Swisstransfusion 2012 · Leo van de Watering Jon J. van Rood Center for Clinical Transfusion...

RBC storage: An updated overview

Swisstransfusion 2012

September 6th – 7th, Basel

Leo van de Watering

Jon J. van Rood Center for Clinical

Transfusion Research

Leiden, the Netherlands

Clinical effects of transfusing older red cell

concentrates: an updated overview

“RBC storage laesions”

Changes in RBC during storage

• Shape ∆

• Membrane flexibility ↓

• 2,3 DPG ↓

• ATP

• Potassium (K+)

• pH

• Lactate

• pO2

• Hb SO2

• Free Hb

• Hb-NO

• CD40L

• ……

Relevance ?

Reversibility

Clinical trials Good enough ?

CD47 expression on RBC

Updated overview

• Observational studies

• Meta-analyses

• RCT’s

Updated overview

• Observational studies

• Meta-analyses

• RCT’s

Pitfalls in RBC storage research

• Dichotomization (<14d vs >14d)

• Oldest unit & #RBC

• “All transfused RBC”

• #Units >“X” days

• ……

≠

} Meta-analyses !

Pitfall-1: Dichotomization

Predefined cut-off value

RBC: ≤14 days vs. >14 days

Example:

Fresh: ≤14 days: 12% complications

Older: >14 days: 30% complications

• Blood should be outdated earlier

• Donation practices should change to

increase #RBC <14d

0%

10%

20%

30%

40%

50%

60%

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Days of storage

Co

mp

lic

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≤14d: 12% >14d: 30%

Pitfall-1: Dichotomization

0%

10%

20%

30%

40%

50%

60%

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Days of storage

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Pitfall-1: Dichotomization

≤14d: 12% >14d: 30%

0%

10%

20%

30%

40%

50%

60%

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Days of storage

Co

mp

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Pitfall-1: Dichotomization

≤14d: 12% >14d: 30%

Pitfall-1: Dichotomization

0%

10%

20%

30%

40%

50%

60%

1 2 3 4 5 6 7 8 9

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Days of storage

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≤14d: 12% >14d: 30%

Using a single predefined cut-off value, like 14 days,

results in NO information on the relevance of this

cut-off value. It may even be the worst possible!

Additional studies using the identical predefined

single cut-off will NOT confirm the importance of this

cut-off value as these studies also carry NO

information on the relevance of this cut-off value

Repeating an error ≠ Correcting it

Pitfall-1: Dichotomization

Van de Watering, Transfusion 2006

Max.age RBC

> 21d

Pitfall-2: Number of RBC and oldest RBC

Oldest RBC

Average of

all RBC

Youngest RBC

Sicker patients have worse prognosis

Always overestimate risk of storage

Scandinavian Journal of Gastroenterology 2000, 35:2 212-217

Need for RBC ≠ storage time !!

Pitfall-2: Number of RBC and oldest RBC

Always overestimate risk of storage

Storage time in non-

transfused patients

Anesthesiology 2003;98: 815-822

Adjusting for the total number of RBC transfused,

all these significant associations with storage time were gone

Always overestimate risk of storage

• Data on all transfused RBC is collected

• Storage time of “oldest” RBC determined

• Oldest RBC related to events?

DVT, infection, MODS, ICU-LOS

Pitfall-3: All transfused RBC

Pitfall-3: All transfused RBC

Fresh event Fresh Fresh

Old event Old Old

Old event Fresh Old

Fresh event Old Old !!

Event: DVT, infection, MODS, ICU-LOS

These events are NOT the end of transfusions

Always overestimate risk of storage

RBC => event => RBC

RBC storage time

Nu

mb

er

of

un

its

Pitfall-4: # units >”X” Days

> X days < X days

X

Am J Surg. 1999; 178: 570-572

RBC storage time

Nu

mb

er

of

un

its

> X days < X days

> X days < X days

# units >”X” Days ≈ Total number of RBC’s

Pitfall-4: # units >”X” Days

“… number of units older than 14 days, and number

of units older than 21 days … independent risk

factors for MOF after controlling for patient age,

base deficit and serum lactate level”

Pitfall-4: # units >”X” Days

Always overestimate risk of storage

Additional RBC are associated with worse prognosis

≠ Storage time

They did NOT adjust for the total number of RBC

transfused !!

# units >0 Days = Total number of RBC’s

Pitfall ..: Adjustment-1 by stratified analysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

1-3

RBC 4-6

RBC 7-10

RBC

Max Δ: 2-3 RBC

Number of transfusions

Nu

mb

er

of

pati

en

ts

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

1-2

RBC 3-5

RBC ≥6

RBC

Max Δ: 1 RBC: NS

Max Δ: 2 RBC: NS

Significance !!

Number of transfusions

Nu

mb

er

of

pati

en

ts

≥3 RBC >14 days

6 or 74 RBC

No adjustment for #RBC >6

Pitfall ..: Adjustment-1 by stratified analysis

Duration of red blood cell storage is associated with increased

incidence of deep vein thrombosis and in-hospital mortality in

patients with traumatic injuries

# RBC matched controls

Missing data !!

# RBC

Yng – Old

8 – 8

10 – 9

11 – 11

22 – 23

42 – 41

43 – 43

X

X

X

X

Pitfall ..: Adjustment-2 by matched controls

N Engl J Med 2008;358: 1229-1239

Pitfall-… : …..…..

Race 0.09

Age 0.05

BSA 0.03

Blood group < 0.001

LV dysfunction < 0.001

NYHA < 0.001

Mitral regurgitation 0.01

Peripheral vascular disease 0.002

Data un-adjusted

for differences in

patient groups

shown in Table 1 !

