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Restrictive Versus Liberal Transfusion Strategies in Perioperative Blood Management: An Evidence-Based Analysis
Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
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Expert Review
Restrictive Versus Liberal Transfusion Strategies in Perioperative Blood Management: An Evidence-Based Analysis Archer Kilbourne Martin, MDn, J. Ross Renew, MDn, Harish Ramakrishna, MD, FASE, FACC†,1 n
†
Department of Anesthesiology, Mayo Clinic in Florida, Jacksonville, FL Division of Cardiovascular and Thoracic Anesthesiology, Mayo Clinic in Arizona, Phoenix, AZ
Perioperative blood management is universally important and a subject characterized by conflicting data. The issue of appropriate transfusion triggers and the pros and cons of liberal versus conservative transfusion strategies continue to provide constantly changing vision for the perioperative clinician. This review aims to summarize the current literature pertaining to this topic and analyzes the debate between liberal versus restrictive transfusion policies both in cardiac and noncardiac surgery. Superstition has long shrouded the practice of blood transfusion within the human species. Indeed, from the first mention of hematologic infusion in Ovid’s Metamorphoses to Hippocrates’ theory of humors, the ancients had a crude yet all-encompassing respect for blood.1 The initial scientific foray into transfusion occurred on November 22, 1667, with the first reported animal-to-human transfusion occurring between a sheep and a human male. Amazingly, the patient was documented to have survived and undergone a second transfusion a month later. As this experiment was repeated across Europe, a trial as a result of patient death led to the banning of the practice by national medical societies as well as the Catholic Pope in 1679.1 Scientific inquiry into the practice of allogeneic blood transfusion (ABT) was halted for centuries, resuming with the first human-to-human transfusion work of James Blundell in the early-to-mid 19th century. Inspired by the postpartum deaths due to hemorrhage he observed in his own practice, he developed several delivery systems and procedures for arterial-to-venous transfusion.2 The discovery of the ABO system in 1900 by Karl Landsteiner paved the way for modern transfusion medicine.3 In 1 Address reprint requests to Harish Ramakrishna, MD, FASE, FACC, Department of Anesthesiology, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ 85054. E-mail address: [email protected] (H. Ramakrishna).
http://dx.doi.org/10.1053/j.jvca.2017.02.009 1053-0770/
1919, John Pemberton at the Mayo Clinic in Rochester, MN published a large series of more than 1,000 successful blood transfusions. John Lundy, an anesthesiologist at the Mayo Clinic, set up the world’s first blood bank in 1935. In addition to establishing a blood bank that allowed storage of blood up to 14 days, Lundy also established the idea of the perioperative hemoglobin (Hgb) “trigger” for high-risk surgical patients.3 Transfusion science was tested on a major scale for the first time in history during World War II. Massive blood replacement due to battlefield injuries resulted in an increased incidence of the hazards of ABT.4 In the 50 years since, clinicians’ understanding of the benefits and hazards of ABT has allowed them significant progress to their modern day practice—where they attempt to maximize transfusion benefits while ameliorating but not eliminating the hazards associated with the administration of blood.4 The primary benefit of administering blood is the support of oxygen supply as transported by the Hgb and delivered to the cells.5 The hazards of administering blood are far more extensive. Infective risks are potential due to bloodborne viruses, bacteria, parasites, and prions. Immunologic risks include hemolytic reactions, immunosuppression, transfusion-related acute lung injury, mistransfusion, and alloimmunization.5 The hazards are not simply physiologic—data from 2011 showed that the mean acquisition cost of 1 packed red blood cell unit was $210.74 USD, while the mean charge to the patient was $343.63.6 There are ample published data reflecting the risks and benefits of liberal versus restrictive transfusion strategies in perioperative medicine. However, there is a universal lack of agreement among clinicians in perioperative medicine when it concerns the decision to transfuse blood products or not. It is within this framework of the modern understanding of transfusion-related hazards and benefits that the authors explored the topic of perioperative transfusion during cardiac
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and non-cardiac surgery. Specifically, the authors examined the published data that have emerged from the liberal versus restrictive transfusion dilemma over the past 5 years.
studies being limited relative to randomized controlled studies due to the possibility of selection bias.22
Blood Transfusion in Cardiac Surgery
Restrictive Versus Liberal Transfusion in Cardiac Surgery – Trial and Meta-analysis Data
ABT is one of the most frequently performed procedures within cardiovascular medicine.7 The transfusion of blood has been shown to be an independent risk factor for morbidity and mortality within the cardiac surgical patient population.8–10 These effects of transfusion within the cardiac surgical population have been observed to be both short-term and long-term in scope.11 Even with this observed risk, the transfusion of red blood cells occurs within this population, often during a variety of observed pathophysiologic conditions—electrocardiographic elevations or depressions in the ST-segments, rhythm disturbances, echocardiographic regional wall motion abnormalities, or diminished mixed venous saturations.12 Despite some of these relatively objective clinical situations, studies have shown significant variation among hospitals when comparing rates of ABT during cardiac surgery.13–16 Incidence of transfusion varies not only within hospital systems, but also with various cardiac procedures.16 Studies have shown that risk factors associated with increased incidence of red blood cell transfusion include female sex, reoperative cardiac surgeries, combination coronary artery bypass grafting or valve surgeries, older age, renal disease, elevated European System for Cardiac Operative Risk Evaluation score, and preoperative anemia.8,16 The development and implementation of a blood management system within an organization via protocol and team training has been shown to reduce overall blood usage in cardiac surgery.7,12,16 Additionally, implementations of patient blood management systems have been shown to reduce direct costs, hospital length of stay, and kidney injury within the cardiac surgical populations.7,17 Despite these benefits, studies have noted that the implementation of cardiac surgical transfusion protocols has met resistance from cardiac surgeons.18 The studies examining implemented protocols have demonstrated various triggers, but generally, the restrictive protocols target Hgb of 7 or 8 g/dL, while liberal protocols have a threshold of 9 or 10.19 Literature describing these systems noted that it is not simply a matter of a restrictive versus liberal trigger, but a comprehensive program involving preoperative screening of anemia and perioperative techniques designed to minimize blood loss itself.16,17,20 These clinical protocols should be constructed for particular patient populations, as they have the potential downside of being inappropriately applied across various patient cohorts.21 There are much data decrying the lack of transfusion standardization within the cardiac surgical arena, calling for evidence-based algorithms that can be applied across various health systems to guide patient care.9 It is within this environment that studies have been constructed to determine cardiac surgical outcomes of restrictive versus liberal transfusion protocols. These studies were both observational and randomized controlled trials (RCTs), with observational
In 2010, Hajjer et al published the Transfusion Requirements after Cardiac Surgery, or TRACS trial.23 The objective of this prospective RCT was to define whether or not a restrictive ABT strategy was non-inferior to a liberal transfusion strategy in elective cardiac surgery. Five-hundred two patients were assigned randomly to a liberal arm, with a trigger of hematocrit 430%, or a restrictive arm with a transfusion trigger of hematocrit 4 24%. The endpoint was a composite of all-cause mortality and severe morbidity.23 The primary endpoint occurred in 10% of the liberal arm, and 11% of the restrictive, resulting in statistically non-inferior rates between the 2 groups. The authors of the study concluded that the data showed a trend toward increased incidence of cardiogenic shock within the restrictive population as compared with the liberal, and noted that the mere transfusion of red blood cells resulted in higher rates of complications after the surgical procedure.23 As a follow-up to TRACS, Nakamura et al in 2015 used a subset of data from the TRACS trial to evaluate outcomes in patients undergoing elective cardiac surgery who were older than 60 as compared to those younger than 60 years. The original 502 patients were divided into 2 groups based on age, with 260 patients older than 60 and 242 patients younger than 60. The primary outcome was the same as the original trial, defined as a composite combination of 30-day all-cause mortality and severe morbidity.24 While no difference was observed between the groups in terms of primary outcomes, the elderly population was seen to have an increased incidence of cardiogenic shock when randomized to the restrictive arm (12.8%) versus the liberal arm (5.2%).24 The next major RCT designed to study outcomes based on transfusion triggers in cardiac surgery was the Transfusion Indication Threshold Reduction (TiTre2) study published in the New England Journal of Medicine in 2015.25 This multicenter RCT was conducted in 17 centers within the United Kingdom. A total of 2,003 patients with postoperative Hgb o9 were randomized into a restrictive or liberal transfusion trigger arm. Of this total, 1,000 patients were placed in a restrictive threshold group, as defined as an Hgb trigger o7.5, with 1,003 patients placed into the liberal threshold trigger arm of 4 9.25 The primary outcome of the trial was defined as either a serious infection or ischemic event within 3 months of randomization. The restrictive transfusion threshold was shown to be non-superior as compared to the liberal threshold with regard to morbidity and healthcare costs.25 While there was no observed statistically significant difference between the 2 arms with regard to primary outcome, there were more deaths by the 3-month mark in the restrictive threshold group as compared with the liberal group (4.2% v 2.6%). Thirty-day
