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Patient Blood Management: Recommendations From the 2018 Frankfurt Consensus Conference
Mueller MM, Van Remoortel H, Meybohm P, Aranko K, Aubron C, Burger R, Carson JL, Cichutek K, De Buck E, Devine D, et al
Jama. 2019;321(10):983-997
Abstract
Importance: Blood transfusion is one of the most frequently used therapies worldwide and is associated with benefits, risks, and costs. Objective: To develop a set of evidence-based recommendations for patient blood management (PBM) and for research. Evidence Review: The scientific committee developed 17 Population/Intervention/Comparison/Outcome (PICO) questions for red blood cell (RBC) transfusion in adult patients in 3 areas: preoperative anemia (3 questions), RBC transfusion thresholds (11 questions), and implementation of PBM programs (3 questions). These questions guided the literature search in 4 biomedical databases (MEDLINE, EMBASE, Cochrane Library, Transfusion Evidence Library), searched from inception to January 2018. Meta-analyses were conducted with the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology and the Evidence-to-Decision framework by 3 panels including clinical and scientific experts, nurses, patient representatives, and methodologists, to develop clinical recommendations during a consensus conference in Frankfurt/Main, Germany, in April 2018. Findings: From 17607 literature citations associated with the 17 PICO questions, 145 studies, including 63 randomized clinical trials with 23143 patients and 82 observational studies with more than 4 million patients, were analyzed. 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, hemoglobin concentration <7 g/dL) as well as for patients undergoing cardiac surgery (recommended threshold for RBC transfusion, hemoglobin concentration <7.5 g/dL). For implementation of PBM programs, 2 clinical and 3 research recommendations were developed, including recommendations to implement comprehensive PBM programs and to use electronic decision support systems (both conditional recommendations) to improve appropriate RBC utilization. Conclusions and Relevance: The 2018 PBM International Consensus Conference defined the current status of the PBM evidence base for practice and research purposes and established 10 clinical recommendations and 12 research recommendations for preoperative anemia, RBC transfusion thresholds for adults, and implementation of PBM programs. The relative paucity of strong evidence to answer many of the PICO questions supports the need for additional research and an international consensus for accepted definitions and hemoglobin thresholds, as well as clinically meaningful end points for multicenter trials.
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Effects of red-cell storage duration on patients undergoing cardiac surgery
Steiner ME, Ness PM, Assmann SF, Triulzi DJ, Sloan SR, Delaney M, Granger S, Bennett-Guerrero E, Blajchman MA, Scavo V, et al
New England Journal of Medicine. 2015;372((15):):1419-29.
Abstract
BACKGROUND Some observational studies have reported that transfusion of red-cell units that have been stored for more than 2 to 3 weeks is associated with serious, even fatal, adverse events. Patients undergoing cardiac surgery may be especially vulnerable to the adverse effects of transfusion.METHODS We conducted a randomized trial at multiple sites from 2010 to 2014. Participants 12 years of age or older who were undergoing complex cardiac surgery and were likely to undergo transfusion of red cells were randomly assigned to receive leukocyte-reduced red cells stored for 10 days or less (shorter-term storage group) or for 21 days or more (longer-term storage group) for all intraoperative and postoperative transfusions. The primary outcome was the change in Multiple Organ Dysfunction Score (MODS; range, 0 to 24, with higher scores indicating more severe organ dysfunction) from the preoperative score to the highest composite score through day 7 or the time of death or discharge.RESULTS The median storage time of red-cell units provided to the 1098 participants who received red-cell transfusion was 7 days in the shorter-term storage group and 28 days in the longer-term storage group. The mean change in MODS was an increase of 8.5 and 8.7 points, respectively (95% confidence interval for the difference, -0.6 to 0.3; P=0.44). The 7-day mortality was 2.8% in the shorter-term storage group and 2.0% in the longer-term storage group (P=0.43); 28-day mortality was 4.4% and 5.3%, respectively (P=0.57). Adverse events did not differ significantly between groups except that hyperbilirubinemia was more common in the longer-term storage group.CONCLUSIONS The duration of red-cell storage was not associated with significant differences in the change in MODS. We did not find that the transfusion of red cells stored for 10 days or less was superior to the transfusion of red cells stored for 21 days or more among patients 12 years of age or older who were undergoing complex cardiac surgery. (Funded by the National Heart, Lung, and Blood Institute; RECESS ClinicalTrials.gov number, NCT00991341.).
