Introduction
Changes occurring to the RBC | Changes occurring in the supernatant |
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Metabolic changes
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• Decreased 2-3 DPG, possibly with impaired oxygen delivery [5] • Decreased phosphate and adenine pool (AMP, ADP, ATP) [24] • Decreased glutathione levels [6] • Decreased S-nitroso hemoglobin [110] • Increased lactate levels | • Decreased pH • Increased potassium concentrations (decreased Na-K-ATPase activity) with increased risks of hyperkalemia • Release of various molecules: ○ Proinflammatory cytokines (IL-1beta, IL-6, IL-8, TNF-alpha) and complement ○ Biologically active lipids such as platelet-activating factor (PAF) [14] ○ Free hemoglobin prone to scavenge nitric oxide (NO) of the recipient (together with Hb-containing microparticles) [109] ○ Heme and iron [12] with potential redox injuries, cytotoxicity and inflammation |
Oxidative stress
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• Protein oxidation including cytoskeleton [111] • Lipid peroxidation, generation of lysophospholipids prone to cause cases of TRALI, generation of prostaglandins and isoprostanes [112] | |
Shape and membrane changes
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• Shift from early reversible echinocytes to irreversible sphero-echinocytes • Generation of microvesicles with procoagulant properties • Increased RBC rigidity and adherence to vascular endothelium2 • Decreased CD47 expression, increased phosphatidylserine exposure |
Materials and methods
Results
First author | Year | Year(s) of enrollment | Design | Country/continent | Leuko-reduction | Setting | Number of patients transfused | Summary of main results |
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Studies addressing mortality
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Purdy et al. [42] | 1997 | 1992 | Retrospective single-center | Canada | NR | ICU septic | 31 | Non-survivors received a greater proportion of older RBCs |
Mynster et al. [53] | 2001 | 1991-1993 | Retrospective multicenter | Europe | No | Cancer | 740 | Mortality not different between patients transfused with RBCs aged more or less than 21 days |
Murrell et al. [48] | 2005 | 2001-2003 | Retrospective single-center | USA | Mix (95% LR) | Trauma | 275 | No correlation between 'dose of aged blood' and hospital mortality |
van de Watering et al. [38] | 2006 | 1993-1999 | Retrospective single-center | Europe | No | Cardiac surgery | 2,732 | No correlation between storage time variables and 30-day mortality |
Koch et al. [32] | 2008 | 1998-2006 | Retrospective single-center | USA | Mix | Cardiac surgery | 6,002 | Higher hospital and one-year mortality rate in older blood group |
Yap et al. [41] | 2008 | 2001-2007 | Retrospective single-center | Australia | Mix (3.8% LR) | Cardiac surgery | 670 | No association between storage duration and mortality |
Dessertaine et al. [43] | 2008 | 2005-2006 | Retrospective single-center | Europe | Yes | ICU | 534 | No association between the age of transfused red cells and mortality |
Weinberg et al. [44] | 2008 | 2000-2007 | Retrospective single-center | USA | Yes | Trauma | 1,813 | Transfusion of large (but not small) volumes of older blood associated with an increased risk of death |
Weinberg et al. [46] | 2008 | 2000-2007 | Retrospective single-center | USA | Yes | Trauma | 430 | Slightly increased mortality with transfusion of older blood (> 14 days old) |
Spinella et al. [47] | 2009 | 2004-2007 | Retrospective single-center | USA | Mix | Trauma | 202 | Hospital mortality higher for patients transfused with older RBCs; increased storage time independently associated with mortality |
Edgren et al. [30] | 2010 | 1995-2002 | Retrospective multicenter | Europe | Mix | Mix | 364,037 | 5% increased mortality after two years of follow-up |
Weinberg et al. [45] | 2010 | 2000-2009 | Retrospective single-center | USA | Yes | Trauma | 1,647 | Trend toward higher mortality rate with older blood when transfused more than three RBC units |
Eikelboom et al. [50] | 2010 | 2002-2006 | Retrospective single-center | Canada | Yes | Cardiovascular disease | 4,933 | Greater risk of hospital mortality in the highest age quartile of RBCs |
