Respiratory Dysfunction Associated With RBC Transfusion in Critically Ill Children: A Prospective Cohort Study* Niina Kleiber, MD, MSc1; Émilie Lefebvre, MD1; France Gauvin, MD, MSc1; Marisa Tucci, MD, BSc1; Nancy Robitaille, MD2; Helen Trottier, PhD3; Philippe Jouvet, MD, PhD1; Thierry Ducruet, MSc4; Nicole Poitras, MSc4; Jacques Lacroix, MD1; Guillaume Emeriaud, MD, PhD1 Objective: Respiratory complications associated with RBC transfusions may be underestimated in PICUs because current definitions exclude patients with preexisting respiratory dysfunction. *See also p. 380. 1 Division of Pediatric Critical Care Medicine, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montreal, Canada. 2 Division of Hematology/Oncology, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montreal, Canada. 3 Department of Preventive and Social Medicine, Université de Montréal and CHU Sainte-Justine, Montreal, Canada. 4 Unité de recherche clinique appliquée, Research Center, CHU SainteJustine, Université de Montréal, Montreal, Canada. Drs. Kleiber and Lefebvre contributed equally. This work was performed at CHU Sainte-Justine, Université de Montréal. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/pccmjournal). Supported, in part, by the Fonds de la Recherche en Santé du Québec (grant no. 24460). Presented, in part, as an abstract at the 40th Annual Congress of the Société de Réanimation de Langue Française, Paris, January 18–20, 2012. Dr. Trottier is receiving a salary award from the Canadian Institutes of Health Research. Dr. Jouvet is receiving a salary award (chercheur-boursier) from the Fonds de la Recherche en Santé du Québec (FRQ-S). Dr. Emeriaud holds a Clinical Research Scholarship from the FRQ-S. Dr. Emeriaud’s institution received grant support from FRQ-S (study was financed by a grant from FRQ-S and Dr. Emeriaud's research program is supported by Clinical Research Scholarship from FRQ-S). Dr. Robitaille consulted for Apopharma and lectured for Novartis and Griffols. Her institution received grant support from Lilly. Dr. Trottier served as board member for Merck Frosst and GSK Belgium; consulted for Merck Frosst, GSK Belgium, and Gilead science; lectured for Merck Frosst and GSK Belgium; received support for the development of educational presentations from Merck Frosst; and received support for travel from Merck Frosst and GSK Belgium. Dr. Jouvet received support for travel from Air Liquide (travel to a meeting on medical device development) and received support from Philips Medical and Maquet Medical (lent a medical device). Dr. Lacroix received royalties (Textbook on pediatric critical care medicine) and received support for article research from FRQ-S. His institution received grant support from FRQ-S (study was financed by this grant). For information regarding this article, E-mail: [email protected] Copyright © 2015 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000365
Pediatric Critical Care Medicine
This study aims to determine the prevalence and characterize the risk factors and outcomes of new or progressive respiratory dysfunction observed after RBC transfusion in critically ill children. Design: Prospective cohort study of all children admitted over a 1-year period. Setting: A multidisciplinary PICU in a tertiary pediatric university hospital. Patients: Patients who received a RBC transfusion while in PICU. Interventions: None. Measurements and Main Results: Two independent adjudicators established the diagnosis of respiratory dysfunction. A respiratory dysfunction associated with transfusion was considered new if it appeared after the first RBC transfusion in PICU. A progressive respiratory dysfunction associated with transfusion was diagnosed if the respiratory dysfunction was present before the transfusion and the Pao2/Fio2 or the Spo2/Fio2 ratio dropped by at least 20% thereafter. Among 842 children admitted into the PICU, 136 received at least one RBC transfusion and were analyzed. Fifty-eight cases of respiratory dysfunction associated with transfusion (43% of transfused patients) were detected, including nine new respiratory dysfunction associated with transfusion (7%) and 49 progressive respiratory dysfunction associated with transfusion (36%). Higher severity of illness, multiple organ dysfunction syndrome prior to transfusion, and volume (mL/kg) of RBC transfusion were independently associated with respiratory dysfunction associated with transfusion. A dose-response relationship was observed between transfusion volume (mL/kg) and the prevalence of respiratory dysfunction associated with transfusion. Patients with respiratory dysfunction associated with transfusion had more progressive multiple organ dysfunction and less ventilation-free and PICU-free days at day 28. Conclusions: Development of respiratory dysfunction associated with transfusion is frequent in PICU and occurs mainly in patients with prior respiratory dysfunction, who would not be identified using current definitions for transfusion-associated complications. A cause-effect relationship cannot be confirmed. However, the high prevalence and the serious adverse outcomes associated with respiratory dysfunction associated with transfusion suggest that this complication should be further studied. (Pediatr Crit Care Med 2015; 16:325–334) www.pccmjournal.org
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Kleiber et al Key Words: child; critical care medicine; erythrocytes; intensive care; mortality; multiple organ dysfunction syndrome; pediatric; red blood cell; respiratory dysfunction; transfusion
R
BC transfusion is a common therapeutic intervention in PICUs (1, 2) that has several benefits and can be potentially lifesaving. RBC transfusion also puts critically ill children at risk for significant complications including the occurrence of several transfusion reactions (3). Systemic inflammatory response syndrome (SIRS) is a frequent occurrence in the critically ill, among adults and children (4, 5), which involves priming and activation of the innate immune response. The presence of SIRS can aggravate the status of the critically ill patient and lead to multiple organ failure when a second inflammatory insult occurs. RBC transfusion is a potential important second hit that can precipitate the cascade leading to multiple organ failure. RBC units contain proinflammatory mediators and also biologically active mediators like blood cells microparticles and bioactive lipids, which can cause both a hyperinflammatory and a immune suppressive response in the recipient (6, 7). Lungs with active inflammatory processes are particularly sensitive to this second hit phenomenon (6, 7). Several respiratory complications of transfusion have been described, including transfusion-related acute lung injury (TRALI), acute respiratory distress syndrome (8–10), nosocomial infections (11–16), and transfusion-associated circulatory overload (TACO) (17–20). All these conditions can lead to respiratory dysfunction (RD) in critically ill patients that is transfusion associated, thus the acronym RDAT in our study. The diagnosis of RDAT is particularly challenging in critically ill patients because many already have RD prior to transfusion and because several risk factors for development of RD are frequently present. The current definitions proposed for the diagnosis of transfusion-related respiratory complications exclude patients with prior RD (21, 22). We hypothesize that RD is frequent after RBC transfusion in PICU patients, but that most of these complications would not be considered because of current definition exclusion criteria, leading to an important underreporting. Transfusion-associated respiratory complications in critically ill adults are indeed underreported (23), although quite frequent (8–10, 17–19). They are likely also underrecognized in critically ill children as reflected by Gauvin et al (24) reporting of only four TRALI cases in PICUs across Canada over a 3-year period. The prevalence of respiratory dysfunction after transfusion in critically ill children with or without preexisting RD is not known. We undertook this study to characterize the prevalence and the risk factors associated with the development of new and progressive RDAT in PICU and to determine the outcome of patients with RDAT. 326
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MATERIAL AND METHODS Study Design This prospective observational cohort study took place in the PICU of Sainte-Justine Hospital, a tertiary care multidisciplinary university-affiliated pediatric hospital. All children consecutively admitted to the PICU over a 1-year period (April 2009 to April 2010) were eligible. The study was approved by the local institutional review board (Comité d’Éthique de la Recherche du CHU Sainte-Justine, project 2870), waiving the requirement for written informed consent. Exclusion criteria included: 1) gestational age less than 40 weeks; 2) postterm age less than 3 days or more than 18 years; 3) pregnancy; and 4) admission to PICU in the postpartum period. Population The study involved patients who received a RBC transfusion while in PICU. Time zero was the time of initiation of the first RBC transfusion in PICU. Any administration of RBCs, regardless of the volume given, was considered a transfusion. Most RBC units were collected from allogeneic whole blood donation except for a few units which were obtained by apheresis. Only prestorage leukocyte-reduced additive solution-3 RBC units were used. Definition of RDAT New or progressive RDAT is the primary outcome measure of this study. According to Goldstein et al (25), a RD is diagnosed when at least one of the following criteria is observed: 1) Pao2/Fio2 ratio less than 300 in the absence of cyanotic heart disease or preexisting lung disease before PICU admission; 2) Paco2 more than 65 mm Hg or 20 mm Hg over baseline Paco2; 3) proven need for more than 50% Fio2 to maintain saturation at least 92%; and 4) need for nonelective invasive or noninvasive mechanical ventilation. When arterial blood gases were not available, the criterion Spo2/Fio2 less than 253 was added as an alternative to Pao2/Fio2 less than 300; the diagnostic value of Spo2/Fio2 ratio has been validated in critically ill children (26). In all instances, the Pao2/Fio2 ratio was considered normal if the Spo2 was at least 99%. We differentiated between new and progressive RDAT. RD was considered new if no RD was present at time zero and appeared after the first RBC transfusion. RDAT was considered progressive when a RD was present at time zero, but worsened after the first RBC transfusion. The severity of RD was considered to have worsened if the Pao2/Fio2 ratio or the Spo2/ Fio2 ratio dropped by at least 20% after the transfusion. This threshold was considered clinically significant by nine pediatric intensivists, using a Delphi method. Transient episodes of Spo2/Fio2 decrease attributable to maneuvers such as endotracheal aspiration were not retained for analysis. Cases of TRALI were also identified based on the definition proposed in 2004 by a panel of experts (27). TRALI was considered when a new acute lung injury with hypoxemia occurred within 6 hours of transfusion, with bilateral pulmonary infiltrates, no evidence of left atrial hypertension, and no temporal May 2015 • Volume 16 • Number 4
