Diagnosis and management of transfusion‐associated circulatory overload in adults and children

Transfusion‐associated circulatory overload (TACO) is a severe transfusion adverse reaction that is associated with increased mortality and morbidity. The incidence of TACO in adults varies from 1% to 8%; the incidence in the paediatric population is variable according to the different studies. TACO usually occurs in patients who receive a large volume of blood product over a short period of time. It is more common in patients with known risk factors such as cardiovascular disease, renal failure and older or younger age. The typical presentation of TACO is respiratory distress (dyspnoea, tachypnea). Associated signs and symptoms are hypoxia, hypertension, tachycardia, positive fluid balance, high central venous pressure and acute or worsening pulmonary oedema on chest X‐ray. Echocardiography and measurement of brain natriuretic peptide is helpful for diagnosis. Several definition criteria have been proposed for TACO, but none are adapted for children, particularly critically ill children who are more at risk. In a recent study, the incidence of TACO was compared among paediatric intensive care unit patients using different definition criteria. TACO incidence varied from 1·5% to 76%, depending on the definition used. With such wide variability, conclusion was that a more operational definition of TACO is needed in paediatrics, particularly for critically ill children. Treatment for TACO is similar to that of any other cardiogenic pulmonary oedema: oxygen, diuresis and ventilatory support. Prevention is possible by avoiding unnecessary transfusions, transfusing only the necessary amount of blood product, avoiding rapid transfusions and using diuretics.     

Transfusion‐associated circulatory overload (TACO): Time to shed light on the pathophysiology

Transfusion‐associated circulatory overload (TACO) is the most frequent pulmonary complication of transfusion and one of the leading causes of transfusion‐related fatalities. TACO is characterized by new or worsening hydrostatic pulmonary oedema which occurs within 6 h of blood transfusion and results in respiratory distress. Major risk factors for TACO include cardiac failure, renal dysfunction and the degree of positive fluid balance. Suboptimal fluid management and inappropriate infusion practices have also been reported as risk factors for TACO. Unfortunately, the TACO pathophysiology is poorly understood. It can be hypothesized that the pathophysiology of TACO may be generally reflected by a 2‐hit model. The first hit in TACO may be represented by the poor adaptability for volume overload in the transfusion recipient, which is supported by the identification of cardiovascular and renal risk factors for the onset of TACO. The second hit may subsequently be conveyed by the transfused blood product. Remarkably, volume overload alone does not appear to be the only factor triggering the onset of TACO. It can be hypothesized that other factors in the transfused product may play a significant role. In addition, inflammation in the transfused recipient may also be an important feature in TACO. To obtain more insight into the TACO pathophysiology, it will be important to assess and validate potential biomarkers in TACO. In addition, development of currently unavailable TACO‐animal models will provide a useful tool for dissecting the pathophysiologic mechanisms. Collectively, this will aid in improving diagnostic approaches and shed light on possible therapeutic interventions.     

Trali et Taco : diagnostic et prise en charge clinique des patients

Transfusion-related acute lung injury (TRALI) is the inflammatory, exudative form and Transfusion-associated cardiac overload (TACO) is the hydrostatic, transudative form of transfusion-induced acute pulmonary edema. The distinction between these two entities may be difficult, but important because of different clinical management strategies and different implications. There is no unique diagnostic tool. The diagnostic search should gather several clinical information and may be helped by various techniques listed in this article.     

Complications pulmonaires de la transfusion (TACO–TRALI)

Pulmonary oedemas occurring during or after a blood transfusion appear as the most frequent serious immediate incidents in the French hemovigilance database. They include transfusion-associated circulatory overload (TACO) and transfusion-related acute lung injury (TRALI). TACO are a major cause of transfusion-related death in France. TRALI are more and more recognized and notified. In no case, pooled fresh frozen plasma (100 donations) treated with solvent–detergent were involved in French TRALI cases. A logigrame will allow hemovigilance officers to better classify pulmonary oedemas in e-fit, the French hemovigilance database.     

