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Red Cell Storage Duration Does Not Affect Outcome after Massive Blood Transfusion in Trauma and Nontrauma Patients: A Retrospective Analysis of 305 Patients.

1. Background

Over 14 million units of blood products are transfused in the United States (U.S.) annually [1]. Massive blood transfusions are given to 3-5% [2] of the civilian and 8-10% [3] of the military trauma patient population. Patients requiring massive blood transfusion are at high risk for adverse clinical outcomes largely because of their serious trauma, but also as a direct consequence of receiving numerous blood products. Transfusions of blood products are associated with several complications and current evidence suggests that transfusions independently increase the risk of morbidity and death in critically ill patients [4-8], with mortality increasing linearly as a function of the amount of blood transfused. For example, a recent trauma registry analysis found that major blood loss constitutes an important prognostic factor for the survival [9] and the authors of the PROMMTT trial [10] demonstrated an adjusted odd ratio of 6-hour mortality for patients receiving [greater than or equal to] 4 units within 30 minutes of 2.1 (95% confidence interval: 1.2--3.5). Overall, adverse consequences of transfusions add about $17 billion to United States healthcare costs which exceeds the costs of blood acquisition and transfusion combined [11].

Koch and colleagues identified a strong association between storage of red cells more than 14 days and major complications and mortality after coronary artery bypass graft (CABG) surgery [1]. The United States Food and Drug Administration allows storage of PRBCs for up to 42 days; however, it is well established that stored red cells undergo substantial biochemical and morphological changes during this period. Important dysfunction includes reduced oxygen delivery resulting from progressive decrease in 2,3-diphosphoglycerate (2,3-DPG) concentrations [12], reduced PRBC-dependent vasodilation [13] (for review see [14, 15]), decreased cell membrane deformability [16,17] which potentially obstructs capillary flow, consumption of clotting factors, and activation of intravascular coagulation through PRBC derived microvesicles [18]. Prolonged PRBC storage is also thought to increase the risk of severe infection after CABG surgery [19].

Other studies, though, do not identify harm from transfusion of older blood. For example, Edgren and colleagues [20] analysed the Scandinavian Donations and Transfusions (SCANDAT) database and found that the initial trend towards a seven-day risk of death reduction diminishes within the 2-year follow-up and that transfusion of older blood is likely to contribute to less than 5% to excess mortality. Saager and colleagues similarly reported no relationship between prolonged median storage duration and mortality in a retrospective analysis of data from noncardiac surgery patients [21]. More importantly, two large randomized trials, RECESS and ABLE, concluded that PRBC storage duration did not affect the outcome after CABG surgery [22] or in critically ill patients [23].

Routine surgical patients, if given blood, usually receive just one or two units. Trauma patients differ in often experiencing major blood loss and consequently requiring large amounts of blood products. Trauma patients, along with nontrauma patients, who are given large amounts of blood (i.e., [greater than or equal to] 10 units) may thus be especially susceptible to injury from blood that has been long stored.

Consistent with this theory, Zallen and colleagues performed a small prospective database analysis in trauma patients and concluded that multiorgan failure was more likely when patients were transfused with blood stored for 30 days than when stored for 24 days [24]. Two similar small studies suggest that prolonged blood storage duration is associated with an increased need [25] and increased duration of critical care [26]. Furthermore Weinberg and colleagues [27] included 176 trauma patients who were given at least one unit of blood within 24 hours after hospital arrival. Those given six units or more of PRBC, with at least three units stored for more than 14 days, had an odds ratio of dying of 7.8 (95% CI 2.3-26.3), twice the odds ratio of patients who received blood stored for less than 14 days. Previous published reports focused mainly on the impact of different storage durations in relative small numbers of transfused PRBCs (i.e., 5-10 units) on clinical outcome [24, 26, 28, 29].

We therefore tested the hypothesis that mean storage duration of transfused PRBC is associated with in-hospital mortality in patients given more than 10 units of PRBC within 24 hours. We also compared the relationship between storage duration and mortality in trauma and nontrauma patients who required massive blood transfusion for elective surgery. Specifically, we tested the secondary hypothesis that the relationship between blood storage duration and mortality is similar in trauma and nontrauma patients given massive amounts of blood.

2. Patients and Methods

The University of Louisville Hospital is a level-one trauma centre with about 3,000 trauma admissions/year. After the approval by the institutional review board at the University of Louisville, we performed this retrospective observational cohort study. Our analysis was restricted to patients who were given more than 10 units of PRBCs within a 24-hour surgical intervention according to the Hospital Blood Bank database. We include neither patients who died within six hours after starting massive blood transfusion and suffered from irreversible lethal injuries (i.e., gunshot to the head, open brain injuries) nor patients with more than 20% incomplete data or inadequate documentation within the medical records into our analysis. In addition to eligibility criteria for the study, we excluded patients for whom storage duration information was unavailable for >10% of their transfused PRBC units.

We accessed the University Hospital Information Management system to retrieve baseline demographic, perioperative, and outcome variables as listed in Table 1. Trauma scores and injury schemes were retrieved from the hospital's trauma database and reviewed by an attending trauma surgeon (J.S.).

