Can Blood Transfusion Be Not Only Ineffective, But Also Injurious? Aryeh Shander, MD, and Lawrence Tim Goodnough, MD Department of Anesthesiology and Critical Care, Englewood Hospital and Medical Center, Englewood, New Jersey; and Departments of Pathology and Medicine, Stanford University School of Medicine, Stanford, California
ransfusion of blood components has been a cornerstone of hemodynamic management during the perioperative period. From the early twentieth century the development of blood banking techniques has been credited, despite little controlled data, with saving the lives of thousands of bleeding patients who would have otherwise most likely died. Since then, many types of asanguineous ﬂuids have been added to the repertoire of clinicians in the operating rooms and wards, reducing the reliance on donated blood. Nonetheless, these simple ﬂuids often fall short of providing a comprehensive replacement for numerous functions of blood beyond simple volume expansion. As a complex tissue with various cells and components, blood is tasked with carrying and supplying oxygen and nutrients to maintain acid-base and electrolyte balance, supporting macrocirculation and microcirculation with appropriate osmotic and viscosity characteristics, as well as providing coagulation and hemostasis. As such, blood has remained as the unrivalled and ultimate ﬂuid of choice for hemodynamic management of bleeding patients. Unchallenged, red blood cell (RBC) transfusion has long been considered to be a safe and effective procedure for rapidly increasing patients’ hemoglobin level and to improve oxygen delivery and hemodynamic. For related article, see page 87
Inherent complexities of allogeneic blood components (and the complexity involved in collecting, preparing, storing, and transfusing them) also become their Achilles’ heel as safe and reliable therapeutics. The residual plasma and white blood cells present in a unit of RBC contain a host of inﬂammatory mediators, free radicals, macromolecule oxidation products, dead and broken cells and vesicles, deranged electrolytes, and other components related to “storage lesions” in addition to loads of foreign antigens present in allogeneic blood, potentially creating unknown and unfavorable consequences of their own [1, 2]. Measures such as leukoreduction and improved storage solutions have generally been able to help with this situation, albeit to limited extents [3, 4]. Allogeneic blood transfusions have been rightfully likened to “organ transplantation”—certainly not a matter Address correspondence to Dr Goodnough, Departments of Pathology and Medicine, Stanford University, Stanford University Medical Center, 300 Pasteur Dr, Rm H-1402, 5626, Stanford, CA 94305-5626; e-mail: [email protected]
Ó 2014 by The Society of Thoracic Surgeons Published by Elsevier Inc
to be taken lightly. Hence, it is no surprise that an ever increasing body of evidence has raised questions about adverse patient outcomes related to injurious consequences of blood transfusion, in addition to casting doubt on the effectiveness of routine blood transfusions. In this issue of The Annals, the study by Paone and associates  adds to the pool of evidence. Arguing that transfusion of 1 to 2 units of blood during hospital stay is an indirect indicator of “discretionary and potentially avoidable” transfusions, the researchers collected data on 16,835 adult patients who underwent coronary artery bypass graft surgery from 2008 to 2011 at 33 hospitals under the Michigan Society of Thoracic and Cardiovascular Surgeons Quality Collaborative (MSTCVS-QC). They compared the data of patients who did not receive any RBC transfusions with data of patients who received 1 to 2 units of blood transfusion. After adjustment for a number of confounders, they showed that transfusion of 1 to 2 units blood was associated with increased mortality and morbidity in their patient population . A glance over the baseline characteristics of the cohorts (Table 1 of Paone and colleagues ) reveals differences that give the edge to patients who were not transfused (eg, younger age, higher body mass, higher preoperative hemoglobin level, lower prevalence of various comorbidities, more elective procedures, and higher ejection fraction). This revives the old question of whether transfusion is an independent cause of worse outcomes or just a marker of increased burden of disease . Apart from a handful (and slowly growing) number of randomized clinical trials , the landscape of reports on the impact of allogeneic blood transfusions on patient outcomes is heavily dominated by retrospective studies. Even those few randomized controlled trials conducted to date have predominantly focused on comparing various transfusion strategies, rather than on comparing the outcomes of transfused patients versus untransfused ones. Controlled clinical trials are commonly performed to evaluate safety and efﬁcacy of new treatments (or new indications of existing treatments). But when the key question being considered is about the risks (eg, whether smoking causes cancer or thalidomide causes congenital deformities), running a trial and exposing patients to the suspected risk factor leads to issues for Institutional Review Boards, and in these situations, data from observational studies and other evidence such as animal studies become paramount. While retrospective studies have provided us with invaluable evidence in many ﬁelds [8, 9], Ann Thorac Surg 2014;97:11–4 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2013.08.007