Robinson et al. [51] | 2010 | 1999-2005 | Retrospective single-center | Canada | NR | PCI | 909 | Storage duration associated with 30-day mortality |
van Straten et al. [40] | 2011 | 1998-2007 | Retrospective single-center | Europe | Yes | Cardiac surgery | 3,597 | No effect of RBC storage duration on early or late postoperative mortality |
McKenny et al. [39] | 2011 | 2002-2007 | Retrospective single-center | Europe | Yes | Cardiac surgery | 1,153 | No association between RBC storage duration and postoperative mortality |
Kekre et al. [54] | 2011 | 2002-2007 | Retrospective single-center | Canada | Yes | HSCT | 555 | Non-relapse 100-day mortality reduced in the subgroup of patients receiving exclusively old blood (> 14 days old) |
Pettila et al. [29] | 2011 | 2008 | Prospective, multicenter | Australia - New Zealand | Mix | ICU | 757 | Exposure to the highest age quartile of RBCs associated with a higher hospital mortality rate compared to lowest quartile |
Hassan et al. [49] | 2011 | 2003-2005 | Retrospective single-center | USA | NR | Trauma | 820 | Number of older units not associated with increased mortality |
Saager et al. [31] | 2012 | 2005-2009 | Retrospective single-center | USA | Yes | Non-cardiac surgery | 6,994 | No relationship between median RBC storage duration and postoperative mortality (up to two years) |
Dunn et al. [52] | 2012 | 2000-2010 | Retrospective single-center | USA | NR | Liver transplant | 509 | Transfusion of older blood not associated with increased two-year mortality |
Kor et al. [28] | 2012 | 2008-2010 | Randomized single-center study | USA | Yes | ICU | 100 | Similar mortality between fresh and standard issue RBCs but not powered for this outcome |
Studies addressing ICU or hospital length of stay
| ||||||||
Vamvakas et al. [56] | 2000 | 1995 | Retrospective single-center | USA | Mix (mostly not) | Cardiac surgery | 268 | No association between RBC storage duration and postoperative ICU and hospital LOS |
Keller et al. [58] | 2002 | 1998-1999 | Retrospective single-center | USA | No | Trauma | 86 | Number of units of blood older than 14 days associated with an increased hospital LOS |
Leal-Noval et al. [55] | 2003 | 1998-2000 | Prospective single-center | Europe | No | Cardiac surgery | 585 | No association between mean duration of RBC storage and ICU LOS |
Murrell et al. [48] | 2005 | 2001-2003 | Retrospective single-center | USA | Mix (95% LR) | Trauma | 275 | Association between 'dose of aged blood' and ICU LOS |
van de Watering et al. [38] | 2006 | 1993-1999 | Retrospective single-center | Europe | No | Cardiac surgery | 2,732 | No correlation between storage time variables and ICU LOS |
Yap et al. [41] | 2008 | 2001-2007 | Retrospective single-center | Australia | Mix (3.8% LR) | Cardiac surgery | 670 | No association between length of storage and ICU LOS |
McKenny et al. [39] | 2011 | 2002-2007 | Retrospective single-center | Europe | Yes | Cardiac surgery | 1,153 | No association between length of storage and ICU LOS |
Sanders et al. [57] | 2011 | 2005-2007 | Retrospective single-center | Europe | Yes | Cardiac surgery | 444 | Age of blood was a significant but modest predictor of postoperative LOS |
Kekre et al. [54] | 2011 | 2002-2007 | Retrospective single-center | Canada | Yes | HSCT | 555 | No correlation between age of transfused RBCs and hospital LOS |
Studies addressing age of transfused RBCs and occurrence of infections
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Edna et al. [61] | 1998 | 1980-1992 | Retrospective single-center | Europe | No | Cancer | 240 | Age of RBCs not different in subjects developing postoperative infections and those who did not |
Vamvakas et al. [59] | 1999 | 1995 | Retrospective single-center | USA | Mix | Cardiac surgery | 256 | Independent relationship between the age of transfused RBCs and the incidence of postoperative pneumonia or wound infection |
Mynster et al. [53] | 2001 | 1991-1993 | Retrospective multicenter | Europe | No | Cancer | 740 | Increased risks of postoperative infections with transfusions of RBCs aged 20 days or more |
Offner et al. [64] | 2002 | 1992- | Retrospective single-center | USA | No | Trauma | 61 | Number of units older than 14 and 21 days as an independent risk factor for major infections |
