HOW DO I...? How we view and approach transfusion-associated circulatory overload: pathogenesis, diagnosis, management, mitigation, and prevention Chester Andrzejewski Jr,1 Mark A. Casey,2,3 and Mark A. Popovsky4,5
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ince blood transfusion’s introduction into modern clinical practice in the first part of the 20th century problems with hemotherapy (HT)related circulatory overload in patients have been appreciated. As early as the second decade of the 20th century and into the 1940s, issues regarding hypervolemia associated with whole blood transfusions were raised, but with the introduction of blood component therapy, clinical concerns about it abated.1-4 While physicians acknowledged that transfusion was a risk factor for hydrostatic pulmonary edema, the perception generally was, and remains, that circulatory overload is infrequent or inconsequential or could be easily treated once it presents. It was not until the 1980s when transfusion-related acute lung injury (TRALI) was placed
ABBREVIATIONS: ALI = acute lung injury; BB/TMS = blood bank and/or transfusion medicine service; BNP = brain natriuretic peptide; CVP = central venous pressure; EHR(s) = electronic health record(s); FC(s) = fluid challenge(s); FY = Fiscal Year; HT = hemotherapy; ICD = International Classification of Diseases; ICU = intensive care unit; NP = natriuretic peptide; PP = pulse pressure; STR(s) = suspected transfusion reaction(s); TACO = transfusionassociated circulatory overload; UCT(s) = uncomplicated transfusion(s); VSV(s) = vital sign value(s). From the 1Transfusion Medicine Services, Department of Pathology, and the 2Department of Medicine, Cardiology Division, Baystate Medical Center, Baystate Health, Springfield, Massachusetts; the 3Department of Medicine, Cooley Dickinson Hospital, Northampton, Massachusetts; 4Haemonetics Corporation, Braintree, Massachusetts; and 5Beth Israel Deaconess Medical Center, Boston, Massachusetts. Address reprint requests to: Chester Andrzejewski Jr, PhD, MD, Baystate Health, Springfield, MA 01199; e-mail: [email protected]. Received for publication April 11, 2013; revision received August 27, 2013, and accepted August 27, 2013. doi: 10.1111/trf.12454 TRANSFUSION 2013;53:3037-3047.
on the transfusion medicine radar screen that renewed interest in this iatrogenic fluid challenge (FC) emerged with the designation of it using the term transfusionassociated circulatory overload (TACO), first appearing in the literature in 1996.5 As TRALI’s contribution to morbidity and mortality gained prominence, TACO followed on its heels identified as the “other” transfusion complication requiring clinical reckoning. TACO, however, was for the most part perceived solely to be a consequence of large volumes of blood transfused rapidly and restricted either to the very young or old, concepts that have now been called into question.
DEFINING AND DIAGNOSING TACO Although a formal universally accepted case definition for it currently does not exist, TACO may be generally defined as an adverse HT outcome occurring in transfusion recipients unable to effectively physiologically process a HT FC due to either high infusion rates and/or volumes or an underlying cardiac, renal, and/or pulmonary pathology. Even in countries that have well-established hemovigilance networks variability in the identifying attributes of TACO cases is observed.6,7 TACO is essentially a clinical diagnosis and certain data that have historically been used in the clinical assessment of presumed cases of it (e.g., chest radiographic changes, increased central venous pressure [CVP], response to diuretic therapy) may not always be available for review in every care setting. Certain features nevertheless have been routinely cited as evidence for circulatory overload including increases in CVP, congestion of the pulmonary vasculature, dyspnea, tachycardia, and acute hypertension eventually resulting in pulmonary edema and left- or right-sided heart failure.8 Although both hypertension and pulmonary edema are considered “hallmark” signs of TACO, the former may not always be causative of the latter. Other signs and symptoms include tachypnea, dry cough, jugular or pedal venous distension, pulmonary rales, and a widened pulse pressure (PP).9 These signs and symptoms most frequently present within 2 hours of the onset of transfusion but may take up to 6 hours to manifest. Delayed manifestations of Volume 53, December 2013 TRANSFUSION
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TACO, however, have been reported10 and in a recent data analysis from the well-established UK Hemovigilance Network it was noted that 11.3% of TACO cases can be encountered between 6 and 24 hours after HT.11 The majority of evidence to invoke a diagnosis of TACO involves clinical signs and symptomatology. With regard to the former, no threshold values have been promulgated to trigger concern at the bedside. Diagnostic testing, such as chest radiographs and invasive cardiovascular monitoring devices, if available, may help in patient assessment, but the appearance of signature disease features specific for TACO using such technologies have not been reported. Although no pathognomonic laboratory test exists to diagnose TACO, natriuretic peptide (NP) hormone levels may be helpful but not definitive in investigations.9,12-15 Various international hemovigilance networks have promulgated TACO case definition criteria to facilitate recognition and reporting of such adverse events by their member institutions. Such case definitional criteria should be viewed as beginnings and not endpoints in the discussion of a uniform “gold standard” diagnostic classification. Generally these definitional criteria are similar in scope between networks but may differ slightly among them in select attributes, for example, time periods of symptom onset. Such case definitions are subject to possible revision as occurred in 2013 when the Centers for Disease Control National Healthcare Safety Network in the United States slightly revised the TACO case definition criteria in its biovigilance component to reflect a change in the timeline of attribute onset to “within 6 hours of cessation of transfusion.” The current case definition criteria for TACO in this biovigilance network are summarized below and in Table 1: New onset or exacerbation of three or more of the following within 6 hours of cessation of transfusion: acute respiratory distress (dyspnea, orthopnea, cough); elevated brain natriuretic peptide (BNP); elevated CVP; evidence of left heart failure; evidence of positive fluid balance; and radiographic evidence of pulmonary edema.7 With no universally accepted diagnostic criteria for TACO, its recognition and diagnosis remain problematic, potentially contributing to observed variations in its perceived frequency. As data accrue from the various national hemovigilance networks and are analyzed and vetted in the context of data from previously reported studies regarding TACO, the evolution of a uniformly internationally agreed upon case definition as a gold standard for TACO hopefully will emerge. Additionally, information regarding TACO obtained from a prospective multicenter observational study evaluating severe transfusion reactions as part of the National Heart Lung and Blood Institute (NHLBI) Recipient Epidemiology and Donor 3038
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Evaluation Study-III (REDS-III) program (currently scheduled to start in 2014) may also provide further insight into this entity. Since a TACO paradigm is still being constructed, results from it and other such studies along with the historical literature will be informative in its assembly.
CLINICAL SIGNIFICANCE AND REPORTING The Food and Drug Administration (FDA) began to include TACO as a specific category designation in its annual reporting of adverse transfusion events in Fiscal Year (FY) 2005. In that year 2% of transfusion-related fatalities reported to the FDA were attributed to this complication. Recognition of TACO as a separately defined serious hazard of transfusion entity by the UK Hemovigiliance Network followed in 2007. By FY 2009, TACO accounted for 27% of all fatalities reported to the FDA second only to TRALI in frequency.16 While it may be likely that the increase in TACO incidence is largely the result of heightened awareness and improved recognition, contributions from increased endorsement of the use of massive transfusion protocols also cannot be excluded as contributing to a true increasing incidence. The case-fatality rate has been reported to vary from 1.4% to 8.3%, making TACO one of the most deadly of transfusion complications.17-19 In addition to patient mortality, TACO contributes to patient morbidity, impacting on hospital length of stay. Twenty-one percent of cases are life-threatening with increases in intensive care unit (ICU) and hospital lengths of stay contributed to by its occurrence.5,18,20 Before October 1, 2010, there was no specific International Classification of Diseases (ICD)-9-CM diagnosis code for TACO and if it was reported to and captured by medical billing coders was typically placed in the existing code category 276.6 Fluid Overload. At the September 2009 ICD-9-CM Coordination and Maintenance Committee meeting, a proposal from the FDA CBER for a unique code for TACO (ICD-9-CM 276.61) was presented and accepted with implementation beginning in FY 2011. On October 1, 2014, all US health care organizations will transition to the next generation of the ICD-10 with the code for TACO becoming ICD-10-CM E87.71.
FREQUENCY The incidence of TACO is not firmly established. Varying institutional definitions and patient case mixes most likely impact its recognition and occurrence reporting. In orthopedic surgery patients, TACO is clearly a common event. In a five-hospital study of US Medicare patients undergoing hip or knee replacement surgery, 1% of transfused patients developed TACO.5 Patients with TACO were older, with a mean age of 87 years and there was a positive fluid imbalance of 2.5 L before transfusion. TACO was also noted to occur even in the context of autologous
TACO DIAGNOSIS, MANAGEMENT, AND MITIGATION
TABLE 1. TACO: key concepts and features Case definition* and pathogenesis New onset or exacerbation of three or more of the following within 6 hr of cessation of transfusion: • Acute respiratory distress (dyspnea, orthopnea, cough); • Elevated BNP; • Elevated CVP; • Evidence of left heart failure; • Evidence of positive fluid balance; • Radiographic evidence of pulmonary edema. Severity ratings*: nonsevere, severe, life-threatening, death, not determined; Imputability*: definite, probable, possible, not determined, doubtful, ruled out. *Centers for Disease Control National Healthcare Safety Network Biovigilance Module. January 2013 Pathogenesis: Increased hydrostatic pressure in the pulmonary blood circuit leading to extravascular fluid accumulation in the lungs.
Diagnosis and patient risk factors Transfusion recipients unable to effectively physiologically process a HT FC due to either high infusion rates and/or volumes or an underlying cardiac, renal, and/or pulmonary pathology. Signature features include dyspnea, orthopnea cyanosis, rales, tachycardia, cough, headache, increased BP, hypoxemia, CXR consistent with pulmonary edema. Risk factors include but are not limited to cardiac or renal dysfunction; younger and advanced aged patients; female sex; severe anemia (i.e., expanded plasma volume); positive fluid balance; and HT involving multiple products including plasma and PLTs. TACO is common (perhaps approx. 1% of transfusions) and significantly impacts recipient outcomes. Need for patient transfer to higher acuity care settings, longer lengths of stay, and fatal outcomes recognized. TACO remains underreported, in part due to inconsistent definitions, recognition bias of only most severe cases, and the lack of a gold standard diagnostic test. NP hormone levels may be of value.12 No single sign, symptom, or laboratory test pathognomonic for TACO.
Treatment and management 1) Stopping transfusion or other fluids, bedside stabilization, and upright postural placement of patient by nursing; 2) alerting of physician and blood bank staff notification; 3) providing respiratory support (e.g., supplemental oxygen, ventilatory assistance); 4) diuretic administration where not contraindicated; 5) blood bank investigations to rule out other transfusion adverse effects (e.g., hemolysis, sepsis, TRALI); 6) cornerstone of successful TACO management is stopping the transfusion and achieving a negative fluid balance.
