Transfusion of fresher versus older red blood cells for all conditions

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects of using fresher versus older red blood cells in people requiring a red blood cell transfusion.

Background

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.

Objectives

To assess the effects of using fresher versus older red blood cells in people requiring a red blood cell transfusion.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) comparing transfusion of fresher red blood cells with older red blood cells.

Types of participants

People, of any age, requiring transfusion for investigator diagnosed and defined anaemia of any aetiology.

Types of interventions

No consensus upon what defines 'fresher' or 'older' red blood cell units has been reached. Arbitrarily defining 'fresher' and 'older' red blood cell units for the purposes of this review is scientifically unsound, invites legitimate criticism of the clinical validity of the review's results and also risks excluding a large proportion of the available data. Consequently, all definitions of fresher and older red cells will be included. Studies comparing the following groups will thus be eligible for inclusion:

  • fresher red blood cell transfusion versus an intervention arm actively transfused older red blood cells;

  • fresher red blood cell transfusion versus current standard practice. Here the age of the older red blood cells is dictated by standard inventory management practice;

  • fresher red blood cell transfusion (given as a historical standard of practice in neonatal patients) versus an intervention arm actively transfused older red blood cells.

Types of outcome measures

Primary outcomes
  • Mortality measured at two time points: immediately (occurring within seven days in hospital) and short term (up to 30 days)

Secondary outcomes
  • Long-term mortality (analysed at appropriately similar time-points, e.g. using medium and long term mortality as appropriate)

  • Clinically accepted measures of multiple organ dysfunction (e.g. Multiple Organ Dysfunction Score (MODS) and Sequential Organ Failure Assessment (SOFA) score) and numbers of dysfunctional organs reported per patient

  • Incidence of in hospital infections

  • Duration of respiratory support (invasive and non-invasive ventilation), haemodynamic support (inotropic) and renal support (haemofiltration)

  • Length of hospital and ICU stay

  • Adverse transfusion reactions

  • Physiologic markers of oxygen consumption or alterations of microcirculation

  • Assessment of economic or blood stock inventory outcomes

Search methods for identification of studies

We will not restrict our search by language or publication status.

Electronic searches

We will search the following electronic databases:

  • Cochrane Injuries Group Specialised Register;

  • Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) (latest issue) (Appendix 1);

  • MEDLINE (OvidSP) (1948 to present) (Appendix 2);

  • Embase (OvidSP) (1974 to present) (Appendix 3);

  • CINAHL (EBSCOHost) (1982 to present) (Appendix 4);

  • PubMed (current e-publications only) (Appendix 5);

  • UKBTS SRI Transfusion Evidence Library (www.transfusionevidencelibrary.com) (1980 to present) (Appendix 6);

  • LILACS (1982 to present) (Appendix 7);

  • ISI Web of Science: Conference Proceedings Citation Index-Science (CPCI-S) (1990 to present) (Appendix 8).

We will also search the following databases for ongoing trials (all years):

  • ISRCTN Register (Appendix 9);

  • EU Clinical Trials Register (EUDRACT) (Appendix 9);

  • ClinicalTrials.gov (Appendix 10);

  • WHO International Clinical Trials Registry Platform (ICTRP) (Appendix 11);

  • UMIN-CTR Japanese Clinical Trials Registry and the Hong Kong Clinical Trials Registry (Appendix 12).

We will combine searches in MEDLINE, Embase and CINAHL with adaptations of the Cochrane RCT search filter as detailed in Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2011).

Searching other resources

We will check references of all identified trials, relevant review articles, and current treatment guidelines for further literature. We will limit these searches to the 'first-generation' reference lists. We will also contact authors of relevant studies, study groups and experts worldwide who are known to be active in the field for unpublished material or further information on ongoing studies.

Data collection and analysis

Selection of studies

One author (CD) will screen all titles and abstracts of papers identified through the electronic searches; only clearly irrelevant references will be excluded at this stage. We will subsequently retrieve the full-texts for the remaining references and they will be independently assessed for inclusion by two authors (RG and SB) using a study-specific eligibility form. Where necessary, disagreements will be resolved by an adjudicator (SS).