Leal-Noval et al. [55] | 2003 | 1998-2000 | Prospective single-center | Europe | No | Cardiac surgery | 585 | Independent relation between the oldest RBC unit and postoperative pneumonia |
Taylor et al. [66] | 2006 | 2001-2003 | Prospective | USA | Mix | ICU | 449 | Maximum age of transfused RBCs not associated with increased risks of nosocomial infections |
Koch et al. [32] | 2008 | 1998-2006 | Retrospective single-center | USA | Mix | Cardiac surgery | 6,002 | Higher rates of postoperative sepsis or septicemia (but not pneumonia or wound infections) with older RBCs |
Weinberg et al. [46] | 2008 | 2000-2007 | Retrospective single-center | USA | Yes | Trauma | 430 | Occurrence of pneumonia related to the volume of old blood (> 14 days old) transfused |
Yap et al. [41] | 2008 | 2001-2007 | Retrospective single-center | Australia | Mix (3.8% LR) | Cardiac surgery | 670 | No association between storage of RBCs and postoperative pneumonia |
Dessertaine et al. [43] | 2008 | 2005-2006 | Retrospective single-center | Europe | Yes | ICU | 534 | No independent association between the age of RBCs and nosocomial infections |
Vandromme et al. [63] | 2009 | 2004-2007 | Retrospective single-center | USA | Yes | Trauma | 1,183 | Increased risks of pneumonia after transfusion of exclusively old RBCs (> 14 days) |
Basora et al. [113] | 2010 | 2004-2005 | Retrospective single-center | Europe | Yes | Knee arthroplasty | 335 | No independent association between age of transfused RBCs and postoperative wound infection |
McKenny et al. [39] | 2011 | 2002-2007 | Retrospective single-center | Europe | Yes | Cardiac surgery | 1,153 | No association between storage of RBCs and postoperative pneumonia |
Andreasen et al. [60] | 2011 | 2003-2008 | Retrospective multicenter | Europe | No | Cardiac surgery | 1,748 | Greater risk of postoperative wound infections and septicemia with RBCs older than 14 days |
Hassan et al. [49] | 2011 | 2003-2005 | Retrospective single-center | USA | NR | Trauma | 820 | Number of units older than 14 days as a significant risk factor for severe sepsis or septic shock |
Juffermans et al. [67] | 2011 | 2004-2007 | Retrospective single-center | Europe | Yes | ICU septic | 67 | Storage time as a confounder for the association of RBCs with infection |
Juffermans et al. [65] | 2012 | 2004-2007 | Retrospective single-center | Europe | Yes | Trauma/TBI | 196 | Modest association between transfusion of RBCs older than 14 days and occurrence of new infections |
Dunn et al. [52] | 2012 | 2000-2010 | Retrospective single-center | USA | NR | Liver transplant | 509 | No independent association between the age of RBCs and postoperative infections |
Studies addressing organ failure
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Zallen et al. [68] | 1999 | NR | Retrospective single-center | USA | NR | Trauma | 63 | Mean age of blood (or number of units older than 14 or 21 days) as independent risk factors for MOF |
Vamvakas et al. [56] | 2000 | 1995 | Retrospective single-center | USA | Mix (mostly not) | Cardiac surgery | 268 | Length of RBC storage not associated with prolonged endotracheal intubation |
Keller et al. [58] | 2002 | 1998-1999 | Retrospective single-center | USA | No | Trauma | 86 | Duration of MV not associated with RBC storage duration |
Leal-Noval et al. [55] | 2003 | 1998-2000 | Prospective single-center | Europe | No | Cardiac surgery | 585 | No relationship between RBC storage duration and prolonged MV |
Gajic et al. [70] | 2004 | 2001 | Retrospective single-center | USA | Mix | ICU | 181 | No association between mean age or age of the oldest unit transfused and occurrence of ALI |
Yap et al. [41] | 2008 | 2001-2007 | Retrospective single-center | Australia | Mix (3.8% LR) | Cardiac surgery | 670 | No association between storage duration and occurrence of postoperative renal failure or prolonged MV |
Koch et al. [32] | 2008 | 1998-2006 | Retrospective single-center | USA | Mix | Cardiac surgery | 6,002 | Increased risk of a composite outcome (including MOF and renal failure) with transfusion of older blood; higher rates of MV > 72 hours when patients transfused only old RBC |
