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Ann Thorac Surg 2012;93:1563-1569. doi:10.1016/j.athoracsur.2011.08.075
© 2012 The Society of Thoracic Surgeons
Original Articles: Pediatric Cardiac
Longer Blood Storage Is Associated With Suboptimal Outcomes in High-Risk Pediatric Cardiac Surgery
Cedric Manlhiot, BSa,
Brian W. McCrindle, MD, MPHa,
Ines B. Menjak, MDa,
Hyeamin Yoon, MDa,
Helen M. Holtby, MDa,
Leonardo R. Brandão, MDb,
Anthony K. Chan, MDc,
Steven M. Schwartz, MDa,
V. Ben Sivarajan, MDa,
Lynn Crawford-Lean, BS, CPCa,
Celeste Foreman, CPCa,
Christopher A. Caldarone, MDa,
Glen S. Van Arsdell, MDa,
Colleen E. Gruenwald, PhD, CPCa,*
a Labatt Family Heart Centre, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada
b Division of Hematology/Oncology, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada
c Division of Pediatric Hematology/Oncology, McMaster University, McMaster Children's Medical Centre, Hamilton, Ontario, Canada
Accepted for publication August 24, 2011.
* Address correspondence to Dr Gruenwald, Department of Pediatrics, Labatt Family Heart Centre, The Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8, Canada (Email: colleen.gruenwald{at}sickkids.ca).
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Abstract
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Background: The negative effects of long-term storage of allogeneic red blood cells (RBCs) on outcomes in adult cardiac surgery have been established, but evidence of a similar effect in pediatric cardiac surgery is limited.
Methods: The weighted average duration of storage for RBC units used in 1,225 pediatric cardiac operations was determined. Operations were divided into high RBC use (more than 4 units or more than 150 mL/kg) or low RBC use. For both categories, associations between storage duration and surgical outcomes, adjusted for relevant patient characteristics, were evaluated.
Results: High RBC use was associated with higher surgical complexity. Storage duration for patients who received low RBC volumes was not associated with surgical outcomes. For patients with high RBC transfusion volumes, longer storage duration (per day) was associated with higher odds of bleeding complications (odds ratio 1.029, p = 0.07), renal insufficiency (odds ratio 1.085, p = 0.001), higher inotrope score after surgery (12 to 24 hours +0.08, p = 0.002; 24 to 48 hours +0.07, p < 0.001), greater chest tube drainage (24 hours +1.5 mL/kg, p < 0.001), longer postoperative hospitalization (+0.3 days p = 0.02), and increased in-hospital mortality (odds ratio 1.054, p = 0.03). Effects of RBC transfusions on postoperative bleeding were greatest for storage duration longer than 14 days.
Conclusions: The freshest RBC units available should be used for pediatric cardiac operations expected to require more than 4 units or more than 150 mL/kg of allogeneic RBC transfusions, with no units more than 14 days old being transfused whenever possible.
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Introduction
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| CARDIOTHORACIC ANESTHESIOLOGY:
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Children undergoing cardiac surgery with cardiopulmonary bypass (CPB) are among the greatest pediatric users of allogeneic red blood cells (RBCs) [1]. Currently, the only source of RBCs for transfusion purposes is allogeneic blood donation whose supply is maintained and managed by central blood banks. Blood product management is a fine balance between maintaining adequate blood supply and providing the freshest product possible. Long-term storage of allogeneic RBCs (as long as 42 days) for the purpose of blood transfusion is associated with biochemical changes and altered function of the cells. Collectively, those changes are referred to as "storage lesion." The clinical impact of long-term RBCs storage on outcomes in adult cardiac surgery has been established [2, 3]. Evidence of a similar clinical impact in children receiving blood transfusions for cardiac surgery is limited [4–6]. We sought to determine the extent of the association between RBC storage duration and clinical outcomes for pediatric patients undergoing cardiac surgery.
