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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

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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

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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

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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

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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

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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

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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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Crit Care Med 2007 Vol.35, No.7

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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

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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

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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.”

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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

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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.

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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.

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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.

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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

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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

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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

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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

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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

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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?)

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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

Comments? Questions?