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The Art and Science of Infusion Nursing
Evidence-Based Guidelines for Blood
Transfusion
ABSTRACT
The AABB has initiated a process to develop evi-
dence-based guidelines for blood transfusion to
assist clinicians, other health professionals, and
patients in their transfusion decisions. In this arti-
cle, the author discusses the process of develop-
ing the recently published guidelines for plasma
transfusion using the GRADE (Grading of
Recommendations, Assessment, Development,
and Evaluation) methodology.
B
lood transfusion is one of the most common
of all clinical interventions. In many
instances, physicians order blood transfu-
sions after conducting a detailed analysis of
the patients clinical presentation, laboratory
values, and consultations with transfusion and hematol-
ogy professionals to make certain that this therapy is
indicated. However, in other instances, physicians have
been known anecdotally to order transfusions for more
Author Affiliation: Center for Transfusion and Cellular Therapies,
Department of Pathology and Laboratory Medicine, Emory
University School of Medicine, Atlanta, Georgia.
John D. Roback, MD, PhD, is associate professor in the
Department of Pathology and Laboratory Medicine at the Emory
University School of Medicine, director of the Emory Center for
Transfusion and Cellular Therapies, and medical director of the
blood banks at Emory University Hospital and Emory University
Orthopaedics and Spine Hospital. He is editor of AABBs Technical
Manual and was a past chair of the AABB Clinical Transfusion
Medicine Committee.
Corresponding Author: John D. Roback, MD, PhD, Center for
Transfusion and Cellular Therapies, Department of Pathology and
Laboratory Medicine, Emory University School of Medicine, Room
D-655, 1364 Clifton Road, NE, Atlanta, GA 30322
(jroback@emory.edu).
The author of this article has no conflicts of interest to disclose.
DOI: 10.1097/NAN.0b013e31824d29fe
VOLUME 35 | NUMBER 3 | MAY/JUNE 2012
Copyright 2012 Infusion Nurses Society. Unauthorized reproduction of this article is prohibited.
John D. Roback, MD, PhD
subjective and questionable reasons, including desires to
increase patients sense of well-being and to reach
unnecessarily high posttransfusion laboratory values.
In part, these questionable practices are due to an
incomplete understanding of the possible adverse effects
of transfusion, including infectious disease transmis-
sion, circulatory overload, transfusion-related acute
lung injury, and hemolytic transfusion reactions.
Furthermore, many physicians have learned transfusion
practice by on-the-job training from attending physi-
cians, fellows, and residents who themselves may not
have been well trained in transfusion practice. In addi-
tion, the transfusion medicine profession has also been
slow to develop evidence-based guidelines for transfu-
sion that could help promote more appropriate and
effective blood transfusion-ordering practices.
What are evidence-based practice guidelines (PGs)?
They are systematically developed statements that are pro-
duced to help physicians, other practitioners, and patients
decide about the use of specific interventions under certain
clinical circumstances.1 Well-developed, high-quality PGs
should be valid, reliable, reproducible, and clinically
applicable statements developed using the principles of
evidence-based medicine (EBM). The first principle of
EBM is that PGs should be based on thorough, unbiased,
and critically evaluated systematic reviews of the applica-
ble medical literature. The second principle is that evi-
dence is necessary, but not sufficient, for decision making
and that an assessment of the quality of the evidence
should be issued separately from the guidelines.
Both of these principles are supported through a
methodology promoted by the GRADE (Grading of
Recommendations, Assessment, Development, and
Evaluation) Working Group. This approach is becom-
ing the worldwide standard for formulating evidence-
based clinical PGs and has been adopted by many pro-
fessional organizations.2,3 In the GRADE system, the
strength of the guideline recommendations is based on
the quality of evidence as well as trade-offs between
benefits and harms, variability in patient preferences,
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practice setting, and uncertainty about whether the
intervention represents a wise use of resources.4 The
strength of the recommendation should represent the
extent to which that recommendation will do more
good than harm.