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Liberal versus restrictive blood transfusion strategy: 3-year survival and cause of death results from the FOCUS randomised controlled trial
Carson JL, Sieber F, Cook DR, Hoover DR, Noveck H, ChaitmanBR, Fleisher L, Beaupre L, Macaulay W, Rhoads GG, et al
Lancet. 2015;385((9974):):1183-9
Abstract
BACKGROUND Blood transfusion might affect long-term mortality by changing immune function and thus potentially increasing the risk of subsequent infections and cancer recurrence. Compared with a restrictive transfusion strategy, a more liberal strategy could reduce cardiac complications by lowering myocardial damage, thereby reducing future deaths from cardiovascular disease. We aimed to establish the effect of a liberal transfusion strategy on long-term survival compared with a restrictive transfusion strategy. METHODS In the randomised controlled FOCUS trial, adult patients aged 50 years and older, with a history of or risk factors for cardiovascular disease, and with postoperative haemoglobin concentrations lower than 100 g/L within 3 days of surgery to repair a hip fracture, were eligible for enrolment. Patients were recruited from 47 participating hospitals in the USA and Canada, and eligible participants were randomly allocated in a 1:1 ratio by a central telephone system to either liberal transfusion in which they received blood transfusion to maintain haemoglobin level at 100 g/L or higher, or restrictive transfusion in which they received blood transfusion when haemoglobin level was lower than 80 g/L or if they had symptoms of anaemia. In this study, we analysed the long-term mortality of patients assigned to the two transfusion strategies, which was a secondary outcome of the FOCUS trial. Long-term mortality was established by linking the study participants to national death registries in the USA and Canada. Treatment assignment was not masked, but investigators who ascertained mortality and cause of death were masked to group assignment. Analyses were by intention to treat. The FOCUS trial is registered with ClinicalTrials.gov, number NCT00071032. FINDINGS Between July 19, 2004, and Feb 28, 2009, 2016 patients were enrolled and randomly assigned to the two treatment groups: 1007 to the liberal transfusion strategy and 1009 to the restrictive transfusion strategy. The median duration of follow-up was 31 years (IQR 24-41 years), during which 841 (42%) patients died. Long-term mortality did not differ significantly between the liberal transfusion strategy (432 deaths) and the restrictive transfusion strategy (409 deaths) (hazard ratio 109 [95% CI 095-125]; p=021). INTERPRETATION Liberal blood transfusion did not affect mortality compared with a restrictive transfusion strategy in a high-risk group of elderly patients with underlying cardiovascular disease or risk factors. The underlying causes of death did not differ between the trial groups. These findings do not support hypotheses that blood transfusion leads to long-term immunosuppression that is severe enough to affect long-term mortality rate by more than 20-25% or cause of death. FUNDING National Heart, Lung, and Blood Institute.Copyright © 2015 Elsevier Ltd. All rights reserved.
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A randomized clinical trial of liberal versus restrictive transfusion strategy evaluating long term survival and cause of death: results from the FOCUS trial
Carson JL, Sieber F, Hoover DR, Noveck H, Chaitman BR, Beaupre L, Macaulay W, Rhoads G, Fleisher L, Cook DR, et al
Blood. 2014;124((21)): Abstract No. 757
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Delirium outcomes in a randomized trial of blood transfusion thresholds in hospitalized older adults with hip fracture
Gruber-Baldini AL, Marcantonio E, Orwig D, Magaziner J, Terrin M, Barr E, Brown JP, Paris B, Zagorin A, Roffey DM, et al
Journal of the American Geriatrics Society. 2013;61((8):):1286-95.
