ORIGINAL ARTICLE Transfusion-associated circulatory overload in Ireland: a review of cases reported to the National Haemovigilance Office 2000 to 2010 Andrea Piccin,1,2,3 Marina Cronin,1 Róisín Brady,1 Jackie Sweeney,1 Luigi Marcheselli,4 and Emer Lawlor1,2
BACKGROUND: Transfusion-associated circulatory overload (TACO) is an increasingly reported condition but symptoms and signs are still unrecognized. We present a review of the incidence and clinical features of TACO reported to the National Haemovigilance Office at the Irish Blood Transfusion Service. STUDY DESIGN AND METHODS: Between 2000 and 2010, a total of 1071 cases of serious transfusionrelated reactions were reported, of which 221 (21%) cases were TACO. RESULTS: A total of 2,000,684 blood components were issued, with a TACO incidence of one in 9177. The TACO incidence per red blood cells, plasma, and platelet components issued was one in 8000, one in 16,000, and one in 57,884, respectively. The majority of cases (68%, n = 151) were elderly patients, while no sex difference was seen. Twenty-eight (13%) patients experienced severe morbidity; 31 (14%) deaths were reported, of which five (2%) were considered due to TACO and the other deaths considered due to and underlying conditions, which in most cases were cardiovascular (76%). An increased risk of mortality was found in patients on diuretics either before transfusion as part of their routine therapy or given as pretransfusion medication (odds ratio, 2.49; 95% confidence interval, 1.06-6.01). In 19 (21%) cases, TACO reaction was due to human error. CONCLUSIONS: The strong association between TACO and human errors supports the role of hemovigilance and of adequate transfusion medicine teaching for preventing morbidity and mortality associated with TACO.
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ransfusion-associated circulatory overload (TACO) is increasingly being recognized as an important cause of morbidity and mortality by the UK Serious Hazards of Transfusion scheme1 and is the second most common cause of transfusion-related deaths reported to the Food and Drug Administration;2 however, this condition is often misdiagnosed and underreported.3 TACO is characterized by the development of acute pulmonary edema during or shortly after transfusion and is associated with symptoms and signs of congestive cardiac failure. The pathophysiology of this condition is believed to be caused by increased hydrostatic blood pressure due to volume overload leading to fluid leakage into the alveolar space, emulating congestive cardiac failure.4 The clinical signs and symptoms of TACO include dyspnea, orthopnea associated with tachycardia, hypertension, elevated central venous pressure, and pulmonary and/or sacral or ankle edema.5 Chest X-ray finding shows pulmonary edema and heart size may be normal or
ABBREVIATIONS: IBTS = Irish Blood Transfusion Service; ICU = intensive care unit; NHO = National Haemovigilance Office; RR = relative ratio; SAR(s) = serious transfusion-related reaction(s); TACO = transfusion-associated circulatory overload. From the 1Irish Blood Transfusion Service and 2Trinity College University, Dublin, Ireland; the 3Hematology Department, San Maurizio Regional Hospital, South Tyrol, Italy; and the 4 Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy. Address reprint requests to: Andrea Piccin, MD, PhD, Haematology Department, San Maurizio Regional Hospital, 39100 Bolzano, South Tirol, Italy; e-mail: [email protected]. Received for publication April 3, 2014; revision received October 27, 2014, and accepted October 27, 2014. doi: 10.1111/trf.12965 © 2014 AABB TRANSFUSION **;**:**-**. Volume **, ** **
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enlarged. It may be difficult to differentiate TACO from transfusion-related acute lung injury (TRALI) as hypoxemia and bilateral infiltrates on chest X-ray are features of both and the differentiating factor is evidence of circulatory failure, which may be difficult to ascertain clinically. Thus, TACO cases are often reported as TRALI and the other way around. The National Haemovigilance Office (NHO) at the Irish Blood Transfusion Service (IBTS) has collected reports of respiratory reactions associated with transfusion including both TACO and TRALI since its inception in 1999. We present a review of the incidence, clinical features, and outcomes of 221 TACO cases reported to the NHO from 2000 to 2010. We discuss and compare our findings with the recent literature.
strict time frame posttransfusion within which the reaction had to be diagnosed to be classified as TACO, and the decision to accept the reaction as TACO was based on the clinical picture and patient characteristics. The reaction could include any or all of the following: dyspnea, orthopnea, cyanosis, tachycardia, hypertension, and/or pulmonary and/or pedal edema. Pulmonary edema was diagnosed on the presence of rales on ausculation and/or by appearance on a chest X-ray. All reports accepted and reported as TACO in the annual NHO report between 2000 and 2010 were retrospectively reviewed for inclusion in this article.
TACO associated with error
MATERIALS AND METHODS Serious adverse reaction reporting Reports of serious transfusion-related reactions (SARs) from Irish hospitals are submitted to the NHO by dedicated hemovigilance officers, usually nurses, after review by the consultant hematologist in charge of the hospital blood transfusion laboratory. From 2000 to 2006 reporting to the NHO was on a professional responsibility basis. From November 2006 onward as a result of the EU Directives 2002/98/EC and Commission Directive 2005/61/EC, reporting of reactions became mandatory. Reports of respiratory complications of transfusion such as TACO and TRALI have been accepted by the NHO since its inception in 1999 and reports of transfusion-associated dyspnea have also been accepted since 2007.