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mortality was 2.6% in the restrictive group versus 1.9% in the liberal group. The authors noted that the higher frequency of death in the restrictive group persisted in sensitivity analyses, and that these results raised questions as to the use of restrictive transfusion triggers in the setting of cardiac surgery.25 Curley et al published a systematic review and metaanalysis in 2014 examining whether or not restrictive transfusion triggers were associated with inferior clinical outcomes in RCTs within the cardiac surgical population.26 A total of 7 studies with 1,262 subjects were included in the review. When the data were pooled, there was no statistically significant effect between restrictive and liberal triggers on hospital mortality or risk of major morbidity, to include myocardial infarction, stroke, and acute renal failure.26 However, the authors did note a trend of increased mortality within the restrictive trigger transfusion group of cardiac surgical patients. A second major systematic review and meta-analysis published in 2015 by Patel et al reviewed evidence from RCTs and observational studies to determine transfusion decisions in adult cardiac surgery.27 While the data included 6 cardiac surgical RCTs, it also examined 19 non-cardiac surgical trials and 39 observational studies within the cardiac surgical literature. Upon examining the 6 cardiac surgical RCTs totaling 3,352 patients, the authors noted that there was no evidence that liberal transfusion triggers led to increased pulmonary, acute renal, or infectious morbidity as compared with the restrictive strategy. There was a statistically nonsignificant benefit observed with the liberal strategy as compared with the restrictive strategy with regard to mortality within these trials. When the meta-analysis was applied to 7 trials with active cardiac disease patients (5 surgical and 2 non-surgical myocardial infarction patients), liberal red blood cell transfusion was shown to reduce mortality as compared to restrictive transfusion thresholds. This contrasted significantly with the meta-analysis of 12 RCTs within this study of patients who either had stable or no cardiac disease. This patient subset was seen to have increased mortality with liberal red blood cell transfusion strategies as compared to a restrictive strategy. The results of the observational studies analyses within the cardiac surgical population study suggested that the transfusion of red blood cells was associated with increased mortality and morbidity. Whereas the RCTs examined liberal versus restrictive triggers for transfusion, the observational studies predominatly studied the risks of transfusion versus no transfusion. The authors concluded that results from observational studies and non-cardiac surgical trials should not be applied to transfusion protocol development or clinical care decisions within the cardiac surgical population.27 Hovaguimian and Myles recently confirmed the importance of constructing transfusion-trigger protocols within a contextspecific setting in their 2016 systematic review and metaanalysis.28 Multiple literature sources were searched from inception until November 2015 for RCTs comparing restrictive and liberal transfusion strategies in adult surgical and critically ill patients. Risk ratios were calculated for several factors,
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including 30-day complications due to inadequate oxygen supply, mortality, a composite of both, and infections. A total of 8 of the 31 trials were related to patients undergoing cardiac or vascular procedures. Restrictive strategies in this population increased the risk of each event category except infections. The authors concluded that restrictive strategies should be applied with caution in high-risk patients undergoing major surgery, and that future protocols should be constructed considering both patient comorbidities and surgical settings.28 The debate as to the superiority of liberal versus restrictive triggers for cardiac surgical patients continues to be waged within the literature. With 1 large trial demonstrating noninferiority of the restrictive versus liberal transfusion strategy with regard to mortality and morbidity, there were other data showing trends toward increased cardiogenic shock and mortality when the restrictive trigger was used within the cardiac surgical population. Meta-analysis data showed differences when comparing patients with active cardiac versus no cardiac disease, as well as suggesting increased risk to the patient when applying restrictive protocols within the cardiac surgical setting. A consistent theme within the literature is the importance of constructing transfusion protocols within the context of the patient’s disease state and procedure, and thus the authors next discuss the literature within the non-cardiac surgical patient population. Analysis of the Liberal Versus Restrictive Transfusion Debate in Non-cardiac Surgery In the current era of trying to deliver cost-effective care while maintaining high standards for patient safety, much work has been done to determine the risks associated with anemia, the role of ABT, and appropriate Hgb concentrations that trigger such interventions in a variety of clinical settings. A recent retrospective study of more than 400,000 non-cardiac major surgeries performed at VA hospitals found the incidence of blood transfusion to be as high as 9%.29 With ABT being so common in non-cardiac surgery, surprisingly few multicenter RCTs exist examining appropriate perioperative Hgb triggers to help guide clinicians. As such, many anesthesiologists extrapolate blood management data from studies on critically ill, non-surgical patients.30 The Transfusion Requirements In Critical Care (TRICC) study demonstrated that a restrictive transfusion strategy was at least as effective as a liberal transfusion trigger in most clinical settings.30 The etiology of anemia in the intensive care unit is usually more gradual as a result of decreased red cell production and frequent laboratory studies in patients who often have multi-organ dysfunction. This anemia clearly is different from the brisk, hemodynamically challenging bleeding that can occur during non-cardiac surgery. Caution must be taken when applying transfusion strategies from one clinical setting to another. In addition to the critical care prospective trials, numerous retrospective cohort studies have examined blood transfusion strategies in non-cardiac surgery.31–35 These efforts can provide valuable insight into the effects of ABT strategies for specific populations undergoing certain operations.
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However, clinicians must be careful when applying transfusion concepts from such homogenous patient populations to differing clinical settings. For instance, a patient with coronary artery disease undergoing a pancreatic resection may have a higher Hgb transfusion trigger than a younger patient undergoing orthopedic surgery. While these 2 scenarios clearly are different and at extreme ends of the spectrum, they reinforce that ABT practice must be individualized and interpretation of data needs a nuanced approach. Fortunately, major societal guidelines do exist to assist clinicians; however, such recommendations have the limitations of relying heavily on expert opinion,36 are based on a single RCT,37 or rely on assumptions of their previous guidelines.38 The American Society of Anesthesiologists’ Task Force on Blood Management described restrictive strategies as effective at reducing the usage of ABT; however, the findings for morbidity were equivocal. It is not surprising that dramatic variability exists in transfusion practices during non-cardiac surgery.39 In general, blood transfusion in any setting has been associated with various negative consequences such as immune modulation, risk of transfusion reaction, circulatory overload, the consumption of a finite resource,5 and a significant financial burden.6 When focusing on patients undergoing non-cardiac surgery, preoperative anemia exists as a significant perioperative risk and has been associated independently with increased mortality.40,41 In addition, treatment of such anemia with intraoperative ABT also has been associated with higher risk of morbidity and mortality.42 When evaluating the effects of ABT, it is difficult to elucidate if poor outcomes are due to the actual intervention of ABT or the presence of perioperative anemia, even when researchers attempt to control for such confounders. The “second-hit” theory has been presented as an explanation for such increased mortality and morbidity. This notion proposes that the perioperative anemia itself is the first insult to the patient. The “second hit” is from the additional sequelae associated with ABT, which has been discussed previously in the opening paragraphs. Because not intervening by withholding autologous blood avoids the aforementioned risks, researchers only have to demonstrate non-inferior results when determining that restrictive transfusion strategies are indeed the more appropriate practice. Evidence for Restrictive Strategies in Non-cardiac Surgery By setting an Hgb transfusion trigger of 7-to-8 g/dL, clinicians strive to conserve a limited, expensive resource and perform ABT only when the risk profile of anemia outweighs the potential harmful effects of ABT. Restrictive transfusion strategies result in less ABT being performed in the perioperative setting, allowing clinicians to avoid exposing patients to such risks. With the immune modulation that occurs with ABT, many studies have focused on the role of blood transfusion in oncologic surgery. In patients undergoing oropharyngeal cancer surgery, ABT was associated independently with postoperative morbidity in a dose-dependent manner.43 In patients