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Abstract
OBJECTIVES To determine whether a higher blood transfusion threshold would prevent new or worsening delirium symptoms in the hospital after hip fracture surgery. DESIGN Ancillary study to a randomized clinical trial. SETTING Thirteen hospitals in the United States and Canada. PARTICIPANTS One hundred thirty-nine individuals hospitalized with hip fracture aged 50 and older (mean age 81.5+/-9.1) with cardiovascular disease or risk factors and hemoglobin concentrations of less than 10g/dL within 3days of surgery recruited in an ancillary study of the Transfusion Trigger Trial for Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair. INTERVENTION Individuals in the liberal treatment group received one unit of packed red blood cells and as much blood as needed to maintain hemoglobin concentrations at greater than 10g/dL; those in the restrictive treatment group received transfusions if they developed symptoms of anemia or their hemoglobin fell below 8g/dL. MEASUREMENTS Delirium assessments were performed before randomization and up to three times after randomization. The primary outcome was severity of delirium according to the Memorial Delirium Assessment Scale (MDAS). The secondary outcome was the presence or absence of delirium defined according to the Confusion Assessment Method (CAM). RESULTS The liberal group received a median two units of blood and the restrictive group zero units of blood. Hemoglobin concentration on Day 1 after randomization was 1.4g/dL higher in the liberal group. Treatment groups did not differ significantly at any time point or over time on MDAS delirium severity (P=.28) or CAM delirium presence (P=.83). CONCLUSION Blood transfusion to maintain hemoglobin concentrations greater than 10g/dL alone is unlikely to influence delirium severity or rate in individuals with hip fracture after surgery with a hemoglobin concentration less than 10g/dL. 2013, Copyright the Authors Journal compilation 2013, The American Geriatrics Society.
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Liberal or restrictive transfusion in high-risk patients after hip surgery
Carson JL, Terrin ML, Noveck H, Sanders DW, Chaitman BR, Rhoads GG, Nemo G, Dragert K, Beaupre L, Hildebrand K, et al
The New England Journal of Medicine. 2011;365((26):):2453-62.
Abstract
BACKGROUND The hemoglobin threshold at which postoperative red-cell transfusion is warranted is controversial. We conducted a randomized trial to determine whether a higher threshold for blood transfusion would improve recovery in patients who had undergone surgery for hip fracture. METHODS We enrolled 2016 patients who were 50 years of age or older, who had either a history of or risk factors for cardiovascular disease, and whose hemoglobin level was below 10 g per deciliter after hip-fracture surgery. We randomly assigned patients to a liberal transfusion strategy (a hemoglobin threshold of 10 g per deciliter) or a restrictive transfusion strategy (symptoms of anemia or at physician discretion for a hemoglobin level of <8 g per deciliter). The primary outcome was death or an inability to walk across a room without human assistance on 60-day follow-up. RESULTS A median of 2 units of red cells were transfused in the liberal-strategy group and none in the restrictive-strategy group. The rates of the primary outcome were 35.2% in the liberal-strategy group and 34.7% in the restrictive-strategy group (odds ratio in the liberal-strategy group, 1.01; 95% confidence interval [CI], 0.84 to 1.22), for an absolute risk difference of 0.5 percentage points (95% CI, -3.7 to 4.7). The rates of in-hospital acute coronary syndrome or death were 4.3% and 5.2%, respectively (absolute risk difference, -0.9%; 99% CI, -3.3 to 1.6), and rates of death on 60-day follow-up were 7.6% and 6.6%, respectively (absolute risk difference, 1.0%; 99% CI, -1.9 to 4.0). The rates of other complications were similar in the two groups. CONCLUSIONS A liberal transfusion strategy, as compared with a restrictive strategy, did not reduce rates of death or inability to walk independently on 60-day follow-up or reduce in-hospital morbidity in elderly patients at high cardiovascular risk. (Funded by the National Heart, Lung, and Blood Institute; FOCUS ClinicalTrials.gov number, NCT00071032.).