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Patients and Methods
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This retrospective study included all pediatric patients (less than 18 years of age) with congenital or acquired heart disease who underwent cardiac surgery between September 1, 2004, and December 31, 2007, at The Hospital for Sick Children. Multiple discrete surgical procedures required as part of a staged primary management strategy were included (for example, a Fontan procedure after a cavopulmonary shunt). Early reoperations for surgical complications during the same hospital admission and delayed sternal closure were excluded. Isolated closure of patent ductus arteriosus, placement or removal of an implantable cardioverter defibrillator, pacemaker, ventricular assist device implantation, or use of extracorporeal membrane oxygenation, and any noncardiac operation requiring the use of CPB were excluded. Operations not requiring blood products, those with restricted blood utilization directives, and those using autologous or directed donations were also excluded. Multiple procedures performed on an individual patient during the study interval were treated as independent entities, and the entire data collection was repeated for each procedure. The study protocol was approved by The Hospital for Sick Children Research Ethics Board; requirement for individual patient consent was waived for this study.
For every surgery, we abstracted from the medical record the patient's demographic characteristics, preoperative status and medical history, type of surgery, and details of the surgical procedure. Cardiac operations were classified according to the International Nomenclature for Congenital Heart Surgery, and the Aristotle score was used as an indicator of case complexity [7, 8]. Inotropic score was calculated using the following formula: dopamine + dobutamine + (epinephrine x 100) + (norepinephrine x 100) + (milrinone x 10). Drug dosages were expressed as μg · kg–1 · min–1 [9]. Surgical outcomes were assessed until hospital discharge. Major bleeding complications were defined as any of the following events: intracranial hemorrhage, pulmonary hemorrhage, clinically important (requiring treatment) hematuria, intraocular, retroperitoneal or gastrointestinal bleed or any bleeding episode requiring blood transfusion equivalent to two full blood volumes in the postoperative period, requiring transfusion of recombinant activated factor VII concentrate or use of desmopressin/vasopressin.
Blood transfusion protocols for pediatric cardiac surgery at our institution are user and patient dependent with considerable variability between clinicians. Canadian Blood Services (CBS) is the national blood agency collecting and managing all blood inventory for the country excluding Quebec. As per CBS protocol, all RBC units are donated from a single donor and leukoreduced by prestorage filtration using the Leukotrap system (Pall Corporation, Mississauga, ON, Canada). The institutional transfusion laboratory manages the local supply. As per its standard operating procedures, the oldest ABO blood group-compatible RBC units available are used in priority for all patients with rare exceptions for patients in critical condition. Storage duration for each unit (defined as time between donation and transfusion to patient) was obtained from the CBS central database. For each patient, we calculated the total number of units (each unit is equivalent to one donor exposure), the total volume (indexed to patient's weight), and the weighted average storage duration of all units. Patients were then divided into two groups based on their use of RBC during the surgery and in the following 48 hours: high RBC use was defined as either more than 4 units transfused or total RBCs transfusion volume more than 150 mL/kg. The remaining patients were classified as low RBC recipients. These threshold values were defined as they represent the 75th percentile for both number of units transfused and total RBC transfusion volume in this population. These thresholds allowed for some adjustment for surgical complexity and total volume used when assessing the effect of age of blood. Use of other blood products, such as albumin, fresh frozen plasma, cryoprecipitate, antithrombin, and recombinant activated factor VII, was also recorded.
Statistical Analysis
Data are reported as means with standard deviations, median with 5th and 95th percentile and frequencies as appropriate. Differences between high and low RBC users were estimated using 
2 tests and Student's t test. Associations between average duration of blood storage (modeled as a continuous variable) and outcomes were estimated in multivariable linear or logistic regression models, as appropriate, stratified by RBC use and adjusted for age at operation, previous surgery, systemic oxygen saturation before surgery, surgical complexity (Aristotle score), total duration of CPB and aortic cross clamping, use of deep hypothermic circulatory arrest, heparin dose (as mL · kg–1· h–1 CPB), use of antifibrinolytic drugs, and heart transplantation. All statistical analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC). Data analysis was performed by two of the authors (C.M. and B.M.), and all authors had access to the primary clinical data.
