Background Stored red cells undergo progressive structural andfunctional changes over time. We tested the hypothesis thatserious complications and mortality after cardiac surgery areincreased when transfused red cells are stored for more than2 weeks.
Methods We examined data from patients given red-cell transfusionsduring coronary-artery bypass grafting, heart-valve surgery,or both between June 30, 1998, and January 30, 2006. A totalof 2872 patients received 8802 units of blood that had beenstored for 14 days or less ("newer blood"), and 3130 patientsreceived 10,782 units of blood that had been stored for morethan 14 days ("older blood"). Multivariable logistic regressionwith propensity-score methods was used to examine the effectof the duration of storage on outcomes. Survival was estimatedby the Kaplan–Meier method and Blackstone's decompositionmethod.
Results The median duration of storage was 11 days for newerblood and 20 days for older blood. Patients who were given olderunits had higher rates of in-hospital mortality (2.8% vs. 1.7%,P=0.004), intubation beyond 72 hours (9.7% vs. 5.6%, P<0.001),renal failure (2.7% vs. 1.6%, P=0.003), and sepsis or septicemia(4.0% vs. 2.8%, P=0.01). A composite of complications was morecommon in patients given older blood (25.9% vs. 22.4%, P=0.001).Similarly, older blood was associated with an increase in therisk-adjusted rate of the composite outcome (P=0.03). At 1 year,mortality was significantly less in patients given newer blood(7.4% vs. 11.0%, P<0.001).
Conclusions In patients undergoing cardiac surgery, transfusionof red cells that had been stored for more than 2 weeks wasassociated with a significantly increased risk of postoperativecomplications as well as reduced short-term and long-term survival.
More than 14 million units of blood are transfused annuallyin the United States.1 Considerable evidence suggests that transfusionincreases the risk of serious complications and death in criticallyill patients,2,3,4 especially in patients who are undergoingcardiac surgery.5,6,7,8,9,10,11,12
Some studies have suggested that the risk of complications aftertransfusion also increases when transfused blood has been storedfor long periods.13,14,15,16,17,18 Blood collection and storagesystems licensed by the Food and Drug Administration allow redcells to be stored for up to 42 days. (The median duration ofstorage of transfused red-cell units in the United States is15 days.1) During storage, preserved blood cells undergo progressivestructural and functional changes that may reduce red-cell functionand viability after transfusion.18,19,20,21,22
The clinical importance of transfusing older red cells versusnewer red cells remains unclear, with some studies identifyingadverse consequences13,14,15,16,17 and others not.23,24 Previousinvestigations, however, have been limited by small sample sizes,15,25heterogeneous patient populations,15 and inadequate controlof confounding factors.25 Furthermore, many reported end points,such as duration of hospitalization, lack sensitivity for specificorgan function.24 We tested the hypothesis that serious complicationsand mortality after cardiac surgery increase when red-cell unitsare transfused after they have been stored for more than 2 weeks.
Methods
Patients
The patient population consisted of adult patients (18 yearsof age or older) who were undergoing coronary-artery bypassgrafting, cardiac-valve surgery, or a combination of the twoprocedures at the Cleveland Clinic from June 30, 1998 (whenblood-bank data became available electronically), until January30, 2006. We included data from patients who received exclusivelyred-cell units that had been stored for 14 days or less ("newerblood") or exclusively units that had been stored for more than14 days ("older blood"). To reduce confounding factors, datafrom patients who received a mixture of newer and older bloodwere excluded from the study.
Standard cardiac surgical practice during the period under studyincluded the administration of aminocaproic acid (a plasmininhibitor) to reduce intraoperative bleeding, as well as theuse of cardiotomy suction to retrieve shed blood during theoperation and return it to the patient's circulation througha cardiopulmonary-bypass pump. There was no uniform protocolfor perioperative transfusion, although it has been our generalpractice to minimize the use of blood products. When blood wasordered for transfusion, the blood bank provided the oldestavailable matching unit for each request.
Data Sources
We accessed Cleveland Clinic's cardiac anesthesia registry toretrieve baseline demographic and perioperative variables thathad been prospectively collected by clinical coordinators concurrentlywith patient care and entered into the database by trained data-managementpersonnel. The clinic's cardiovascular information registrywas also accessed for additional variables. The clinic's blood-bank database was queried for the storage time of the red-cellunits, their ABO blood type, and their leukocyte-reduced status.All three databases have been approved by the institutionalreview board of the Cleveland Clinic for use in research withpatient consent waived.