Patients' medical records were reviewed from the time they arrived in the Emergency Department (ED, trauma patients) or the start of massive blood transfusion (nontrauma patients) until the time of discharge. We considered Emergency Department, Surgical and Anaesthesia, Laboratory, and Blood Bank records. Only initial surgical procedures were considered.

Information regarding storage duration of blood components, ABO blood type, and the time at which each product was released by the University of Louisville Hospital Blood Bank was collected from the same database. All PRBCs were leukoreduced by the blood supplier (usually the American Red Cross) and stored in AS-1 solution.

Preprocedure biochemistry and blood gas data were retrieved from either ED records or, if not available, from the initial intraoperative blood collection. Postprocedure biochemistry and haematological values were obtained from the final intraoperative or initial postanesthesia care unit blood samples.

2.1. Statistical Methods. Data analysis followed a stepwise approach: first, baseline potential confounding variables were assessed for balance using standard univariable numerical summaries across quartiles of observed mean PRBC storage duration.

To evaluate the principal hypothesis of the study, namely, that mean PRBC storage duration is associated with in-hospital mortality, we conducted both a univariable analysis and a (primary) multivariable analysis. Within our logistic regression models, patient mean PRBC storage duration was analysed as a continuous variable. Potential nonlinearities in the relationship between patient mean PRBC storage duration and mortality were assessed using a Chi-squared goodness of fit test, which compared a model that incorporated restricted cubic splines to a model that assumed a linear effect. The secondary hypotheses regarding the existence of differential relationships for trauma and nontrauma patients were evaluated by adding an interaction term between patient mean PRBC storage duration and an indicator for trauma to these models.

To construct the multivariable model, we used backward stepwise variable selection, starting with a "full" model that included the variables listed in Table 1 (excluding the indicator variables describing the type of trauma that occurred in lieu of the fact that we analysed trauma as a binary variable that was linearly dependent on these indicator variables) provided the variables were not >10% missing. Variable selection was implemented in a penalized fashion, based on Akaike's Information Criterion (AIC) [30]. By introducing a penalty proportional to each additional parameter in the model, the AIC encourages parsimonious models.

The potential confounding variables we considered were year of admission, age, female sex, patient blood type, along with a history of heart disease, pulmonary disease, renal disease, hypertension, diabetes mellitus, carcinoma, liver disease, tobacco use, alcohol use, or illicit drug use. We also considered preprocedural hemoglobins, heart rate, systolic blood pressure, blood pH, platelet count, international normalized ratio, prothrombin time, activated partial thromboplastin time, and number of transfused PRBC units. And finally, we also included duration of surgery. The multivariable models included only patients with complete information on these covariates.

R statistical software version 3.2.0 (The R Foundation for Statistical Computing, Vienna, Austria) for 64-bit Microsoft Windows operating system was used to perform all analyses. We used a Type I error rate of 5% for the evaluation of all hypotheses.

3. Results

We identified 496 consecutive trauma and nontrauma patients who were given more than 10 units of PRBCs within 24 hours of surgery over a six-year period. 191 were excluded, mostly because patients died within six hours or because of missing data or failure to meet inclusion criteria. A detailed enrolment scheme is attached as Figure 1 and a summary of baseline characteristics for the four quartile groups of patient mean PRBC storage duration defined among the remaining 305 patients is given in Table 1. Baseline characteristics by type of surgery (trauma versus nontrauma) are presented in Table 2. With patients staying an average of 21 days (minimum: 1 day, maximum: 138 days) in the hospital, the overall in-hospital mortality was 101/305 (33.1%), including 23/90 (25.6%) of nontrauma patients and 76/213 (35.7%) of trauma patients.

Overall, patient mean PRBC storage duration ranged from 8 to 37 days, with a mean [+ or -] standard deviation storage duration of 22 [+ or -] 6 days. Figure 2(a) displays a histogram, as well as the estimated (nonlinear) relationship with in-hospital mortality, based on the univariable logistic regression model. The restricted cubic spline term which characterized the nonlinear relationship did not significantly improve the model fit (P = 0.78, Chi-squared goodness of fit test), suggesting that a linear approximation sufficed. Based on this simpler model, the odds ratio (95% confidence interval) for in-hospital mortality corresponding to a one-day increase in patient mean PRBC storage duration was estimated at 0.99 (0.95,1.03, P = 0.77, Chi-squared test for model coefficients). No significant evidence of differential relationships between trauma and nontrauma patients was found (P = 0.87 for the interaction between trauma and patient mean PRBC storage duration; see Figure 2(b)).

Data from 259 patients were included in our multivariable modelling. The stepwise variable selection procedure identified age, renal disease, alcohol use, preprocedure blood pH, activated partial thromboplastin time, and number of units transfused as covariates for the final multivariable model. However, results were similar to those obtained from the univariable modelling. The adjusted odds ratio (95% CI) for patient mean PRBC storage duration was 0.98 (0.93, 1.04).

Secondary outcomes are summarized in Tables 3 and 4. There was no significant relationship between mean storage duration and in-hospital mortality. Patients who were given blood of the first and third quartile had a slightly (nonsignificantly) longer hospitalization, ICU stay, and mechanical ventilation than patients given blood from the second or fourth storage duration quartile.