Data extraction and management

Two authors (RG and SB) will independently undertake data extraction using a piloted study-specific data extraction form. Disagreements will be resolved by consensus between the review authors. Where necessary, we will attempt to contact authors of the original trials to provide further details. One author (RG) will enter the data into the Cochrane Collaboration's statistical software, Review Manager 2013, and data entry will be checked by the other author (SB).

We will perform data extraction in accordance with guidance detailed in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). With regard to the intervention, we expect heterogeneity within the definition of the fresh versus older red blood cell units. We also anticipate potential issues with protocol non-adherence. Such problems are likely to have influenced the success with which the experimental arms were exposed to distinct, non overlapping ages of red blood cell units. Consequently we will specifically extract intervention data upon:

  • age of red blood cell units transfused in the intervention group and the control group;

  • total volume of red blood cells exposure in both intervention groups.

Due to the possible heterogeneity of the red cell product specification we will also specifically extract data on the use of:

  • irradiated blood;

  • whole blood;

  • red cell leucodepletion.

We will also record any additional interventions which may have relevant impacts in relation to red cell transfusions (e.g. red cell salvage).

In order to minimise biases that could arise in the 'sub-categorisation' of studies by their definition of 'fresher' and 'older' red blood cells, authors responsible for data extraction (RG and SB) will not be involved in categorising the studies by their definition of 'fresher' and 'older' red cells for the interpretation and analysis of outcome data. This categorisation of studies will be undertaken by the other authors (SS, KW and MT).

Assessment of risk of bias in included studies

Two authors (RG and SB) will independently assess risk of bias for each trial using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011c). Disagreements will be resolved by discussion or by involving a third author (SS). For each of the included trials, we will assess the risk of bias (as either low risk, high risk, or unclear) for the following domains:

  1. generation of random sequence (selection bias);

  2. concealment of treatment allocation (selection bias);

  3. blinding of participants and personnel (person(s) delivering the treatment) to treatment allocation (performance bias);

  4. blinding of outcome assessors to treatment allocation (detection bias);

  5. completeness of the outcome data (including checks for possible attrition bias through withdrawals, loss to follow-up and protocol violations);

  6. selective reporting of outcome (reporting bias);

  7. other sources of bias (other bias). An assessment will be made as to whether each trial was free of problems, not identified by those listed above, that could put it at risk of bias.

Measures of treatment effect

We will calculate risk ratios (RRs) for dichotomous outcomes including long-term mortality. We will express treatment effects for continuous outcome data outcomes as mean differences (MDs); if the outcomes are measured using different methods, we will use the standardised mean differences (SMDs).

Regarding the incidence of new hospital infections, we will estimate incidence ratios as the ratio of the new observed cases over expected number of cases for exposed patients. If the absolute risk of infections is rather low, then measures of association yield similar estimates with the relative risk. In such cases where the incidence ratio of rare events isn't available, we will consider the RR instead. We will calculate the corresponding 95% confidence intervals (CIs) throughout.

We will not formally analyse data on length of hospital stay. If this outcome is appropriately reported by each study we will report the median length of stay per clinical patient group. Where a study does not report this outcome by clinical patient group, we will make reference to this in the review but not seek to use the outcome data further.

In the absence of appropriate skills in our facility to fully analyse economic and blood stock inventory outcomes at this time, the data will be presented in a narrative format.

Unit of analysis issues

Cross-over and cluster randomised trials are not anticipated in this review. Should either of these be found, we will make appropriate adjustments according to the advice in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). The level of measurement will always be the patient.

Dealing with missing data

Where possible, we will obtain missing data directly from the author(s) of the individual trial(s). For all included trials, levels of attrition will be noted and, where appropriate, sensitivity analysis will be carried out to examine the impact of losses for dichotomous outcomes.

