Description of the condition
The haemoglobin (Hb) contained within red blood cells is essential for oxygen transportation. Anaemia, defined by the World Health Organization (WHO) as a Hb concentration of <13 g/dL in men and <12 g/dL in women, describes a clinical state in which this physiological process is disturbed and tissue hypoxia may occur (Beutler 2006). Anaemia has no single cause, rather it is the consequence of a variety of aetiological factors. In high income countries the overall prevalence of anaemia is estimated to be 10% (McLean 2009). However, this figure varies significantly with demographic profiles and patterns of co-morbid diagnoses (McLean 2009; Tettamanti 2010). Children and older adults are often the people most commonly affected by anaemia. For example almost 90% of preterm infants with a birth weight <1.0 kg are anaemic (Martin 2010). In later life rates rise again, largely due to the increasing incidence of co-morbid diagnoses.
The aetiology of anaemia can be broadly divided into disease processes which impair red blood cell production and those in which the lifespan or distribution of the red blood cells is altered. In the former group, disorders such as acquired and iatrogenic marrow dysfunction, nutritional deficiencies and cytokine-driven processes such as the anaemia of chronic disease are commonplace. In the latter group examples include disease processes such as pathological bleeding and immune haemolysis.
Where possible, reversing the primary cause of the anaemia remains the treatment of choice, however this cannot always be achieved. Furthermore, where severe anaemia results in life threatening organ dysfunction, rapid correction is required. In these instances red blood cell transfusion is the only viable treatment modality capable of restoring tissue oxygenation.
Description of the intervention
Red blood cell transfusion
Red blood cell transfusion has been a commonplace treatment for anaemia for well over three decades (Alter 2008). It is a very widely practiced intervention. In the UK around two million red blood cell units are issued for transfusion annually (Stainsby 2006). This equates to the transfusion of approximately 45 units per 1000 population per year, a figure not dissimilar to the rest of the developed world (Cobain 2007). For such a ubiquitous intervention, it seems surprising that a recent systematic overview concluded that rigorous clinical trial data are lacking to support the benefits of many of the currently employed transfusion practices (Wilkinson 2011). As a generalisation, the evidence that exists from randomised controlled trials (Carson 2012), indicates little or no benefit from red cell transfusion at higher haemoglobin concentration thresholds (commonly termed 'liberal' policies for red cell transfusion). Red cell transfusions are also associated with some well described risks (Stainsby 2006). As biological products, hazards such as bacterial contamination and allergic reactions are well recognised. Other risks posed by red blood cell transfusion, whilst less tangible, are potentially far more common. Key amongst these is the long debated risk posed by red blood cells with a prolonged storage age (see below) (Schrier 1979). Therefore, practice guidelines for red cell transfusion in many clinical settings now promote more restrictive policies for red cell transfusion (Carson 2013). But despite this, red cell transfusion remains a very common intervention. For example, as many as 60% of patients admitted to critical care units develop anaemia (Vincent 2002; Corwin 2004), but only 10-15% of patients have a history of chronic anaemia prior to admission to the intensive care unit (ICU). Unless modified by red cell transfusions, haemoglobin values typically decrease by about 0.5g/dL/day during critical illness, for reasons including illness, co-morbidities, bleeding and phlebotomy. As a result, between 20-50% of critically ill patients receive a red cell transfusion, especially those with multiple organ failure. About 8-10% of the UK blood supply is transfused to patients in an ICU.
Red blood cell units and their storage
One major concern about red cell transfusion is uncertainty regarding the clinical consequences of transfusing red cell units that have been stored for longer periods prior to transfusion. This hypothesis of harm related to transfusion of a longer stored product was re-ignited by the authors of the Transfusion Requirements in Critical Care (TRICC) trial (Hebert 1999). This landmark randomised control trial compared liberal and restrictive transfusion practices in critically ill people. The investigators showed that restricting transfusions to maintain Hb concentration at 7 to 9 g/dL was safe and in some subgroups of patients superior to more liberal red blood cell use. Crucially, the authors suggested that the common practice of storing red blood cell units for prolonged periods of time may be one factor to explain the unexpected adverse effects of liberal transfusion.
