Plasma transfusion strategies for critically ill patients

Plasma transfusion strategies for critically ill patients (Review)

Karam O, Tucci M, Combescure C, Lacroix J, Rimensberger PC

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2013, Issue 12

http://www.thecochranelibrary.com

Plasma transfusion strategies for critically ill patients (Review)

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

8DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

iPlasma transfusion strategies for critically ill patients (Review)


[Intervention Review]

Plasma transfusion strategies for critically ill patients

Oliver Karam1, Marisa Tucci2 , Christophe Combescure3, Jacques Lacroix2 , Peter C Rimensberger1

1Pediatric Critical Care Unit, Geneva University Hospital, Geneva, Switzerland. 2Pediatric Intensive Care Unit, CHU Sainte Justine,

University of Montreal, Montreal, Canada. 3Center for Clinical Research, Geneva University Hospital, Geneva, Switzerland

Contact address: Oliver Karam, Pediatric Critical Care Unit, Geneva University Hospital, 6 rue Willy Donzé, Geneva, 1211, Switzerland.

[email protected].

Editorial group: Cochrane Injuries Group.

Publication status and date: New, published in Issue 12, 2013.

Review content assessed as up-to-date: 15 August 2013.

Citation: Karam O, Tucci M, Combescure C, Lacroix J, Rimensberger PC. Plasma transfusion strategies for critically ill patients.

Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD010654. DOI: 10.1002/14651858.CD010654.pub2.


A B S T R A C T

Background

Although plasma transfusions are frequently prescribed for critically ill patients, most clinical uses of plasma are not supported by

evidence. Plasma transfusions do not seem to correct mild coagulation abnormalities based on international normalised ratio (INR)

testing, but they seem to be independently associated with worse clinical outcomes in non-massively bleeding patients. Current

recommendations on plasma transfusion strategies advocate limiting plasma transfusions to patients who are actively bleeding or who

are at risk of bleeding and concomitantly have moderately abnormal coagulation tests.

Objectives

To determine whether use of a restrictive versus a liberal plasma transfusion threshold affects mortality or morbidity in critically ill

patients, and to assess the clinical effects of different plasma transfusion thresholds in critically ill patients.

Search methods

A search for studies was run on 15 August 2013. We searched the Cochrane Injuries Group Specialised Register, the Cochrane Central

Register of Controlled Trials (CENTRAL), MEDLINE(R) Ovid, MEDLINE(R) Ovid In-Process & Other Non-Indexed Citations,

MEDLINE(R) Ovid Daily and OLDMEDLINE(R) Ovid, EMBASE Classic + EMBASE (Ovid SP), reference lists, related websites

and trial registries and checked lists of references.

Selection criteria

Randomised clinical trials that assessed the effects of two plasma transfusion strategies, using a restrictive and a liberal threshold of at

least one coagulation test, in critically ill participants.

Data collection and analysis

Two review authors independently extracted data and assessed trial quality using the standard methods of the Cochrane Handbook for

Systematic Reviews of Interventions.

Main results

Of 843 references identified by our search, none of the trials satisfied our predefined inclusion criteria. No studies are included in this

review.

1Plasma transfusion strategies for critically ill patients (Review)


mailto:[email protected]

Authors’ conclusions

This review highlights the lack of evidence that is available to guide plasma transfusions in critically ill patients. Randomised controlled

trials are needed to determine the appropriate plasma transfusion strategy in critically ill patients.

P L A I N L A N G U A G E S U M M A R Y

Plasma transfusion strategies for critically ill patients

Plasma transfusions are a frequently used treatment for critically ill patients, and they are usually prescribed to correct abnormal

coagulation tests and to prevent or stop bleeding. Although plasma transfusions are frequently prescribed for critically ill patients, some

of the reasons for their use are not supported by evidence from medical research. Some research has found an association of plasma

transfusions with worse outcomes, and other studies have suggested that plasma transfusions do not help to return blood to its normal

thickness. It is important to identify which patients, if any, may benefit from plasma transfusions.

We searched the medical literature for reports of randomised controlled trials of plasma transfusion in people with a critical illness.

Upon reading 843 study records, we found that currently no randomised trials have compared different plasma transfusion strategies.

Such studies are needed to help physicians prescribe plasma transfusion only for patients who will benefit from them.

Two main obstacles are associated with designing a randomised controlled trial on this topic, but they can be overcome. Currently,

no consensus has been reached on the best way to determine whether a patient requires a plasma transfusion. Another obstacle is the

difficulty involved in identifying important bleeding, as one must consider not only the amount of bleeding but also its location, the

body’s own response to the bleeding (haemodynamic response) and the need for red blood cell transfusions.

B A C K G R O U N D

Plasma transfusions have been used since 1941 (Schmidt 2012).

In 2008, 4,484,000 plasma units were transfused in patients in

the United States (National Survey 2009). More than 10% of

critically ill patients, both adults and children, receive a plasma

transfusion during their hospital stay, making plasma transfusion

a frequently used treatment modality (Luk 2002; Puetz 2012;

Stanworth 2011). In current practice, plasma transfusions are

widely used in critical care; they are administered most often to

correct abnormal coagulation tests or to prevent bleeding (Vlaar

2009).

