Best Practice & Research Clinical Anaesthesiology 26 (2012) 475484

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Best Practice & Research Clinical Anaesthesiology

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Blood transfusion in the perioperative period

Raymond A. Zollo, M.D., Associate Professor of Anaesthesiology *, Michael P. Eaton, M.D., Professor and Chair of Anaesthesiology, Marcin Karcz, M.D., Resident in Anaesthesiology, Robert Pasternak, M.D., Assistant Professor of Anaesthesiology, Laurent G. Glance, M.D., Professor of Anaesthesiology
Department of Anaesthesiology, University of Rochester School of Medicine, 601 Elmwood Ave, Rochester, NY 14642, United States

Keywords: anemia blood transfusion perioperative period transfusion triggers transfusion targets transfusion recommendations acute coronary syndrome

Anemia is associated with perioperative mortality and morbidity. Since the presence of anemia and blood transfusion often go hand in hand, it can be difcult to separate the effects of anemia from the effects of perioperative transfusion. The role for blood transfusion in mitigating the mortality and morbidity associated with anemia is unclear. A restrictive transfusion strategy has been advocated for hemodynamically stable patients, as blood transfusion exposes the patient to both infectious and non-infectious complications. Further research is warranted in patients with the acute coronary syndrome, as there is insufcient evidence to make recommendations for this patient population. Additional multi-center randomized controlled trials need to be conducted in perioperative and critically ill patients with large enough sample sizes to examine differences in mortality and major complications between liberal and restrictive transfusion strategies. Further trials need to incorporate current practices in improved blood storage and leukoreduction techniques. 2012 Elsevier Ltd. All rights reserved.

Introduction Anemia is associated with increased risk for postoperative mortality and adverse events in patients undergoing cardiac and non-cardiac surgery.1 Blood transfusion is the cornerstone of therapy to increase oxygen delivery in anemic patients when tissue oxygen requirements exceed oxygen
* Corresponding author. Tel.: 1 585 293 8317. E-mail address: raymond_zollo@urmc.rochester.edu (R.A. Zollo). 1521-6896/$ see front matter 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bpa.2012.10.001

