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1
Transfusion from male-only versus female donors in critically ill
recipients of high plasma volume components
Crit Care Med 2007, 35(7):1645-1648.
TRM JC – September 11, 2007
Maggie Constantine, MD, FRCPC
Resident, Transfusion Med
2
OverviewTRALI – same, but not equal
Anti-HLA and/or anti-granulocytic antibodies in donors Male donors - <1% Female donors – 17% overall
Significantly correlated with parity 0-3 pregnancies -> 7.8 to 26.3%
Anti-neutrophil antigen antibodies Very low
Densmore TL et al. Transfusion 1999;39(1):103-6
3
OverviewTRALI – smoking gun?
Palfi M et al. Transfusion 2001;41:317-322. “… is plasma from multiparous blood donors dangerous?”
5 post transfusion reactions 4 reactions post multiparous females plasma
Significantly lower oxygen saturation and higher TNFα concentrations
4
OverviewTRALI – smoking gun? UK experience
2003 Male donors to be used, as far as possible, for
FFP plasma for suspension of buffy coat derived platelet
pools (60% of platelet production) Achieved for >90% FFP; >85% platelet pools
2004-2005 Decrease in number of TRALI and number of
TRALI-related deaths
Chapman CE et al. Vox Sang 2006;91(s3): 227
5
OverviewTRALI – smoking gun? American experience, 2003-05
35 ARC blood centers – active solicitation for AEs
Fatalities probably due to TRALI 72 reported fatalities linked to TRALI
38 fatalities “probably” TRALI 63% post plasma transfusion Female WBC antibody + donors significantly more
likely to be associated with probable TRALI cases
Eder AF et al. Transfusion 2007;47:599-607
6
OverviewTRALI – smoking gun?
Canadian perspective 2001 to 2006
N=53 definite and possible TRALI 11.9% plasma (65.7% high plasma volume-containing
components) RBC 35.5%
46.8% of donors were female 33 cases – donor + for antibodies
14 cases-females, 9 cases-male, 10-both
Lin Y et al. Transfusion Med 2007;17:225-249
7
OverviewTRALI – the cavalry arrives aaBB Association Bulletin – Nov 3, 2006
“Blood collecting facilities should implement interventions to minimize the preparation of high plasma-volume components from donors known to be… at risk of leukocyte alloimmunization.”
“Preparing high plasma-volume components intended for transfusion from male donors.”
Canadian Blood Services – July 2007 Similar policy to start September 2007
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MethodsCrit Care Med 2007 Vol.35, No.7 Retrospective, case-controlled 1999-2005 4 ICUs: 1 med, 2 surg, 1 mixed
Mayo Clinic Consecutive patients who received > 2
units FFP or apheresis platelets Exclusions: “patients who refused research
authorization”
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MethodsCrit Care Med 2007 Vol.35, No.7
Patients (‘cases’) Received high plasma volume components from only
male donors Controls
Patients who had received 3 or more female-donor components with or without additional male components
Matched for Severity of illness Postop state Number of transfusions
3 or more female donations +/- additional male components
Afessa B et al. Mayo Clin Proc 2005;80:174-180.
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MethodsCrit Care Med 2007 Vol.35, No.7
Main outcomes Development of acute lung injury (ALI)
American European Consensus Conference Post-transfusional hypoxemia
PaO2/FiO2 Hospital mortality Duration of mechanical ventilation
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ResultsCrit Care Med 2007 Vol.35, No.7 PaO2/FiO2
In 49 matched pairs with ABGs pre- and post-transfusion Worsened significantly after the female
Indications for transfusion (FFP and/or platelets) Active bleeding – 35% Postoperative anemia – 16% Severe thrombocytopenia – 4% Plasma exchange – 1% Other – 9% “25% of patients received transfusions outside practice
guidelines”
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DiscussionCrit Care Med 2007 Vol.35, No.7
Limitations Differences in measured and unmeasured
prognostic factors may decrease the confidence in observed findings and limit causal inference
Absence of female donor parity data Discrete imbalance in pre-transfusion PaO2/FiO2
16
ConclusionsCrit Care Med 2007 Vol.35, No.7 “critically ill recipients of high plasma volume
components from male-only donors had… less impairment of gas exchange… [and] higher number of ventilator-free days”
“prospective studies are needed to evaluate the effects of AABB recommendations not only on the incidence of TRALI… but also on morbidity and mortality of transfused critically ill patients.”