About 22% of all patients suffered from disseminated intravascular coagulation, independent of blood storage duration, and the incidence of myocardial infarction appeared to increase with storage duration. A third of all patients suffered from infections (i.e., surgical site infection or pneumonia), while almost 40% of all patients developed acute respiratory distress syndrome with no particular prevalence towards a particular mean storage duration.

4. Discussion

We included patients given massive transfusion, defined by transfusion of 10 or more units of PRBCs within 24 hours. Only about 5% of the estimated annual 50 million trauma cases in the U.S. require this much blood, but they account for 10 to 15% of all transfused blood products [2] and accrue more than 4 billion dollars of health care cost [31]. Blood transfusion is a strong independent predictor of mortality in trauma and nontrauma patients [32], especially in massively transfused patients [33]. Our results are consistent in that mortality was high in our massively transfused patients, many of whom did not even live six hours. Among those who lived and thus qualified for our analysis, a third died during their initial hospitalization.

Two recent meta-analyses evaluated the relationship between PRBC storage duration and long-term mortality, multiple organ failure, in-hospital infections, duration of mechanical ventilation, and respiratory failure requiring ventilator support [34, 35]. The analysis suggested that storage duration did not affect outcome, but the authors noted considerable heterogeneity concerning patient populations, diversity of interventions, and measurement of clinical outcome. In contrast, Wang and colleagues analysed 21 studies including a total of 409,966 patients concluding that older blood is associated with increased mortality [36].

Patients having cardiovascular/CABG surgery are well studied, but both prospective and retrospective data conflict regarding the potential harm of prolonged stored blood products [1, 37-40]. The most recent large prospective trials in cardiac surgery patients [22] and critically ill patients [23] demonstrate no difference in outcomes including the incidence of multiorgan dysfunction syndrome or mortality [22], the incidence of major illnesses, duration of hemodynamic instability, renal or ventilator support, length of stay in the hospital, or transfusion reactions [23]. However, patients in both studies were typically given just one or two units of red cells.

Trauma patients are likely to experience multiorgan failure [24, 41], infection [28], kidney failure [27], pneumonia [42, 43], deep vein thrombosis [41], and death [27, 41, 43, 44]. Risk is presumably largely related to tissue injury, but the need for large amounts of blood products contributes [33].

Massively transfused patients have been underrepresented in previous studies. For example, only 13% of patients in Edgren's database [20] received more than five units of PRBCs, the RECESS trial [22] included only 145 patients who received more than eight units, and only 156 trauma patients in the ABLE trial were given more than four units of blood [23]. Even in the recently published INFORM trial [45] including 30,000 patients randomized to transfusion of short-term or long-term stored PRBCs, the number of trauma patients and massive transfused patients was negligible similar to other studies including even fewer massively transfused patients [24, 28, 42, 43]. Our analysis is the first focusing exclusively on patients who received a minimum of at least ten units of PRBCs within 24 hours, representing transfusion of 8,046 units in just 305 patients. Nonetheless, there was no association between mean storage duration of PRBCs and in-hospital mortality. Nor was there a differential effect amongst trauma and nontrauma patients.

Stored PRBCs undergo progressive structural and conformational changes associated with proposed subsequent worsening of quality, function, and viability of PRBC after transfusion [17,46,47]. Assessing effects of blood product age in our patient population receiving at least 10 units of PRBCs is challenging as the majority of patients do not receive exclusively old nor young blood products, but a mixture of both.

Unfortunately, no clear cut-off time has been defined after which changes during storage become clinically important with the result that various investigators have used arbitrary storage thresholds (i.e., 14 days [27], 21 days [22], or 28 days [41] of storage time) or based their analyses on the oldest unit [41]. As most blood banks in the U.S. and worldwide follow the inventory principle "first-in-first-out" to avoid outdating of stored blood products [23, 48], massively transfused patients typically receive PRBCs with a considerable range of storage durations because a single patient may use a considerable fraction of the matching units for an entire hospital, even in a major trauma centre like the University of Louisville Hospital. We therefore used mean storage time as a continuous variable, with a consequence that the difference between the first and fourth quartile of PRBC storage duration was only six days. However, histograms displaying the distribution of PRBC storage duration considering median, minimum, and maximum storage duration revealed a similar difference between patients receiving short or prolonged stored products (Figure 3). With the relative broad distribution of storage times of PRBCs/patient, it is not possible to determine whether a specific storage threshold exists (i.e., 35 days [49]) beyond which age will effect outcome in this particular patient population. While this relatively small range limits our ability to assess the specific effects of blood age on mortality, our conclusion that storage duration and mortality are unassociated probably applies broadly.

Mortality within 6 hours after hospital admission increased is doubled in patients who receive 4 or more units of resuscitation fluid [50]. We excluded 36 patients who died within the first 6 hours after starting massive transfusion as most experienced such severe trauma (i.e., penetrating trauma to major vessels and organs with 50% of the patient during initial surgery) that the storage lesion of transfused red cells is unlikely to have caused their demise. In fact, some investigators postulate that some detrimental effects of prolonged red cell storage become evident more than two weeks after transfusion [1]. Our average observation time was 21 days (minimum: 1 day, maximum: 138 days) and therefore remains possible that we missed longer-term transfusion-related outcomes.

