EDITORIAL Red blood cell transfusion thresholds: can we go even lower?
T
he pendulum has swung toward using lower transfusion thresholds. The probable reasons for this change in practice toward using lower transfusion thresholds include accumulating evidence that use of less blood is safe in most patients,1 recommendations from practice guidelines,2,3 and growing influence of blood management programs.4-8 There are now more than 7000 patients that have been enrolled in trials that compared restrictive transfusion threshold between 7 and 8 g/dL and liberal transfusion threshold between 9 and 10 g/dL.1,9 One trial permitted symptoms to trigger transfusion.10 Overall, these trials suggest that a restrictive transfusion approach is as safe as, and in one trial superior to, liberal transfusion.11 There is a trend toward lower mortality at 30 days1 and lower risk of bacterial infection in patients assigned to the restrictive transfusion groups.12 The one exception is in patients with acute myocardial infarction. Small trials raise the possibility that mortality is lower using a liberal transfusion threshold than restrictive transfusion threshold.13,14 Further studies are needed in this important group of patients.15 The most influential trials used a restrictive transfusion threshold between 7 and 8 g/dL.10,11,16 Since patients were not harmed by these lower thresholds, it is reasonable to hypothesize that patients might tolerate an even lower transfusion threshold and further avoid exposure to transfusions. The results from the article by Shander and colleagues17 in this issue of TRANSFUSION suggest that an even lower transfusion threshold might be possible. This single-center study evaluated the mortality and morbidity in 293 patients undergoing surgery with postoperative hemoglobin (Hb) level less than 8 g/dL who declined blood transfusion. The investigators closely replicated the methods used in our prior analysis of 300 similar patients published in 2002.18 Mortality was assessed at 30 days postsurgery. The composite outcome of morbidity included arrhythmia, infections, myocardial infarction, and congestive heart failure. The overall mortality was 8.2% (95% confidence interval [CI], 5%-11.3%) and the adjusted odds of death for each gram decrement in Hb concentration was 1.82 (95% CI, 1.27-2.59). The adjusted odds ratio (OR) for composite morbidity outcome was similar.
© 2014 AABB
Table 1 examines the unadjusted rate of death by 1 g/dL decrements of the nadir postoperative Hb level in the two series of bloodless surgery patients. In contrast to the authors’ interpretation, we conclude that the risk of death is very similar between the two series of patients even though they were hospitalized decades apart. The rate of death was very low in patients with postoperative Hb levels between 7.0 and 7.9 g/dL. Importantly, mortality appears to increase gradually but then accelerates when the Hb level is below 5 g/dL. Furthermore, the adjusted OR of death between the two studies for each gram decrease of Hb have overlapping CIs—1.82 (95% CI, 1.272.59)17 in the present study versus 2.5 (95% CI, 1.9-3.2) in our 2002 study.18 These results suggest that it would be reasonable to conduct a clinical trial comparing patients randomly allocated to 5 or 6 g/dL threshold versus 7 to 8 g/dL threshold. It seems possible that patients would tolerate these lower thresholds, although we could also find that transfusion reduces mortality and/or morbidity at these lower thresholds. Such a trial might best be performed in locations where clinicians frequently use lower thresholds either because of less availability of blood and/or because the risk of blood transfusion is higher, a common situation in the developing world. The study by Shander and colleagues provides important insights to the care of bloodless patients and the data needed to inform patients about their risks associated with declining transfusion. These data also provide critical information needed to identify at what Hb level the risk of death increases and provide rational targets to use in trials. Perhaps we can use an even lower transfusion trigger. It is time to perform that trial.