In situations in which active bleeding is attributable to a co-

agulation factor deficiency, plasma transfusions can constitute a

life-saving intervention by improving coagulation factor deficit

(Stanworth 2007), especially in patients requiring massive trans-

fusion (Zink 2009). However, in less dramatic situations, some

researchers have shown that transfusing plasma often fails to cor-

rect mild coagulation abnormalities (Abdel-Wahab 2006; Holland

2006). Furthermore, currently available evidence derived from sev-

eral retrospective studies in adults suggests that plasma transfusions

are associated with increased odds of acute lung injury (Dara 2005;

Khan 2007; van Stein 2010), nosocomial infection (Sarani 2008)

and transfusion-associated circulatory overload (Narick 2012). In

critically ill adults with haemorrhagic shock, a prospective study

reported an independent association between plasma transfusions

and worse outcomes such as multiple organ failure and acute res-

piratory distress syndrome (ARDS) (Watson 2009). In critically

ill children, a prospective observational study also reported an in-

dependent association between plasma transfusions and multiple

organ failure and nosocomial infection (Karam 2013).

Description of the intervention

Transfusion strategies can be viewed as liberal or restrictive. A

liberal transfusion strategy implies that blood products are trans-

fused for lower thresholds than with a restrictive transfusion strat-

egy. Transfusion strategies have been evaluated for red blood cells

(RBCs) (Carson 2012). RBC transfusions are a common treat-

ment in both adult and paediatric critical care settings (Bateman

2008), as it is hypothesised that critically ill patients could benefit

from RBC transfusions to enhance oxygen delivery. Nevertheless,

as for plasma, it has been recognised that RBC transfusions are

associated with increased morbidity (Bateman 2008; Gong 2005)

and mortality (Kneyber 2007). Adequate RBC transfusion strate-



gies have been evaluated in critically ill patients, in whom a restric-

tive haemoglobin strategy, as compared with a liberal strategy, de-

creased transfusion requirements without increasing adverse out-

comes (Hébert 1999; Lacroix 2007; Villanueva 2013).

Why it is important to do this review

Current recommendations on plasma transfusion strategies ad-

vocate limiting plasma transfusions to patients who are actively

bleeding or are at risk of bleeding and who concomitantly have

moderately abnormal coagulation tests (Crosby 1997; Liumbruno

2009; O’Shaughnessy 2004). However, these recommendations

fail to cite randomised controlled trials (RCTs).

Plasma transfusions are a frequent treatment in critical care set-

tings, although they seem to be associated with unfavourable out-

comes if not administered wisely. No systematic review of RCTs

has yet been published to guide physicians in selecting appropriate

plasma transfusion strategies for use in critically ill patients.

O B J E C T I V E S

To determine whether use of a restrictive versus a liberal plasma

transfusion threshold affects mortality or morbidity in critically

ill patients, and to assess the clinical effects of different plasma

transfusion thresholds in critically ill patients.

M E T H O D S

Criteria for considering studies for this review

Types of studies

We considered all randomised clinical trials for inclusion (irre-

spective of language, blinding, publication status or sample size)

if two thresholds (restrictive and liberal) and at least one coagu-

lation test (international normalised ratio (INR), activated par-

tial thromboplastin time (aPTT), fibrinogen or thromboelastog-

raphy) were compared.

Trials on plasmapheresis and plasma exchanges were not included.

Types of participants

All critically ill patients of all ages (neonates, children and adults)

requiring plasma transfusion.

Types of interventions

The intervention in the experimental group should follow a pro-

tocol with one defined threshold required for plasma transfusion.

The intervention in the control group should consist of another

threshold or standard treatment. We planned to extract the num-

bers of plasma transfusions from the original studies to describe

the intervention in experimental and control groups. By defini-

tion, we named “liberal” a transfusion strategy based on a thresh-

old allowing for more transfusions, and “restrictive” a transfusion

strategy based on a threshold allowing for fewer transfusions.

We planned to extract data on co-interventions (i.e. transfusion of

red blood cells and platelets, fibrinogen or other specific coagula-

tion factors, steroids, need for surgery and need for extracorporeal

life support) related to the main outcome.

Types of outcome measures

Primary outcomes

• All-cause mortality, at the end of the follow-up period in

each trial.

Secondary outcomes

• Nosocomial infections.

• Multiple-organ dysfunction (new or progressive).

• Volume of blood lost.

• Transfusion of RBCs and platelets.

• Transfusion reactions.

Search methods for identification of studies

The search was not restricted by date, language or publication

status.

Electronic searches

The Cochrane Injuries Group Trials Search Co-ordinator searched

the following.

• Cochrane Injuries Group Specialised Register (15 August

2013).

• Cochrane Central Register of Controlled Trials

(CENTRAL) (2013, Issue 7 of 12).

• MEDLINE(R) Ovid, MEDLINE(R) Ovid In-Process &

Other Non-Indexed Citations, MEDLINE(R) Ovid Daily and

OLDMEDLINE(R) Ovid (1946 to 15 August 2013).