with gastric cancer, ABT has been associated with decreased long-term survival.44 When sorting through the American College of Surgeons National Surgical Quality Improvement Program, Al-Refaie found that more than 5,000 surgical oncology patients received perioperative ABT and these patients had higher rates of 30-day operative mortality, major complications, total number of complications, and prolonged length of stay.45 Again, consideration must be given to the fact that cancer patients requiring ABT are arguably in worse clinical condition and controlling for such confounders remains difficult. In a retrospective study of 422 oncologic patients undergoing hepatobiliary surgery, similar mortality was reported for patients transfused under a restrictive transfusion trigger when compared with a liberal transfusion trigger.32 Similarly, Wehry et al demonstrated no increase in morbidity when utilizing a restrictive strategy in managing 415 patients undergoing surgery for abdominal malignancies. Not surprisingly, this prospective study also demonstrated significantly less transfusion utilizing the conservative protocol.34 In orthopedic surgery, the results of the Functional Outcomes in Cardiovascular patients Undergoing Surgical repair of hip fracture (FOCUS) trial commonly are cited as evidence in favor of restrictive transfusion strategy. When hip surgery patients were assigned to a transfusion trigger o 8 g/dL (rather than o 10 g/dL), there were no significant differences in 30-day mortality or complications.46 In patients undergoing hip and knee replacement, a multicenter prospective trial of 603 patients found no difference in hospital length of stay between liberal and restrictive transfusion strategies.47 Similar results were published by Grover et al in looking at 260 orthopedic patients. In addition to no difference in hospital length of stay, a restrictive strategy had no significant increase in silent myocardial ischemia when compared with liberal transfusion strategies.48 When early ambulation was the primary outcome, there was no difference in liberal versus restrictive transfusion strategies in elderly hip fracture patients.49 In a retrospective Veterans Administration study of nearly 240,000 patients undergoing major non-cardiac surgery, Wu and colleagues described important qualifiers to the appropriateness of intraoperative transfusion. They found that transfusion was beneficial in patients with lower preoperative hematocrit levels (o24%) who experienced substantial blood loss (4500 mL). When such conditions were not met, ABT was associated with increased 30-day mortality.35 Similar results were described by Bursi et al when they found that ABT was associated with increased 30-day mortality, morbidity, and increased hospital stay in elective vascular surgery when non-anemic (Hgb 49 g/dL) patients were transfused. Such an association did not exist when anemic patients received ABT.31 Investigators also have evaluated the impact of restrictive and liberal ABT strategies in neurosurgery. In a prospective RCT of 200 patients with traumatic brain injury, more than a third of whom required surgical intervention, targeting an Hgb value above 10 g/dL had no impact on 6-month neurologic outcomes when compared with targeting an Hgb above 7 g/dL. In fact, the liberal transfusion group had significantly higher incidence of thromboembolic events and a higher percentage
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of patients experiencing worse neurologic outcomes, although this did not reach statistical significance.50 A 2012 Cochrane review examined outcomes of patients treated with a restrictive or liberal transfusion trigger. Of the 19 eligible studies, 8 of these occurred in the context of surgery. Of these studies, only 5 studies evaluated allogeneic blood transfusion triggers in non-cardiac surgery. While the authors concluded restrictive strategies were associated with a reduction in hospital mortality, 97% of the included patients were from 2 sources—the TRICC trial of non-surgical patients and the FOCUS trial of orthopedic patients.51 Liberal Strategies and Supporting Data Whether clinicians are targeting an Hgb concentration of 49 or 4 10 g/dL, these higher values are selected in an effort to maximize oxygen delivery in surgical patients. As previously discussed, in order for studies to favor targeting higher Hgb concentrations, they must surpass equivocal results and actually show benefit versus restrictive strategies in order to overcome the risk–benefit ratio associated with ABT. In a recent trial of 184 surgical oncologic patients, a restrictive blood transfusion strategy was found to result in nearly twice the morbidity and mortality than the liberal transfusion group (35.6% v 19.6%, respectively).52 The authors attributed such a difference in favor of the liberal group to several items. Only 21% of the restrictive limb received ABT, a lower figure than prior studies.46 The transfused blood also was leukocyte-depleted and had shorter storage times compared with prior studies.46 Furthermore, the authors proposed that patients with cancer are more susceptible to altered oxygen delivery in the postoperative period and demonstrated improved outcomes when maintaining higher Hgb concentrations.52 The Transfusion Requirements In Frail Elderly (TRIFE) trial aimed to determine outcomes in frail, anemic, elderly patients with hip fracture receiving ABT. The investigators randomized 284 surgical patients to either restrictive (Hgb o9.7 g/dL) or liberal (Hgb o 11.3 g/dL) ABT strategies. While no difference was found in functional postoperative physical abilities, the restrictive strategy had higher 90-day mortality (36%) when compared with the liberal group (20%).53 Fominskiy et al recently published the strongest evidence in support of liberal transfusion strategies in the perioperative setting.54 Seventeen trials of more than 11,000 surgical patients were included in this meta-analysis. Those treated with a liberal transfusion strategy had significantly lower allcause mortality when compared with those receiving a restrictive strategy. Interestingly, no difference in mortality was found when examining 10 trials investigating critically ill, nonsurgical patients. This meta-analysis was the first of its kind favoring liberal transfusion and came after previous metaanalyses supported restrictive strategies.51 The authors attribute this novelty to the inclusion of 3 RCT’s published in 2015 that demonstrated a mortality reduction in the setting of a liberal strategy.26,52,53 Notably, 2 of these RCTs enrolled patients undergoing non-cardiac surgery.52,53
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The aforementioned recent meta-analysis by Hovaguimian et al28 included 9 RCT’s investigating patients undergoing non-cardiac surgery. All but 1 of these RCT’s was included in the Fominskiy et al meta-analysis,54 and not surprisingly these 2 temporally related analyses reached similar conclusions. After compiling the included studies, Hoyaguimian et al found the application of a restrictive transfusion trigger resulted in an increase in mortality and signs of end-organ ischemia when compared with a liberal transfusion trigger. It should be noted that both the Fominskiy and Hoyaguimian analyses include RCT’s involving mostly elderly patients undergoing orthopedic surgery, demonstrating the importance for putting the clinical situation into appropriate context when deciding upon an Hgb trigger.28 Conclusion The past 5 years have seen the emergence of large, randomized, controlled trials and extensive meta-analyses examining transfusion triggers within the cardiac and noncardiac surgical literature (Tables 1 and 2). Within the cardiac surgical literature, the TRACS trial noted non-inferiority of restrictive versus liberal transfusion triggers, with trends that suggested some benefit of using the liberal transfusion triggers within this population. These trends were confirmed in several major meta-analyses that have been discussed. This is contrasted with the latest RCT, TiTre2,25 which raised questions as to the use of restrictive triggers within cardiac surgery. Within the non-cardiac literature, a more nuanced picture emerges from the studies. Some orthopedic surgical data showed no difference between the liberal and restrictive arms with regard to morbidity and mortality, while the TRIFE trial showed higher mortality within the restrictive strategy group. Additionally, the latest meta-analyses28,54 in the published literature have showed increased risk when restrictive strategy was applied to elderly orthopedic patients. Such a mixed picture also emerges when examining trials from the oncologic patients undergoing abdominal surgery. Recently, the AABB (formerly known as the American Association of Blood Banks) has updated its guidelines regarding red cell transfusion thresholds and storage.55 Since this organization’s first guidelines were released in 2012, the number of patients enrolled in RCTs investigating transfusion practices has nearly doubled. This group recommended a restrictive transfusion threshold of 7 g/dL for stable inpatients, including those in the intensive care unit. An Hgb threshold of 8 g/dL for cardiac and orthopedic surgical patients was also recommended. They postulated that there is likely no difference between an Hgb value of 7 g/dL and 8 g/dL, rather these were the thresholds selected by the various RCT investigators. The accompanying editorial cautions relying solely on Hgb values to guide ABT and encourages clinicians to consider the clinical context and incorporate markers of oxygen delivery such as base deficit, cerebral oximetry, and lactate levels into the decision to transfuse.56 The authors agree with both the AABB’s updated guidelines and the accompanying editorial, but would add the caveat that a restrictive strategy may not be
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Table 1 Randomized, Controlled Trials and Meta-analyses Evaluating Restrictive Versus Liberal Transfusion Strategies in Cardiac Surgery Author
Year
Journal
Clinical Setting
Hajjer23 (RCT)
2010
JAMA
Elective cardiac surgery
Murphy25 (RCT)
2015
N Engl J Med
Nakamura24 (RCT subset)
2015
J Thorac Cardiovasc Surg
Curley26 (Meta)
2014
Crit Care Med
Patel27 (Meta)
2015
Lancet Haematol
Hovaguimian28 (Meta)
2016
Anesthesiology
No. of Patients
No. of Trial Centers/RCTs
Primary Endpoint
502
1 center
Non-emergency cardiac surgery
2003
17 centers
Elective cardiac surgery in patients 460 or o60 years of age Transfusion threshold RCTs in cardiac and vascular surgery Transfusion threshold RCTs in cardiac and non-cardiac surgery Adult surgical or critically ill patients
502
1 RCT
Composite endpoint of 30-day all-cause mortality and severe morbidity Serious infection or ischemic event within 3 months of randomization 30-day all-cause mortality and morbidity
1,262
7 RCTs
All-cause mortality
3,352
6 RCTs
30-day mortality
3,300
8 RCTs
30-day inadequate oxygen supply complications, mortality, composite of both, and infections
Abbreviation: RCT, randomized controlled trials.
suitable for all surgical patients and ABT must be an individualized intervention. Interestingly, this update also provided the first recommendation of how long RBC units can be stored prior to ABT. The AABB confirmed the routine practice of blood banks releasing the oldest units of red cells first as a safe technique that does not expose patients to increased risk when compared to administering shorterstorage-duration red blood cells. Although the risks and benefits of allogeneic blood transfusion are well documented within the cardiac and non-cardiac surgical literature, the question that still remains to be
definitively answered is when the benefit of transfusion outweighs the risks for a given patient in a specific clinical setting. Two major themes appeared to emerge from the data within the cardiac and non-cardiac surgical populations. First, protocols should be driven by data from studies specific for the patient population at risk. Second, more large-scale, randomized, controlled trials are needed to objectively provide therapeutic guidelines for perioperative clinicians. As described by Beattie in a recent Anesthesiology editorial, ABT should be considered the “last resort” in addressing perioperative Hgb deficiency within patient populations.