Weinberg et al. [46] | 2008 | 2000-2007 | Retrospective single-center | USA | Yes | Trauma | 430 | Old blood (> 14 days) associated with acute renal dysfunction after adjustment |
McKenny et al. [39] | 2011 | 2002-2007 | Retrospective single-center | Europe | Yes | Cardiac surgery | 1,153 | No association between storage duration and occurrence of postoperative renal failure or prolonged MV |
Sanders et al. [57] | 2011 | 2005-2007 | Retrospective single-center | Europe | Yes | Cardiac surgery | 444 | Higher rates of renal failure among patients transfused with old blood |
Kor et al. [28] | 2012 | 2008-2010 | Randomized single-center study | USA | Yes | ICU | 100 | Similar measures of pulmonary function after transfusion of either fresh or standard issue RBCs |
Weiskopf et al. [69] | 2012 | NR | Randomized single-center study | USA | Mix | Volunteers | 35 | Equivalent mild decrements in pulmonary gas exchange variables after transfusion of either fresh (1.7 hour) or older (> 21 days) RBCs |
Studies addressing tissue oxygenation and microcirculation
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Marik et al. [71] | 1993 | NR | Prospective single-center study | USA | NR | ICU | 23 | Inverse correlation between the age of transfused RBCs and the maximal change in gastric mucosal pH (pHi) |
Fernandes et al. [72] | 2001 | 1996 | Randomized single-center study | South America | NR | ICU septic | 15 | No correlation between the age of transfused RBCs and the pHi |
Walsh et al. [73] | 2004 | 1999-2000 | Randomized single-center study | Europe | Yes | ICU | 22 | No difference in pHi or gastric to arterial PCO2 gap with transfusions of fresh or older RBCs |
Sakr et al. [75] | 2007 | NR | Prospective single-center | Europe | Yes | ICU | 35 | No correlation between the storage time and the changes in capillary perfusion |
Leal-Noval et al. [77] | 2008 | 2004-2006 | Prospective single-center | Europe | Yes | Severe TBI | 66 | Transfusion of RBCs aged more than 19 days failed to increase cerebral tissue oxygenation |
Kiraly et al. [79] | 2009 | NR | Prospective single-center | USA | NR | Trauma | 32 | Patients transfused with > 21 days old RBCs had a significant decrease in the area under the curve of tissue saturation (StO2) |
Creteur et al. [81] | 2009 | NR | Prospective single-center | Europe | Yes | ICU | 44 | No association between RBC storage time and oxygenation variables (NIRS) |
Yuruk et al. [76] | 2012 | NR | Randomized single-center study | Europe | Yes | Hematology patients | 20 | Increase in perfused vessel density similar in both RBC age groups |
Berra et al. [82] | 2012 | 2010 | Randomized single-center study | USA | Yes | Healthy volunteers | 9 | Reactive hyperemia index unchanged after transfusion of 40-day stored blood compared with transfusion of three-day stored blood |
Roberson et al. [83] | 2012 | NR | Prospective single-center | USA | Yes | Healthy volunteers | 8 | No effect of storage duration on tissue oxygen saturation and sublingual microcirculatory flow index |
Kopterides et al. [84] | 2012 | 2008-2011 | Prospective single-center | Europe | Mix | ICU septic | 37 | No relationship between age of RBCs and change in lactate/pyruvate ratio (microdialysis) |
Other outcomes
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Wasser et al. [87] | 1989 | NR | Randomized single-center study | Europe | No | Cardiac surgery | 237 | No differences in postoperative bleeding, coagulation tests, or transfusion requirements |
Mynster et al. [53] | 2001 | 1991-1993 | Retrospective multicenter | Europe | No | Cancer | 740 | Higher recurrence rate of cancer in patients who received a transfusion of RBCs stored < 21 days |
Leal-Noval et al. [55] | 2003 | 1998-2000 | Prospective single-center | Europe | No | Cardiac surgery | 585 | No association between duration of storage of RBCs and postoperative myocardial infarction |
Weiskopf et al. [88] | 2006 | NR | Randomized single-center study | USA | No | Volunteers | 9 | Reversal of anemia-induced cognitive dysfunction similar after transfusion of fresh or stored RBCs |
Spinella et al. [47] | 2009 | 2004-2007 | Retrospective single-center | USA | Mix | Trauma | 202 | Association between maximum age of RBCs (> 21 or 28 days) and deep vein thrombosis (DVT) |