• EMBASE Classic + EMBASE (Ovid SP) (1947 to 2013

week 32).

Search strategies are listed in Appendix 1.



Searching other resources

On 20 August 2013, we searched the following databases for on-

going and unpublished trials.

• The Clinical Trials Search Portal of the World Health

Organization (http://apps.who.int/trialsearch/).

• The Clinical Trials Registry of the U.S. National Institutes

of Health (http://clinicaltrials.gov).

We searched the following websites on 20 August 2013.

• Transfusion Evidence Library (http://

transfusionguidelines.org).

• http://www.evidence.nhs.uk/.

• American Association of Blood Banks (http://

www.aabb.org).

In addition, we checked the reference lists of identified material

for further relevant trials.

Data collection and analysis

Selection of studies

Two review authors (OK and MT) independently screened titles

and abstracts in the literature search. Authors of primary studies

that seemed eligible for inclusion would have been contacted for

clarification of data and to obtain missing information.

Study eligibility was assessed against defined inclusion criteria. We

planned to assess separately methodological quality, including par-

ticipant randomisation; blinding of participants, investigators and

outcome assessors; intention-to-treat analysis; and completeness

of follow-up.

We planned to request the consensus of an additional review au-

thor (JL) to resolve any disagreement between the primary review

authors.

Data extraction and management

Two review authors (OK and MT) would have independently

extracted data from the selected trials using a standardised data

extraction form. We planned to consult JL in the event of any

disagreements, which we would have resolved through discussion

and consensus.

We planned to independently extract the following data.

• Year and language of publication.

• Country in which the trial was conducted.

• Year of conduct of the trial.

• Inclusion and exclusion criteria.

• Sample size.

• Plasma transfusion thresholds (INR, aPTT, fibrinogen,

thromboelastography) for the restrictive and liberal strategy

groups.

• Outcomes (in each group).

• Methodological quality.

We planned to seek any unclear or missing information by contact-

ing the authors of the individual trials. Had there been any doubt

whether trial reports shared the same participants-completely or

partially (by identifying common authors and centres)-the authors

of the trials would have been contacted to clarify whether the trial

had been duplicated. We planned to resolve any differences in

opinion through discussion or arbitration with a third review au-

thor (JL).

Assessment of risk of bias in included studies

We planned that two review authors (OK and MT) would inde-

pendently assess each trial for risk of bias. In cases of disagreement,

consensus would have been reached by discussion with a third re-

view author (JL). Risk of bias for RCTs that met eligibility criteria

would have been assessed using The Cochrane Collaboration tool

for assessment of risk of bias provided in Chapter 8 of the Cochrane

Handbook for Systematic Reviews of Interventions (Higgins 2011).

We planned to assess the following areas.

Was the allocation sequence adequately generated?

• Criteria for a judgement of ’low risk for bias’: Random

sequence generation was performed by using a random number

table, a computer random number generator or other accepted

method.

• Criteria for the judgement of ’unclear risk of bias’: The

study was described as randomised, but the method for sequence

generation was not described, or the method for sequence

generation was inadequately described to permit assessment of

risk of bias.

• Criteria for the judgement of ’high risk of bias’: The

method for sequence generation was described but was not

random. Quasi-randomised trials, which base allocation on

factors such as date of birth, day of the week or medical record

number, will be considered as having a high risk of bias.

Was allocation adequately concealed?

• Criteria for a judgement of ’low risk for bias’: Allocation

concealment was described and would not allow investigators

enrolling participants to foresee participant assignment.

Acceptable methods of allocation concealment include central

allocation and sequentially numbered, opaque, sealed envelopes.


method for allocation concealment was not described, or the

method for allocation concealment was inadequately described

to permit assessment of risk of bias.

• Criteria for the judgement of ’high risk of bias’: The

method for allocation concealment was described but might

allow investigators to foresee participant assignment. Studies

using an open random allocation schedule, assignment envelopes

without appropriate safeguards and alternation or rotation or any



other unconcealed method would be considered as having a high

risk of bias.

Was knowledge of the allocated intervention concealed from outcome

assessors?

• Criteria for a judgement of ’low risk for bias’: Outcome

assessment was not blinded, but the outcome and the outcome

measurement were not likely to be influenced by lack of

blinding; or outcome assessment was blinded.


study contained insufficient information to permit judgement of

the presence or absence of blinding.

• Criteria for the judgement of ’high risk of bias’: Outcome

assessment was not blinded, and the outcome or the outcome

measurement was likely to be influenced by lack of blinding.

Given that blinding of study physicians to the transfusion strategy

would not be possible, we do not anticipate that any studies will

include blinding of study physicians. Blinding of study partici-

pants is likely to occur because of the severity of their injuries and

their physiological derangement, but this is unlikely to influence

outcomes.

This potential source of bias will be assessed for each outcome.

Were incomplete outcome data adequately addressed?

• Criteria for a judgement of ’low risk of bias’: No

participants were lost to follow-up or withdrew from the study

post-randomisation; loss to follow-up or withdrawal from the

study was balanced across groups and was likely unrelated to true

outcomes.