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FOCUS study: transfusion trigger in patients with cardiovascular disease undergoing hip fracture surgery
Carson JL
Transfusion Alternatives in Transfusion Medicine. 2010;11((Suppl 2):):7. Abstract No. S13.
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Transfusion trigger trial for functional outcomes in cardiovascular patients undergoing surgical hip fracture repair (FOCUS): the principal results
Carson JL, Terrin ML, Magaziner J, Sanders D, Cook DR, Hildebrand K
Blood. 2009;114((22):): Abstract No. LBA-6.
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Transfusion trigger trial for functional outcomes in cardiovascular patients undergoing surgical hip fracture repair (FOCUS)
Carson JL, Terrin ML, Magaziner J, Chaitman BR, Apple FS, Heck DA, Sanders D
Transfusion. 2006;46((12):):2192-206.
Abstract
Laboratory and clinical data suggest that patients with cardiovascular disease are vulnerable to anemia. Several observational studies suggest that cardiovascular disease patients might benefit from higher transfusion thresholds. One randomized clinical trial (TRICC) demonstrated that a 7 g per dL threshold was at least as safe as, and may be preferable to, a 10 g per dL threshold in critical care patients. Comparing two widely used approaches to transfusion practice, FOCUS has the potential to provide definitive evidence on whether higher transfusion triggers are needed in hip fracture patients with cardiovascular disease or cardiovascular disease risk factors. copyright 2006 American Association of Blood Banks. Copyright © 2011 Elsevier B. V. , Amsterdam. All Rights Reserved.
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A pilot randomized trial comparing symptomatic vs. hemoglobin-level-driven red blood cell transfusions following hip fracture
Carson JL, Terrin ML, Barton FB, Aaron R, Greenburg AG, Heck DA, Magaziner J, Merlino FE, Bunce G, McClelland B, et al
Transfusion. 1998;38((6):):522-9.
Abstract
BACKGROUND The indications for transfusion have never been evaluated in an adequately sized clinical trial. A pilot study was conducted to plan larger clinical trials. STUDY DESIGN AND METHODS Hip fracture patients undergoing surgical repair who had postoperative hemoglobin levels less than 10 g per dL were randomly assigned to receive 1) symptomatic transfusion: that is, transfusion for symptoms of anemia or for a hemoglobin level that dropped below 8 g per dL or 2) threshold transfusion: that is, patients receive 1 unit of packed RBCs at the time of random assignment and as much blood as necessary to keep the hemoglobin level above 10 g per dL. Outcomes were 60-day mortality, morbidity, functional status, and place of residence. RESULTS Among 84 eligible patients enrolled, mean (+/- SD) prerandomization hemoglobin was 9.1 (+/- 0.6) g/ dL. The median number of units transfused in the threshold transfusion group was 2 (interquartile range, = 1-2), and that in the symptomatic transfusion group was 0 (6; interquartile range, = 0-2) (p < 0.001). Mean hemoglobin levels were approximately 1 g per dL higher in the threshold group than in the symptomatic group: for example, on Day 2, 10.3 (+/- 0.9) g per dL versus 9.3 (+/- 1.2) g per dL, respectively (p < 0.001). At 60 days, death or inability to walk across the room without assistance occurred in 16 (39.0%) of the symptomatic transfusion group and 19 (45.2%) of the threshold transfusion group. Death occurred by 60 days in 5 (11.9%) of the symptomatic transfusion group and 2 (4.8%) in the threshold transfusion group (relative risk = 2.5; 95% CI, 0.5-12.2). Other outcomes were similar for the two groups. CONCLUSIONS Symptomatic transfusion may be an effective blood-sparing protocol associated with the transfusion of appreciably fewer units of RBCs and lower mean hemoglobin levels than are associated with the threshold transfusion policy. However, it is unknown whether these two clinical strategies have comparable mortality, morbidity, or functional status. A definitive trial is needed.