Data collection Information collected from the NHO on SAR report forms includes patient demographics such as age and sex, symptomatology and physical signs associated with the reaction, underlying diagnosis, any chronic existing conditions, and the blood product type(s) implicated in the reaction. Data are also collected on investigations, treatment, and patient outcome after the reaction. In the case of suspected TACO or TRALI reactions, the rate of transfused blood products, total volume of blood products transfused, and the use and timing of diuretics are collected. These data are entered by NHO staff on to the NHO database and following review, if accepted, are included in the annual NHO report for that year.
Definition of TACO A reaction was accepted as TACO based on the criteria suggested by Popovsky and colleagues6,7 characterized by the development of signs and symptoms of acute pulmonary edema secondary to congestive cardiac failure during, or within some hours of transfusion. There was no 2
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From 2007, hospital-based hemovigilance officers reporting all SARs were asked to assess if errors contributed to the occurrence of SAR. This not only involved assessment of the development and treatment of the reaction, but also required a detailed review of human and system factors underpinning patient care. Reporters included a short description of reasons underpinning these errors.
Incidence of TACO and statistical analysis The incidence of TACO was calculated on red blood cell (RBC), platelet (PLT), and plasma units issued from the IBTS between 2000 and 2010 obtained from the IBTS (Progesa, Brescia, Italy) transfusion database. Comparative analysis of patient demographic and clinical data was made using Fisher’s exact test (GraphPad PRISM statistical package, GraphPad, San Diego, CA). The association between the overall mortality and the clinical and demographic data was analyzed by means of the logistic regression analysis, either in univariate or in multiple regression. The effect size was expressed as odds ratio (OR). Since the specific mortality related to transfusion follow a Poisson distribution, we analyzed the data using, in univariate and multiple analysis, the Poisson regression. The effect size was expressed as relative ratio (RR). The Pearson chi-square goodness of fit was used as diagnostic test to check the model form of the logistic and Poisson regression models. The confidence intervals (CIs) were set at 95% of probability. It was an observational study and we did not plan a sample size; we considered a p value of less than 0.05 as moderate strength against the null hypothesis. All the statistical tests were two sided. The regression analysis was performed with computer software (Stata 10/SE, StataCorp, College Station, TX).
RESULTS Between 2000 and 2010, a total of 1071 SAR cases were reported to the NHO. A total of 221 (21%) cases were
TACO INCIDENCE AND OUTCOME IN IRELAND
classified as TACO. Twelve of these cases had been initially submitted as TRALI but were reassigned as TACO after investigations and review by the NHO. A total of 186 cases (84%) involved SAGM RBCs, 17 (8%) involved fresh-frozen plasma (FFP) or solvent/detergent (S/D) plasma, five (2%) involved PLTs (four cases of apheresis PLTs, one case of a pooled PLT), and 13 (6%) involved multiple components.
TACO incidence During the study period, a total of 2,000,684 blood components were issued giving a TACO incidence of one in 9177 per component. Excluding 13 TACO reports involving multiple components (Table 1), the TACO incidence per RBCs, plasma, and PLT component issued was one in 8000, one in 16,000, and one in 57,884, respectively, with a total incidence of one in 9665. The incidence of TACO per unit of plasma fell from a peak of one in 4506 in 2001 to one in 23,324 in 2010 giving an overall incidence of one in 16,000 per unit over the period.
Patient demographics Patients of all ages were at risk of developing TACO. While the majority of patients (68%, n = 151) developing TACO were elderly (>70 years), 60 (27%) patients aged between 31 and 69 years developed TACO and 10 (5%) were young patients less than 30 years of age, with two of these patients less than 4 years of age. There was no significant difference in sex (male, 101; female, 120; p = 0.201).
TABLE 1. Incidence of TACO per component 2000 to 2010 Component issues 1,486,041 272,105 231,538 2,000,684
Component RBCs Plasma PLTs Total
TACO cases 186 17 5 208
1 1 1 1
Incidence per 8,000 per 16,000 per 46,300 in 9,665
Existing condition A total of 215 patients (97%) had reported existing conditions predominantly cardiovascular, respiratory, or renal conditions. These data are presented in Table 2. Patients often presented with one or more underlying existing condition. A total of 168 had underlying cardiovascular disease, and 162 of these patients had an additional underlying condition. Only six patients had no reported existing cardiovascular disease or other condition.
Transfusion volume The median transfused volume was 250 mL (range, 60-9500 mL). A total of 110 (50%) TACO reports followed a single unit of blood component, 106 involving RBCs and four involving PLTs, and in 10 cases, all involving RBCs, not more than 100 mL was transfused before the onset of TACO. Eighty-one cases (74%) of these single-unit transfusions involved elderly patients over 70 years of age and two children under 4 years of age. Weight ranges were reported for only 110 of 221 (50%) patients. An additional three were reported as being of low weight, but no details were given. Thirtyseven (34%) patients had weights reported of less than 60 kg and 16 (14.5%) had weights below 50 kg. Twentyone patients weighed between 50 and 60 kg, 10 weighed between 40 and 50 kg, and six patients weighed less than 40 kg. The 21 patients with weights between 50 and 60 kg were all adults of whom 14 (66%) were aged over 70 years. The 10 patients with weights between 40 and 50 kg were all adults, of whom five (50%) were over 70 years. The median volume transfused in both these groups was 500 mL. The six patients with weights below 40 kg received between 250 and 500 mL, each with a median of 350 mL. Two of these six were children aged under 4 years and were reported as receiving a full unit of RBCs and PLTs each. The other four patients were aged over 70 years.
