Journal of Critical Care 30 (2015) 55–59
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Incidence, risk factors, and outcome of transfusion-related acute lung injury in critically ill children: A retrospective study☆ Hilde D. Mulder, MD a,1, Quinten J.J. Augustijn, MSc a,1, Job B. van Woensel, MD, PhD a, Albert P. Bos, MD, PhD a, Nicole P. Juffermans, MD, PhD b, Roelie M. Wösten-van Asperen, MD, PhD a,⁎ a b
Department of Pediatric Intensive Care, Emma Children's Hospital/Academic Medical Centre, Amsterdam, the Netherlands Department of Intensive Care, Academic Medical Centre, Amsterdam, the Netherlands
a r t i c l e
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Keywords: Transfusions Lung injury Pediatric Intensive care Blood products Critically ill
a b s t r a c t Purpose: Acute lung injury (ALI) that develops within 6 hours after transfusion (TRALI) is the leading cause of transfusion-related morbidity and mortality. Both incidence and patient and transfusion-related risk factors are well studied in the adult critically ill patient population. Clinical data on TRALI in the pediatric population are sparse and are mainly limited to case reports and hemovigilance reporting systems. The objective of this study was to determine incidence, risk factors, and outcome of TRALI in critically ill children. Materials and Methods: In a retrospective cohort study, all first-time admissions to the pediatric intensive care unit from January 1, 2009, until December 31, 2012, were screened for onset of TRALI using the consensus criteria. Results: Of 2294 admitted patients, 304 were transfused, of whom 21 (6.9%) developed TRALI. Compared with transfused control subjects, risk factors for TRALI were mechanical ventilation (odds ratio, 18.94 [2.382452.56]), sepsis (odds ratio, 7.20 [2.69-19.69]), and high Pediatric Risk of Mortality III score (odds ratio, 1.05 [1.01-1.10]). Patients with TRALI had a higher mortality and a longer duration of mechanical ventilation when compared with transfused control subjects. Conclusions: Transfusion-related ALI is relatively common in critically ill children. The incidence in the pediatric intensive care unit population is similar to that in adult intensive care unit patients. High PRISM score on admission, mechanical ventilation and sepsis were identified as independent risk factors, which may help to assess the risks and benefits of transfusion in critically ill patients. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Transfusion-related acute lung injury (TRALI) is a serious complication associated with increased morbidity and mortality after the transfusion of blood products [1–4]. The estimated incidence of TRALI amongst adults varies between 0.08% and 15% per transfused patient [5]. This wide variation can be explained by the fact that TRALI is often underrecognized and underreported, due to a previous lack of a uniform definition of TRALI and by differences in study design. According to the international definition, acknowledged by the American-European Consensus Conference in 2004, TRALI is defined as acute lung injury (ALI) developing during or within 6 hours of transfusion, with a PaO2/ FIO2 ratio of 300 mm Hg or less or worsening of PaO2/FIO2 ratio, bilateral chest infiltrates in the absence of cardiogenic pulmonary edema, and no other risk factor for ALI present [1,6,7]. This distinct clinical syndrome is characterized as classical or suspected TRALI. Possible TRALI is defined as ALI developing during or within 6 hours of ☆ The authors have disclosed no potential conflicts of interest. ⁎ Corresponding author at: Department of Pediatric Intensive Care, Emma Children's Hospital/Academic Medical Centre, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands. Tel.: +31 20 5665769. E-mail address: [email protected] (R.M. Wösten-van Asperen). 1 These authors contributed equally to this study. http://dx.doi.org/10.1016/j.jcrc.2014.10.005 0883-9441/© 2014 Elsevier Inc. All rights reserved.
transfusion, and there is a clear temporal relationship to an alternative risk factor for ALI (eg, sepsis, pneumonia, and lung contusion) [1,6,7]. As with ALI/acute respiratory distress syndrome (ARDS), there is no specific treatment of TRALI besides supportive care measures and a restrictive transfusion policy. Studies on TRALI in the pediatric population are mostly limited to case reports. A recent survey of the Canadian Blood Services showed an incident rate of reported TRALI cases of 5.58 in children and 3.75 in adults per 100 000 red blood cell (RBC) transfusions, suggesting a similar incidence of TRALI in children and adults [8]. However, data on the incidence of TRALI in critically ill children are still lacking. The main objective of this study was to determine the incidence, risk factors, and outcome of TRALI in critically ill children. We performed a retrospective cohort study on our pediatric intensive care unit (PICU) using the consensus TRALI definition.