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relationship to an alternative risk factor for acute lung injury. A possible TRALI was considered when the last criterion was missing (27). Adjudicating Process An adjudicating committee ascertained the diagnosis of new/ progressive RDAT and TRALI. Two investigators (N.K., E.L.) independently reviewed the patient medical charts and filled out a validated adjudication form. If the two adjudicators did not agree on the diagnosis, they were asked to review their assessment of the data. If consensus could not be reached, a third adjudicator (G.E.) reviewed the case. Consensus was considered to be reached when two of the three adjudicators agreed on the diagnosis. When RDAT was diagnosed, adjudicators rated their degree of certainty for the diagnosis as well as their degree of certainty that there was a causal link between RBC transfusion and development of RD on a 7-point Likert scale. The lowest score (1) meant that a causal link between RBC transfusion and development of RD was very unlikely given the available data and the definition used, whereas a score of 7 reflected a high likelihood (quasi certainty) that RD was caused by RBC transfusion. No specific criteria were a priori established to define the causality. Potential Risk Factors and Outcome Variables To prevent any protopathic bias, only events occurring before time zero were considered as possible risk factors for RDAT; events appearing after time zero were considered as possible adverse events. The following variables were a priori considered as possible risk factors or risk markers for RDAT: age, severity of illness at time zero as evaluated by the Pediatric Risk of Mortality (PRISM) score (28) and the Pediatric Logistic Organ Dysfunction (PELOD) score (29), prior chronic illness (chronic hematologic, cardiac, or oncologic diseases), presence of multiple organ dysfunction syndrome (MODS) as defined by Goldstein et al (25) at time zero, total number of RBC transfusions, volume (mL/kg) of RBCs received, RBC storage time, and transfusion of other blood products (plasma and platelet concentrates). Possible complications of RDAT were monitored daily; this included development of sepsis, severe sepsis, septic shock, and MODS as well as daily PELOD scores, mortality, duration of endotracheal intubation, and PICU length of stay. The occurrence of nosocomial infections after the first RBC transfusion was also recorded. The ventilation-free days and PICU-free days at day 28 were calculated as the number of days spent alive and without ventilation (or outside the PICU) by day 28. Data Management A validated case report form was used to prospectively collect the following data from admission to PICU discharge: demographic data, medical history, admission diagnosis, clinical data, laboratory results, transfusions, mechanical ventilation, fluid balance, new and/or progressive RD criteria, MODS, PICU length of stay, and mortality. The following data were collected Pediatric Critical Care Medicine
hourly in transfused patients from a time point 2 hours prior to transfusion (start of transfusion = time zero) to 24 hours after time zero and then at least once daily until PICU discharge: worse respiratory rate, ventilatory settings, lowest Spo2, lowest Pao2/Fio2 ratio, and Spo2/Fio2 ratio. Data management fulfilled all requirements of standard good clinical data management practice, and all data were treated anonymously. Transfusion Policy In the PICU, no written protocol exists regarding transfusion. In line with the Transfusion Requirements in the Pediatric Intensive Care Unit study (30), the general attitude during the study period was to avoid transfusion when hemoglobin exceeded 7 g/dL in stabilized patients. Statistical Analysis Concordance and κ scores were calculated to assess the reproducibility of the adjudication process. Categorical variables were described by frequency distribution and compared using chi-square or Fisher exact probability test. Continuous variables were reported as mean and sd and/or median and interquartile range and compared across groups using Student t test or nonparametric Wilcoxon tests. Univariate and multivariate logistic regression analyses were done for potential risk factors by calculating unadjusted and adjusted odds ratios (OR) and their 95% CI. Age, severity of illness (PRISM and PELOD scores), and volume (mL/kg) of RBC units given were categorized by quartiles. Statistically significant determinants after univariate analysis (p < 0.05) were included in the multivariate logistic regression. Age and congenital heart disease diagnosis were also included because they are known determinants involved in the decision to transfuse (31). PELOD score was a priori excluded from the model because of its collinearity with PRISM; highest lactate level was a posteriori excluded because these data were missing in more than 25% of patients. The association between RDAT and adverse outcomes was analyzed using univariate chi-square or Student t test. Two-tailed p value of less than 0.05 was considered statistically significant. All analyses were performed by a statistician (T.D.) who used SAS 9.2 (SAS Institute, Cary, NC).
RESULTS Population Nine hundred thirteen patients were admitted to the PICU of Sainte Justine-Hospital during the study year; 71 were excluded because they met at least one exclusion criterion (Fig. 1). Among the remaining 842 patients, 144 (16.9%) received at least one RBC transfusion while in PICU. Eight of the 144 transfused patients were excluded from the adjudication process because no impact on respiratory function could be evaluated, as they were transfused while on extracorporeal membrane oxygenation (n = 4), in the operating room (n = 3), or in the hour preceding death (n = 1). www.pccmjournal.org
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136 transfused patients (65%). No TRALI and two possible TRALIs were identified using the criteria proposed by Kleinman et al (27). Supplemental Table 2 (Supplemental Digital Content 2, http://links.lww. com/PCC/A146) details the frequency and reproducibility of the diagnostic criteria. Concordance between adjudicators for the respiratory dysfunction criteria ranged from 63% to 100% with κ scores ranging from 0.63 to 1.00. Figure 2 illustrates the timing of new or progressive RDAT occurrence after time zero: 52 (89%) appeared within the first 24 hours after the first RBC transfusion, four (7%) during the second day, one (2%) on the Figure 1. Patient flow chart. aSome patients presented more than one exclusion criterion. ECMO = extracorpothird day, and one (2%) more real membrane oxygenation, RDAT = respiratory dysfunction associated with transfusion. than 3 days after time zero. The two adjudicators rated their degree of certainty with Diagnosis of Respiratory Dysfunction regard to the diagnosis of RDAT as strong. With regard to the As reported in Supplemental Table 1 (Supplemental Digicausal link between RBC transfusion and respiratory dysfunctal Content 1, http://links.lww.com/PCC/A145), 58 RDATs tion, the degree of certainty was lower: on a Likert scale of 1 (43%) were diagnosed, including nine new RD and 49 (very unlikely) to 7 (certain), the mean causality rates were 1.8 progressive RD. The concordance between the two adjuand 2.7 for new and progressive RDAT, respectively, and the dicators for the diagnosis of new and progressive RD was highest value rated by the adjudicators for a cause-effect relaperfect. It is of importance to note that RD was present at tionship was 3. time zero (i.e., before the first RBC transfusion) in 89 of the
Figure 2. Length of time between first RBC transfusion in PICU (time zero) and appearance of nine new cases of respiratory dysfunction associated with transfusion (RDAT) (black bars) and 49 progressive RDAT (gray bars).
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Epidemiology of RDAT Table 1 describes the RBC transfusions received by children with or without RDAT. Patients with RDAT were significantly sicker than those without RDAT before receiving the first RBC transfusion in PICU, as illustrated by higher PRISM (p < 0.001) and daily PELOD scores (p = 0.001). Patients with RDAT had a higher hemoglobin level before the first RBC transfusion (p = 0.04) and were exposed to a higher number (p < 0.001) and a larger volume (p < 0.001) of RBC transfusions. RBC unit storage times were similar in both groups. Age, weight, gender, and admission diagnosis were not risk factors associated with RDAT. As detailed in the May 2015 • Volume 16 • Number 4
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Table 1. Description of the RBC Transfusions in Patients With and Without Respiratory Dysfunction Associated With Transfusion All Transfused Patients
With RDAT
Without RDAT
n = 136
n = 58
n = 78
p
57 (41.9)
23 (39.7)
34 (43.6)
0.65
Pediatric Risk of Mortality score on day of first RBC transfusion
7.9 ± 6.3
10.5 ± 6.4
5.9 ± 5.4
< 0.001
Daily Pediatric Logistic Organ Dysfunction score on day of first RBC transfusion
8.4 ± 8.0
10.9 ± 8.5
6.5 ± 7.1
0.001
Hemoglobin level before first RBC transfusion (g/dL)
7.6 ± 2.2
8.1 ± 2.0
7.3 ± 2.3
0.04
1.3 ± 2.1
1.3 ± 2.1
1.3 ± 2.1
0.90
13.2 ± 14.1
16.6 ± 20.4
10.1 ± 5.1
0.02
12 (7–24)
10 (7–23)
13 (7–25)
0.40
3.7 ± 7.1
6.3 ± 10.3
1.8 ± 1.5
< 0.001
Total volume of RBCs (mL/kg/patient) (n = 136)
45.5 ± 83.7
80.4 ± 117.0
19.6 ± 23.8
< 0.001
Median storage time for all RBC transfusions (d)
13 (8–23)
14 (9–23)
13 (8–22)
0. 40
Maximum storage time for all RBC transfusion (d)
16 (9–27)
18 (9–32)
16 (9–25)
0.27
Variable
RBC transfusions within 24 hr before PICU admission Patients transfused before PICU entry, n (%) RBC transfusions after entry into PICU (mean ± sd)
Description of first RBC transfusion Time from admission to first RBC transfusion (d) RBC transfusion volume (mL/kg) Median RBC storage time (d) Description of all RBC transfusions given during PICU stay
a
Number of transfusions per patient (n = 136)
RDAT = respiratory dysfunction associated with transfusion. a These data describe all RBC transfusions given during PICU stay, including the ones received after RDAT diagnosis. Data are reported as number (percentage) or mean ± sd, except for storage times which are reported as median (interquartile).