Naidech et al. [86] | 2011 | NR | Retrospective single-center | USA | NR | SAH | 119 | No association between age of RBCs and vasospasm or cerebral infarction |
Katsios et al. [85] | 2011 | 2001-2002 | Prospective single-center | Canada | No | ICU | 261 | No association between the age of transfused RBCs and the occurrence of DVT |
Cata et al. [89] | 2011 | 1998-2007 | Retrospective single-center | USA | NR | Prostate cancer | 316 | No association between the age of transfused RBCs and the five-year prostate cancer recurrence |
First author | Year published (recruitment period) | Country/region | Leuko-reduction | Setting | Number of patients | Number of units transfused | Age of RBCs in each group | Outcome(s) reported | Summary of results |
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Wasser et al. [87] | 1989 (NR) | Europe | No | Cardiac surgery | 237 (118 in fresh group, 119 in old group) | 5.4 +/-1.9 (fresh group) and 6.0+/-2.4 (older group) | < 12 h (fresh group) vs. 2-5 days (older group) | Postoperative bleeding | No differences in postoperative bleeding, coagulation tests, or transfusion requirements |
Fernandes et al. [72] | 2001 (1996) | South America | NR | ICU septic patients | 15 (10 transfused, 5 receiving 5% albumin) | 1 unit | 12.8 ± 8.1 days in transfused group | Oxygen delivery and consumption; changes in pHi (tonometry) | No correlation between the age of transfused RBCs and the pHi |
Walsh et al. [73] | 2004 (1999-2000) | Europe | Yes | ICU patients with MV | 22 (10 in fresh group, 22 in old group) | 2 units | 2 days vs. 28 days (median durations) | pHi or gastric to arterial PCO2 gap | No difference in pHi or gastric to arterial PCO2 gap between fresh or older RBCs |
Weiskopf et al. [88] | 2006 (NR) | USA | No | Healthy volunteers | 9 (crossover design) | 2 autologous units | 3.4 hours vs. 23 days (median durations) | Cognitive dysfunction | Reversal of anemia-induced cognitive dysfunction similar after transfusion of fresh or stored RBCs |
Berra et al. [82] | 2012 (2010) | USA | Yes | Healthy volunteers | 9 (crossover design) | 1 autologous unit | 3 days vs. 40 days | Reactive hyperhemia index | Reactive hyperemia index unchanged after transfusion of 40-day stored blood compared with transfusion of three-day stored blood |
Yuruk et al. [76] | 2012 (NR) | Europe | Yes | Hematology patients | 20 (10 per arm) | 3 units | 7 days vs. 23 days (median durations) | Sublingual microcirculation variables | Increase in perfused vessel density similar in both RBC age groups |
Weiskopf et al. [69] | 2012 (NR) | USA | Mix (57% LR) | Healthy volunteers | 35 (crossover design) | 2 autologous units | 1.7 hours vs. 24.5 days | Pulmonary function tests (A-aDO2, VD/VT)) | Equivalent mild decrements in pulmonary gas exchange variables after transfusion of either fresh or older RBCs |
Kor et al. [28] | 2012 (2008-2010) | USA | Yes | ICU patients with MV | 100 (50 per arm) | 1 unit in each group | 4 days vs. 26.5 days (median durations) | Pulmonary function tests; mortality (not powered for this) | Similar measures of pulmonary function (and mortality) after transfusion of either fresh or standard issue RBCs |
Effect on mortality
Influence on hospital or ICU length of stay
Influence on infections
Influence on organ failure (including acute kidney injury and respiratory failure)
Influence on tissue oxygenation and the microcirculation
Other outcomes
Discussion
Key messages
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The duration of red blood cell (RBC) storage before transfusion may alter RBC function and, hence, potentially influence the incidence of complications or even mortality, but this is controversial.
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Fifty-five studies were identified that had reported the effects of age of transfused RBCs on mortality or morbidity in adult patients, but the marked heterogeneity among studies prevented a formal meta-analysis.
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Half of the studies showed no deleterious effects of aged compared to fresh blood on any endpoint.
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This systematic review found no definitive argument to support the superiority of fresh over older RBCs for transfusion.