Newer blood

Older

blood

Comparison of very different patient

groups gives different results !

apples

oranges

Overestimate risk of storage

Updated overview

• Observational studies

• Meta-analyses

• RCT’s

Meta analyses

• Statistical technique to combine results from

several studies on similar topic

• More precise estimate of the effect size

(correction for random error)

Meta analyses

<= Effect size =>

Stu

dy

size

Meta analyses

<= Effect size =>

Stu

dy

size

Meta analyses

Effect size

Stu

dy

size

Meta analyses

Effect size

Stu

dy

size

Consistent over subgroups

Meta analyses

• A statistical technique combining results

from several studies

• More precise estimate of the effect size

(correction for random error)

• The quality of search/included studies

determines the validity of the meta-analysis

Meta analyses

Effect size

Stu

dy

size

Too few studies, too heterogeneous

Updated overview

• Observational studies

• Meta-analyses

• RCT’s

Started “Age of Blood” RCTs

1. NCT00141674 AoB in brain injury (Canada, D Chittock)

<5d vs >20d; Cerebr. O2 extr.ratio 24h post-BT

2. NCT00326924 “ARIPI” (Canada, D. Fergusson)

<7d vs St.; Composite endpoint in premature infants

3. NCT00751322 “TRALI2” (US, O. Gajic / D. Kor)

<6d vs St.; Pulmonal function and immune activation in

mechanically ventilated ICU patients

4. ISRCTN44878718 “ABLE” (Canada, J. Lacroix)

<8d vs St.; 90 day mortality in high risk ICU patients

5. NCT00991341 (01274390) Recess (RECAP) (US, NHLBI)

<11d vs >20d; MODS (O2 saturation) compl.cardiac surgery

6. NCT00458783 (US, C. Koch)

<14d vs >20d; Morbid outcomes < 30d, in cardiac surgery

1. NCT00141674 AoB in brain injury (Canada, D Chittock)

<5d vs >20d; Cerebr. O2 extr.ratio 24h post-BT

2. NCT00326924 “ARIPI” (Canada, D. Fergusson)

<7d vs St.; Composite endpoint in premature infants

3. NCT00751322 “TRALI2” (US, O. Gajic / D. Kor)

<6d vs St.; Pulmonal function and immune activation in

mechanically ventilated ICU patients

4. ISRCTN44878718 “ABLE” (Canada, J. Lacroix)

<8d vs St.; 90 day mortality in high risk ICU patients

5. NCT00991341 (01274390) Recess (RECAP) (US, NHLBI)

<11d vs >20d; MODS (O2 saturation) compl.cardiac surgery

6. NCT00458783 (US, C. Koch)

<14d vs >20d; Morbid outcomes < 30d, in cardiac surgery

Started “Age of Blood” RCTs

Storage time in non-

transfused patients

Started AoB RCTs

1. NCT00141674 AoB in brain injury (Canada, D Chittock)

<5d vs >20d; Cerebr. O2 extr.ratio 24h post-BT

2. NCT00326924 “ARIPI” (Canada, D. Fergusson)

<7d vs St.; Composite endpoint in premature infants

3. NCT00751322 “TRALI2” (US, O. Gajic / D. Kor)

<6d vs St.; Pulmonal function and immune activation in

mechanically ventilated ICU patients

4. ISRCTN44878718 “ABLE” (Canada, UK, F, NL, J. Lacroix)

<8d vs St.; 90 day mortality in high risk ICU patients

5. NCT00991341 (01274390) Recess (RECAP) (US, NHLBI)

<11d vs >20d; MODS (O2 saturation) compl.cardiac surgery

6. NCT00458783 (US, C. Koch)

<14d vs >20d; Morbid outcomes < 30d, in cardiac surgery

NCT00141674 AoB in brain injury (Canada, D Chittock)

Patients: Traumatic Brain Injury; GCS<8; Hb<10 g/dL

Randomisation: <5d vs >20d

Prim. endpoint(s):

Cerebral oxygen extraction ratio, for 24 hours

Status:

Started March 2005

Completed December 2007 (2x 30 patients)

Results not published (yet?)

NCT00326924 “ARIPI” (Canada, D. Fergusson)

Patients: Premature infants (<37 w; <1250 g)

Randomisation: <7d vs Standard

Prim. endpoint(s): Composite outcome:

• Necrotizing enterocolitis

• Intraventricular hemorrhage

• Bronchopulmonary dysplasia

• Retinopathy of prematurity

+ Mortality

Status: Submitted for publication

NO DIFFERENCE

NCT00751322 “TRALI2” (US, O. Gajic / D. Kor)

Patients: Mechanically ventilated ICU patients

Randomisation: <6d vs Standard (single RBC)

Prim. endpoint(s):

• Pulmonary function (∆ Pa02/FiO2)

• Immune activation

Status: Published, 2x 50 patients

Conclusion: In this randomized clinical trial,

no differences were noted in early

measures of pulmonary function or in

immunologic or coagulation status when

comparing fresh versus standard issue

single-unit RBC transfusion

Summary

• In the observational literature there is no consensus

on possible adverse effects of “older” blood

• Many studies have flaw(s) in their design and/or

analyses introducing bias that results in an

overestimation of the association, thereby also

hampering reliable meta-analyses.

•The first results from the RCTs show no differences

• Why adverse associations are mainly reported from

Northern-America remains a mystery, …

Hard spin - soft spin vs Soft spin - hard spin?

SWISSTRANSFUSION

ROCKS

This presentation is now open for discussion