Table 2, patients in whom RDAT developed had higher PRISM (p < 0.01) and PELOD scores (p = 0.05), more elevated blood lactate levels (p = 0.006) at the time of admission, and a higher prevalence of MODS (p < 0.001) on the day prior to the first RBC transfusion. The occurrence of plasma and platelet transfusions was also associated with RDAT (p = 0.001 and 0.003, respectively), as well as their respective volume (mL/ kg for plasma, p = 0.03, and unit/kg for platelets, p < 0.001). A multiple logistic regression analysis was conducted, including the following variables: age, congenital heart disease diagnosis, PRISM score, presence of MODS at time zero, volume (mL/kg) of RBC transfusion, and plasma and platelet transfusions. Three independent risk factors for RDAT were identified (Table 2): higher PRISM score (p = 0.02), presence of MODS at time zero (p < 0.01), and a greater volume of RBC transfusion (p < 0.01). We observed a dose-effect relationship between the volume of RBCs transfused and occurrence of new or progressive RD: using the first quartile (0–10 mL/kg) as reference, the OR for development of RDAT attained a value of 6.8 (95% CI, 1.6–28.2; p = 0.001) in patients who received more than 38 mL/kg of RBCs. A sensitivity analysis was conducted in order to explore the impact of the volume (per kg) of plasma or platelet transfusions. The entry of these two variables as continuous rather than as categorical variables did not change Pediatric Critical Care Medicine
the results of the model. The weight of the independent factors was not modified, whereas the volume of plasma or platelet transfusion was not independently associated with RDAT (p = 0.21 and 0.38, respectively). Outcome Outcome data are detailed in Table 3. In univariate analysis, patients with RDAT developed more progressive MODS (p < 0.001). More nosocomial bacteremias were observed in patients with RDAT (p < 0.05). RDAT was also associated with a more prolonged period of endotracheal intubation (p = 0.006) and PICU length of stay (p = 0.01). PICU mortality was almost three-fold higher in patients with RDAT (5.1% vs 19%; p = 0.01). At day 28, the PICU-free days and ventilationfree days were lower in the RDAT group (p < 0.001 and p < 0.0001, respectively)
DISCUSSION Recent literature has reported an association between blood transfusion and adverse outcome and has described numerous respiratory complications that can occur after transfusion. Many of these studies have been carried out in patients with no prior RD in whom it is fairly straightforward to identify new onset RD. As most ICU patients already present respiratory www.pccmjournal.org
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Table 2.
Variables Associated With Respiratory Dysfunction Associated With Transfusion Transfused Patients
With RDAT
Without RDAT
Univariate Analysis
n = 136
n = 58
n = 78
OR (95% CI)
60.6 ± 75.3
56.7 ± 73.2
63.4 ± 77.2
≤ 28 d, patients, n (%)
20 (14.7)
12 (20.7)
8 (10.3)
2.25 (0.82–6.21)
29–364 d, patients, n (%)
46 (33.8)
18 (13.2)
28 (35.9)
0.96 (0.45–2.06)
> 364 d, patients, n (%)
70 (51.5)
28 (48.3)
42 (53.8)
Reference
Weight (kg), mean ± sd
21 ± 22.4
Gender (male), n (%)
69 (50.7)
29 (50)
40 (51.3)
0.95 (0.48–1.88)
0.88
15 (11)
5 (8.6)
10 (12.8)
0.64 (0.21–1.99)
0.44
Congenital heart disease, cyanotic
33 (24.3)
16 (27.6)
17 (21.8
1.37 (0.62–3.01)
0.43
1.80 (0.66–4.92)
0.25
Congenital heart disease, noncyanotic
25 (18.4)
10 (17.2)
15 (19.2)
0.88 (0.36–2.12)
0.77
0.81 (0.26–2.48)
0.71
9 (6.6)
4 (6.9)
5 (6.4)
1.08 (0.28–4.22)
0.99
32 (23.5)
13 (22.4)
19 (24.4)
0.90 (0.40–2.01)
0.79
6 (4.4)
4 (6.9)
2 (2.6)
2.82 (0.50–15.92)
0.40
PRISM score, mean ± sd
9.5 ± 7.1
11.6 ± 7.3
7.9 ± 6.6
0.002
First quartile: PRISM = 0–4, n (%)
37 (27.2)
9 (15.5)
28 (35.9) Reference
0.004
Second quartile: PRISM = 5–8, n (%)
35 (25.7)
15 (25.9)
20 (25.6)
2.33 (0.85–6.38)
0.21
2.89 (0.88–9.48)
0.08
Third quartile: PRISM = 9–14, n (%)
34 (25)
13 (22.4)
21 (26.9)
1.93 (0.69–5.35)
0.10
1.50 (0.44–5.11)
0.52
Fourth quartile: PRISM > 14, n (%)
30 (22.1)
21 (36.2)
9 (11.5)
7.26 (2.46–21.45)
0.001
5.02 (1.33–19.0)
0.02
Pediatric Logistic Organ Dysfunction score, mean ± sd
8.9 ± 8.5
10.7 ± 10.1
7.6 ± 6.8
Possible Risk Factors
Multivariate Analysis Adjusted OR (95% CI)
p
0.12
0.90 (0.23–3.54)
0.88
0.93
0.58 (0.21–1.59)
0.29
p
Clinical data at PICU admission Age (mo), mean ± sd
0.61
20.7 ± 23.8 21.1 ± 21.4
Reference 0.92
Previous diseases, n (%) Anemia
Primary diagnosis, n (%) Septic shock Cardiac surgery Trauma
Reference
0.05
Laboratory data at PICU admission, mean ± sd Worst Pao2 (n = 41) (mm Hg)
131.5 ± 84.8 133.9 ± 86.3 129.3 ± 84.4
0.82
Lowest hemoglobin (n = 129) (g/dL)
9.0 ± 2.9
9.3 ± 2.7
8.8 ± 3.0
0.25
Highest lactate level (n = 101) (mmol/L)
4.9 ± 5.2
6.8 ± 6.8
3.3 ± 2.5
0.006 (Continued)
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Table 2. (Continued). Variables Associated With Respiratory Dysfunction Associated With Transfusion
Possible Risk Factors
Transfused Patients
With RDAT
Without RDAT
Univariate Analysis
n = 136
n = 58
n = 78
OR (95% CI)
Multivariate Analysis Adjusted OR (95% CI)
p
p
Syndromes before first RBC transfusion in PICU Systemic inflammatory response syndrome, n (%)
77 (56.6)
32 (55.2)
45 (57.7)
0.88 (0.44–1.74)
0.70
Sepsis
48 (35.3)
21 (36.2)
27 (34.6)
1.05 (0.52–2.14)
0.89
Severe sepsis
18 (13.2)
10 (17.2)
8 (10.3)
1.80 (0.66–4.88)
0.25
Septic shock
11 (8.1)
6 (10.3)
5 (6.4)
1.66 (0.48–5.74)
0.53
Multiple organ dysfunction syndrome, n (%)
75 (55.1)
42 (72.4)
33 (42.3)
3.58 (1.73–7.43)
< 0.001
7 (5.1)
5 (8.6)
2 (2.6)
Septic states, n (%)
Cardiovascular dysfunction, n (%)
3.58 (0.67–19.17)
3.53 (1.39–8.94) 0.008
0.14
Number and volume of transfusions given in PICU Volume of RBC transfusion received, n (%) First quartile: 0–10 mL/kg
36 (26.5)
11 (19.0)
25 (32.1)
Reference
Second quartile: 10–16.3 mL/kg
32 (23.5)
7 (12.1)
25 (32.1)
0.64 (0.21–1.91)
0.42
0.53 (0.16–1.81) 0.31
Third quartile: 16.3–38 mL/kg
35 (25.7)
15 (25.9)
20 (25.6)
1.71 (0.64–4.52)
0.28
1.44 (0.45–4.66) 0.54
Fourth quartile: > 38 mL/kg
33 (24.3)
25 (43.1)
8 (10.3)
7.10 (2.44–20.6) < 0.001
6.83 (1.65–28.2) 0.008
68 (50)
38 (65.5)
30 (38.5)
3.20 (1.57–6.54)
1.21 (0.46–3.21) 0.70
Plasma transfusion, n (%) Volume (mL/kg): mean ± sd Platelet transfusion, n (%) Platelets (units/kg): mean ± sd
52.0 ± 178.5 95.2 ± 262.0 19.9 ± 51.3 47 (34.6)
28 (48.3)
19 (24.4)
0.21 ± 0.66 0.30 ± 0.56 0.14 ± 0.72
Reference
0.001 0.03
2.98 (1.44–6.24)
0.003
0.86 (0.28–2.64) 0.79
< 0.001
RDAT = respiratory dysfunction associated with transfusion, OR = odds ratio, PRISM = Pediatric Risk of Mortality.