As in all observational studies--particularly, those involving emergency surgeries in trauma patients--missing data are a major concern. We reviewed the records of 498 patients who had massive blood transfusions. Despite all efforts, we were unable to retrieve complete data for many patients, a problem that has been noted in previous studies [51]. We therefore only included patients in whom more than 80% of all study-related data were available. A limitation of our analysis is that we cannot determine the effect of missing data in the patients we included, much less the effect of excluding patients who had much missing data.

In summary, our data suggest that the median storage time of PRBCs transfused is not associated with in-hospital mortality amongst patients given at least 10 units of PRBC within 24 hours.

https://doi.org/10.1155/2017/3718615

Disclosure

The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors' Contributions

Daniel I. Sessler and Detlef Obal were responsible for study design and concept; Alexander Bautista, Theodore B. Wright, Janice Meany, Sunitha K. Kandadai, Benjamin Brown, Kareim Khalafalla, and Saeed Hashem were responsible for data collection; Jason W. Smith was responsible for assigning trauma scores and evaluation of trauma severity; Tayyeb M. Ayyoubi and Janice Meanywere responsible for reviewing Blood Bank data; Jarrod E. Dalton and Detlef Obal were responsible for statistical analysis; Tayyeb M. Ayyoubi, Jarrod E. Dalton, Anupama Wadhwa, and Detlef Obal were responsible for data analysis; Alexander Bautista, Theodore B. Wright, Anupama Wadhwa, Daniel I. Sessler, and Detlef Obal were responsible for writing manuscript. Alexander Bautista and Theodore B. Wright contributed equally to this work.

Acknowledgments

Dr. Dalton's effort was supported by the Clinical and Translational Science Collaborative of Cleveland from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health and NIH roadmap for Medical Research (KL2TR000440).

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Alexander Bautista, (1) Theodore B. Wright, (1) Janice Meany, (2) Sunitha K. Kandadai, (1) Benjamin Brown, (1) Kareim Khalafalla, (1) Saeed Hashem, (1) Jason W. Smith, (3) Tayyeb M. Ayyoubi, (2) Jarrod E. Dalton, (4,5) Anupama Wadhwa, (1) Daniel I. Sessler, (5) and Detlef Obal (1)

(1) Department of Anaesthesiology and Perioperative Medicine, University of Louisville, Louisville, KY, USA

(2) Blood Bank University Hospital, Institute of Pathology, University of Louisville, Louisville, KY, USA

(3) Trauma Institute, Department of Surgery, University of Louisville, Louisville, KY, USA

(4) Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA

(5) Department of Outcomes Research, Anaesthesiology Institute, Cleveland Clinic, Cleveland, OH, USA

Correspondence should be addressed to Detlef Obal; d.obal@louisville.edu

Received 26 October 2016; Revised 23 March 2017; Accepted 5 April 2017; Published 14 May 2017

Academic Editor: Nikolaos K. Kanakaris

Caption: Figure 1: Enrolment scheme.

Caption: Figure 2: (a) Univariable relationship between patient mean red blood cell (RBC) storage duration and in-hospital mortality. Results presented as estimate and pointwise 95% confidence interval. A histogram of the observed values of patient mean RBC storage duration underlies the plot. The P value represents a Chi-squared test of association for a univariable logistic regression model which incorporated restricted cubic splines to allow for nonlinearities. (b) Univariable relationship between patient mean red blood cell (RBC) storage duration and in-hospital mortality, separately for trauma (dashed lines) and nontrauma (continuous line/shaded region) patients. Results presented as group-specific estimates and pointwise 95% confidence intervals. Histograms of the observed values of patient mean RBC storage duration underlie the plot. The lack of significance indicated by the P value in the figure indicates that our data did not support the hypothesis that the nature of the relationship differed among the groups (i.e., test for the interaction between group and patient mean RBC storage duration).

Caption: Figure 3: Histograms of the observed values of patient RBC storage duration assembled taking (a) mean, (b) median, (c) minimum, and (d) maximum storage duration as dependent variable. The histogram indicates lack of discrimination between short and prolonged stored blood products.
Table 1: Summary of baseline patient characteristics by quartiles of
patient-specific mean storage duration of transfused red blood cells.
Statistics reported as a percentage, mean [+ or -] standard deviation,
or median [first quartile, third quartile]. Medians and quartiles are
reported when the sample skewness coefficient is >0.9 in absolute
value.