Transfusion-associated circulatory overload

Transfusion-associated circulatory overload (TACO) is cardiogenic pulmonary oedema due to infusion of rapid or large volume blood product. TACO is a frequent, serious, but under-recognized complication of haemotherapy. Presenting symptoms include dyspnoea, cyanosis, tachycardia and increased blood pressure. Pedal oedema, headache, chest tightness and dry cough are additional manifestations. Chest radiographs reveal pulmonary oedema and cardiomegaly. Vulnerable patients are the very young and persons over 60 years. While rapid infusion or massive transfusion are frequently the precipitating factors, relatively small volumes (1–2 units) are sufficient to trigger the congestive heart failure. Both haeme and non-haeme fluids account for the positive fluid balance. Fresh-frozen plasma (FFP) and autologous red blood cells have been implicated as well. Consequences include longer length of intensive care unit and hospital stay. The fatality rate has been reported to be 1–3%, but this may understate the true rate. The incidence has been reported to be 1–8% in orthopaedic surgical populations. In general hospital populations a range of 1 : 708–1 : 4075 red blood cell transfusions is associated with TACO. In the intensive care setting, an incidence of 1 : 356 components has been demonstrated. TACO is frequently confused with transfusion-related acute lung injury (TRALI). In some cases, TRALI and TACO may co-exist. A potentially important diagnostic tool is brain natriuretic peptide. Brain natriuretic peptide is elevated in TACO and a post-transfusion-to-pre-transfusion ratio of 1·5 is indicative of the diagnosis. The test has a sensitivity of 81% and a specificity of 89%. Treatment includes supplementary oxygen, diuretics, placing the patient in a sitting position and therapeutic phlebotomy in 250-ml increments. While rapid infusion is believed to be a contributing factor, optimal infusion rates for the non-emergency situation have not been determined. TACO has been observed with flow rates between 0·9 and 48·1 ml/min. Preventive measures include use of evidence-based transfusion and controlled-rate infusion. Measures that insure the use of standardized blood components, such as derived through apheresis, are likely to favourably impact the incidence of this complication.     

How clinicians can minimize transfusion-related adverse events?

Objectives

Transfusion-related adverse events (TRAE) can contribute to patient morbidity and mortality. In this brief narrative review, the strategies that clinicians can apply at the bedside to avoid TRAE are discussed.

Transfusion-related respiratory complications in intensive care: A diagnosis challenge

Transfusion-related respiratory complications can be challenging to diagnose especially in mechanically-ventilated patients in the intensive care unit (ICU) due to the concurrent respiratory symptoms associated with the patients’ primary diagnoses. In this narrative review, transfusion-related respiratory complications, including transfusion-associated dyspnea (TAD), transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), and transfusion-related allergic reaction (TRAR), are briefly presented in light of the recent consensus or experts’ definitions; and the diagnosis issues for ICU patients are discussed. Acute respiratory failure occurring during, or within 6 to 24 hours, of transfusion might be a transfusion-related respiratory complication. The recent updated definitions for TRALI and TACO should assist clinicians to differentiate between possible diagnoses. The issues for ICU clinicians are first to recognize the acute respiratory deterioration and the possible causality between the deterioration and blood transfusion and secondly to make the proper diagnosis. This remains challenging for mechanically-ventilated patients. Clinical assessment to identify ICU patients at particular risk of transfusion-related respiratory complications and non-invasive investigation tools could be beneficial and may help to remind clinicians to be alert to the link between transfusion and worsening of respiratory symptoms in these vulnerable critically ill patients.     

Diagnosis of transfusion-related acute lung injury: TRALI or not TRALI?