symptoms before the transfusion (65% in the present study) and/or have other risk factors for development of RD, the currently available definitions underestimate the prevalence of transfusion-associated respiratory complications in the critically ill. The objective of the present work is to evaluate the magnitude of potential underestimation of RDAT consecutive to these restrictive definitions. The study aimed to determine the prevalence rate of RDAT in critically ill children, without exclusion criteria based on prior RD presence. We report the occurrence of new cases of new RDAT and 49 cases of progressive RDAT in 136 critically ill children, while only two possible TRALI were identified. The role of RBC transfusion on the respiratory function of critically ill patients is of interest for ICU practitioners and Pediatric Critical Care Medicine
experts in hemovigilance. Many hemovigilance systems and expert consensus definitions do not consider that respiratory complications are transfusion reactions if some respiratory symptoms were present before transfusion (21, 22, 27). The absence of a broader definition that allows identification of both new and progressive RD is a major obstacle in estimating the true prevalence of RDAT. In this study, we introduce the concept of worsening RD and advocate that some attention should be paid to progressive RDAT. Progressive RDAT is indeed much more frequent than new RDAT and was present in 55% of transfused PICU patients with preexisting RD (vs 19% new RDAT). The length of monitoring for acute transfusion reactions involving the respiratory system is also a matter of debate. www.pccmjournal.org
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Table 3. Univariate Association Between Respiratory Dysfunction Associated With Transfusion and Outcomes Transfused Patients n = 136
With RDAT n = 58
New MODS
22 (16.2)
13 (22.4)
Progressive MODS
41 (30.1)
29 (50)
Outcome Data, n (%) or Mean ± sd
Without RDAT n = 78
p
MODS and organ dysfunction, n (%)
Worst Pediatric Logistic Organ Dysfunction score post first RBC transfusion (n = 127)
11.0 ± 9.8
Acute respiratory distress syndrome (n = 124)
7 (6)
Length of endotracheal intubation (d)
8.4 ± 26.5
15.2 ± 10.8 3 (5) 15.9 ± 39.2
9 (11.5)
0.24
12 (15.4)
< 0.001
7.5 ± 7.4
0.07
4 (6)
0.90
2.8 ± 4.4
0.006
Nosocomial infections post first RBC transfusions (n = 122), n (%) Pneumonia
4 (3)
3 (5)
1 (1)
0.22
Tracheitis
2 (2)
1 (2)
1 (1)
0.89
Bacteremia
5 (4)
5 (9)
0 (0)
< 0.05
Urinary infections
6 (5)
5 (9)
1 (1)
0.053
Other infections
6 (5)
5 (9)
1 (1)
0.053
Ventilation-free days at day 28
20.1 ± 10.2
15.0 ± 11.3
23.8 ± 7.4
< 0.0001
Length of PICU stay (d) (n = 134)
11.9 ± 27.0
19.4 ± 39.4
6.3 ± 6.0
PICU-free days at day 28
16.9 ± 9.7
12.3 ± 10.2
20.4 ± 7.7
< 0.001
0.01
Mortality, n (%) PICU mortality
15 (11.0)
11 (19)
4 (5.1)
0.01
28-day all-cause mortality
14 (10.3)
10 (17.2)
4 (5.1)
0.02
3 (2.2)
2 (3.4)
1 (1.3)
0.6
Hospital mortality post-PICU
RDAT = respiratory dysfunction associated with transfusion, MODS = multiple organ dysfunction syndrome.
Some experts believe that TRALI should be monitored only up to 6 hours after transfusion (27, 32), whereas others argue that 72 hours should be considered (10). We observed 28 cases of RDAT (48%) within 6 hours, 24 (41%) between 6 and 24 hours, and six (10%) between 24 and 72 hours after the first RBC transfusion (Fig. 2). Although certain mechanisms such as fluid overload, passive antibody transfer, and allergic reactions can trigger a RD within 6 hours (7, 33), a delayed occurrence of RDAT could be otherwise explained by inflammatory reaction in the critically ill. SIRS is observed in most critically ill children (5). This systemic inflammation primes patients to overreact to additional insults (two-hit phenomenon) (7), which may aggravate the inflammatory status within a period of time that surpasses the time frames used in current definitions (34). RBC transfusion can be a second hit for the critically ill patient with SIRS (33), which can lead to multiple organ failure, involving worsening RD. There is also strong evidence that transfusion can cause some immune suppression (35). This can explain why an association is frequently reported between transfusion and an increased risk of nosocomial infections (14). The duration of the immune suppression related to transfusion is unknown but may range from a 332
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few days to months (14, 36). The optimal time frame during which RDAT should be monitored remains to be determined; our results and numerous pathophysiologic hypotheses suggest that 6 hours may be too short. We characterize risk factors and risk markers for RDAT in critically ill children. High severity-of-illness scores and presence of MODS before transfusion were closely associated with the occurrence of RDAT. The major question arising from our results is whether the RDs observed after transfusion are adverse consequences of the transfusion itself, facilitated by the inflammatory status of severely ill patients, or whether this association is observed because both transfusion and RD are more frequent in the most severely ill patients (37). An observational study cannot distinguish a risk factor (cause-effect relationship) from a risk marker (simple association) (38). Causality between the occurrence of RDAT and RBC transfusion was unclear in the adjudicators’ mind, as illustrated by the low degree of certainty reported with regard to a cause-effect relationship. This reflects the fact that it is very difficult to identify the causes of evolving RD in severely ill patients with multiple potential etiological triggers of RD. On the other hand, two results are in support of a possible causal role of transfusion: May 2015 • Volume 16 • Number 4
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the dose-effect relationship observed between RBC transfusion volume and RDAT occurrence and the fact that this dose-effect relationship remains significant even when adjusting for severity categories in the multivariate analysis. Future studies are warranted to properly address this question, in particular with matched cohort study design and ultimately with randomized controlled design. We observed that RDAT was associated with a worse course, including more progressive organ dysfunctions and MODS, higher PICU mortality, and a longer duration of intubation and PICU stay. This observation obviously reflects the direct effect of severity of illness on outcome, but RBC transfusion reaction could also have had a direct impact. The unfavorable outcome observed in patients with RDAT supports further study on this potential complication. In the last decade, more attention has been paid to TRALI and TACO (33), but most cases are presently unrecognized in the critically ill because currently used definitions curtail their identification. We suggest that consideration should also be given to progressive RDAT because this concept is likely relevant in critically ill patients. We confirmed that the reproducibility of the diagnosis of new and progressive RDAT in transfused PICU patients is very good. We also observed a strong association between RDAT and adverse outcomes. The concept of progressive RDAT may result in a novel understanding of the medium- and long-term respiratory complications associated with transfusion in the critically ill. This study is not without limitations. Its observational and noncontrolled nature precludes any conclusion on a cause-effect relationship. We conducted a multivariate logistic analysis to limit the impact of the confounding association between patient severity and transfusion, but residual confounding cannot be excluded (37). The limited sample size (136 patients) can prevent the characterization of less frequent risk factors. Although the RD criteria were checked as soon as 2 hours prior to the transfusion, it is conceivable that a process leading to RD started before the transfusion but was not yet severe enough to reach RD definition, therefore conducting to an overestimation of new RDAT prevalence. The RDAT cases were not classified depending on their possible causes (TRALI, TACO, infections, and other) because many of the RDAT patients had exclusion criteria for these diagnoses, and further studies should address the prevalence of those complications with definitions adapted to critically ill patients. The study was conducted in a single center, in which a rather restrictive strategy for RBC transfusion is in place (30, 31); this should be taken into account to evaluate the external generalizability of our results. The study also has several strengths. The study was prospective and minimized selection bias and seasonal variation by including all consecutive admissions to PICU over a 1-year period. The diagnosis of RDAT was ascertained by an adjudicating committee who used definitions advocated by expert panels and/or scientific bodies. Protopathic bias was prevented by ensuring that RDAT occurred after the first RBC transfusion. Furthermore, Pediatric Critical Care Medicine
attention was paid not only to new RDAT but also to progressive RDAT.
CONCLUSION RDAT, as defined in this single-center study, is common in PICU. Severity of illness, MODS, and volume of RBCs transfused are important risk factors for the development of RDAT. Most cases of RDAT are progressive, occurring in patients with preexisting RD, and were observed after the first 6 hours. Consequently, most transfusion-associated respiratory complications observed in critically ill children would be missed with currently used definitions. Higher mortality rate, prolonged endotracheal intubation, prolonged PICU length of stay, and increased prevalence of MODS were observed in patients with RDAT. Although the causal relationship between transfusion and the occurrence of RDAT and associated adverse outcome cannot be determined from our study, new and progressive RDAT merits further attention from pediatric intensivists and hemovigilance systems.
ACKNOWLEDGMENTS We thank Marilyn Gaudreault, Mariana Dumitrascu, and Evelyne Biffiger who extracted the data.
