Transfusion and Apheresis Science xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
The relationship between total red blood cells and plasma transfusion and acute lung injury risk after cardiac surgery: A retrospective study Kun Liu a, Hong-Lin Chen b, Qing-Sheng You a, Zhi-Wei Wang c,⇑ a
Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Xi Si Road 20# Nantong City, Jiangsu Province 226001, PR China Nantong University, Qi Xiu Road 19# Nantong City, Jiangsu Province 226001, PR China c Department of General Surgery, Affiliated Hospital of Nantong University, Xi Si Road 20# Nantong City, Jiangsu Province 226001, PR China b
a r t i c l e
i n f o
Article history: Received 7 November 2013 Received in revised form 8 January 2014 Accepted 4 March 2014 Available online xxxx Keywords: Cardiac surgery Acute lung injury Red blood cells Fresh-frozen plasma Retrospective study
a b s t r a c t The aim of our study was to determine whether red blood cells (RBCs) and fresh frozen plasma (FFP) transfusion is independently associated with the development of acute lung injury (ALI) in patients after cardiac surgery. In retrospective study, 165 patients were included. The results showed total fresh RBCs transfusion were not significantly increased in patients who developed ALI compared with patients who did not develop ALI (4.7 ± 2.4, 4 [0–12] units VS 4.0 ± 1.9, 3 [0–9] units, P = 0.119). FFP transfusion were also not significantly increased (704.1 ± 832.5, 600 [150–6500] ml VS 533.9 ± 323.6, 400 [125–3100] ml, P = 0.053). Multivariable logistic regression analysis showed that only age and CPB time were independent factors for ALI, but not for total RBCs and FFP transfused, with the adjusted OR 0.952 (95% CI 0.762–1.189, P = 0.664), and 1.000 (95% CI 0.999–1.001, P = 0.480), respectively. In subgroup analysis, female patients showed a lower ALI incidence in low RBCs transfused group (23.9% VS 45.0%, OR 0.38, 95% CI 0.15–0.98) and in low FFP transfused group (22.0% VS 44.4%, OR 0.35, 95% CI 0.14–0.90). Our study demonstrates that red blood cells and fresh-frozen plasma transfusion are not related with ALI after cardiac surgery in our institution. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Cardiac surgery with cardiopulmonary bypass (CPB) has been associated with a frequent complication of acute lung injury (ALI). The estimated ALI incidence was as many as 20% after cardiac surgery, and the related mortality was as high as 80% [1]. Care for patients with acute respiratory distress syndrome is supportive, with low tidal volume ventilation being the mainstay of therapy. Careful fluid management, minimization of blood product transfusion, appropriate nutrition, and early physical rehabilitation ⇑ Corresponding author. E-mail address: [email protected] (Z.-W. Wang).
may improve outcomes [1]. Patients developing ALI were longer ventilated and had a greater length of ICU and hospital stay (P < .05 for all, respectively) [2]. ALI will also increase the cost of the treatment. Studies have shown that the etiology of lung injury is multifactorial, including pulmonary hypoperfusion, the induction of inflammatory mediators, hypothermia, and blood contact with the foreign surfaces of the CPB system [3]. Transfusion of multiple units has long been considered a risk factor for ALI [4,5]. The incidence of transfusion-related ALI in the critically ill patients ranged from 5.4% to 8% [6,7]. Leukocyte antibodies, present in fresh frozen plasma and platelet concentrates from multiparous donors, and neutrophil priming agents released in stored cellular
http://dx.doi.org/10.1016/j.transci.2014.03.001 1473-0502/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Liu K et al. The relationship between total red blood cells and plasma transfusion and acute lung injury risk after cardiac surgery: A retrospective study. Transf Apheres Sci (2014), http://dx.doi.org/10.1016/j.transci.2014.03.001
2
K. Liu et al. / Transfusion and Apheresis Science xxx (2014) xxx–xxx
blood components have been considered to be causative [8]. In the perioperative period of cardiac surgery, patients often require transfusions of blood products. Studies have confirmed platelet transfusion was associated with ALI after cardiac surgery [9]. However, the relationship between red blood cells (RBCs) and fresh-frozen plasma (FFP) transfusion and the development of ALI after cardiac surgery has not been confirmed. The specific aim of our study was to determine whether RBCs and FFP transfusion is independently associated with the development of ALI in patients after cardiac surgery.
2. Methods 2.1. Patients The study was performed in a university hospital in China. There are about 150–250 cases of cardiac surgery carried out each year. We performed a retrospective analysis among consecutive patients with cardiac surgery between January 2012 and December 2012. The study was approved by the medical ethics committee of the hospital. Pediatric and adult patients of any age undergoing cardiac surgery with cardiopulmonary bypass met the inclusion criteria. Exclusion criteria included the following: r cardiac surgery without cardiopulmonary bypass (such as off-pump coronary artery bypass grafting, transpleural and extrapleural ligation of patent ductus arteriosus); s percutaneous transluminal coronary angioplasty.
2.2. ALI definition ALI was defined according to the standard American– European Consensus Conference on acute respiratory distress syndrome (ARDS) definition [10] as follows: r oxygenation: PaO2/FiO2 < 300 mm Hg (regardless of positive end-expiratory pressure); s chest radiograph: bilateral infiltrates seen on frontal chest radiograph; t pulmonary artery occlusion pressure: 618 mm Hg when measured or no clinical evidence of left atrial hypertension.