Complications
We characterized individual in-hospital complications with theuse of the definitions of the Society of Thoracic Surgeons (www.sts.org).Our primary end point, defined before analysis, was a compositeof serious adverse events that included in-hospital death, myocardialinfarction, asystole, ventricular tachycardia or fibrillation,tamponade, femoral or aortic dissection, renal failure, sepsis,respiratory insufficiency, pulmonary embolism, pneumonia, cerebralvascular accident, coma, deep or superficial sternal-wound infection,prolonged postoperative ventilation (>72 hours), multiorganfailure, and acute limb ischemia. This specific list of seriousadverse events is based on the set of complications definedin the adult cardiac surgery database of the Society of ThoracicSurgeons. Each of these adverse events was also examined separately.Our secondary end point was long-term survival. Follow-up survivalstatus of the patients was obtained from the Social SecurityDeath Index.26,27,28 The closing date was September 20, 2006.
Statistical Analysis
Baseline characteristics, operative factors, and univariateoutcomes were compared between patients receiving exclusivelynewer blood and those receiving exclusively older blood withtwo-sample tests. The Wilcoxon rank-sum test and the chi-squaretest were used for group comparisons among continuous and categoricalvariables, respectively.
In order to understand the dose–response relationshipbetween the storage time of blood and the composite outcome,we defined a summary variable for the storage time for eachpatient as the longest storage time of all transfused unitsreceived by that patient when a patient received multiple unitsof blood with different storage times. We then performed a nonparametriclogistic-regression analysis of the composite outcome and thissummary variable.
To adjust for potential confounders, we used multivariable logistic-regressionanalysis of the composite outcome for all baseline variablesand the groups receiving newer and older blood. A stepwise variable-selectionprocedure was applied to identify variables associated withthe composite outcome. To control for confounding, a propensityscore was calculated from a logistic regression as the probabilityof being in the group receiving newer blood, given all the baselinevariables. This propensity score was then forced in the logisticmodel for the composite outcome to further adjust for confounding.
Kaplan–Meier analysis was used to examine differencesin unadjusted survival, with the Wilcoxon and Tarone tests usedfor comparisons. The Wilcoxon and Tarone tests are generalizationsof the log-rank tests with various weighting functions thathave good power against early differences in survival curves.Risk-adjusted long-term survival was examined with the parametrichazard-decomposition method of Blackstone et al.29
Results
Age of Red Cells
The maximum storage time of the transfused red cells was 42days, and the median time was 15 days. Because newer and olderblood units were delineated by the median storage time (i.e.,15 days), the number of patients receiving newer units and thenumber receiving older units were nearly equal. A total of 2872patients received 8802 units of newer blood, and 3130 patientsreceived 10,782 units of older blood. The numbers of units transfusedper patient were similar in the group receiving exclusivelynewer blood and in the group receiving exclusively older blood(Figure 1A). Figure 1B depicts the mean duration of storageper number of red-cell units transfused for both patient groups.There were also 2364 patients in our study sample who receiveda mixture of units of newer and older blood and were not includedin the analysis. These patients received considerably more unitsthan those in either study group.
Figure 1. Number of Red-Cell Units Transfused in Relation to the Percentage of Patients Receiving Transfusion and Box Plots of the Duration of Storage of Blood.
Panel A shows the distribution of the number of red-cell units transfused in 2872 patients who were given exclusively newer blood (stored for 14 days or less) and in 3130 patients given exclusively older blood (stored for more than 14 days). The distributions are similar in the two groups (P=0.99 by the Wilcoxon rank-sum test). Panel B shows the number of red-cell units transfused per patient in relation to the duration of storage of newer blood and older blood. The lower and upper bounds of the boxes represent the 25th and 75th percentiles, and the heavy horizontal lines represent means. The I bars represent the maximum and minimum values for each group, excluding the possible outliers, which are represented by open circles.
Table 1 displays baseline and operative variables for patientsreceiving newer and older blood. Many of the baseline and operativevariables were similar between the groups. However, the distributionof ABO blood types, both for the recipients and for the unitstransfused, differed between the two groups (P<0.001 forboth comparisons). In addition, patients given newer blood wereless likely to receive leukocyte-reduced red-cell units (36.1%vs. 55.0%, P<0.001), were more often classified as New YorkHeart Association class IV (13.3% vs. 9.9%, P<0.001), andhad a smaller body-surface area (1.93 vs. 1.94 m2, P=0.03).In contrast, slightly more patients in the group receiving olderblood had preoperative mitral regurgitation (67.3% vs. 64.1%,P=0.01), abnormal left ventricular function (63.1% vs. 57.9%,P<0.001), and peripheral vascular disease (58.5% vs. 54.4%,P=0.002).