REFERENCES
1. Corwin HL, Gettinger A, Pearl RG, et al: The CRIT Study: Anemia and blood transfusion in the critically ill–current clinical practice in the United States. Crit Care Med 2004; 32:39–52 2. Bateman ST, Lacroix J, Boven K, et al; Pediatric Acute Lung Injury and Sepsis Investigators Network: Anemia, blood loss, and blood transfusions in North American children in the intensive care unit. Am J Respir Crit Care Med 2008; 178:26–33 3. Gauvin F, Lacroix J, Robillard P, et al: Acute transfusion reactions in the pediatric intensive care unit. Transfusion 2006; 46:1899–1908 4. Brun-Buisson C: The epidemiology of the systemic inflammatory response. Intensive Care Med 2000; 26(Suppl 1):S64–S74 5. Proulx F, Fayon M, Farrell CA, et al: Epidemiology of sepsis and multiple organ dysfunction syndrome in children. Chest 1996; 109:1033–1037 6. West FB, Silliman CC: Transfusion-related acute lung injury: Advances in understanding the role of proinflammatory mediators in its genesis. Expert Rev Hematol 2013; 6:265–276 7. Vlaar AP, Juffermans NP: Transfusion-related acute lung injury: A clinical review. Lancet 2013; 382:984–994 8. Moore SB: Transfusion-related acute lung injury (TRALI): Clinical presentation, treatment, and prognosis. Crit Care Med 2006; 34:S114–S117 9. Gajic O, Rana R, Winters JL, et al: Transfusion-related acute lung injury in the critically ill: Prospective nested case-control study. Am J Respir Crit Care Med 2007; 176:886–891 10. Marik PE, Corwin HL: Acute lung injury following blood transfusion: Expanding the definition. Crit Care Med 2008; 36:3080–3084 11. Gazmuri RJ, Shakeri SA: Blood transfusion and the risk of nosocomial infection: An underreported complication? Crit Care Med 2002; 30:2389–2391 12. Vamvakas EC: Pneumonia as a complication of blood product transfusion in the critically ill: Transfusion-related immunomodulation (TRIM). Crit Care Med 2006; 34:S151–S159 13. Taylor RW, Manganaro L, O’Brien J, et al: Impact of allogenic packed red blood cell transfusion on nosocomial infection rates in the critically ill patient. Crit Care Med 2002; 30:2249–2254 www.pccmjournal.org
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consensus conference: Definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005; 6:2–8 26. Thomas NJ, Shaffer ML, Willson DF, et al: Defining acute lung disease in children with the oxygenation saturation index. Pediatr Crit Care Med 2010; 11:12–17 27. Kleinman S, Caulfield T, Chan P, et al: Toward an understanding of transfusion-related acute lung injury: Statement of a consensus panel. Transfusion 2004; 44:1774–1789 28. Pollack MM, Ruttimann UE, Getson PR: Pediatric risk of mortality (PRISM) score. Crit Care Med 1988; 16:1110–1116 29. Leteurtre S, Martinot A, Duhamel A, et al: Validation of the paediatric logistic organ dysfunction (PELOD) score: Prospective, observational, multicentre study. Lancet 2003; 362:192–197 3 0. Lacroix J, Hébert PC, Hutchison JS, et al; TRIPICU Investigators; Canadian Critical Care Trials Group; Pediatric Acute Lung Injury and Sepsis Investigators Network: Transfusion strategies for patients in pediatric intensive care units. N Engl J Med 2007; 356:1609–1619 31. Demaret P, Tucci M, Ducruet T, et al: Red blood cell transfusion in critically ill children (CME). Transfusion 2014; 54:365–375; quiz 364 32. Rashid N, Al-Sufayan F, Seshia MM, et al: Post transfusion lung injury in the neonatal population. J Perinatol 2013; 33:292–296 33. Refaai MA, Blumberg N: The transfusion dilemma–weighing the known and newly proposed risks of blood transfusions against the uncertain benefits. Best Pract Res Clin Anaesthesiol 2013; 27:17–35 3 4. Despond O, Proulx F, Carcillo JA, et al: Pediatric sepsis and multiple organ dysfunction syndrome. Curr Opin Pediatr 2001; 13:247–253 35. Vamvakas EC, Blajchman MA: Transfusion-related immunomodulation (TRIM): An update. Blood Rev 2007; 21:327–348 36. Opelz G, Sengar DP, Mickey MR, et al: Effect of blood transfusions on subsequent kidney transplants. Transplant Proc 1973; 5:253–259 37. van de Watering L, for the Biomedical Excellence for Safer Transfusion (BEST) Collaborative: Pitfalls in the current published observational literature on the effects of red blood cell storage. Transfusion 2011; 51:1847–1854 38. Lacroix J: Red cell transfusion: Risk marker or risk factor in cardiac children? Pediatr Crit Care Med 2013; 14:330–331
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This study aims to determine the prevalence and characterize the risk factors and outcomes of new or progressive respiratory dysfunction observed after RBC transfusion in critically ill children. Design: Prospective cohort study of all children admitted over a 1-year period. Setting: A multidisciplinary PICU in a tertiary pediatric university hospital. Patients: Patients who received a RBC transfusion while in PICU. Interventions: None. Measurements and Main Results: Two independent adjudicators established the diagnosis of respiratory dysfunction. A respiratory dysfunction associated with transfusion was considered new if it appeared after the first RBC transfusion in PICU. A progressive respiratory dysfunction associated with transfusion was diagnosed if the respiratory dysfunction was present before the transfusion and the Pao2/Fio2 or the Spo2/Fio2 ratio dropped by at least 20% thereafter. Among 842 children admitted into the PICU, 136 received at least one RBC transfusion and were analyzed. Fifty-eight cases of respiratory dysfunction associated with transfusion (43% of transfused patients) were detected, including nine new respiratory dysfunction associated with transfusion (7%) and 49 progressive respiratory dysfunction associated with transfusion (36%). Higher severity of illness, multiple organ dysfunction syndrome prior to transfusion, and volume (mL/kg) of RBC transfusion were independently associated with respiratory dysfunction associated with transfusion. A dose-response relationship was observed between transfusion volume (mL/kg) and the prevalence of respiratory dysfunction associated with transfusion. Patients with respiratory dysfunction associated with transfusion had more progressive multiple organ dysfunction and less ventilation-free and PICU-free days at day 28. Conclusions: Development of respiratory dysfunction associated with transfusion is frequent in PICU and occurs mainly in patients with prior respiratory dysfunction, who would not be identified using current definitions for transfusion-associated complications. A cause-effect relationship cannot be confirmed. However, the high prevalence and the serious adverse outcomes associated with respiratory dysfunction associated with transfusion suggest that this complication should be further studied. (Pediatr Crit Care Med 2015; 16:325–334) www.pccmjournal.org
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Kleiber et al Key Words: child; critical care medicine; erythrocytes; intensive care; mortality; multiple organ dysfunction syndrome; pediatric; red blood cell; respiratory dysfunction; transfusion
R
BC transfusion is a common therapeutic intervention in PICUs (1, 2) that has several benefits and can be potentially lifesaving. RBC transfusion also puts critically ill children at risk for significant complications including the occurrence of several transfusion reactions (3). Systemic inflammatory response syndrome (SIRS) is a frequent occurrence in the critically ill, among adults and children (4, 5), which involves priming and activation of the innate immune response. The presence of SIRS can aggravate the status of the critically ill patient and lead to multiple organ failure when a second inflammatory insult occurs. RBC transfusion is a potential important second hit that can precipitate the cascade leading to multiple organ failure. RBC units contain proinflammatory mediators and also biologically active mediators like blood cells microparticles and bioactive lipids, which can cause both a hyperinflammatory and a immune suppressive response in the recipient (6, 7). Lungs with active inflammatory processes are particularly sensitive to this second hit phenomenon (6, 7). Several respiratory complications of transfusion have been described, including transfusion-related acute lung injury (TRALI), acute respiratory distress syndrome (8–10), nosocomial infections (11–16), and transfusion-associated circulatory overload (TACO) (17–20). All these conditions can lead to respiratory dysfunction (RD) in critically ill patients that is transfusion associated, thus the acronym RDAT in our study. The diagnosis of RDAT is particularly challenging in critically ill patients because many already have RD prior to transfusion and because several risk factors for development of RD are frequently present. The current definitions proposed for the diagnosis of transfusion-related respiratory complications exclude patients with prior RD (21, 22). We hypothesize that RD is frequent after RBC transfusion in PICU patients, but that most of these complications would not be considered because of current definition exclusion criteria, leading to an important underreporting. Transfusion-associated respiratory complications in critically ill adults are indeed underreported (23), although quite frequent (8–10, 17–19). They are likely also underrecognized in critically ill children as reflected by Gauvin et al (24) reporting of only four TRALI cases in PICUs across Canada over a 3-year period. The prevalence of respiratory dysfunction after transfusion in critically ill children with or without preexisting RD is not known. We undertook this study to characterize the prevalence and the risk factors associated with the development of new and progressive RDAT in PICU and to determine the outcome of patients with RDAT. 326
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MATERIAL AND METHODS Study Design This prospective observational cohort study took place in the PICU of Sainte-Justine Hospital, a tertiary care multidisciplinary university-affiliated pediatric hospital. All children consecutively admitted to the PICU over a 1-year period (April 2009 to April 2010) were eligible. The study was approved by the local institutional review board (Comité d’Éthique de la Recherche du CHU Sainte-Justine, project 2870), waiving the requirement for written informed consent. Exclusion criteria included: 1) gestational age less than 40 weeks; 2) postterm age less than 3 days or more than 18 years; 3) pregnancy; and 4) admission to PICU in the postpartum period. Population The study involved patients who received a RBC transfusion while in PICU. Time zero was the time of initiation of the first RBC transfusion in PICU. Any administration of RBCs, regardless of the volume given, was considered a transfusion. Most RBC units were collected from allogeneic whole blood donation except for a few units which were obtained by apheresis. Only prestorage leukocyte-reduced additive solution-3 RBC units were used. Definition of RDAT New or progressive RDAT is the primary outcome measure of this study. According to Goldstein et al (25), a RD is diagnosed when at least one of the following criteria is observed: 1) Pao2/Fio2 ratio less than 300 in the absence of cyanotic heart disease or preexisting lung disease before PICU admission; 2) Paco2 more than 65 mm Hg or 20 mm Hg over baseline Paco2; 3) proven need for more than 50% Fio2 to maintain saturation at least 92%; and 4) need for nonelective invasive or noninvasive mechanical ventilation. When arterial blood gases were not available, the criterion Spo2/Fio2 less than 253 was added as an alternative to Pao2/Fio2 less than 300; the diagnostic value of Spo2/Fio2 ratio has been validated in critically ill children (26). In all instances, the Pao2/Fio2 ratio was considered normal if the Spo2 was at least 99%. We differentiated between new and progressive RDAT. RD was considered new if no RD was present at time zero and appeared after the first RBC transfusion. RDAT was considered progressive when a RD was present at time zero, but worsened after the first RBC transfusion. The severity of RD was considered to have worsened if the Pao2/Fio2 ratio or the Spo2/ Fio2 ratio dropped by at least 20% after the transfusion. This threshold was considered clinically significant by nine pediatric intensivists, using a Delphi method. Transient episodes of Spo2/Fio2 decrease attributable to maneuvers such as endotracheal aspiration were not retained for analysis. Cases of TRALI were also identified based on the definition proposed in 2004 by a panel of experts (27). TRALI was considered when a new acute lung injury with hypoxemia occurred within 6 hours of transfusion, with bilateral pulmonary infiltrates, no evidence of left atrial hypertension, and no temporal May 2015 • Volume 16 • Number 4