In this article, the author will discuss the approach of
producing transfusion PGs with the GRADE methodol-
ogy by using guidelines for plasma transfusion that were
recently developed and published.5,6
THE NEED FOR PLASMA
TRANSFUSION PGs
In 2006, about 4 million units of plasma were trans-
fused in the United States, which is comparable to,
although somewhat higher than, the numbers of plasma
units transfused in other developed countries.7 Many
indications for plasma transfusion are of questionable
usefulness and may produce more harm than good.8 On
the other hand, there may be some reasonable uses of
plasma that are not widely practiced. In either case, any
potential benefits of plasma transfusion have to be bal-
anced against possible harm this therapy may cause.9,10
The AABB (formerly American Association of Blood
Banks) commissioned its Clinical Transfusion Medicine
Committee (CTMC), chaired by the author of this arti-
cle, to develop evidence-based PGs for plasma transfu-
sion based on the GRADE approach. The process
required 4 steps. (1) A committee was formed, begin-
ning with an 11-member subset of the CTMC, and sup-
plemented with a multidisciplinary group of 6 subject-
matter experts from other professional organizations
whose members extensively use plasma transfusions. In
addition, 3 consultants who were methodologists were
also employed by the panel to perform tasks including
the systematic review, meta-analysis, and advisory activ-
ities during the guidelines process. (2) A set of clinical
questions was generated, addressing clinical issues with
plasma transfusion that are frequent points of contro-
versy regarding appropriate plasma use. (3) The group
performed a detailed systematic review of the transfu-
sion literature, including both observational and ran-
domized clinical trials that addressed the relevant ques-
tions. This work included a meta-analysis to assign odds
ratios (ORs) to the effectiveness of plasma in different
clinical situations. (4) The committee then analyzed the
systematic review and meta-analysis using GRADE
methodologies to produce the guidelines.
CLINICAL QUESTIONS
REGARDING APPROPRIATE
USES OF PLASMA TRANSFUSION
The 6 questions produced by the guidelines group were
focused on common clinical scenarios for plasma trans-
188 Copyright 2012 Infusion Nurses Society
Copyright 2012 Infusion Nurses Society. Unauthorized reproduction of this article is prohibited.
fusion that the panelists regularly encountered. All
questions were formulated in terms of patient groups,
intervention (plasma transfusion), and comparator/con-
trol treatment (defined in most cases as no plasma
transfusion for these guidelines). The primary outcome
of interest for all questions was mortality. The questions
were as follows:
1. Should plasma transfusion (vs no plasma) be used
in trauma patients requiring massive transfusion?
2. Should a plasma:red blood cell (RBC) transfusion
ratio of 1:3 (vs 1:3) be used in trauma patients
requiring massive transfusion?
3. Should plasma transfusion (vs no plasma) be used
in surgical and/or trauma patients in the absence
of massive transfusion?
4. Should plasma transfusion (vs no plasma) be used
for patients with warfarin anticoagulation-related
intracranial hemorrhage?
5. Should plasma transfusion (vs no plasma) be used
to reverse warfarin anticoagulation in patients
without intracranial hemorrhage?
6. Should plasma transfusion (vs no plasma) be used
in other groups of patients (eg, in the absence of
massive transfusion, surgery, bleeding, or overan-
ticoagulation)?
During the process of developing the questions, the
committee discussed many additional questions that
also had validity to plasma transfusion. Many of these
questions, however, could not be addressed because of
limited relevant data from clinical studies. For this rea-
son, the panel unanimously agreed to limit the analysis
to these 6 questions, which represent the types of ques-
tions most often asked of transfusion medicine practi-
tioners and clinicians.
SYSTEMATIC REVIEW AND
META-ANALYSIS
The systematic review used the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses11
and the reporting Meta-analysis of Observational
Studies in Epidemiology12 approaches. A reference
librarian with expertise in performing systematic
reviews designed and conducted the electronic search
strategy with input from study investigators. The
researchers searched a large number of electronic
databases (MEDLINE, Embase, CINAHL, Cochrane
CENTRAL, Web of Science, and Scopus) in addition
to bibliographies of included trials and the Institute
for Scientific Information Science Citation Index. The
search used a combination of terms, including blood
component transfusion, blood transfusion, plasma,
transfusion related lung injury, adverse effects, sur-
vival, mortality, multiple organ failure, brain injuries,
ischemia, thrombosis, respiratory distress, stroke,
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myocardial infarction, blood group incompatibility,
anaphylaxis, and hemolysis.