Table 2 Randomized, Controlled Trials Evaluating Restrictive Versus Liberal Transfusion Strategies in Non-cardiac Surgery Author
Year
Journal
Clinical Setting
No. of Patients
No. of Trial Centers
Primary Endpoint
So-Osman47
2010
Vox Sang
Hip/knee replacement
619
3
Carson46
2011
N Engl J Med
2016
47
Gregersen53
2015
Acta Orthop
284
1
de Almeida52
2015
Anesthesiology
Patients Z50 years old with CV disease or risk factors for CV disease undergoing primary repair of hip fracture Patients Z65 years old from assisted living facilities with hip fracture repair Abdominal oncology surgery requiring postoperative ICU care
No change in RBC transfusions or hospital length of stay No difference in 60-day mortality or ability to walk unassisted across room
198
1
Abbreviations: CV, cardiovascular; ICU, intensive care unit; RBC, red blood cell.
No difference in 90-day mortality or ability to perform daily living activities Mortality and morbidity were twice as common in restrictive group
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Although significant advancements have been made since the first documented transfusion in the 17th century, the next phase of strategies should focus not only on optimizing the risk and benefit calculation of ABT within context-specific patient populations, but also on developing all-encompassing perioperative strategies to decrease the need for ABT altogether. These strategies should include preoperative clinic assessment for the utility of iron and erythropoietin infusions, intraoperative fluid management, and surgical technique, as well as appropriate perioperative management of hematologically active pharmacologic agents.57 References 1 Learoyd P. The history of blood transfusion prior to the 20th century–part 1. Transfus Med 2012;22:308–14. 2 Learoyd P. The history of blood transfusion prior to the 20th century–part 2. Transfus Med 2012;22:372–6. 3 Moore SB. A brief history of the early years of blood transfusion at the Mayo Clinic: The first blood bank in the United States (1935). Transfus Med Rev 2005;19:241–5. 4 Alter HJ, Klein HG. The hazards of blood transfusion in historical perspective. Blood 2008;112:2617–26. 5 Madjdpour C, Heindl V, Spahn DR Risks. benefits, alternatives and indications of allogenic blood transfusions. Minerva Anestesiol 2006;72: 283–98. 6 Toner RW, Pizzi L, Leas B, et al. Costs to hospitals of acquiring and processing blood in the US: A survey of hospital-based blood banks and transfusion services. Appl Health Econ Health Policy 2011;9:29–37. 7 Goodnough LT, Shah N. Is there a "magic" hemoglobin number? Clinical decision support promoting restrictive blood transfusion practices. Am J Hematol 2015;90:927–33. 8 Galas FR, Almeida JP, Fukushima JT, et al. Blood transfusion in cardiac surgery is a risk factor for increased hospital length of stay in adult patients. J Cardiothorac Surg 2013;8:54. 9 Kilic A, Whitman GJ. Blood transfusions in cardiac surgery: Indications, risks, and conservation strategies. Ann Thorac Surg 2014;97:726–34. 10 van Straten AH, Bekker MW, Soliman Hamad MA, et al. Transfusion of red blood cells: the impact on short-term and long-term survival after coronary artery bypass grafting, a ten-year follow-up. Interact Cardiovasc Thorac Surg 2010;10:37–42. 11 Bhaskar B, Dulhunty J, Mullany DV, et al. Impact of blood product transfusion on short and long-term survival after cardiac surgery: more evidence. Ann Thorac Surg 2012;94:460–7. 12 Muller MM, Geisen C, Zacharowski K, et al. Transfusion of packed red cells: Indications, triggers and adverse events. Dtsch Arztebl Int 2015;112: 507–17. quiz 518. 13 Bennett-Guerrero E, Zhao Y, O'Brien SM, et al. Variation in use of blood transfusion in coronary artery bypass graft surgery. JAMA 2010;304: 1568–75. 14 Goodnough LT, Murphy MF. Do liberal blood transfusions cause more harm than good?. BMJ 2014;349:g6897. 15 Murphy MF, Goodnough LT. The scientific basis for patient blood management. Transfus Clin Biol 2015;22:90–6. 16 Yaffee DW, Smith DE 3rd, Ursomanno PA, et al. Management of blood transfusion in aortic valve surgery: Impact of a blood conservation strategy. Ann Thorac Surg 2014;97:95–101. 17 Gross I, Seifert B, Hofmann A, et al. Patient blood management in cardiac surgery results in fewer transfusions and better outcome. Transfusion 2015;55:1075–81. 18 Varghese R, Jhang J. Blood conservation in cardiac surgery: In need of a transfusion revolution. Semin Cardiothorac Vasc Anesth 2015;19: 293–301. 19 Carson JL, Hebert PC. Should we universally adopt a restrictive approach to blood transfusion? It's all about the number. Am J Med 2014;127:103–4.
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20 Spahn DR, Spahn GH, Stein P. Evidence base for restrictive transfusion triggers in high-risk patients. Transfus Med Hemother 2015;42:110–4. 21 Mirski MA, Frank SM, Kor DJ, et al. Restrictive and liberal red cell transfusion strategies in adult patients: Reconciling clinical data with best practice. Crit Care 2015;19:202. 22 Zollo RA, Eaton MP, Karcz M, et al. Blood transfusion in the perioperative period. Best Pract Res Clin Anaesthesiol 2012;26:475–84. 23 Hajjar LA, Vincent JL, Galas FR, et al. Transfusion requirements after cardiac surgery: The TRACS randomized controlled trial. JAMA 2010;304:1559–67. 24 Nakamura RE, Vincent JL, Fukushima JT, et al. A liberal strategy of red blood cell transfusion reduces cardiogenic shock in elderly patients undergoing cardiac surgery. J Thorac Cardiovasc Surg 2015;150:1314–20. 25 Murphy GJ, Pike K, Rogers CA, et al. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med 2015;372:997–1008. 26 Curley GF, Shehata N, Mazer CD, et al. Transfusion triggers for guiding RBC transfusion for cardiovascular surgery: A systematic review and meta-analysis. Crit Care Med 2014;42:2611–24. 27 Patel NN, Avlonitis VS, Jones HE, et al. Indications for red blood cell transfusion in cardiac surgery: A systematic review and meta-analysis. Lancet Haematol 2015;2:e543–53. 28 Hovaguimian F, Myles PS. Restrictive versus liberal transfusion strategy in the perioperative and acute care settings: A context-specific systematic review and meta-analysis of randomized controlled trials. Anesthesiology 2016;125:46–61. 29 Chen A, Trivedi AN, Jiang L, et al. Hospital blood transfusion patterns during major noncardiac surgery and surgical mortality. Medicine (Baltimore) 2015;94:e1342. 30 Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999;340:409–17. 31 Bursi F, Barbieri A, Politi L, et al. Perioperative red blood cell transfusion and outcome in stable patients after elective major vascular surgery. Eur J Vasc Endovasc Surg 2009;37:311–8. 32 Ejaz A, Spolverato G, Kim Y, et al. Impact of blood transfusions and transfusion practices on long-term outcome following hepatopancreaticobiliary surgery. J Gastrointest Surg 2015;19:887–96. 33 Hollis RH, Singletary BA, McMurtrie JT, et al. Blood transfusion and 30-day mortality in patients with coronary artery disease and anemia following noncardiac surgery. JAMA Surg 2016;151:139–45. 34 Wehry J, Agle S, Philips P, et al. Restrictive blood transfusion protocol in malignant upper gastrointestinal and pancreatic resections patients reduces blood transfusions with no increase in patient morbidity. Am J Surg 2015;210:1197–204. discussion 1204–05. 35 Wu WC, Smith TS, Henderson WG, et al. Operative blood loss, blood transfusion, and 30-day mortality in older patients after major noncardiac surgery. Ann Surg 2010;252:11–7. 36 Ferraris VA, Brown JR, Despotis GJ, et al. Society of Thoracic Surgeons Blood Conservation Guideline Task Force. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg 2011;91:944–82. 37 Carson JL, Grossman BJ, Kleinman S, et al. Red blood cell transfusion: a clinical practice guideline from the AABB*. Ann Intern Med 2012;157:49–58. 38 Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol 2014;64:e77–137. 39 Qian F, Osler TM, Eaton MP, et al. Variation of blood transfusion in patients undergoing major noncardiac surgery. Ann Surg 2013;257: 266–78. 40 Beattie WS, Karkouti K, Wijeysundera DN, et al. Risk associated with preoperative anemia in noncardiac surgery: A single-center cohort study. Anesthesiology 2009;110:574–81. 41 Musallam KM, Tamim HM, Richards T, et al. Preoperative anaemia and postoperative outcomes in non-cardiac surgery: A retrospective cohort study. Lancet 2011;378:1396–407.