EDITORIAL SHANDER AND GOODNOUGH BLOOD TRANSFUSIONS
they can suffer from issues such as confounders that blur the causal relationships, keeping the observations within the bounds of the realm of association [6, 10]. This problem is not new or unique to transfusion medicine. Half a century ago, acknowledging the ethical issues of running a randomized clinical trial to establish the health risks of smoking, Bradford Hill  put forward nine criteria to aid in bridging the gap between observed association and underlying causation: availability of experimental evidence, strength of association, temporality, biologic gradient (dose-response relationship), biologic plausibility, coherence, consistency, analogy, and speciﬁcity. The same principles can be applied to transfusion medicine when evaluating the evidence from observational studies . The data from multitudes of studies on outcomes of transfusion ﬁt most of these criteria, leaving little doubt on the causal relationship between allogeneic blood transfusions and unfavorable clinical outcomes. Not only do confounders make it difﬁcult to prove causation, they also interfere with quantifying the effect size. Quantifying the dose-response effect is often a case in point. In the Paone and associates  cohorts, a patient receiving 1 to 2 units of blood was on average 2.44 times more likely to die, compared with a not-transfused patient. To adjust the risk of unfavorable outcomes attributed to transfusion for other confounders in their study, they used propensity scoring. In this approach, the investigators ﬁrst construct a regression model to predict the risk or propensity of the patients being transfused (or more accurately, a model predicting the probability of the patients ending up in the transfused versus nottransfused cohorts). The model is used to calculate the transfusion probability or propensity score for each patient (a number between 0 and 1 depending on the way the dependent variable is coded). The patients can then be matched between the transfused and not-transfused cohorts based on their propensity scores, or alternatively, as done in the study by Paone and colleagues , the propensity score can be entered as an independent variable into the regression analysis alongside with transfusion to adjust the effect of transfusion on the outcomes. This approach is limited by the predictive value of the model used to calculate the transfusion propensity scores, which is in turn limited by the available baseline data. A transfusion propensity regression analysis is essentially an effort to understand and model transfusion decision making—a complex and often stochastic process—based on a relatively short list of parameters. Substantial variability in transfusion rates of more or less similar patients at different institutes (or even between different clinicians at the same center) illustrates the challenges faced in modeling transfusion practices . Although it has been suggested that many perioperative transfusions can be explained by the level of hemoglobin and surgical blood loss, a large part of the variability, however, remains unexplained . Paone and coworkers  did not report the predictive value or any other similar measures of the regression model used to calculate the propensity scores,
Ann Thorac Surg 2014;97:11–4
and it is not known how much of the variation in transfusion is explained by their analyzed variables. Nevertheless, after adjustment for the transfusion propensity score, patients in the transfused cohort were still on average 1.86 times more likely to die than the nottransfused cohort. A few other issues are likely to further undermine the reported odds ratio of unfavorable outcomes in the Paone study . While meeting all nine Bradford Hill criteria is not an absolute necessity to deduce causation from association, some criteria, such as temporality, are more important than others. Logically, cause must precede the effect, which means that transfusion must occur before a complication to be able to consider the former the cause of the latter. In the Paone study , however, it seems that any transfusions occurring during the index admission and any postoperative complications have been considered, which could possibly result in a complication (other than death) taking place before the transfusion being attributed to the RBC. The observation that a sizeable number of transfusions are given in the postoperative period further upholds this concern . Despite its importance, it must be noted that the rarity of mortality as an endpoint reduces the power of a study and could possibly prevent it from identifying the observed difference as statistically signiﬁcant. Without venturing into retrospective power and sample calculations and just to illustrate the impact of the lowoccurrence outcomes on the required sample size, more than 10,000 patients are needed per cohort to be able to detect a difference in mortality rate of 1% versus 1.5% in the cohorts with power of 90% and statistical signiﬁcance level of 0.05 . For reference, the overall mortality rate among the 5,951 patients who received 1 or 2 units of packed RBC in this study was about 1.3%, which suggests