The results were refined to randomized controlled
clinical trials (RCTs) and controlled observational stud-
ies that enrolled a group of adult patients who received
plasma transfusion and a control group who received
either medical management without plasma transfu-
sion, a lower dose of plasma, or a lower plasma:RBC
transfusion ratio. Studies were included only if they
reported outcomes of interest, including death, nonfatal
myocardial infarction, stroke (hemorrhagic and
ischemic), acute lung injury, multiorgan failure, blood
loss, and RBC transfusion requirements. Studies in
which control groups received whole blood or autolo-
gous platelet-rich plasma were excluded to avoid the
possible confounding beneficial effects on hemostatic
activity of platelets in these components. Studies in
which plasma was used for plasmapheresis were also
not included.
Two specially trained blinded reviewers worked inde-
pendently to analyze each reference and then extract the
relevant information from each. The chance-adjusted
interreviewer agreement (kappa statistic) for study eligi-
bility was 0.84 (range 0.71-0.96). Disagreements were
resolved by consensus (the 2 reviewers discussed the
study and reached an agreement) without the need for
arbitration (adjudication by a third reviewer).
Data extracted included study size, number of
patients in each study arm, patient age, the presence of
chronic liver disease, treatment with anticoagulants
and mean international normalized ratio, operative
status, the presence of active bleeding, and description
of any interventional procedure as well as the control
procedure.
Pooled ORs for outcomes of interest were then calcu-
lated. ORs of 1.00 indicate no treatment effect; values
below 1.00 indicate that plasma reduced the risk of a
particular outcome, whereas values greater than 1.00
indicated an adverse effect of plasma transfusion on
that outcome.
The collected data included studies analyzing a total
of 12 421 patients transfused with 1 to 10 units of plas-
ma. In general, the studies were of low to moderate
quality. Assessment of study quality was based on a
number of factors, including the following: study design
(observational studies vs RCTs), biases (including unin-
tended bias), allocation concealment, and blinding. The
sum of quality factors led to the overall quality being
considered low, moderate, or high. Thirteen of the 37
included studies were RCTs, of which 5 (38%) con-
cealed allocation and 6 (46%) blinded patients. Data
collectors, outcome assessors, and caregivers were only
rarely blinded in these studies. Randomization was
inadequate in 1 study.
For an example, consider the analyses performed for
Question 1 (Should plasma transfusion [vs no plasma] be
used in trauma patients requiring massive transfusion?)
VOLUME 35 | NUMBER 3 | MAY/JUNE 2012
Copyright 2012 Infusion Nurses Society. Unauthorized reproduction of this article is prohibited.
and Question 2 (Should a plasma:RBC transfusion ratio
1:3 [vs 1:3] be used in trauma patients requiring
massive transfusion?). Researchers identified 10 obser-
vational studies that investigated the effects of plasma
transfusion on mortality in trauma patients (there were
no randomized clinical trials addressing this question).
In these studies, the transfusion of plasma at
plasma:RBC ratios greater than 1:3 was associated with
reduced mortality (OR: 0.38; 95% CI, 0.24-0.60).
Additional analyses, however, showed that plasma
transfusion was also associated with adverse effects. For
example, 5 observational studies reported the incidence
of pulmonary complications after a plasma transfusion
in which the transfusion was associated with a signifi-
cantly increased risk of developing pulmonary compli-
cations (OR: 2.92; CI, 1.99-4.29; I2 0%). On the
other hand, the transfusion of plasma significantly
reduced the risk of multiorgan failure (OR: 0.40; CI,
0.26-0.60; I2 0%).6 These data were considered in
total when developing the PGs, as described below.