TRALI is a challenging diagnosis for both the transfusion specialist and the clinician. A Canadian consensus panel has recently proposed guidelines to better define TRALI and its implications. The guidelines recommend classifying each suspected case in one of the following 3 categories: (1) "TRALI," (2) "Possible TRALI," or (3) "Not TRALI." We report the clinical presentation, laboratory evaluation, and management of 3 patients with respiratory failure (RF) following allogeneic blood transfusions. These patients all experienced RF within 6 hr post-transfusion. Based on a review of the clinical and laboratory data and applying the Canadian guidelines, the first patient, a 67-yr-old man with chronic myelomonocytic leukemia, was diagnosed as "TRALI" due to the sudden onset of RF requiring intensive resuscitation. The second patient, a 55-yr-old man with aplastic anemia, was diagnosed as "Possible TRALI" due to pre-existing RF that worsened after blood transfusion. The third patient, a 1-yr-old male, was diagnosed as transfusion associated circulatory overload (TACO) and "Possible TRALI," although his RF improved after treatment with diuretics. In all 3 cases, the blood donor center was informed of the suspected TRALI reactions. The remaining blood products from the donors associated with these reactions were quarantined. After review of the clinical data, the donors associated with cases #1 and #3 were screened by the blood center for granulocyte and HLA antibodies. Using a Luminex flow bead array, the following class I and class II antibodies specific for patient #1 were identified in the respective donor: anti-A25, B8, B18, and anti-DR15, DR 17. Subsequently, donor #1 was permanently deferred. A non-specific IgM anti-granulocyte antibody was identified in the donor associated with case #3, and this donor was subsequently disqualified from plasma and platelet donations. In conclusion, the Canadian guidelines to categorize patients suspected of TRALI provide a useful framework for evaluation of these patients and their respective blood donors.     

Aktualny stan wiedzy na temat patofizjologii,diagnostyki i zapobiegania TRALI

Transfusion-related acute lung injury (TRALI) is the leading cause of mortality following transfusion of blood components. Characteristic for TRALI is acute hypoxemia during or up to 6 h after transfusion provided that cardiogenic respiratory failure and transfusion-associated circulatory overload (TACO) are excluded.In this article we present: 1) Etiology and pathomechanism of TRALI syndrome including the numerous issues that are still unresolved. Currently accepted is the multiple-event model which involves both the patient and the transfused blood components. The TRALI syndrome may be either immunological or nonimmunological dependant on the various factors that activate neutrophils – the main cells in TRALI pathogenesis. 2) TRALI diagnosis should be based mainly on the clinical presentation due to the variety of pathomechanism of the syndrome; however testing of anti-leukocyte antibodies in transfused blood components, according to ISBT guidelines, is recommended in order to prevent TRALI incidence. 3) Different strategies of TRALI prevention, although up to date no ultimate provisions have been accepted. Transfusion of plasma collected only from men seems to be a promising solution as in many countries that adapted this preventive measure the number of TRALI cases has substantially decreased. 4) Different methods of proceeding with donors who donated blood components that were the cause of TRALI in transfused patients. It still remains an open question whether to defer donors with anti-leukocyte antibodies or multi pregnant women.     

The recipient side of TRALI – the role of patient neutrophils

Transfusion‐related acute lung injury (TRALI) is a serious and potentially fatal complication of blood transfusions. The fact that TRALI has been the top cause of transfusion‐related mortalities in the USA over the last 3 years (2004–06) [ 1 ] provides irrefutable evidence of the clinical significance of this syndrome. From this perspective, its importance in transfusion complications surpasses that of blood‐borne viruses and bacterial infections. Despite this, we still do not clearly understand the pathophysiology and pathogenesis of TRALI. This paper presents a TRALI patient or recipient perspective by discussing how thorough serological investigations can be utilized to provide evidence that patient neutrophils are the target cell and to identify the implicated donation/s when there are multiple associated donations.     

Presence of HLA antibodies in single‐donor‐derived fresh frozen plasma compared with pooled,solvent detergent‐treated plasma (Octaplas®)

Adverse reactions to plasma transfusion are well documented. One of the most serious hazards of transfusion, transfusion‐related acute lung injury (TRALI), has nearly as high an incidence of mortality and major morbidity as that reported for the transfusion of incorrect blood components. The specific mechanisms of plasma component‐induced adverse reactions remain unclear, but a major contribution may be related to the presence of alloantibodies. In this study, a laboratory analysis was undertaken to determine the presence of HLA antibodies in leucodepleted single‐donor‐derived fresh frozen plasma (FFP). A comparison was made with a pooled plasma product that has undergone solvent detergent treatment. In total, 58 plasma samples from single‐donor units of leucodepleted FFP were tested along with samples from 12 units (three for each ABO blood group) of the pooled plasma (Octaplas^®; Octapharma Ltd, Coventry, UK), for the presence of HLA antibodies. HLA‐specific enzyme‐linked immunosorbent assay (ELISA) methods were used to screen for their presence, and complement‐dependent cytotoxicity and flow cytometry analyses were used to further define their presence, specificity and class [immunoglobulin G (IgG)/IgM]. In the study groups, HLA antibodies were found to be present in five of the single‐donor units (9%) while the pooled plasma samples tested negative.     