17
Critical AppraisalCrit Care Med 2007 Vol.35, No.7 Are the results of the study valid?
Retrospective ICU patients
EXCLUDED: neurology, pediatric, coronary or CV surgery ICUs
Case-controlled But may fit definition of ‘cohort’ better Would be ‘case-control’ if cases of TRALI
identified and then rates of female plasma exposure determined
18
Critical Appraisal – Cohort studiesCrit Care Med 2007 Vol.35, No.7 Why cohort study?
‘natural experiments’ in which outcomes measured in ‘real world’ rather than experimental settings
Can evaluate large groups of diverse individuals Longer follow-up
Useful if outcomes – such as adverse events – are rare
Large samples needed for RCTs are prohibitive
Rochon PA et al. BMJ 2005;330:895-896.
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Critical Appraisal – Cohort studiesCrit Care Med 2007 Vol.35, No.7 Comparison groups
“counterfactural’ or “potential outcome” Ideal comparison group Does not exist in reality General population
Intervention v alternative intervention Intervention v no intervention
Restricted population Intervention v alternative intervention Intervention v no intervention
Rochon PA et al. BMJ 2005;330:895-896.
20
Critical Appraisal – Cohort studiesCrit Care Med 2007 Vol.35, No.7 Potential pitfalls
Selection bias A systemic error in creating intervention groups
Differ with respect to prognosis Measured or unmeasured
Confounder A situation in which the estimated intervention
effect is biased Factor must differ between the comparison groups and
predict the outcome of interest
Rochon PA et al. BMJ 2005;330:895-896.
21
Critical Appraisal – Cohort studiesCrit Care Med 2007 Vol.35, No.7 How can these pitfalls be amended?
Inclusion restriction Regression – adjusted effect
Linear Logistic Proportional hazards
Stratification – division of sample into subgroups for confounding factors
Effects of intervention are then measured within each subgroup
Rochon PA et al. BMJ 2005;330:895-896.
22
Critical AppraisalCrit Care Med 2007 Vol.35, No.7
Are the results valid? Unclear Retrospective, cohort study
No power calculations Apparent elimination of selection (indication) bias
Assignment of transfusion products, with respect to donor gender, was by chance
23
Critical AppraisalCrit Care Med 2007 Vol.35, No.7 Potential confounders – no regression analyses
or stratification Measured
Renal replacement therapy Pre-transfusion edema
Not measured Risk factors for ALI
Pneumonia, shock, multiple trauma, burn injury, acute pancreatitis, drug o/d
Red cell usage Female donor parity Presence of anti-HLA, anti-neutrophil Abs in donor /
recipients
24
Critical AppraisalCrit Care Med 2007 Vol.35, No.7 Were exposures and outcomes measured
in the same way? YES +/- hypoxemia, ALI, risk factors for ALI were
ascertained by co-investigators blinded to the specific transfusion characteristics
Was follow-up sufficiently long and complete? Unclear Follow-up not explicitly stated Any patients missing data? – not stated
25
Critical AppraisalCrit Care Med 2007 Vol.35, No.7 Temporal relationship correct? YES Dose-response gradient? NOT studied What is the magnitude of risk?
Relative risk of ‘new ALI’ = 0.75 Relative risk of ‘post-transfusion hypoxemia’=1.21 Absolute risk increase of PTH = 12%
Number needed to treat to see harm = 8
How precise is this estimate of risk? NO CI provided
26
Critical AppraisalCrit Care Med 2007 Vol.35, No.7 Should I attempt to stop the exposure?
Not based on this study Narrow adult ICU population No power calculations: underpowered for ‘new ALI’? Unclear clinical relevance of increase in post-transfusion
hypoxemia Trend towards increased hospital mortality and
significantly fewer vent free days But cannot say if the relationship is causal
27
Critical AppraisalCrit Care Med 2007 Vol.35, No.7 Context within current evidence
Post-transfusion hypoxemia Consistent with Palfi et al. 2001
TRALI Consistent with Canadian experience (Lin et al. 2007)
Future Research: Prospective cohort Case – female +/- male donor transfusion products Control – male only
Determine HLA antibody status of products Outcome – TRALI and / or post-transfusion hypoxemia
(clinical relevance?)