Table 1. Characteristics of Transfused Blood and Demographic and Clinical Features of the Patients.
Complications
Patients who were given older blood had greater in-hospitalmortality (2.8% vs. 1.7%, P=0.004), were more likely to needprolonged ventilatory support (9.7% vs. 5.6%, P<0.001), andwere more likely to have renal failure (2.7% vs. 1.6%, P=0.003),septicemia or sepsis (4.0% vs. 2.8%, P=0.01), or multisystemorgan failure (0.7% vs. 0.2%, P=0.007) than patients who weregiven newer blood (Table 2). Patients who were given older bloodwere also more likely to have the composite outcome of multipleserious adverse events (25.9% vs. 22.4%, P=0.001). The dose–responserelationship between the composite outcome and the maximum ageof blood for each patient is presented in Figure 2. This unadjustedrelationship indicates a trend, especially for the group receivingolder blood, toward an association between blood-storage timeand the composite outcome. This association remained significantafter adjustment for the baseline risk factors listed in Table 1(adjusted odds ratio for patients receiving older blood as comparedwith those receiving newer blood, 1.16; 95% confidence interval,1.01 to 1.33; P=0.03).
Figure 2. Statistical Model Showing Dose–Response Relationship between the Maximum Number of Days of Storage of All the Red-Cell Units Each Patient Received and the Probability of the Composite Outcome.
The probability curves were calculated from nonparametric logistic-regression analysis of data from 2872 patients who were given exclusively newer blood (stored for 14 days or less) and 3130 patients given exclusively older blood (stored for more than 14 days). An increasing linear trend is noted, especially for patients who received exclusively older blood.
Survival was lower and the risk of death was higher for patientswho received older blood (P=0.001 by the Wilcoxon test, P=0.004by the Tarone test). The 1-year survival rate was 92.6% forthe group receiving newer blood and 89.0% for the group receivingolder blood (P<0.001) (Figure 3); the corresponding 1-yearrates of death from all causes were 7.4% and 11.0%, respectively.On the basis of these results, it would be necessary to restrictblood-storage time to 2 weeks or less for 28 patients undergoingcardiac surgery to prevent one death during the first year afterthe operation. Hazard-rate analysis indicates that most deathsassociated with the transfusion of older blood occurred withinthe first 6 postoperative months (Figure 3, inset). The multivariatemodel that we developed can be used to estimate the predictedsurvival of a patient undergoing heart surgery, given the relevantclinical characteristics and the age and number of units oftransfused blood (see the Supplementary Appendix, availablewith the full text of this article at www.nejm.org).
Figure 3. Kaplan–Meier Estimates of Survival and Death.
The curves show data from 2872 patients who were given exclusively newer blood (stored for 14 days or less) and 3130 patients given exclusively older blood (stored for more than 14 days). The numbers above and below the curves represent the numbers of patients who were alive and under follow-up observation in each group at that time. The solid lines of the same color represent estimated survival or the rate of death, and the dotted lines represent pointwise 95% confidence intervals. The nonparametric survival estimator (orange squares or blue circles), as determined by the Kaplan–Meier method, is superimposed on the parametric survival function estimator. In this unadjusted comparison, the percentage of patients receiving older blood who survived was lower than the percentage of those receiving newer blood who survived, especially during the initial follow-up period.
Discussion
Transfusion of red cells that had been stored for more than14 days was associated with a significantly increased risk ofpostoperative complications and reduced survival after cardiacsurgery. In-hospital death, prolonged intubation, renal failure,septicemia or sepsis, multiorgan failure, and a composite ofserious complications were all more frequent in patients givenblood stored for more than 14 days. Furthermore, survival —particularly in the first 6 months after surgery — wassignificantly reduced. The adverse effects of transfusing olderblood persisted even after adjustment for perioperative factorsknown to be associated with an adverse outcome in this population,including the number and ABO blood group of the transfused red-cellunits, the blood group of the patient, the demographic characteristicsof the patient, laboratory values, coexisting conditions, andthe type of operative procedure.