TABLE 2. Existing conditions predominantly cardiovascular, respiratory, or renal conditions* Existing condition Cardiovascular Respiratory Renal Malignancy Anemia Hemorrhage Surgical Miscellaneous None Total
Examples Ischemic heart disease, congestive heart failure, myocardial infarction, valve incompetence, atrial fibrillation, hypertension Chronic obstructive airways disease, respiratory infection, pleural effusion, asthma Renal impairment, renal failure Both solid tumor and leukemia • Existing condition associated with other existing conditions (29) • Stand-alone anemia (9) Postoperative (3), other (8) Abdominal surgery, mastectomy, above-knee amputation Diabetes, sepsis, gastritis, hepatic dysfunction No reported underlying history
Number 168
Percentage of patients 76
57 41 38 38
26 19 17 17
11 5 24 6 221
5 2 11 3
* Some patients had more than one underlying comorbidity.
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Large-volume transfusions
Outcome
However, 10% (22) of cases involved large-volume transfusion with a median of 1500 mL (range, 1000-9500 mL). While only one of these transfusions met the clinical definition of a massive transfusion (150 mL/min), patients in this cohort received between 200 and up to 2375 mL per hour. Three patients received between 1800 and 4300 mL urgently, with no time specified. Six patients (27%) were more than 70 years of age, and nine patients (41%) had associated underlying cardiovascular conditions. Five patients (23%) developed minor sequelae, and three patients (14%) required admission to intensive care unit (ICU) as a result of development of TACO. Three patients who received large-volume transfusions died and one of these deaths was possibly attributed to TACO. Five (23%) cases involved young female patients (age ≤ 30 years) without any underlying cardiovascular condition, who developed massive bleeding associated with delivery. Although one patient had a history of asthma, she did not take regular medication. These patients were being transfused for obstetric or gynecologic bleeding, and also received large volumes of crystalloids and colloids. All five patients recovered although two patients were admitted to the ICU.
Patient outcome was reported in 220 cases. A total of 161 (73%) patients recovered after TACO. Twenty-eight (13%) patients experienced severe morbidity ranging from prolonged resolution of symptoms, admission to hospital, transfer to ICU, and cancellation of surgery and two patients developed myocardial infarction. Thirty-one (14%) deaths were reported. Twenty-three deaths involved RBC transfusion, four patients died after FFP and S/D plasma transfusion, and four patients died after transfusion of multiple components. In multiple regressions analysis the risk of death was increased with transfusion other than RBCs (OR, 2.74; 95% CI, 1.06-7.12; p = 0.037; Table 3). Only five deaths, however, were considered probably attributable to TACO (Table 4). Three of these involved plasma (Cases 1, 2, and 4) and two (Cases 3 and 5) involved RBCs. The TACO-specific relative risk of death was increased with transfusion other than RBCs when compared to transfusion of RBCs only (RR, 7.97; 95% CI 1.33-47.7) and was confirmed in multiple regression analysis. The possibility of TRALI was considered and outruled in these cases involving plasma. Two of the three fatalities were associated with the transfusion of plasma to reverse warfarin overdosage, one (Case 1) involving large volumes of plasma and the second (Case 2) involving plasma given over a short period of time.
Transfusion rate Information on the prescribed rate for a single type of blood product (RBCs only, plasma only, PLTs only) was available in 166 (75%) reports. Of these 146 (87%) involved RBCs, 15 (10%) involved plasma, and five (3%) involved PLTs. RBC units were prescribed over greater than 4 hours per unit in 43 cases (29%), over 3 to 4 hours in 87 cases (59%), and less than 3 hours in 16 cases (11%), with a median of 3 to 4 hours. Plasma (15) or PLT transfusions (5) were prescribed over 15 to 30 minutes per unit in five cases (25%), over 30 to 60 minutes in 10 cases (50%), between 90 and 120 minutes in three cases (20%), and over 2 hours in two cases (10%) with a median of 30 to 60 minutes. Information on the actual rate of transfusion was available in 156 (70%) of these reports. Transfusions were administered at a faster rate than prescribed in 35 (25%) of the 140 assessable RBC transfusions and in one (8%) of 12 plasma transfusions. However, faster rate and mortality were not shown to have a significant correlation (p = 0.559).
Effect of diuretic treatment on outcome A total of 199 (90%) patients received diuretics before, during, or after transfusion as follows: before (n = 43), during (n = 34), or after transfusion (n = 162). Twenty patients (9%) did not receive diuretics. Information on use was not available in two cases. Twenty-five of the 31 deaths reported were in cardiovascular patients. The multiple regression analysis showed an increased risk of mortality in patients treated with diuretics before transfusion (OR, 2.49; 95% CI, 1.03-6.01), which was also confirmed in the specific mortality, both in univariate (RR, 5.33; 95% CI, 0.89-31.9) and multiple regression (RR, 7.84; 95% CI, 1.2250.6). Two of the five patients whose death was directly attributable to TACO (Cases 3 and 5; Table 4) had received diuretics either before or after transfusion but in Case 5 the dosage was inadequate on both occasions. One patient, Case 4 had received diuretics during transfusion, and Case 1 had received a posttransfusion diuretic. The final patient, Case 2 had received no diuretic at any stage.