• Criteria for the judgement of ’unclear risk of bias’:

Reporting of attrition or exclusions was insufficient to permit

judgement regarding the risk of bias.

• Criteria for the judgement of ’high risk of bias’: Participants

were lost to follow-up or withdrew from the study for reasons

likely related to true outcomes; outcomes were not assessed using

an intention-to-treat analysis and with substantial departure of

the intervention received from that assigned at randomisation;

the number of participants lost to follow-up might induce

clinically relevant bias in the effect estimate or the effect size.

This potential source of bias will be assessed for each outcome.

Are reports of the study free of the suggestion of selective outcome

reporting?

• Criteria for a judgement of ’low risk of bias’: In studies with

an available study protocol, all of the study’s prespecified

outcomes were reported in the prespecified manner; in studies

for which the study protocol is not available, published reports

included all expected outcomes, including those that were

prespecified (convincing text of this nature may be uncommon).

• Criteria for the judgement of ’unclear risk of bias’:

Information was insufficient to allow assessment of whether the

risk of selective outcome reporting was present.

• Criteria for the judgement of ’high risk of bias’: In studies

with an available study protocol, not all of the study’s

prespecified outcomes were reported, or outcomes were not

reported in the prespecified manner, or outcomes were changed

during the course of the study.

Was the study free of other significant sources of bias?

• Criteria for a judgement of ’low risk of bias’: Studies

appeared to be free of other sources of bias.

• Criteria for the judgement of ’unclear risk of bias’: Risk of

bias may be present, information was insufficient to allow

assessment of whether an important risk of bias exists, or the

rationale or evidence that an identified problem will introduce

bias was insufficient.

• Criteria for the judgement of ’high risk of bias’: At least one

important source of bias was present, such as early stoppage of

the study due to a data-dependent process, extreme baseline

imbalance across study groups or potential bias due to source of

study funding.

Measures of treatment effect

The meta-analysis was planned to study the relationship between

a plasma transfusion threshold and an outcome. The arms of the

RCTs would have been labelled “Restrictive threshold” and “Lib-

eral threshold”. For dichotomous outcomes, we planned to express

results as risk ratios (RRs) with 95% confidence intervals (CIs).

For continuous outcomes, we planned to express results as mean

differences (MDs) (or standardised mean differences (SMDs) if

different scales of measurement had been used) with 95% CIs.

Dealing with missing data

If the main data (primary and secondary outcomes of the meta-

analysis) were not provided in the report of a study, we planned to

contact the study authors. If data could not have been obtained,

a sensitivity analysis would have been performed by including the

studies with missing data and extrapolating the data considering

extreme scenarios. The purpose of this sensitivity analysis would

have been to check the robustness of the conclusion while taking

into account missing data.

Assessment of heterogeneity

We planned to assess the clinical diversity (clinical heterogeneity)

of the included studies. We would have undertaken subgroup anal-

ysis to examine possible clinical variability when the I2 statistic was

50% or less but heterogeneity remained statistically significant.

We planned to analyse statistical heterogeneity using the Chi2 test

on N-1 degrees of freedom, with an alpha of 0.1 used for statistical

significance and with the I2 statistic (Higgins 2011). I2 ranges

between 0 to 25%, 26 to 50%, 51 to 75%, and 76 to 100%

corresponded to categories of low, medium, high and very high

levels of statistical heterogeneity, respectively. We would have set an

I2 threshold of greater than 76% to indicate substantial variation



across trials due to heterogeneity. We would have used a fixed-

effect model if we would had found low to high heterogeneity

between trials. We would have used a random-effects model if very

high heterogeneity had existed between trials (Higgins 2011).

We planned to test for homogeneity between trials for each out-

come using Cochran’s Q statistic, with P value less than or equal

to 0.10.

Assessment of reporting biases

We would have analysed possible publication bias using a funnel

plot if at least 10 studies were available for each outcome.

Data synthesis

As plasma transfusion strategies are likely to be different among

neonates, children and adults, meta-analysis would have been per-

formed separately for each of these age groups.

For the primary outcome, as well as for each of the secondary

outcomes, we planned to present in plain words the number of

trials reporting the outcome under evaluation, the effect of the

intervention and the heterogeneity noted among those trials.

We planned to analyse dichotomous data using an RR and to anal-

yse continuous data using weighted MDs (or SMDs accordingly).

A Mantel-Haenszel model would have been used, and pooled es-

timates would have been reported with a 95% CI.

We planned to present the intervention effect using a forest plot

to display effect estimates and confidence intervals for individual

studies.

Subgroup analysis and investigation of heterogeneity

To assess clinical heterogeneity, we planned to perform the follow-

ing subgroup analyses.

• Coagulation tests: INR, aPTT, fibrinogen,

thromboelastography.

• Admission categories: cardiac surgery participants, trauma

participants, burn participants.

• Severity of the condition: severity at admission, severity of

bleeding.

• Age of the participant.