2. Materials and methods 2.1. Setting The study was performed on a 16-bed, tertiary, mixed medicalsurgical PICU within a university hospital in the Netherlands. The PICU
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H.D. Mulder et al. / Journal of Critical Care 30 (2015) 55–59
is a closed unit in which patients are under the direct specialist care of the PICU team consisting of intensivists, subspecialty fellows, and residents. 2.2. Study design The study was approved by the Ethics Committee of our hospital, and the criteria for informed consent were waived as a result of its retrospective nature. Using an electronic patient data monitoring system, all patients admitted to our PICU from January 1, 2009, until December 31, 2012 who received 1 or multiple blood products were screened for TRALI in accordance with the consensus TRALI definition (Figure). Patients who were readmitted and cases with insufficient data were excluded. No other exclusion criteria were applied. Control subjects were transfused patients not developing TRALI. Suspected TRALI was defined as new-onset of hypoxia or deterioration defined as PaO2/FIO2 ratio less than 300 mm Hg (or SpO2/FIO2 ratio b 250 when SpO2 b 97% if no arterial catheter was present), within 6 hours of transfusion with bilateral pulmonary infiltrates on the chest radiographs in the absence of cardiogenic pulmonary edema [1,6,7]. Cardiogenic pulmonary edema was assessed either clinically or by echocardiogram. An echocardiogram was performed at the discretion of the intensive care team. All echocardiograms were interpreted by attending cardiologists on staff. Patients judged to have moderate to severe left ventricular dysfunction and/or left atrial hypertension were excluded from this study. Possible TRALI was defined as the occurrence of TRALI in patients with other risk factors for ALI. Chest radiographs were scored for the presence of new-onset bilateral interstitial abnormalities by 2 independent physicians who were blinded to patient data. When interpretation differed, chest radiograph and screening for onset of TRALI were reviewed by a third independent physician to reach consensus.
2.3. Patient data collection The Pediatric Risk of Mortality (PRISM) III score was calculated for each patient according to the published algorithms [9]. Clinical and laboratory data for the PRISM III score were collected within the first 24 hours after PICU admission. The following data were retrospectively collected in a Microsoft Access database, Redmond, WA, USA from patient clinical files or from our patient data management system: standard demographic data, comorbidities, laboratory test results, medication, mechanical ventilator settings, duration of mechanical ventilation, and length of PICU stay. Potential risk factors were scored as positive when present 48 hours before onset of TRALI. Factors included were based on TRALI risk factors in the adult population as well as risk factors for ALI in the pediatric population [10–12]. These factors included liver failure, diabetes, elective and emergency (cardiac) surgery, hematologic malignancy, mechanical ventilation, sepsis, aspiration, pneumonia, trauma, disseminated intravascular coagulation, immune compromised condition, and near drowning. Prior to the onset of TRALI, the following data were collected: body temperature, platelet count, and leukocyte count. Tidal volume was retrieved from the electronic patient data monitoring system. Mean tidal volume per kilogram body weight was calculated using data from the 6-hour period preceding transfusion. Fluid balance was determined 24 hours prior to onset of TRALI. All previously mentioned data were also collected for the control group, with the first transfusion used as a reference time point. 2.4. Transfusion data collection Transfusion was defined as infusion of filtered RBCs, fresh-frozen plasma (FFP), or platelets. A restrictive transfusion policy was pursued
Figure. Flowchart outlining the inclusion of patients in this cohort study.
H.D. Mulder et al. / Journal of Critical Care 30 (2015) 55–59
according to international guidelines [13,14]. Routinely, the volume per transfusion was 10 to 15 mL/kg. Transfused RBCs were leukocyte depleted. The platelet concentrates were pooled products using 5 donor buffy coats, with 1 of the 5 donors to provide the plasma fraction. Since June 1st 2007, exclusion of female donors for FFP became effective in the Netherlands.
2.5. Statistics Continuous normally distributed variables were expressed as mean and SD, and nonnormally distributed variables as medians and interquartile ranges. Categorical variables were expressed as n (%). To test groups of continuous variables, Student t test or Mann-Whitney U test were used, depending on their distribution. Differences between distributions of categorical variables were analyzed by χ 2 test or Fisher exact test, when appropriate. Univariate analyses examined the effect of patient clinical characteristics on outcome (TRALI or no TRALI). Thereafter, multiple logistic regression analysis was applied to the outcomes. Factors achieving P ≤ .1 in our univariate analyses were entered into the model predicting the risk for the onset of TRALI. Statistical significance was defined as P ≤ .05. Analyses were performed using SPSS 20.0 software (SPSS, Chicago, Ill) and R 2.15.0 (R Foundation, Vienna, Austria).
3. Results During the screening period, 2294 patients were admitted to our PICU. Of these admissions, 1964 children were not transfused and 26 patients were excluded due to readmission or missing data, leaving 304 patients for inclusion in the study (Figure). Twenty-one patients conformed to the diagnostic criteria for TRALI (6.9%). Of these, 19 (90%) patients had a risk factor for ALI prior to transfusion and were diagnosed as possible TRALI. Of these patients, 7 had sepsis, 5 had pneumonia, 3 had traumatic injuries, 1 had inhalation trauma, 1 had aspiration, 1 had a oncological disorder, and 1 had near drowning. The mean time interval between initiation of transfusion and onset of symptoms was 118 minutes. Two patients presented with symptoms within 30 minutes after commencement of transfusion. The incidence of TRALI cases in the screened cohort was 0.9% (21/2294). The interobserver agreement for the diagnosis of TRALI was good (weighed κ = 0.76). In total, 1367 blood products were transfused; these consisted of 631 RBCs, 308 FFPs, and 428 platelet transfusions. The incidence of TRALI per product transfused was 1.5 % (21/1367). None of the patients diagnosed as having TRALI were reported to the blood bank by the treating physician.