Assessment of heterogeneity

We will use the I2 statistic to quantify the possible degree of heterogeneity of treatment effects between trials (where I2 > 50% indicates moderate heterogeneity and I2 > 80% considerable heterogeneity). Due to the nature of the studies, we expect moderate heterogeneity and hence in the first instance analysis will employ a random-effects model. If heterogeneity is found to be at levels lower than expected, then we will use both the random-effects and fixed-effect models for exploratory reasons. We will explore potential causes of heterogeneity by sensitivity and subgroup analysis. For assessment of clinical heterogeneity, we will include consideration of patient characteristics (e.g. underlying morbidity, age or volume of red blood cells transfused), trial design and risk of bias, outcome definition, outcome measurement and age of red cells transfused.

Assessment of reporting biases

Although every effort will be made to identify unpublished studies, we will assess publication bias using funnel plots provided there are at least 10 studies included in each meta-analysis.

Data synthesis

The comparisons made within the primary studies are likely to be diverse due to the absence of an accepted definition of fresher and older red blood. Following data extraction, we will assess if the included studies are suitable, in terms of the definitions of fresher and older blood employed, for inclusion into a single meta-analysis, with an intervention size for our primary outcome being 2500 participants (calculation estimated from the sample size calculations made for the Age of Blood Evaluation (ABLE) trial (Lacroix 2011), which is based on estimations from previous research (Hebert 1999). The ABLE trial is seeking an expected risk reduction in the intervention arm of 5% from a baseline mortality rate of 25%, with a power of 0.8 and a significance level of 5%) (Lacroix 2011). Even if this intervention size was reached, the meta-analysis may still be underpowered to detect differences in this outcome (Pereira 2013). If a single analysis can be performed, we anticipate employing a random-effects model. If heterogeneity is found to be lower than expected, then we will use both the random-effects and fixed-effect models for exploratory reasons. If significant diversity does exist in the comparisons made by the primary studies, their separation into more homogeneous groups may be required for the purpose of analysis. Until data has been extracted from the included studies, we will be unable to provide definitions for such groups.

Subgroup analysis and investigation of heterogeneity

If there are sufficient data, we will undertake the following subgroup analyses to examine for significant differences in treatment effect:

  • age groups (e.g. neonates);

  • transfusion indication (long term transfusion dependence vs. support during an acute illness).

If any other subgroup effects are identified, they will be clearly indicated as hypothesis-generating. We will use the test for subgroup differences provided in Review Manager 2013 to establish whether the subgroups are statistically significantly different from one another.

Sensitivity analysis

If data are available, we will perform sensitivity analyses exploring aspects of trial and review methodology. These will include exploring the effects of removing trials at high or unclear risk of the following domains of bias:

  1. selection bias (reflecting lack of confirmation of random sequence generation and allocation concealment);

  2. detection bias (reflecting lack of assessor blinding);

  3. attrition bias, such as from high levels of missing data.

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Erythrocyte Transfusion] explode all trees
#2 (red cell* or red blood cell* or erythrocyte* or RBC* or blood) near/1 (transfus* or infus* or hypertransfus* or retransfus*)
#3 MeSH descriptor: [Blood Transfusion] this term only
#4 MeSH descriptor: [Blood Component Transfusion] this term only
#5 #3 or #4
#6 MeSH descriptor: [Erythrocytes] this term only
#7 red cell* or red blood cell* or erythrocyte* or RBC* or whole blood
#8 #6 or #7
#9 #5 and #8
#10 (red cell* or red blood cell* or erythrocyte* or RBC* or whole blood):ti
#11 #1 or #2 or #9 or #10
#12 MeSH descriptor: [Blood Preservation] explode all trees
#13 (age or aged or aging or fresh* or old or older or oldest or new or newer or newest or young or younger or youngest or store* or storage or storing or preserv*):ti
#14 #12 or #13
#15 #11 and #14
#16 ((red cell* or red blood cell* or erythrocyte* or RBC* or blood or transfus*) near/5 (age or aged or aging or fresh* or old or older or oldest or new or newer or newest or young or younger or youngest or store* or storage or storing or preserv*)):ti
#17 #15 or #16