                                                   First quartile
                                                   (8.0-17.7 days)
Factor                                 Level          (N = 77)

Year of admission                      2006              16
                                       2007              13
                                       2008              31
                                       2009               9
                                       2010              16
                                       2011              16

Age                                                41 [+ or -] 18
Female sex                                               32
Body mass index (kg/[m.sup.2])                       26 [22,29]

Patient blood type                      A-                8
                                        A+               19
                                        AB+               0
                                        B-                1
                                        B+                8
                                        O-               13
                                        O+               51

Type of surgery                       Trauma             74
                                      Cancer             10
                                      General             6
                                     Vascular             4
                                   Gynecological          4
                                    Orthopedic            1

Heart disease                                            13
Pulmonary disease                                        14
Renal disease                                             0
Hypertension                                             26
Diabetes mellitus                                        13
Carcinoma                                                10
Liver disease                                             9
Tobacco use                                              29
Alcohol use                                              12
Illicit drug use                                          9
Initial heart rate (beats per                      107 [+ or -] 35
minute)
Initial systolic blood pressure                     108 [82,122]
(mmHg)
Initial temperature ([degrees]C)                     36 [36,37]
ED crystalloids (L)                                 2.6 [1.0,4.0]
Length of surgery (min)                             146 [100,240]
Total number of units transfused                     23 [17,38]
Minimum RBC storage duration                        8 [+ or -] 3
Maximum RBC storage duration                         33 [20,37]

Initial laboratory values
Hemoglobin (g/dL)                                     10 [8,12]
Blood pH                                            7.2 [7.1,7.3]
Platelet count (k/mcL)                              190 [120,227]
International normalized ratio                      1.5 [1.2,1.9]
Activated prothrombin time (s)                       16 [13,20]
Activated partial thromboplastin                     37 [29,59]
time (s)

Subset of trauma patients                             (N = 57)

Blunt injury                                             65
Penetrating injury                                       25
Other type of injury                                     11
Injury severity score                              30 [+ or -] 10
Glasgow coma score                                  10 [+ or -] 5

                                                   Second quartile
                                                   (17.7-21.6 days)
Factor                                 Level           (N = 76)

Year of admission                      2006               8
                                       2007               11
                                       2008               26
                                       2009               17
                                       2010               16
                                       2011               22

Age                                                 45 [+ or -] 19
Female sex                                                33
Body mass index (kg/[m.sup.2])                        26 [24,32]

Patient blood type                      A-                11
                                        A+                30
                                        AB+               4
                                        B-                3
                                        B+                7
                                        O-                3
                                        O+                43

Type of surgery                       Trauma              73
                                      Cancer              7
                                      General             9
                                     Vascular             9
                                   Gynecological          0
                                    Orthopedic            1

Heart disease                                             20
Pulmonary disease                                         11
Renal disease                                             5
Hypertension                                              39
Diabetes mellitus                                         4
Carcinoma                                                 16
Liver disease                                             16
Tobacco use                                               29
Alcohol use                                               11
Illicit drug use                                          7
Initial heart rate (beats per                      105 [+ or -] 37
minute)
Initial systolic blood pressure                      100 [84,123]
(mmHg)
Initial temperature ([degrees]C)                      36 [35,37]
ED crystalloids (L)                                 2.0 [1.0,2.6]
Length of surgery (min)                              140 [99,214]
Total number of units transfused                      23 [16,35]
Minimum RBC storage duration                        11 [+ or -] 4
Maximum RBC storage duration                          37 [32,40]

Initial laboratory values
Hemoglobin (g/dL)                                     11 [8,12]
Blood pH                                            7.2 [7.0,7.3]
Platelet count (k/mcL)                               180 [94,256]
International normalized ratio                      1.5 [1.2,1.9]
Activated prothrombin time (s)                        15 [13,20]
Activated partial thromboplastin                      35 [27,57]
time (s)

Subset of trauma patients                              (N = 55)

Blunt injury                                              65
Penetrating injury                                        25
Other type of injury                                      9
Injury severity score                               29 [+ or -] 14
Glasgow coma score                                   9 [+ or -] 6

                                                    Third quartile
                                                   (21.6-26.6 days)
Factor                                 Level           (N = 76)

Year of admission                      2006               5
                                       2007               11
                                       2008               27
                                       2009               23
                                       2010               17
                                       2011               17

Age                                                 48 [+ or -] 18
Female sex                                                28
Body mass index (kg/[m.sup.2])                        26 [23,32]

Patient blood type                      A-                12
                                        A+                33
                                        AB+               3
                                        B-                4
                                        B+                8
                                        O-                12
                                        O+                29

Type of surgery                       Trauma              70
                                      Cancer              11
                                      General             11
                                     Vascular             5
                                   Gynecological          4
                                    Orthopedic            0

Heart disease                                             17
Pulmonary disease                                         7
Renal disease                                             1
Hypertension                                              41
Diabetes mellitus                                         16
Carcinoma                                                 12
Liver disease                                             12
Tobacco use                                               21
Alcohol use                                               11
Illicit drug use                                          5
Initial heart rate (beats per                      102 [+ or -] 35
minute)
Initial systolic blood pressure                      101 [88,123]
(mmHg)
Initial temperature ([degrees]C)                      36 [36,37]
ED crystalloids (L)                                 1.5 [1.0,2.3]
Length of surgery (min)                              141 [94,253]
Total number of units transfused                      22 [17,31]
Minimum RBC storage duration                        14 [+ or -] 5
Maximum RBC storage duration                          37 [34,41]

Initial laboratory values
Hemoglobin (g/dL)                                     11 [9,12]
Blood pH                                            7.2 [7.1,7.3]
Platelet count (k/mcL)                              187 [111,248]
International normalized ratio                      1.5 [1.2,1.8]
Activated prothrombin time (s)                        15 [12,20]
Activated partial thromboplastin                      40 [27,55]
time (s)

Subset of trauma patients                              {N= 53)