3.1. Risk factors for the development of TRALI Table 1 summarizes the differences in demographic characteristics and clinical variables between patients developing TRALI and transfused control subjects. Patients developing TRALI had a higher PRISM III score, a higher incidence of sepsis, and disseminated intravascular coagulation and were mechanically ventilated more frequently in comparison with transfused controls. In addition, patients developing TRALI had a lower mean platelet count and a more positive fluid balance prior to transfusion. Neither the amount of RBC, nor the amount of FFP or platelet transfusions in the TRALI group differed from those in the transfused control group (Table 2). A multivariate logistic regression model was used to identify independent risk factors for the development of TRALI. Factors predictive of the development of TRALI in the univariate analyses were tested in the multivariate model and are reported in Table 3. Significant predictors for the development of TRALI were high PRISM III score upon admission, sepsis, and requirement for mechanical ventilation.
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Table 1 Demographic data, clinical data, and TRALI risk factors of patients developing TRALI compared with transfused control subjects
Demographic characteristics Age (y), mean (SD) Male sex, n (%) Weight (kg), mean (SD) PICU admission category, n (%) Medicine Respiratory Cardiovascular Neurology Surgery Neurosurgery Cardiac surgery PRISM III score, mean (SD) Liver failure, n (%) Diabetes, n (%) Cardiac surgery, n (%) Hematologic malignancy, n (%) Mechanical ventilation, n (%) Sepsis, n (%) Aspiration, n (%) Surgery, n (%) Trauma, n (%) Pneumonia, n (%) DIC, n (%) Immune compromised, n (%) Near drowning, n (%) Vt/kg BW, mean (SD) Temperature (°C), mean (SD) Platelet count (109/L), median (IQR) Leuco count (109/L), median (IQR) Fluid balance, L/24 h, median (IQR) Outcomes PICU mortality, n (%) PICU length of stay (h), median (IQR) Ventilation time (h), median (IQR)
TRALI (n = 21)
No TRALI (n = 283)
4.6 (5.2) 13 (61.9) 19.5 (19.7)
5.0 (5.8) 172 (60.8) 20.6 (20.1)
17 (81.0) 1 (4.8) 1 (4.8) 0 2 (9.5) 0 0 22.4 (13.2) 2 (9.5) 0 0 3 (14.3) 21 (100.0) 11 (52.4) 2 (9.5) 5 (23.8) 3 (14.3) 4 (19.0) 7 (33.3) 5 (23.8) 1 (4.8) 7.7 (2.6) 37.2 (1.6) 78 (44-213)
106 (37.5) 41 (14.5) 11 (3.9) 16 (5.7) 83 (29.3) 20 (7.1) 6 (2.1) 12.8 (9.2) 8 (2.8) 1 (0.4) 6 (2.1) 21 (7.4) 179 (63.3) 35 (12.4) 6 (2.1) 120 (42.4) 22 (7.8) 31 (11.0) 21 (7.4) 28 (9.9) 1 (0.4) 7.5 (1.5) 37.2 (1.2) 204 (107-311)
b.0001 .33 .58 .99 .07 .38 .99 b.0001 .15 .33 .99 .22 b.0001 b.0001 .10 .10 .40 .28 b.0001 .06 .13 .51 .94 .002
9.9 (6.0-15.5) 0.4 (0.1-0.8)
.08 .001
5.3 (3.3-17.3) 1.0 (0.4-2.0)
P
.79 .91 .80
16 (76.2) 227 (88-354)
32 (11.3) 101 (43-231)
b.0001 .07
183 (52-282)
25 (0-139)
.002
DIC indicates disseminated intravascular coagulation; Vt/kg BW, tidal volume per kilogram bodyweight; IQR, interquartile range.
3.2. Outcome The overall PICU mortality of the patients who were transfused was 16%. Patients who developed TRALI had a significantly higher PICU mortality than did the transfused control subjects (76.2% vs 11.3%, P b .001), and necessitated a longer period of mechanical ventilation (183 [52282] hours vs 25 [0-139] hours, P b .002). There was no significant difference between the 2 groups in PICU length of stay. Most patients (75%) who died had multiorgan system failure. Six percent had a “do not resuscitate” or “no escalation of care” order instituted preceding their death, 7% were declared as brain dead, and in 13%, the treatment was considered medically futile and support was withdrawn. We performed a multivariate logistic regression analysis to adjust for PRISM III score (in which the PaO2/FIO2 is embedded) and presence of dis-
Table 2 Transfusion characteristics of patients developing TRALI compared with transfused control subject
RBC (units) FFP (units) Platelets (units) Data are mean ± SD.
TRALI (n = 21)
No TRALI (n = 287)
P
0.8 ± 0.7 0.5 ± 0.6 0.3 ± 0.5
1.3 ± 3.5 0.5 ± 1.6 0.5 ± 6.0
.54 .85 .90
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Table 3 Multivariate analysis of patient-related risk factors for the onset of TRALI Variable
P
Odds ratio
95% Confidence interval
PRIMS III score Mechanical ventilation Sepsis Fluid balance
.02 .002 b.001 .18
1.05 18.94 7.20 1.00
1.01-1.10 2.38-2452.56 2.69-19.69 0.99-1.00
seminated intravascular coagulation, which are known to be strong independent predictors of patient mortality [12]. The analysis indicated that the development of TRALI was independently associated with increased mortality (odds ratio, 17.2 [5.3-56.0], P b .0001; Table 4).