TABLE 1. Unadjusted rate of death by 1 g/dL decrements of the nadir postoperative Hb level in the two series of bloodless surgery patients Shander et al., Carson et al., 18 201417 (n = 293) Totals (n = 593) Postoperative 2002 (n = 300) Number Mortality* Number Mortality* Number Mortality* Hb 1.1-2.0 2.1-3.0 3.1-4.0 4.1-5.0 5.1-6.0 6.1-7.0 7.1-8.0
7 24 28 32 54 56 99
7 (100) 13 (54.2) 7 (25.0) 11 (34.4) 5 (9.3) 5 (8.9) 0 (0)
0 6 16 25 49 58 133
— 3 (50) 3 (18.8) 6 (19.4) 7 (14.3) 3 (5.2) 2 (1.5)
7 30 44 57 103 114 232
7 (100) 16 (53.3) 10 (22.7) 17 (29.8) 12 (11.7) 8 (7.0) 2 (0.9)
* Data are reported as number (%).
TRANSFUSION 2014;54:2593-2594. Volume 54, October 2014 TRANSFUSION
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EDITORIAL
CONFLICT OF INTEREST The authors have disclosed no conflicts of interest.
Jeffrey L. Carson, MD e-mail: [email protected] Manish S. Patel, MD Division of General Internal Medicine Rutgers Robert Wood Johnson Medical School Rutgers Biomedical and Health Sciences Rutgers, The State University of New Jersey New Brunswick, NJ
institution-wide change in transfusion practices. Transfusion 2014;54:2617-24. 9. Carson JL, Carless PA, Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev 2012;(4): CD002042. 10. Carson JL, Terrin ML, Noveck H, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med 2011;365:2453-62. 11. Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 2013;368:11-21. 12. Rohde JM, Dimcheff DE, Blumberg N, et al. Health care-
REFERENCES 1. Carson JL, Carless PA, Hebert PC. Outcomes using lower vs higher hemoglobin thresholds for red blood cell transfusion. JAMA 2013;309:83-4. 2. Carson JL, Grossman BJ, Kleinman S, et al.; Clinical Transfusion Medicine Committee of the AABB. Red blood cell transfusion: a clinical practice guideline from the AABB*. Ann Intern Med 2012;157:49-58. 3. Retter A, Wyncoll D, Pearse R, et al.; British Committee for Standards in Haematolog. Guidelines on the management of anaemia and red cell transfusion in adult critically ill patients. Br J Haematol 2012;160:445-64.
associated infection after red blood cell transfusion: a systematic review and meta-analysis. JAMA 2014;311:1317-26. 13. Cooper HA, Rao SV, Greenberg MD, et al. Conservative versus liberal red cell transfusion in acute myocardial infarction (the CRIT Randomized Pilot Study). Am J Cardiol 2011;108:1108-11. 14. Carson JL, Brooks MM, Abbott JD, et al. Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease. Am Heart J 2013;165:96471. 15. Sherwood MW, Wang Y, Curtis JP, et al. Patterns and outcomes of red blood cell transfusion in patients undergoing percutaneous coronary intervention. JAMA 2014;311:836-
4. National Blood Authority, Australia. Patient blood management guidelines. 2012. [cited 2014 Jul 30]. Available from: http://www.blood.gov.au/pbm-guidelines
43. 16. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion require-
5. Waters JH, Ness PM. Patient blood management: a growing
ments in critical care. Transfusion Requirements in Critical
challenge and opportunity. Transfusion 2011;51:902-3. 6. Cohn CS, Welbig J, Bowman R, et al. A data-driven approach to patient blood management. Transfusion 2014; 54:316-22. 7. Leahy MF, Roberts H, Mukhtar SA, et al.; Western Australian Patient Blood Management Program. A pragmatic approach to embedding patient blood management in a tertiary hospital. Transfusion 2014;54:1133-45. 8. Oliver JC, Griffin RL, Hannon T, et al. The success of our patient blood management program depended on an
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Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999;340:409-17. 17. Shander A. An update on mortality and morbidity in patients with very low postoperative hemoglobin levels who decline blood transfusion. Transfusion 2014;54: 2688-95. 18. Carson JL, Noveck H, Berlin JA, et al. Mortality and morbidity in patients with very low postoperative Hb levels who decline blood transfusion. Transfusion 2002;42: 812-8.