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relationship to an alternative risk factor for acute lung injury. A possible TRALI was considered when the last criterion was missing (27). Adjudicating Process An adjudicating committee ascertained the diagnosis of new/ progressive RDAT and TRALI. Two investigators (N.K., E.L.) independently reviewed the patient medical charts and filled out a validated adjudication form. If the two adjudicators did not agree on the diagnosis, they were asked to review their assessment of the data. If consensus could not be reached, a third adjudicator (G.E.) reviewed the case. Consensus was considered to be reached when two of the three adjudicators agreed on the diagnosis. When RDAT was diagnosed, adjudicators rated their degree of certainty for the diagnosis as well as their degree of certainty that there was a causal link between RBC transfusion and development of RD on a 7-point Likert scale. The lowest score (1) meant that a causal link between RBC transfusion and development of RD was very unlikely given the available data and the definition used, whereas a score of 7 reflected a high likelihood (quasi certainty) that RD was caused by RBC transfusion. No specific criteria were a priori established to define the causality. Potential Risk Factors and Outcome Variables To prevent any protopathic bias, only events occurring before time zero were considered as possible risk factors for RDAT; events appearing after time zero were considered as possible adverse events. The following variables were a priori considered as possible risk factors or risk markers for RDAT: age, severity of illness at time zero as evaluated by the Pediatric Risk of Mortality (PRISM) score (28) and the Pediatric Logistic Organ Dysfunction (PELOD) score (29), prior chronic illness (chronic hematologic, cardiac, or oncologic diseases), presence of multiple organ dysfunction syndrome (MODS) as defined by Goldstein et al (25) at time zero, total number of RBC transfusions, volume (mL/kg) of RBCs received, RBC storage time, and transfusion of other blood products (plasma and platelet concentrates). Possible complications of RDAT were monitored daily; this included development of sepsis, severe sepsis, septic shock, and MODS as well as daily PELOD scores, mortality, duration of endotracheal intubation, and PICU length of stay. The occurrence of nosocomial infections after the first RBC transfusion was also recorded. The ventilation-free days and PICU-free days at day 28 were calculated as the number of days spent alive and without ventilation (or outside the PICU) by day 28. Data Management A validated case report form was used to prospectively collect the following data from admission to PICU discharge: demographic data, medical history, admission diagnosis, clinical data, laboratory results, transfusions, mechanical ventilation, fluid balance, new and/or progressive RD criteria, MODS, PICU length of stay, and mortality. The following data were collected Pediatric Critical Care Medicine
hourly in transfused patients from a time point 2 hours prior to transfusion (start of transfusion = time zero) to 24 hours after time zero and then at least once daily until PICU discharge: worse respiratory rate, ventilatory settings, lowest Spo2, lowest Pao2/Fio2 ratio, and Spo2/Fio2 ratio. Data management fulfilled all requirements of standard good clinical data management practice, and all data were treated anonymously. Transfusion Policy In the PICU, no written protocol exists regarding transfusion. In line with the Transfusion Requirements in the Pediatric Intensive Care Unit study (30), the general attitude during the study period was to avoid transfusion when hemoglobin exceeded 7 g/dL in stabilized patients. Statistical Analysis Concordance and κ scores were calculated to assess the reproducibility of the adjudication process. Categorical variables were described by frequency distribution and compared using chi-square or Fisher exact probability test. Continuous variables were reported as mean and sd and/or median and interquartile range and compared across groups using Student t test or nonparametric Wilcoxon tests. Univariate and multivariate logistic regression analyses were done for potential risk factors by calculating unadjusted and adjusted odds ratios (OR) and their 95% CI. Age, severity of illness (PRISM and PELOD scores), and volume (mL/kg) of RBC units given were categorized by quartiles. Statistically significant determinants after univariate analysis (p < 0.05) were included in the multivariate logistic regression. Age and congenital heart disease diagnosis were also included because they are known determinants involved in the decision to transfuse (31). PELOD score was a priori excluded from the model because of its collinearity with PRISM; highest lactate level was a posteriori excluded because these data were missing in more than 25% of patients. The association between RDAT and adverse outcomes was analyzed using univariate chi-square or Student t test. Two-tailed p value of less than 0.05 was considered statistically significant. All analyses were performed by a statistician (T.D.) who used SAS 9.2 (SAS Institute, Cary, NC).
RESULTS Population Nine hundred thirteen patients were admitted to the PICU of Sainte Justine-Hospital during the study year; 71 were excluded because they met at least one exclusion criterion (Fig. 1). Among the remaining 842 patients, 144 (16.9%) received at least one RBC transfusion while in PICU. Eight of the 144 transfused patients were excluded from the adjudication process because no impact on respiratory function could be evaluated, as they were transfused while on extracorporeal membrane oxygenation (n = 4), in the operating room (n = 3), or in the hour preceding death (n = 1). www.pccmjournal.org
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136 transfused patients (65%). No TRALI and two possible TRALIs were identified using the criteria proposed by Kleinman et al (27). Supplemental Table 2 (Supplemental Digital Content 2, http://links.lww. com/PCC/A146) details the frequency and reproducibility of the diagnostic criteria. Concordance between adjudicators for the respiratory dysfunction criteria ranged from 63% to 100% with κ scores ranging from 0.63 to 1.00. Figure 2 illustrates the timing of new or progressive RDAT occurrence after time zero: 52 (89%) appeared within the first 24 hours after the first RBC transfusion, four (7%) during the second day, one (2%) on the Figure 1. Patient flow chart. aSome patients presented more than one exclusion criterion. ECMO = extracorpothird day, and one (2%) more real membrane oxygenation, RDAT = respiratory dysfunction associated with transfusion. than 3 days after time zero. The two adjudicators rated their degree of certainty with Diagnosis of Respiratory Dysfunction regard to the diagnosis of RDAT as strong. With regard to the As reported in Supplemental Table 1 (Supplemental Digicausal link between RBC transfusion and respiratory dysfunctal Content 1, http://links.lww.com/PCC/A145), 58 RDATs tion, the degree of certainty was lower: on a Likert scale of 1 (43%) were diagnosed, including nine new RD and 49 (very unlikely) to 7 (certain), the mean causality rates were 1.8 progressive RD. The concordance between the two adjuand 2.7 for new and progressive RDAT, respectively, and the dicators for the diagnosis of new and progressive RD was highest value rated by the adjudicators for a cause-effect relaperfect. It is of importance to note that RD was present at tionship was 3. time zero (i.e., before the first RBC transfusion) in 89 of the
Figure 2. Length of time between first RBC transfusion in PICU (time zero) and appearance of nine new cases of respiratory dysfunction associated with transfusion (RDAT) (black bars) and 49 progressive RDAT (gray bars).
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Epidemiology of RDAT Table 1 describes the RBC transfusions received by children with or without RDAT. Patients with RDAT were significantly sicker than those without RDAT before receiving the first RBC transfusion in PICU, as illustrated by higher PRISM (p < 0.001) and daily PELOD scores (p = 0.001). Patients with RDAT had a higher hemoglobin level before the first RBC transfusion (p = 0.04) and were exposed to a higher number (p < 0.001) and a larger volume (p < 0.001) of RBC transfusions. RBC unit storage times were similar in both groups. Age, weight, gender, and admission diagnosis were not risk factors associated with RDAT. As detailed in the May 2015 • Volume 16 • Number 4
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Table 1. Description of the RBC Transfusions in Patients With and Without Respiratory Dysfunction Associated With Transfusion All Transfused Patients
With RDAT
Without RDAT
n = 136
n = 58
n = 78
p
57 (41.9)
23 (39.7)
34 (43.6)
0.65
Pediatric Risk of Mortality score on day of first RBC transfusion
7.9 ± 6.3
10.5 ± 6.4
5.9 ± 5.4
< 0.001
Daily Pediatric Logistic Organ Dysfunction score on day of first RBC transfusion
8.4 ± 8.0
10.9 ± 8.5
6.5 ± 7.1
0.001
Hemoglobin level before first RBC transfusion (g/dL)
7.6 ± 2.2
8.1 ± 2.0
7.3 ± 2.3
0.04
1.3 ± 2.1
1.3 ± 2.1
1.3 ± 2.1
0.90
13.2 ± 14.1
16.6 ± 20.4
10.1 ± 5.1
0.02
12 (7–24)
10 (7–23)
13 (7–25)
0.40
3.7 ± 7.1
6.3 ± 10.3
1.8 ± 1.5
< 0.001
Total volume of RBCs (mL/kg/patient) (n = 136)
45.5 ± 83.7
80.4 ± 117.0
19.6 ± 23.8
< 0.001
Median storage time for all RBC transfusions (d)
13 (8–23)
14 (9–23)
13 (8–22)
0. 40
Maximum storage time for all RBC transfusion (d)
16 (9–27)
18 (9–32)
16 (9–25)
0.27
Variable
RBC transfusions within 24 hr before PICU admission Patients transfused before PICU entry, n (%) RBC transfusions after entry into PICU (mean ± sd)
Description of first RBC transfusion Time from admission to first RBC transfusion (d) RBC transfusion volume (mL/kg) Median RBC storage time (d) Description of all RBC transfusions given during PICU stay
a
Number of transfusions per patient (n = 136)
RDAT = respiratory dysfunction associated with transfusion. a These data describe all RBC transfusions given during PICU stay, including the ones received after RDAT diagnosis. Data are reported as number (percentage) or mean ± sd, except for storage times which are reported as median (interquartile).