2.3. Data collection All data were obtained by reviewing patients’ medical records. Data were retrieved by trained medical personnel using specifically tailored data forms. We collected data on patient demographics and admission diagnosis. Transfusion data collection included the total amount of transfused leuko-reduced fresh RBCs and FFP. All the blood products were centrifuged, separated, and frozen solid at 30 °C within 6 h of collection, and the storage age of RBCs was no more than 5 days. The blood products form multiparous female donors were avoid. We also collected potential risk factors for onset of ALI, including smoking (P100 cigarettes for lifetime), chronic obstructive pulmonary disease, diabetes mellitus, hypertension, alcohol abuse (more than 40 g of alcohol per day), and cardiopulmonary bypass time.
2.4. Statistical analysis Demographics and baseline characteristics were compared between patients in whom ALI developed and those in whom it did not develop. Continuous data were firstly checked for distribution. Normal distributed data were analyzed using analysis of unpaired student’s t test. Non-normal distribution data were analyzed using Mann–Whitney U test. Categorical data were analyzed with the v2 test. In order to exclude potential confounding factors of ALI, we (1) conducted multivariable logistic regression analysis after univariate analysis; (2) used Mantel–Haenszel tests stratified by the each subgroup. A twosided p value of 60 Type of surgery Congenital heart disease Valve heart disease Others Alcohol abuse Yes No Smoking Yes No Diabetes mellitus Yes No Hypertension Yes No COPD Yes No CPB time (min), mean ± SD, median [range] 0–60 60–120 120–180 180–240 >240 Total RBCs transfused (unit), mean ± SD, median [range] 0–4 4–8 >8 Total FFP transfused (ml), mean ± SD, median [range] 0–400 400–800 >800
Total (n = 165)
ALI (n = 56)
No ALI (n = 109)
P value 0.951
79 (47.9%) 86 (52.1%) 50.9 ± 17.7, 55 [1–81] 14 (8.5%) 16 (9.7%) 85 (51.5%) 50 (30.3%)
27 (48.2%) 29 (51.8%) 56.9 ± 13.3, 58 [5–81] 1 (1.8%) 4 (7.1%) 26 (46.4%) 25 (44.6%)
52 (47.7%) 57 (52.3%) 47.8 ± 18.9, 53 [1–80] 13 (11.9%) 12 (11.0%) 59 (54.1%) 25 (22.9%)
28 (17.0%) 111 (67.3%) 26 (15.8%)
4 (7.1%) 42 (75.0%) 10 (17.9%)
24 (22.0%) 69 (63.3%) 16 (14.7%)
4 (2.4%) 161 (97.6%)
1 (1.8%) 55 (98.2%)
3 (2.8%) 106 (97.2%)
6 (3.6%) 159 (96.4%)
3 (5.4%) 53 (94.6%)
3 (2.8%) 106 (97.2%)
3 (1.8%) 162 (98.2%)
2 (3.6%) 54 (96.4%)
1 (0.9%) 108 (99.1%)
20 (12.1%) 145 (87.9%)
9 (16.1%) 47 (83.9%)
11 (10.1%) 98 (89.9%)
4 (2.4%) 161 (97.6%) 124.3 ± 52.6, 116 [38–330] 12 (7.3%) 78 (47.3%) 54 (32.7%) 16 (9.7%) 5 (3.0%) 4.3 ± 2.1, 3.5 [0–12] 99 (60.0%) 59 (35.8%) 7 (4.2%) 591.4 ± 554.9, 500 [125–2500] 78 (47.3%) 72 (43.6%) 15 (9.1%)
2 (3.6%) 54 (96.4%) 142.1 ± 55.9, 126.5 [60–330] 1 (1.8%) 22 (42.9%) 24 (39.3%) 5 (8.9%) 4 (7.1%) 4.7 ± 2.4, 4 [0–12] 30 (53.6%) 22 (39.3%) 4 (7.1%) 704.1 ± 832.5, 600 [150–6500] 22 (39.3%) 25 (44.6%) 9 (16.1%)
2 (1.8%) 107 (98.2%) 115.2 ± 48.5, 107 [38–268]
0.002* 0.011*
0.055
0.702
0.397
0.227
0.265
0.492
11 (10.1%) 54 (49.5%) 32 (29.4%) 11 (10.1%) 1 (0.9%) 4.0 ± 1.9, 3 [0–9] 69 (63.3%) 37 (33.9%) 3 (2.8%) 533.9 ± 323.6, 400 [125–3100] 56 (51.4%) 47 (43.1%) 6 (5.5%)
0.002* 0.045*
0.119 0.278
0.053 0.058
COPD = chronic obstructive pulmonary disease; SD = standard deviation. Significant value.
*
significantly different between ALI group and no ALI group (Table 1). The overall ALI incidence in low RBCs transfused group (0–4 units) was 30.3% (30/99), and 39.4% (26/66) in high RBCs transfused group (>4 units). No difference was found between two groups, with the OR 0.67 (95% CI, 0.36–1.29; v2 = 1.46, P = 0.227). The overall ALI incidence in low FFP transfused group (0–400 ml) was 28.2% (22/78), and 39.1% (34/87) in high FFP transfused group (>400 ml). No difference was found between two groups, with the OR 0.61 (95% CI, 0.30–1.23; v2 = 2.17, P = 0.141). Multivariable logistic regression analysis showed that total RBCs transfused amount and total FFP transfused amount were not the independent factors for ALI, after adjustment for gender, age, type of surgery, alcohol abuse, smoking, diabetes mellitus, hypertension, chronic obstructive pulmonary diseases, and CPB time. The adjusted OR was 0.952 (95% CI 0.762–1.189, P = 0.664), and
1.000 (95% CI 0.999–1.001, P = 0.480), respectively. Multivariable regression analysis showed that only patients’ age and CPB time were the independent factors for ALI after cardiac surgery, with the adjusted OR 1.036 (95% CI 1.004–1.069, P = 0.026), and 1.010 (95% CI 1.002–1.018, P = 0.019), respectively. Table 2 shows the multivariate analysis results of risk factors for the onset of ALI after cardiac surgery. 3.3. Subgroup analysis In gender subgroup, female patients had a lower ALI incidence of 23.9% (11/46) in low RBCs transfused group, compared with 45.0% (18/40) in high RBCs transfused group, with the OR 0.38 (95% CI 0.15–0.98). Male patients had the same ALI incidence between low RBCs transfused group and high RBCs transfused group (35.8%, 19/53 VS 30.8%, 8/26), with the OR 1.26 (95% CI 0.46–3.43). No ALI
Please cite this article in press as: Liu K et al. The relationship between total red blood cells and plasma transfusion and acute lung injury risk after cardiac surgery: A retrospective study. Transf Apheres Sci (2014), http://dx.doi.org/10.1016/j.transci.2014.03.001
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K. Liu et al. / Transfusion and Apheresis Science xxx (2014) xxx–xxx
a
b
c
d
Fig. 1. Continuous data (including total RBCs transfused, total plasma transfused, age and CPB time) comparison according to patients developing ALI or those who did not develop ALI.