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42 Glance LG, Dick AW, Mukamel DB, et al. Association between intraoperative blood transfusion and mortality and morbidity in patients undergoing noncardiac surgery. Anesthesiology 2011;114:283–92. 43 Perisanidis C, Dettke M, Papadogeorgakis N, et al. Transfusion of allogenic leukocyte-depleted packed red blood cells is associated with postoperative morbidity in patients undergoing oral and oropharyngeal cancer surgery. Oral Oncol 2012;48:372–8. 44 Ojima T, Iwahashi M, Nakamori M, et al. Association of allogeneic blood transfusions and long-term survival of patients with gastric cancer after curative gastrectomy. J Gastrointest Surg 2009;13:1821–30. 45 Al-Refaie WB, Parsons HM, Markin A, et al. Blood transfusion and cancer surgery outcomes: A continued reason for concern. Surgery 2012;152:344–54. 46 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. 47 So-Osman C, Nelissen R, Te Slaa R, et al. A randomized comparison of transfusion triggers in elective orthopaedic surgery using leucocytedepleted red blood cells. Vox Sang 2010;98:56–64. 48 Grover M, Talwalkar S, Casbard A, et al. Silent myocardial ischaemia and haemoglobin concentration: a randomized controlled trial of transfusion strategy in lower limb arthroplasty. Vox Sang 2006;90:105–12. 49 Foss NB, Kristensen MT, Jensen PS, et al. The effects of liberal versus restrictive transfusion thresholds on ambulation after hip fracture surgery. Transfusion 2009;49:227–34.
50 Robertson CS, Hannay HJ, Yamal JM, et al. Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: A randomized clinical trial. JAMA 2014;312:36–47. 51 Carson JL, Carless PA, Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev CD:002042, 2012. 52 de Almeida JP, Vincent JL, Galas FR, et al. Transfusion requirements in surgical oncology patients: A prospective, randomized controlled trial. Anesthesiology 2015;122:29–38. 53 Gregersen M, Borris LC, Damsgaard EM. Postoperative blood transfusion strategy in frail, anemic elderly patients with hip fracture: the TRIFE randomized controlled trial. Acta Orthop 2015;86:363–72. 54 Fominskiy E, Putzu A, Monaco F, et al. Liberal transfusion strategy improves survival in perioperative but not in critically ill patients. A metaanalysis of randomised trials. Br J Anaesth 2015;115:511–9. 55 Carson JL, Guyatt G, Heddle NM, et al. Clinical practice guidelines from the AABB: Red blood cell transfusion thresholds and storage. JAMA 2016;316:2025–35. 56 Yazer MH, Triulzi DJ. AABB red blood cell transfusion guidelines: Something for almost everyone. JAMA 2016;316:1984–5. 57 Beattie WS, Wijeysundera DN. Approaching a safe last resort: Triggers for perioperative blood transfusion. Anesthesiology 2016;125: 11–3.
Contents lists available at ScienceDirect
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Expert Review
Restrictive Versus Liberal Transfusion Strategies in Perioperative Blood Management: An Evidence-Based Analysis Archer Kilbourne Martin, MDn, J. Ross Renew, MDn, Harish Ramakrishna, MD, FASE, FACC†,1 n
†
Department of Anesthesiology, Mayo Clinic in Florida, Jacksonville, FL Division of Cardiovascular and Thoracic Anesthesiology, Mayo Clinic in Arizona, Phoenix, AZ
Perioperative blood management is universally important and a subject characterized by conflicting data. The issue of appropriate transfusion triggers and the pros and cons of liberal versus conservative transfusion strategies continue to provide constantly changing vision for the perioperative clinician. This review aims to summarize the current literature pertaining to this topic and analyzes the debate between liberal versus restrictive transfusion policies both in cardiac and noncardiac surgery. Superstition has long shrouded the practice of blood transfusion within the human species. Indeed, from the first mention of hematologic infusion in Ovid’s Metamorphoses to Hippocrates’ theory of humors, the ancients had a crude yet all-encompassing respect for blood.1 The initial scientific foray into transfusion occurred on November 22, 1667, with the first reported animal-to-human transfusion occurring between a sheep and a human male. Amazingly, the patient was documented to have survived and undergone a second transfusion a month later. As this experiment was repeated across Europe, a trial as a result of patient death led to the banning of the practice by national medical societies as well as the Catholic Pope in 1679.1 Scientific inquiry into the practice of allogeneic blood transfusion (ABT) was halted for centuries, resuming with the first human-to-human transfusion work of James Blundell in the early-to-mid 19th century. Inspired by the postpartum deaths due to hemorrhage he observed in his own practice, he developed several delivery systems and procedures for arterial-to-venous transfusion.2 The discovery of the ABO system in 1900 by Karl Landsteiner paved the way for modern transfusion medicine.3 In 1 Address reprint requests to Harish Ramakrishna, MD, FASE, FACC, Department of Anesthesiology, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ 85054. E-mail address: [email protected] (H. Ramakrishna).
http://dx.doi.org/10.1053/j.jvca.2017.02.009 1053-0770/
1919, John Pemberton at the Mayo Clinic in Rochester, MN published a large series of more than 1,000 successful blood transfusions. John Lundy, an anesthesiologist at the Mayo Clinic, set up the world’s first blood bank in 1935. In addition to establishing a blood bank that allowed storage of blood up to 14 days, Lundy also established the idea of the perioperative hemoglobin (Hgb) “trigger” for high-risk surgical patients.3 Transfusion science was tested on a major scale for the first time in history during World War II. Massive blood replacement due to battlefield injuries resulted in an increased incidence of the hazards of ABT.4 In the 50 years since, clinicians’ understanding of the benefits and hazards of ABT has allowed them significant progress to their modern day practice—where they attempt to maximize transfusion benefits while ameliorating but not eliminating the hazards associated with the administration of blood.4 The primary benefit of administering blood is the support of oxygen supply as transported by the Hgb and delivered to the cells.5 The hazards of administering blood are far more extensive. Infective risks are potential due to bloodborne viruses, bacteria, parasites, and prions. Immunologic risks include hemolytic reactions, immunosuppression, transfusion-related acute lung injury, mistransfusion, and alloimmunization.5 The hazards are not simply physiologic—data from 2011 showed that the mean acquisition cost of 1 packed red blood cell unit was $210.74 USD, while the mean charge to the patient was $343.63.6 There are ample published data reflecting the risks and benefits of liberal versus restrictive transfusion strategies in perioperative medicine. However, there is a universal lack of agreement among clinicians in perioperative medicine when it concerns the decision to transfuse blood products or not. It is within this framework of the modern understanding of transfusion-related hazards and benefits that the authors explored the topic of perioperative transfusion during cardiac
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and non-cardiac surgery. Specifically, the authors examined the published data that have emerged from the liberal versus restrictive transfusion dilemma over the past 5 years.