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Results
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In all, 1,225 cardiac operations performed in 1,067 patients were reviewed; 752 operations (61%) were classified as low RBC users, and 473 (39%) were classified as high RBCs users. For these operations, a total of 4,301 RBC units were allocated (1,883 units for low users [44%] versus 2,418 for high users [56%]) and 3,762 units of platelets (1,728 units for low users [46%] versus 2,034 for high users [54%]) during the perioperative period and in the first 48 hours after surgery. Surgery characteristics stratified by blood use (high versus low use) are noted in Table 1. High RBC use operations represent the higher complexity end of the surgical spectrum, with a predominance of infant patients, more complex (higher Aristotle score) surgery, and longer duration of CPB.
Details of blood product use are noted in Table 2. Patients in the high RBC user group also received a higher number of units of platelets, and were more likely to be given albumin, fresh frozen plasma, cryoprecipitate, and recombinant activated factor VII. Average age of RBCs (Fig 1) was similar between both low and high RBC users.
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Table 2 Details of Allogeneic Blood Transfusions Stratified by High RBC Use (>4 RBC Units or >150 mL/kg) Versus Low RBC Use
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Fig 1. (A) Average red blood cell (RBC) age and (B) maximum RBC age, with median RBC storage duration stratified by high RBC use (more than 4 RBC units or more than 150 mL/kg) versus low RBC use. Boxplot: central line represents distribution median; upper and lower limits of the box represent 75th and 25th percentiles, and whiskers represent 5th and 95th percentile.
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Surgical outcomes were universally worse for patients who received high volumes of RBCs (Table 3). For patients with low volumes of RBC use, none of the surgical outcomes were significantly associated with average age of blood. However, for operations where high volumes of RBCs were used, patients who received older blood required greater inotropic support, had higher volume of chest tube losses in the first 24 hours after surgery, and had longer duration of mechanical ventilation and intensive care unit and hospital stays. These patients were also more likely to have major bleeding complications, delayed sternal closure, renal, liver insufficiency/failure, early unplanned reoperation, and death before hospital discharge (Table 3). Age of blood was not associated with infection/sepsis, need for extracorporeal support in the postoperative period, or intravascular thrombosis.
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Table 3 Surgical Outcomes Stratified by High RBC Use (>4 RBC Units or >150 mL/kg) Versus Low RBC Use (left) and Association Between Average RBC Storage Duration and Surgical Outcomes for Patients With High RBC Use (right)
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Using the entire cohort, we determined that transfusion of each additional unit of RBC 7 days old or less was associated with an average increase of 1.6 mL/kg in chest tube volume loss at 24 hours, compared with an increase of 1.9 mL/kg for each units 8 to 14 days old, 5.2 mL/kg for each unit 15 to 28 days old, and 6.5 mL/kg for each unit more than 28 days old (p < 0.001; Fig 2).
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Fig 2. Increase in chest tube drainage over the first 24 postoperative hours for each additional allogeneic red blood cell (RBC) unit by duration of storage.
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Comment
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For pediatric cardiac operations during which high volumes of allogeneic RBCs are used, we noted that longer duration of RBC storage was significantly associated with numerous adverse outcomes including increased bleeding complications, longer duration of hospital stay, and higher in-hospital mortality. These associations remained significant after adjustment for patient and surgical factors known to be associated with surgical outcomes. It is quite possible that a similar effect is present in low blood use operations; however, the effect sizes may be undetectable in smaller trials. A large randomized controlled trial of fresh versus old RBCs in this context, using the same transfusion algorithm for both intervention groups is required and has already been proposed [10]. Several other studies of blood storage time in adults have reported an association between increased storage time with morbidity and mortality [2, 3]. In the pediatric setting, relevant studies on the clinical impact of prolonged RBC storage are rare but have found similar results [4, 6, 11].
Physiologic changes in RBCs that occur with prolonged storage time are collectively referred to as "storage lesion." These changes occur gradually, with increasing magnitude proportional to the duration of storage [12–14]. Delivery of oxygen to the tissues may be impaired by the depletion of 2,3-diphosphoglycerate in RBCs that are stored for more than 48 hours. Additional biochemical changes associated with prolonged RBC storage include a depletion of adenosine triphosphate [13], membrane phospholipid loss and translocation, and loss of cell deformability [13, 15]. These result in altered or diminished oxygen transport capacity [16], increase adhesiveness and aggregability, decreased clotting response [12–14], increased RBC-endothelial interactions that compromise microvascular flow [17, 18], and decreased RBC viability resulting in increased platelet activation and inflammation in response to exposure [13].