Mitigation and prevention 1) Staff education; 2) thoughtful assessments regarding HT need and fluid status; 3) careful recording or monitoring of patients’ VSVs during HT; 4) slower infusion rates and/or reduced volume blood products; 5) limited infusion of nonsanguineous fluids during HT; 6) avoidance of multiunit HT or encouragement of single-unit transfusions; and 7) peritransfusion diuretic administration; 8) computerized clinical decision support alert notifications regarding high-risk patients and clinical profiling. Only definitive way to prevent TACO is no HT.
Unappreciated aspects to TACO 1) Recognized early in history of blood transfusion (early 1900s) as a possible adverse consequence; 2) clinically acknowledged but typically ignored as an entity of concern; 3) multiphasic illness with protean manifestations spanning a spectrum from mild to life-threatening severity; 4) pulmonary features may be lacking in mild early stage presentations; 5) may occur during or within several hours of transfusion (delayed expressions possible); 6) risk factors include transfusion-related variables such as volume of HT and rate of infusion as well as recipient factors such as baseline physiology and comorbidities; 7) TACO incidence and impact may be attenuated by implementing meaningful bedside biovigilance strategies; and 8) an underappreciated TACO pathologic mechanism may relate to the mechanical or physical impact of HT on the vascular endothelium. Select key references: Drummond,3 Popovsky et al.,5 Robillard et al.,22 Li et al.,24 Andrzejewski et al.,26 Clifford et al.,33 Murphy et al.20
BP = blood pressure; CXR = chest X-ray.
transfusions.5 In a much larger multicenter study involving 9482 patients, TACO was diagnosed in 8% of those receiving an allogeneic transfusion. The TACO patient group received 1.8 to 2.7 RBC units per patient, underscoring the fact that large fluid volumes are not necessary to trigger the reaction in the patient.21 During the years 2000 to 2004, the reported incidence increased almost twofold, from 1 in 10,360 (2000-2001) to 1 in 4075 RBC units transfused.17 These data originate from passive hemovigilance systems. When active surveillance systems are used, it becomes apparent that TACO is greatly underestimated. At one major medical center, the historical prevalence of TACO over one 6-year period was 1 in 1566.19 When a prospective, active surveillance system was introduced for fresh-frozen plasma (FFP), the TACO reaction rate soared to 4.8% and, of those cases, none were
reported to the hospital’s blood bank. The prevalence rate was in 1 in 68. The mean amount of FFP transfused before the reaction was 4 units. Thus, both cellular and noncellular components can trigger or exacerbate TACO.
EPIDEMIOLOGY AND RISK FACTORS While many patients diagnosed with TACO are 70 years or older, Robillard and colleagues22 using data from a national hemovigilance reporting network demonstrated that younger individuals are also at risk observing TACO occurrences in 6.9% of patients aged 18 to 49 years, 7.3% of those between the ages of 50 to 59 years, and 19.3% of patients aged 60 to 69 years. In a case-control study involving 47,783 patients who received blood products, Murphy and colleagues20 found that the risk factors Volume 53, December 2013 TRANSFUSION
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included female sex, a past history of congestive heart failure, history of hemodialysis, mechanical ventilation, recent vasopressors, and positive fluid balance. When adjusted for age, sex, hospital, and transfusion intensity, TACO was associated with more than threefold increased in-hospital mortality. Significantly increased longer hospital and ICU lengths of stay were also observed. The relationship of blood product fluid volumes in the induction of TACO is still controversial. As noted earlier, it is generally believed that TACO is precipitated by the transfusion of large quantities of blood products. In a 1985 study, Popovsky and Taswell23 found that 20% of cases involved a single unit of RBCs. In the Quebec Hemovigilance System database, the mean number of RBC units transfused in documented TACO cases was only 2.11 units (P. Robillard, personal communication, 2009). The infusion flow rate of blood products is also thought to be an important contributing factor in TACO occurrences. Current AABB recommendations for RBC infusion rates are 240 mL/hr (4 mL/min) and 300 mL/hr for both FFP and platelet (PLT) products. Current reality is that the appropriate flow rates for these components are not known or evidence based. Clearly, the underlying cardiac reserve capacity and fluid status of the patient are important contributors to a patient’s susceptibility to TACO. In one study of 47 TACO patients, the mean infusion flow rate was 4.5 mL/min but the range was 0.9 to 48.1 mL/min.9 In a medical ICU setting, Li and colleagues24 reported that compared with controls, TACO patients were transfused with larger amounts of plasma and at a faster rate, 225 mL/hr, compared with 168 mL/hr. Patients with TACO were significantly more likely to have evidence of left-sided ventricular dysfunction before transfusion. These investigators also noted that baseline cardiovascular function and FFP ordered for the reversal of anticoagulant therapy were strong predicators of TACO before its clinical onset.
ASSESSING TACO IN THE BLOOD BANK When TACO is suspected by bedside practitioners, notification of the blood bank and/or transfusion medicine service (BB/TMS) should occur via the standard mechanisms that institutions have established for the reporting and investigation of any adverse transfusion event. Many times patients do not present with distinguishing features at the bedside that would allow for the exclusion of other adverse transfusion sequelae, for example, a hemolytic transfusion reaction, TRALI, or septic unit transfusion, so an evaluation of the potential adverse event to exclude these entities must occur in the blood bank. Such occurrences typically require further discussions with the medical and nursing staff involved with the transfusion to obtain additional clinical information and the practitioner’s insight into the suspected reaction. This exchange 3040
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not only highlights the value of the participation of the bedside practitioners in the diagnostic differentiation of the adverse event but additionally affords an opportunity for blood bank staff to educate clinical colleagues regarding the spectrum of adverse transfusion complications. Although the extent of the work-up performed may vary between institutions, at a minimum the blood bank should perform routine pertinent clerical documentation checks, review the patient’s blood bank historical records for the occurrence of prior transfusion reactions or antibody problems, examine the returned unit for any nonconforming features (i.e., a “content/container integrity check”), and assess for the presence of hemolysis in the posttransfusion specimens provided. The decision to extend testing beyond these initial investigations should be based on the results obtained from these studies, the severity of the patient’s clinical presentation, BB/TMS physician review of the patient’s medical record, and any additional pertinent information obtained via consultations with the involved medical and nursing staff reporting the suspected reaction. Particular attention should be directed toward an examination of the patient’s fluid balance, blood product infusion rates, medications administered including any diuretic agents, primary diagnosis and comorbidities, results from any pertinent radiographic imaging studies, and any recent weight changes documented for the patient. As stated previously there is no pathognomic laboratory test for TACO. The measurement of NP hormone levels, such as NT-proBNP, may be informative but is not definitive since elevated levels can be encountered in various conditions.25 At one of the institutions of two of the authors, serial measurements of NT-proBNP levels are performed using select peritransfusion specimens from the patient.26 Results from such peritransfusion serial studies are then analyzed by the BB/TMS medical staff for the presence of any rising trend changes in this analyte and correlated with other clinical data to help in further assessment of the event. The value of serial NP level determinations, typically using pretransfusion and immediately posttransfusion specimens, in the assessment of TACO has been reported by several investigators.12,13
APPROACHING TACO FROM A BEDSIDE BIOVIGILANCE PERSPECTIVE In reviewing the HT care map27 several pertinent areas of it can be identified that can contribute potentially to improving TACO diagnosis, management, and mitigation. At the hospitals of two of the authors a strategy focusing on “bedside biovigilance” during transfusions has been a meaningful approach for enhancing TACO monitoring and mitigation. Coupled with ongoing staff education, the lynchpin of these efforts centers on the recording and monitoring of patients’ vital sign values
TACO DIAGNOSIS, MANAGEMENT, AND MITIGATION
(VSVs) during HT and their role in the bedside assessment of adverse transfusion events. Using the perspective of comparing what happens to patients’ VSVs during “uncomplicated transfusions” (UCTs) to those encountered in patients experiencing various types of suspected transfusion reactions (STRs), informative differences between patients were identified via a variety of quality improvement projects that helped to guide institutional development of HT electronic records documentation and alerting, HT infusion rate guidance, automatic BB/TMS STR notifications, and BB/TMS evaluation protocols pertinent to TACO/FC STRs.26,27 Our studies have led us to view TACO as a multiphasic spectrum illness. By this we mean that like many disorders in medicine, TACO just does not happen, but rather manifests in a prodromal manner, especially when examined from the perspective of a “surge capacity” of the patient’s vascular system to temporally respond to a continuum of ongoing FCs. A potential model depicting this multiphasic aspect of TACO is illustrated in Fig. 1. In our studies examining the VSVs of patients undergoing UCTs compared to those experiencing STRs, we noted increases in blood pressure measurements over the course of the transfusion in most STR patients characterized as having a TACO/FC aspect to their adverse event.26 In these individuals, these blood pressure increases were typically evident by 15 minutes into the transfusion of the RBC unit with continued rises noted in most by the time the infusions were halted (see Table 2). Interestingly, when compared to the UCT group mean starting PP, the mean of the initial PP of the TACO/FC cohort patients was higher suggesting the possibility that these individuals were already physiologically “primed,” rendering them more susceptible to additional fluid infusions.
AN UNAPPRECIATED FEBRILE OR INFLAMMATORY ASPECT IN TACO It is generally held that in contrast to TRALI, patients with TACO typically do not present with fever or hypotension.28 In our previously cited study of patients’ VSVs during transfusions, we observed that a marked percentage (approx. 65%) of patients with TACO/FC STRs exhibited an inflammatory or febrile aspect in their bedside presentation.26 This was evidenced also in the increases seen in the actual recorded measurements of the cohorts’ mean VSV for end of transfusion temperatures and the corresponding temperature deltas from the baseline values (see Table 2 and Fig. 2). Such an observation has also been reported in data from the Québec Hemovigilance System29 as well as in earlier medical literature reports regarding concerns about the adverse consequences of rapid transfusion rates and large product volume infusions and their contributions to circulatory overload in HT patients.1-4 Of interest also is the work of Blumberg and colleagues,30
which showed that the incidence of TACO decreased after the implementation of universal leukoreduction at their institution. Given these findings clinicians should not be dismissive of TACO in the patient presenting with an elevated temperature or inflammatory reaction features.