studies being limited relative to randomized controlled studies due to the possibility of selection bias.22
Blood Transfusion in Cardiac Surgery
Restrictive Versus Liberal Transfusion in Cardiac Surgery – Trial and Meta-analysis Data
ABT is one of the most frequently performed procedures within cardiovascular medicine.7 The transfusion of blood has been shown to be an independent risk factor for morbidity and mortality within the cardiac surgical patient population.8–10 These effects of transfusion within the cardiac surgical population have been observed to be both short-term and long-term in scope.11 Even with this observed risk, the transfusion of red blood cells occurs within this population, often during a variety of observed pathophysiologic conditions—electrocardiographic elevations or depressions in the ST-segments, rhythm disturbances, echocardiographic regional wall motion abnormalities, or diminished mixed venous saturations.12 Despite some of these relatively objective clinical situations, studies have shown significant variation among hospitals when comparing rates of ABT during cardiac surgery.13–16 Incidence of transfusion varies not only within hospital systems, but also with various cardiac procedures.16 Studies have shown that risk factors associated with increased incidence of red blood cell transfusion include female sex, reoperative cardiac surgeries, combination coronary artery bypass grafting or valve surgeries, older age, renal disease, elevated European System for Cardiac Operative Risk Evaluation score, and preoperative anemia.8,16 The development and implementation of a blood management system within an organization via protocol and team training has been shown to reduce overall blood usage in cardiac surgery.7,12,16 Additionally, implementations of patient blood management systems have been shown to reduce direct costs, hospital length of stay, and kidney injury within the cardiac surgical populations.7,17 Despite these benefits, studies have noted that the implementation of cardiac surgical transfusion protocols has met resistance from cardiac surgeons.18 The studies examining implemented protocols have demonstrated various triggers, but generally, the restrictive protocols target Hgb of 7 or 8 g/dL, while liberal protocols have a threshold of 9 or 10.19 Literature describing these systems noted that it is not simply a matter of a restrictive versus liberal trigger, but a comprehensive program involving preoperative screening of anemia and perioperative techniques designed to minimize blood loss itself.16,17,20 These clinical protocols should be constructed for particular patient populations, as they have the potential downside of being inappropriately applied across various patient cohorts.21 There are much data decrying the lack of transfusion standardization within the cardiac surgical arena, calling for evidence-based algorithms that can be applied across various health systems to guide patient care.9 It is within this environment that studies have been constructed to determine cardiac surgical outcomes of restrictive versus liberal transfusion protocols. These studies were both observational and randomized controlled trials (RCTs), with observational
In 2010, Hajjer et al published the Transfusion Requirements after Cardiac Surgery, or TRACS trial.23 The objective of this prospective RCT was to define whether or not a restrictive ABT strategy was non-inferior to a liberal transfusion strategy in elective cardiac surgery. Five-hundred two patients were assigned randomly to a liberal arm, with a trigger of hematocrit 430%, or a restrictive arm with a transfusion trigger of hematocrit 4 24%. The endpoint was a composite of all-cause mortality and severe morbidity.23 The primary endpoint occurred in 10% of the liberal arm, and 11% of the restrictive, resulting in statistically non-inferior rates between the 2 groups. The authors of the study concluded that the data showed a trend toward increased incidence of cardiogenic shock within the restrictive population as compared with the liberal, and noted that the mere transfusion of red blood cells resulted in higher rates of complications after the surgical procedure.23 As a follow-up to TRACS, Nakamura et al in 2015 used a subset of data from the TRACS trial to evaluate outcomes in patients undergoing elective cardiac surgery who were older than 60 as compared to those younger than 60 years. The original 502 patients were divided into 2 groups based on age, with 260 patients older than 60 and 242 patients younger than 60. The primary outcome was the same as the original trial, defined as a composite combination of 30-day all-cause mortality and severe morbidity.24 While no difference was observed between the groups in terms of primary outcomes, the elderly population was seen to have an increased incidence of cardiogenic shock when randomized to the restrictive arm (12.8%) versus the liberal arm (5.2%).24 The next major RCT designed to study outcomes based on transfusion triggers in cardiac surgery was the Transfusion Indication Threshold Reduction (TiTre2) study published in the New England Journal of Medicine in 2015.25 This multicenter RCT was conducted in 17 centers within the United Kingdom. A total of 2,003 patients with postoperative Hgb o9 were randomized into a restrictive or liberal transfusion trigger arm. Of this total, 1,000 patients were placed in a restrictive threshold group, as defined as an Hgb trigger o7.5, with 1,003 patients placed into the liberal threshold trigger arm of 4 9.25 The primary outcome of the trial was defined as either a serious infection or ischemic event within 3 months of randomization. The restrictive transfusion threshold was shown to be non-superior as compared to the liberal threshold with regard to morbidity and healthcare costs.25 While there was no observed statistically significant difference between the 2 arms with regard to primary outcome, there were more deaths by the 3-month mark in the restrictive threshold group as compared with the liberal group (4.2% v 2.6%). Thirty-day
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mortality was 2.6% in the restrictive group versus 1.9% in the liberal group. The authors noted that the higher frequency of death in the restrictive group persisted in sensitivity analyses, and that these results raised questions as to the use of restrictive transfusion triggers in the setting of cardiac surgery.25 Curley et al published a systematic review and metaanalysis in 2014 examining whether or not restrictive transfusion triggers were associated with inferior clinical outcomes in RCTs within the cardiac surgical population.26 A total of 7 studies with 1,262 subjects were included in the review. When the data were pooled, there was no statistically significant effect between restrictive and liberal triggers on hospital mortality or risk of major morbidity, to include myocardial infarction, stroke, and acute renal failure.26 However, the authors did note a trend of increased mortality within the restrictive trigger transfusion group of cardiac surgical patients. A second major systematic review and meta-analysis published in 2015 by Patel et al reviewed evidence from RCTs and observational studies to determine transfusion decisions in adult cardiac surgery.27 While the data included 6 cardiac surgical RCTs, it also examined 19 non-cardiac surgical trials and 39 observational studies within the cardiac surgical literature. Upon examining the 6 cardiac surgical RCTs totaling 3,352 patients, the authors noted that there was no evidence that liberal transfusion triggers led to increased pulmonary, acute renal, or infectious morbidity as compared with the restrictive strategy. There was a statistically nonsignificant benefit observed with the liberal strategy as compared with the restrictive strategy with regard to mortality within these trials. When the meta-analysis was applied to 7 trials with active cardiac disease patients (5 surgical and 2 non-surgical myocardial infarction patients), liberal red blood cell transfusion was shown to reduce mortality as compared to restrictive transfusion thresholds. This contrasted significantly with the meta-analysis of 12 RCTs within this study of patients who either had stable or no cardiac disease. This patient subset was seen to have increased mortality with liberal red blood cell transfusion strategies as compared to a restrictive strategy. The results of the observational studies analyses within the cardiac surgical population study suggested that the transfusion of red blood cells was associated with increased mortality and morbidity. Whereas the RCTs examined liberal versus restrictive triggers for transfusion, the observational studies predominatly studied the risks of transfusion versus no transfusion. The authors concluded that results from observational studies and non-cardiac surgical trials should not be applied to transfusion protocol development or clinical care decisions within the cardiac surgical population.27 Hovaguimian and Myles recently confirmed the importance of constructing transfusion-trigger protocols within a contextspecific setting in their 2016 systematic review and metaanalysis.28 Multiple literature sources were searched from inception until November 2015 for RCTs comparing restrictive and liberal transfusion strategies in adult surgical and critically ill patients. Risk ratios were calculated for several factors,
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including 30-day complications due to inadequate oxygen supply, mortality, a composite of both, and infections. A total of 8 of the 31 trials were related to patients undergoing cardiac or vascular procedures. Restrictive strategies in this population increased the risk of each event category except infections. The authors concluded that restrictive strategies should be applied with caution in high-risk patients undergoing major surgery, and that future protocols should be constructed considering both patient comorbidities and surgical settings.28 The debate as to the superiority of liberal versus restrictive triggers for cardiac surgical patients continues to be waged within the literature. With 1 large trial demonstrating noninferiority of the restrictive versus liberal transfusion strategy with regard to mortality and morbidity, there were other data showing trends toward increased cardiogenic shock and mortality when the restrictive trigger was used within the cardiac surgical population. Meta-analysis data showed differences when comparing patients with active cardiac versus no cardiac disease, as well as suggesting increased risk to the patient when applying restrictive protocols within the cardiac surgical setting. A consistent theme within the literature is the importance of constructing transfusion protocols within the context of the patient’s disease state and procedure, and thus the authors next discuss the literature within the non-cardiac surgical patient population. Analysis of the Liberal Versus Restrictive Transfusion Debate in Non-cardiac Surgery In the current era of trying to deliver cost-effective care while maintaining high standards for patient safety, much work has been done to determine the risks associated with anemia, the role of ABT, and appropriate Hgb concentrations that trigger such interventions in a variety of clinical settings. A recent retrospective study of more than 400,000 non-cardiac major surgeries performed at VA hospitals found the incidence of blood transfusion to be as high as 9%.29 With ABT being so common in non-cardiac surgery, surprisingly few multicenter RCTs exist examining appropriate perioperative Hgb triggers to help guide clinicians. As such, many anesthesiologists extrapolate blood management data from studies on critically ill, non-surgical patients.30 The Transfusion Requirements In Critical Care (TRICC) study demonstrated that a restrictive transfusion strategy was at least as effective as a liberal transfusion trigger in most clinical settings.30 The etiology of anemia in the intensive care unit is usually more gradual as a result of decreased red cell production and frequent laboratory studies in patients who often have multi-organ dysfunction. This anemia clearly is different from the brisk, hemodynamically challenging bleeding that can occur during non-cardiac surgery. Caution must be taken when applying transfusion strategies from one clinical setting to another. In addition to the critical care prospective trials, numerous retrospective cohort studies have examined blood transfusion strategies in non-cardiac surgery.31–35 These efforts can provide valuable insight into the effects of ABT strategies for specific populations undergoing certain operations.