Sensitivity analysis

A sensitivity analysis was planned to check the robustness of the

conclusions with regard to missing data. We had also planned

to compare trials with low risk of bias (adequate generation of

allocation sequence and follow-up) versus trials with high risk of

bias (one or more of the two components inadequate or unclear). If

a study would have been visibly different to others, we would have

conducted another sensitivity analysis by temporarily removing

that study to check whether the conclusions were similar.

R E S U L T S

Description of studies

We identified no published or ongoing trials that met our inclusion

criteria.

Results of the search

The search identified 843 records (Figure 1).



Figure 1. Study flow diagram.



Included studies

We identified no RCTs that evaluated plasma transfusion strategies

according to predetermined coagulation test thresholds.

Excluded studies

We identified the protocol for an RCT on plasma transfusion

strategies, as designed by Müller et al (Müller 2011). The study

authors described a non-inferiority randomised trial in critically ill

adults with abnormal coagulation tests (INR 1.5 to 3.0) requiring

an invasive procedure. In the control group, a prophylactic plasma

transfusion was administered before the invasive procedure was

performed, whereas the plasma transfusion was omitted in the in-

tervention group. The study authors planned to enrol 200 partici-

pants per treatment arm (400 participants in total). Although this

study randomly assigned two plasma transfusion strategies (pro-

phylactic plasma transfusion vs no plasma transfusion), it did not

randomly assign two strategies based on coagulation test results.

Therefore, it did not meet our inclusion criteria.

Risk of bias in included studies

No studies are included in this review.

Effects of interventions

No studies are included in this review.

D I S C U S S I O N

This systematic review shows that, in critically ill patients, no

randomised controlled trials have evaluated plasma transfusion

strategies based on coagulation test thresholds.

We identified only one protocol of a trial on plasma transfusions

(Müller 2011). In critically ill adults with mildly abnormal co-

agulation tests (INR 1.5 to 3.0) who need invasive procedures

(insertion of a central venous catheter, thoracocentesis, etc.), the

study authors planned to randomly assign a prophylactic plasma

transfusion versus no transfusion and to assess the occurrence of

significant bleeding during the procedure. This is an important

question, as one study suggests that 17% of plasma transfusions

are given to non-bleeding patients with abnormal coagulation tests

who need a procedure (Lauzier 2007). However, this trial will not

provide information on similar patients with higher INR levels,

nor on non-bleeding patients who do not need the invasive pro-

cedure, although these individuals represent 33% of patients re-

ceiving plasma transfusions (Lauzier 2007). Research is needed to

inform treatment decisions in patients with these characteristics.

Despite the paucity of evidence to guide their use, plasma trans-

fusions are nonetheless a common treatment in critically ill pa-

tients, as more than 10% of critically ill patients receive a plasma

transfusion during their hospital stay (Luk 2002; Puetz 2012;

Stanworth 2011). Obervational data, however, suggest that plasma

transfusions fail to correct mildly abnormal coagulation tests

(Abdel-Wahab 2006; Holland 2006) and are associated with worse

clinical outcomes in non-massively bleeding patients (Dara 2005;

Karam 2013; Khan 2007; Narick 2012; Sarani 2008; van Stein

2010; Watson 2009). However, these observational studies might

suffer from a “confounding by indication” bias, as prognostic fac-

tors perceived by the attending physician may influence treatment

decisions. Therefore, in the absence of randomised controlled tri-

als assessing appropriate transfusion strategies, the decision to pro-

ceed with plasma transfusion must be based on individualised in-

dications, with balance of the risks and benefits.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

We found no randomised controlled trials assessing the effects of

different plasma transfusion strategies in critically ill participants.

Implications for research

Given the frequency of plasma transfusions and the association

between this intervention and worse clinical outcomes in non-

massively bleeding patients, trials to determine which patients will

benefit from this intervention are warranted. More than 60 years

after the introduction of plasma transfusions, no such trials have

been published. Randomised controlled trials on plasma transfu-

sion strategies are necessary.

The paucity of randomised controlled trials on plasma transfusion

strategies might be explained by the difficulties involved in design-

ing such trials. In contrast to trials on red blood cell transfusion

strategies, in which the thresholds are haemoglobin levels, no con-

sensus has been reached on the appropriate trigger for plasma trans-

fusions. Some authors suggest using INR (Abdel-Wahab 2006;

Lauzier 2007), whereas others suggest using prothrombin time or

activated partial thromboplastin time ratios (Liumbruno 2009) or

thromboelastography (Afshari 2011), which assesses the viscoelas-

tic property of clot formation under low shear conditions. An-

other obstacle to designing a randomised controlled trial is the dif-



ficulty involved in assessing clinically significant bleeding, as one

must incorporate not only the volume but also its localisation, the

haemodynamic response to bleeding and the need for red blood

cell transfusions.

A C K N O W L E D G E M E N T S

We would like to thank Dr Serge Grazioli and Dr Sonia Labarinas

for their input on this review.