Based on the results from this study, we recommend the use of fresh RBCs for all pediatric cardiac operations for which it might be expected that high volumes of RBC transfusion will be needed. Previous studies have found that use of units with storage times less than 14 days were associated with improved outcomes [2], which is also supported by our results. Our recommendation is to use the freshest possible RBC units for those cardiac operations anticipated to have high transfusion requirements, and to not use RBC units stored more than 14 days for those operations. This recommendation may impose additional stress to the blood bank system; as such, strategies to maximize blood supply efficiency should be a primary focus of research. In the meantime, we believe that in the presence of a known detrimental effect of older blood in this population, prioritizing fresher units for those patients is reasonable. To better preselect potentially high risk surgery, we reviewed patients characteristics (Table 1) and selected six groups of patients most likely to require high RBC volumes: (1) patients who undergo surgery at less than 3 months of age; (2) operations with Aristotle category IV; (3) heart transplantation; (4) expected duration of CPB more than 3 hours; (5) use of deep hypothermic circulatory arrest; and (6) patients on extracorporeal membrane oxygenation or ventricular assist device before surgery. In our population, approximately 80% to 85% of operations that eventually used high RBC volumes met at least one of those six criteria.
Results from our study apply only to the use of leukoreduced blood products. In Canada, RBCs have been universally filtered for leukocytes before storage since 1999. White blood cells are thought to have indirect effects on RBC viability in storage medium by consuming glucose. In addition, white blood cell enzymes, such as elastase, collagenase, cathepsin G, and neuraminidases are thought to compromise the RBC membrane and to target RBCs for early destruction by macrophages [19, 20]. Leukoreduction of RBC units reduces storage hemolysis by approximately 50% [21], and has been shown in vitro to decrease adhesion of RBCs to endothelial cells under flow conditions [17, 22]. Leukoreduced RBC units also show better morphology scores, adenosine triphosphate content, vesicle protein shed, and lower potassium compared with nonleukoreduced units [19, 23]. It is possible that the effects of prolonged storage of RBCs may be magnified in nonleukoreduced RBC units owing to accelerated RBC destruction.
The use of cell washing or anaerobic storage was not investigated in this study. Cell washing before transfusion was not employed in our center during the study period, and could represent a potential intervention by which at least some of the biochemical changes associated with prolonged RBC storage could be reduced or even eliminated altogether. Anaerobic storage of blood products has recently been developed, and has been shown to delay the development of storage lesion [24]. Therefore, it is possible that our recommendation of using fresh RBCs for selected pediatric cardiac operations could be replaced by a recommendation to wash older RBC units before transfusion or to store blood products under anaerobic conditions. However, some of the changes to RBC physiology associated with long-term storage are likely permanent and irreversible.
This study should be considered in light of the fact that it is a retrospective study, with clinical and surgical data limited to what was documented in the medical records. Use of units based on duration of storage was not randomized. Although we used advanced statistical techniques to adjust for some of these differences, we cannot exclude the presence of any bias. Finally, we did not assess the temporal link between blood transfusions and postoperative outcomes. It is theoretically possible (although likely a rare event), that early outcomes happened before the 48 hours' postoperative mark that was used to characterize RBC usage and that some of the transfusions followed rather than preceded the outcome.
In conclusion, for pediatric cardiac operations that were associated with the use of high volumes of allogeneic RBC transfusions, prolonged duration of RBC storage was associated with an increased prevalence and severity of postoperative complications and suboptimal clinical outcomes. Based on our findings, we recommend that the freshest RBCs be used for pediatric cardiac operations for which it might be expected that more than 4 units or more than 150 mL/kg of allogeneic RBC transfusions are required, with no units more than 14 days old being transfused.
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Acknowledgments
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This work was supported by the Labatt Family Heart Centre Innovations Fund and by the CIBC World Markets Children's Miracle Foundation Endowed Chair in Child Health Research.
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Invited Commentary
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Ann. Thorac. Surg. 2012 93: 1569-1570.
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J. W. Gaynor, D. R. Jobes, and D. Sesok-Pizzini
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Ann. Thorac. Surg.,
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Abstract
Introduction