MANAGEMENT AND TREATMENT Once TACO is diagnosed in a patient receiving HT, stopping the transfusion should occur with bedside measures taken immediately to stabilize the patient depending on symptomatology and degree of clinical severity. These include placing the patient in a more upright posture (i.e., Fowler position), stopping infusion of other intravenous (IV) fluids, providing respiratory support (e.g., supplemental oxygen), and administering diuretic medications if not contraindicated. The application of diuretic medications in the treatment of TACO has not been standardized and their use is empiric. Caution should be used in patients with unstable or borderline hemodynamics since such medications may lead to or exacerbate clinically significant hypotension and thus should be avoided. In some institutions it is not uncommon for physicians to initially administer a small “test dose” of diuretics to patients whom they suspect may be in fluid overload. Results from such “therapeutic diagnostic” interventions, especially if performed early in the onset of clinical symptomatology, can be of further help in assessing the nature of an adverse transfusion event and in its management. Loop diuretics, such as furosemide, which reduces cardiac preload acutely via direct venodilation when given IV, may be particularly useful in patients needing marked diuresis especially in those with severe heart failure or with acute pulmonary edema.31 Medical staff and blood bank notifications should occur as soon as possible once the patient is acutely stabilized. Depending on the level of clinical compromise, notification, and involvement of rapid response care teams, typically for patients with severe respiratory distress and those who potentially may require positive pressure ventilation may need to be consulted. For patients in non–critical care settings, arrangements for patient transfer to higher acuity level care areas may also need to be considered. In refractory cases of TACO, hemodialysis may be of clinical benefit. In less severe presentations of TACO temporally stopping the transfusion with concomitant bedside stabilization of the patient as described above may be sufficient to potentially allow for restarting of the unit, albeit at a slower rate. Given the overlapping nature of TACO’s bedside presentation with other severe adverse transfusion sequelae, however, this should not be an encouraged practice. Volume 53, December 2013 TRANSFUSION
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MITIGATION AND PREVENTION Viewing TACO as a multiphasic entity allows for several areas on the HT care map to be incorporated into the designs of meaningful and successful strategies to decrease its occurrence.27 Early in the HT decision making and ordering process section of the care map, several
opportunities exist to enhance TACO mitigation including: 1) thoughtful assessment of the need for HT and evaluation of the patient’s fluid status; 2) clinical decision alerts notifying physicians and nurses about the potential for TACO development in high-risk patients (e.g., those with diagnoses of CHF, renal insufficiency); 3) prescriptive guidance suggesting the use of slower infusion rates
The Multiphasic Spectrum of TACO NP Levels
BP ▲’s Pulmonary Signs/Symptoms Time Stage
I No TACO
(Normovolemia)
• Hemotherapy and Non-Blood Fluid Challenges
↓ • Concept of “Surge
Early
Middle
II
III
Mild TACO
Moderate TACO
Late
IV Severe TACO
Hypervolemia
Bedside Biovigilance : Monitoring of Patient’s Signs and Symptoms During Hemotherapy
Capacity” in Patient’s Cardiovascular Space
1. Constellation of ClinicoLaboratory Features 2. Patient Profiling and Risk Stratification 3. Computer Assisted Diagnosis/Management Adapted and modified from C. Andrzejewski, Ph.D., M.D. AABB Annual Mtg 2008
Fig. 1. Viewing TACO as a multiphasic spectrum entity. Schematic depiction of a multiphasic model of TACO/FCs associated with HT and the body’s response. In such a model TACO/FCs occur over a time interval characterized by four stages (I-IV) with a normal euvolemic state as Stage I and late-phase TACO as Stage IV. These stages correlate, though not necessarily in a directly linear relationship, with the amount of fluid delivered, including nonblood fluids, and the degree of clinical severity manifested by the patient. Variable physiologic responses (↑↓) in at-risk patients are reflected temporally within an increasing severity gradient of the patient’s clinical status as manifested by varying VSVs, clinical symptomatology, and NP hormone levels. The depiction of the up-down arrows in the model is an acknowledgment that patients may present differentially during the course of their TACO development depending on when a suspected reaction is identified at the bedside. For example, not all patients may exhibit elevated blood pressures at the time of respiratory distress onset. Depending on when these variables are measured in the evolution of the TACO episode, magnitude variations between patients may be exhibited. The arrows indicate these variability possibilities with regard to the identified variables. Excess fluid accommodation, either through blood vessel distention and/or through diversion into low flow capillary networks, that is, the surge capacity of the vascular compartment, allows the individual to effectively manage the FC to varying degrees based on an individual’s innate physiology and pathologic status, for example, degree of existent anemia; cardiac, renal, or pulmonary dysfunction, etc. Aspects of this model were first presented in the presentation “TACO in the Community Hospital: Quality Improvement Insights,” Session on TRALI and TACO: New Insights & Pursuing Better Clinical Outcomes, 2008 Annual Meeting of the AABB, Montreal, Quebec, Canada. 3042
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TACO DIAGNOSIS, MANAGEMENT, AND MITIGATION
TABLE 2. Mean VSVs for PP and temperature (T) observed in various patient transfusion cohorts at select transfusion time points* Cohort Variable PP (mm Hg) Mean ±SD Number T (°C) Mean ±SD Number * † ‡ § ||
UCT control (UCT group) Before 15 min End
Non-TACO/FC STR (NFC STR group) Before 15 min End
TACO/FC STR (TACO/FC STR group) Before 15 min End
56 ±19.1 147
57 ±19.2 119
56 ±17.9 126
58 ±17.0 232
59 ±18.2 139
60 ±18.8 225
63†‡ ±23.5 94
69†‡ ±21.8 60
75†‡§ ±27 91
36.7 ±1.3 139
36.8 ±1.1 121
36.7 ±1.1 129
37.0|| ±0.6 232
37.6§|| ±0.8 143
38.0§|| ±0.9 226
37.0† ±0.7 95
37.2†‡§ ±0.8 63
37.6†‡§ ±1.0 91
t test (p ≤ 0.050). Adapted and modified from Andrzejewski et al.,26 Table 3. See reference for details. UCT versus TACO/FC STR. Non-fluid challenge (NFC) STR versus TACO/FC STR. Intragroup. UCT versus NFC STR.
original nonaliquoted product facilitating patient blood management decisions in its subsequent issuance for that patient or another needing an aliquoted unit. Logistic and financial concerns about the preparation and provision of divided products in limited staffing environments coupled with possible increases in workload must be balanced with the potential clinical benefits to patients. Additionally, aside from the enhanced patient safety perspectives from this type of patient blood management, decreases in TACO induction with Temperature (°C) its related clinical consequences may be realized including financial considerFig. 2. Mean temperature deltas with 95% CIs at select times during HT in various ations as in the costs associated with cohorts of patients receiving RBC transfusions. NFC = non–fluid challenge cohort; transfusion reaction investigations, open bar = mean temperature at 15 minutes; patterned bar = mean temperature at related diagnostic studies, and the transend of transfusion. Lines with arrows represent the range of the 95% CIs of the temfer of patients to higher acuity more perature deltas for the indicated cohorts at the select peritransfusion time points. All expensive care settings. variable pairwise combinations tested were significant at p < 0.015 (see Table 4 in During the transfusion event and in 26 Andrzejewski et al. for full details). the posttransfusion interval, the monitoring of patient VSVs as discussed previously may also and/or reduced volume products; 4) highlighting the help in decreasing the development of TACO. In addition value of single-unit transfusion and avoidance of multito a manual viewing of VSVs by nurses and physicians on unit transfusions given over a short time interval; and 5) a paper-based blood unit tag, if a hospital’s electronic recommendations of peritransfusion diuretic use. health record (EHR) allows for the capture and graphic The use of reduced volume products has often been display of peritransfusion VSVs, and provided that such cited as a strategy to manage patients with fluid overload data are entered electronically on a “real-time” basis, the concerns. Although intuitively reasonable there are no development of computer-assisted clinical alerting algoprospective double-blind randomized control studies rithms regarding the detection of “threshold” deviations supporting or refuting this strategy. The extent of its from baseline values and their trend monitoring becomes application in the transfusion medicine community is more feasible helping to augment more informed bedside unknown. When used, units can be aliquoted either HT care decisions. In patients with a history of TACO directly or through the use of a sterile connection device. documented via prior blood bank investigations, notation The advantage of using the latter is that the shelf life of such in BB/TMS records and/or the patient’s EHR of the retained split unit remains the same as the Volume 53, December 2013 TRANSFUSION
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Fig. 3. Computer screen display of transfusion medicine “TACO alert” appearing in the EHR of a patient at risk for TACO activated at time of blood ordering based on patient’s diagnoses or problem list as identified in the patient’s EHR. Baystate Health, Springfield, MA.
(e.g., the patient’s problem list) may be of value in alerting both TMS and clinical staff regarding at-risk patients and in modifying HT so as to minimize the potential for TACO development. Ongoing education of medical and nursing staff about TACO is valuable and essential in the design of meaningful TACO mitigation strategies. BB/TMS technical staffs also need to be vigilant in proactively identifying potential patients at risk for TACO and engage BB/TMS medical staff to clarify ambiguous or confusing transfusion rate orders and component selection options. These activities along with an EHR alerting system notifying practitioners of potential at-risk patients,27 especially at the time of computerized provider order entry of HT (see Fig. 3) or the use of EHRs surveillance algorithms that facilitate the detection of transfusion-related pulmonary complications32-34 may help in TACO mitigation efforts. Such mitigation strategies are critical in attempting to prevent TACO, since from a purely preventive perspective the only sure way to avoid TACO is to avoid blood transfusions.
A TACO RELATIONSHIP WITH “LIBERAL TRANSFUSION STRATEGIES”? Studies examining liberal versus conservative transfusion strategies generally agree that therapeutic plans limiting blood transfusions are not clinically inferior to more aggressive HT approaches.35,36 When cohort data from such studies are examined closely with regard to the magnitude of the amount of blood products given (typically 3044
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quantified just in total unit numbers given rather than actual total volumes transfused) cohort differences suggest a potentially provocative contribution from TACO in the adverse outcomes identified in liberally transfused patients. In a recently published study examining liberal versus restrictive transfusion strategies in patients with gastrointestinal bleeding, Villanueva and colleagues36 speculated that liberal transfusion strategies may cause hemostasis or biochemical coagulation impairments. We believe that such findings could also be due to mechanical or physical aspects of HT. Rather than just a possible chemical imbalance as hypothesized by these investigators, we suggest that physical mechanical forces associated with increased blood pressure gradients resulting from the rapid infusion of high oncotic fluids like blood products may adversely impact sensitive vascular circuits. Depending on the intrinsic ability of the vasculature to accommodate such FCs, the resultant forces could potentially dislodge newly formed hemostatic plugs leading to increased vascular bleeding in injured blood vessels. The variations observed by Villanueva and coworkers in their cohorts’ frequencies for TACO and pulmonary edema, RBC median number or amounts of crystalloids given, cardiac complications, and portal pressure gradient increases in their transfusion liberal cohort patients all support this possibility. In addition, these authors noted that the rate of further bleeding was significantly higher in the liberal transfusion group. Mechanical or physical concerns related to resuscitative fluid volumes have also been raised in prior studies of bleeding trauma patients where the amount of crystalloid fluid given could increase a patient’s PP resulting in “mechanical” disruption of a formed clot37 and in animal models where attempts to restore blood pressure with crystalloid fluids in animals with near-fatal hemorrhage due to vascular injury resulted in increased bleeding and mortality.38 Nearly 100 years ago Bernheim1 noted when writing about transfusion overload that “. . . a great amount of blood will simply raise the blood-pressure to such an extent that it will literally blow out any soft young plugs that might be all that is holding body and soul together. . . .” Villanueva and colleagues’ speculation regarding a “transfusion impairment of hemostasis” in liberally transfused patients may in part be a modern-day reflection of this earlier observation and its implied mechanical or physical aspect by Bernheim.