DEVELOPMENT OF PLASMA
TRANSFUSION GUIDELINES
After its completion, the systematic review was distrib-
uted to members of the guidelines committee along with
GRADE evidence profiles developed by consulting
methodologists. Each committee member voted anony-
mously on an appropriate recommendation for each
question (including the strength of that recommenda-
tion) and also on the overall quality of the evidence.13
To provide the voters with guidance, it was agreed that
a strong recommendation (eg, We recommend...)
would be made if 70% of the panel members voted
strongly for (or against) that intervention. A weak rec-
ommendation (eg, We suggest...) was made when
there were not enough votes for a strong recommenda-
tion, but 70% of panel members were strongly and
weakly for (or against) the intervention. If 70% or more
of the committee was not in favor of (or opposed to) the
intervention, no recommendation was issued (eg, We
cannot recommend...).
For Question 1, the committees analysis of the evi-
dence led to the following recommendation: We suggest
that plasma be transfused to trauma patients requiring
massive transfusion (quality of evidence moderate).
This recommendation was made because, although all
panel members suggested that plasma be transfused to
trauma patients during massive transfusion, less than
70% were strongly in favor of this practice, leading to
a weak recommendation (We suggest...). Based on
this recommendation, it was the committees opinion
that most practitioners would likely choose to infuse
plasma to trauma patients, although a substantial
minority may not. In other words, the benefits of this
therapy likely outweigh any potential harm.
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For Question 2, however, the committee could not
issue a specific recommendation: We cannot recom-
mend for or against transfusion of plasma at a
plasma:RBC ratio of 1:3 in trauma patients during
massive transfusion (quality of evidence low). This
committee decision shows some important subtleties of
the guidelines process. For example, although transfu-
sion of plasma at plasma:RBC ratios greater than 1:3
was associated with significant reductions in mortality,
as described above, these data were derived from obser-
vational studies, which are potentially fraught with
unintended biases. For example, more plasma transfu-
sions could have been administered to patients deemed
most likely to survive; in this case, surviving patients
may have coincidentally received more plasma transfu-
sions, unrelated to an effect of plasma transfusion on
survival. Furthermore, when one considers that plasma
transfusion was associated with an almost 3-fold
increased risk of acute lung injury, the panel was divid-
ed over promoting higher plasma:RBC transfusion
ratios based on these data. During the voting process,
half the panel was weakly in favor of using a ratio 1:3
in this setting, and only 1 panelist was strongly in favor
of this practice. Because less than 70% of the panel
voted for this practice, no recommendation could be
issued. In contrast to the first question, 75% of the
panel believed that the evidence supporting this decision
was of low or very low quality. This vote established the
state of equipoise: there were insufficient data for or
against this practice, justifying RCTs in trauma patients
to evaluate plasma at a ratio of at least 1:3 with RBCs.
Recommendations and detailed analyses for the
other 4 questions can be found in the published system-
atic review and guidelines document.5,6 It is important
for readers to understand that AABB considers adher-
ence to these guidelines to be voluntary. Guidelines can-
not take individual variation among patients into
account and should not be considered to supplant
physician judgment.
SUMMARY
The AABB has begun an initiative to develop evidence-
based guidelines for transfusion of major blood compo-
nents, beginning with transfusion of plasma as
described here. To the authors knowledge, this is the
first GRADE-based systematic review, meta-analysis,
and PG effort focused on plasma transfusion. The
author believes that this is an important step toward
190 Copyright 2012 Infusion Nurses Society
Copyright 2012 Infusion Nurses Society. Unauthorized reproduction of this article is prohibited.
optimizing the outcomes of transfusion therapy. The
availability of high-quality, evidence-based transfusion
guidelines should improve patient outcomes, improve
clinical practice, minimize inappropriate practice varia-
tion, provide decision support tools for practitioners
and points of reference for medical orientation and edu-
cation, and may provide criteria for self-evaluation and
assistance with reimbursement and coverage decisions.
The future availability of additional randomized studies
addressing many of the common plasma transfusion sit-
uations should allow the development of more compre-
hensive and definitive guidance for plasma transfusion.
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Journal of Infusion Nursing