Blunt injury                                              64
Penetrating injury                                        32
Other type of injury                                      4
Injury severity score                               28 [+ or -] 13
Glasgow coma score                                  10 [+ or -] 5

                                                   Fourth quartile
                                                   (26.6-36.6 days)
Factor                                 Level           (N = 76)

Year of admission                      2006               7
                                       2007               5
                                       2008               13
                                       2009               41
                                       2010               16
                                       2011               17

Age                                                 47 [+ or -] 18
Female sex                                                29
Body mass index (kg/[m.sup.2])                        25 [24,30]

Patient blood type                      A-                7
                                        A+                37
                                        AB+               7
                                        B-                1
                                        B+                12
                                        O-                4
                                        O+                33

Type of surgery                       Trauma              64
                                      Cancer              12
                                      General             12
                                     Vascular             7
                                   Gynecological          3
                                    Orthopedic            3

Heart disease                                             18
Pulmonary disease                                         8
Renal disease                                             1
Hypertension                                              37
Diabetes mellitus                                         12
Carcinoma                                                 16
Liver disease                                             13
Tobacco use                                               24
Alcohol use                                               8
Illicit drug use                                          8
Initial heart rate (beats per                      103 [+ or -] 32
minute)
Initial systolic blood pressure                      111 [87,130]
(mmHg)
Initial temperature ([degrees]C)                      36 [35,37]
ED crystalloids (L)                                 2.0 [1.0,2.5]
Length of surgery (min)                             140 [104,240]
Total number of units transfused                      18 [15,25]
Minimum RBC storage duration                        19 [+ or -] 7
Maximum RBC storage duration                          39 [36,41]

Initial laboratory values
Hemoglobin (g/dL)                                     10 [9,12]
Blood pH                                            7.2 [7.1.7.4]
Platelet count (k/mcL)                              184 [100,264]
International normalized ratio                       1.4 [14,2.0]
Activated prothrombin time (s)                        15 [12,20]
Activated partial thromboplastin                      33 [26,64]
time (s)

Subset of trauma patients                              {N = 48)

Blunt injury                                              58
Penetrating injury                                        27
Other type of injury                                      15
Injury severity score                               27 [+ or -] 11
Glasgow coma score                                  10 [+ or -] 5

                                                   Percent
Factor                                 Level       missing

Year of admission                      2006          0.7
                                       2007
                                       2008
                                       2009
                                       2010
                                       2011

Age
Female sex
Body mass index (kg/[m.sup.2])                      36.7

Patient blood type                      A-           0.7
                                        A+
                                        AB+
                                        B-
                                        B+
                                        O-
                                        O+

Type of surgery                       Trauma         0.7
                                      Cancer
                                      General
                                     Vascular
                                   Gynecological
                                    Orthopedic

Heart disease
Pulmonary disease
Renal disease
Hypertension
Diabetes mellitus
Carcinoma
Liver disease
Tobacco use
Alcohol use
Illicit drug use
Initial heart rate (beats per                        1.3
minute)
Initial systolic blood pressure                      0.7
(mmHg)
Initial temperature ([degrees]C)                    14.1
ED crystalloids (L)                                 32.1
Length of surgery (min)                              6.9
Total number of units transfused
Minimum RBC storage duration
Maximum RBC storage duration

Initial laboratory values
Hemoglobin (g/dL)                                    4.3
Blood pH                                             2.3
Platelet count (k/mcL)                               2.3
International normalized ratio                       4.9
Activated prothrombin time (s)                       5.2
Activated partial thromboplastin                     4.9
time (s)

Subset of trauma patients                            --

Blunt injury
Penetrating injury
Other type of injury
Injury severity score                                2.8
Glasgow coma score

Table 2: Summary of baseline patient characteristics by type of
surgery. Statistics reported as a percentage, mean [+ or -] standard
deviation, or median [first quartile, third quartile]. Medians and
quartiles are reported when the sample skewness coefficient is >0.9 in
absolute value.

                                                       Nontrauma
Factor                                      Level      (N = 91)

Year of admission                           2006           2
                                            2007          10
                                            2008          29
                                            2009          27
                                            2010          16
                                            2011          15

Age                                                 53 [+ or -] 15
Female sex                                                42
Body mass index (kg/[m.sup.2])                        25 [23,31]

Patient blood type                           A-            8
                                             A+           32
                                             AB+           4
                                             B-            1
                                             B+            7
                                             O-           12
                                             O+           36

Heart disease                                             33
Pulmonary disease                                         15
Renal disease                                              5
Hypertension                                              60
Diabetes mellitus                                         22
Carcinoma                                                 36
Liver disease                                             21
Tobacco use                                               36
Alcohol use                                               12
Illicit drug use                                           3
Initial heart rate (beats per minute)                 91 [79,110]
Initial systolic blood pressure (mmHg)              116 [+ or -] 25
Initial temperature ([degrees]C)                      36 [36,37]
ED crystalloids (L)                                  0.6 [0.5,1.8]
Length of surgery (min)                              214 [120,400]
Total number of units transfused                      18 [14,24]
Minimum PRBC storage duration                        15 [+ or -] 7
Maximum PRBC storage duration                         37 [34,40]

