Ann Thorac Surg 2008;86:554-559. doi:10.1016/j.athoracsur.2008.04.040
© 2008 The Society of Thoracic Surgeons
Original Articles: Adult Cardiac
Age of Transfused Red Cells and Early Outcomes After Cardiac Surgery
Cheng-Hon Yap, MBBS, MSa,*,
Lawrence Lau, MBBSa,
Mayur Krishnaswamy, MBBSa,
Mary Gaskell, BSb,
Michael Yii, MBBS, MSa,c
a Department of Cardiothoracic Surgery, University of Melbourne, St. Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia
b Department of Pathology (Blood Transfusion Laboratory), University of Melbourne, St. Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia
c Department of Surgery, University of Melbourne, St. Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia
Accepted for publication April 14, 2008.
* Address correspondence to Dr Yap, Department of Cardiothoracic Surgery, St. Vincent's Hospital Melbourne, Fitzroy, Victoria, 3065, Australia (Email: chenghonyap{at}hotmail.com).
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Abstract
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Background: Red blood cells (RBC) undergo many changes during storage. Such changes are associated with reduced oxygen-carrying capacity and transfusion-related inflammatory reactions. The clinical significance of these changes in the cardiac surgical setting is unclear. This observational cohort study investigates the association between age of transfused RBC and early outcomes after cardiac surgery.
Methods: The cardiac surgery database at St. Vincent's Hospital Melbourne was cross-referenced with the Blood Transfusion Services database. In all, 670 consecutive patients who had nonemergency coronary artery bypass grafting or aortic valve replacement, or both, between June 2001 and June 2007 and had at least 2 RBC units transfused were studied. The storage variables studied were mean age of RBC, age of oldest RBC unit transfused, and transfusion of RBC stored longer than 30 days. Age of transfused blood was analyzed using logistic and linear regression analysis to determine an independent association with clinical outcomes: postoperative early mortality, renal failure, pneumonia, intensive care unit stay, and ventilation hours. Patient preoperative risk profile (EuroSCORE) and total number of RBC units transfused were adjusted for.
Results: The storage age of RBC was not independently associated with any of the endpoints studied. The total quantity of RBC transfused was significantly associated with all studied endpoints.
Conclusions: Under current transfusion practice, the age of transfused RBC is not associated with early mortality and morbidity after cardiac surgery.
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Introduction
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Red blood cells (RBC) are transfused in approximately 40% of patients undergoing cardiac surgery in Australia [1]. Concerns have recently been raised about the safety and efficacy of transfusing stored RBC. This opinion has been triggered by increased awareness of transfusion-transmitted infections and, more recently, by clinical trials and animal experiments that cast doubt on the benefits of RBC transfusions [2]. Red blood cells in most countries, including Australia, can be stored for as long as 42 days at 2° to 6°C with the appropriate additives. Given that blood is a scarce resource, the ability to store RBC for this duration confers the benefit of increasing its supply and minimizing RBC wastage. However, the quality of stored RBC deteriorates over this period. For instance, RBC adenosine triphosphate and 2,3-diphosphoglycerate levels are depleted with storage [3]. Red blood cells also undergo morphologic changes that decrease their deformability. These changes may ultimately reduce tissue oxygen delivery [4, 5]. Cytokines that accumulate with storage of RBC are associated with transfusion-mediated systemic inflammatory reactions and higher risk of bacterial infections [6–9]. Despite the high transfusion rates in cardiac surgery and ongoing uncertainty regarding the clinical relevance of RBC storage lesions [10, 11], the influence of duration of RBC storage on post–cardiac surgery morbidity and mortality has not been widely studied. We thus aimed to investigate the association between the storage age of transfused RBC and early morbidity and mortality after cardiac surgery in our institution by performing a retrospective cohort study.
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Patients and Methods
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Using the St. Vincent's Hospital Melbourne cardiac surgery database, we identified 901 consecutive patients who had undergone nonemergency first-time, on-pump coronary artery bypass graft surgery, aortic valve replacement, or both between June 2001 and July 2007, and who had received RBC transfusion during the postoperative hospital stay. We reviewed the transfusion records of these patients through the Hospital Blood Transfusion Service computer system to determine the date, type, number of units, and age of blood product transfused. We included only patients who were transfused at least two units of RBC intraoperatively or postoperatively. Patients who were transfused their first unit of RBC after the first 48 postoperative hours were not included, as these patients were deemed to be outside their critical period by this time. A total of 670 patients met the study criteria and were included in the current study. The Institutional Review Board had previously approved the use of these databases for research, and hence, the need for individual patient consent was waived.
The hospital cardiac surgery database is part of the Australasian Society of Cardiac and Thoracic Surgeons (ASCTS) cardiac surgery database project [12]. The database is subject to external audit every 3 years. It contains prospectively collected data that are obtained as part of clinical care and follow-up by surgeons, perfusionist, resident medical officers, and database managers. Thirty-day mortality information was obtained by telephone contact with patient, family member, or medical practitioner.