4. Discussion To the best of our knowledge, this is the first study describing incidence and risk factors of TRALI in critically ill children. The present study demonstrated that TRALI is relatively common in critically ill children, affecting 6.9% of the transfused children in our population. Most of these patients (90%) had a preexistent risk factor for ALI prior to the onset of TRALI and were thus diagnosed as possible TRALI. High PRISM III score, sepsis, and mechanical ventilation were identified as independent risk factors for the development of TRALI. The incidence found in the present study is higher compared with previous incidence reports on TRALI in the pediatric population [4,8,15–17]. This may partly be explained by the study design. Most earlier reports are overviews following passive reporting via a National Hemovigilance System. In contrast, we actively searched for patients with TRALI. A second explanation for the higher incidence of TRALI found in our study population may be due to differences in population. The high TRALI incidence in critically ill children in our study compared with the general population may be explained by the “2-hit” hypothesis [18]. The “first hit” being the underlying inflammatory condition that leads to adherence of primed neutrophils to the pulmonary endothelial cells. The second hit is the transfusion itself, resulting from either transfused antibodies or other inflammatory mediators that accumulate during storage of cell-containing blood products. This second hit results in activation of the primed neutrophils and subsequently in tissue damage and capillary leakage. In concordance with this 2-hit hypothesis, a so-called TRALI threshold model has been proposed [19]. According to this model, the onset of TRALI depends on the interaction between the severity of the underlying disease and the quantity of antibodies or inflammatory mediators in the transfused component. Because of the presence of a proinflammatory state in most of the critically ill patients, these patients are thought to be particularly prone to developing TRALI. Measuring the presence of donor antibodies directed against recipient human leukocyte antigen class I or II, granulocyte-specific antibodies, levels of proinflammatory cytokines, or neutrophil-priming activity in plasma of TRALI patients might give more insight into the molecular mechanisms playing a central role in the development of TRALI [20,21]. To date, only one study of acute transfusion reactions in the PICU reported the incidence of TRALI [22]. Their reported incidence was 0.04 % per product transfused, which is lower than the incidence
Table 4 Multivariate analysis of risk factors for mortality Variable
P
Odds ratio
TRALI PRISM III score Disseminated intravascular coagulation
b.0001 17.25 b.0001 1.10 .15 2.18
95% Confidence interval 5.32-55.97 1.06-1.15 0.76-6.25
we found. However, limited detailed information on demographic and clinical data was provided, making it difficult to compare the studies. There are striking differences between children and adults in incidence and outcome of ALI/ARDS, possibly due to the on pathophysiological differences in the development of these conditions [12,23,24]. Of interest is that the incidence of TRALI found in this study is similar to that found in adult intensive care unit populations [10]. Given that the presence of other ALI risk factors is less common in the pediatric population than in adults, this finding was unexpected. A possible explanation may be related to specific pathophysiological mechanisms of TRALI with a common response to the presence of antibodies or other bioactive substances in blood products. Unfortunately, because of the retrospective study design, we were unable to measure these antibodies or other inflammatory mediators. In the present study, given the large odds ratio, mechanical ventilation appears to be a prerequisite for the development of TRALI. In adults, mechanical ventilation is also a risk factor [10]. The increased risk was found to be associated with tidal volume, suggesting synergy between mechanical ventilation and transfusion in the development of lung injury. Indeed, unequivocal evidence suggests that mechanical ventilation has the potential to aggravate and precipitate lung injury [25]. However, whether children are more susceptible to the harmful effects of mechanical ventilation (and that as such mechanical ventilation may more easily serve as a first hit), is a subject of much controversy [26–28]. Sepsis also proved to be a risk factor in this study, which is in line with the 2-hit hypothesis. Sepsis is typically characterized by a proinflammatory state. Pulmonary neutrophils may be primed via an endovascular-mediated proinflammatory host response thereby serving as a first hit in the development of TRALI. No association was found to suggest that the volume of transfused blood products (RBCs, FFPs, or platelets) has an effect on the development of TRALI. In accordance with this, patient-related risk factors were also more important than transfusion-related risk factors in the adult population [10]. Interestingly, TRALI was associated with high mortality and a longer period of mechanical ventilation, even after correcting for severity of illness. It has already been shown that there is an association between blood product transfusions and worse outcomes in pediatric patients with ALI/ARDS [29–31]. Church et al [29] reported mortality rates of 40% to 70% in patients who received platelets and/or FFP transfusions. Some of these patients may have had TRALI. However, caution is advised in drawing firm conclusions concerning the association of TRALI with mortality. Most of the TRALI patients in the present study had a risk factor for ALI prior to transfusion and were thus diagnosed as having possible TRALI. A prospective nested case-control study also including patients with ALI without transfusions is needed to determine whether risk factors for ALI may actually contribute more to adverse outcome than merely the transfusion of blood products. Nevertheless, a restrictive transfusion policy is still strongly advised. There are some limitations of our study. First, the absence of an arterial catheter in some of our non-TRALI patients, precluding calculation of the PaO2/FIO2 ratio, may be a potential limitation. However, it has earlier been demonstrated that there is a strong correlation between the SpO2/FIO2 ratio and the PaO2/FIO2 ratio [32–34]. Second, the retrospective analysis of data could have influenced the availability of the data collected. Nevertheless, only 10 patients had to be excluded as a result of missing data. Finally, our study was a single-center study, which may limit the generalization of our results. In conclusion, this study shows that TRALI in pediatric critically ill patients is as common as in the adult critically ill patient population. Risk factors are a high PRISM III score on admission, sepsis, and mechanical ventilation. The recognition of these factors may assist in the riskbenefit assessment and consequent decision whether or not to transfuse. Transfusion-related ALI is independently associated with a worse outcome, emphasizing the need for more rigorous prospective studies in these patients.