T
he pendulum has swung toward using lower transfusion thresholds. The probable reasons for this change in practice toward using lower transfusion thresholds include accumulating evidence that use of less blood is safe in most patients,1 recommendations from practice guidelines,2,3 and growing influence of blood management programs.4-8 There are now more than 7000 patients that have been enrolled in trials that compared restrictive transfusion threshold between 7 and 8 g/dL and liberal transfusion threshold between 9 and 10 g/dL.1,9 One trial permitted symptoms to trigger transfusion.10 Overall, these trials suggest that a restrictive transfusion approach is as safe as, and in one trial superior to, liberal transfusion.11 There is a trend toward lower mortality at 30 days1 and lower risk of bacterial infection in patients assigned to the restrictive transfusion groups.12 The one exception is in patients with acute myocardial infarction. Small trials raise the possibility that mortality is lower using a liberal transfusion threshold than restrictive transfusion threshold.13,14 Further studies are needed in this important group of patients.15 The most influential trials used a restrictive transfusion threshold between 7 and 8 g/dL.10,11,16 Since patients were not harmed by these lower thresholds, it is reasonable to hypothesize that patients might tolerate an even lower transfusion threshold and further avoid exposure to transfusions. The results from the article by Shander and colleagues17 in this issue of TRANSFUSION suggest that an even lower transfusion threshold might be possible. This single-center study evaluated the mortality and morbidity in 293 patients undergoing surgery with postoperative hemoglobin (Hb) level less than 8 g/dL who declined blood transfusion. The investigators closely replicated the methods used in our prior analysis of 300 similar patients published in 2002.18 Mortality was assessed at 30 days postsurgery. The composite outcome of morbidity included arrhythmia, infections, myocardial infarction, and congestive heart failure. The overall mortality was 8.2% (95% confidence interval [CI], 5%-11.3%) and the adjusted odds of death for each gram decrement in Hb concentration was 1.82 (95% CI, 1.27-2.59). The adjusted odds ratio (OR) for composite morbidity outcome was similar.
© 2014 AABB
Table 1 examines the unadjusted rate of death by 1 g/dL decrements of the nadir postoperative Hb level in the two series of bloodless surgery patients. In contrast to the authors’ interpretation, we conclude that the risk of death is very similar between the two series of patients even though they were hospitalized decades apart. The rate of death was very low in patients with postoperative Hb levels between 7.0 and 7.9 g/dL. Importantly, mortality appears to increase gradually but then accelerates when the Hb level is below 5 g/dL. Furthermore, the adjusted OR of death between the two studies for each gram decrease of Hb have overlapping CIs—1.82 (95% CI, 1.272.59)17 in the present study versus 2.5 (95% CI, 1.9-3.2) in our 2002 study.18 These results suggest that it would be reasonable to conduct a clinical trial comparing patients randomly allocated to 5 or 6 g/dL threshold versus 7 to 8 g/dL threshold. It seems possible that patients would tolerate these lower thresholds, although we could also find that transfusion reduces mortality and/or morbidity at these lower thresholds. Such a trial might best be performed in locations where clinicians frequently use lower thresholds either because of less availability of blood and/or because the risk of blood transfusion is higher, a common situation in the developing world. The study by Shander and colleagues provides important insights to the care of bloodless patients and the data needed to inform patients about their risks associated with declining transfusion. These data also provide critical information needed to identify at what Hb level the risk of death increases and provide rational targets to use in trials. Perhaps we can use an even lower transfusion trigger. It is time to perform that trial.