R E F E R E N C E S

References to studies excluded from this review

Müller 2011 {published data only (unpublished sought but not used)}

Müller MC, de Jonge E, Arbous MS, Spoelstra-de Man

AM, Karakus A, Vroom MB, et al.Transfusion of fresh

frozen plasma in non-bleeding ICU patients-TOPIC trial:

study protocol for a randomized controlled trial. Trials

2011;12(266):1–7. [PUBMED: 22196464]

Additional references

Abdel-Wahab 2006

Abdel-Wahab OI, Healy B, Dzik WH. Effect of fresh-frozen

plasma transfusion on prothrombin time and bleeding in

patients with mild coagulation abnormalities. Transfusion

2006;46(8):1279–85. [PUBMED: 16934060]

Afshari 2011

Afshari A, Wikkelsø A, Brok J, Møller AM, Wetterslev

J. Thrombelastography (TEG) or thromboelastometry

(ROTEM) to monitor haemotherapy versus usual care

in patients with massive transfusion. Cochrane Database

of Systematic Reviews 2011, Issue 3. [DOI: 10.1002/

14651858.CD007871.pub2; PUBMED: 21412912]

Bateman 2008

Bateman ST, Lacroix J, Boven K, Forbes P, Barton

R, Thomas NJ, et al.Anemia, blood loss, and blood

transfusions in North American children in the intensive

care unit. American Journal of Respiratory and Critical Care

Medicine 2008;178(1):26–33. [PUBMED: 18420962]

Carson 2012

Carson JL, Carless PA, Hebert PC. Transfusion thresholds

and other strategies for guiding allogeneic red blood cell

transfusion. Cochrane Database of Systematic Reviews 2012,

Issue 4. [DOI: 10.1002/14651858.CD002042.pub3]

Crosby 1997

Expert Working Group. Guidelines for red blood cell

and plasma transfusion for adults and children. Canadian

Medical Association Journal 1997;156(11 suppl):S1–24.

Dara 2005

Dara SI, Rana R, Afessa B, Moore SB, Gajic O. Fresh

frozen plasma transfusion in critically ill medical patients

with coagulopathy. Critical Care Medicine 2005;33(11):

2667–71. [PUBMED: 16276195]

Gong 2005

Gong MN, Thompson BT, Williams P, Pothier L, Boyce

PD, Christiani DC. Clinical predictors of and mortality in

acute respiratory distress syndrome: potential role of red

cell transfusion. Critical Care Medicine 2005;33(6):1191–8.

[PUBMED: 15942330]

Higgins 2011

Higgins JPT, Green S (editors). Cochrane Handbook for

Systematic Reviews of Interventions Version 5.1.0 [updated

March 2011]. The Cochrane Collaboration, 2011.

www.cochrane-handbook.org.

Holland 2006

Holland LL, Brooks JP. Toward rational fresh frozen plasma

transfusion: the effect of plasma transfusion on coagulation

test results. American Journal of Clinical Pathology 2006;126

(1):133–9. [PUBMED: 16753596]

Hébert 1999

Hébert PC, Wells G, Blajchman MA, Marshall J, Martin C,

Pagliarello G, et al.A multicenter, randomized, controlled

clinical trial of transfusion requirements in critical care.

New England Journal of Medicine 1999;340(6):409–17.

[PUBMED: 9971864]

Karam 2013

Karam O, Lacroix J, Robitaille N, Rimensberger PC, Tucci

M. Association between plasma transfusions and clinical

outcome in critically ill children: a prospective observational

study. Vox Sanguinis 2013 Mai;104(4):342–9. [PUBMED:

23294337]

Karam 2013a

Karam O, Tucci M, Lacroix J, Rimensberger PC.

International survey on plasma transfusion practices in

critically ill children. Transfusion. In press.

Khan 2007

Khan H, Belsher J, Yilmaz M, Afessa B, Winters JL, Moore

SB, et al.Fresh-frozen plasma and platelet transfusions

are associated with development of acute lung injury in

critically ill medical patients. Chest 2007;131(5):1308–14.

[PUBMED: 17400669]



Kneyber 2007

Kneyber MC, Hersi MI, Twisk JW, Markhorst DG, Plötz

FB. Red blood cell transfusion in critically ill children

is independently associated with increased mortality.

Intensive Care Medicine 2007;33(8):1414–22. [PUBMED:

17572875]

Lacroix 2007

Lacroix J, Hébert PC, Hutchison JS, Hume HA, Tucci

M, Ducruet T, et al.Transfusion strategies for patients in

pediatric intensive care units. New England Journal of

Medicine 2007;356(16):1609–19. [PUBMED: 17442904]

Lauzier 2007

Lauzier F, Cook D, Griffith L, Upton J, Crowther M. Fresh

frozen plasma transfusion in critically ill patients. Crt Care

Med 2007;35(7):1655–9. [PUBMED: 17522577]

Liumbruno 2009

Liumbruno G, Bennardello F, Lattanzio A, Piccoli P,

Rossetti G. Recommendations for the transfusion of

plasma and platelets. Blood Transfusion 2009;7(2):132–50.

[PUBMED: 19503635]

Luk 2002

Luk C, Eckert KM, Barr RM, Chin-Yee IH. Prospective

audit of the use of fresh-frozen plasma, based on Canadian

Medical Association transfusion guidelines. Canadian

Medical Association Journal 2002;166(12):1539–40.