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Incidence, risk factors, and outcome of transfusion-related acute lung injury in critically ill children: A retrospective study☆ Hilde D. Mulder, MD a,1, Quinten J.J. Augustijn, MSc a,1, Job B. van Woensel, MD, PhD a, Albert P. Bos, MD, PhD a, Nicole P. Juffermans, MD, PhD b, Roelie M. Wösten-van Asperen, MD, PhD a,⁎ a b
Department of Pediatric Intensive Care, Emma Children's Hospital/Academic Medical Centre, Amsterdam, the Netherlands Department of Intensive Care, Academic Medical Centre, Amsterdam, the Netherlands
a r t i c l e
i n f o
Keywords: Transfusions Lung injury Pediatric Intensive care Blood products Critically ill
a b s t r a c t Purpose: Acute lung injury (ALI) that develops within 6 hours after transfusion (TRALI) is the leading cause of transfusion-related morbidity and mortality. Both incidence and patient and transfusion-related risk factors are well studied in the adult critically ill patient population. Clinical data on TRALI in the pediatric population are sparse and are mainly limited to case reports and hemovigilance reporting systems. The objective of this study was to determine incidence, risk factors, and outcome of TRALI in critically ill children. Materials and Methods: In a retrospective cohort study, all first-time admissions to the pediatric intensive care unit from January 1, 2009, until December 31, 2012, were screened for onset of TRALI using the consensus criteria. Results: Of 2294 admitted patients, 304 were transfused, of whom 21 (6.9%) developed TRALI. Compared with transfused control subjects, risk factors for TRALI were mechanical ventilation (odds ratio, 18.94 [2.382452.56]), sepsis (odds ratio, 7.20 [2.69-19.69]), and high Pediatric Risk of Mortality III score (odds ratio, 1.05 [1.01-1.10]). Patients with TRALI had a higher mortality and a longer duration of mechanical ventilation when compared with transfused control subjects. Conclusions: Transfusion-related ALI is relatively common in critically ill children. The incidence in the pediatric intensive care unit population is similar to that in adult intensive care unit patients. High PRISM score on admission, mechanical ventilation and sepsis were identified as independent risk factors, which may help to assess the risks and benefits of transfusion in critically ill patients. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Transfusion-related acute lung injury (TRALI) is a serious complication associated with increased morbidity and mortality after the transfusion of blood products [1–4]. The estimated incidence of TRALI amongst adults varies between 0.08% and 15% per transfused patient [5]. This wide variation can be explained by the fact that TRALI is often underrecognized and underreported, due to a previous lack of a uniform definition of TRALI and by differences in study design. According to the international definition, acknowledged by the American-European Consensus Conference in 2004, TRALI is defined as acute lung injury (ALI) developing during or within 6 hours of transfusion, with a PaO2/ FIO2 ratio of 300 mm Hg or less or worsening of PaO2/FIO2 ratio, bilateral chest infiltrates in the absence of cardiogenic pulmonary edema, and no other risk factor for ALI present [1,6,7]. This distinct clinical syndrome is characterized as classical or suspected TRALI. Possible TRALI is defined as ALI developing during or within 6 hours of ☆ The authors have disclosed no potential conflicts of interest. ⁎ Corresponding author at: Department of Pediatric Intensive Care, Emma Children's Hospital/Academic Medical Centre, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands. Tel.: +31 20 5665769. E-mail address: [email protected] (R.M. Wösten-van Asperen). 1 These authors contributed equally to this study. http://dx.doi.org/10.1016/j.jcrc.2014.10.005 0883-9441/© 2014 Elsevier Inc. All rights reserved.
transfusion, and there is a clear temporal relationship to an alternative risk factor for ALI (eg, sepsis, pneumonia, and lung contusion) [1,6,7]. As with ALI/acute respiratory distress syndrome (ARDS), there is no specific treatment of TRALI besides supportive care measures and a restrictive transfusion policy. Studies on TRALI in the pediatric population are mostly limited to case reports. A recent survey of the Canadian Blood Services showed an incident rate of reported TRALI cases of 5.58 in children and 3.75 in adults per 100 000 red blood cell (RBC) transfusions, suggesting a similar incidence of TRALI in children and adults [8]. However, data on the incidence of TRALI in critically ill children are still lacking. The main objective of this study was to determine the incidence, risk factors, and outcome of TRALI in critically ill children. We performed a retrospective cohort study on our pediatric intensive care unit (PICU) using the consensus TRALI definition.