Les complications respiratoires de la transfusion

Respiratory complications of blood transfusion have several possible causes. Transfusion-Associated Circulatory Overload (TACO) is often the first mentioned. Transfusion-Related Acute Lung Injury (TRALI), better defined since the consensus conference of Toronto in 2004, is rarely mentioned. French incidence is low. Non-hemolytic febrile reactions, allergies, infections and pulmonary embolism are also reported. The objective of this work was to determine the statistical importance of the different respiratory complications of blood transfusion. This work was conducted retrospectively on transfusion accidents in six health centers in Champagne-Ardenne, reported to Hemovigilance between 2000 and 2009 and having respiratory symptoms. The analysis of data was conducted by an expert committee. Eighty-three cases of respiratory complications are found (316,864 blood products). We have counted 26 TACO, 12 TRALI (only 6 cases were identified in the original investigation of Hemovigilance), 18 non-hemolytic febrile reactions, 16 cases of allergies, 5 transfusions transmitted bacterial infections and 2 pulmonary embolisms. Six new TRALI were diagnosed previously labeled TACO for 2 of them, allergy and infection in 2 other cases and diagnosis considered unknown for the last 2. Our study found an incidence of TRALI 2 times higher than that reported previously. Interpretation of the data by a multidisciplinary committee amended 20 % of diagnoses. This study shows the imperfections of our system for reporting accidents of blood transfusion when a single observer analyses the medical records.     

Les TRALI au CHU de Nancy : une incidence reconsidérée après l’application stricte des critères de Toronto

“Transfusion-related acute lung injury” (TRALI) is a post-transfusion lesional pulmonary edema, potentially severe, better defined since the conference of Toronto in 2004. The incidence of TRALI reported in France remains low in part because of its ignorance by physicians. The objective of our study was to evaluate retrospectively transfusion accidents with respiratory complications that occurred in Nancy University Hospital and reported to the haemovigilance between 1996 and 2006, from the software “Traceline” listing all the blood transfusion complications from signs observed. The analysis of the files has been performed by applying rigorously diagnostic criteria of Toronto. Forty-one cases of respiratory complications were found in 34,573 blood products. Ten cases of TRALI were diagnosed while only one case had been reported to the haemovigilance. The remaining nine cases were previously labeled transfusion-associated circulatory overload (TACO). No cases of TRALI have been identified in the ICU. Our work can find an incidence of TRALI 10 times greater than previously reported. Ignorance of TRALI and the lack of consensus definition before 2004 are not sufficient to explain these results. This study demonstrates the potential interest of database and computerized declaration system based on the symptoms observed. It highlights the vulnerability of the current haemovigilance too dependent on a single medical observer. Although TRALI are recognized as serious complications, sometimes requiring resuscitative care, our work was not isolated severe TRALI in ICU. Physician awareness of TRALI to the identification and to the declaration, including ICU should be continued. Finally, the diagnostic criteria for TRALI must be adapted to the ICU.     

Evidence behind the pathophysiology of TRALI

Transfusion-related acute lung injury (TRALI) is a serious transfusion complication that may lead to significant morbidity and mortality. This has driven a significant research effort focused on understanding why and how TRALI develops. The ultimate goal must be prevention or at least mitigation of the clinical consequences of TRALI. The underlying pathophysiology of TRALI is presently best described by two hypotheses which are not mutually exclusive. These are the antibody mediated TRALI mechanism and the two-event or priming TRALI mechanism. One of the key initial findings in TRALI research was the frequent presence of leucocyte antibodies in associated blood products, providing strong evidence for an antibody driven pathogenesis. In contrast, the two-event mechanism proposed that these transfused antibodies activated neutrophils that had first been primed by the patient’s clinical condition. Together, data from haemovigilance programs, clinical reports and experimental findings have led several countries to introduce TRALI risk-reduction strategies. These include either limiting the transfusion of plasma from female donors or, screening female donors for the presence of leucocyte antibodies. Both approaches are justified by adoption of the immune mechanism as the prime driver of the pathogenesis of TRALI. TRALI incidence has gratifyingly been reduced by these measures. Nevertheless, TRALI cases persist and they remain a major concern because of continuing significant morbidity and mortality. While the majority of earlier TRALI research has focused on the role of antibodies in TRALI, evidence for the role of non-antibody factors in TRALI is now growing, based on an increasing number of in vitro, ex vivo and in vivo models. This review aims to present data from such models, which are the foundation for our current understanding of the pathophysiology behind antibody mediated and non-antibody mediated TRALI.     