Table 2 Multivariate analysis of risk factors for the onset of ALI in cardiac surgery patients. Characteristics
B
S.E.
Wald
P value
OR
95% CI for OR
Gender Age Type of surgery Type of surgery (1) Type of surgery (2) Alcohol abuse Smoking Hypertension Diabetes mellitus COPD Total RBCs transfused Total plasma transfused CPB time Constant
0.135 0.036
0.388 0.016
0.535–2.448 1.004–1.069
0.775 0.511 1.434 1.019 0.560 1.287 1.068 0.113 0.001 0.004 1.177
0.727 0.026* 0.692 0.638 0.396 0.241 0.104 0.863 0.281 0.457 0.664 0.480 0.019* 0.001
1.145 1.036
0.365 0.435 1.683 1.659 0.097 1.386 794 –0.049 0.000 0.010 3.741
0.122 4.980 0.735 0.222 0.722 1.377 2.648 0.030 1.161 0.553 0.189 0.500 5.515 10.097
0.694 0.648 0.186 5.253 0.908 3.999 2.212 0.952 1.000 1.010 0.024
0.152–3.170 0.238–1.764 0.011–3.090 0.712–38.744 0.303–2.720 0.321–49.791 0.273–17.937 0.762–1.189 0.999–1.001 1.002–1.018
COPD = chronic obstructive pulmonary disease; SD = standard deviation. Significant value.
*
incidence differences were found between other subgroups compared low RBCs transfused group and high RBCs transfused group. In gender subgroup, female patients had a lower ALI incidence of 22.0% (9/41) in low FFP transfused group, compared with 44.4% (20/45) in high FFP transfused group,
with the OR 0.35 (95% CI 0.14–0.90). Male patients had the same ALI incidence between low FFP transfused group and high FFP transfused group (35.1%, 13/37 VS 33.3%, 14/42), with the OR 1.08 (95% CI 0.43–2.75). No ALI incidence differences were found between other subgroups compared low FFP transfused group and high FFP transfused group.
Please cite this article in press as: Liu K et al. The relationship between total red blood cells and plasma transfusion and acute lung injury risk after cardiac surgery: A retrospective study. Transf Apheres Sci (2014), http://dx.doi.org/10.1016/j.transci.2014.03.001
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4. Discussion In a case control study, Tuinman PR reported transfusion during cardiac surgery was associated with activation of inflammation and coagulation in the pulmonary compartment, bronchoalveolar lavage fluid (BALF) levels of IL-8, tumor necrosis factor a (TNFa) and thrombin– antithrombin complex (TATc) were increased after multiple transfusions (P < 0.01, P < 0.001 and P < 0.01, respectively) compared to nontransfused controls [11]. Vlaar AP also reported transfusion was associated with systemic and pulmonary inflammation and activation of neutrophils, as well as enhanced coagulation and suppressed fibrinolysis [12]. These evidences showed transfusion maybe also play an important role in ALI after cardiac surgery. However, our data suggest that RBCs and FFP transfusion are not related with ALI after cardiac surgery according to the consensus definition. In cardiac surgery with cardiopulmonary bypass, pulmonary hypoperfusion, the induction of inflammatory mediators, hypothermia, and blood contact with the foreign surfaces of the CPB system were the important risk factors for ALI. Compared with these important factors, the role of blood transfusion may be very small for ALI. Koch C also reported the similar results: in the 16,847 cardiac surgery patients, the ICU admission PaO2/FiO2 ratios were similar among 2941 pairs of propensity-matched patients between RBC transfusion versus no RBC transfusion (257 [185, 340] VS 248 [182, 330], p = 0.169) and among 625 propensity-matched pairs of patients between FFP transfusion versus no FFP transfusion (227 [153,323] VS 238 [167,328], p = 0.25). However, Koch C also reported transfusion was associated with many measures of postoperative pulmonary morbidity, which included respiratory distress, respiratory failure, longer intubation times, acute respiratory distress syndrome, and reintubation. They believed it was difficult to differentiate lung injury related to transfusion with PaO2/FiO2 criteria measures [13]. The known benefit of blood products transfusion include an increased blood volume, increased oxygen-carrying capacity of blood, improved tissue oxygenation, and improved hemostasis. We believe RBCs and FFP transfusion should not be limited after cardiac surgery when thinking about transfusion related ALI. However, our study also found female cardiac surgery patients seem to be susceptible to ALI after transfusion, with ALI incidence OR 0.38 (95% CI 0.15–0.98) for low RBCs transfused and OR 0.35 (95% CI 0.14–0.90) for low FFP transfused. Rogers MA also reported in cardiac surgery, women receive allogeneic RBCs or platelets had a greater risk of infection (p = 0.005), pulmonary dysfunction (p = 0.005), and mortality (p = 0.007) than men during hospitalization [14,15]. They believed the reason was that women were more likely to receive blood products than men (odds ratio [OR] 21.6, 95% CI 3.8, 124.2) and a greater quantity than men. In our study, we believed there must be another reasons for gender differences in transfusion complications. Some studies are needed. In our study, we only assessed the relationship between total blood products transfused amount and transfusionrelated ALI. In a prospective nested case-control study,