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However, clinicians must be careful when applying transfusion concepts from such homogenous patient populations to differing clinical settings. For instance, a patient with coronary artery disease undergoing a pancreatic resection may have a higher Hgb transfusion trigger than a younger patient undergoing orthopedic surgery. While these 2 scenarios clearly are different and at extreme ends of the spectrum, they reinforce that ABT practice must be individualized and interpretation of data needs a nuanced approach. Fortunately, major societal guidelines do exist to assist clinicians; however, such recommendations have the limitations of relying heavily on expert opinion,36 are based on a single RCT,37 or rely on assumptions of their previous guidelines.38 The American Society of Anesthesiologists’ Task Force on Blood Management described restrictive strategies as effective at reducing the usage of ABT; however, the findings for morbidity were equivocal. It is not surprising that dramatic variability exists in transfusion practices during non-cardiac surgery.39 In general, blood transfusion in any setting has been associated with various negative consequences such as immune modulation, risk of transfusion reaction, circulatory overload, the consumption of a finite resource,5 and a significant financial burden.6 When focusing on patients undergoing non-cardiac surgery, preoperative anemia exists as a significant perioperative risk and has been associated independently with increased mortality.40,41 In addition, treatment of such anemia with intraoperative ABT also has been associated with higher risk of morbidity and mortality.42 When evaluating the effects of ABT, it is difficult to elucidate if poor outcomes are due to the actual intervention of ABT or the presence of perioperative anemia, even when researchers attempt to control for such confounders. The “second-hit” theory has been presented as an explanation for such increased mortality and morbidity. This notion proposes that the perioperative anemia itself is the first insult to the patient. The “second hit” is from the additional sequelae associated with ABT, which has been discussed previously in the opening paragraphs. Because not intervening by withholding autologous blood avoids the aforementioned risks, researchers only have to demonstrate non-inferior results when determining that restrictive transfusion strategies are indeed the more appropriate practice. Evidence for Restrictive Strategies in Non-cardiac Surgery By setting an Hgb transfusion trigger of 7-to-8 g/dL, clinicians strive to conserve a limited, expensive resource and perform ABT only when the risk profile of anemia outweighs the potential harmful effects of ABT. Restrictive transfusion strategies result in less ABT being performed in the perioperative setting, allowing clinicians to avoid exposing patients to such risks. With the immune modulation that occurs with ABT, many studies have focused on the role of blood transfusion in oncologic surgery. In patients undergoing oropharyngeal cancer surgery, ABT was associated independently with postoperative morbidity in a dose-dependent manner.43 In patients
with gastric cancer, ABT has been associated with decreased long-term survival.44 When sorting through the American College of Surgeons National Surgical Quality Improvement Program, Al-Refaie found that more than 5,000 surgical oncology patients received perioperative ABT and these patients had higher rates of 30-day operative mortality, major complications, total number of complications, and prolonged length of stay.45 Again, consideration must be given to the fact that cancer patients requiring ABT are arguably in worse clinical condition and controlling for such confounders remains difficult. In a retrospective study of 422 oncologic patients undergoing hepatobiliary surgery, similar mortality was reported for patients transfused under a restrictive transfusion trigger when compared with a liberal transfusion trigger.32 Similarly, Wehry et al demonstrated no increase in morbidity when utilizing a restrictive strategy in managing 415 patients undergoing surgery for abdominal malignancies. Not surprisingly, this prospective study also demonstrated significantly less transfusion utilizing the conservative protocol.34 In orthopedic surgery, the results of the Functional Outcomes in Cardiovascular patients Undergoing Surgical repair of hip fracture (FOCUS) trial commonly are cited as evidence in favor of restrictive transfusion strategy. When hip surgery patients were assigned to a transfusion trigger o 8 g/dL (rather than o 10 g/dL), there were no significant differences in 30-day mortality or complications.46 In patients undergoing hip and knee replacement, a multicenter prospective trial of 603 patients found no difference in hospital length of stay between liberal and restrictive transfusion strategies.47 Similar results were published by Grover et al in looking at 260 orthopedic patients. In addition to no difference in hospital length of stay, a restrictive strategy had no significant increase in silent myocardial ischemia when compared with liberal transfusion strategies.48 When early ambulation was the primary outcome, there was no difference in liberal versus restrictive transfusion strategies in elderly hip fracture patients.49 In a retrospective Veterans Administration study of nearly 240,000 patients undergoing major non-cardiac surgery, Wu and colleagues described important qualifiers to the appropriateness of intraoperative transfusion. They found that transfusion was beneficial in patients with lower preoperative hematocrit levels (o24%) who experienced substantial blood loss (4500 mL). When such conditions were not met, ABT was associated with increased 30-day mortality.35 Similar results were described by Bursi et al when they found that ABT was associated with increased 30-day mortality, morbidity, and increased hospital stay in elective vascular surgery when non-anemic (Hgb 49 g/dL) patients were transfused. Such an association did not exist when anemic patients received ABT.31 Investigators also have evaluated the impact of restrictive and liberal ABT strategies in neurosurgery. In a prospective RCT of 200 patients with traumatic brain injury, more than a third of whom required surgical intervention, targeting an Hgb value above 10 g/dL had no impact on 6-month neurologic outcomes when compared with targeting an Hgb above 7 g/dL. In fact, the liberal transfusion group had significantly higher incidence of thromboembolic events and a higher percentage
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of patients experiencing worse neurologic outcomes, although this did not reach statistical significance.50 A 2012 Cochrane review examined outcomes of patients treated with a restrictive or liberal transfusion trigger. Of the 19 eligible studies, 8 of these occurred in the context of surgery. Of these studies, only 5 studies evaluated allogeneic blood transfusion triggers in non-cardiac surgery. While the authors concluded restrictive strategies were associated with a reduction in hospital mortality, 97% of the included patients were from 2 sources—the TRICC trial of non-surgical patients and the FOCUS trial of orthopedic patients.51 Liberal Strategies and Supporting Data Whether clinicians are targeting an Hgb concentration of 49 or 4 10 g/dL, these higher values are selected in an effort to maximize oxygen delivery in surgical patients. As previously discussed, in order for studies to favor targeting higher Hgb concentrations, they must surpass equivocal results and actually show benefit versus restrictive strategies in order to overcome the risk–benefit ratio associated with ABT. In a recent trial of 184 surgical oncologic patients, a restrictive blood transfusion strategy was found to result in nearly twice the morbidity and mortality than the liberal transfusion group (35.6% v 19.6%, respectively).52 The authors attributed such a difference in favor of the liberal group to several items. Only 21% of the restrictive limb received ABT, a lower figure than prior studies.46 The transfused blood also was leukocyte-depleted and had shorter storage times compared with prior studies.46 Furthermore, the authors proposed that patients with cancer are more susceptible to altered oxygen delivery in the postoperative period and demonstrated improved outcomes when maintaining higher Hgb concentrations.52 The Transfusion Requirements In Frail Elderly (TRIFE) trial aimed to determine outcomes in frail, anemic, elderly patients with hip fracture receiving ABT. The investigators randomized 284 surgical patients to either restrictive (Hgb o9.7 g/dL) or liberal (Hgb o 11.3 g/dL) ABT strategies. While no difference was found in functional postoperative physical abilities, the restrictive strategy had higher 90-day mortality (36%) when compared with the liberal group (20%).53 Fominskiy et al recently published the strongest evidence in support of liberal transfusion strategies in the perioperative setting.54 Seventeen trials of more than 11,000 surgical patients were included in this meta-analysis. Those treated with a liberal transfusion strategy had significantly lower allcause mortality when compared with those receiving a restrictive strategy. Interestingly, no difference in mortality was found when examining 10 trials investigating critically ill, nonsurgical patients. This meta-analysis was the first of its kind favoring liberal transfusion and came after previous metaanalyses supported restrictive strategies.51 The authors attribute this novelty to the inclusion of 3 RCT’s published in 2015 that demonstrated a mortality reduction in the setting of a liberal strategy.26,52,53 Notably, 2 of these RCTs enrolled patients undergoing non-cardiac surgery.52,53
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The aforementioned recent meta-analysis by Hovaguimian et al28 included 9 RCT’s investigating patients undergoing non-cardiac surgery. All but 1 of these RCT’s was included in the Fominskiy et al meta-analysis,54 and not surprisingly these 2 temporally related analyses reached similar conclusions. After compiling the included studies, Hoyaguimian et al found the application of a restrictive transfusion trigger resulted in an increase in mortality and signs of end-organ ischemia when compared with a liberal transfusion trigger. It should be noted that both the Fominskiy and Hoyaguimian analyses include RCT’s involving mostly elderly patients undergoing orthopedic surgery, demonstrating the importance for putting the clinical situation into appropriate context when deciding upon an Hgb trigger.28 Conclusion The past 5 years have seen the emergence of large, randomized, controlled trials and extensive meta-analyses examining transfusion triggers within the cardiac and noncardiac surgical literature (Tables 1 and 2). Within the cardiac surgical literature, the TRACS trial noted non-inferiority of restrictive versus liberal transfusion triggers, with trends that suggested some benefit of using the liberal transfusion triggers within this population. These trends were confirmed in several major meta-analyses that have been discussed. This is contrasted with the latest RCT, TiTre2,25 which raised questions as to the use of restrictive triggers within cardiac surgery. Within the non-cardiac literature, a more nuanced picture emerges from the studies. Some orthopedic surgical data showed no difference between the liberal and restrictive arms with regard to morbidity and mortality, while the TRIFE trial showed higher mortality within the restrictive strategy group. Additionally, the latest meta-analyses28,54 in the published literature have showed increased risk when restrictive strategy was applied to elderly orthopedic patients. Such a mixed picture also emerges when examining trials from the oncologic patients undergoing abdominal surgery. Recently, the AABB (formerly known as the American Association of Blood Banks) has updated its guidelines regarding red cell transfusion thresholds and storage.55 Since this organization’s first guidelines were released in 2012, the number of patients enrolled in RCTs investigating transfusion practices has nearly doubled. This group recommended a restrictive transfusion threshold of 7 g/dL for stable inpatients, including those in the intensive care unit. An Hgb threshold of 8 g/dL for cardiac and orthopedic surgical patients was also recommended. They postulated that there is likely no difference between an Hgb value of 7 g/dL and 8 g/dL, rather these were the thresholds selected by the various RCT investigators. The accompanying editorial cautions relying solely on Hgb values to guide ABT and encourages clinicians to consider the clinical context and incorporate markers of oxygen delivery such as base deficit, cerebral oximetry, and lactate levels into the decision to transfuse.56 The authors agree with both the AABB’s updated guidelines and the accompanying editorial, but would add the caveat that a restrictive strategy may not be
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Table 1 Randomized, Controlled Trials and Meta-analyses Evaluating Restrictive Versus Liberal Transfusion Strategies in Cardiac Surgery Author
Year
Journal
Clinical Setting
Hajjer23 (RCT)
2010
JAMA
Elective cardiac surgery
Murphy25 (RCT)
2015
N Engl J Med
Nakamura24 (RCT subset)
2015
J Thorac Cardiovasc Surg
Curley26 (Meta)
2014
Crit Care Med
Patel27 (Meta)
2015
Lancet Haematol
Hovaguimian28 (Meta)
2016
Anesthesiology
No. of Patients
No. of Trial Centers/RCTs
Primary Endpoint
502
1 center
Non-emergency cardiac surgery
2003
17 centers
Elective cardiac surgery in patients 460 or o60 years of age Transfusion threshold RCTs in cardiac and vascular surgery Transfusion threshold RCTs in cardiac and non-cardiac surgery Adult surgical or critically ill patients
502
1 RCT
Composite endpoint of 30-day all-cause mortality and severe morbidity Serious infection or ischemic event within 3 months of randomization 30-day all-cause mortality and morbidity
1,262
7 RCTs
All-cause mortality
3,352
6 RCTs
30-day mortality
3,300
8 RCTs
30-day inadequate oxygen supply complications, mortality, composite of both, and infections
Abbreviation: RCT, randomized controlled trials.