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delivery.2 Fifteen million units of red blood cells and whole blood were transfused in 2008.3 Although blood transfusion was once believed to be a low-risk treatment for anemia, the liberal use of blood transfusions has been increasingly questioned.4 A recent systematic review based on over 270,000 patients found that blood transfusion is associated with 70% increased risk of mortality and an 80% higher risk of infectious complications in adult intensive care unit, trauma, and surgical patients.5 Despite evidence that blood transfusion is associated with signicant complications, and the existence of practice guidelines from several national organizations (National Institutes of Health,6 American College of Physicians,7 Society of Thoracic Surgeons, American Society of Anesthesiologists),8 there is wide variability in the rates of transfusion in patients undergoing cardiac and noncardiac surgery. Hospital transfusion rates for patients undergoing coronary artery bypass graft surgery varies between 8% and 93%.9 In patients undergoing non-cardiac surgery at major academic medical centers, there is a ve-fold difference in the risk of transfusion between high and lowtransfusion hospitals.10 In part, this wide variability in blood transfusion reects gaps in our understanding of the true risks and benets of the use of blood during the perioperative period. The decision to transfuse blood should not be made lightly, particularly in the perioperative period. Appropriate blood management requires taking into account patient characteristics such as age, cardiovascular reserve, hemodynamic stability, and surgical issues such as blood loss. Transfusion decisions should also consider the potential risks of blood use, both infectious and non-infectious. Recent guidelines from the American Association of Blood Banks advocate a restrictive transfusion strategy, recommending blood use only in postoperative patients with a hemoglobin concentration of 8 g/dl or less, or for symptoms such as chest pain.11 Some have criticized these guidelines for relying too much on a single number, and have suggested that transfusion decisions need to integrate other important clinical information.12 In this review, we will discuss the risks associated with anemia in the perioperative period. We will review the evidence from observational and randomized controlled trials that have been used to construct practice guidelines for blood use. We will discuss the risks of both infectious and noninfectious complications associated with blood transfusion. Finally, we will review the most recent guidelines for transfusion in the perioperative period. Anemia Anemia is dened by the World Health Organization as a hemoglobin concentration of less than 12.0 g/dl for women and less than 13.0 g/dl for men.13 It is the most common hematologic problem in the preoperative patient, and the strongest predictor of transfusion of blood components.14 The physiologic aspects of anemia are more fully discussed another review in this series. Briey, adaptation to anemia occurs by several mechanisms. The primary compensatory response to anemia is an increase in cardiac output. There is an increase in vascular tone due to an increase in sympathetic outow. The reninangiotensinaldosterone system is stimulated to increase the retention of sodium and water. Decreased red cell mass decreases blood viscosity thereby reducing resistance to ow in the microcirculation. There is increased synthesis of 2,3 DPG by red cells which results in the right shift in the hemoglobin dissociation curve, favoring greater oxygen release in the tissues. The Bohr effect due to increased CO2 level also plays a minor role in this shift. Transfused blood has less oxygen delivery capacity than native blood. Red cell storage decreases levels of 2,3 DPG causing a left shift in the hemoglobin dissociation curve, thereby reducing the ability of blood to unload oxygen. Further, red cell storage decreases red cell membrane deformability, which is necessary for red cell access to the microcirculation. Thus, transfused red cells may impair blood ow and oxygen delivery to the microcirculation.15 The human myocardium extracts 6075% of all of the oxygen delivered to it, which makes it unique among all circulations in the human. This high extraction ratio makes the myocardium particularly sensitive to a reduction in blood oxygen carrying capacity. Indeed, the myocardium can only increase its oxygen supply with an increase in blood ow produced by vasodilation.16 The presence of a owlimiting lesion in a major epicardial coronary artery causes ischemia to occur at a much higher hemoglobin level than that which would induce ischemia with a normal vasculature.17 It follows, that there would be increased concern with the prospect of anemia and decreased oxygen carrying capacity in patients with acute coronary syndromes and increased cardiovascular risk.