The clinical endpoints studied were postoperative mortality (30-day mortality or in-hospital mortality beyond 30 days), new renal failure, pneumonia, intensive care unit (ICU) length of stay (LOS), and ventilation hours. Intensive care unit LOS and ventilation times were measured in hours. New renal failure is defined as at least two of the following: creatinine increased to greater than 200 µmol/L; doubling or greater increase in creatinine over preoperative value; new requirement for dialysis or hemofiltration. Pneumonia is diagnosed by positive sputum cultures and the presence of clinical findings.
The storage time of transfused RBC was the variable studied. The storage time of RBC for each patient was studied in three ways: (1) The mean length of storage of RBC units transfused per patient was studied as a continuous variable to correlate storage time to early adverse outcomes. (2) The storage time of the oldest RBC transfused per patient was studied as a continuous variable to investigate whether adverse outcomes were mainly correlated with older blood. (3) Any transfusion of a unit of RBC stored longer than 30 days was studied as a categorical variable to investigate whether very old blood (> 30 days represents the oldest eighth percentile of RBC units given) was correlated with adverse outcomes.
Continuous variables are presented as mean ± 1 SD if the distribution is normal, or median (25%, 75%) if distribution is not normal, as assessed by the Kolmogorov-Smirnov test of normality. For univariate analyses, the Mann-Whitney rank-sum test or the 
2 test was used. Correlation between two continuous variables was assessed by the Spearman's rank correlation coefficient. To assess if the study variable was independently associated with each clinical outcome, we entered one study variable together with the number of RBC units transfused and the EuroSCORE (European System for Cardiac Operative Risk Evaluation), to adjust for patient risk profile, into a multiple linear or logistic regression analyses as appropriate. Hence, each of the three study variables was modeled separately. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using standard statistical methods. The additive EuroSCORE was calculated for each study patient according to previously described methods [13, 14]. Power analysis of univariate tests showed the study had a greater than 80% power to detect differences of 5 days or more in mean RBC storage times between groups with and without the outcomes analyzed, and to detect a correlation between RBC storage variables and ICU LOS or ventilation times given coefficient values of 0.1 or greater. All calculated p values were two-sided; values less than 0.05 were considered significant. Statistical analysis was performed using SPSS 14.0 (SPSS, Chicago, Illinois).
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Results
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Preoperative characteristics of the 670 patients studied are shown in Table 1. A total of 3,030 allogeneic RBC units were transfused in the 670 study patients. Of those, 2,148 units (70.9%) were buffy-coat removed RBC, 115 (3.8%) were leukocyte depleted prestorage, and the remaining 767 units (25.3%) were not subject to either process. No patients were transfused autologous banked blood. Median number of units transfused per patient was 3.0 (2.0, 5.0). Figure 1
shows the distribution of the length of storage of RBC given to patients in this study. Median length of storage of RBC units transfused was 13.0 (8.0, 19.0). One hundred thirteen patients (16.9%) received at least one unit of RBC that had been stored more than 30 days.
Postoperative Mortality
There were 33 postoperative deaths, giving a postoperative mortality of 4.93%. Mean lengths of storage of RBC units transfused were similar between patients who survived and patients who died (Table 2). Using multiple logistic regression analysis, none of the three RBC storage variables was associated with postoperative mortality, whereas the EuroSCORE and number of RBC units transfused were associated with postoperative mortality (Table 2).
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Table 2 Univariate and Multiple Variable Analyses of Red Blood Cell (RBC) Storage Variables in Relation to Early Postoperative Mortality
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New Renal Failure
New postoperative renal failure occurred in 56 patients (8.36%). Mean length of storage of RBC units transfused was not associated with new renal failure (Table 3). Using multiple logistic regression analysis, no RBC storage variable was associated with new renal failure. The EuroSCORE and number of RBC units transfused were consistently associated with new postoperative renal failure (Table 3).
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Table 3 Univariate and Multiple Variable Analyses of Red Blood Cell (RBC) Storage Variables in Relation to Postoperative Renal Failure
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Pneumonia
Pneumonia occurred in 46 patients (6.86%). Mean length of storage of RBC units was not associated with pneumonia (Table 4). By logistic regression, only the number of RBC units transfused was associated with pneumonia (Table 4).
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Table 4 Univariate and Multiple Variable Analyses of Red Blood Cell (RBC) Storage Variables in Relation to Postoperative Pneumonia
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Ventilation Hours
Ventilation time ranged between 1 and 811 hours, with a median of 14 hours (10, 20). There was a positive correlation between the age of the oldest RBC unit transfused and ventilation hours. Furthermore, patients who received a RBC unit aged more than 30 days were ventilated for longer (Table 5). However, all three storage variables were not significantly associated with ventilation hours on linear regression analysis. The number of RBC units was a significant predictor of ventilation hours (Table 5).
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Table 5 Univariate and Multiple Variable Analyses of Red Blood Cell (RBC) Storage Variables in Relation to Postoperative Ventilation Hours
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Intensive Care Unit Length of Stay
Intensive care unit LOS ranged from 1 to 857 hours, with a median of 24 hours (20, 46). There were no univariate associations between RBC storage and ICU LOS. The three RBC storage variables were not associated with ICU LOS on regression analysis (Table 6). The number of RBC units was a significant predictor of ICU LOS (Table 6).