TACO associated with errors (2007-2010) Time to detection of TACO Time from transfusion to detection of TACO was assessable in 191 of 221 (86%) cases. It was under 6 hours in 164 of the assessable cases (86%), between 6 and 12 hours in 20 cases (10%), and over 12 hours in seven (4%). 4
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Between 2007 and 2010, a total of 99 TACO reactions were reported and in 19 (19%) of these reports, human error caused or contributed to the reaction. In seven of these cases, more than one human error was reported. These human errors are summarized as follows:
TACO INCIDENCE AND OUTCOME IN IRELAND
TABLE 3. Univariate and multiple regression over overall mortality (A) and directly attributable to TACO (B)* Factor OR A. Overall mortality (n = 31), logistic regression Age > 70 years 0.59 Sex, female 0.76 Diuretic, before 1.99 Diuretic, after 0.53 Cardiovascular 1.37 Respiratory 0.99 Renal 1.33 Cancer/leukemia 2.27 Miscellaneous 2.41 Transfusion other than RBCs 2.10
Univariate regression 95% CI
p value
0.27-1.29 0.35-1.62 0.86-4.60 0.24-1.21 0.53-3.54 0.42-2.38 0.53-3.36 0.95-5.42 0.97-5.98 0.86-5.17
0.189 0.477 0.109 0.134 0.567 0.998 0.535 0.065 0.059 0.107
B. Mortality attributable to TACO (n = 5), Poisson regression Age > 70 years 0.69 0.12-4.16 Sex, female 0.21 0.02-1.88 Diuretic, before 5.33 0.89-31.9 Diuretic, after 0.08 0.01-0.73 Cardiovascular 1.26 0.14-11.3 Respiratory 0.72 0.08-6.43 Renal 1.08 0.12-9.81 Cancer/leukemia 3.21 0.54-19.2 Miscellaneous 1.48 0.16-13.2 Transfusion other than RBC 7.97 1.33-47.7
0.691 0.163 0.067 0.025 0.835 0.768 0.934 0.201 0.727 0.022
Multiple regression 95% CI
OR
p value
2.49
1.03-6.01
0.043
2.78
1.11-6.95
0.029
2.74
1.06-7.12 Pearson GOF: p = 0.277
7.84 0.09
10.5
1.22-50.6 0.05-0.78
0.037
0.030 0.030
1.64-67.6 Pearson GOF: p = 0.990
0.013
* In multiple regression was selected the factors with p < 0.25 from univariate analysis and the final model was obtained by means of likelihood ratio test. GOF = goodness of fit.
TABLE 4. Deaths probably associated with TACO
Year 2007
Case 5
Age (years) Elderly (70+)
Sex Female
Volume transfused (mL) 250
2005
4
Elderly (70+)
Male
NA
S/D plasma
Diuretic B (before), D (during), A (after) B and A but inadequate dosage D
2004
3
63
Male
500
RBCs
B, A
2003
2
83
Male
1600 (8 units over 7 hr)
S/D plasma
None at any stage
2000
1
63
Male
500 over 30-40 min
FFP
A
Component RBCs
Reason for transfusion and/or underlying condition Anemia and CCF Abnormal INR due to liver disease Anemia, cardiomyopathy CA lung INR 11.9 sepsis, cardiac disease malignancy, and renal problems. Already in positive fluid balance of 1800 mL INR 8.8 due to overanticoagulation, cardiac failure on diuretics
CA = cancer; CCF = congestive cardiac failure; INR = international normalized ratio.
•
•
Failure to follow hospital policies regarding transfusion monitoring of vital signs and of fluid balance (17). Communication and coordination of health care, for example, components prescribed and transfused by two doctors resulting in a patient receiving 6 RBC units instead of 3, failure to administer diuretics before transfusion, and failure to cancel prescription for RBCs that were subsequently transfused (5).
•
Knowledge deficits on the part of clinical staff where there was a failure to assess the patient before transfusion or to recognize earlier symptoms of pending overload (5).
All of these human errors involved clinical staff and occurred in clinical areas. Four reports (21%) also reported system failure in conjunction with these human failures. Volume **, ** **
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TABLE 5. The incidence of SAR caused by error (p value, Fisher’s exact test) Denominator SAR TACO
Accepted 511 99
Caused by error 33 19
Percent 6.5 19.2
p value 70 years) is consistent with clinical teaching and is consistent with a small previous TACO study published in abstract form that reported a mean age of 60 years.16 In 50% of patients a single unit was sufficient to precipitate TACO with 10 patients experiencing TACO when less than 100 mL had been transfused, suggesting the presence of circulatory failure before the transfusion began. Transfusion volumes prescribed also need to be adjusted to take account of lower blood volumes not just in children but in low-weight patients particularly the elderly at risk of overload. Information on patient weight was available in only 50% of patients in our series but 14.5% of the patients where weight was recorded weighed less than 50 kg. All but two of these were adults and of these adults, 64% were aged over 70. Clinicians should be aware of the risk of TACO in these patients and ensure that accurate fluid balance and/or body weight are recorded in all critically ill patients before transfusion and prompt diuretics administered, where TACO is suspected. The majority of cases of TACO associated with transfusion of large volumes were also associated with older age and with underlying cardiovascular conditions. However, five cases involved young female patients who had no underlying cardiovascular condition. These five patients were being treated for obstetric-gynecologic bleeding and received large volumes of crystalloid and RBCs. All recovered after a significant diuresis. Although the differential between TRALI and TACO in these cases can be difficult and large fluid overload10,17 has been found in some series of cases classified on clinical findings by experts as TRALI, the possibility of TACO should be considered. Errors associated with TACO are not uncommon and probably underrecognized. Over the 10-year period, 20 patients did not receive diuretics, suggesting that the diagnosis of TACO had been missed. Before 2007, errors associated with TACO had been reported in a number of cases, but since 2007 when data on error associated with TACO was formally collected, 20% of cases of TACO were found to be associated with error, a rate three times higher than with any other SAR (
BACKGROUND: Transfusion-associated circulatory overload (TACO) is an increasingly reported condition but symptoms and signs are still unrecognized. We present a review of the incidence and clinical features of TACO reported to the National Haemovigilance Office at the Irish Blood Transfusion Service. STUDY DESIGN AND METHODS: Between 2000 and 2010, a total of 1071 cases of serious transfusionrelated reactions were reported, of which 221 (21%) cases were TACO. RESULTS: A total of 2,000,684 blood components were issued, with a TACO incidence of one in 9177. The TACO incidence per red blood cells, plasma, and platelet components issued was one in 8000, one in 16,000, and one in 57,884, respectively. The majority of cases (68%, n = 151) were elderly patients, while no sex difference was seen. Twenty-eight (13%) patients experienced severe morbidity; 31 (14%) deaths were reported, of which five (2%) were considered due to TACO and the other deaths considered due to and underlying conditions, which in most cases were cardiovascular (76%). An increased risk of mortality was found in patients on diuretics either before transfusion as part of their routine therapy or given as pretransfusion medication (odds ratio, 2.49; 95% confidence interval, 1.06-6.01). In 19 (21%) cases, TACO reaction was due to human error. CONCLUSIONS: The strong association between TACO and human errors supports the role of hemovigilance and of adequate transfusion medicine teaching for preventing morbidity and mortality associated with TACO.