Initial laboratory values
Hemoglobin (g/dL)                                      10 [8,12]
Blood pH                                             73 [7.2,7.4]
Platelet count (k/mcL)                               178 [97,260]
International normalized ratio                       1.3 [1.1,1.6]
Activated prothrombin time (s)                        14 [12,17]
Activated partial thromboplastin time (s)             34 [27,44]

                                                        Trauma
Factor                                      Level     (N = 214)

Year of admission                           2006          12
                                            2007          10
                                            2008          23
                                            2009          20
                                            2010          16
                                            2011          19

Age                                                 42 [+ or -] 18
Female sex                                                26
Body mass index (kg/[m.sup.2])                        27 [24,30]

Patient blood type                           A-           10
                                             A+           29
                                             AB+          3
                                             B-           3
                                             B+           9
                                             O-           6
                                             O+           40

Heart disease                                             10
Pulmonary disease                                         7
Renal disease                                             0
Hypertension                                              25
Diabetes mellitus                                         7
Carcinoma                                                 4
Liver disease                                             9
Tobacco use                                               21
Alcohol use                                               9
Illicit drug use                                          9
Initial heart rate (beats per minute)                112 [88,132]
Initial systolic blood pressure (mmHg)              98 [+ or -] 36
Initial temperature ([degrees]C)                      36 [35,37]
ED crystalloids (L)                                 2.0 [1.0,3.0]
Length of surgery (min)                              130 [90,206]
Total number of units transfused                      23 [16,34]
Minimum PRBC storage duration                       12 [+ or -] 6
Maximum PRBC storage duration                         37 [32,40]

Initial laboratory values
Hemoglobin (g/dL)                                     11 [9,12]
Blood pH                                            7.2 [7.1,7.3]
Platelet count (k/mcL)                              189 [112,248]
International normalized ratio                      1.5 [1.2,2.0]
Activated prothrombin time (s)                        16 [13,20]
Activated partial thromboplastin time (s)             39 [28,63]

                                                    Percent
Factor                                      Level   missing

Year of admission                           2006      0.7
                                            2007
                                            2008
                                            2009
                                            2010
                                            2011

Age
Female sex
Body mass index (kg/[m.sup.2])                       36.3

Patient blood type                           A-       0.7
                                             A+
                                             AB+
                                             B-
                                             B+
                                             O-
                                             O+

Heart disease
Pulmonary disease
Renal disease
Hypertension
Diabetes mellitus
Carcinoma
Liver disease
Tobacco use
Alcohol use
Illicit drug use
Initial heart rate (beats per minute)                 1.3
Initial systolic blood pressure (mmHg)                0.7
Initial temperature ([degrees]C)                     14.1
ED crystalloids (L)                                  32.1
Length of surgery (min)                               6.9
Total number of units transfused
Minimum PRBC storage duration
Maximum PRBC storage duration

Initial laboratory values
Hemoglobin (g/dL)                                     4.3
Blood pH                                              2.3
Platelet count (k/mcL)                                2.3
International normalized ratio                        4.9
Activated prothrombin time (s)                        5.2
Activated partial thromboplastin time (s)             4.9

Table 3: Summary statistics of outcomes by quartiles of patient-
specific mean storage duration of transfused red blood cells.
Statistics reported as a percentage, mean [+ or -] standard deviation,
or median [first quartile, third quartile]. Results reflect 305
patients included in the univariable analyses (see Methods). Medians
and quartiles are reported when the sample skewness coefficient is
>0.9 in absolute value.

                                            First quartile
                                            (8.0-17.7 days)
Outcome variable                               (N = 77)

Primary outcome
  In-hospital mortality                           29
Secondary outcomes
  30-day mortality                                29
  Duration of hospitalization (d)              21 [7,34]
  Duration of ICU stay (h)                   312 [95,484]
  Duration of mechanical ventilation (h)     126 [29,304]
  Disseminated intravascular coagulopathy         29
  Shock                                           78
  Sepsis                                          19
  Wound infection                                 30
  Arrhythmia                                      34
  Myocardial infarction                            1
  Acute respiratory distress syndrome             39
  Acute kidney injury                             14
  Pneumonia                                       38
  Pulmonary embolism                               3
  Transfusion-related acute lung injury            1

                                            Second quartile
                                            (17.7-21.6 days)
Outcome variable                                (N = 76)

Primary outcome
  In-hospital mortality                            43
Secondary outcomes
  30-day mortality                                 43
  Duration of hospitalization (d)              15 [4,30]
  Duration of ICU stay (h)                    182 [35,408]
  Duration of mechanical ventilation (h)      104 [24,318]
  Disseminated intravascular coagulopathy          14
  Shock                                            78
  Sepsis                                           21
  Wound infection                                  25
  Arrhythmia                                       38
  Myocardial infarction                            4
  Acute respiratory distress syndrome              42
  Acute kidney injury                              30
  Pneumonia                                        33
  Pulmonary embolism                               0
  Transfusion-related acute lung injury            1

                                             Third quartile
                                            (21.6-26.6 days)
Outcome variable                                (N = 76)