Appendix 2. MEDLINE (OvidSP) search strategy

1. ERYTHROCYTE TRANSFUSION/
2. ((blood or erythrocyte* or red cell* or red blood cell* or RBC*) adj1 (transfus* or infus* or retransfus*)).ti,ab.
3. BLOOD TRANSFUSION/ or BLOOD COMPONENT TRANSFUSION/
4. ERYTHROCYTES/
5. (red cell* or red blood cell* or erythrocyte* or RBC* or whole blood).tw.
6. 4 or 5
7. 3 and 6
8. (RBC* or red cell* or red blood cell* or erythrocyte* or whole blood).ti.
9. 1 or 2 or 7 or 8
10. exp Blood Preservation/
11. *Time Factors/
12. (age or aged or aging or fresh* or old or older or oldest or new or newer or newest or young or younger or youngest or store* or storage or storing or preserv*).ti.
13. 10 or 11 or 12
14. 9 and 13
15. ((red cell* or red blood cell* or erythrocyte* or RBC* or blood or transfus*) adj5 (age or aged or aging or fresh* or old or older or oldest or new or newer or newest or young or younger or youngest or store* or storage or storing or preserv*)).ti.
16. ((red cell* or red blood cell* or erythrocyte* or RBC* or whole blood) adj3 (store* or storage or storing or preserv* or fresh* or old or older or oldest or new or newer or newest or young or younger or youngest)).ab.
17. 14 or 15 or 16 

Appendix 3. Embase (OvidSP) search strategy

1. ERYTHROCYTE TRANSFUSION/
2. ((blood or erythrocyte* or red cell* or red blood cell* or RBC*) adj1 (transfus* or infus* or retransfus*)).ti,ab.
3. BLOOD TRANSFUSION/ or BLOOD COMPONENT THERAPY/
4. ERYTHROCYTE/ or ERYTHROCYTE CONCENTRATE/
5. (red cell* or red blood cell* or erythrocyte* or RBC* or whole blood).tw.
6. 4 or 5
7. 3 and 6
8. (RBC* or red cell* or red blood cell* or erythrocyte* or whole blood).ti.
9. 1 or 2 or 7 or 8
10. BLOOD STORAGE/
11. ERYTHROCYTE PRESERVATION/
12. STORAGE TIME/
13. *TIME/
14. (age or aged or aging or fresh* or old or older or oldest or new or newer or newest or young or younger or youngest or store* or storage or storing or preserv*).ti.
15. 10 or 11 or 12 or 13 or 14
16. 9 and 15
17. ((red cell* or red blood cell* or erythrocyte* or RBC* or blood or transfus*) adj5 (age or aged or aging or fresh* or old or older or oldest or new or newer or newest or young or younger or youngest or store* or storage or storing or preserv*)).ti.
18. ((red cell* or red blood cell* or erythrocyte* or RBC* or whole blood) adj3 (store* or storage or storing or preserv* or fresh* or old or older or oldest or new or newer or newest or young or younger or youngest)).ab.
19. 16 or 17 or 18

Appendix 4. CINAHL (EBSCOhost) search strategy

1.   (MH "Erythrocyte Transfusion")
2.   TI ((red cell* or red blood cell* or erythrocyte* or RBC* or blood) N1 (transfus* or infus* or retransfus*)) OR AB ((red cell* or red blood cell* or erythrocyte* or RBC* or blood) N1 (transfus* or infus* or retransfus*))
3.   (MH "Blood Transfusion") OR (MH "Blood Component Transfusion")
4.   (MH "Erythrocytes")
5.   TI (red cell* or red blood cell* or erythrocyte* or RBC* or whole blood) OR AB (red cell* or red blood cell* or erythrocyte* or RBC* or whole blood)
6.   S4 OR S5
7.   S3 AND S6
8.   TI (red cell* or red blood cell* or erythrocyte* or RBC* or whole blood)
9.   S1 OR S2 OR S7 OR S8
10. (MH "Blood Preservation")
11. (MM "Time Factors")
12. TI (age or aged or aging or fresh* or old or older or oldest or new or newer or newest or young or younger or youngest or store* or storage or storing or preserv*)
13. S10 OR S11 OR S12
14. S9 AND S13
15. TI ((red cell* or red blood cell* or erythrocyte* or RBC* or blood or transfus*) N5 (age or aged or aging or fresh* or old or older or oldest or new or newer or newest or young or younger or youngest or store* or storage or storing or preserv*))
16. AB ((red cell* or red blood cell* or erythrocyte* or RBC* or whole blood) N3 (store* or storage or storing or preserv* or fresh* or old or older or oldest or new or newer or newest or young or younger or youngest))
17. S14 OR S15 OR S16