T
ransfusion-associated circulatory overload (TACO) is increasingly being recognized as an important cause of morbidity and mortality by the UK Serious Hazards of Transfusion scheme1 and is the second most common cause of transfusion-related deaths reported to the Food and Drug Administration;2 however, this condition is often misdiagnosed and underreported.3 TACO is characterized by the development of acute pulmonary edema during or shortly after transfusion and is associated with symptoms and signs of congestive cardiac failure. The pathophysiology of this condition is believed to be caused by increased hydrostatic blood pressure due to volume overload leading to fluid leakage into the alveolar space, emulating congestive cardiac failure.4 The clinical signs and symptoms of TACO include dyspnea, orthopnea associated with tachycardia, hypertension, elevated central venous pressure, and pulmonary and/or sacral or ankle edema.5 Chest X-ray finding shows pulmonary edema and heart size may be normal or
ABBREVIATIONS: IBTS = Irish Blood Transfusion Service; ICU = intensive care unit; NHO = National Haemovigilance Office; RR = relative ratio; SAR(s) = serious transfusion-related reaction(s); TACO = transfusion-associated circulatory overload. From the 1Irish Blood Transfusion Service and 2Trinity College University, Dublin, Ireland; the 3Hematology Department, San Maurizio Regional Hospital, South Tyrol, Italy; and the 4 Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy. Address reprint requests to: Andrea Piccin, MD, PhD, Haematology Department, San Maurizio Regional Hospital, 39100 Bolzano, South Tirol, Italy; e-mail: [email protected]. Received for publication April 3, 2014; revision received October 27, 2014, and accepted October 27, 2014. doi: 10.1111/trf.12965 © 2014 AABB TRANSFUSION **;**:**-**. Volume **, ** **
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enlarged. It may be difficult to differentiate TACO from transfusion-related acute lung injury (TRALI) as hypoxemia and bilateral infiltrates on chest X-ray are features of both and the differentiating factor is evidence of circulatory failure, which may be difficult to ascertain clinically. Thus, TACO cases are often reported as TRALI and the other way around. The National Haemovigilance Office (NHO) at the Irish Blood Transfusion Service (IBTS) has collected reports of respiratory reactions associated with transfusion including both TACO and TRALI since its inception in 1999. We present a review of the incidence, clinical features, and outcomes of 221 TACO cases reported to the NHO from 2000 to 2010. We discuss and compare our findings with the recent literature.
strict time frame posttransfusion within which the reaction had to be diagnosed to be classified as TACO, and the decision to accept the reaction as TACO was based on the clinical picture and patient characteristics. The reaction could include any or all of the following: dyspnea, orthopnea, cyanosis, tachycardia, hypertension, and/or pulmonary and/or pedal edema. Pulmonary edema was diagnosed on the presence of rales on ausculation and/or by appearance on a chest X-ray. All reports accepted and reported as TACO in the annual NHO report between 2000 and 2010 were retrospectively reviewed for inclusion in this article.
TACO associated with error
MATERIALS AND METHODS Serious adverse reaction reporting Reports of serious transfusion-related reactions (SARs) from Irish hospitals are submitted to the NHO by dedicated hemovigilance officers, usually nurses, after review by the consultant hematologist in charge of the hospital blood transfusion laboratory. From 2000 to 2006 reporting to the NHO was on a professional responsibility basis. From November 2006 onward as a result of the EU Directives 2002/98/EC and Commission Directive 2005/61/EC, reporting of reactions became mandatory. Reports of respiratory complications of transfusion such as TACO and TRALI have been accepted by the NHO since its inception in 1999 and reports of transfusion-associated dyspnea have also been accepted since 2007.
Data collection Information collected from the NHO on SAR report forms includes patient demographics such as age and sex, symptomatology and physical signs associated with the reaction, underlying diagnosis, any chronic existing conditions, and the blood product type(s) implicated in the reaction. Data are also collected on investigations, treatment, and patient outcome after the reaction. In the case of suspected TACO or TRALI reactions, the rate of transfused blood products, total volume of blood products transfused, and the use and timing of diuretics are collected. These data are entered by NHO staff on to the NHO database and following review, if accepted, are included in the annual NHO report for that year.