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Transfusion and clinical outcomes: retrospective studies Most retrospective studies report increased mortality and complications in patients who are transfused compared to patients not receiving blood. Anemia increases mortality and morbidity in patients undergoing both cardiac and non-cardiac surgery, and in patients with an acute coronary syndrome.1,13,14,1820 Yet the correction of anemia with transfusion does not necessarily improve outcomes. Blood transfusion is associated with worse outcomes in cardiac surgical patients,2124 ICU patients5,2527 and patients with acute coronary syndromes2831 In a study of over 8000 patients undergoing lower extremity revascularization, receiving a blood transfusion of 1 or 2 units was associated with increased mortality, morbidity, shock/sepsis, pulmonary complications and the need to return to the operating room.32 A larger observational study examining outcomes in over 900,000 operations using data from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) revealed similar ndings. Transfusion of a single unit of packed cells was associated with increased mortality, renal, pulmonary, and infectious complications.33 Since the presence of anemia and blood transfusion often go hand in hand, it can be difcult to separate the effects anemia from the effects of intraoperative transfusion. Although observational studies consistently demonstrate worse outcomes in transfused patients, blood transfusion is more frequently administered to sick patients and sick patients more frequently develop infections and die.34 A recent observational study, also based on data from ACS NSQIP, tries to separate these effects by examining the effects of intraoperative transfusion in patients with severe baseline anemia receiving just one or two units of blood. In this setting, transfusion was more likely to occur as a result of the underlying anemia rather than the presence of signicant blood loss during surgery. Intraoperative transfusion was associated with an increased risk of death, pulmonary complications, sepsis, thromboembolic complications, or wound complications.35 Anemia is clearly associated with adverse outcomes. However, observational studies have not demonstrated the clinical effectiveness of treating anemia with blood transfusion. It is important to understand the limitations of observational data. Because observational studies do not randomize patients to receive or not receive blood, it is very difcult to rule out the possibility of selection bias. In other words, even after using appropriate multivariate statistical techniques to adjust for confounding, it is still possible that treatment and control groups have large enough unobserved differences in patient characteristics to account for difference in outcomes. Patients receiving blood during the perioperative period may simply be sicker than patients not receiving blood transfusion. For example, using data from ACS NSQIP, Bernard and colleagues reported that patients undergoing noncardiac surgery who received 3 or 4 units of red blood cells had a two-fold higher risk of mortality compared to patients not receiving blood.36 However, since their propensity-based analysis does not control for intraoperative blood loss, it is impossible to know if transfusion itself resulted in worse outcomes, or was instead a marker for increased blood loss which itself resulted in worse outcomes.37 Transfusion and clinical outcomes: randomized controlled trials Only three large randomized controlled trials have examined the effects of blood transfusion on clinical outcomes. The Transfusion Requirements in Critical Care (TRICC) study is perhaps the bestknown RCT designed to study the benets of blood transfusion. TRICC is a multicenter trial which enrolled 838 critically ill patients who were euvolemic after treatment and who had hemoglobin concentrations less than 9.0 g/dl after admission to the ICU. Patients were randomly assigned to a restrictive blood transfusion strategy (trigger Hb <7.0 g/dl, target Hb 7.09.0 g/dl) or a liberal blood transfusion strategy (trigger Hb <10.0 g/dl, target Hb 10.012.0 g/dl). The 30-day mortality rate was similar in both groups. In a subgroup analysis of healthier patients (Acute Physiology and Chronic Health Evaluation II score of 20 and among patients less than 55 years old), mortality rates were signicantly lower for restrictive vs. liberal transfusion strategy. Patients with clinically signicant cardiac disease had similar outcomes.38 The TRICC study is one of the very few large adequately powered studies, and as such carries considerable weight in current clinical recommendations.11 However, some limitations of this study lead to questions regarding the generalizability of the results. The study was conducted over 10 years ago before improvements in blood preservation

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techniques and leukoreduction came into practice. Further, only 13% of the evaluated patients were enrolled, bringing into question the role of clinical selection bias.12 It is possible that clinicians only allowed patients to be entered into this study whom they believed would tolerate severe anemia without receiving blood. The Transfusion Requirements after Cardiac Surgery (TRACS) is the only RCT to examine the potential risks of blood transfusion during the intraoperative period. TRACS is a single-center trial, which randomized 502 elective cardiac surgical patients to either a restrictive transfusion strategy (target Hct 24%) or a liberal transfusion strategy (target Hct 30%) during the intraoperative and ICU period. Use of the restrictive transfusion strategy compared with the liberal strategy resulted in noninferior rates of 30-day all-cause mortality and severe morbidity. Additionally, the number of transfused units was an independent risk factor for clinical complications or death at 30 days. This risk was independent of transfusion strategy and increased for each additional unit transfused.39 The major limitation of this study is that it was conducted in a single center, limiting its generalizability. Finally, the Transfusion Trigger Trial for Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair (FOCUS) is a recently completed NHLBI-funded trial designed to determine whether a higher threshold for blood transfusion would lead to better functional outcomes, and lower rates of morbidity and mortality in patients with cardiac disease. Patients with either a history of, or risk factors for cardiovascular disease and whose Hb level was less than 10 g/dl following hip fracture surgery were randomized to a restrictive transfusion strategy (symptoms of anemia or a trigger Hb <8 g/dl) or a liberal strategy (trigger Hb <10 g/dl). There was no difference in the composite outcome of death or ability to walk independently on 60-day follow-up between the liberal and restrictive group.40 This study could be criticized for using a composite outcome, which combines mortality and functional outcome. Basing the power analysis on this choice of composite outcome makes it impossible to study potentially more important clinical outcomes such as mortality and major complications. Of course practical considerations may have made it impossible to power this study for a different set of clinical outcomes.41 Taken together, these randomized controlled trials do not point to clinically important differences in outcomes using a more traditional liberal transfusion trigger vs. a more restrictive transfusion trigger. However, it is important to keep in mind that all of the major RCTs have important limitations: (1) TRICC excluded over 85% of eligible patients; (2) TRACS is a single-center trial; and (3) FOCUS was not adequately powered for mortality and major complications. Observational trials, on the other hand, suggest a very strong association between transfusion and clinical outcomes. However, it may be impossible to determine if surgical patients who receive more blood have worse outcomes due to the effects of blood transfusion, or due to complications from the blood loss. Taken together, the evidence base appears incomplete and not yet robust enough for formulating a strong set of clinical recommendations. Infectious complications The blood supply in the US and much of the developed world continues to get safer with respect to transmissible infectious diseases. This is due to improvements in donor screening and biologic testing. Infection risks continue to decrease, although when transfusion-related infections occur, it is most often devastating and in some cases completely untreatable. Concern and public perception regarding the safety of the blood supply play as much a role as the probability of infection. This is clearly evident with human variant CreutzfeldtJacob disease (mad cow disease), which is extremely rare but unfortunately has been transmitted via blood transfusion and is uniformly fatal.42 This led the AABBs transfusion-transmitted disease committee to label CJ disease as an agent of highest concern.43 Infectious risks are listed in Table 1. Non-infectious complications Most clinicians are aware of the infectious complications of blood transfusion and how rarely they occur. This may cause them to underestimate the overall risk of transfusion, which is much higher and primarily related to non-infectious risks. With the continual reduction of infectious pathogens in