an underpowered study for the mortality outcome, comparing the subgroups with 1-unit and 2-unit transfusions. Nonetheless, Paone and associates  included morbidity outcomes in their main analyses. While we agree that mortality events must be included among the studied outcomes of any transfusion studies, reliance on them and ignoring other outcomes related to morbidity, quality of life, and resource utilization is likely to limit perspective, and one is bound to miss outcomes that are important for the patient . Presence of a dose-response relationship is another often-cited Bradford Hill criterion, which was excluded by design from analysis in this study. Additionally, the investigators did not include transfusion of other allogeneic blood components (platelets, plasma, and cryoprecipitate) in their analysis. These components may not be transfused as commonly as packed RBCs, but given the relative rare occurrence of mortality and major morbidity outcomes, they can still play important roles and their potential impact cannot be ignored. Lastly, the impact of survival bias remains uncertain. Despite the limitations of cohort studies, the evidence alleging allogeneic blood transfusion as culprit for worsening patient outcomes keeps accumulating. Recently, Hopewell and coworkers  systematically reviewed the
Ann Thorac Surg 2014;97:11–4
published literature from 2006 to 2010 and reafﬁrmed the link between blood transfusion and mortality outcomes. They also acknowledged that some confounding effects often remain despite statistical adjustments. The metaanalysis of Chatterjee and associates  of studies on the impact of transfusion on mortality among patients with myocardial infarction published from 1966 to 2012 offers similar ﬁndings, although the groups who favor transfusion over other therapeutic modalities may not be convinced . Here, the study by Paone and associates  is likely to be more than “just a brick in the wall.” Not many cohort studies can beneﬁt from a ﬁve-ﬁgure sequential patient population with data collected and validated systemically under a 33-hospital collaborative . Given all these data and more, how many of these studies are needed to alert the skeptics within the medical community that transfusion of blood is not benign? Although a case can be made for blood transfusion to an actively bleeding and symptomatic patient whose hemoglobin level is dropping quickly to very low levels, a substantial proportion of blood transfusions that take place in practice today are 1- to-3 unit transfusions to relatively stable patients, and therefore are considered as “prophylactic.” However, any patient groups who beneﬁt from this strategy have not yet been deﬁned. In the meanwhile, clinical trials focusing on restrictive versus liberal transfusion strategies continue to try to deﬁne a hemoglobin level for transfusion rather than identify patients who will actually beneﬁt from a blood transfusion, as evidenced by improved clinical outcomes. Indeed, some have advocated that one needs only to “ask any trauma surgeon” to know that blood transfusion has obvious clinical beneﬁts ; yet it is noteworthy that a recently published trial  demonstrated that aggressive blood component support in ﬁxed ratios of 1:1:1 (RBC, plasma, and platelets) resulted in a 13% mortality rate compared with 1.8% for patients transfused in response to laboratory test results (p ¼ 0.032). A National Heart, Lung, and Blood Institute trial—the Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial (available at: http://clinicaltrials.gov/ show/nct01545232)—is now under way and involving massively bleeding trauma patients to study whether a 1:1:1 ratio of blood components is superior to blood components issued in response to laboratory-based test results . The debate on the impact of transfusion on patient outcomes is likely to continue. If transfusion is indeed providing sick patients with beneﬁt and not harm, why are their mortality and morbidity rates still much worse than their untransfused counterparts? The Red Cell Storage Duration study (available at: http://clinicaltrials.gov/show/ NCT00991341) is under way to identify possibly injurious consequences of older stored blood versus fresher blood in patients undergoing cardiothoracic surgery. If a transfusion of 1 to 2 units of blood can be avoided, why not shift the focus from transfusion as a default treatment in many settings to when its beneﬁts are most likely to outweigh the risks ? Recognition of anemia and its underlying etiology, and its proper management, should be the goal for any patient who is at risk for
SHANDER AND GOODNOUGH BLOOD TRANSFUSIONS
hospitalization for surgical or nonsurgical reasons. This is a view shared by the leading health care quality organizations: the American Medical Association has identiﬁed blood transfusions in a list of the ﬁve most overused therapeutic procedures in the United States . A blood transfusion given by the mobile transfusion unit of Dr Norman Bethune would have been a “gift of life” to a severely injured soldier during the Spanish Civil War, but considering the observations of Paone and colleagues  and many others, and along with the availability of alternative treatments [6, 26–29], is blood transfusion not only unnecessary but actually injurious for the mildly anemic, asymptomatic patient after cardiovascular surgery?