5
Vlaar AP reported number of red blood cells stored more than 14 days was a risk factor for transfusion-related ALI in cardiac surgery patients, with OR 1.6 (95% CI, 1.04– 2.37) [2]. In our study, we used the fresh red blood cells in all of the patients with the storage age was no more than 5 days. We did not assess the blood products storage age for transfusion-related ALI risk factor. However, we still suggest the fresh blood products should be used in cardiac surgery patients. There are some limitations in our study. First, it was a retrospective case control study. Although we have used multivariable logistic regression analysis and Mantel– Haenszel tests subgroup analysis to exclude potential confounding factors of ALI, it is likely that some unknown risk factors have been missed and were actually responsible for ALI after cardiac surgery. Second, many values of the blood products storage age are missing. We cannot assess the storage age and ALI risk factor. New prospective cohort studies with large sample are needed. In summary, our study demonstrates that red blood cells and fresh-frozen plasma transfusion are not related with ALI after cardiac surgery regarding whole population in our institution. However, female cardiac surgery patients seem to be susceptible to ALI after transfusion. Further larger cohorts are needed to confirm our findings. Acknowledgments This research was supported by Nantong city social development project (HS2012025), Jiangsu province postdoctoral research foundation (1301072C), and China Postdoctoral Science Foundation (2103M541705) . We thank the editor and anonymous reviewers for several insightful comments that significantly improved the paper. References [1] Stephens RS, Shah AS, Whitman GJ. Lung injury and acute respiratory distress syndrome after cardiac surgery. Ann Thorac Surg 2013 ;95(3):1122–9. [2] Vlaar AP, Hofstra JJ, Determann RM, Veelo DP, Paulus F, Kulik W, et al. The incidence, risk factors, and outcome of transfusion-related acute lung injury in a cohort of cardiac surgery patients: a prospective nested case-control study. Blood 2011;117(16): 4218–25. [3] Ng CS, Wan S, Yim AP, Arifi AA. Pulmonary dysfunction after cardiac surgery. Chest 2002;121(4):1269–77. [4] Marik PE, Corwin HL. Acute lung injury following blood transfusion: expanding the definition. Crit Care Med 2008;36(11):3080–4. [5] Silliman CC, Ambruso DR, Boshkov LK. Transfusion-related acute lung injury. Blood 2005;105(6):2266–73. [6] Vlaar AP, Binnekade JM, Prins D, van Stein D, Hofstra JJ, Schultz MJ, et al. Risk factors and outcome of transfusion-related acute lung injury in the critically ill: a nested case-control study. Crit Care Med 2010;38(3):771–8. [7] Gajic O, Rana R, Winters JL, Yilmaz M, Mendez JL, Rickman OB, et al. Transfusion-related acute lung injury in the critically ill: prospective nested case-control study. Am J Respir Crit Care Med 2007;176(9):886–91. [8] Bux J, Sachs UJ. The pathogenesis of transfusion-related acute lung injury (TRALI). Br J Haematol 2007;136(6):788–99. [9] Fitzmaurice GJ, Parissis HD. Platelet transfusion associated with acute lung injury after coronary artery bypass grafting. Ann Thorac Surg 2011;91(6):1977–9. [10] Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al. Report of the American–European consensus conference on ARDS:
Please cite this article in press as: Liu K et al. The relationship between total red blood cells and plasma transfusion and acute lung injury risk after cardiac surgery: A retrospective study. Transf Apheres Sci (2014), http://dx.doi.org/10.1016/j.transci.2014.03.001
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definitions, mechanisms, relevant outcomes and clinical trial coordination. The consensus committee. Intensive Care Med 1994;20(3):225–32. [11] Tuinman PR, Vlaar AP, Cornet AD, Hofstra JJ, Levi M, Meijers JC, et al. Blood transfusion during cardiac surgery is associated with inflammation and coagulation in the lung: a case control study. Crit Care 2011;15(1):R59. [12] Vlaar AP, Hofstra JJ, Determann RM, Veelo DP, Paulus F, Levi M, et al. Transfusion-related acute lung injury in cardiac surgery patients is characterized by pulmonary inflammation and coagulopathy: a prospective nested case-control study. Crit Care Med 2012;40(10):2813–20.
[13] Koch C, Li L, Figueroa P, Mihaljevic T, Svensson L, Blackstone EH. Transfusion and pulmonary morbidity after cardiac surgery. Ann Thorac Surg 2009;88(5):1410–8. [14] Rogers MA, Blumberg N, Heal JM, Hicks Jr GL. Increased risk of infection and mortality in women after cardiac surgery related to allogeneic blood transfusion. J Womens Health (Larchmt) 2007;16(10):1412–20. [15] Rogers MA, Blumberg N, Saint SK, Kim C, Nallamothu BK, Langa KM. Allogeneic blood transfusions explain increased mortality in women after coronary artery bypass graft surgery. Am Heart J 2006;152(6):1028–34.