Definition of TACO A reaction was accepted as TACO based on the criteria suggested by Popovsky and colleagues6,7 characterized by the development of signs and symptoms of acute pulmonary edema secondary to congestive cardiac failure during, or within some hours of transfusion. There was no 2
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From 2007, hospital-based hemovigilance officers reporting all SARs were asked to assess if errors contributed to the occurrence of SAR. This not only involved assessment of the development and treatment of the reaction, but also required a detailed review of human and system factors underpinning patient care. Reporters included a short description of reasons underpinning these errors.
Incidence of TACO and statistical analysis The incidence of TACO was calculated on red blood cell (RBC), platelet (PLT), and plasma units issued from the IBTS between 2000 and 2010 obtained from the IBTS (Progesa, Brescia, Italy) transfusion database. Comparative analysis of patient demographic and clinical data was made using Fisher’s exact test (GraphPad PRISM statistical package, GraphPad, San Diego, CA). The association between the overall mortality and the clinical and demographic data was analyzed by means of the logistic regression analysis, either in univariate or in multiple regression. The effect size was expressed as odds ratio (OR). Since the specific mortality related to transfusion follow a Poisson distribution, we analyzed the data using, in univariate and multiple analysis, the Poisson regression. The effect size was expressed as relative ratio (RR). The Pearson chi-square goodness of fit was used as diagnostic test to check the model form of the logistic and Poisson regression models. The confidence intervals (CIs) were set at 95% of probability. It was an observational study and we did not plan a sample size; we considered a p value of less than 0.05 as moderate strength against the null hypothesis. All the statistical tests were two sided. The regression analysis was performed with computer software (Stata 10/SE, StataCorp, College Station, TX).
RESULTS Between 2000 and 2010, a total of 1071 SAR cases were reported to the NHO. A total of 221 (21%) cases were
TACO INCIDENCE AND OUTCOME IN IRELAND
classified as TACO. Twelve of these cases had been initially submitted as TRALI but were reassigned as TACO after investigations and review by the NHO. A total of 186 cases (84%) involved SAGM RBCs, 17 (8%) involved fresh-frozen plasma (FFP) or solvent/detergent (S/D) plasma, five (2%) involved PLTs (four cases of apheresis PLTs, one case of a pooled PLT), and 13 (6%) involved multiple components.
TACO incidence During the study period, a total of 2,000,684 blood components were issued giving a TACO incidence of one in 9177 per component. Excluding 13 TACO reports involving multiple components (Table 1), the TACO incidence per RBCs, plasma, and PLT component issued was one in 8000, one in 16,000, and one in 57,884, respectively, with a total incidence of one in 9665. The incidence of TACO per unit of plasma fell from a peak of one in 4506 in 2001 to one in 23,324 in 2010 giving an overall incidence of one in 16,000 per unit over the period.
Patient demographics Patients of all ages were at risk of developing TACO. While the majority of patients (68%, n = 151) developing TACO were elderly (>70 years), 60 (27%) patients aged between 31 and 69 years developed TACO and 10 (5%) were young patients less than 30 years of age, with two of these patients less than 4 years of age. There was no significant difference in sex (male, 101; female, 120; p = 0.201).
TABLE 1. Incidence of TACO per component 2000 to 2010 Component issues 1,486,041 272,105 231,538 2,000,684
Component RBCs Plasma PLTs Total
TACO cases 186 17 5 208
1 1 1 1
Incidence per 8,000 per 16,000 per 46,300 in 9,665
Existing condition A total of 215 patients (97%) had reported existing conditions predominantly cardiovascular, respiratory, or renal conditions. These data are presented in Table 2. Patients often presented with one or more underlying existing condition. A total of 168 had underlying cardiovascular disease, and 162 of these patients had an additional underlying condition. Only six patients had no reported existing cardiovascular disease or other condition.
Transfusion volume The median transfused volume was 250 mL (range, 60-9500 mL). A total of 110 (50%) TACO reports followed a single unit of blood component, 106 involving RBCs and four involving PLTs, and in 10 cases, all involving RBCs, not more than 100 mL was transfused before the onset of TACO. Eighty-one cases (74%) of these single-unit transfusions involved elderly patients over 70 years of age and two children under 4 years of age. Weight ranges were reported for only 110 of 221 (50%) patients. An additional three were reported as being of low weight, but no details were given. Thirtyseven (34%) patients had weights reported of less than 60 kg and 16 (14.5%) had weights below 50 kg. Twentyone patients weighed between 50 and 60 kg, 10 weighed between 40 and 50 kg, and six patients weighed less than 40 kg. The 21 patients with weights between 50 and 60 kg were all adults of whom 14 (66%) were aged over 70 years. The 10 patients with weights between 40 and 50 kg were all adults, of whom five (50%) were over 70 years. The median volume transfused in both these groups was 500 mL. The six patients with weights below 40 kg received between 250 and 500 mL, each with a median of 350 mL. Two of these six were children aged under 4 years and were reported as receiving a full unit of RBCs and PLTs each. The other four patients were aged over 70 years.