[PUBMED: 12074120]

Narick 2012

Narick C, Triulzi DJ, Yazer MH. Transfusion-associated

circulatory overload after plasma transfusion. Transfusion

2012;52(1):160–5. [PUBMED: 21762464]

National Survey 2009

Office of the Assistant Secretary for Health. The 2009

National Blood Collection and Utilization Survey Report.

Washington, DC: US Department of Health and Human

Services, 2011. [: 9781563953286]

O’Shaughnessy 2004

O’Shaughnessy DF, Atterbury C, Bolton Maggs P, Murphy

M, Thomas D, Yates S, et al.Guidelines for the use of fresh-

frozen plasma, cryoprecipitate and cryosupernatant. British

Journal of Haematology 2004;126(1):11–28. [PUBMED:

15198728]

Puetz 2012

Puetz J, Witmer C, Huang Y, Raffini L. Widespread use

of fresh frozen plasma in US children’s hospitals despite

limited evidence demonstrating a beneficial effect. Journal

of Pediatrics 2012;160(2):210–5. [PUBMED: 21924435]

Sarani 2008

Sarani B, Dunkman WJ, Dean L, Sonnad S, Rohrbach JI,

Gracias VH. Transfusion of fresh frozen plasma in critically

ill surgical patients is associated with an increased risk

of infection. Critical Care Medicine 2008;36(4):1114–8.

[PUBMED: 18379235]

Schmidt 2012

Schmidt PJ. The plasma wars: a history. Transfusion 2012;

52(S1):2S–4S. [PUBMED: 22578368]

Stanworth 2007

Stanworth SJ, Hyde CJ, Murphy MF. Evidence for

indications of fresh frozen plasma. Transfusion Clinique et

Biologique 2007;14(6):551–6. [PUBMED: 18430602]

Stanworth 2011

Stanworth SJ, Walsh TS, Prescott RJ, Lee RJ, Watson DM,

Wyncoll D. A national study of plasma use in critical care:

clinical indications, dose and effect on prothrombin time.

Critical Care 2011;15(2):R108. [PUBMED: 21466676]

van Stein 2010

van Stein D, Beckers EA, Sintnicolaas K, Porcelijn L,

Danovic F, Wollersheim JA, et al.Transfusion-related acute

lung injury reports in the Netherlands: an observational

study. Transfusion 2010;50(1):213–20. [PUBMED:

19694998]

Villanueva 2013

Villanueva C, Colomo A, Bosch A, Concepción M,

Hernandez-Gea V, Aracil C, et al.Transfusion strategies for

acute upper gastrointestinal bleeding. New England Journal

of Medicine 2013;368(1):11–21. [PUBMED: 23281973]

Vlaar 2009

Vlaar AP, in der Maur AL, Binnekade JM, Schultz MJ,

Juffermans NP. A survey of physicians’ reasons to transfuse

plasma and platelets in the critically ill: a prospective single-

centre cohort study. Transfusion Medicine 2009;19(4):

207–12. [PUBMED: 19706138]

Watson 2009

Watson GA, Sperry JL, Rosengart MR, Minei JP, Harbrecht

BG, Moore EE, et al.Fresh frozen plasma is independently

associated with a higher risk of multiple organ failure and

acute respiratory distress syndrome. Journal of Trauma

2009;67(2):221–7. [PUBMED: 19667872]

Zink 2009

Zink KA, Sambasivan CN, Holcomb JB, Chisholm G,

Schreiber MA. A high ratio of plasma and platelets to packed

red blood cells in the first 6 hours of massive transfusion

improves outcomes in a large multicenter study. American

Journal of Surgery 2009;197(5):565–70. [PUBMED:

19393349]∗ Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Müller 2011 Randomly assigns two plasma transfusion strategies (prophylactic plasma transfusion vs no plasma transfusion) but

does not randomly assign two strategies based on coagulation test thresholds



D A T A A N D A N A L Y S E S

This review has no analyses.

A P P E N D I C E S

Appendix 1. Search strategies

Cochrane Injuries Group Specialised Register

#1 ((“critical illness”) OR (“critical care”) OR (“intensive care”) OR (“hospitalization”)) AND (INREGISTER) [REFERENCE]

[STANDARD]

#2 ((plasma or “plasma exchange” or “blood component transfusion”)) AND ( INREGISTER) [REFERENCE] [STANDARD]

#3 (((ffp or frozen or fresh) AND plasma) OR ((transfus* or infus* or administrat*) and plasma) OR ((therap* or treatment*) and

plasma)) AND ( INREGISTER) [REFERENCE] [STANDARD]

#4 (((restrict* or liberal*) and tranfus*)) AND ( INREGISTER) [REFERENCE] [STANDARD]

#5 #2 OR #3 OR #4 [REFERENCE] [STANDARD]

#6 #1 AND #5 [REFERENCE] [STANDARD]

Cochrane Central Register of Controlled Trials (CENTRAL)

#1MeSH descriptor: [Critical Illness] explode all trees

#2MeSH descriptor: [Critical Care] explode all trees

#3MeSH descriptor: [Intensive Care Units] explode all trees

#4MeSH descriptor: [Hospitalization] explode all trees

#5critical* near/5 ill*:ti,ab,kw (Word variations have been searched)