Table 2, patients in whom RDAT developed had higher PRISM (p < 0.01) and PELOD scores (p = 0.05), more elevated blood lactate levels (p = 0.006) at the time of admission, and a higher prevalence of MODS (p < 0.001) on the day prior to the first RBC transfusion. The occurrence of plasma and platelet transfusions was also associated with RDAT (p = 0.001 and 0.003, respectively), as well as their respective volume (mL/ kg for plasma, p = 0.03, and unit/kg for platelets, p < 0.001). A multiple logistic regression analysis was conducted, including the following variables: age, congenital heart disease diagnosis, PRISM score, presence of MODS at time zero, volume (mL/kg) of RBC transfusion, and plasma and platelet transfusions. Three independent risk factors for RDAT were identified (Table 2): higher PRISM score (p = 0.02), presence of MODS at time zero (p < 0.01), and a greater volume of RBC transfusion (p < 0.01). We observed a dose-effect relationship between the volume of RBCs transfused and occurrence of new or progressive RD: using the first quartile (0–10 mL/kg) as reference, the OR for development of RDAT attained a value of 6.8 (95% CI, 1.6–28.2; p = 0.001) in patients who received more than 38 mL/kg of RBCs. A sensitivity analysis was conducted in order to explore the impact of the volume (per kg) of plasma or platelet transfusions. The entry of these two variables as continuous rather than as categorical variables did not change Pediatric Critical Care Medicine
the results of the model. The weight of the independent factors was not modified, whereas the volume of plasma or platelet transfusion was not independently associated with RDAT (p = 0.21 and 0.38, respectively). Outcome Outcome data are detailed in Table 3. In univariate analysis, patients with RDAT developed more progressive MODS (p < 0.001). More nosocomial bacteremias were observed in patients with RDAT (p < 0.05). RDAT was also associated with a more prolonged period of endotracheal intubation (p = 0.006) and PICU length of stay (p = 0.01). PICU mortality was almost three-fold higher in patients with RDAT (5.1% vs 19%; p = 0.01). At day 28, the PICU-free days and ventilationfree days were lower in the RDAT group (p < 0.001 and p < 0.0001, respectively)
DISCUSSION Recent literature has reported an association between blood transfusion and adverse outcome and has described numerous respiratory complications that can occur after transfusion. Many of these studies have been carried out in patients with no prior RD in whom it is fairly straightforward to identify new onset RD. As most ICU patients already present respiratory www.pccmjournal.org
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Table 2.
Variables Associated With Respiratory Dysfunction Associated With Transfusion Transfused Patients
With RDAT
Without RDAT
Univariate Analysis
n = 136
n = 58
n = 78
OR (95% CI)
60.6 ± 75.3
56.7 ± 73.2
63.4 ± 77.2
≤ 28 d, patients, n (%)
20 (14.7)
12 (20.7)
8 (10.3)
2.25 (0.82–6.21)
29–364 d, patients, n (%)
46 (33.8)
18 (13.2)
28 (35.9)
0.96 (0.45–2.06)
> 364 d, patients, n (%)
70 (51.5)
28 (48.3)
42 (53.8)
Reference
Weight (kg), mean ± sd
21 ± 22.4
Gender (male), n (%)
69 (50.7)
29 (50)
40 (51.3)
0.95 (0.48–1.88)
0.88
15 (11)
5 (8.6)
10 (12.8)
0.64 (0.21–1.99)
0.44
Congenital heart disease, cyanotic
33 (24.3)
16 (27.6)
17 (21.8
1.37 (0.62–3.01)
0.43
1.80 (0.66–4.92)
0.25
Congenital heart disease, noncyanotic
25 (18.4)
10 (17.2)
15 (19.2)
0.88 (0.36–2.12)
0.77
0.81 (0.26–2.48)
0.71
9 (6.6)
4 (6.9)
5 (6.4)
1.08 (0.28–4.22)
0.99
32 (23.5)
13 (22.4)
19 (24.4)
0.90 (0.40–2.01)
0.79
6 (4.4)
4 (6.9)
2 (2.6)
2.82 (0.50–15.92)
0.40
PRISM score, mean ± sd
9.5 ± 7.1
11.6 ± 7.3
7.9 ± 6.6
0.002
First quartile: PRISM = 0–4, n (%)
37 (27.2)
9 (15.5)
28 (35.9) Reference
0.004
Second quartile: PRISM = 5–8, n (%)
35 (25.7)
15 (25.9)
20 (25.6)
2.33 (0.85–6.38)
0.21
2.89 (0.88–9.48)
0.08
Third quartile: PRISM = 9–14, n (%)
34 (25)
13 (22.4)
21 (26.9)
1.93 (0.69–5.35)
0.10
1.50 (0.44–5.11)
0.52
Fourth quartile: PRISM > 14, n (%)
30 (22.1)
21 (36.2)
9 (11.5)
7.26 (2.46–21.45)
0.001
5.02 (1.33–19.0)
0.02
Pediatric Logistic Organ Dysfunction score, mean ± sd
8.9 ± 8.5
10.7 ± 10.1
7.6 ± 6.8
Possible Risk Factors
Multivariate Analysis Adjusted OR (95% CI)
p
0.12
0.90 (0.23–3.54)
0.88
0.93
0.58 (0.21–1.59)
0.29
p
Clinical data at PICU admission Age (mo), mean ± sd
0.61
20.7 ± 23.8 21.1 ± 21.4
Reference 0.92
Previous diseases, n (%) Anemia
Primary diagnosis, n (%) Septic shock Cardiac surgery Trauma
Reference
0.05
Laboratory data at PICU admission, mean ± sd Worst Pao2 (n = 41) (mm Hg)
131.5 ± 84.8 133.9 ± 86.3 129.3 ± 84.4
0.82
Lowest hemoglobin (n = 129) (g/dL)
9.0 ± 2.9
9.3 ± 2.7
8.8 ± 3.0
0.25
Highest lactate level (n = 101) (mmol/L)
4.9 ± 5.2
6.8 ± 6.8
3.3 ± 2.5
0.006 (Continued)
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Table 2. (Continued). Variables Associated With Respiratory Dysfunction Associated With Transfusion
Possible Risk Factors
Transfused Patients
With RDAT
Without RDAT
Univariate Analysis
n = 136
n = 58
n = 78
OR (95% CI)
Multivariate Analysis Adjusted OR (95% CI)
p
p
Syndromes before first RBC transfusion in PICU Systemic inflammatory response syndrome, n (%)
77 (56.6)
32 (55.2)
45 (57.7)
0.88 (0.44–1.74)
0.70
Sepsis
48 (35.3)
21 (36.2)
27 (34.6)
1.05 (0.52–2.14)
0.89
Severe sepsis
18 (13.2)
10 (17.2)
8 (10.3)
1.80 (0.66–4.88)
0.25
Septic shock
11 (8.1)
6 (10.3)
5 (6.4)
1.66 (0.48–5.74)
0.53
Multiple organ dysfunction syndrome, n (%)
75 (55.1)
42 (72.4)
33 (42.3)
3.58 (1.73–7.43)
< 0.001
7 (5.1)
5 (8.6)
2 (2.6)
Septic states, n (%)
Cardiovascular dysfunction, n (%)
3.58 (0.67–19.17)
3.53 (1.39–8.94) 0.008
0.14
Number and volume of transfusions given in PICU Volume of RBC transfusion received, n (%) First quartile: 0–10 mL/kg
36 (26.5)
11 (19.0)
25 (32.1)
Reference
Second quartile: 10–16.3 mL/kg
32 (23.5)
7 (12.1)
25 (32.1)
0.64 (0.21–1.91)
0.42
0.53 (0.16–1.81) 0.31
Third quartile: 16.3–38 mL/kg
35 (25.7)
15 (25.9)
20 (25.6)
1.71 (0.64–4.52)
0.28
1.44 (0.45–4.66) 0.54
Fourth quartile: > 38 mL/kg
33 (24.3)
25 (43.1)
8 (10.3)
7.10 (2.44–20.6) < 0.001
6.83 (1.65–28.2) 0.008
68 (50)
38 (65.5)
30 (38.5)
3.20 (1.57–6.54)
1.21 (0.46–3.21) 0.70
Plasma transfusion, n (%) Volume (mL/kg): mean ± sd Platelet transfusion, n (%) Platelets (units/kg): mean ± sd
52.0 ± 178.5 95.2 ± 262.0 19.9 ± 51.3 47 (34.6)
28 (48.3)
19 (24.4)
0.21 ± 0.66 0.30 ± 0.56 0.14 ± 0.72
Reference
0.001 0.03
2.98 (1.44–6.24)
0.003
0.86 (0.28–2.64) 0.79
< 0.001
RDAT = respiratory dysfunction associated with transfusion, OR = odds ratio, PRISM = Pediatric Risk of Mortality.