A TACO ASSOCIATION WITH TRALI? Etiopathogenetically TACO and TRALI are distinct entities with the former attributed to hydrodynamic forces and the latter resulting from either immune complex formation involving HLA and/or granulocyte antigens or antibodies or alternatively biologic mediators such as
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bioactive lipids.39-41 By consensus panel definition, the diagnosis of TRALI is excluded if TACO or acute lung injury (ALI) are coexistent in a patient’s clinical presentation.39 When either TACO or ALI may be biologically present in patients with transfusion-associated adverse pulmonary sequelae thought secondary to putative initiators of TRALI, however, the case designation of a “possible TRALI” may be applied. While both TRALI and possible TRALI require new ALI that develops during or within 6 hours of transfusion, their difference is whether there is a temporal relationship to another alternate ALI risk factor. Both can have an ALI risk factor; in TRALI there is no temporal relationship to the ALI risk factor, whereas in possible TRALI, there is a temporal relationship. Such cooccurrences, however, may indicate a potential pathophysiologic connection between TACO, ALI, and TRALI or possible TRALI from the perspective of the “two-event” model of TRALI.39-41 In such a scenario, TACO may directly contribute to vascular endothelium damage by mechanical or physical forces in circulatory circuits that are sensitive to such increases in vascular pressure. Such vascular “barotrauma” could be the first step in a multistep process culminating in increased vascular permeability where lesser amounts of immune reactants or biologically active lipids may be needed in the further disruption of vascular integrity resulting in TRALI or possible TRALI consequences. Such mechanical or physical aspects to excessive transfusions as cited previously with liberal transfusion strategies may thus “physiologically prime” the endovascular space (“endothelial cell priming”) making it more vulnerable to immune reactants and/or bioactive lipids. We believe that further examination of the role excessive transfusions might contribute to TRALI induction should be considered.
CLOSING THOUGHTS: TACKLING TACO . . . AND TAMING IT? TACO is a common adverse consequence of HT that has been recognized since the introduction of blood transfusions into routine clinical practice. It accounts for significant patient morbidity, mortality, and health care costs. Its diagnosis can be obscured by its similarities with TRALI. Viewing TACO as a multiphasic spectrum condition may allow for earlier recognition, affording greater opportunities to minimize its impact on patient-important outcomes. Approaches and strategies to enhance TACO mitigation include: 1) education of physician and nursing staff about this adverse transfusion event; 2) computerized clinical decision support alerts notifying physicians and nurses about the potential for TACO development in highrisk patients especially at the time of electronic order entry; 3) careful recording and monitoring of patients’
VSVs during HT; 4) prescriptive guidance regarding the use of slower infusion rates and/or reduced volume blood products; 5) limited simultaneous use of nonsanguineous fluids during HT; 6) emphasizing the value of single-unit transfusion and avoidance of multiunit transfusions given over a short time interval in hemodynamically stable patients; and 7) highlighting prophylactic and therapeutic recommendations for increased peritransfusion diuretic use especially in patients at severe risk for TACO induction. Hospital transfusion services along with physician and nursing colleagues involved in the delivery of HT services are critical to enhancing processes to curb TACO’s development in at-risk patients. Due to the complexities and difficulties of fluid management in patients receiving HT, however, the total elimination of TACO as an adverse transfusion event will never be fully realized, but decreasing its occurrence and enhancing patient HT safety through the adoption of some of the measures identified here may be possible. ACKNOWLEDGMENTS The authors thank Loretta Grikis, MLS, AHIP, of the Baystate Medical Center’s Health Sciences Library for her assistance in the acquisition of some of the reference materials and Jacqueline Wise for her help in the preparation of the manuscript. CONFLICT OF INTEREST The authors report no conflicts of interest or funding sources.
REFERENCES 1. Bernheim BM. Blood transfusion hemorrhage and the anemias. Philadelphia (PA): Lippincott; 1917. pp. 53-60, 104-5. 2. Plummer NS. Blood transfusion, a report of six facilities. Br Med J 1936;2:1186-9. 3. Drummond R. Transfusion reactions and fatalities consequent on circulatory overloading. Br Med J 1943;2: 319-22. 4. Scott RB. Complications of blood transfusion (section III). In: Keyes G, Brewer HF, editors. Blood transfusion. Baltimore (MD): Williams and Wilkins; 1949. pp. 134-5, 182-6. 5. Popovsky MA, Audet AM, Andrzejewski C Jr. Transfusionassociated circulatory overload in orthopedic surgery patients: a multi-institutional study. Immunohematology 1996;12:87-9. 6. Serious Hazards of Transfusion (SHOT). Definitions of current SHOT categories and what to report. Revised November 2012. [cited 2013 Mar 20]. Available from: http://www.shotuk.org/wp-content/uploads/2010/03/ SHOT-definitions-Nov012-final.pdf 7. Ellsworth B, Ellsworth P, Stevens WT. Adverse reaction case definition criteria from Appendix A of the Biovigilance Volume 53, December 2013 TRANSFUSION
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Component of the National Healthcare Safety Network (NHSN) manual. 2013. [cited 2013 Oct 15]. Available from: http://www.cdc.gov/nhsn/bio.html 8. Pomper GJ. Febrile, allergic and nonimmune transfusion reactions. In: Simon TL, Snyder EL, Solheim BG, et al., editors. Rossi’s principles of transfusion medicine. 4th ed. Bethesda (MD): American Association of Blood Banks Press; 2009. pp. 826-46. 9. Popovsky MA. Transfusion-associated circulatory overload. In: Popovsky MA, editor. Transfusion reactions. 4th ed. Bethesda (MD): American Association of Blood Banks Press; 2012. pp. 327-37. 10. Giblett ER. Blood groups and blood transfusion. In: Thorn GW, Adams RD, Braunwald E, et al., editors. Harrison’s principles of internal medicine. 8th ed. New York: McGrawHill, Inc; 1977. p. 1705. 11. Cohen H. Transfusion-associated circulatory overload (TACO). In: Serious Hazards of Transfusion (SHOT) Steer-
culatory overload after plasma transfusion. Transfusion 2012;52:160-65. 20. Murphy EL, Kwaan N, Looney M, et al. Risk factors and outcomes in transfusion associated circulatory overload (TACO). Am J Med 2013;126:357.e29-38. 21. Bierbaum B, Callaghan J, Galante J, et al. An analysis of blood management in patients having a total hip or knee arthroplasty. J Bone Joint Surg Am 1999;81: 2-10. 22. Robillard P, Nawej K, Chapdelaine A. Transfusionassociated circulatory overload (TACO): current leading cause of transfusion associated fatalities reported to the Québec Hemovigilance System. Transfus Med 2009;19: 280-1. 23. Popovsky MA, Taswell HF. Circulatory overload: an underdiagnosed consequence of transfusion. Transfusion 1985; 25:469.
ing Group. The 2011 Annual SHOT Report. 2012. pp. 114-18 [cited 2013 Mar 19]. Available from: http://www .shotuk.org/wp-content/uploads/2012/07/SHOT
24. Li G, Rachmale S, Kojicic M, et al. Incidence and transfusion risk factors for transfusion-associated circulatory overload among medical intensive care unit patients.
-ANNUAL-REPORT_FinalWebVersionBookmarked _2012_06_22.pdf
Transfusion 2011;51:338-43. 25. Bux J, Sachs UJH. Pulmonary transfusion reactions.
12. Zhou I, Giacherio D, Cooling L, et al. Use of B-natriuretic peptide as a diagnostic marker in the differential diagnosis of transfusion-associated circulatory overload. Transfusion 2005;45:1056-63. 13. Tobian AA, Sokoll LJ, Tisch DJ, et al. N-terminal pro-brain natriuretic peptide is a useful diagnostic marker for transfusion-associated circulatory overload. Transfusion 2008;48:1143-50. 14. Andrzejewski C Jr, Popovsky MA. Transfusion-associated adverse pulmonary sequelae: widening our perspective. Transfusion 2005;45:1048-50. 15. Li G, Daniels CE, Kojicic M, et al. The accuracy of natriuretic peptides (brain natriuretic peptide and N-terminal pro-brain natriuretic) in the differentiation between transfusion-related acute lung injury and transfusionrelated circulatory overload in the critically ill. Transfusion 2009;29:13-20. 16. Food and Drug Administration. Fatalities reported to FDA following blood collection and transfusion: annual summary for fiscal year 2010. Rockville, MD: CBER Office of Communication, Outreach, and Development. 2011 [cited 2012 Feb 28]. Available from: http://www.fda.gov/ BiologicsBloodVaccines/SafetyAvailability/ ReportaProblem/TransfusionDonationFatalities/ ucm302847.htm 17. David B. Haemovigilance: a comparison of three national systems. 27th Congress of the International Society of the Blood Transfusion, 24-28 August 2002. Vancouver. 18. Robillard P, Itaj NK, Chapdelaine A. Increasing incidence of transfusion-associated circulatory overload reported to the Quebec Hemovigilance System, 2000-2006. Transfusion 2008;48(Suppl):204A.
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19. Narick C, Triulzi DJ, Yazer MH. Transfusion-associated cir-
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Transfus Med Hemother 2008;35:337-45. 26. Andrzejewski C Jr, Popovsky MA, Stec TC, et al. Hemotherapy bedside biovigilance involving vital sign values and characteristics of patients with suspected transfusion reactions associated with fluid challenges: can some cases of transfusion associated circulatory overload have proinflammatory aspects? Transfusion 2012;52:2310-20. 27. Andrzejewski C Jr, McGirr J. Nursing hemotherapy bedside biovigilance in the recognition and management of suspected transfusion reactions. In: Popovsky MA, editor. Transfusion reactions. 4th ed. Bethesda (MD): American Association of Blood Banks Press; 2012. pp. 551-77. 28. Katz EA. Blood transfusion, friend or foe. AACN Adv Crit Care 2009;20:155-63. 29. Robillard P, Itaj K, Chapdelaine A. Transfusion-Associated Circulatory Overload (TACO): The new leading cause of transfusion-associated fatalities reported to the Québec Hemovigilance System. [cited 2013 Mar 20]. Available from: http://ihn.withtoast.co.uk/wpcontent/uploads/2011/02/ TACO-data-2000-2008-Poster-ISBT-2010.pdf 30. Blumberg N, Heal JM, Gettings KF, et al. An association between decreased cardiopulmonary complications (transfusion-related acute lung injury and transfusionassociated circulatory overload) and implementation of universal leukoreduction of blood transfusions. Transfusion 2010;50:2738-44. 31. Ewald GA, Garmany RG, Krainik AJ. Heart failure, cardiomyopathy, and valvular heart disease. In: Cooper DH, Krainik AJ, Lubner SJ, et al., editors. The Washington manual of medical therapeutics. 32nd ed. Philadelphia (PA): Wolters Kluwer, Lippincott Williams & Wilkins; 2007. pp. 170, 173.