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Table 6 Univariate and Multiple Variable Analyses of Red Blood Cell (RBC) Storage Variables in Relation to Postoperative Intensive Care Unit Length of Stay (ICU LOS)
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Comment
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We found that RBC storage duration was not associated with early postoperative mortality, renal failure, pneumonia, long ICU stay, or prolonged ventilation. Our results are generally consistent with the findings of Vamvakas and Carven [15], Leal-Noval and coworkers [16], and van de Watering and associates[17]. However, unlike Vamvakas and Carven [18] and Leal-Noval and coworkers [16], we did not find an association between the occurrence of postoperative pneumonia and longer RBC storage times.
We chose to study patients undergoing the most common types of cardiac surgery in our institution, this being on-pump coronary artery bypass graft surgery and aortic valve replacement, to avoid the confounding effects of other complex surgery such as aortic surgery or multiple valve surgery. Furthermore, we restricted the study to only patients receiving more than 1 unit of RBC and patients receiving transfusions during the first 48 hours of surgery in an attempt to include only patients who received a substantial amount of RBC transfusion at a physiologically critical time in their surgical course. Thus, we excluded patients who are less likely to be affected by any deleterious effect of RBC transfusions.
Leukocytes are thought to play a major role in the deleterious effect of RBC transfusions. Leukocytes deteriorate with time in stored blood and release various bioactive substances that may depress the recipient immune function and lead to various adverse transfusion effects [19, 20]. It is important to note that universal prestorage leukocyte depletion is not practiced in Australia. In our study, only 3.8% of units underwent this process. In contrast, a significantly higher proportion of RBC units studied by Vamvakas and Carven [18] were leukocyte depleted. Such differences in the practice of prestorage leukocyte depletion make the comparison of studies difficult.
The consistent finding in this study that the transfusion of larger amounts of RBC is associated with adverse outcomes studied has been well known [21]. For instance, a large observational study of patients who underwent coronary artery bypass graft surgery surgery at the Cleveland Clinic found that RBC transfusion was independently associated with early [22] and late mortality [23], as well as the complications of renal failure, prolonged ventilation, serious infections, cardiac events and neurologic complications [22]. The risk of these events increased incrementally with each unit of RBC transfused. However, given the lack of prospective randomized trials on this subject, it is difficult to know if the association between RBC transfusion and adverse outcomes represents a causal relationship or whether transfusion of RBC is simply a marker of more severe levels of patient comorbidity and surgical trauma. Until large-scale prospective studies are performed to assess the role of RBC transfusions in the critically ill, it is unlikely that current transfusion practices will alter.
Older age of transfused RBC has been correlated with poor outcomes after major trauma [24, 25] and in the setting of severe sepsis [26]. Whether older age of transfused RBC correlates with poorer early outcomes after cardiac surgery has been investigated by several authors [15–18, 27]. The aim of this study was to investigate the possibility of a relationship between age to transfused RBC and early adverse outcomes after cardiac surgery. Despite a large body of evidence documenting the existence of storage lesions [3–5, 9, 20, 28] in stored RBC, no good evidence exists that storage lesions constitute a clinically relevant phenomena in the cardiac surgical setting. The only study that suggests a correlation between prolonged storage of RBC and poor cardiac surgical outcomes is the single-center retrospective cohort study by Basran and associates [27] of 321 reoperative cardiac surgery patients. They found that prolonged RBC storage was associated with all the outcomes studied: in-hospital and medium-term mortality, acute renal failure, and prolonged ICU and hospital stay. Given that the study was confined to reoperative cardiac surgery patients, its findings cannot be generalized to the wider cardiac surgical setting. To determine the significance of storage lesions in cardiac surgery, we need prospective, preferably multicenter, randomized studies. However, this is unlikely to occur given the general shortage of blood supply, the logistic difficulties, and the ethical issues that would impose on the allocation of fresh RBC units in a trial setting.
This study has several limitations. Firstly, being a retrospective observational study, we could not correct for confounding factors that were either unknown or not collected in the cardiac surgery database. Secondly, most patients received a mix of RBC units of widely varying ages. Furthermore, the relationship between older age of RBC and any adverse effects may not be a linear association. The storage variables studied and statistical techniques used in this study may not have been sensitive enough to account for such nonlinear associations. Finally, the use of the EuroSCORE as the means of risk-adjustment in the regression analyses may not have adequately adjusted for all important confounding factors for any given patient outcome.
In conclusion, we found no correlation between duration of storage of RBC and early adverse outcomes after cardiac surgery. There is no justification at present to change current RBC storage and allocation practices in cardiac surgery. We should continue to preferentially allocate the oldest RBC units first to maximize a margin of safety in the supply of RBC.
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Acknowledgments
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The Australasian Society of Cardiac and Thoracic Surgeons (ASCTS) Cardiac Surgery Database is an initiative of the ASCTS and is funded by the Department of Human Services, Victoria.
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References
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Abstract
Introduction
