Title
Benefits and harms related to a restrictive transfusion approach during the perioperative phase or in the
acute care setting. A systematic review and meta-analysis of randomised controlled trials
Hovaguimian F, Myles P
1. INTRODUCTION
1.1 Background and rationale
Several observational studies suggesting a higher risk of morbidity and mortality in patients receiving blood
transfusions have stressed the need to develop strategies aiming at minimising the use of allogenic blood
products.1-3 To achieve this goal, a growing number of institutions have implemented patient blood
management (PBM) programmes, which are based on 3 core principles: optimising erythropoiesis,
minimising blood loss and managing anaemia.4 The latter aspect has yielded the development of restrictive
transfusion strategies, i.e. the use of “low” haemoglobin thresholds as a trigger for the administration of
red blood cells (RBC).
Although the use of a restrictive versus liberal transfusion strategy has been investigated in multiple trials,59
it remains unclear if the restrictive approach is truly related to better outcome. In a recently published
Cochrane review, there was no significant difference between groups with respect to most adverse events
and recovery indicators included in the analysis.10 This lack of evidence might result, among other factors,
from indiscriminate pooling of data obtained in various settings. Moreover, since a restrictive transfusion
approach is usually applied with other measures aiming at reducing perioperative RBC administration (such
as antifibrinolytics or clotting factors), it remains unclear if the effects of a restrictive transfusion strategy
are due to the lower number of RBC administered exclusively or to other PBM strategies, or both. Finally, a
restrictive transfusion strategy might have been applied not only to RBC but also to other blood products
such as fresh frozen plasma (FFP), platelets (PLT) or cryoprecipitates. In this case, the restrictive use of
these blood products may have played a participatory role in the observed effect. To date, these aspects
have not been addressed in a systematic review.
1.2 Objectives
The aim of this systematic review is to provide a comprehensive summary of the benefits and harms
related to the use of a restrictive versus liberal transfusion strategy. The scope of this review will be
restricted to randomised controlled trials performed in adult patients during the perioperative phase or in
the acute care setting. The role of other factors (i.e. use of other PBM measures) in the effect of a
restrictive transfusion approach will be explored through specific subgroup analyses.
2. METHODS
2.1 Eligibility criteria
2.1.1 Type of studies
Only fully published reports of randomised controlled trials will be considered. Studies using a factorial or
cross-over design, studies without a control group or studies including less than 15 participants will be
excluded.
2.1.2 Type of participants and settings
We will consider trials performed in adult patients (18 years old) undergoing any surgical procedure and
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trials performed in adults admitted to an acute care facility (emergency or intensive care unit (ICU)) for
acute bleeding with or without subsequent indication for surgery (e.g. trauma, gastrointestinal bleeding,
post-partum haemorrhage). Data from animal studies, trials including paediatric patients only, studies
including both children and adults where results from adult patients could not be extracted separately or
studies performed in a setting other than acute care will be excluded.
2.1.3 Type of intervention
We will search for trials reporting on transfusion strategies related to the administration of red blood cells
(RBC). We will consider all trials comparing a restrictive versus a liberal strategy. If the strategy is applied to
several allogenic blood products in addition to RBC (i.e. PLT, FFP or cryoprecipitates), data specific to RBC
will be extracted separately. Trials investigating restrictive transfusion strategies that were not guided by
cut-off values of haemoglobin or that were not applied to RBC will be excluded.
2.2 Outcomes measures
The primary outcomes will be mortality and morbidity rates at 30 days, or later at follow-up when data
were available (e.g. at 3, 6 or 12 months). Morbidity will be arbitrarily defined as any adverse event
requiring the administration of a new medication or a new medical intervention.
The following endpoints will be considered as secondary outcomes: haemoglobin/haematocrit levels, need
for allogeneic blood products (type and number of units per patient), concomitant application of other PBM
measures (such as antifibrinolytics, clotting factors, erythropoiesis stimulating agents, blood-sparing
surgical techniques) and length of stay.
2.3 Search methods for identification of studies
We will perform a systematic and comprehensive electronic search for relevant reports in the
Medline(Ovid), Embase and Central databases, using the strategy provided in Appendix 1 (search terms will
be adapted to meet specific databases requirements). The following sources of grey literature will be
screened: OpenSIGLE, NTIS, International Clinical Trials Registry Platform, ClinicalTrials.gov. Additional
reports will be identified by hand searching bibliographies of retrieved articles. No language or date
restriction will be applied. Potentially relevant articles published in foreign languages will be translated and
eventually assessed for eligibility.