TABLE 2. Existing conditions predominantly cardiovascular, respiratory, or renal conditions* Existing condition Cardiovascular Respiratory Renal Malignancy Anemia Hemorrhage Surgical Miscellaneous None Total
Examples Ischemic heart disease, congestive heart failure, myocardial infarction, valve incompetence, atrial fibrillation, hypertension Chronic obstructive airways disease, respiratory infection, pleural effusion, asthma Renal impairment, renal failure Both solid tumor and leukemia • Existing condition associated with other existing conditions (29) • Stand-alone anemia (9) Postoperative (3), other (8) Abdominal surgery, mastectomy, above-knee amputation Diabetes, sepsis, gastritis, hepatic dysfunction No reported underlying history
Number 168
Percentage of patients 76
57 41 38 38
26 19 17 17
11 5 24 6 221
5 2 11 3
* Some patients had more than one underlying comorbidity.
Volume **, ** **
TRANSFUSION
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Large-volume transfusions
Outcome
However, 10% (22) of cases involved large-volume transfusion with a median of 1500 mL (range, 1000-9500 mL). While only one of these transfusions met the clinical definition of a massive transfusion (150 mL/min), patients in this cohort received between 200 and up to 2375 mL per hour. Three patients received between 1800 and 4300 mL urgently, with no time specified. Six patients (27%) were more than 70 years of age, and nine patients (41%) had associated underlying cardiovascular conditions. Five patients (23%) developed minor sequelae, and three patients (14%) required admission to intensive care unit (ICU) as a result of development of TACO. Three patients who received large-volume transfusions died and one of these deaths was possibly attributed to TACO. Five (23%) cases involved young female patients (age ≤ 30 years) without any underlying cardiovascular condition, who developed massive bleeding associated with delivery. Although one patient had a history of asthma, she did not take regular medication. These patients were being transfused for obstetric or gynecologic bleeding, and also received large volumes of crystalloids and colloids. All five patients recovered although two patients were admitted to the ICU.
Patient outcome was reported in 220 cases. A total of 161 (73%) patients recovered after TACO. Twenty-eight (13%) patients experienced severe morbidity ranging from prolonged resolution of symptoms, admission to hospital, transfer to ICU, and cancellation of surgery and two patients developed myocardial infarction. Thirty-one (14%) deaths were reported. Twenty-three deaths involved RBC transfusion, four patients died after FFP and S/D plasma transfusion, and four patients died after transfusion of multiple components. In multiple regressions analysis the risk of death was increased with transfusion other than RBCs (OR, 2.74; 95% CI, 1.06-7.12; p = 0.037; Table 3). Only five deaths, however, were considered probably attributable to TACO (Table 4). Three of these involved plasma (Cases 1, 2, and 4) and two (Cases 3 and 5) involved RBCs. The TACO-specific relative risk of death was increased with transfusion other than RBCs when compared to transfusion of RBCs only (RR, 7.97; 95% CI 1.33-47.7) and was confirmed in multiple regression analysis. The possibility of TRALI was considered and outruled in these cases involving plasma. Two of the three fatalities were associated with the transfusion of plasma to reverse warfarin overdosage, one (Case 1) involving large volumes of plasma and the second (Case 2) involving plasma given over a short period of time.
Transfusion rate Information on the prescribed rate for a single type of blood product (RBCs only, plasma only, PLTs only) was available in 166 (75%) reports. Of these 146 (87%) involved RBCs, 15 (10%) involved plasma, and five (3%) involved PLTs. RBC units were prescribed over greater than 4 hours per unit in 43 cases (29%), over 3 to 4 hours in 87 cases (59%), and less than 3 hours in 16 cases (11%), with a median of 3 to 4 hours. Plasma (15) or PLT transfusions (5) were prescribed over 15 to 30 minutes per unit in five cases (25%), over 30 to 60 minutes in 10 cases (50%), between 90 and 120 minutes in three cases (20%), and over 2 hours in two cases (10%) with a median of 30 to 60 minutes. Information on the actual rate of transfusion was available in 156 (70%) of these reports. Transfusions were administered at a faster rate than prescribed in 35 (25%) of the 140 assessable RBC transfusions and in one (8%) of 12 plasma transfusions. However, faster rate and mortality were not shown to have a significant correlation (p = 0.559).
Effect of diuretic treatment on outcome A total of 199 (90%) patients received diuretics before, during, or after transfusion as follows: before (n = 43), during (n = 34), or after transfusion (n = 162). Twenty patients (9%) did not receive diuretics. Information on use was not available in two cases. Twenty-five of the 31 deaths reported were in cardiovascular patients. The multiple regression analysis showed an increased risk of mortality in patients treated with diuretics before transfusion (OR, 2.49; 95% CI, 1.03-6.01), which was also confirmed in the specific mortality, both in univariate (RR, 5.33; 95% CI, 0.89-31.9) and multiple regression (RR, 7.84; 95% CI, 1.2250.6). Two of the five patients whose death was directly attributable to TACO (Cases 3 and 5; Table 4) had received diuretics either before or after transfusion but in Case 5 the dosage was inadequate on both occasions. One patient, Case 4 had received diuretics during transfusion, and Case 1 had received a posttransfusion diuretic. The final patient, Case 2 had received no diuretic at any stage.