2. Materials and methods 2.1. Setting The study was performed on a 16-bed, tertiary, mixed medicalsurgical PICU within a university hospital in the Netherlands. The PICU
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is a closed unit in which patients are under the direct specialist care of the PICU team consisting of intensivists, subspecialty fellows, and residents. 2.2. Study design The study was approved by the Ethics Committee of our hospital, and the criteria for informed consent were waived as a result of its retrospective nature. Using an electronic patient data monitoring system, all patients admitted to our PICU from January 1, 2009, until December 31, 2012 who received 1 or multiple blood products were screened for TRALI in accordance with the consensus TRALI definition (Figure). Patients who were readmitted and cases with insufficient data were excluded. No other exclusion criteria were applied. Control subjects were transfused patients not developing TRALI. Suspected TRALI was defined as new-onset of hypoxia or deterioration defined as PaO2/FIO2 ratio less than 300 mm Hg (or SpO2/FIO2 ratio b 250 when SpO2 b 97% if no arterial catheter was present), within 6 hours of transfusion with bilateral pulmonary infiltrates on the chest radiographs in the absence of cardiogenic pulmonary edema [1,6,7]. Cardiogenic pulmonary edema was assessed either clinically or by echocardiogram. An echocardiogram was performed at the discretion of the intensive care team. All echocardiograms were interpreted by attending cardiologists on staff. Patients judged to have moderate to severe left ventricular dysfunction and/or left atrial hypertension were excluded from this study. Possible TRALI was defined as the occurrence of TRALI in patients with other risk factors for ALI. Chest radiographs were scored for the presence of new-onset bilateral interstitial abnormalities by 2 independent physicians who were blinded to patient data. When interpretation differed, chest radiograph and screening for onset of TRALI were reviewed by a third independent physician to reach consensus.
2.3. Patient data collection The Pediatric Risk of Mortality (PRISM) III score was calculated for each patient according to the published algorithms [9]. Clinical and laboratory data for the PRISM III score were collected within the first 24 hours after PICU admission. The following data were retrospectively collected in a Microsoft Access database, Redmond, WA, USA from patient clinical files or from our patient data management system: standard demographic data, comorbidities, laboratory test results, medication, mechanical ventilator settings, duration of mechanical ventilation, and length of PICU stay. Potential risk factors were scored as positive when present 48 hours before onset of TRALI. Factors included were based on TRALI risk factors in the adult population as well as risk factors for ALI in the pediatric population [10–12]. These factors included liver failure, diabetes, elective and emergency (cardiac) surgery, hematologic malignancy, mechanical ventilation, sepsis, aspiration, pneumonia, trauma, disseminated intravascular coagulation, immune compromised condition, and near drowning. Prior to the onset of TRALI, the following data were collected: body temperature, platelet count, and leukocyte count. Tidal volume was retrieved from the electronic patient data monitoring system. Mean tidal volume per kilogram body weight was calculated using data from the 6-hour period preceding transfusion. Fluid balance was determined 24 hours prior to onset of TRALI. All previously mentioned data were also collected for the control group, with the first transfusion used as a reference time point. 2.4. Transfusion data collection Transfusion was defined as infusion of filtered RBCs, fresh-frozen plasma (FFP), or platelets. A restrictive transfusion policy was pursued
Figure. Flowchart outlining the inclusion of patients in this cohort study.
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according to international guidelines [13,14]. Routinely, the volume per transfusion was 10 to 15 mL/kg. Transfused RBCs were leukocyte depleted. The platelet concentrates were pooled products using 5 donor buffy coats, with 1 of the 5 donors to provide the plasma fraction. Since June 1st 2007, exclusion of female donors for FFP became effective in the Netherlands.
2.5. Statistics Continuous normally distributed variables were expressed as mean and SD, and nonnormally distributed variables as medians and interquartile ranges. Categorical variables were expressed as n (%). To test groups of continuous variables, Student t test or Mann-Whitney U test were used, depending on their distribution. Differences between distributions of categorical variables were analyzed by χ 2 test or Fisher exact test, when appropriate. Univariate analyses examined the effect of patient clinical characteristics on outcome (TRALI or no TRALI). Thereafter, multiple logistic regression analysis was applied to the outcomes. Factors achieving P ≤ .1 in our univariate analyses were entered into the model predicting the risk for the onset of TRALI. Statistical significance was defined as P ≤ .05. Analyses were performed using SPSS 20.0 software (SPSS, Chicago, Ill) and R 2.15.0 (R Foundation, Vienna, Austria).
3. Results During the screening period, 2294 patients were admitted to our PICU. Of these admissions, 1964 children were not transfused and 26 patients were excluded due to readmission or missing data, leaving 304 patients for inclusion in the study (Figure). Twenty-one patients conformed to the diagnostic criteria for TRALI (6.9%). Of these, 19 (90%) patients had a risk factor for ALI prior to transfusion and were diagnosed as possible TRALI. Of these patients, 7 had sepsis, 5 had pneumonia, 3 had traumatic injuries, 1 had inhalation trauma, 1 had aspiration, 1 had a oncological disorder, and 1 had near drowning. The mean time interval between initiation of transfusion and onset of symptoms was 118 minutes. Two patients presented with symptoms within 30 minutes after commencement of transfusion. The incidence of TRALI cases in the screened cohort was 0.9% (21/2294). The interobserver agreement for the diagnosis of TRALI was good (weighed κ = 0.76). In total, 1367 blood products were transfused; these consisted of 631 RBCs, 308 FFPs, and 428 platelet transfusions. The incidence of TRALI per product transfused was 1.5 % (21/1367). None of the patients diagnosed as having TRALI were reported to the blood bank by the treating physician.
3.1. Risk factors for the development of TRALI Table 1 summarizes the differences in demographic characteristics and clinical variables between patients developing TRALI and transfused control subjects. Patients developing TRALI had a higher PRISM III score, a higher incidence of sepsis, and disseminated intravascular coagulation and were mechanically ventilated more frequently in comparison with transfused controls. In addition, patients developing TRALI had a lower mean platelet count and a more positive fluid balance prior to transfusion. Neither the amount of RBC, nor the amount of FFP or platelet transfusions in the TRALI group differed from those in the transfused control group (Table 2). A multivariate logistic regression model was used to identify independent risk factors for the development of TRALI. Factors predictive of the development of TRALI in the univariate analyses were tested in the multivariate model and are reported in Table 3. Significant predictors for the development of TRALI were high PRISM III score upon admission, sepsis, and requirement for mechanical ventilation.
