1 University Department of Anaesthetics, Critical Care and Pain Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK 2 Scottish National Blood Transfusion Service, Royal Infirmary of Edinburgh, Edinburgh, UK
Blood transfusion has been practiced for almost 100 yr. This life-saving therapy was once regarded as one of the great advances in modern medicine.1 Times have changed; there are now very real concerns about the safety and efficacy of allogeneic stored blood. This shift in opinion has been precipitated by the greater awareness of transfusion-transmitted infections, most notably human immunodeficiency virus. More recently, clinical trials and animal experiments have raised doubts about the efficacy of transfusion.24 A recent editorial in this journal stated that blood transfusion (particularly with old blood) can paradoxically decrease microcirculatory oxygen delivery and contribute to tissue hypoxia.5
Such statements need to be supported by sound evidence, as they lead us to believe that we should be demanding fresh blood for our patients. This is not a new idea, but such a change in practice could have crippling consequences for the UKs blood services, which face serious challenges to meet demand. To make blood available for essential patient needs when supplies are short, storage times need to increase rather than decrease.
Red blood cell (RBC) transfusion, like all therapies, carries risks. The risks of receiving a blood transfusion must be balanced against the risks of not receiving it. Some of the risks of transfusion are well documented and have been quantified, such as transfusion reactions and transmission of viral infections.6 7 However, the importance of others, such as transfusion-related immunosuppression and the effect of storage on oxygen transport and delivery capabilities of RBCs after transfusion, are poorly understood. Even less is known about the potential for transmitting variant Creutzfeldt Jakob disease (vCJD) via blood transfusion. It is these unquantified risks that usually raise concerns among clinicians.
One of the problems with interpreting the evidence is that the properties of red cell concentrates vary greatly. Each donor unit contains a different amount of haemoglobin and even with national standards and guidelines, differences as a result of local variations in processing are inevitable.8 In the UK, whole blood is collected into citrate-phosphate-dextrose anticoagulant and separated by centrifugation into red cell, platelet, and plasma components. The red cells are ultimately transferred into a pack containing an additive solution and stored at 4 (SD 2)°C. The currently used additive solution is a saline-adenine-glucose-mannitol (SAGM) solution, which, in the UK, is licensed for the storage of RBCs for up to 35 days. Other additive solutions are available, some of which, such as Adsol Preservation Solutions 1 and 3, are licensed for the storage of RBCs for up to 42 days. The collection and storage processes, and the regulations governing RBC storage, focus on maintaining cell integrity and viability; there are remarkably few studies looking at RBC function following transfusion.
Since 1999, all blood for transfusion in the UK has been leucodepleted at the point of initial processing. Leucodepletion was introduced in the hope that it would reduce the possible risk of vCJD transmission by blood transfusion. Secondary benefits of leucodepletion may be a reduction in the incidence of other adverse effects such as non-haemolytic transfusion reactions, cytomegalovirus transmission, alloimmunization, graft-vs-host disease, and transfusion-associated immunosuppression. There is also some evidence to suggest that white blood cells (WBCs) compromise the quality of red cell storage.911 It is important to appreciate that most published studies of red cell transfusion used non-leucodepleted red cells rather than the product that we now use in the UK. This includes the TRICC study4 that was discussed in the recent editorial in this journal.5 The TRICC data suggest equivalent mortality with restrictive and liberal transfusion strategies, and provide compelling evidence that anaemia is well tolerated by most critically ill patients. The data showed a trend towards higher mortality in liberally transfused patients, particularly if young or less severely ill.
What evidence is there that the transfusion of stored blood has adverse clinical consequences?