Appendix 5. PubMed (e-publications only)

(red cell*[TI] OR blood[TI] OR erythrocyte*[TI] OR transfus*[TI] or RBC*[TI]) AND (random* or trial* OR controlled OR control group OR blind* OR systematic*) AND (age[TI] or aged[TI] or aging[TI] or fresh*[TI] or old[TI] or older[TI] or oldest[TI] or new[TI] or newer[TI] or newest[TI] or young[TI] or younger[TI] or youngest[TI] or store*[TI] or storage[TI] or storing[TI] or preserv*[TI]) AND (publisher[sb] NOT pubstatusnihms)

Appendix 6. Transfusion Evidence Library search strategy

(red cell* or red blood cell* or erythrocyte* or RBC* or blood or transfus*) [in Record Title] AND (age or aged or aging or fresh* or old or older or oldest or new or newer or newest or young or younger or youngest or store* or storage or storing or preserv*) [in Record Title]

Appendix 7. LILACS search strategy

db:("LILACS") AND type_of_study:("clinical_trials" OR "systematic_reviews" OR "guideline" OR "evidence_synthesis") AND (tw:("red cells" OR "red blood cells" OR "age of blood" OR "blood transfusion" OR transfus*) OR ti:(blood)) AND limit:("humans")

Appendix 8. Web of Science (CPCI-S) search strategy

Title: (red cell* or red blood cell* or erythrocyte* or RBC* or blood or transfus*) AND Title: (age or aged or aging or fresh* or old or older or oldest or new or newer or newest or young or younger or youngest or store* or storage or storing or preserv*) AND RCT Filter/Topic: (random* or blind* or trial* or control*)

Appendix 9. ISRCTN and EUDRACT search strategy

(red cells OR red blood cells OR erythrocytes OR RBCs OR blood OR transfusion) AND (age OR aged OR aging OR fresh OR fresher OR freshest OR old OR older OR oldest OR new OR newer OR newest OR young OR younger OR youngest OR stored OR storage OR storing OR preserved)

Appendix 10. ClinicalTrials.gov search strategy

Search Terms: (age OR aging OR fresh OR fresher OR freshest OR old OR older OR oldest OR new OR newer OR newest OR young OR younger OR youngest OR stored OR storage) AND transfusion AND red blood cells

Appendix 11. ICTRP search strategy

Title: (age OR aged OR aging OR fresh OR fresher OR freshest OR old OR older OR oldest OR new OR newer OR newest OR young OR younger OR youngest OR stored OR storage OR storing)
Intervention: transfusion

Appendix 12. UMIN-CTR Japanese Clinical Trials Registry and the Hong Kong Clinical Trials Registry

transfusion OR red cells OR red blood cells [N.B. Terms searched for individually]

Contributions of authors

Richard Gregg is a content expert for this review (clinical haematology) and led the preparation of the protocol.

Susan Brunskill is a methodological expert for this review who assisted in the preparation of the protocol.

Kirstin Wilkinson is a content expert for this review (cardiac anaesthesia) and contributed to the preparation of the protocol.

Carolyn Dorée is the information specialist who developed the search strategies and drafted the text for the search section.

Marialena Trivella is a methodological expert for this review who provided support with writing the data analysis section of the protocol and contributed to the preparation of the protocol.

Simon Stanworth is a content expert for this review (red cells and transfusion) and contributed to the preparation of the protocol.

All authors have seen and commented on drafts and the final version of the protocol.

Declarations of interest

MT: My position at the UKCC and as a statistical editor/referee for 5 Cochrane groups (Anaesthesia, Wounds, Injuries, Breast Cancer, and Sexually Transmitted Infections), are independent to my involvement in this review. I declare that my involvement here as an author has no related financial relationships.

All others: None known.

Sources of support

Internal sources

  • NHS Blood and Transplant, Research and Development, UK, Not specified.

External sources

  • No sources of support supplied

Ancillary