R.A. Zollo et al. / Best Practice & Research Clinical Anaesthesiology 26 (2012) 475484 Table 1 Infectious complications of blood transfusion.44 Pathogen HIV Hep C Hep B HTLV CMV Malaria Babesiosis Estimated risk per unit transfused 1:1.5 million 1:1.1 million 1:280,000 1:2.9 million Comments

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<1:4 million <1:4 million

Toxoplasmosis Chagas disease Human variant CreutzfeldtJacob disease

Unknown

Seronegative donors and leukoreduction for immunocompromized recipients Deferral of donors from endemic regions Tick borne illness, no screen available, transfusion transmission has been rarely documented; can be fatal in immunocompromized Transfusion related in immunocompromized Transfusion related cases in immunocompromized Rare; no screening, no treatment; donors traveling to endemic areas eliminated; role of leukoreduction and ltering unknown.

donated blood through improved donor screening and blood testing, non-infectious complications are 10,000 times more likely to occur. It is important for the perioperative physician to have increased vigilance for these complications, as many of the cardinal signs and symptoms will be absent in the anesthetized or sedated patient. For example, of the signs and symptoms of a potential fatal hemolytic transfusion reaction (fever, chills, rigors, chest/back/abdominal pain, nausea, vomiting, hypotension, hemoglobinuria, oliguria, bleeding and sense of impending doom), only hemoglobinuria, oliguria and hypotension may be apparent in the anesthetized or sedated patient. Transfusion related acute lung injury (TRALI) is an important cause of transfusion related mortality/ morbidity and is a leading cause of transfusion related death. Fresh frozen plasma and other plasma containing products have been the most frequently implicated blood components. In most cases neutrophil-specic or HLA antibodies have been found in the implicated donor, most who are multiparous women.45 A 2 hit model has been proposed to explain the pathophysiology of TRALI. An initial insult to pulmonary vascular endothelium occurs due to surgery, trauma, infection, or massive transfusion, attracting neutrophils to the endothelium. The second hit occurs by elements in the transfused plasma, activating the primed neutrophils to release oxidases that damage the endothelium and produce the capillary leak and lung injury.46 Treatment is mechanical ventilation and supportive measures. Diuretics are not helpful. Patients, although profoundly ill, typically recover with a case fatality ratio of 10%.47 Transfusion Related Immunomodulation (TRIM) is a demonstrated biological phenomenon with a historically established benecial clinical effect (increased survival of renal allografts) and a host of proposed detrimental effects (increased susceptibility to bacterial and viral infections, multi-organ failure, increased risk of cancer recurrence and metastasis). While the results of observational studies suggest this association, adverse TRIM effects have only been a consistent nding in RCTs in cardiac surgery patients. It must be stated that RCTs have not been performed in patient populations with cancers most likely inuenced by immunomodulation, so the potential effect of TRIM on cancer recurrence and metastasis remains unknown. Leukoreduction of blood components is justied in cardiac surgery patients. Universal leukoreduction of blood components for all patients, while not yet supported by available TRIM studies, is probably justied based on other WBC related effects.48 Table 2 lists non-infectious complications of blood transfusion. Recommendations for perioperative blood management Available practice guidelines applicable to the perioperative blood management stress the importance of an appropriate preoperative evaluation to identify risk factors for organ ischemia (cardiac disease) that may be important in the selection of an appropriate transfusion trigger. Additionally,