suitable for all surgical patients and ABT must be an individualized intervention. Interestingly, this update also provided the first recommendation of how long RBC units can be stored prior to ABT. The AABB confirmed the routine practice of blood banks releasing the oldest units of red cells first as a safe technique that does not expose patients to increased risk when compared to administering shorterstorage-duration red blood cells. Although the risks and benefits of allogeneic blood transfusion are well documented within the cardiac and non-cardiac surgical literature, the question that still remains to be
definitively answered is when the benefit of transfusion outweighs the risks for a given patient in a specific clinical setting. Two major themes appeared to emerge from the data within the cardiac and non-cardiac surgical populations. First, protocols should be driven by data from studies specific for the patient population at risk. Second, more large-scale, randomized, controlled trials are needed to objectively provide therapeutic guidelines for perioperative clinicians. As described by Beattie in a recent Anesthesiology editorial, ABT should be considered the “last resort” in addressing perioperative Hgb deficiency within patient populations.
Table 2 Randomized, Controlled Trials Evaluating Restrictive Versus Liberal Transfusion Strategies in Non-cardiac Surgery Author
Year
Journal
Clinical Setting
No. of Patients
No. of Trial Centers
Primary Endpoint
So-Osman47
2010
Vox Sang
Hip/knee replacement
619
3
Carson46
2011
N Engl J Med
2016
47
Gregersen53
2015
Acta Orthop
284
1
de Almeida52
2015
Anesthesiology
Patients Z50 years old with CV disease or risk factors for CV disease undergoing primary repair of hip fracture Patients Z65 years old from assisted living facilities with hip fracture repair Abdominal oncology surgery requiring postoperative ICU care
No change in RBC transfusions or hospital length of stay No difference in 60-day mortality or ability to walk unassisted across room
198
1
Abbreviations: CV, cardiovascular; ICU, intensive care unit; RBC, red blood cell.
No difference in 90-day mortality or ability to perform daily living activities Mortality and morbidity were twice as common in restrictive group
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Although significant advancements have been made since the first documented transfusion in the 17th century, the next phase of strategies should focus not only on optimizing the risk and benefit calculation of ABT within context-specific patient populations, but also on developing all-encompassing perioperative strategies to decrease the need for ABT altogether. These strategies should include preoperative clinic assessment for the utility of iron and erythropoietin infusions, intraoperative fluid management, and surgical technique, as well as appropriate perioperative management of hematologically active pharmacologic agents.57 References 1 Learoyd P. The history of blood transfusion prior to the 20th century–part 1. Transfus Med 2012;22:308–14. 2 Learoyd P. The history of blood transfusion prior to the 20th century–part 2. Transfus Med 2012;22:372–6. 3 Moore SB. A brief history of the early years of blood transfusion at the Mayo Clinic: The first blood bank in the United States (1935). Transfus Med Rev 2005;19:241–5. 4 Alter HJ, Klein HG. The hazards of blood transfusion in historical perspective. Blood 2008;112:2617–26. 5 Madjdpour C, Heindl V, Spahn DR Risks. benefits, alternatives and indications of allogenic blood transfusions. Minerva Anestesiol 2006;72: 283–98. 6 Toner RW, Pizzi L, Leas B, et al. Costs to hospitals of acquiring and processing blood in the US: A survey of hospital-based blood banks and transfusion services. Appl Health Econ Health Policy 2011;9:29–37. 7 Goodnough LT, Shah N. Is there a "magic" hemoglobin number? Clinical decision support promoting restrictive blood transfusion practices. Am J Hematol 2015;90:927–33. 8 Galas FR, Almeida JP, Fukushima JT, et al. Blood transfusion in cardiac surgery is a risk factor for increased hospital length of stay in adult patients. J Cardiothorac Surg 2013;8:54. 9 Kilic A, Whitman GJ. Blood transfusions in cardiac surgery: Indications, risks, and conservation strategies. Ann Thorac Surg 2014;97:726–34. 10 van Straten AH, Bekker MW, Soliman Hamad MA, et al. Transfusion of red blood cells: the impact on short-term and long-term survival after coronary artery bypass grafting, a ten-year follow-up. Interact Cardiovasc Thorac Surg 2010;10:37–42. 11 Bhaskar B, Dulhunty J, Mullany DV, et al. Impact of blood product transfusion on short and long-term survival after cardiac surgery: more evidence. Ann Thorac Surg 2012;94:460–7. 12 Muller MM, Geisen C, Zacharowski K, et al. Transfusion of packed red cells: Indications, triggers and adverse events. Dtsch Arztebl Int 2015;112: 507–17. quiz 518. 13 Bennett-Guerrero E, Zhao Y, O'Brien SM, et al. Variation in use of blood transfusion in coronary artery bypass graft surgery. JAMA 2010;304: 1568–75. 14 Goodnough LT, Murphy MF. Do liberal blood transfusions cause more harm than good?. BMJ 2014;349:g6897. 15 Murphy MF, Goodnough LT. The scientific basis for patient blood management. Transfus Clin Biol 2015;22:90–6. 16 Yaffee DW, Smith DE 3rd, Ursomanno PA, et al. Management of blood transfusion in aortic valve surgery: Impact of a blood conservation strategy. Ann Thorac Surg 2014;97:95–101. 17 Gross I, Seifert B, Hofmann A, et al. Patient blood management in cardiac surgery results in fewer transfusions and better outcome. Transfusion 2015;55:1075–81. 18 Varghese R, Jhang J. Blood conservation in cardiac surgery: In need of a transfusion revolution. Semin Cardiothorac Vasc Anesth 2015;19: 293–301. 19 Carson JL, Hebert PC. Should we universally adopt a restrictive approach to blood transfusion? It's all about the number. Am J Med 2014;127:103–4.
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50 Robertson CS, Hannay HJ, Yamal JM, et al. Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: A randomized clinical trial. JAMA 2014;312:36–47. 51 Carson JL, Carless PA, Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev CD:002042, 2012. 52 de Almeida JP, Vincent JL, Galas FR, et al. Transfusion requirements in surgical oncology patients: A prospective, randomized controlled trial. Anesthesiology 2015;122:29–38. 53 Gregersen M, Borris LC, Damsgaard EM. Postoperative blood transfusion strategy in frail, anemic elderly patients with hip fracture: the TRIFE randomized controlled trial. Acta Orthop 2015;86:363–72. 54 Fominskiy E, Putzu A, Monaco F, et al. Liberal transfusion strategy improves survival in perioperative but not in critically ill patients. A metaanalysis of randomised trials. Br J Anaesth 2015;115:511–9. 55 Carson JL, Guyatt G, Heddle NM, et al. Clinical practice guidelines from the AABB: Red blood cell transfusion thresholds and storage. JAMA 2016;316:2025–35. 56 Yazer MH, Triulzi DJ. AABB red blood cell transfusion guidelines: Something for almost everyone. JAMA 2016;316:1984–5. 57 Beattie WS, Wijeysundera DN. Approaching a safe last resort: Triggers for perioperative blood transfusion. Anesthesiology 2016;125: 11–3.