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Table 1 Demographic data, clinical data, and TRALI risk factors of patients developing TRALI compared with transfused control subjects
Demographic characteristics Age (y), mean (SD) Male sex, n (%) Weight (kg), mean (SD) PICU admission category, n (%) Medicine Respiratory Cardiovascular Neurology Surgery Neurosurgery Cardiac surgery PRISM III score, mean (SD) Liver failure, n (%) Diabetes, n (%) Cardiac surgery, n (%) Hematologic malignancy, n (%) Mechanical ventilation, n (%) Sepsis, n (%) Aspiration, n (%) Surgery, n (%) Trauma, n (%) Pneumonia, n (%) DIC, n (%) Immune compromised, n (%) Near drowning, n (%) Vt/kg BW, mean (SD) Temperature (°C), mean (SD) Platelet count (109/L), median (IQR) Leuco count (109/L), median (IQR) Fluid balance, L/24 h, median (IQR) Outcomes PICU mortality, n (%) PICU length of stay (h), median (IQR) Ventilation time (h), median (IQR)
TRALI (n = 21)
No TRALI (n = 283)
4.6 (5.2) 13 (61.9) 19.5 (19.7)
5.0 (5.8) 172 (60.8) 20.6 (20.1)
17 (81.0) 1 (4.8) 1 (4.8) 0 2 (9.5) 0 0 22.4 (13.2) 2 (9.5) 0 0 3 (14.3) 21 (100.0) 11 (52.4) 2 (9.5) 5 (23.8) 3 (14.3) 4 (19.0) 7 (33.3) 5 (23.8) 1 (4.8) 7.7 (2.6) 37.2 (1.6) 78 (44-213)
106 (37.5) 41 (14.5) 11 (3.9) 16 (5.7) 83 (29.3) 20 (7.1) 6 (2.1) 12.8 (9.2) 8 (2.8) 1 (0.4) 6 (2.1) 21 (7.4) 179 (63.3) 35 (12.4) 6 (2.1) 120 (42.4) 22 (7.8) 31 (11.0) 21 (7.4) 28 (9.9) 1 (0.4) 7.5 (1.5) 37.2 (1.2) 204 (107-311)
b.0001 .33 .58 .99 .07 .38 .99 b.0001 .15 .33 .99 .22 b.0001 b.0001 .10 .10 .40 .28 b.0001 .06 .13 .51 .94 .002
9.9 (6.0-15.5) 0.4 (0.1-0.8)
.08 .001
5.3 (3.3-17.3) 1.0 (0.4-2.0)
P
.79 .91 .80
16 (76.2) 227 (88-354)
32 (11.3) 101 (43-231)
b.0001 .07
183 (52-282)
25 (0-139)
.002
DIC indicates disseminated intravascular coagulation; Vt/kg BW, tidal volume per kilogram bodyweight; IQR, interquartile range.
3.2. Outcome The overall PICU mortality of the patients who were transfused was 16%. Patients who developed TRALI had a significantly higher PICU mortality than did the transfused control subjects (76.2% vs 11.3%, P b .001), and necessitated a longer period of mechanical ventilation (183 [52282] hours vs 25 [0-139] hours, P b .002). There was no significant difference between the 2 groups in PICU length of stay. Most patients (75%) who died had multiorgan system failure. Six percent had a “do not resuscitate” or “no escalation of care” order instituted preceding their death, 7% were declared as brain dead, and in 13%, the treatment was considered medically futile and support was withdrawn. We performed a multivariate logistic regression analysis to adjust for PRISM III score (in which the PaO2/FIO2 is embedded) and presence of dis-
Table 2 Transfusion characteristics of patients developing TRALI compared with transfused control subject
RBC (units) FFP (units) Platelets (units) Data are mean ± SD.
TRALI (n = 21)
No TRALI (n = 287)
P
0.8 ± 0.7 0.5 ± 0.6 0.3 ± 0.5
1.3 ± 3.5 0.5 ± 1.6 0.5 ± 6.0
.54 .85 .90
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Table 3 Multivariate analysis of patient-related risk factors for the onset of TRALI Variable
P
Odds ratio
95% Confidence interval
PRIMS III score Mechanical ventilation Sepsis Fluid balance
.02 .002 b.001 .18
1.05 18.94 7.20 1.00
1.01-1.10 2.38-2452.56 2.69-19.69 0.99-1.00
seminated intravascular coagulation, which are known to be strong independent predictors of patient mortality [12]. The analysis indicated that the development of TRALI was independently associated with increased mortality (odds ratio, 17.2 [5.3-56.0], P b .0001; Table 4).