#6“intensive care” or intensive-care or “critical care” or critical-care:ti,ab,kw (Word variations have been searched)

#7#1 or #2 or #3 or #4 or #5 or #6

#8MeSH descriptor: [Plasma] explode all trees

#9MeSH descriptor: [Blood Component Transfusion] explode all trees

#10MeSH descriptor: [Plasma Exchange] explode all trees

#11((ffp or frozen or fresh) near/3 plasma):ti,ab,kw (Word variations have been searched)

#12(plasma near/3 (transfus* or infus* or administrat*)):ti,ab,kw (Word variations have been searched)

#13(plasma near/3 (therap$ or treatment$)):ti,ab,kw (Word variations have been searched)

#14(transfus* near/5 (restrict* or liberal*)):ti,ab,kw (Word variations have been searched)

#15#8 or #9 or #10 or #11 or #12 or #13 or #14

#16#7 and #15

MEDLINE(R) Ovid, MEDLINE(R) Ovid In-Process & Other Non-Indexed Citations, MEDLINE(R) Ovid Daily and

OLDMEDLINE(R) Ovid

1. Critical Illness/

2. exp Critical Care/

3. exp Intensive Care Units/

4. exp Hospitalization/

5. (critical$ adj5 ill$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary

concept, rare disease supplementary concept, unique identifier]

6. (“intensive care” or intensive-care or “critical care” or critical-care).mp. [mp=title, abstract, original title, name of substance word,

subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]

7. 1 or 2 or 3 or 4 or 5 or 6

8. exp Plasma/

9. exp Blood Component Transfusion/

10. exp Plasma Exchange/

11. ((ffp or frozen or fresh) adj3 plasma).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol

supplementary concept, rare disease supplementary concept, unique identifier]



12. (plasma adj3 (transfus$ or infus$ or administrat$)).mp. [mp=title, abstract, original title, name of substance word, subject heading

word, protocol supplementary concept, rare disease supplementary concept, unique identifier]

13. (plasma adj3 (therap$ or treatment$)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol


14. (transfus* adj5 (restrict* or liberal*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, protocol


15. 8 or 9 or 10 or 11 or 12 or 13 or 14

16. 7 and 15

17. randomi?ed.ab,ti.

18. randomised controlled trial.pt.

19. controlled clinical trial.pt.

20. placebo.ab.

21. clinical trials as topic.sh.

22. randomly.ab.

23. trial.ti.

24. 17 or 18 or 19 or 20 or 21 or 22 or 23

25. (animals not (humans and animals)).sh.

26. 24 not 25

27. 16 and 26

EMBASE Classic + EMBASE (Ovid SP)

1. Critical Illness/

2. exp Critical Care/

3. exp Intensive Care Units/

4. exp Hospitalization/

5. (critical$ adj5 ill$).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer,

drug manufacturer, device trade name, keyword]

6. (“intensive care” or intensive-care or “critical care” or critical-care).mp. [mp=title, abstract, subject headings, heading word, drug

trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

7. 1 or 2 or 3 or 4 or 5 or 6

8. exp Plasma/

9. exp Blood Component Transfusion/

10. exp Plasma Exchange/

11. ((ffp or frozen or fresh) adj3 plasma).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device

manufacturer, drug manufacturer, device trade name, keyword]

12. (plasma adj3 (transfus$ or infus$ or administrat$)).mp. [mp=title, abstract, subject headings, heading word, drug trade name,

original title, device manufacturer, drug manufacturer, device trade name, keyword]

13. (plasma adj3 (therap$ or treatment$)).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title,

device manufacturer, drug manufacturer, device trade name, keyword]

14. (transfus* adj5 (restrict* or liberal*)).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device

manufacturer, drug manufacturer, device trade name, keyword]

15. 8 or 9 or 10 or 11 or 12 or 13 or 14

16. 7 and 15

17. exp Randomized Controlled Trial/

18. exp controlled clinical trial/

19. exp controlled study/

20. comparative study/

21. randomi?ed.ab,ti.

22. placebo.ab.

23. *Clinical Trial/

24. exp major clinical study/

25. randomly.ab.

26. (trial or study).ti.

27. 17 or 18 or 19 or 21 or 22 or 23 or 24 or 25 or 26



28. exp animal/ not (exp human/ and exp animal/)

29. 27 not 28

30. 16 and 29

31. limit 30 to exclude medline journals

C O N T R I B U T I O N S O F A U T H O R S

All authors contributed to the protocol and to the systematic review.

D E C L A R A T I O N S O F I N T E R E S T

JL: All grants that were received to conduct studies in the field of transfusion medicine came from public agencies. JL also received

royalties for books that he edited completely or in part. None of these sources of revenue are in conflict with this review.

All other review authors: none known.

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

We have removed the criteria that “Studies deemed to have a high risk of bias in any domain will not be included in data synthesis”,

as we will conduct a sensitivity analysis on study quality, and it is unlikely that many studies will be judged to have low risk of bias in

every domain.



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Plasma transfusion strategies for critically ill patients