Although the mechanism linking adverse outcomes with increasedduration of red-cell storage remains unclear, several factorsmay contribute. Preserved blood cells undergo progressive functionaland structural changes.19,20,21,30 This "storage lesion" isan amalgamation of reversible and irreversible changes thatbegin after 2 to 3 weeks of storage, progress with durationof storage,20 and reduce red-cell function and viability aftertransfusion.21 The effects of prolonged storage on red cellsinclude decreased deformability, which can impede microvascularflow19,20,31; depletion of 2,3-diphosphoglycerate (2,3-DPG),which shifts the oxyhemoglobin dissociation curve to the leftand reduces oxygen delivery32; increased adhesiveness and aggregability31;reduction in the concentrations of nitric oxide and adenosinetriphosphate33; and accumulation of proinflammatory bioactivesubstances.31 Impairment results in part from priming of thenicotinamide adenine dinucleotide phosphate oxidase system,which is thought to result from accumulation of proinflammatorylipids.34,35,36 Abnormal flow and abnormal biochemical propertiesof blood cells in stored blood are partially reversible by restorationof intracellular 2,3-DPG. However, recovery of 2,3-DPG is aslow process, and 2,3-DPG levels remain at only 50 to 70% ofthe normal range 24 hours after red-cell transfusion.37,38
Because the storage lesion becomes apparent after about 2 weeks,we dichotomized our population into a group that was given onlyblood stored for 14 days or less and a group given blood thatwas stored for more than 14 days. It happened that the medianred-cell storage time was 15 days, so that a 2-week cutoff resultedin two groups of nearly equal size.
The results of previous studies evaluating the effect of red-cellage on outcomes are contradictory, perhaps because most studieswere small and had substantial methodologic limitations. Forexample, Marik and Sibbald39 noted an inverse association betweenchanges in gastric intramucosal pH and the age of transfusedblood for patients who received red cells stored for more than15 days. In addition, evidence of splanchnic ischemia developedin patients given older blood.39 Other studies demonstratedan association between an increased duration of storage andmultiorgan failure,13 infectious complications,14,15,16 anddeath.17
Other investigations, however, showed no relationship betweenthe duration of red-cell storage and adverse outcomes.23,24,40,41,42Van de Watering and colleagues24 examined broad outcome measures,such as length of stay and 30-day mortality, in 945 patientsreceiving exclusively red cells stored for less than 18 daysand in 950 patients receiving exclusively red cells stored formore than 18 days. The authors reported similar outcomes inboth groups; however, there were only a small number of outcomeevents.
Our study, which is based on data from patients receiving morethan 19,000 units of transfused red cells in cardiac surgery,is a very large investigation of the effect of the durationof red-cell storage. Furthermore, the homogeneous patient populationin our study did not include patients with trauma or patientswith heterogeneous chronic diseases.
One limitation of transfusion studies is that "duration of storage"becomes difficult to define meaningfully if more than 1 unitis used. Previous investigators have used average, median, ormaximum duration of storage.23,24 We instead restricted ouranalysis to patients given only newer blood or only older bloodto better characterize the effect of duration of storage onmajor illnesses and death.
Observational cohort investigations may result in an imbalancein confounding variables among groups under comparison whengroup assignment is not at random. The provision of units ofblood by a blood bank is not a random process, since it is constrainedby blood-type compatibility. In addition, the blood bank isnot blinded to the identity of transfusion recipients, and staffmay become aware of the specific blood requirements of a rapidlybleeding patient. Such knowledge could influence decisions aboutthe units of blood provided for transfusion. This effect wasprobably minimized by the fact that, during the period of thestudy, the blood bank routinely prepared 2 to 4 units of redcells the evening before planned surgical procedures and deliveredthem to the operating rooms the morning of surgery. Actual useof these units did not necessitate a call to the blood bank.As shown in Figure 1, a majority of patients received 1 or 2units of blood, amounts not associated with active bleeding.
Nonetheless, given the fact that the distribution of blood unitswas not truly random, we investigated potential differencesbetween the two study groups that might confound the comparisonof interest. Although most baseline variables were similarlydistributed between patients given older blood and those givennewer blood, some were not (Table 1). We therefore used multivariableregression as well as propensity-score methods to adjust forthe imbalance in potentially confounding variables. The homogeneityof the patient population and the incorporation of a propensityscore in the multivariable analyses strengthened the findingof an association between increased duration of storage andadverse outcomes.
There is increasing observational evidence that the risk ofadverse outcomes increases incrementally with each unit of redcells that is transfused.5,6,7 However, the number and distributionof units transfused in the two groups were fully balanced, andthe number of units was included as a variable in the multivariablemodeling; therefore, the adverse effects of transfusion perse do not confound our conclusion that outcomes are worse witholder blood. In contrast, since patients given a mixture ofolder and newer blood received substantially more blood thaneither study group, we did not include them in our analysis.