4. Discussion To the best of our knowledge, this is the first study describing incidence and risk factors of TRALI in critically ill children. The present study demonstrated that TRALI is relatively common in critically ill children, affecting 6.9% of the transfused children in our population. Most of these patients (90%) had a preexistent risk factor for ALI prior to the onset of TRALI and were thus diagnosed as possible TRALI. High PRISM III score, sepsis, and mechanical ventilation were identified as independent risk factors for the development of TRALI. The incidence found in the present study is higher compared with previous incidence reports on TRALI in the pediatric population [4,8,15–17]. This may partly be explained by the study design. Most earlier reports are overviews following passive reporting via a National Hemovigilance System. In contrast, we actively searched for patients with TRALI. A second explanation for the higher incidence of TRALI found in our study population may be due to differences in population. The high TRALI incidence in critically ill children in our study compared with the general population may be explained by the “2-hit” hypothesis [18]. The “first hit” being the underlying inflammatory condition that leads to adherence of primed neutrophils to the pulmonary endothelial cells. The second hit is the transfusion itself, resulting from either transfused antibodies or other inflammatory mediators that accumulate during storage of cell-containing blood products. This second hit results in activation of the primed neutrophils and subsequently in tissue damage and capillary leakage. In concordance with this 2-hit hypothesis, a so-called TRALI threshold model has been proposed [19]. According to this model, the onset of TRALI depends on the interaction between the severity of the underlying disease and the quantity of antibodies or inflammatory mediators in the transfused component. Because of the presence of a proinflammatory state in most of the critically ill patients, these patients are thought to be particularly prone to developing TRALI. Measuring the presence of donor antibodies directed against recipient human leukocyte antigen class I or II, granulocyte-specific antibodies, levels of proinflammatory cytokines, or neutrophil-priming activity in plasma of TRALI patients might give more insight into the molecular mechanisms playing a central role in the development of TRALI [20,21]. To date, only one study of acute transfusion reactions in the PICU reported the incidence of TRALI [22]. Their reported incidence was 0.04 % per product transfused, which is lower than the incidence
Table 4 Multivariate analysis of risk factors for mortality Variable
P
Odds ratio
TRALI PRISM III score Disseminated intravascular coagulation
b.0001 17.25 b.0001 1.10 .15 2.18
95% Confidence interval 5.32-55.97 1.06-1.15 0.76-6.25
we found. However, limited detailed information on demographic and clinical data was provided, making it difficult to compare the studies. There are striking differences between children and adults in incidence and outcome of ALI/ARDS, possibly due to the on pathophysiological differences in the development of these conditions [12,23,24]. Of interest is that the incidence of TRALI found in this study is similar to that found in adult intensive care unit populations [10]. Given that the presence of other ALI risk factors is less common in the pediatric population than in adults, this finding was unexpected. A possible explanation may be related to specific pathophysiological mechanisms of TRALI with a common response to the presence of antibodies or other bioactive substances in blood products. Unfortunately, because of the retrospective study design, we were unable to measure these antibodies or other inflammatory mediators. In the present study, given the large odds ratio, mechanical ventilation appears to be a prerequisite for the development of TRALI. In adults, mechanical ventilation is also a risk factor [10]. The increased risk was found to be associated with tidal volume, suggesting synergy between mechanical ventilation and transfusion in the development of lung injury. Indeed, unequivocal evidence suggests that mechanical ventilation has the potential to aggravate and precipitate lung injury [25]. However, whether children are more susceptible to the harmful effects of mechanical ventilation (and that as such mechanical ventilation may more easily serve as a first hit), is a subject of much controversy [26–28]. Sepsis also proved to be a risk factor in this study, which is in line with the 2-hit hypothesis. Sepsis is typically characterized by a proinflammatory state. Pulmonary neutrophils may be primed via an endovascular-mediated proinflammatory host response thereby serving as a first hit in the development of TRALI. No association was found to suggest that the volume of transfused blood products (RBCs, FFPs, or platelets) has an effect on the development of TRALI. In accordance with this, patient-related risk factors were also more important than transfusion-related risk factors in the adult population [10]. Interestingly, TRALI was associated with high mortality and a longer period of mechanical ventilation, even after correcting for severity of illness. It has already been shown that there is an association between blood product transfusions and worse outcomes in pediatric patients with ALI/ARDS [29–31]. Church et al [29] reported mortality rates of 40% to 70% in patients who received platelets and/or FFP transfusions. Some of these patients may have had TRALI. However, caution is advised in drawing firm conclusions concerning the association of TRALI with mortality. Most of the TRALI patients in the present study had a risk factor for ALI prior to transfusion and were thus diagnosed as having possible TRALI. A prospective nested case-control study also including patients with ALI without transfusions is needed to determine whether risk factors for ALI may actually contribute more to adverse outcome than merely the transfusion of blood products. Nevertheless, a restrictive transfusion policy is still strongly advised. There are some limitations of our study. First, the absence of an arterial catheter in some of our non-TRALI patients, precluding calculation of the PaO2/FIO2 ratio, may be a potential limitation. However, it has earlier been demonstrated that there is a strong correlation between the SpO2/FIO2 ratio and the PaO2/FIO2 ratio [32–34]. Second, the retrospective analysis of data could have influenced the availability of the data collected. Nevertheless, only 10 patients had to be excluded as a result of missing data. Finally, our study was a single-center study, which may limit the generalization of our results. In conclusion, this study shows that TRALI in pediatric critically ill patients is as common as in the adult critically ill patient population. Risk factors are a high PRISM III score on admission, sepsis, and mechanical ventilation. The recognition of these factors may assist in the riskbenefit assessment and consequent decision whether or not to transfuse. Transfusion-related ALI is independently associated with a worse outcome, emphasizing the need for more rigorous prospective studies in these patients.
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