1 Transfusion from male-only versus female donors in critically ill recipients of high plasma volume components Crit Care Med 2007, 35(7): TRM JC – September 11, 2007 Maggie Constantine, MD, FRCPC Resident, Transfusion Med

2 Overview TRALI – 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 Overview TRALI – smoking gun? Palfi M et al. Transfusion 2001;41: “… 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 Overview TRALI – 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 Decrease in number of TRALI and number of TRALI-related deaths Chapman CE et al. Vox Sang 2006;91(s3): 227

5 Overview TRALI – smoking gun? American experience, 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:

6 Overview TRALI – 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:

7 Overview TRALI – 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

8 Crit Care Med 2007 Vol.35, No.7

9 Methods Crit Care Med 2007 Vol.35, No.7 Retrospective, case-controlled 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”

10 Methods Crit 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:

11 Methods Crit 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

12 Results Crit Care Med 2007 Vol.35, No.7

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14 Results Crit 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”

15 Discussion Crit 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 Conclusions Crit 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 Appraisal Crit 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 studies Crit 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:

19 Critical Appraisal – Cohort studies Crit 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:

20 Critical Appraisal – Cohort studies Crit 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:

21 Critical Appraisal – Cohort studies Crit 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:

22 Critical Appraisal Crit 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 Appraisal Crit 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 Appraisal Crit 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 Appraisal Crit 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 Appraisal Crit 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 Appraisal Crit Care Med 2007 Vol.35, No.7 Context within current evidence Post-transfusion hypoxemia Consistent with Palfi et al 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?)

28 Transfusion from male-only versus female donors in critically ill recipients of high plasma volume components Crit Care Med 2007, 35(7): TRM JC – September 11, 2007 Maggie Constantine, MD, FRCPC Resident, Transfusion Med Comments? Questions?