There is substantial evidence from in vitro studies documenting the changes that RBCs undergo during storage (the so-called red cell storage lesion). Red cell adenosine triphosphate decreases by 50% during storage and 2,3-diphosphoglycerate (2,3-DPG) is not maintained beyond 10 days. These changes increase the affinity of haemoglobin for oxygen and shift the oxygen dissociation curve leftwards. Red cells also undergo marked morphological changes during storage. These begin immediately after collection and consist largely of echinocytic change (the RBCs develop finger-like projections and adopt a spiky appearance). This shape change is initially reversible but with increasing duration of storage it becomes permanent as the finger-like projections bud off to form microvesicles (approximately 25% of membrane phospholipid is lost during 42 days of storage). The net effect of these morphological changes is a decrease in red cell deformability. Such observations make it reasonable to suggest that transfusing RBCs that are both 2,3-DPG depleted and poorly deformable could be ineffective and/or harmful, but there is scanty evidence to support this. Animal studies are problematic, because interspecies differences in RBC metabolism and structure mean that RBCs from different species behave differently during storage. For example, a much-quoted study found that 28-day-old rat blood failed to improve systemic oxygen consumption in rats in contrast to fresh rat blood.3 Subsequent work has shown that rat RBCs deteriorate much more rapidly during storage than human RBCs and that after 28 days of storage, only 5% remain viable.12
Studies in humans attempting to determine the effect of blood transfusion on oxygen kinetics have not provided any clear answers. A recent review identified 14 studies evaluating the impact of RBC transfusion on oxygen kinetics.13 Blood transfusion consistently increased oxygen delivery (DO2), but oxygen consumption (VO2) increased in only five of the studies. Several points warrant further consideration when interpreting these studies. First, most of the studies, including the five that reported an increase, calculated VO2 which can introduce mathematical errors that erroneously link DO2 and VO2.14 Secondly, the pre-transfusion haemoglobin concentration in these studies ranged from 8.3 to 11 g dl1, which is high compared with the TRICC study. Thirdly, the critical DO2 threshold in critically ill patients is lower than previously thought, such that pathological oxygen supply dependency is not present in most clinically resuscitated critically ill patients with a haemoglobin concentration greater than 78 g dl1.15 This questions the rationale for attempting to increase DO2 by transfusion if haemoglobin concentration is above this level.
The data support a restrictive transfusion strategy but do not prove that the transfusion of stored RBCs has adverse effects or that they lack oxygen-carrying/delivering ability. An often-cited study of critically ill patients found, on retrospective analysis, an inverse association between the change in gastric intramucosal pH (pHi) and the age of the transfused blood.2 Patients receiving non-leucodepleted blood that had been stored for more than 15 days had a decrease in pHi following RBC transfusion, which was interpreted as indicating worsening gastric oxygenation. A recent prospective, double blind, study randomized stable ICU patients to receive fresh (median storage age 2.3 days) or stored (median storage age 28.2 days) leucodepleted red cell concentrates when pre-transfusion haemoglobin concentration was approximately 8 g dl1.16 There was no change in PCO2 gap, pHi or any measured oxygenation index following the transfusion of stored red cells.
There is very little evidence of an association between the storage age of transfused blood and patient outcome measures, such as morbidity and mortality. A retrospective study in patients with severe sepsis found that the duration of storage of transfused red cells was independently associated with ICU mortality, although the study was small (n=31).17 A retrospective analysis of 268 patients who underwent coronary artery bypass graft surgery found a positive correlation between the duration of storage of the transfused red cells and the development of postoperative pneumonia.18 In contrast, a subsequent study, from the same group, found no association between the transfusion of old red cells and increased morbidity in cardiac patients (time to extubation, duration of ICU and hospital stay).19 All of these studies were retrospective and they were unable to control the storage age of the transfused red cells, so that patients who received multiple transfusions often received blood of markedly different storage ages. In addition, all of these studies used non-leucodepleted red cells. To our knowledge, there are no published prospective, randomized studies comparing outcome when blood of different storage ages is administered. A recent randomized controlled trial that reduced allogeneic red cell transfusion in critically ill patients using erythropoietin found no difference in mortality between the two groups, although the study was not powered for this end-point.20
The best available evidence to date supports the use of a restrictive transfusion policy in most critically ill patients. Where transfusion is indicated, the clinical evidence to support a request for fresh RBCs is, however, poor. Interpreting the evidence is difficult because the introduction of universal leucodepletion has probably changed the properties of the current red cell product. One consequence of a move to requesting fresh blood for our patients would be to increase the risk of critical shortages and, therefore, to create new risks for patients whose management necessitates transfusion. Such a shift in practice would have to be based on sound evidence. This evidence has yet to be provided.
References
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