TABLE 1. Unadjusted rate of death by 1 g/dL decrements of the nadir postoperative Hb level in the two series of bloodless surgery patients Shander et al., Carson et al., 18 201417 (n = 293) Totals (n = 593) Postoperative 2002 (n = 300) Number Mortality* Number Mortality* Number Mortality* Hb 1.1-2.0 2.1-3.0 3.1-4.0 4.1-5.0 5.1-6.0 6.1-7.0 7.1-8.0
7 24 28 32 54 56 99
7 (100) 13 (54.2) 7 (25.0) 11 (34.4) 5 (9.3) 5 (8.9) 0 (0)
0 6 16 25 49 58 133
— 3 (50) 3 (18.8) 6 (19.4) 7 (14.3) 3 (5.2) 2 (1.5)
7 30 44 57 103 114 232
7 (100) 16 (53.3) 10 (22.7) 17 (29.8) 12 (11.7) 8 (7.0) 2 (0.9)
* Data are reported as number (%).
TRANSFUSION 2014;54:2593-2594. Volume 54, October 2014 TRANSFUSION
2593
EDITORIAL
CONFLICT OF INTEREST The authors have disclosed no conflicts of interest.
Jeffrey L. Carson, MD e-mail: [email protected] Manish S. Patel, MD Division of General Internal Medicine Rutgers Robert Wood Johnson Medical School Rutgers Biomedical and Health Sciences Rutgers, The State University of New Jersey New Brunswick, NJ
institution-wide change in transfusion practices. Transfusion 2014;54:2617-24. 9. Carson JL, Carless PA, Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev 2012;(4): CD002042. 10. Carson JL, Terrin ML, Noveck H, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med 2011;365:2453-62. 11. Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 2013;368:11-21. 12. Rohde JM, Dimcheff DE, Blumberg N, et al. Health care-
REFERENCES 1. Carson JL, Carless PA, Hebert PC. Outcomes using lower vs higher hemoglobin thresholds for red blood cell transfusion. JAMA 2013;309:83-4. 2. Carson JL, Grossman BJ, Kleinman S, et al.; Clinical Transfusion Medicine Committee of the AABB. Red blood cell transfusion: a clinical practice guideline from the AABB*. Ann Intern Med 2012;157:49-58. 3. Retter A, Wyncoll D, Pearse R, et al.; British Committee for Standards in Haematolog. Guidelines on the management of anaemia and red cell transfusion in adult critically ill patients. Br J Haematol 2012;160:445-64.
associated infection after red blood cell transfusion: a systematic review and meta-analysis. JAMA 2014;311:1317-26. 13. Cooper HA, Rao SV, Greenberg MD, et al. Conservative versus liberal red cell transfusion in acute myocardial infarction (the CRIT Randomized Pilot Study). Am J Cardiol 2011;108:1108-11. 14. Carson JL, Brooks MM, Abbott JD, et al. Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease. Am Heart J 2013;165:96471. 15. Sherwood MW, Wang Y, Curtis JP, et al. Patterns and outcomes of red blood cell transfusion in patients undergoing percutaneous coronary intervention. JAMA 2014;311:836-
4. National Blood Authority, Australia. Patient blood management guidelines. 2012. [cited 2014 Jul 30]. Available from: http://www.blood.gov.au/pbm-guidelines
43. 16. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion require-
5. Waters JH, Ness PM. Patient blood management: a growing
ments in critical care. Transfusion Requirements in Critical
challenge and opportunity. Transfusion 2011;51:902-3. 6. Cohn CS, Welbig J, Bowman R, et al. A data-driven approach to patient blood management. Transfusion 2014; 54:316-22. 7. Leahy MF, Roberts H, Mukhtar SA, et al.; Western Australian Patient Blood Management Program. A pragmatic approach to embedding patient blood management in a tertiary hospital. Transfusion 2014;54:1133-45. 8. Oliver JC, Griffin RL, Hannon T, et al. The success of our patient blood management program depended on an
2594
TRANSFUSION Volume 54, October 2014
Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999;340:409-17. 17. Shander A. An update on mortality and morbidity in patients with very low postoperative hemoglobin levels who decline blood transfusion. Transfusion 2014;54: 2688-95. 18. Carson JL, Noveck H, Berlin JA, et al. Mortality and morbidity in patients with very low postoperative Hb levels who decline blood transfusion. Transfusion 2002;42: 812-8.