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32. Finlay HE, Cassorla L, Feiner J, et al. Designing and testing a computer-based screening system for transfusion-related acute lung injury. Am J Clin Pathol 2005;124:601-9. 33. Clifford L, Singh A, Wilson GA, et al. Electronic health
37. Roberts I, Evans P, Bunn F, et al. Is the normalization of blood pressure in bleeding trauma patients harmful? Lancet 2001;357:385-7. 38. Stern SA, Dronen SC, Birrer P, et al. Effect of blood pres-
record surveillance algorithms facilitate the detection of
sure on hemorrhage volume and survival in a near-fatal
transfusion-related pulmonary complications. Transfusion 2013;53:1205-16.
hemorrhage model incorporating a vascular injury. Ann Emerg Med 1993;22:155-63.
34. Skeate RC. Transfusion medicine data as product. Transfu-
39. Kleinman S, Caulfield T, Chan P, et al. Toward an under-
sion 2013;53:1153-6. 35. Hill S, Carless PA, Henry DA, et al. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion (Review). The Cochrane Collaboration. John Wiley & Sons, Ltd. 2009 [cited 2013 Apr 2]. Available from: http://www.thecochranelibrary.com/userfiles/ccoch/file/ CD002042.pdf
standing of transfusion-related acute lung injury: statement of a consensus panel. Transfusion 2004;44: 1774-89. 40. Shaz BH, Stowell SR, Hillyer CD. Transfusion-related acute lung injury: from bedside to bench and back. Blood 2011; 117:1463-82. 41. Kopko PM, Popovsky MA. Transfusion-related acute lung
36. Villanueva C, Colomo A, Bosch A, et al. Transfusion strate-
injury. In: Popovsky MA, editor. Transfusion reactions. 4th
gies for acute upper gastrointestinal bleeding. N Engl J Med 2013;368:11-21.
ed. Bethesda (MD): American Association of Blood Banks Press; 2012. pp. 191-215.
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S
ince blood transfusion’s introduction into modern clinical practice in the first part of the 20th century problems with hemotherapy (HT)related circulatory overload in patients have been appreciated. As early as the second decade of the 20th century and into the 1940s, issues regarding hypervolemia associated with whole blood transfusions were raised, but with the introduction of blood component therapy, clinical concerns about it abated.1-4 While physicians acknowledged that transfusion was a risk factor for hydrostatic pulmonary edema, the perception generally was, and remains, that circulatory overload is infrequent or inconsequential or could be easily treated once it presents. It was not until the 1980s when transfusion-related acute lung injury (TRALI) was placed
ABBREVIATIONS: ALI = acute lung injury; BB/TMS = blood bank and/or transfusion medicine service; BNP = brain natriuretic peptide; CVP = central venous pressure; EHR(s) = electronic health record(s); FC(s) = fluid challenge(s); FY = Fiscal Year; HT = hemotherapy; ICD = International Classification of Diseases; ICU = intensive care unit; NP = natriuretic peptide; PP = pulse pressure; STR(s) = suspected transfusion reaction(s); TACO = transfusionassociated circulatory overload; UCT(s) = uncomplicated transfusion(s); VSV(s) = vital sign value(s). From the 1Transfusion Medicine Services, Department of Pathology, and the 2Department of Medicine, Cardiology Division, Baystate Medical Center, Baystate Health, Springfield, Massachusetts; the 3Department of Medicine, Cooley Dickinson Hospital, Northampton, Massachusetts; 4Haemonetics Corporation, Braintree, Massachusetts; and 5Beth Israel Deaconess Medical Center, Boston, Massachusetts. Address reprint requests to: Chester Andrzejewski Jr, PhD, MD, Baystate Health, Springfield, MA 01199; e-mail: [email protected]. Received for publication April 11, 2013; revision received August 27, 2013, and accepted August 27, 2013. doi: 10.1111/trf.12454 TRANSFUSION 2013;53:3037-3047.
on the transfusion medicine radar screen that renewed interest in this iatrogenic fluid challenge (FC) emerged with the designation of it using the term transfusionassociated circulatory overload (TACO), first appearing in the literature in 1996.5 As TRALI’s contribution to morbidity and mortality gained prominence, TACO followed on its heels identified as the “other” transfusion complication requiring clinical reckoning. TACO, however, was for the most part perceived solely to be a consequence of large volumes of blood transfused rapidly and restricted either to the very young or old, concepts that have now been called into question.
DEFINING AND DIAGNOSING TACO Although a formal universally accepted case definition for it currently does not exist, TACO may be generally defined as an adverse HT outcome occurring in transfusion recipients unable to effectively physiologically process a HT FC due to either high infusion rates and/or volumes or an underlying cardiac, renal, and/or pulmonary pathology. Even in countries that have well-established hemovigilance networks variability in the identifying attributes of TACO cases is observed.6,7 TACO is essentially a clinical diagnosis and certain data that have historically been used in the clinical assessment of presumed cases of it (e.g., chest radiographic changes, increased central venous pressure [CVP], response to diuretic therapy) may not always be available for review in every care setting. Certain features nevertheless have been routinely cited as evidence for circulatory overload including increases in CVP, congestion of the pulmonary vasculature, dyspnea, tachycardia, and acute hypertension eventually resulting in pulmonary edema and left- or right-sided heart failure.8 Although both hypertension and pulmonary edema are considered “hallmark” signs of TACO, the former may not always be causative of the latter. Other signs and symptoms include tachypnea, dry cough, jugular or pedal venous distension, pulmonary rales, and a widened pulse pressure (PP).9 These signs and symptoms most frequently present within 2 hours of the onset of transfusion but may take up to 6 hours to manifest. Delayed manifestations of Volume 53, December 2013 TRANSFUSION
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TACO, however, have been reported10 and in a recent data analysis from the well-established UK Hemovigilance Network it was noted that 11.3% of TACO cases can be encountered between 6 and 24 hours after HT.11 The majority of evidence to invoke a diagnosis of TACO involves clinical signs and symptomatology. With regard to the former, no threshold values have been promulgated to trigger concern at the bedside. Diagnostic testing, such as chest radiographs and invasive cardiovascular monitoring devices, if available, may help in patient assessment, but the appearance of signature disease features specific for TACO using such technologies have not been reported. Although no pathognomonic laboratory test exists to diagnose TACO, natriuretic peptide (NP) hormone levels may be helpful but not definitive in investigations.9,12-15 Various international hemovigilance networks have promulgated TACO case definition criteria to facilitate recognition and reporting of such adverse events by their member institutions. Such case definitional criteria should be viewed as beginnings and not endpoints in the discussion of a uniform “gold standard” diagnostic classification. Generally these definitional criteria are similar in scope between networks but may differ slightly among them in select attributes, for example, time periods of symptom onset. Such case definitions are subject to possible revision as occurred in 2013 when the Centers for Disease Control National Healthcare Safety Network in the United States slightly revised the TACO case definition criteria in its biovigilance component to reflect a change in the timeline of attribute onset to “within 6 hours of cessation of transfusion.” The current case definition criteria for TACO in this biovigilance network are summarized below and in Table 1: New onset or exacerbation of three or more of the following within 6 hours of cessation of transfusion: acute respiratory distress (dyspnea, orthopnea, cough); elevated brain natriuretic peptide (BNP); elevated CVP; evidence of left heart failure; evidence of positive fluid balance; and radiographic evidence of pulmonary edema.7 With no universally accepted diagnostic criteria for TACO, its recognition and diagnosis remain problematic, potentially contributing to observed variations in its perceived frequency. As data accrue from the various national hemovigilance networks and are analyzed and vetted in the context of data from previously reported studies regarding TACO, the evolution of a uniformly internationally agreed upon case definition as a gold standard for TACO hopefully will emerge. Additionally, information regarding TACO obtained from a prospective multicenter observational study evaluating severe transfusion reactions as part of the National Heart Lung and Blood Institute (NHLBI) Recipient Epidemiology and Donor 3038
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Evaluation Study-III (REDS-III) program (currently scheduled to start in 2014) may also provide further insight into this entity. Since a TACO paradigm is still being constructed, results from it and other such studies along with the historical literature will be informative in its assembly.
CLINICAL SIGNIFICANCE AND REPORTING The Food and Drug Administration (FDA) began to include TACO as a specific category designation in its annual reporting of adverse transfusion events in Fiscal Year (FY) 2005. In that year 2% of transfusion-related fatalities reported to the FDA were attributed to this complication. Recognition of TACO as a separately defined serious hazard of transfusion entity by the UK Hemovigiliance Network followed in 2007. By FY 2009, TACO accounted for 27% of all fatalities reported to the FDA second only to TRALI in frequency.16 While it may be likely that the increase in TACO incidence is largely the result of heightened awareness and improved recognition, contributions from increased endorsement of the use of massive transfusion protocols also cannot be excluded as contributing to a true increasing incidence. The case-fatality rate has been reported to vary from 1.4% to 8.3%, making TACO one of the most deadly of transfusion complications.17-19 In addition to patient mortality, TACO contributes to patient morbidity, impacting on hospital length of stay. Twenty-one percent of cases are life-threatening with increases in intensive care unit (ICU) and hospital lengths of stay contributed to by its occurrence.5,18,20 Before October 1, 2010, there was no specific International Classification of Diseases (ICD)-9-CM diagnosis code for TACO and if it was reported to and captured by medical billing coders was typically placed in the existing code category 276.6 Fluid Overload. At the September 2009 ICD-9-CM Coordination and Maintenance Committee meeting, a proposal from the FDA CBER for a unique code for TACO (ICD-9-CM 276.61) was presented and accepted with implementation beginning in FY 2011. On October 1, 2014, all US health care organizations will transition to the next generation of the ICD-10 with the code for TACO becoming ICD-10-CM E87.71.