TACO associated with errors (2007-2010) Time to detection of TACO Time from transfusion to detection of TACO was assessable in 191 of 221 (86%) cases. It was under 6 hours in 164 of the assessable cases (86%), between 6 and 12 hours in 20 cases (10%), and over 12 hours in seven (4%). 4
TRANSFUSION Volume **, ** **
Between 2007 and 2010, a total of 99 TACO reactions were reported and in 19 (19%) of these reports, human error caused or contributed to the reaction. In seven of these cases, more than one human error was reported. These human errors are summarized as follows:
TACO INCIDENCE AND OUTCOME IN IRELAND
TABLE 3. Univariate and multiple regression over overall mortality (A) and directly attributable to TACO (B)* Factor OR A. Overall mortality (n = 31), logistic regression Age > 70 years 0.59 Sex, female 0.76 Diuretic, before 1.99 Diuretic, after 0.53 Cardiovascular 1.37 Respiratory 0.99 Renal 1.33 Cancer/leukemia 2.27 Miscellaneous 2.41 Transfusion other than RBCs 2.10
Univariate regression 95% CI
p value
0.27-1.29 0.35-1.62 0.86-4.60 0.24-1.21 0.53-3.54 0.42-2.38 0.53-3.36 0.95-5.42 0.97-5.98 0.86-5.17
0.189 0.477 0.109 0.134 0.567 0.998 0.535 0.065 0.059 0.107
B. Mortality attributable to TACO (n = 5), Poisson regression Age > 70 years 0.69 0.12-4.16 Sex, female 0.21 0.02-1.88 Diuretic, before 5.33 0.89-31.9 Diuretic, after 0.08 0.01-0.73 Cardiovascular 1.26 0.14-11.3 Respiratory 0.72 0.08-6.43 Renal 1.08 0.12-9.81 Cancer/leukemia 3.21 0.54-19.2 Miscellaneous 1.48 0.16-13.2 Transfusion other than RBC 7.97 1.33-47.7
0.691 0.163 0.067 0.025 0.835 0.768 0.934 0.201 0.727 0.022
Multiple regression 95% CI
OR
p value
2.49
1.03-6.01
0.043
2.78
1.11-6.95
0.029
2.74
1.06-7.12 Pearson GOF: p = 0.277
7.84 0.09
10.5
1.22-50.6 0.05-0.78
0.037
0.030 0.030
1.64-67.6 Pearson GOF: p = 0.990
0.013
* In multiple regression was selected the factors with p < 0.25 from univariate analysis and the final model was obtained by means of likelihood ratio test. GOF = goodness of fit.
TABLE 4. Deaths probably associated with TACO
Year 2007
Case 5
Age (years) Elderly (70+)
Sex Female
Volume transfused (mL) 250
2005
4
Elderly (70+)
Male
NA
S/D plasma
Diuretic B (before), D (during), A (after) B and A but inadequate dosage D
2004
3
63
Male
500
RBCs
B, A
2003
2
83
Male
1600 (8 units over 7 hr)
S/D plasma
None at any stage
2000
1
63
Male
500 over 30-40 min
FFP
A
Component RBCs
Reason for transfusion and/or underlying condition Anemia and CCF Abnormal INR due to liver disease Anemia, cardiomyopathy CA lung INR 11.9 sepsis, cardiac disease malignancy, and renal problems. Already in positive fluid balance of 1800 mL INR 8.8 due to overanticoagulation, cardiac failure on diuretics
CA = cancer; CCF = congestive cardiac failure; INR = international normalized ratio.
•
•
Failure to follow hospital policies regarding transfusion monitoring of vital signs and of fluid balance (17). Communication and coordination of health care, for example, components prescribed and transfused by two doctors resulting in a patient receiving 6 RBC units instead of 3, failure to administer diuretics before transfusion, and failure to cancel prescription for RBCs that were subsequently transfused (5).
•
Knowledge deficits on the part of clinical staff where there was a failure to assess the patient before transfusion or to recognize earlier symptoms of pending overload (5).
All of these human errors involved clinical staff and occurred in clinical areas. Four reports (21%) also reported system failure in conjunction with these human failures. Volume **, ** **
TRANSFUSION
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TABLE 5. The incidence of SAR caused by error (p value, Fisher’s exact test) Denominator SAR TACO
Accepted 511 99
Caused by error 33 19
Percent 6.5 19.2
p value 70 years) is consistent with clinical teaching and is consistent with a small previous TACO study published in abstract form that reported a mean age of 60 years.16 In 50% of patients a single unit was sufficient to precipitate TACO with 10 patients experiencing TACO when less than 100 mL had been transfused, suggesting the presence of circulatory failure before the transfusion began. Transfusion volumes prescribed also need to be adjusted to take account of lower blood volumes not just in children but in low-weight patients particularly the elderly at risk of overload. Information on patient weight was available in only 50% of patients in our series but 14.5% of the patients where weight was recorded weighed less than 50 kg. All but two of these were adults and of these adults, 64% were aged over 70. Clinicians should be aware of the risk of TACO in these patients and ensure that accurate fluid balance and/or body weight are recorded in all critically ill patients before transfusion and prompt diuretics administered, where TACO is suspected. The majority of cases of TACO associated with transfusion of large volumes were also associated with older age and with underlying cardiovascular conditions. However, five cases involved young female patients who had no underlying cardiovascular condition. These five patients were being treated for obstetric-gynecologic bleeding and received large volumes of crystalloid and RBCs. All recovered after a significant diuresis. Although the differential between TRALI and TACO in these cases can be difficult and large fluid overload10,17 has been found in some series of cases classified on clinical findings by experts as TRALI, the possibility of TACO should be considered. Errors associated with TACO are not uncommon and probably underrecognized. Over the 10-year period, 20 patients did not receive diuretics, suggesting that the diagnosis of TACO had been missed. Before 2007, errors associated with TACO had been reported in a number of cases, but since 2007 when data on error associated with TACO was formally collected, 20% of cases of TACO were found to be associated with error, a rate three times higher than with any other SAR (