Please cite this article in press as: Liu K et al. The relationship between total red blood cells and plasma transfusion and acute lung injury risk after cardiac surgery: A retrospective study. Transf Apheres Sci (2014), http://dx.doi.org/10.1016/j.transci.2014.03.001
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
The relationship between total red blood cells and plasma transfusion and acute lung injury risk after cardiac surgery: A retrospective study Kun Liu a, Hong-Lin Chen b, Qing-Sheng You a, Zhi-Wei Wang c,⇑ a
Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Xi Si Road 20# Nantong City, Jiangsu Province 226001, PR China Nantong University, Qi Xiu Road 19# Nantong City, Jiangsu Province 226001, PR China c Department of General Surgery, Affiliated Hospital of Nantong University, Xi Si Road 20# Nantong City, Jiangsu Province 226001, PR China b
a r t i c l e
i n f o
Article history: Received 7 November 2013 Received in revised form 8 January 2014 Accepted 4 March 2014 Available online xxxx Keywords: Cardiac surgery Acute lung injury Red blood cells Fresh-frozen plasma Retrospective study
a b s t r a c t The aim of our study was to determine whether red blood cells (RBCs) and fresh frozen plasma (FFP) transfusion is independently associated with the development of acute lung injury (ALI) in patients after cardiac surgery. In retrospective study, 165 patients were included. The results showed total fresh RBCs transfusion were not significantly increased in patients who developed ALI compared with patients who did not develop ALI (4.7 ± 2.4, 4 [0–12] units VS 4.0 ± 1.9, 3 [0–9] units, P = 0.119). FFP transfusion were also not significantly increased (704.1 ± 832.5, 600 [150–6500] ml VS 533.9 ± 323.6, 400 [125–3100] ml, P = 0.053). Multivariable logistic regression analysis showed that only age and CPB time were independent factors for ALI, but not for total RBCs and FFP transfused, with the adjusted OR 0.952 (95% CI 0.762–1.189, P = 0.664), and 1.000 (95% CI 0.999–1.001, P = 0.480), respectively. In subgroup analysis, female patients showed a lower ALI incidence in low RBCs transfused group (23.9% VS 45.0%, OR 0.38, 95% CI 0.15–0.98) and in low FFP transfused group (22.0% VS 44.4%, OR 0.35, 95% CI 0.14–0.90). Our study demonstrates that red blood cells and fresh-frozen plasma transfusion are not related with ALI after cardiac surgery in our institution. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Cardiac surgery with cardiopulmonary bypass (CPB) has been associated with a frequent complication of acute lung injury (ALI). The estimated ALI incidence was as many as 20% after cardiac surgery, and the related mortality was as high as 80% [1]. Care for patients with acute respiratory distress syndrome is supportive, with low tidal volume ventilation being the mainstay of therapy. Careful fluid management, minimization of blood product transfusion, appropriate nutrition, and early physical rehabilitation ⇑ Corresponding author. E-mail address: [email protected] (Z.-W. Wang).
may improve outcomes [1]. Patients developing ALI were longer ventilated and had a greater length of ICU and hospital stay (P < .05 for all, respectively) [2]. ALI will also increase the cost of the treatment. Studies have shown that the etiology of lung injury is multifactorial, including pulmonary hypoperfusion, the induction of inflammatory mediators, hypothermia, and blood contact with the foreign surfaces of the CPB system [3]. Transfusion of multiple units has long been considered a risk factor for ALI [4,5]. The incidence of transfusion-related ALI in the critically ill patients ranged from 5.4% to 8% [6,7]. Leukocyte antibodies, present in fresh frozen plasma and platelet concentrates from multiparous donors, and neutrophil priming agents released in stored cellular
http://dx.doi.org/10.1016/j.transci.2014.03.001 1473-0502/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Liu K et al. The relationship between total red blood cells and plasma transfusion and acute lung injury risk after cardiac surgery: A retrospective study. Transf Apheres Sci (2014), http://dx.doi.org/10.1016/j.transci.2014.03.001
2
K. Liu et al. / Transfusion and Apheresis Science xxx (2014) xxx–xxx
blood components have been considered to be causative [8]. In the perioperative period of cardiac surgery, patients often require transfusions of blood products. Studies have confirmed platelet transfusion was associated with ALI after cardiac surgery [9]. However, the relationship between red blood cells (RBCs) and fresh-frozen plasma (FFP) transfusion and the development of ALI after cardiac surgery has not been confirmed. The specific aim of our study was to determine whether RBCs and FFP transfusion is independently associated with the development of ALI in patients after cardiac surgery.
2. Methods 2.1. Patients The study was performed in a university hospital in China. There are about 150–250 cases of cardiac surgery carried out each year. We performed a retrospective analysis among consecutive patients with cardiac surgery between January 2012 and December 2012. The study was approved by the medical ethics committee of the hospital. Pediatric and adult patients of any age undergoing cardiac surgery with cardiopulmonary bypass met the inclusion criteria. Exclusion criteria included the following: r cardiac surgery without cardiopulmonary bypass (such as off-pump coronary artery bypass grafting, transpleural and extrapleural ligation of patent ductus arteriosus); s percutaneous transluminal coronary angioplasty.
2.2. ALI definition ALI was defined according to the standard American– European Consensus Conference on acute respiratory distress syndrome (ARDS) definition [10] as follows: r oxygenation: PaO2/FiO2 < 300 mm Hg (regardless of positive end-expiratory pressure); s chest radiograph: bilateral infiltrates seen on frontal chest radiograph; t pulmonary artery occlusion pressure: 618 mm Hg when measured or no clinical evidence of left atrial hypertension.