FREQUENCY The incidence of TACO is not firmly established. Varying institutional definitions and patient case mixes most likely impact its recognition and occurrence reporting. In orthopedic surgery patients, TACO is clearly a common event. In a five-hospital study of US Medicare patients undergoing hip or knee replacement surgery, 1% of transfused patients developed TACO.5 Patients with TACO were older, with a mean age of 87 years and there was a positive fluid imbalance of 2.5 L before transfusion. TACO was also noted to occur even in the context of autologous
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TABLE 1. TACO: key concepts and features Case definition* and pathogenesis New onset or exacerbation of three or more of the following within 6 hr of cessation of transfusion: • Acute respiratory distress (dyspnea, orthopnea, cough); • Elevated BNP; • Elevated CVP; • Evidence of left heart failure; • Evidence of positive fluid balance; • Radiographic evidence of pulmonary edema. Severity ratings*: nonsevere, severe, life-threatening, death, not determined; Imputability*: definite, probable, possible, not determined, doubtful, ruled out. *Centers for Disease Control National Healthcare Safety Network Biovigilance Module. January 2013 Pathogenesis: Increased hydrostatic pressure in the pulmonary blood circuit leading to extravascular fluid accumulation in the lungs.
Diagnosis and patient risk factors Transfusion recipients unable to effectively physiologically process a HT FC due to either high infusion rates and/or volumes or an underlying cardiac, renal, and/or pulmonary pathology. Signature features include dyspnea, orthopnea cyanosis, rales, tachycardia, cough, headache, increased BP, hypoxemia, CXR consistent with pulmonary edema. Risk factors include but are not limited to cardiac or renal dysfunction; younger and advanced aged patients; female sex; severe anemia (i.e., expanded plasma volume); positive fluid balance; and HT involving multiple products including plasma and PLTs. TACO is common (perhaps approx. 1% of transfusions) and significantly impacts recipient outcomes. Need for patient transfer to higher acuity care settings, longer lengths of stay, and fatal outcomes recognized. TACO remains underreported, in part due to inconsistent definitions, recognition bias of only most severe cases, and the lack of a gold standard diagnostic test. NP hormone levels may be of value.12 No single sign, symptom, or laboratory test pathognomonic for TACO.
Treatment and management 1) Stopping transfusion or other fluids, bedside stabilization, and upright postural placement of patient by nursing; 2) alerting of physician and blood bank staff notification; 3) providing respiratory support (e.g., supplemental oxygen, ventilatory assistance); 4) diuretic administration where not contraindicated; 5) blood bank investigations to rule out other transfusion adverse effects (e.g., hemolysis, sepsis, TRALI); 6) cornerstone of successful TACO management is stopping the transfusion and achieving a negative fluid balance.
Mitigation and prevention 1) Staff education; 2) thoughtful assessments regarding HT need and fluid status; 3) careful recording or monitoring of patients’ VSVs during HT; 4) slower infusion rates and/or reduced volume blood products; 5) limited infusion of nonsanguineous fluids during HT; 6) avoidance of multiunit HT or encouragement of single-unit transfusions; and 7) peritransfusion diuretic administration; 8) computerized clinical decision support alert notifications regarding high-risk patients and clinical profiling. Only definitive way to prevent TACO is no HT.
Unappreciated aspects to TACO 1) Recognized early in history of blood transfusion (early 1900s) as a possible adverse consequence; 2) clinically acknowledged but typically ignored as an entity of concern; 3) multiphasic illness with protean manifestations spanning a spectrum from mild to life-threatening severity; 4) pulmonary features may be lacking in mild early stage presentations; 5) may occur during or within several hours of transfusion (delayed expressions possible); 6) risk factors include transfusion-related variables such as volume of HT and rate of infusion as well as recipient factors such as baseline physiology and comorbidities; 7) TACO incidence and impact may be attenuated by implementing meaningful bedside biovigilance strategies; and 8) an underappreciated TACO pathologic mechanism may relate to the mechanical or physical impact of HT on the vascular endothelium. Select key references: Drummond,3 Popovsky et al.,5 Robillard et al.,22 Li et al.,24 Andrzejewski et al.,26 Clifford et al.,33 Murphy et al.20
BP = blood pressure; CXR = chest X-ray.
transfusions.5 In a much larger multicenter study involving 9482 patients, TACO was diagnosed in 8% of those receiving an allogeneic transfusion. The TACO patient group received 1.8 to 2.7 RBC units per patient, underscoring the fact that large fluid volumes are not necessary to trigger the reaction in the patient.21 During the years 2000 to 2004, the reported incidence increased almost twofold, from 1 in 10,360 (2000-2001) to 1 in 4075 RBC units transfused.17 These data originate from passive hemovigilance systems. When active surveillance systems are used, it becomes apparent that TACO is greatly underestimated. At one major medical center, the historical prevalence of TACO over one 6-year period was 1 in 1566.19 When a prospective, active surveillance system was introduced for fresh-frozen plasma (FFP), the TACO reaction rate soared to 4.8% and, of those cases, none were
reported to the hospital’s blood bank. The prevalence rate was in 1 in 68. The mean amount of FFP transfused before the reaction was 4 units. Thus, both cellular and noncellular components can trigger or exacerbate TACO.
EPIDEMIOLOGY AND RISK FACTORS While many patients diagnosed with TACO are 70 years or older, Robillard and colleagues22 using data from a national hemovigilance reporting network demonstrated that younger individuals are also at risk observing TACO occurrences in 6.9% of patients aged 18 to 49 years, 7.3% of those between the ages of 50 to 59 years, and 19.3% of patients aged 60 to 69 years. In a case-control study involving 47,783 patients who received blood products, Murphy and colleagues20 found that the risk factors Volume 53, December 2013 TRANSFUSION
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included female sex, a past history of congestive heart failure, history of hemodialysis, mechanical ventilation, recent vasopressors, and positive fluid balance. When adjusted for age, sex, hospital, and transfusion intensity, TACO was associated with more than threefold increased in-hospital mortality. Significantly increased longer hospital and ICU lengths of stay were also observed. The relationship of blood product fluid volumes in the induction of TACO is still controversial. As noted earlier, it is generally believed that TACO is precipitated by the transfusion of large quantities of blood products. In a 1985 study, Popovsky and Taswell23 found that 20% of cases involved a single unit of RBCs. In the Quebec Hemovigilance System database, the mean number of RBC units transfused in documented TACO cases was only 2.11 units (P. Robillard, personal communication, 2009). The infusion flow rate of blood products is also thought to be an important contributing factor in TACO occurrences. Current AABB recommendations for RBC infusion rates are 240 mL/hr (4 mL/min) and 300 mL/hr for both FFP and platelet (PLT) products. Current reality is that the appropriate flow rates for these components are not known or evidence based. Clearly, the underlying cardiac reserve capacity and fluid status of the patient are important contributors to a patient’s susceptibility to TACO. In one study of 47 TACO patients, the mean infusion flow rate was 4.5 mL/min but the range was 0.9 to 48.1 mL/min.9 In a medical ICU setting, Li and colleagues24 reported that compared with controls, TACO patients were transfused with larger amounts of plasma and at a faster rate, 225 mL/hr, compared with 168 mL/hr. Patients with TACO were significantly more likely to have evidence of left-sided ventricular dysfunction before transfusion. These investigators also noted that baseline cardiovascular function and FFP ordered for the reversal of anticoagulant therapy were strong predicators of TACO before its clinical onset.
ASSESSING TACO IN THE BLOOD BANK When TACO is suspected by bedside practitioners, notification of the blood bank and/or transfusion medicine service (BB/TMS) should occur via the standard mechanisms that institutions have established for the reporting and investigation of any adverse transfusion event. Many times patients do not present with distinguishing features at the bedside that would allow for the exclusion of other adverse transfusion sequelae, for example, a hemolytic transfusion reaction, TRALI, or septic unit transfusion, so an evaluation of the potential adverse event to exclude these entities must occur in the blood bank. Such occurrences typically require further discussions with the medical and nursing staff involved with the transfusion to obtain additional clinical information and the practitioner’s insight into the suspected reaction. This exchange 3040
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not only highlights the value of the participation of the bedside practitioners in the diagnostic differentiation of the adverse event but additionally affords an opportunity for blood bank staff to educate clinical colleagues regarding the spectrum of adverse transfusion complications. Although the extent of the work-up performed may vary between institutions, at a minimum the blood bank should perform routine pertinent clerical documentation checks, review the patient’s blood bank historical records for the occurrence of prior transfusion reactions or antibody problems, examine the returned unit for any nonconforming features (i.e., a “content/container integrity check”), and assess for the presence of hemolysis in the posttransfusion specimens provided. The decision to extend testing beyond these initial investigations should be based on the results obtained from these studies, the severity of the patient’s clinical presentation, BB/TMS physician review of the patient’s medical record, and any additional pertinent information obtained via consultations with the involved medical and nursing staff reporting the suspected reaction. Particular attention should be directed toward an examination of the patient’s fluid balance, blood product infusion rates, medications administered including any diuretic agents, primary diagnosis and comorbidities, results from any pertinent radiographic imaging studies, and any recent weight changes documented for the patient. As stated previously there is no pathognomic laboratory test for TACO. The measurement of NP hormone levels, such as NT-proBNP, may be informative but is not definitive since elevated levels can be encountered in various conditions.25 At one of the institutions of two of the authors, serial measurements of NT-proBNP levels are performed using select peritransfusion specimens from the patient.26 Results from such peritransfusion serial studies are then analyzed by the BB/TMS medical staff for the presence of any rising trend changes in this analyte and correlated with other clinical data to help in further assessment of the event. The value of serial NP level determinations, typically using pretransfusion and immediately posttransfusion specimens, in the assessment of TACO has been reported by several investigators.12,13
APPROACHING TACO FROM A BEDSIDE BIOVIGILANCE PERSPECTIVE In reviewing the HT care map27 several pertinent areas of it can be identified that can contribute potentially to improving TACO diagnosis, management, and mitigation. At the hospitals of two of the authors a strategy focusing on “bedside biovigilance” during transfusions has been a meaningful approach for enhancing TACO monitoring and mitigation. Coupled with ongoing staff education, the lynchpin of these efforts centers on the recording and monitoring of patients’ vital sign values
TACO DIAGNOSIS, MANAGEMENT, AND MITIGATION
(VSVs) during HT and their role in the bedside assessment of adverse transfusion events. Using the perspective of comparing what happens to patients’ VSVs during “uncomplicated transfusions” (UCTs) to those encountered in patients experiencing various types of suspected transfusion reactions (STRs), informative differences between patients were identified via a variety of quality improvement projects that helped to guide institutional development of HT electronic records documentation and alerting, HT infusion rate guidance, automatic BB/TMS STR notifications, and BB/TMS evaluation protocols pertinent to TACO/FC STRs.26,27 Our studies have led us to view TACO as a multiphasic spectrum illness. By this we mean that like many disorders in medicine, TACO just does not happen, but rather manifests in a prodromal manner, especially when examined from the perspective of a “surge capacity” of the patient’s vascular system to temporally respond to a continuum of ongoing FCs. A potential model depicting this multiphasic aspect of TACO is illustrated in Fig. 1. In our studies examining the VSVs of patients undergoing UCTs compared to those experiencing STRs, we noted increases in blood pressure measurements over the course of the transfusion in most STR patients characterized as having a TACO/FC aspect to their adverse event.26 In these individuals, these blood pressure increases were typically evident by 15 minutes into the transfusion of the RBC unit with continued rises noted in most by the time the infusions were halted (see Table 2). Interestingly, when compared to the UCT group mean starting PP, the mean of the initial PP of the TACO/FC cohort patients was higher suggesting the possibility that these individuals were already physiologically “primed,” rendering them more susceptible to additional fluid infusions.