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Table 2 Non-infectious complications of blood transfusion.49 Condition Hemolytic reaction Cause Transfusion to patients with preexisting antibodiesdABO incompatibility Hemolytic reaction 35 days post transfusion in patients with increased transfusion history More common with platelet transfusionsdrecipient alloantibodies; leukocyte derived cytokines released during storage Bacterial infection of products Risk 1/10,0001/50,000 Safety measure ABO compatibility Proper blood handling Treatment Supportive

Delayed hemolytic reaction

Identify patients at risk, Supportive select antigen negative blood

Febrile non hemolytic reaction

135% of platelet transfusions

Reduced with use of leukoreduction

Supportive

Septic transfusion reaction

Allergic reaction

? IgA deciency in recipient Incorrect blood product to incorrect patient New acute injury that develops with a clear temporal relationship to transfusion in patient without other risk for acute lung injury Volume overload from transfusion

Mistransfusion

1/250,000 RBC transfusions; 1/25,000 platelet transfusions (room temp, pooled) Hives 13% Anaphylaxis 1/20,0001/50,000 Often underreported

Improvements in collection and storage methods

Supportive, very high mortality rate Supportive

Transfusion related lung injury (TRALI)

Transfusion related Circulatory Overload (TACO) Post Transfusion Purpura

Improved patient identication and redundant systems Leading cause of Associated with female transfusion related multiparous donors; death; anti-neutrophil male only plasma antibodies, anti HLA donors; female antibodies; more nulliparous donors common after plasma with neg HLA antibody transfusion testing 1% of transfusions Increased awareness, increase risk in infants, care in high risk and patients with heart patients or kidney disease Unknown

Supportive

Supportive, diuretics not helpful

Transfusion related Graft vs. Host disease

Rare 300 cases Delayed reported world wide thrombocytopenic purpura-Autoantibodies to platelet specic antigens Engraftment of donor Rare immunocompetent T lymphocytes 16 weeks post transfusion

Diuretics useful, supportive, decrease transfusion rates in at risk patients IV Ig Plasmapheresis

Microchimeraisms

Donor lymphocytes persist in recipient Transfusion Improved survival related in renal allografts; immunomodulation increased cancer (TRIM) recurrence; increased perioperative infections; increased mortality

Rare, described in trauma patients Believed to be common although studies conicting

Increased risk in immunocompromized recipient; gamma irradiate cellular products (RBCs, platelets, granulocytes) Unknown Suggested protective role for leukoreduction

Supportive; often fatal

Long term effects unknown Supportive

R.A. Zollo et al. / Best Practice & Research Clinical Anaesthesiology 26 (2012) 475484 Table 2 (continued ) Condition Alloimmunization Cause Chronically transfused patients develop alloantibodies Citrate toxicity, hypocalcemia; hyperkalemia; hypothermia Dilutional and consumptive coagulopathy Risk 28% chronically transfused patients; 40% in sickle cell patients More often seen in massive transfusion Safety measure Transfusion of HLA matched platelets; awareness of patients at risk Awareness of storage effects; washing to reduce K load; warming to prevent hypothermia Massive transfusion protocols Treatment Supportive