References 1. Lannan KL, Sahler J, Spinelli SL, Phipps RP, Blumberg N. Transfusion immunomodulation—the case for leukoreduced and (perhaps) washed transfusions. Blood Cells Mol Dis 2013;50:61–8. 2. Schonewille H, de Vries RR, Brand A. Alloimmune response after additional red blood cell antigen challenge in immunized hematooncology patients. Transfusion 2009;49:453–7. 3. Pavenski K, Saidenberg E, Lavoie M, Tokessy M, Branch DR. Red blood cell storage lesions and related transfusion issues: a Canadian Blood Services research and development symposium. Transfus Med Rev 2012;26:68–84. 4. Blumberg N, Zhao H, Wang H, Messing S, Heal JM, Lyman GH. The intention-to-treat principle in clinical trials and meta-analyses of leukoreduced blood transfusions in surgical patients. Transfusion 2007;47:573–81. 5. Paone G, Likosky DS, Brewer R, et al. Transfusion of 1 and 2 units of red blood cells is associated with increased morbidity and mortality. Ann Thorac Surg 2014;97:87–94. 6. Shander A, Javidroozi M, Ozawa S, Hare GM. What is really dangerous: anaemia or transfusion? Br J Anaesth 2011;107(Suppl 1):i41–59. 7. Goodnough LT, Levy JH, Murphy MF. Concepts of blood transfusion in adults. Lancet 2013;381:1845–54. 8. Wynder EL, Graham EA. Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma; a study of 684 proved cases. JAMA 1950;143:329–36. 9. Cochrane AL. The detection of pulmonary tuberculosis in a community. Br Med Bull 1954;10:91–5. 10. Gross I, Shander A, Sweeney J. Patient blood management and outcome, too early or not? Best Pract Res Clin Anaesthesiol 2013;27:161–72. 11. Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965;58:295–300. 12. Isbister JP, Shander A, Spahn DR, Erhard J, Farmer SL, Hofmann A. Adverse blood transfusion outcomes: establishing causation. Transfus Med Rev 2011;25:89–101. 13. Shander A, Puzio T, Javidroozi M. Variability in transfusion practice and effectiveness of strategies to improve it. J Cardiothorac Vasc Anesth 2012;26:541–4. 14. Gombotz H, Rehak PH, Shander A, Hofmann A. Blood use in elective surgery: the Austrian benchmark study. Transfusion 2007;47:1468–80. 15. Shander A, Spence RK, Adams D, Shore-Lesserson L, Walawander CA. Timing and incidence of postoperative infections associated with blood transfusion: analysis of 1,489 orthopedic and cardiac surgery patients. Surg Infect 2009;10: 277–83. 16. Dupont WD, Plummer WD Jr. Power and sample size calculations. A review and computer program. Control Clin Trials 1990;11:116–28. 17. Koch CG, Li L, Sessler DI, et al. Duration of red-cell storage and complications after cardiac surgery. N Engl J Med 2008;358:1229–39.
EDITORIAL SHANDER AND GOODNOUGH BLOOD TRANSFUSIONS
18. Hopewell S, Omar O, Hyde C, Yu LM, Doree C, Murphy MF. A systematic review of the effect of red blood cell transfusion on mortality: evidence from large-scale observational studies published between 2006 and 2010. BMJ 2013 May 2 [E-Pub ahead of print]. 19. Chatterjee S, Wetterslev J, Sharma A, Lichstein E, Mukherjee D. Association of blood transfusion with increased mortality in myocardial infarction: a meta-analysis and diversity-adjusted study sequential analysis. JAMA Intern Med 2013;173:132–9. 20. Carson JL, Hebert PC. Here we go again—blood transfusion kills patients? Comment on “Association of blood transfusion with increased mortality in myocardial infarction: a metaanalysis and diversity-adjusted study sequential analysis.” JAMA Intern Med 2013;173:139–41. 21. Carson JL, Reynolds RC, Klein HG. Bad bad blood? Crit Care Med 2008;36:2707–8. 22. Nascimento B, Callum J, Tien H, et al. Effect of a ﬁxed-ratio (1:1:1) transfusion protocol versus laboratoryresults-guided transfusion in patients with severe trauma: a randomized feasibility trial. CMAJ 2013 July 15 [E-Pub ahead of print].
Ann Thorac Surg 2014;97:11–4
23. Shander A, Javidroozi M, Goodnough LT. Anemia screening in elective surgery: deﬁnition, signiﬁcance and patients’ interests [letter]. Anesth Analg 2006;103:778–9 [author reply 9–80]. 24. Shander A, Fink A, Javidroozi M, et al. Appropriateness of allogeneic red blood cell transfusion: the International Consensus Conference on Transfusion Outcomes. Transfus Med Rev 2011;25:232–46. 25. Proceedings from the National Summit on Overuse. September 24, 2012. 2013. The Joint Commission. Available at: http://www.jointcommission.org/overuse_summit/. Accessed July 23, 2013. 26. Goodnough LT, Shander A. Patient blood management. Anesthesiology 2012;116:1367–76. 27. Shander A, Hofmann A, Isbister J, Van Aken H. Patient blood management—the new frontier. Best Pract Res Clin Anaesthesiol 2013;27:5–10. 28. Goodnough LT, Maniatis A, Earnshaw P, et al. Detection, evaluation, and management of preoperative anaemia in the elective orthopaedic surgical patient: NATA guidelines. Br J Anaesth 2011;106:13–22. 29. Spahn DR, Goodnough LT. Alternatives to blood transfusion. Lancet 2013;381:1855–65.