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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• Blood should be outdated earlier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%
1 2 3 4 5 6 7 8 9
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Days of storage
Co
mp
lic
ati
on
ris
k
≤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
Co
mp
lic
ati
on
ris
k
Pitfall-1: Dichotomization
≤14d: 12% >14d: 30%
0%
10%
20%
30%
40%
50%
60%
1 2 3 4 5 6 7 8 9
10
11
12
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15
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Days of storage
Co
mp
lic
ati
on
ris
k
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
10
11
12
13
14
15
16
17
18
19
20
21
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25
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Days of storage
Co
mp
lic
ati
on
ris
k
≤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