2.3. Data collection All data were obtained by reviewing patients’ medical records. Data were retrieved by trained medical personnel using specifically tailored data forms. We collected data on patient demographics and admission diagnosis. Transfusion data collection included the total amount of transfused leuko-reduced fresh RBCs and FFP. All the blood products were centrifuged, separated, and frozen solid at 30 °C within 6 h of collection, and the storage age of RBCs was no more than 5 days. The blood products form multiparous female donors were avoid. We also collected potential risk factors for onset of ALI, including smoking (P100 cigarettes for lifetime), chronic obstructive pulmonary disease, diabetes mellitus, hypertension, alcohol abuse (more than 40 g of alcohol per day), and cardiopulmonary bypass time.
2.4. Statistical analysis Demographics and baseline characteristics were compared between patients in whom ALI developed and those in whom it did not develop. Continuous data were firstly checked for distribution. Normal distributed data were analyzed using analysis of unpaired student’s t test. Non-normal distribution data were analyzed using Mann–Whitney U test. Categorical data were analyzed with the v2 test. In order to exclude potential confounding factors of ALI, we (1) conducted multivariable logistic regression analysis after univariate analysis; (2) used Mantel–Haenszel tests stratified by the each subgroup. A twosided p value of 60 Type of surgery Congenital heart disease Valve heart disease Others Alcohol abuse Yes No Smoking Yes No Diabetes mellitus Yes No Hypertension Yes No COPD Yes No CPB time (min), mean ± SD, median [range] 0–60 60–120 120–180 180–240 >240 Total RBCs transfused (unit), mean ± SD, median [range] 0–4 4–8 >8 Total FFP transfused (ml), mean ± SD, median [range] 0–400 400–800 >800
Total (n = 165)
ALI (n = 56)
No ALI (n = 109)
P value 0.951
79 (47.9%) 86 (52.1%) 50.9 ± 17.7, 55 [1–81] 14 (8.5%) 16 (9.7%) 85 (51.5%) 50 (30.3%)
27 (48.2%) 29 (51.8%) 56.9 ± 13.3, 58 [5–81] 1 (1.8%) 4 (7.1%) 26 (46.4%) 25 (44.6%)
52 (47.7%) 57 (52.3%) 47.8 ± 18.9, 53 [1–80] 13 (11.9%) 12 (11.0%) 59 (54.1%) 25 (22.9%)
28 (17.0%) 111 (67.3%) 26 (15.8%)
4 (7.1%) 42 (75.0%) 10 (17.9%)
24 (22.0%) 69 (63.3%) 16 (14.7%)
4 (2.4%) 161 (97.6%)
1 (1.8%) 55 (98.2%)
3 (2.8%) 106 (97.2%)
6 (3.6%) 159 (96.4%)
3 (5.4%) 53 (94.6%)
3 (2.8%) 106 (97.2%)
3 (1.8%) 162 (98.2%)
2 (3.6%) 54 (96.4%)
1 (0.9%) 108 (99.1%)
20 (12.1%) 145 (87.9%)
9 (16.1%) 47 (83.9%)
11 (10.1%) 98 (89.9%)
4 (2.4%) 161 (97.6%) 124.3 ± 52.6, 116 [38–330] 12 (7.3%) 78 (47.3%) 54 (32.7%) 16 (9.7%) 5 (3.0%) 4.3 ± 2.1, 3.5 [0–12] 99 (60.0%) 59 (35.8%) 7 (4.2%) 591.4 ± 554.9, 500 [125–2500] 78 (47.3%) 72 (43.6%) 15 (9.1%)
2 (3.6%) 54 (96.4%) 142.1 ± 55.9, 126.5 [60–330] 1 (1.8%) 22 (42.9%) 24 (39.3%) 5 (8.9%) 4 (7.1%) 4.7 ± 2.4, 4 [0–12] 30 (53.6%) 22 (39.3%) 4 (7.1%) 704.1 ± 832.5, 600 [150–6500] 22 (39.3%) 25 (44.6%) 9 (16.1%)
2 (1.8%) 107 (98.2%) 115.2 ± 48.5, 107 [38–268]
0.002* 0.011*
0.055
0.702
0.397
0.227
0.265
0.492
11 (10.1%) 54 (49.5%) 32 (29.4%) 11 (10.1%) 1 (0.9%) 4.0 ± 1.9, 3 [0–9] 69 (63.3%) 37 (33.9%) 3 (2.8%) 533.9 ± 323.6, 400 [125–3100] 56 (51.4%) 47 (43.1%) 6 (5.5%)
0.002* 0.045*
0.119 0.278
0.053 0.058
COPD = chronic obstructive pulmonary disease; SD = standard deviation. Significant value.