481

Metabolic derangements

Coagulopathic derangements

Associated with massive transfusion (> than 2 blood volumes) Essentially 100%. Longer RBC storage times >14 days associated with increased mortality and morbidity Restrictive associated with better outcome with possible exception in patients with acute coronary syndromes Chronic transfusion therapy

Storage lesions

Decreased 2,3 DPG left shift; decreased S-nitro Hb impaired deformability

Decrease storage times; role of leukoreduction unclear

Correct metabolic problem, increased awareness in massive transfusion; supportive Replacement of components; correction of hypothermia and acidosis Supportive

Over/under transfusion

Restrictive vs. liberal transfusion triggers

Risk vs. benet analysis for individual patient before transfusion; increased awareness Increased awareness

Supportive

Iron overload

Chronic transfusions, iron deposition in liver, heart, skin, endocrine organs

Exchange transfusions (increases blood exposure); iron chelation therapy often poorly tolerated

patients should be screened for the presence of congenital or acquired blood disorders and the use of drugs that affect coagulation. Patients should be counseled on the risks vs. benets of blood transfusion and their preferences should be discussed. The results of previous testing should be reviewed and the need for additional preoperative testing should be guided by the anticipated surgery and the patients preoperative health status.8,50 Routine testing in the absence of clinical suspicion of should be avoided. It is likely that proper attention to he diagnosis and treatment of preoperative anemia will reduce the incidence of transfusions in surgical patients.51 A red blood cell transfusion clinical practice guideline was recently published from the AABB. The authors examined available evidence published in all languages from 1990 to February 2010. The most emphasis was given to the results of 3 randomized controlled clinical trials, 2 in adults (discussed above) and 1 in children. The two trials in adults provided 60% of the data.11 The AABB recommends adhering to a restrictive transfusion strategy (Hb 78 g/dl) for hospitalized, stable patients. The AABB suggests adhering to a restrictive strategy in hospitalized patients with pre-existing cardiovascular disease or postoperative patients. Transfusion should be considered for patients with symptoms of anemia or an Hb of 8 g/dl or less. The evidence is insufcient to recommend for or against a restrictive or liberal transfusion threshold for hospitalized hemodynamically stable patients with the acute coronary syndrome. Finally the AABB recommends that clinical symptoms as well as Hb levels should inuence transfusion decisions.11 Patients should be carefully monitored for adverse effects of transfusion in the perioperative period with a high index of suspicion as signs and symptoms may be masked by surgery and anesthesia. Recognizing the uncertainties in risk-benet calculations for blood transfusion, the Joint Commission (TJC) has begun to take an interest in blood management.52 At this time TJC is only recommending performance measures, but it is likely that more directive measures will follow. It

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behooves the medical community to better dene the risks and benets of blood transfusion in surgical patients, and implement care pathways that improve outcomes associated with anemia and transfusion. Summary Anemia is associated with perioperative mortality and morbidity. Sicker patients receive more blood. Patients undergoing more complex surgical procedures tend to receive more blood. The role for blood transfusion in mitigating the increased mortality and morbidity associated with anemia is unclear. The perioperative physician should carefully consider the risk vs. benet of transfusion for the individual patient.

Practice points  When considering blood transfusion for perioperative anemia, the patients clinical status and goals of therapy should inform a risk vs. benet analysis.  A restrictive transfusion strategy is favored for hemodynamically stable hospitalized patients.  There is insufcient evidence to recommend a restrictive therapy for patients with an acute coronary syndrome.

Research agenda  Additional multi-center randomized controlled trials need to be conducted in perioperative and critically ill patients with large enough sample sizes to examine differences in mortality and major complications between liberal and restrictive transfusion strategies.  Further research is warranted in patients with the acute coronary syndrome.  Future trials need to incorporate current practices of improved blood storage and leukoreduction techniques.

Conicts of interest None. References

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