Transcript G - Transfusion medicine

The Massive Transfusion
Protocols are coming!
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Okay, okay
2 years too late
Outline
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Why did we not see this coming?
 What was the consequence of not
recognizing the rush to MTP before it got
here?
 3 TMR reviews on MTP reports from 2009
 Discussion of potential trial design for
transfusion support in trauma

 What
two transfusion arms should be
compared?
Was their an early warning that trauma programs were
going to take up 1:1 resuscitation?
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Discussed in every coffee line up for a
month at my hospital
Stopped in the hallway by trauma and
anesthesia
1st paper presented at city-wide resident
trauma rounds
Discussed at trauma, anesthesia, and ICU
rounds
A few hospitals implemented them – their
transfusion medicine clinicians must have
known
Did they think they were the only ones so
the impact was going to be small?
Why did none of us have the foresight to
pull the alarm?
What were the consequences of implementing MTP before
the evidence was out and we were ready?
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
Increased use of AB plasma (clinician and protocol
driven)
 Inventory
issues for hospitals and CBS not addressed
before the shortage happened
 Safety issue – AB plasma used for non-AB patient
when thawed for a trauma and not used
 Is
all AB plasma male-only?
 Are these innocent bystanders taking a risk they have not
consented to?
 Increase
in ‘thawed not used’ wastage?
Femme Fatale
Which group do you want?
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100
90
80
70
60
Male
Female
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40
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10
0
O
A
B
AB
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Issues of AB plasma by month for the last 4
years in Canada
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AB Plasma Units Shipped to Hospitals by Month
1,950
1,750
950
750
50% increase
1,550
1,350
1,150
Publications
On 1:1
What were the consequences of implementing MTP
before the evidence was out?
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
Clinician confusion
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In the middle of a trauma I
was paged and asked
should they adopt 1:1 for
the current case because of
the paper this month in J
Trauma
The patient is CT with a
rapidly expanding
retroperitoneal bleed
This is not the time to
implement a new protocol!
Why did clinicians jump so fast?
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Was it the remarkable 55% reduction in trauma deaths so
appealing that we failed to see that such a benefit was
impossible?
Do clinicians find that it is so difficult to get laboratory
numbers that this was an answer to poor TAT and lack of
POC testing?
Do clinicians have problems remembering the transfusion
rules – ordering a ‘box’ is nice and easy
Was it a Paul Revere type that quickly convinced his/her
colleagues to change?
Paul Revere & William Dawes
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How does communication spread?
Paul Revere – ‘midnight ride’ to north of Boston to
Lexington
 Mobilized
the entire militia so that when the British
started their march the next morning they were ready
and waiting

William Dawes – ‘midnight ride’ to the west of
Boston to Lexington
 He
was unable to convince anyone to mobilize despite
carrying the same message
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Why did we not get on the phone to
CBS and NAC immediately?
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
NAC should have addressed this with the first
publication
I
take full responsibility! I failed to make this call too.
 A discussion should have taken place with transfusion
medicine specialists and the trauma society - to review
the studies and make a recommendation jointly