*
significantly different between ALI group and no ALI group (Table 1). The overall ALI incidence in low RBCs transfused group (0–4 units) was 30.3% (30/99), and 39.4% (26/66) in high RBCs transfused group (>4 units). No difference was found between two groups, with the OR 0.67 (95% CI, 0.36–1.29; v2 = 1.46, P = 0.227). The overall ALI incidence in low FFP transfused group (0–400 ml) was 28.2% (22/78), and 39.1% (34/87) in high FFP transfused group (>400 ml). No difference was found between two groups, with the OR 0.61 (95% CI, 0.30–1.23; v2 = 2.17, P = 0.141). Multivariable logistic regression analysis showed that total RBCs transfused amount and total FFP transfused amount were not the independent factors for ALI, after adjustment for gender, age, type of surgery, alcohol abuse, smoking, diabetes mellitus, hypertension, chronic obstructive pulmonary diseases, and CPB time. The adjusted OR was 0.952 (95% CI 0.762–1.189, P = 0.664), and
1.000 (95% CI 0.999–1.001, P = 0.480), respectively. Multivariable regression analysis showed that only patients’ age and CPB time were the independent factors for ALI after cardiac surgery, with the adjusted OR 1.036 (95% CI 1.004–1.069, P = 0.026), and 1.010 (95% CI 1.002–1.018, P = 0.019), respectively. Table 2 shows the multivariate analysis results of risk factors for the onset of ALI after cardiac surgery. 3.3. Subgroup analysis In gender subgroup, female patients had a lower ALI incidence of 23.9% (11/46) in low RBCs transfused group, compared with 45.0% (18/40) in high RBCs transfused group, with the OR 0.38 (95% CI 0.15–0.98). Male patients had the same ALI incidence between low RBCs transfused group and high RBCs transfused group (35.8%, 19/53 VS 30.8%, 8/26), with the OR 1.26 (95% CI 0.46–3.43). No ALI
Please cite this article in press as: Liu K et al. The relationship between total red blood cells and plasma transfusion and acute lung injury risk after cardiac surgery: A retrospective study. Transf Apheres Sci (2014), http://dx.doi.org/10.1016/j.transci.2014.03.001
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K. Liu et al. / Transfusion and Apheresis Science xxx (2014) xxx–xxx
a
b
c
d
Fig. 1. Continuous data (including total RBCs transfused, total plasma transfused, age and CPB time) comparison according to patients developing ALI or those who did not develop ALI.
Table 2 Multivariate analysis of risk factors for the onset of ALI in cardiac surgery patients. Characteristics
B
S.E.
Wald
P value
OR
95% CI for OR
Gender Age Type of surgery Type of surgery (1) Type of surgery (2) Alcohol abuse Smoking Hypertension Diabetes mellitus COPD Total RBCs transfused Total plasma transfused CPB time Constant
0.135 0.036
0.388 0.016
0.535–2.448 1.004–1.069
0.775 0.511 1.434 1.019 0.560 1.287 1.068 0.113 0.001 0.004 1.177
0.727 0.026* 0.692 0.638 0.396 0.241 0.104 0.863 0.281 0.457 0.664 0.480 0.019* 0.001
1.145 1.036
0.365 0.435 1.683 1.659 0.097 1.386 794 –0.049 0.000 0.010 3.741
0.122 4.980 0.735 0.222 0.722 1.377 2.648 0.030 1.161 0.553 0.189 0.500 5.515 10.097
0.694 0.648 0.186 5.253 0.908 3.999 2.212 0.952 1.000 1.010 0.024
0.152–3.170 0.238–1.764 0.011–3.090 0.712–38.744 0.303–2.720 0.321–49.791 0.273–17.937 0.762–1.189 0.999–1.001 1.002–1.018
COPD = chronic obstructive pulmonary disease; SD = standard deviation. Significant value.
*
incidence differences were found between other subgroups compared low RBCs transfused group and high RBCs transfused group. In gender subgroup, female patients had a lower ALI incidence of 22.0% (9/41) in low FFP transfused group, compared with 44.4% (20/45) in high FFP transfused group,
with the OR 0.35 (95% CI 0.14–0.90). Male patients had the same ALI incidence between low FFP transfused group and high FFP transfused group (35.1%, 13/37 VS 33.3%, 14/42), with the OR 1.08 (95% CI 0.43–2.75). No ALI incidence differences were found between other subgroups compared low FFP transfused group and high FFP transfused group.
Please cite this article in press as: Liu K et al. The relationship between total red blood cells and plasma transfusion and acute lung injury risk after cardiac surgery: A retrospective study. Transf Apheres Sci (2014), http://dx.doi.org/10.1016/j.transci.2014.03.001
K. Liu et al. / Transfusion and Apheresis Science xxx (2014) xxx–xxx
4. Discussion In a case control study, Tuinman PR reported transfusion during cardiac surgery was associated with activation of inflammation and coagulation in the pulmonary compartment, bronchoalveolar lavage fluid (BALF) levels of IL-8, tumor necrosis factor a (TNFa) and thrombin– antithrombin complex (TATc) were increased after multiple transfusions (P < 0.01, P < 0.001 and P < 0.01, respectively) compared to nontransfused controls [11]. Vlaar AP also reported transfusion was associated with systemic and pulmonary inflammation and activation of neutrophils, as well as enhanced coagulation and suppressed fibrinolysis [12]. These evidences showed transfusion maybe also play an important role in ALI after cardiac surgery. However, our data suggest that RBCs and FFP transfusion are not related with ALI after cardiac surgery according to the consensus definition. In cardiac surgery with cardiopulmonary bypass, pulmonary hypoperfusion, the induction of inflammatory mediators, hypothermia, and blood contact with the foreign surfaces of the CPB system were the important risk factors for ALI. Compared with these important factors, the role of blood transfusion may be very small for ALI. Koch C also reported the similar results: in the 16,847 cardiac surgery patients, the ICU admission PaO2/FiO2 ratios were similar among 2941 pairs of propensity-matched patients between RBC transfusion versus no RBC transfusion (257 [185, 340] VS 248 [182, 330], p = 0.169) and among 625 propensity-matched pairs of patients between FFP transfusion versus no FFP transfusion (227 [153,323] VS 238 [167,328], p = 0.25). However, Koch C also reported transfusion was associated with many measures of postoperative pulmonary morbidity, which included respiratory distress, respiratory failure, longer intubation times, acute respiratory distress syndrome, and reintubation. They believed it was difficult to differentiate lung injury related to