2.4 Data collection and extraction
Titles and abstracts of retrieved articles will be screened by two independent reviewers and potentially
relevant reports will be subsequently assessed for eligibility. Duplicate publications will be identified
through comparison of reports for: shared author names; similar date/duration of the study; similar setting
or intervention; identical number of participants or baseline data. Disagreements will be resolved through
discussion between the two reviewers.
The following information will be extracted: general information about the study (first author, year of
publication, trial registry number, related articles, source); eligibility criteria (RCT, human, 18 years,
acute/perioperative care setting, blood product = RBC, restrictive versus liberal transfusion strategy); study
characteristics (design, duration, setting); patients characteristics (total number of participants, particular
eligibility criteria, age, gender, chronic disease, laboratory values, relevant medication); intervention
characteristics (definition of experimental and control groups, description of the intervention (cut-off
values used, administration schema), number of participants in each group, compliance to intervention, use
of other PBM measures, administration of other blood products); outcome characteristics (definition of
primary and secondary outcomes, units/limits used, how and when the outcomes were detected). Only
pre-specified outcomes as outlined in 2.2 will be collected.
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Data will be extracted from original reports by one reviewer using a data extraction form specifically
designed for this review (Microsoft Excel spread sheet). The second reviewer will verify the extracted data
and any queries will be addressed as described previously. If data are missing, unclear or incomplete in the
original report, the authors will be contacted for further clarification. Data obtained from duplicate
publications will be extracted and merged under a unique study identification name.
All data will be subsequently entered into the Cochrane Review Manager software (RevMan 5.2.3) by one
reviewer and checked by a second reviewer.
2.5 Quality assessment
Quality of data reporting will be assessed using the Cochrane “Risk of bias” tool, which evaluates: method
of randomisation, concealment of treatment allocation, blinding of participants and personnel, blinding of
outcome assessor, risk of incomplete outcome data (reporting of dropouts) and risk of selective reporting
(Cochrane Handbook for Systematic Reviews of Interventions – version 5.1.0, accessed online Sept 2014 at
http://www.cochrane.org/handbook). Other sources of bias not included in this tool (i.e. ethics approval
and informed consent; funding; potential conflict of interest; statistical issues) will also be assessed. If the
risk of bias is considered as high, a sensitivity analysis will be performed to explore the impact of these
studies on the results.
2.6 Synthesis of results
Dichotomous outcomes will be reported as risk ratios with 95% confidence intervals (CI), while continuous
data will be expressed as weighted mean differences with 95% CI. If data handling is necessary (such as
data combination for several groups, data transformation for trials using different outcome scales), the
methods used during processing will be reported.
2.7 Methods of analysis
All statistical analyses will be performed using the RevMan software. We will perform heterogeneity testing:
homogenous data (P ≥ 0.1) will be combined using a fixed effect model; for heterogeneous data (P < 0.1),
we will search for sources of heterogeneity and perform further sensitivity analysis. If the source of
heterogeneity cannot be identified, a random effects model will be used. The risk of publication bias will be
explored by the use of a funnel plot.
For the primary outcomes, the following subgroup analyses will be performed: setting (perioperative versus
acute care); type of surgical procedure; age (< 55 years verus >= 55 years); number of RBC units
administrated; administration of other blood products (PLT, FFP, cryoprecipitates); and use of other PBM
measures (antifibrinolytics, clotting factors, erythropoiesis stimulating agents, blood-sparing surgical
techniques).
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Appendix 1 – Search strategy
1. Medline/Ovid
1. exp perioperative care/ or exp perioperative period/
2. critical care/ or intensive care/
3. perioperative.tw.
4. intensive care.tw.
5. critical care.tw.
6. surgery.tw.
7. 1 or 2 or 3 or 4 or 5 or 6
8. blood transfusion/ or blood component transfusion/ or erythrocyte transfusion/
9. (Erythrocyt* adj2 transfusion*).tw.
10. transfusion.tw.
11. (red adj blood adj cell*).tw.
12. RBC*.tw.
13. (blood adj product*).tw.
14. h?emotherap*.tw.
15. 8 or 9 or 10 or 11 or 12 or 13 or 14
16. 7 and 15
17. exp clinical trials as topic/ or intervention studies/
18. Random Allocation/
19. random*.tw.
20. placebo.tw.
21. randomi#ed controlled trial*.pt.
22. trial.tw.
23. groups.tw.
24. 17 or 18 or 19 or 20 or 21 or 22 or 23
25. exp animals/ not humans.sh.
26. 24 not 25
27. 16 and 26
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