Work‐up in the case of granulocyte antibodies

Granulocyte allo‐ and autoantibodies have been implicated in a variety of clinical conditions such as primary and secondary autoimmune neutropenia (AIN), alloimmune neutropenia (NAIN), transfusion‐related acute lung injury (TRALI) as well as febrile and severe pulmonary transfusion reactions. The classic granulocyte agglutination test (GAT) in combination with the granulocyte indirect immunofluorescence test (GIFT) can detect nearly all relevant antibodies. HNA‐1, ‐2, 4, 5 and HLA class I antibodies are clearly detectable in the GIFT while HNA‐3 antibodies strongly agglutinate neutrophils in the GAT. The glycoprotein‐specific and highly sensitive monoclonal antibody‐specific immobilization of granulocyte antigens (MAIGA) test detects all human neutrophil antigen (HNA) antibodies except for HNA‐3 but is time‐consuming and requires highly skilled personnel. For TRALI diagnostics, laboratory testing is completed by the indirect lymphocyte immunofluorescence test (LIFT), and HLA class I and II ELISAs or fluorescent bead‐based assays (Luminex). The latter also enable faster and more automated HNA antibody detection but to date not all specificities, especially HNA‐3, can be reliably detected so that still the classical tests have to complete the methodological spectrum. HNA allelotyping by PCR methods is the first choice for all HNA except for HNA‐2 because the molecular reason for the HNA‐2_null phenotype is not completely understood. Establishing a PCR‐SSP reaction for the main CD177*787A>T polymorphism comprises the risk to miss other causes so that HNA‐2 is still typed serologically. Granulocyte serology even today is widely based on a variety of manual methods, requires experienced laboratory staff and profound knowledge of granulocyte immunobiology.     

A threshold model for the susceptibility to transfusion-related acute lung injury

Transfusion-related acute lung injury (TRALI) is a serious, often life-threatening pulmonary transfusion reaction characterized by non-cardiogenic lung oedema, hypoxemia and respiratory distress in temporal association with blood transfusion. The critical mechanism in TRALI is the sudden increase in permeability of the pulmonary endothelium and the subsequent, often extensive shift of fluid into the alveolae. The rapid clinical recovery seen in most patients makes it likely that this is a temporary phenomenon. Reactive oxygen species released by neutrophils or other cells are attractive candidate mediators of this process. There is experimental and clinical evidence that several pathways can induce barrier breakdown in TRALI, a concept known as the threshold model of TRALI. Surprisingly, neutrophils may not always be required. Other cells may play a role as multipliers or attenuators of TRALI, depending on recipient-related and transfusion-related factors involved. This review will summarize recent findings on pathophysiology, with a focus on newly discovered or disenchanted recipient-related and transfusion-related risk factors for TRALI and will present the threshold model of TRALI as a unifying concept on how TRALI develops.     

Transfusion and lung injury.