AN UNAPPRECIATED FEBRILE OR INFLAMMATORY ASPECT IN TACO It is generally held that in contrast to TRALI, patients with TACO typically do not present with fever or hypotension.28 In our previously cited study of patients’ VSVs during transfusions, we observed that a marked percentage (approx. 65%) of patients with TACO/FC STRs exhibited an inflammatory or febrile aspect in their bedside presentation.26 This was evidenced also in the increases seen in the actual recorded measurements of the cohorts’ mean VSV for end of transfusion temperatures and the corresponding temperature deltas from the baseline values (see Table 2 and Fig. 2). Such an observation has also been reported in data from the Québec Hemovigilance System29 as well as in earlier medical literature reports regarding concerns about the adverse consequences of rapid transfusion rates and large product volume infusions and their contributions to circulatory overload in HT patients.1-4 Of interest also is the work of Blumberg and colleagues,30
which showed that the incidence of TACO decreased after the implementation of universal leukoreduction at their institution. Given these findings clinicians should not be dismissive of TACO in the patient presenting with an elevated temperature or inflammatory reaction features.
MANAGEMENT AND TREATMENT Once TACO is diagnosed in a patient receiving HT, stopping the transfusion should occur with bedside measures taken immediately to stabilize the patient depending on symptomatology and degree of clinical severity. These include placing the patient in a more upright posture (i.e., Fowler position), stopping infusion of other intravenous (IV) fluids, providing respiratory support (e.g., supplemental oxygen), and administering diuretic medications if not contraindicated. The application of diuretic medications in the treatment of TACO has not been standardized and their use is empiric. Caution should be used in patients with unstable or borderline hemodynamics since such medications may lead to or exacerbate clinically significant hypotension and thus should be avoided. In some institutions it is not uncommon for physicians to initially administer a small “test dose” of diuretics to patients whom they suspect may be in fluid overload. Results from such “therapeutic diagnostic” interventions, especially if performed early in the onset of clinical symptomatology, can be of further help in assessing the nature of an adverse transfusion event and in its management. Loop diuretics, such as furosemide, which reduces cardiac preload acutely via direct venodilation when given IV, may be particularly useful in patients needing marked diuresis especially in those with severe heart failure or with acute pulmonary edema.31 Medical staff and blood bank notifications should occur as soon as possible once the patient is acutely stabilized. Depending on the level of clinical compromise, notification, and involvement of rapid response care teams, typically for patients with severe respiratory distress and those who potentially may require positive pressure ventilation may need to be consulted. For patients in non–critical care settings, arrangements for patient transfer to higher acuity level care areas may also need to be considered. In refractory cases of TACO, hemodialysis may be of clinical benefit. In less severe presentations of TACO temporally stopping the transfusion with concomitant bedside stabilization of the patient as described above may be sufficient to potentially allow for restarting of the unit, albeit at a slower rate. Given the overlapping nature of TACO’s bedside presentation with other severe adverse transfusion sequelae, however, this should not be an encouraged practice. Volume 53, December 2013 TRANSFUSION
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MITIGATION AND PREVENTION Viewing TACO as a multiphasic entity allows for several areas on the HT care map to be incorporated into the designs of meaningful and successful strategies to decrease its occurrence.27 Early in the HT decision making and ordering process section of the care map, several
opportunities exist to enhance TACO mitigation including: 1) thoughtful assessment of the need for HT and evaluation of the patient’s fluid status; 2) clinical decision alerts notifying physicians and nurses about the potential for TACO development in high-risk patients (e.g., those with diagnoses of CHF, renal insufficiency); 3) prescriptive guidance suggesting the use of slower infusion rates
The Multiphasic Spectrum of TACO NP Levels
BP ▲’s Pulmonary Signs/Symptoms Time Stage
I No TACO
(Normovolemia)
• Hemotherapy and Non-Blood Fluid Challenges
↓ • Concept of “Surge
Early
Middle
II
III
Mild TACO
Moderate TACO
Late
IV Severe TACO
Hypervolemia
Bedside Biovigilance : Monitoring of Patient’s Signs and Symptoms During Hemotherapy
Capacity” in Patient’s Cardiovascular Space
1. Constellation of ClinicoLaboratory Features 2. Patient Profiling and Risk Stratification 3. Computer Assisted Diagnosis/Management Adapted and modified from C. Andrzejewski, Ph.D., M.D. AABB Annual Mtg 2008
Fig. 1. Viewing TACO as a multiphasic spectrum entity. Schematic depiction of a multiphasic model of TACO/FCs associated with HT and the body’s response. In such a model TACO/FCs occur over a time interval characterized by four stages (I-IV) with a normal euvolemic state as Stage I and late-phase TACO as Stage IV. These stages correlate, though not necessarily in a directly linear relationship, with the amount of fluid delivered, including nonblood fluids, and the degree of clinical severity manifested by the patient. Variable physiologic responses (↑↓) in at-risk patients are reflected temporally within an increasing severity gradient of the patient’s clinical status as manifested by varying VSVs, clinical symptomatology, and NP hormone levels. The depiction of the up-down arrows in the model is an acknowledgment that patients may present differentially during the course of their TACO development depending on when a suspected reaction is identified at the bedside. For example, not all patients may exhibit elevated blood pressures at the time of respiratory distress onset. Depending on when these variables are measured in the evolution of the TACO episode, magnitude variations between patients may be exhibited. The arrows indicate these variability possibilities with regard to the identified variables. Excess fluid accommodation, either through blood vessel distention and/or through diversion into low flow capillary networks, that is, the surge capacity of the vascular compartment, allows the individual to effectively manage the FC to varying degrees based on an individual’s innate physiology and pathologic status, for example, degree of existent anemia; cardiac, renal, or pulmonary dysfunction, etc. Aspects of this model were first presented in the presentation “TACO in the Community Hospital: Quality Improvement Insights,” Session on TRALI and TACO: New Insights & Pursuing Better Clinical Outcomes, 2008 Annual Meeting of the AABB, Montreal, Quebec, Canada. 3042
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TACO DIAGNOSIS, MANAGEMENT, AND MITIGATION
TABLE 2. Mean VSVs for PP and temperature (T) observed in various patient transfusion cohorts at select transfusion time points* Cohort Variable PP (mm Hg) Mean ±SD Number T (°C) Mean ±SD Number * † ‡ § ||
UCT control (UCT group) Before 15 min End
Non-TACO/FC STR (NFC STR group) Before 15 min End
TACO/FC STR (TACO/FC STR group) Before 15 min End
56 ±19.1 147
57 ±19.2 119
56 ±17.9 126
58 ±17.0 232
59 ±18.2 139
60 ±18.8 225
63†‡ ±23.5 94
69†‡ ±21.8 60
75†‡§ ±27 91
36.7 ±1.3 139
36.8 ±1.1 121
36.7 ±1.1 129
37.0|| ±0.6 232
37.6§|| ±0.8 143
38.0§|| ±0.9 226
37.0† ±0.7 95
37.2†‡§ ±0.8 63
37.6†‡§ ±1.0 91
t test (p ≤ 0.050). Adapted and modified from Andrzejewski et al.,26 Table 3. See reference for details. UCT versus TACO/FC STR. Non-fluid challenge (NFC) STR versus TACO/FC STR. Intragroup. UCT versus NFC STR.
original nonaliquoted product facilitating patient blood management decisions in its subsequent issuance for that patient or another needing an aliquoted unit. Logistic and financial concerns about the preparation and provision of divided products in limited staffing environments coupled with possible increases in workload must be balanced with the potential clinical benefits to patients. Additionally, aside from the enhanced patient safety perspectives from this type of patient blood management, decreases in TACO induction with Temperature (°C) its related clinical consequences may be realized including financial considerFig. 2. Mean temperature deltas with 95% CIs at select times during HT in various ations as in the costs associated with cohorts of patients receiving RBC transfusions. NFC = non–fluid challenge cohort; transfusion reaction investigations, open bar = mean temperature at 15 minutes; patterned bar = mean temperature at related diagnostic studies, and the transend of transfusion. Lines with arrows represent the range of the 95% CIs of the temfer of patients to higher acuity more perature deltas for the indicated cohorts at the select peritransfusion time points. All expensive care settings. variable pairwise combinations tested were significant at p < 0.015 (see Table 4 in During the transfusion event and in 26 Andrzejewski et al. for full details). the posttransfusion interval, the monitoring of patient VSVs as discussed previously may also and/or reduced volume products; 4) highlighting the help in decreasing the development of TACO. In addition value of single-unit transfusion and avoidance of multito a manual viewing of VSVs by nurses and physicians on unit transfusions given over a short time interval; and 5) a paper-based blood unit tag, if a hospital’s electronic recommendations of peritransfusion diuretic use. health record (EHR) allows for the capture and graphic The use of reduced volume products has often been display of peritransfusion VSVs, and provided that such cited as a strategy to manage patients with fluid overload data are entered electronically on a “real-time” basis, the concerns. Although intuitively reasonable there are no development of computer-assisted clinical alerting algoprospective double-blind randomized control studies rithms regarding the detection of “threshold” deviations supporting or refuting this strategy. The extent of its from baseline values and their trend monitoring becomes application in the transfusion medicine community is more feasible helping to augment more informed bedside unknown. When used, units can be aliquoted either HT care decisions. In patients with a history of TACO directly or through the use of a sterile connection device. documented via prior blood bank investigations, notation The advantage of using the latter is that the shelf life of such in BB/TMS records and/or the patient’s EHR of the retained split unit remains the same as the Volume 53, December 2013 TRANSFUSION
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Fig. 3. Computer screen display of transfusion medicine “TACO alert” appearing in the EHR of a patient at risk for TACO activated at time of blood ordering based on patient’s diagnoses or problem list as identified in the patient’s EHR. Baystate Health, Springfield, MA.
(e.g., the patient’s problem list) may be of value in alerting both TMS and clinical staff regarding at-risk patients and in modifying HT so as to minimize the potential for TACO development. Ongoing education of medical and nursing staff about TACO is valuable and essential in the design of meaningful TACO mitigation strategies. BB/TMS technical staffs also need to be vigilant in proactively identifying potential patients at risk for TACO and engage BB/TMS medical staff to clarify ambiguous or confusing transfusion rate orders and component selection options. These activities along with an EHR alerting system notifying practitioners of potential at-risk patients,27 especially at the time of computerized provider order entry of HT (see Fig. 3) or the use of EHRs surveillance algorithms that facilitate the detection of transfusion-related pulmonary complications32-34 may help in TACO mitigation efforts. Such mitigation strategies are critical in attempting to prevent TACO, since from a purely preventive perspective the only sure way to avoid TACO is to avoid blood transfusions.