symptoms before the transfusion (65% in the present study) and/or have other risk factors for development of RD, the currently available definitions underestimate the prevalence of transfusion-associated respiratory complications in the critically ill. The objective of the present work is to evaluate the magnitude of potential underestimation of RDAT consecutive to these restrictive definitions. The study aimed to determine the prevalence rate of RDAT in critically ill children, without exclusion criteria based on prior RD presence. We report the occurrence of new cases of new RDAT and 49 cases of progressive RDAT in 136 critically ill children, while only two possible TRALI were identified. The role of RBC transfusion on the respiratory function of critically ill patients is of interest for ICU practitioners and Pediatric Critical Care Medicine
experts in hemovigilance. Many hemovigilance systems and expert consensus definitions do not consider that respiratory complications are transfusion reactions if some respiratory symptoms were present before transfusion (21, 22, 27). The absence of a broader definition that allows identification of both new and progressive RD is a major obstacle in estimating the true prevalence of RDAT. In this study, we introduce the concept of worsening RD and advocate that some attention should be paid to progressive RDAT. Progressive RDAT is indeed much more frequent than new RDAT and was present in 55% of transfused PICU patients with preexisting RD (vs 19% new RDAT). The length of monitoring for acute transfusion reactions involving the respiratory system is also a matter of debate. www.pccmjournal.org
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Table 3. Univariate Association Between Respiratory Dysfunction Associated With Transfusion and Outcomes Transfused Patients n = 136
With RDAT n = 58
New MODS
22 (16.2)
13 (22.4)
Progressive MODS
41 (30.1)
29 (50)
Outcome Data, n (%) or Mean ± sd
Without RDAT n = 78
p
MODS and organ dysfunction, n (%)
Worst Pediatric Logistic Organ Dysfunction score post first RBC transfusion (n = 127)
11.0 ± 9.8
Acute respiratory distress syndrome (n = 124)
7 (6)
Length of endotracheal intubation (d)
8.4 ± 26.5
15.2 ± 10.8 3 (5) 15.9 ± 39.2
9 (11.5)
0.24
12 (15.4)
< 0.001
7.5 ± 7.4
0.07
4 (6)
0.90
2.8 ± 4.4
0.006
Nosocomial infections post first RBC transfusions (n = 122), n (%) Pneumonia
4 (3)
3 (5)
1 (1)
0.22
Tracheitis
2 (2)
1 (2)
1 (1)
0.89
Bacteremia
5 (4)
5 (9)
0 (0)
< 0.05
Urinary infections
6 (5)
5 (9)
1 (1)
0.053
Other infections
6 (5)
5 (9)
1 (1)
0.053
Ventilation-free days at day 28
20.1 ± 10.2
15.0 ± 11.3
23.8 ± 7.4
< 0.0001
Length of PICU stay (d) (n = 134)
11.9 ± 27.0
19.4 ± 39.4
6.3 ± 6.0
PICU-free days at day 28
16.9 ± 9.7
12.3 ± 10.2
20.4 ± 7.7
< 0.001
0.01
Mortality, n (%) PICU mortality
15 (11.0)
11 (19)
4 (5.1)
0.01
28-day all-cause mortality
14 (10.3)
10 (17.2)
4 (5.1)
0.02
3 (2.2)
2 (3.4)
1 (1.3)
0.6
Hospital mortality post-PICU
RDAT = respiratory dysfunction associated with transfusion, MODS = multiple organ dysfunction syndrome.
Some experts believe that TRALI should be monitored only up to 6 hours after transfusion (27, 32), whereas others argue that 72 hours should be considered (10). We observed 28 cases of RDAT (48%) within 6 hours, 24 (41%) between 6 and 24 hours, and six (10%) between 24 and 72 hours after the first RBC transfusion (Fig. 2). Although certain mechanisms such as fluid overload, passive antibody transfer, and allergic reactions can trigger a RD within 6 hours (7, 33), a delayed occurrence of RDAT could be otherwise explained by inflammatory reaction in the critically ill. SIRS is observed in most critically ill children (5). This systemic inflammation primes patients to overreact to additional insults (two-hit phenomenon) (7), which may aggravate the inflammatory status within a period of time that surpasses the time frames used in current definitions (34). RBC transfusion can be a second hit for the critically ill patient with SIRS (33), which can lead to multiple organ failure, involving worsening RD. There is also strong evidence that transfusion can cause some immune suppression (35). This can explain why an association is frequently reported between transfusion and an increased risk of nosocomial infections (14). The duration of the immune suppression related to transfusion is unknown but may range from a 332
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few days to months (14, 36). The optimal time frame during which RDAT should be monitored remains to be determined; our results and numerous pathophysiologic hypotheses suggest that 6 hours may be too short. We characterize risk factors and risk markers for RDAT in critically ill children. High severity-of-illness scores and presence of MODS before transfusion were closely associated with the occurrence of RDAT. The major question arising from our results is whether the RDs observed after transfusion are adverse consequences of the transfusion itself, facilitated by the inflammatory status of severely ill patients, or whether this association is observed because both transfusion and RD are more frequent in the most severely ill patients (37). An observational study cannot distinguish a risk factor (cause-effect relationship) from a risk marker (simple association) (38). Causality between the occurrence of RDAT and RBC transfusion was unclear in the adjudicators’ mind, as illustrated by the low degree of certainty reported with regard to a cause-effect relationship. This reflects the fact that it is very difficult to identify the causes of evolving RD in severely ill patients with multiple potential etiological triggers of RD. On the other hand, two results are in support of a possible causal role of transfusion: May 2015 • Volume 16 • Number 4
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the dose-effect relationship observed between RBC transfusion volume and RDAT occurrence and the fact that this dose-effect relationship remains significant even when adjusting for severity categories in the multivariate analysis. Future studies are warranted to properly address this question, in particular with matched cohort study design and ultimately with randomized controlled design. We observed that RDAT was associated with a worse course, including more progressive organ dysfunctions and MODS, higher PICU mortality, and a longer duration of intubation and PICU stay. This observation obviously reflects the direct effect of severity of illness on outcome, but RBC transfusion reaction could also have had a direct impact. The unfavorable outcome observed in patients with RDAT supports further study on this potential complication. In the last decade, more attention has been paid to TRALI and TACO (33), but most cases are presently unrecognized in the critically ill because currently used definitions curtail their identification. We suggest that consideration should also be given to progressive RDAT because this concept is likely relevant in critically ill patients. We confirmed that the reproducibility of the diagnosis of new and progressive RDAT in transfused PICU patients is very good. We also observed a strong association between RDAT and adverse outcomes. The concept of progressive RDAT may result in a novel understanding of the medium- and long-term respiratory complications associated with transfusion in the critically ill. This study is not without limitations. Its observational and noncontrolled nature precludes any conclusion on a cause-effect relationship. We conducted a multivariate logistic analysis to limit the impact of the confounding association between patient severity and transfusion, but residual confounding cannot be excluded (37). The limited sample size (136 patients) can prevent the characterization of less frequent risk factors. Although the RD criteria were checked as soon as 2 hours prior to the transfusion, it is conceivable that a process leading to RD started before the transfusion but was not yet severe enough to reach RD definition, therefore conducting to an overestimation of new RDAT prevalence. The RDAT cases were not classified depending on their possible causes (TRALI, TACO, infections, and other) because many of the RDAT patients had exclusion criteria for these diagnoses, and further studies should address the prevalence of those complications with definitions adapted to critically ill patients. The study was conducted in a single center, in which a rather restrictive strategy for RBC transfusion is in place (30, 31); this should be taken into account to evaluate the external generalizability of our results. The study also has several strengths. The study was prospective and minimized selection bias and seasonal variation by including all consecutive admissions to PICU over a 1-year period. The diagnosis of RDAT was ascertained by an adjudicating committee who used definitions advocated by expert panels and/or scientific bodies. Protopathic bias was prevented by ensuring that RDAT occurred after the first RBC transfusion. Furthermore, Pediatric Critical Care Medicine
attention was paid not only to new RDAT but also to progressive RDAT.
CONCLUSION RDAT, as defined in this single-center study, is common in PICU. Severity of illness, MODS, and volume of RBCs transfused are important risk factors for the development of RDAT. Most cases of RDAT are progressive, occurring in patients with preexisting RD, and were observed after the first 6 hours. Consequently, most transfusion-associated respiratory complications observed in critically ill children would be missed with currently used definitions. Higher mortality rate, prolonged endotracheal intubation, prolonged PICU length of stay, and increased prevalence of MODS were observed in patients with RDAT. Although the causal relationship between transfusion and the occurrence of RDAT and associated adverse outcome cannot be determined from our study, new and progressive RDAT merits further attention from pediatric intensivists and hemovigilance systems.
ACKNOWLEDGMENTS We thank Marilyn Gaudreault, Mariana Dumitrascu, and Evelyne Biffiger who extracted the data.
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