables available prior to admission can predict red cell transfusion with very good accuracy. Our model can be used to flag high-risk patients most likely to benefit from pre-operative patient blood management measures.

Systematic reviews and meta-analyses comparing mortality in restrictive and liberal haemoglobin thresholds for red cell transfusion: protocol for an overview of systematic reviews.

INTRODUCTION: There has been a significant increase in the number of systematic reviews and meta-analyses of randomised controlled trials investigating thresholds for red blood cell transfusion. To systematically collate, appraise and synthesise the results of these systematic reviews and meta-analyses, we will conduct an overview of systematic reviews. METHODS AND ANALYSIS: This is a protocol for an overview of systematic reviews. We will search five databases: MEDLINE, Embase, Web of Science Core Collection, PubMed (for prepublication, in process and non-Medline records) and Google Scholar. We will consider systematic reviews and meta-analyses of randomised controlled trials evaluating the effect of haemoglobin thresholds for red blood cell transfusion on mortality. Two authors will independently screen titles and abstracts retrieved in the literature search and select studies meeting the eligibility criteria for full-text review. We will extract data onto a predefined form designed to summarise the key characteristics of each review. We will assess the methodological quality of included reviews and the quality of evidence in included reviews. ETHICS AND DISSEMINATION: Formal ethics approval is not required for this overview as we will only analyse published literature. The findings of this study will be presented at relevant conferences and submitted for peer-review publication. The results are likely to be used by clinicians, policy makers and developers of clinical guidelines and will inform suggestions for future systematic reviews and randomised controlled trials. PROSPERO REGISTRATION NUMBER: CRD42019120503.

The theory and practice of bloodless surgery.

The application of blood conservation strategies to minimise or avoid allogeneic blood transfusion is seen internationally as a desirable objective. Bloodless surgery is a relatively new practice that facilitates that goal. However, the concept is either poorly understood or evokes negative connotations. Bloodless surgery is a term that has evolved in the medical literature to refer to a peri-operative team approach to avoid allogeneic transfusion and improve patient outcomes. Starting as an advocacy in the early 1960s, it has now grown into a serious practice being embraced by internationally respected clinicians and institutions. Central to its success is a coordinated multidisciplinary approach. It encompasses the peri-operative period with surgeons, anaesthetists, haematologists, intensivists, pathologists, transfusion specialists, pharmacists, technicians, and operating room and ward nurses utilising combinations of the numerous blood conservation techniques and transfusion alternatives now available. A comprehensive monograph on the subject of bloodless surgery along with detailed coverage of risks and benefits of each modality (some modalities are discussed in more detail elsewhere in this issue) is beyond the scope of this article. Accordingly, a brief overview of the history, theory and practice of bloodless surgery is presented, along with the clinical and institutional management requirements.

Drivers for change: Western Australia Patient Blood Management Program (WA PBMP), World Health Assembly (WHA) and Advisory Committee on Blood Safety and Availability (ACBSA).

Patient blood management is now high on national and international health-system agendas. Serious supply challenges as a result of changing population dynamics, escalating cost of blood, ongoing safety challenges and questions about transfusion efficacy and outcomes are necessitating change in transfusion practice. Numerous initiatives are underway to bring about change, including the institution of comprehensive patient blood management programmes. In 2008, the Western Australia Department of Health initiated a 5-year project to implement a comprehensive health-system-wide Patient Blood Management Program with the aim of improving patient outcomes while reducing costs. Clinically, the Program was structured on the three pillars of patient blood management, namely (1) optimising the patient's own red cell mass, (2) minimising blood loss and (3) harnessing and optimising the patient-specific anaemia reserve. It employs multiple strategies to bring about a cultural change from a blood-product focus to a patient focus. This Program was undertaken in a State that already had one of the lowest red blood cell issuance rates per 1000 population in the developed world (30.47 red blood cell units per 1000 population). The Program identified reasons and drivers for practice change. From financial years 2008-09 to 2011-12, issuance has progressively decreased in Western Australia to 27.54 units per 1000. During the same years, despite increasing activity, total issuance of red blood cells to the entire State decreased from 70,103 units to 65,742. Nationally and internationally, other initiatives are underway to bring about change and implement patient blood management. The World Health Assembly in May 2010 adopted resolution WHA63.12 endorsing patient blood management and its three-pillar application. The United States Advisory Committee on Blood Safety and Availability met in 2011 to consider the implications of this resolution and its implementation.

Economic considerations on transfusion medicine and patient blood management.

In times of escalating health-care cost, it is of great importance to carefully assess the cost-effectiveness and appropriateness of the most resource-consuming health interventions. A long-standing and common clinical practice that has been underestimated in cost and overestimated in effectiveness is the transfusion of allogeneic blood products. Studies show that this intervention comes with largely underestimated service cost and unacceptably high utilisation variability for matched patients, thus adding billions of unnecessary dollars to the health-care expenditure each year. Moreover, a large and increasing body of literature points to a dose-dependent increase of morbidity and mortality and adverse long-term outcomes associated with transfusion whereas published evidence for benefit is extremely limited. This means that transfusion may be a generator for increased hospital stay and possible re-admissions, resulting in additional billions in unnecessary expenditure for the health system. In contrast to this, there are evidence-based and cost-effective treatment options available to pre-empt and reduce allogeneic transfusions. The patient-specific rather than a product-centred application of these multiple modalities is termed patient blood management (PBM). From a health-economic perspective, the expeditious implementation of PBM programmes is clearly indicated. Both patients and payers could benefit from this concept that has recently been endorsed through the World Health Assembly resolution WHA63.12.

Adverse blood transfusion outcomes: establishing causation.

The transfusion of allogeneic red blood cells (RBCs) and other blood components is ingrained in modern medical practice. The rationale for administering transfusions is based on key assumptions that efficacy is established and risks are acceptable and minimized. Despite the cliché that, "the blood supply is safer than ever," data about risks and lack of efficacy of RBC transfusions in several clinical settings have steadily accumulated. Frequentist statisticians and clinicians demand evidence from randomized clinical trials (RCTs); however, causation for the recognized serious hazards of allogeneic transfusion has never been established in this manner. On the other hand, the preponderance of evidence implicating RBC transfusions in adverse clinical outcomes related to immunomodulation and the storage lesion comes from observational studies, and a broad and critical analysis to evaluate causation is overdue. It is suggested in several circumstances that this cannot wait for the design, execution, and conduct of rigorous RCTs. We begin by examining the nature and definition of causation with relevant examples from transfusion medicine. Deductive deterministic methods may be applied to most of the well-accepted and understood serious hazards of transfusion, with modified Koch's postulates being fulfilled in most circumstances. On the other hand, when several possible interacting risk factors exist and RBC transfusions are associated with adverse clinical outcomes, establishing causation requires inferential probabilistic methodology. In the latter circumstances, the case for RBC transfusions being causal for adverse clinical outcomes can be strengthened by applying modified Bradford Hill criteria to the plethora of existing observational studies. This being the case, a greater precautionary approach to RBC transfusion is necessary and equipoise that justifying RCTs may become problematic.