The clinical implications of our findings require some consideration.About half of all patients undergoing cardiac surgery are givenblood, typically 1 or 2 units. We report that the relative riskof postoperative death is increased by 30% in patients givenblood that has been stored for more than 2 weeks. These resultsmay appear to suggest that blood should be classified as outdatedearlier than current recommendations. However, maintaining anadequate blood supply depends on the balance between blood donationand use. Improving donation is challenging, and obtaining andprocessing blood is expensive. It seems unlikely that donationcan be substantially increased on an ongoing basis, althoughthe public response to disasters and emergencies suggests thepotential to increase donation episodically.43
Other possible approaches to reduce the mean storage time oftransfused blood include a reduction in the amount of bloodtransfused (a course that has been facilitated in part by methodsto retrieve and reuse shed blood during surgery44 and that isreceiving further impetus from studies suggesting that it isdesirable to limit transfusion),5,6,7 the development of newermethods of blood storage to retard the progression of storage-relatedchanges,45 the use of blood substitutes,46 and the use of mathematicalmethods of inventory optimization to increase the preferentialuse of newer blood units without increasing waste.47,48 Furtherinvestigation will be necessary, however, before any substantialchanges in blood-banking practices can be considered for broadimplementation on the basis of our data.
In conclusion, we compared the outcomes among patients undergoingcardiac surgery who received transfusions of blood stored formore than 2 weeks with the outcomes among patients receivingblood stored for 2 weeks or less. Transfusion of red cells storedfor more than 2 weeks was associated with a significantly increasedrisk of postoperative complications and a reduction in bothshort-term and long-term survival after cardiac surgery.
Supported by a grant (GM 061655) from the National Institutesof Health and by the Joseph Drown Foundation.
No potential conflict of interest relevant to this article wasreported.
Source Information
From the Department of Cardiothoracic Anesthesia (C.G.K.), the Department of Quantitative Health Sciences (L.L.), the Department of Outcomes Research (C.G.K., D.I.S.), the Department of Laboratory Medicine and Clinical Pathology (P.F., G.A.H.), and the Department of Thoracic and Cardiovascular Surgery (T.M., E.H.B.), Cleveland Clinic Foundation, Cleveland.
Address reprint requests to Dr. Koch at the Departments of Cardiothoracic Anesthesia and Outcomes Research, Cleveland Clinic, 9500 Euclid Ave. G3, Cleveland, OH 44195, or at kochc{at}ccf.org.
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Hlatky, M. A., Heidenreich, P. A.
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Oddo, M., Milby, A., Chen, I., Frangos, S., MacMurtrie, E., Maloney-Wilensky, E., Stiefel, M., Kofke, W. A., Levine, J. M., Le Roux, P. D.
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Budaj, A., Eikelboom, J. W., Mehta, S. R., Afzal, R., Chrolavicius, S., Bassand, J.-P., Fox, K. A.A., Wallentin, L., Peters, R. J.G., Granger, C. B., Joyner, C. D., Yusuf, S., on behalf of OASIS 5 Investigators,
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(2009). Acute Kidney Injury After Cardiac Surgery: Focus on Modifiable Risk Factors. Circulation
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Sakwa, M. P., Emery, R. W., Shannon, F. L., Altshuler, J. M., Mitchell, D., Zwada, D., Holter, A. R.
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Fernandez-Perez, E R, Sprung, J, Afessa, B, Warner, D O, Vachon, C M, Schroeder, D R, Brown, D R, Hubmayr, R D, Gajic, O
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Mangalmurti, N. S., Xiong, Z., Hulver, M., Ranganathan, M., Liu, X. H., Oriss, T., Fitzpatrick, M., Rubin, M., Triulzi, D., Choi, A., Lee, J. S.
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Bateman, S. T., Lacroix, J., Boven, K., Forbes, P., Barton, R., Thomas, N. J., Jacobs, B., Markovitz, B., Goldstein, B., Hanson, J. H., Li, H. A., Randolph, A. G., for the Pediatric Acute Lung Injury and Sepsis Inv,
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Benjamin, R. J., Dodd, R. Y., Hall, S. W., Habib, R. H., Zacharias, A., Frenzel, T., Sibrowski, W., Westphal, M., Koch, C. G., Li, L., Blackstone, E. H.
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