transfusion with PaO2/FiO2 criteria measures [13]. The known benefit of blood products transfusion include an increased blood volume, increased oxygen-carrying capacity of blood, improved tissue oxygenation, and improved hemostasis. We believe RBCs and FFP transfusion should not be limited after cardiac surgery when thinking about transfusion related ALI. However, our study also found female cardiac surgery patients seem to be susceptible to ALI after transfusion, with ALI incidence OR 0.38 (95% CI 0.15–0.98) for low RBCs transfused and OR 0.35 (95% CI 0.14–0.90) for low FFP transfused. Rogers MA also reported in cardiac surgery, women receive allogeneic RBCs or platelets had a greater risk of infection (p = 0.005), pulmonary dysfunction (p = 0.005), and mortality (p = 0.007) than men during hospitalization [14,15]. They believed the reason was that women were more likely to receive blood products than men (odds ratio [OR] 21.6, 95% CI 3.8, 124.2) and a greater quantity than men. In our study, we believed there must be another reasons for gender differences in transfusion complications. Some studies are needed. In our study, we only assessed the relationship between total blood products transfused amount and transfusionrelated ALI. In a prospective nested case-control study,
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Vlaar AP reported number of red blood cells stored more than 14 days was a risk factor for transfusion-related ALI in cardiac surgery patients, with OR 1.6 (95% CI, 1.04– 2.37) [2]. In our study, we used the fresh red blood cells in all of the patients with the storage age was no more than 5 days. We did not assess the blood products storage age for transfusion-related ALI risk factor. However, we still suggest the fresh blood products should be used in cardiac surgery patients. There are some limitations in our study. First, it was a retrospective case control study. Although we have used multivariable logistic regression analysis and Mantel– Haenszel tests subgroup analysis to exclude potential confounding factors of ALI, it is likely that some unknown risk factors have been missed and were actually responsible for ALI after cardiac surgery. Second, many values of the blood products storage age are missing. We cannot assess the storage age and ALI risk factor. New prospective cohort studies with large sample are needed. In summary, our study demonstrates that red blood cells and fresh-frozen plasma transfusion are not related with ALI after cardiac surgery regarding whole population in our institution. However, female cardiac surgery patients seem to be susceptible to ALI after transfusion. Further larger cohorts are needed to confirm our findings. Acknowledgments This research was supported by Nantong city social development project (HS2012025), Jiangsu province postdoctoral research foundation (1301072C), and China Postdoctoral Science Foundation (2103M541705) . We thank the editor and anonymous reviewers for several insightful comments that significantly improved the paper. References [1] Stephens RS, Shah AS, Whitman GJ. Lung injury and acute respiratory distress syndrome after cardiac surgery. Ann Thorac Surg 2013 ;95(3):1122–9. [2] Vlaar AP, Hofstra JJ, Determann RM, Veelo DP, Paulus F, Kulik W, et al. The incidence, risk factors, and outcome of transfusion-related acute lung injury in a cohort of cardiac surgery patients: a prospective nested case-control study. Blood 2011;117(16): 4218–25. [3] Ng CS, Wan S, Yim AP, Arifi AA. Pulmonary dysfunction after cardiac surgery. Chest 2002;121(4):1269–77. [4] Marik PE, Corwin HL. Acute lung injury following blood transfusion: expanding the definition. Crit Care Med 2008;36(11):3080–4. [5] Silliman CC, Ambruso DR, Boshkov LK. Transfusion-related acute lung injury. Blood 2005;105(6):2266–73. [6] Vlaar AP, Binnekade JM, Prins D, van Stein D, Hofstra JJ, Schultz MJ, et al. Risk factors and outcome of transfusion-related acute lung injury in the critically ill: a nested case-control study. Crit Care Med 2010;38(3):771–8. [7] Gajic O, Rana R, Winters JL, Yilmaz M, Mendez JL, Rickman OB, et al. Transfusion-related acute lung injury in the critically ill: prospective nested case-control study. Am J Respir Crit Care Med 2007;176(9):886–91. [8] Bux J, Sachs UJ. The pathogenesis of transfusion-related acute lung injury (TRALI). Br J Haematol 2007;136(6):788–99. [9] Fitzmaurice GJ, Parissis HD. Platelet transfusion associated with acute lung injury after coronary artery bypass grafting. Ann Thorac Surg 2011;91(6):1977–9. [10] Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al. Report of the American–European consensus conference on ARDS:
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definitions, mechanisms, relevant outcomes and clinical trial coordination. The consensus committee. Intensive Care Med 1994;20(3):225–32. [11] Tuinman PR, Vlaar AP, Cornet AD, Hofstra JJ, Levi M, Meijers JC, et al. Blood transfusion during cardiac surgery is associated with inflammation and coagulation in the lung: a case control study. Crit Care 2011;15(1):R59. [12] Vlaar AP, Hofstra JJ, Determann RM, Veelo DP, Paulus F, Levi M, et al. Transfusion-related acute lung injury in cardiac surgery patients is characterized by pulmonary inflammation and coagulopathy: a prospective nested case-control study. Crit Care Med 2012;40(10):2813–20.
[13] Koch C, Li L, Figueroa P, Mihaljevic T, Svensson L, Blackstone EH. Transfusion and pulmonary morbidity after cardiac surgery. Ann Thorac Surg 2009;88(5):1410–8. [14] Rogers MA, Blumberg N, Heal JM, Hicks Jr GL. Increased risk of infection and mortality in women after cardiac surgery related to allogeneic blood transfusion. J Womens Health (Larchmt) 2007;16(10):1412–20. [15] Rogers MA, Blumberg N, Saint SK, Kim C, Nallamothu BK, Langa KM. Allogeneic blood transfusions explain increased mortality in women after coronary artery bypass graft surgery. Am Heart J 2006;152(6):1028–34.
Please cite this article in press as: Liu K et al. The relationship between total red blood cells and plasma transfusion and acute lung injury risk after cardiac surgery: A retrospective study. Transf Apheres Sci (2014), http://dx.doi.org/10.1016/j.transci.2014.03.001