Primary outcome
  In-hospital mortality                            28
Secondary outcomes
  30-day mortality                                 25
  Duration of hospitalization (d)              20 [8,32]
  Duration of ICU stay (h)                    235 [66,528]
  Duration of mechanical ventilation (h)      124 [48,359]
  Disseminated intravascular coagulopathy          21
  Shock                                            82
  Sepsis                                           20
  Wound infection                                  29
  Arrhythmia                                       37
  Myocardial infarction                            4
  Acute respiratory distress syndrome              47
  Acute kidney injury                              20
  Pneumonia                                        47
  Pulmonary embolism                               8
  Transfusion-related acute lung injury            1

                                            Fourth quartile
                                            (26.6-36.6 days)   Percent
Outcome variable                                (N = 76)       missing

Primary outcome
  In-hospital mortality                            34
Secondary outcomes
  30-day mortality                                 34
  Duration of hospitalization (d)              14 [4,26]
  Duration of ICU stay (h)                    192 [56,338]        1
  Duration of mechanical ventilation (h)      72 [24,213]        1.3
  Disseminated intravascular coagulopathy          25
  Shock                                            76
  Sepsis                                           12
  Wound infection                                  24
  Arrhythmia                                       34
  Myocardial infarction                            5
  Acute respiratory distress syndrome              38
  Acute kidney injury                              17
  Pneumonia                                        29
  Pulmonary embolism                               1
  Transfusion-related acute lung injury            3

Table 4: Independent association between patient-specific mean red
blood cell storage duration and secondary outcomes. All estimates are
adjusted for age, renal disease, liver disease, initial blood pH,
initial antiprothrombin time, and initial activated partial
thromboplastin time. Estimates are reported with 95% confidence
intervals in parentheses. Analyses reflect the same 259 patients that
were included in the multivariable modeling for the primary outcome of
in-hospital mortality. The reported measures of association reflect a
one-day increase in patient mean red blood cell storage duration.

Outcome variable                              Model type

Duration ofhospitalization (d)             Linear regression
Duration of ICU stay (h)                   Linear regression
Duration of mechanical ventilation (h)     Linear regression
Disseminated intravascular coagulopathy   Logistic regression
Shock                                     Logistic regression
Sepsis                                    Logistic regression
Wound infection                           Logistic regression
Arrhythmia                                Logistic regression
Myocardial infarction                     Logistic regression
Acute respiratory distress syndrome       Logistic regression
Acute kidney injury                       Logistic regression
Pneumonia                                 Logistic regression
Pulmonary embolism                        Logistic regression
Transfusion-related acute lung injury     Logistic regression

Outcome variable                          Measure of association

Duration ofhospitalization (d)                Slope (95% CI)
Duration of ICU stay (h)                      Slope (95% CI)
Duration of mechanical ventilation (h)        Slope (95% CI)
Disseminated intravascular coagulopathy    Odds ratio (95% CI)
Shock                                      Odds ratio (95% CI)
Sepsis                                     Odds ratio (95% CI)
Wound infection                            Odds ratio (95% CI)
Arrhythmia                                 Odds ratio (95% CI)
Myocardial infarction                      Odds ratio (95% CI)
Acute respiratory distress syndrome        Odds ratio (95% CI)
Acute kidney injury                        Odds ratio (95% CI)
Pneumonia                                  Odds ratio (95% CI)
Pulmonary embolism                         Odds ratio (95% CI)
Transfusion-related acute lung injury      Odds ratio (95% CI)

Outcome variable                               Estimate

Duration ofhospitalization (d)            -0.27 (-0.68, 0.13)
Duration of ICU stay (h)                  -1.79 (-9.82, 6.24)
Duration of mechanical ventilation (h)    -0.91 (-7.13, 5.30)
Disseminated intravascular coagulopathy    0.98 (0.93, 1.03)
Shock                                      1.00 (0.95, 1.05)
Sepsis                                     0.96 (0.91, 1.02)
Wound infection                            0.97 (0.93, 1.02)
Arrhythmia                                 0.98 (0.93, 1.02)
Myocardial infarction                      1.09 (0.96, 1.25)
Acute respiratory distress syndrome        1.00 (0.96, 1.05)
Acute kidney injury                        1.00 (0.94, 1.05)
Pneumonia                                  0.99 (0.94, 1.03)
Pulmonary embolism                         1.10 (0.96, 1.25)
Transfusion-related acute lung injury      1.06 (0.90, 1.26)

Outcome variable                          P value

Duration ofhospitalization (d)             0.18
Duration of ICU stay (h)                   0.66
Duration of mechanical ventilation (h)     0.77
Disseminated intravascular coagulopathy    0.42
Shock                                      0.97
Sepsis                                     0.19
Wound infection                            0.28
Arrhythmia                                 0.30
Myocardial infarction                      0.18
Acute respiratory distress syndrome        >0.99
Acute kidney injury                        0.94
Pneumonia                                  0.57
Pulmonary embolism                         0.15
Transfusion-related acute lung injury      0.47
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Title Annotation:Research Article
Author:Bautista, Alexander; Wright, Theodore B.; Meany, Janice; Kandadai, Sunitha K.; Brown, Benjamin; Khal
Publication:BioMed Research International
Article Type:Report
Geographic Code:1USA
Date:Jan 1, 2017
Words:7950
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