A TACO RELATIONSHIP WITH “LIBERAL TRANSFUSION STRATEGIES”? Studies examining liberal versus conservative transfusion strategies generally agree that therapeutic plans limiting blood transfusions are not clinically inferior to more aggressive HT approaches.35,36 When cohort data from such studies are examined closely with regard to the magnitude of the amount of blood products given (typically 3044
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quantified just in total unit numbers given rather than actual total volumes transfused) cohort differences suggest a potentially provocative contribution from TACO in the adverse outcomes identified in liberally transfused patients. In a recently published study examining liberal versus restrictive transfusion strategies in patients with gastrointestinal bleeding, Villanueva and colleagues36 speculated that liberal transfusion strategies may cause hemostasis or biochemical coagulation impairments. We believe that such findings could also be due to mechanical or physical aspects of HT. Rather than just a possible chemical imbalance as hypothesized by these investigators, we suggest that physical mechanical forces associated with increased blood pressure gradients resulting from the rapid infusion of high oncotic fluids like blood products may adversely impact sensitive vascular circuits. Depending on the intrinsic ability of the vasculature to accommodate such FCs, the resultant forces could potentially dislodge newly formed hemostatic plugs leading to increased vascular bleeding in injured blood vessels. The variations observed by Villanueva and coworkers in their cohorts’ frequencies for TACO and pulmonary edema, RBC median number or amounts of crystalloids given, cardiac complications, and portal pressure gradient increases in their transfusion liberal cohort patients all support this possibility. In addition, these authors noted that the rate of further bleeding was significantly higher in the liberal transfusion group. Mechanical or physical concerns related to resuscitative fluid volumes have also been raised in prior studies of bleeding trauma patients where the amount of crystalloid fluid given could increase a patient’s PP resulting in “mechanical” disruption of a formed clot37 and in animal models where attempts to restore blood pressure with crystalloid fluids in animals with near-fatal hemorrhage due to vascular injury resulted in increased bleeding and mortality.38 Nearly 100 years ago Bernheim1 noted when writing about transfusion overload that “. . . a great amount of blood will simply raise the blood-pressure to such an extent that it will literally blow out any soft young plugs that might be all that is holding body and soul together. . . .” Villanueva and colleagues’ speculation regarding a “transfusion impairment of hemostasis” in liberally transfused patients may in part be a modern-day reflection of this earlier observation and its implied mechanical or physical aspect by Bernheim.
A TACO ASSOCIATION WITH TRALI? Etiopathogenetically TACO and TRALI are distinct entities with the former attributed to hydrodynamic forces and the latter resulting from either immune complex formation involving HLA and/or granulocyte antigens or antibodies or alternatively biologic mediators such as
TACO DIAGNOSIS, MANAGEMENT, AND MITIGATION
bioactive lipids.39-41 By consensus panel definition, the diagnosis of TRALI is excluded if TACO or acute lung injury (ALI) are coexistent in a patient’s clinical presentation.39 When either TACO or ALI may be biologically present in patients with transfusion-associated adverse pulmonary sequelae thought secondary to putative initiators of TRALI, however, the case designation of a “possible TRALI” may be applied. While both TRALI and possible TRALI require new ALI that develops during or within 6 hours of transfusion, their difference is whether there is a temporal relationship to another alternate ALI risk factor. Both can have an ALI risk factor; in TRALI there is no temporal relationship to the ALI risk factor, whereas in possible TRALI, there is a temporal relationship. Such cooccurrences, however, may indicate a potential pathophysiologic connection between TACO, ALI, and TRALI or possible TRALI from the perspective of the “two-event” model of TRALI.39-41 In such a scenario, TACO may directly contribute to vascular endothelium damage by mechanical or physical forces in circulatory circuits that are sensitive to such increases in vascular pressure. Such vascular “barotrauma” could be the first step in a multistep process culminating in increased vascular permeability where lesser amounts of immune reactants or biologically active lipids may be needed in the further disruption of vascular integrity resulting in TRALI or possible TRALI consequences. Such mechanical or physical aspects to excessive transfusions as cited previously with liberal transfusion strategies may thus “physiologically prime” the endovascular space (“endothelial cell priming”) making it more vulnerable to immune reactants and/or bioactive lipids. We believe that further examination of the role excessive transfusions might contribute to TRALI induction should be considered.
CLOSING THOUGHTS: TACKLING TACO . . . AND TAMING IT? TACO is a common adverse consequence of HT that has been recognized since the introduction of blood transfusions into routine clinical practice. It accounts for significant patient morbidity, mortality, and health care costs. Its diagnosis can be obscured by its similarities with TRALI. Viewing TACO as a multiphasic spectrum condition may allow for earlier recognition, affording greater opportunities to minimize its impact on patient-important outcomes. Approaches and strategies to enhance TACO mitigation include: 1) education of physician and nursing staff about this adverse transfusion event; 2) computerized clinical decision support alerts notifying physicians and nurses about the potential for TACO development in highrisk patients especially at the time of electronic order entry; 3) careful recording and monitoring of patients’
VSVs during HT; 4) prescriptive guidance regarding the use of slower infusion rates and/or reduced volume blood products; 5) limited simultaneous use of nonsanguineous fluids during HT; 6) emphasizing the value of single-unit transfusion and avoidance of multiunit transfusions given over a short time interval in hemodynamically stable patients; and 7) highlighting prophylactic and therapeutic recommendations for increased peritransfusion diuretic use especially in patients at severe risk for TACO induction. Hospital transfusion services along with physician and nursing colleagues involved in the delivery of HT services are critical to enhancing processes to curb TACO’s development in at-risk patients. Due to the complexities and difficulties of fluid management in patients receiving HT, however, the total elimination of TACO as an adverse transfusion event will never be fully realized, but decreasing its occurrence and enhancing patient HT safety through the adoption of some of the measures identified here may be possible. ACKNOWLEDGMENTS The authors thank Loretta Grikis, MLS, AHIP, of the Baystate Medical Center’s Health Sciences Library for her assistance in the acquisition of some of the reference materials and Jacqueline Wise for her help in the preparation of the manuscript. CONFLICT OF INTEREST The authors report no conflicts of interest or funding sources.
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Component of the National Healthcare Safety Network (NHSN) manual. 2013. [cited 2013 Oct 15]. Available from: http://www.cdc.gov/nhsn/bio.html 8. Pomper GJ. Febrile, allergic and nonimmune transfusion reactions. In: Simon TL, Snyder EL, Solheim BG, et al., editors. Rossi’s principles of transfusion medicine. 4th ed. Bethesda (MD): American Association of Blood Banks Press; 2009. pp. 826-46. 9. Popovsky MA. Transfusion-associated circulatory overload. In: Popovsky MA, editor. Transfusion reactions. 4th ed. Bethesda (MD): American Association of Blood Banks Press; 2012. pp. 327-37. 10. Giblett ER. Blood groups and blood transfusion. In: Thorn GW, Adams RD, Braunwald E, et al., editors. Harrison’s principles of internal medicine. 8th ed. New York: McGrawHill, Inc; 1977. p. 1705. 11. Cohen H. Transfusion-associated circulatory overload (TACO). In: Serious Hazards of Transfusion (SHOT) Steer-
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12. Zhou I, Giacherio D, Cooling L, et al. Use of B-natriuretic peptide as a diagnostic marker in the differential diagnosis of transfusion-associated circulatory overload. Transfusion 2005;45:1056-63. 13. Tobian AA, Sokoll LJ, Tisch DJ, et al. N-terminal pro-brain natriuretic peptide is a useful diagnostic marker for transfusion-associated circulatory overload. Transfusion 2008;48:1143-50. 14. Andrzejewski C Jr, Popovsky MA. Transfusion-associated adverse pulmonary sequelae: widening our perspective. Transfusion 2005;45:1048-50. 15. Li G, Daniels CE, Kojicic M, et al. The accuracy of natriuretic peptides (brain natriuretic peptide and N-terminal pro-brain natriuretic) in the differentiation between transfusion-related acute lung injury and transfusionrelated circulatory overload in the critically ill. Transfusion 2009;29:13-20. 16. Food and Drug Administration. Fatalities reported to FDA following blood collection and transfusion: annual summary for fiscal year 2010. Rockville, MD: CBER Office of Communication, Outreach, and Development. 2011 [cited 2012 Feb 28]. Available from: http://www.fda.gov/ BiologicsBloodVaccines/SafetyAvailability/ ReportaProblem/TransfusionDonationFatalities/ ucm302847.htm 17. David B. Haemovigilance: a comparison of three national systems. 27th Congress of the International Society of the Blood Transfusion, 24-28 August 2002. Vancouver. 18. Robillard P, Itaj NK, Chapdelaine A. Increasing incidence of transfusion-associated circulatory overload reported to the Quebec Hemovigilance System, 2000-2006. Transfusion 2008;48(Suppl):204A.
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Transfus Med Hemother 2008;35:337-45. 26. Andrzejewski C Jr, Popovsky MA, Stec TC, et al. Hemotherapy bedside biovigilance involving vital sign values and characteristics of patients with suspected transfusion reactions associated with fluid challenges: can some cases of transfusion associated circulatory overload have proinflammatory aspects? Transfusion 2012;52:2310-20. 27. Andrzejewski C Jr, McGirr J. Nursing hemotherapy bedside biovigilance in the recognition and management of suspected transfusion reactions. In: Popovsky MA, editor. Transfusion reactions. 4th ed. Bethesda (MD): American Association of Blood Banks Press; 2012. pp. 551-77. 28. Katz EA. Blood transfusion, friend or foe. AACN Adv Crit Care 2009;20:155-63. 29. Robillard P, Itaj K, Chapdelaine A. Transfusion-Associated Circulatory Overload (TACO): The new leading cause of transfusion-associated fatalities reported to the Québec Hemovigilance System. [cited 2013 Mar 20]. Available from: http://ihn.withtoast.co.uk/wpcontent/uploads/2011/02/ TACO-data-2000-2008-Poster-ISBT-2010.pdf 30. Blumberg N, Heal JM, Gettings KF, et al. An association between decreased cardiopulmonary complications (transfusion-related acute lung injury and transfusionassociated circulatory overload) and implementation of universal leukoreduction of blood transfusions. Transfusion 2010;50:2738-44. 31. Ewald GA, Garmany RG, Krainik AJ. Heart failure, cardiomyopathy, and valvular heart disease. In: Cooper DH, Krainik AJ, Lubner SJ, et al., editors. The Washington manual of medical therapeutics. 32nd ed. Philadelphia (PA): Wolters Kluwer, Lippincott Williams & Wilkins; 2007. pp. 170, 173.
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