This suggestion is biologically plausible in view of the growing body of evidence demonstrating changes in many cellular and physiological properties of red cells. These in vitro changes that occur during red blood cell storage are commonly known as the 'storage lesion' (D'Alessandro 2010; Glynn 2010). The storage lesion includes biochemical, metabolic and mechanical changes to the red cell, all of which may impair oxygen delivery. The term also encompasses changes which occur in the red cell storage medium, which could theoretically mediate inflammatory or oxidative tissue damage (Sharifi 2000; Kucukakin 2011). The most commonly described biochemical and metabolic components of the storage lesion are impaired nitric oxide metabolism (Stapley 2012), depletion of cellular 2,3-diphosphoglycerate (Vora 1989), and dysfunction of the membrane sodium-potassium pump (D'Alessandro 2010). Nitric oxide depletion induces vasoconstriction, in turn impairing blood flow and oxygenation (Stapley 2012). Altered 2,3-diphosphoglycerate reduces the oxygen affinity of haemoglobin (Sohmer 1979). Membrane sodium-potassium pump dysfunction results in harmful potassium leakage from the red cell into extracellular fluids (Hess 2010). Mechanical changes to the red cell membrane impair fluidity and red cell flow (Hess 2010). Like nitric oxide depletion, this may reduce transit of the red cell through the microscopic vasculature of organs such as the lung and kidney (Roback 2011a). Again such changes may impair oxygen uptake and delivery. Storage medium changes include the generation of inflammatory mediators such as soluble CD40 ligand, interleukin-6 (IL-6) and interleukin-8 (IL-8) (Khan 2006; Kucukakin 2011). Potential oxidative damage may also arise from super-oxide generation in the storage media (Kucukakin 2011).
Extended red blood cell storage, as described above, is fundamental to effective blood stocks management. In the UK, as a consequence of stock rotation processes, the average age of a red blood cell unit at the time of transfusion is 18-21 days (NHSBT 2012). Such a figure is very similar to that found throughout Europe and North America (Bennett-Guerrero 2009; Lacroix 2011; Heddle 2012). The changes of the storage lesion, described above, may be well established by this time. It is biologically plausible, therefore, that critically ill patients may currently be denied the benefits of 'fresher' red cells and exposed to the additional clinical risks posed by older red blood cell units. Limited clinical data would support this notion. Cohort studies have described associations between red blood cell storage age and a wide range of clinically important adverse outcomes (including infections, organ failures, increased hospital stay and death) (Vamvakas 1999; Mynster 2000; Leal-Noval 2003; Basran 2006; Koch 2008). However, the effects are not universally described (Vamvakas 2000; van de Watering 2006); although this is an important message from the literature, many authors point to the presence of significant confounding factors in the evidence (Steiner 2009). In particular, the strong linkage between the total volume transfused (which itself is strongly associated with the presence of co-morbidities, severity of illness and worse prognosis) and the average age of red blood cell units issued makes inferring causality very difficult (Vamvakas 2010).
How the intervention might work
The rationale for administering red cell transfusion is to improve tissue oxygenation by increasing red cell mass. There is a common presumption that lower Hb concentrations represent an accurate measure of diminished oxygen carrying capacity which can be part-corrected by red cell transfusion. Processing methods for red blood cell collection and storage for transfusion have been studied for many years (Alter 2008). Following blood collection, whole blood is centrifuged, plasma depleted and then the red cells are re-suspended in an optimal additive solution for storage within specially designed bags. This process, in conjunction with effective refrigeration, has allowed the duration of red cell concentrate storage to be significantly extended (D'Alessandro 2010). Many countries routinely store red cell concentrates for up to 42 days. This period is defined by the arbitrary requirement that, following storage, more that 75% of red blood cells should survive in the recipient's circulation at 24 hours (Roback 2011b). An extended shelf life facilitates stock management and it is fundamental to effective blood banking. It is standard practice amongst both blood providers and blood banks to issue the oldest stock first in preference to newer stock (Stanger 2012). This is necessary to ensure that the demand for this unique product can be met whilst also minimising wastage of what is a precious and financially costly resource (Stanger 2012).
Why it is important to do this review
This review is required to coalesce and appraise the wider randomised evidence on the impact of storage age on the efficacy and safety of red cell transfusion. Although there have been a number of reviews already published that address this question (including Lelubre 2009; Zimrin 2009; Vamvakas 2010), they are based on observational study data and do not include recently published and ongoing trials in this area (Steiner 2010; Lacroix 2011; Fergusson 2012). Furthermore, mathematical modelling suggests, individually, that the ongoing Steiner 2010 and Lacroix 2011 studies may lack enough power to prove conclusive (Pereira 2013). Therefore, there is a need to undertake quantitative analysis to pool results across all relevant randomised studies.
If studies were to indicate that clinical outcomes are affected by storage age, the implications for inventory management and clinical practice would be significant. Clinicians would rightly expect fresher, safer and more efficacious red blood cell units. The implementation of such a strategy would be likely to place considerable additional strain on blood providers and blood banks. It may also result in increased wastage, higher financial costs and could potentially threaten blood supplies (Glynn 2010). The urgent need to reconcile this issue, because of its potential harms to patients and its massive logistic implications, is keenly felt by clinicians, blood services and policy makers alike. Unfortunately, like so many questions about the efficacy, safety, and utility of red blood cell transfusion the evidence needed to settle the debate is currently not clear.