The respiratory tree has been viewed as an infrequent site of injury arising as a complication of transfusion. In recent years, this view has changed as investigators have shown that two complications--circulatory overload and transfusion-related acute lung injury--are relatively frequent events. Circulatory overload is a result of hypertransfusion to individuals at risk, the very young or old recipient. The reaction is due to fluid infusion which overwhelms the capacity of the left ventricle, resulting in pulmonary edema. While rarely fatal, studies have shown that such incidents result in intensive care and extended hospitalization. In the setting of orthopedic surgery, 1% of elderly patients undergoing hip or knee surgery experience circulatory overload. These events are associated with autologous, as well as allogeneic red blood cells (RBC) and fresh frozen plasma. Transfusionists need to be vigilant with transfusion therapy in this population. Phlebotomy and supplemental oxygen are the key therapies. Transfusion-related acute lung injury (TRALI) is the adult respiratory distress syndrome due to transfusion. It is associated with a significant morbidity and mortality of 5-14%, making it the third most common cause of death from transfusion in developed countries. It is characterized by the onset of acute respiratory distress, bilateral pulmonary edema and hypoxemia. It occurs within 1-2 hours of transfusion of a plasma-containing blood product. All blood components have been associated with the reaction, and rarely, intravenous immune globulin. There is no recognized profile of individuals at increased risk for TRALI. There are two purported mechanisms of injury; the vast majority of cases are associated with passively transfused complement-activating antibodies. These antibodies are either HLA (Class I or II) or granulocyte-specific. These antibodies appear to act as mediators, which result in granulocyte aggregation, activation, and microvascular pulmonary injury. With appropriate respiratory intervention, 80% of patients recover within 96 hours of the original insult. There are no permanent pulmonary sequelae.     

Transfusion-associated circulatory overload: A survey among Dutch intensive care fellows

Objectives

Transfusion-associated circulatory overload (TACO) is a severe pulmonary transfusion reaction and leading cause of transfusion-related morbidity and mortality in Europe. TACO is of particular importance in critically ill patients, since they often receive blood transfusions and have multiple risk factors for TACO. This study investigates transfusion practices in patients at risk of developing TACO, and furthermore knowledge concerning risk factors, diagnoses and treatment strategies among Dutch intensive care unit (ICU) fellows.

Further characterization of transfusion-related acute lung injury: demographics, clinical and laboratory features, and morbidity

According to Food and Drug Administration data, transfusion-related acute lung injury (TRALI) is the third most frequent cause of transfusion-associated death in the United States and is characterized by an acute respiratory distress syndrome-like clinical picture following transfusion of plasma-containing blood components. It may be underdiagnosed due to unfamiliarity of clinicians with the syndrome. This report describes the largest series to date, 46 cases, occurring between 1992 and 1998. The male-to-female ratio was approximately 1:1. The mean age at diagnosis was 54 years. The most frequent presenting symptom or signs were acute respiratory distress, hypotension, and hypertension. Antibodies to human leukocyte antigens or granulocytes were identified in 61 percent of cases, with 50 percent associated with antibodies in a donor whose blood had been transfused to a patient developing TRALI. Clinical recovery occurred in 87 percent of patients, but TRALI contributed to deaths in 13 percent. Clinicians need to recognize and diagnose this syndrome in order to respond with appropriate interventions.     

Transfusion-associated circulatory overload in orthopedic surgery patients: a multi-institutional study

Although recognized as a serious complication of hemotherapy, few data are available on the incidence of transfusion-associated circulatory overload (TACO). Detailed demographic and clinical information was obtained from records of 382 Medicare patients undergoing total hip or knee replacements (and receiving transfusions) from January 1992 to December 1993 at five Massachusetts hospitals. Seventy-eight percent of the patients were women with a mean age of 77 years. Thirty-two percent had co-morbidities including myocardial or coronary disease. Transfusion-related complications and comorbidities were identified and reviewed by transfusion experts. Patients were excluded from consideration if non-transfusion factors such as myocardial disease could have contributed to the development of acute pulmonary edema. Four (3 females, 1 male) patients (1.05%) developed TACO postoperatively. Mean age of these patients was 84 years (range, 75-101) versus 77 years for non-TACO. The mean intraoperative estimated blood loss was 375 mL. Each patient received only 1-2 units of red blood cells prior to onset of TACO, and in two cases only autologous blood was used. The mean positive fluid balance was 2,480 mL. The mean pretransfusion hematocrit prior to circulatory overload (CO) was 26.0 percent. Symptoms were reversed with diuretics. Length of stay was significantly prolonged by these incidents. TACO is a frequent and serious event in an orthopedic surgical setting. It is associated with advanced age, increased health care costs, and may occur in the setting of modest transfusion volumes. The utilization of conservative transfusion criteria and fluid management in the perioperative setting may decrease the incidence of this complication in this population.