CBS should have been told how much more plasma
we were going to need
 We
have good trauma registries – we could predict
how much extra AB we would need
 A letter of concern should have gone out to the trauma
surgeons to let them know the gender distribution of AB
plasma – Do they know there is an increased risk of
TRALI?
We will never see everything coming
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Alternatives to ‘thawed plasma’
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Instead of thawed AB
plasma waiting for a
trauma
 Microwave
devices?
 Thawed A plasma
(works for O and A
patients)?
 Early warning from EMS
for a bad trauma?
This is not the first (and certainly will
not be the last) blind-side
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Recombinant factor VIIa
 One
case report in the Lancet and we were off and
away
Factor VIIa – meta-analysis
Arch Surg 2008; 143: 296-304
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Is there any other problem on the way?
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Inappropriate use of PCCs?
Topical use of buffy coats (macrophages) for wound
healing?
Epidemic spread of albumin use in ICUs?
Dropping pentaspan use completely?
Who should be on the look out and in what forum
should these matters be discussed (quickly)?
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Impact of plasma transfusion in massively transfused
trauma patients. P.G.R. Teixeira, K. Inaba, I. Shulman et
al. J Trauma 66:693-697, 2009
Richard Haspel’s choice
Teixeira et al. 2009
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Of 25,599 patients admitted to a single center from
2000-2005, 383 received >10 U/24 hours and
did not have severe head injury
Primary endpoint: In-hospital mortality
Teixeira et al. 2009
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To identify if FFP:RBC ratio was independently associated with survival,
in a stepwise logistic regression model:
 # variables in any model = 1 variable per 8-10 outcomes (deaths)
 Number of outcomes allowed = 16 variables
 Multivariate = 14 variable
 Choose all with p<0.20, not <0.05
 We are not told the # that they tested in univariate
FFP:RBC ratio was maintained as a continuous variable for the
multivariable model because a clinically relevant cut-point is not currently
established
 AdjOR were derived to identify the optimal FFP:PRBC ratio that would
have an impact on survival
Patients classified into 4 clinically relevant! groups according to ratio: low
(1:8), medium (1:8-1:3), high (1:3-1:2), & vhigh (1:2)
Teixeira et al. 2009
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1.5% of patients!
Teixeira et al. 2009
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Overall mortality
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Limitations
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No start time of products
 Used ratio at a fixed point at the 24 hour mark (as though
everyone made it to this point)
 The transfusion data in their trauma registry was highly
inaccurate when compared with their blood bank database!
Shocking news!
 Begs the question of how much inaccurate data obtained
through registries have been recently published in other 1:1
reports
No disclosure of trauma protocol – did their patients get
thawed plasma on arrival in the trauma room?
No coagulation testing available in the report
Included ‘unmatched’ blood as a risk factor for death???
Most important factors predicting
in-hospital death
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Factor
GCS <8
Vented @ER
Unmatched
ISS>16
sBP<90
Mortality
82 vs 30%
78 vs 33%
47 vs 13%
47 vs 16%
65 vs 33%
P
<0.001
<0.001
<0.001
<0.001
<0.001
Note: ratio not included in this table for univariate
OR
10.5
7.0
5.8
4.7
3.8
Logistic Regression
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ie. if you can get FFP
into patients they ALL
live!
Their conclusion
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The conclusions presented, however, add to the
growing evidence suggesting that a more proactive
and liberal approach regarding FFP replacement
should be considered as part of the resuscitation of
severely injured bleeding patients
No benefit of resuscitation >1:3 ratio
Rich’s conclusion
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No time analysis – is this survivorship bias?
 Do
the findings represent true cause and effect or do
they simply reflect the fact that if someone lives long
enough, they are more likely to receive plasma
transfusions?
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Changing practice overtime – what else was
changing?
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A high ratio of plasma and platelets to packed red blood
cells in the first 6 hours of massive transfusion improves
outcomes in a large multicenter study. Karen A. Zink,
Chitra N. Sambasivan, John B. Holcomb, Gary Chisholm,
Martin A. Schreiber.* Am J Surg 197, 565-570, 2009
Sunny Dzik’s choice
Zink et al 2009
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Multicenter, retrospective analysis was performed at
16 level 1 trauma centers
Injured between July 05-June 06 who received any
RBCs within 24 hours
All patients who died within 30 minutes of arrival to
ER were excluded (n=1!)
Blood products received from admission to the
emergency room (0–6 & 6–24 hours)
1,489 patients who received at least 1 U of RBCs,
including 466 massive transfusion patients (>10)
Zink et al 2009
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The study data were assessed for differences in
outcome based on the ratio in the first 6 hours
Compared low, medium, and high ratios of FFP:RBCs
and PLTs:RBCs, specifically at ratios of 1:4, 1:4 to
1:1, and 1:1.
Primary outcome - in-hospital mortality
Secondary outcomes - mortality at 6 hrs, overall
RBCs transfused in first 24 hours, and vent-free
days
Zink et al 2009
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Zink et al 2009
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Note: Niagara Falls
Note: Parallel
Zink et al 2009
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Their conclusion
is associated with
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The early administration of high ratios of FFP and
platelets improves survival and decreases overall
PRBC need in massively transfused patients.
The largest difference in mortality occurs during the
first 6 hours after admission, suggesting that the
early administration of FFP and platelets is critical.
Sunny’s conclusion
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Survivorship bias: grouping patients based on ratio
data - those receiving the most RBCs would, by
definition, be more likely to have a low ratio of FFP
to RBC
Don’t rush to MTP: To keep the door open for such a
much-needed trial, the medical community will do
well not to rush to conclusions regarding blood
ratios.
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The relationship of blood product ratio to
mortality: survival benefit or survival bias.
C.W. Snyder, J.A. Weinberg, G. McGwin et al.
J Trauma 66:358-364, 2009
My choice
Synder et al 2009
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The authors sought to control for survivorship bias
by controlling for the timing of the FFP transfusion in
retrospective cohort study of severely injured
trauma patients
2 way analysis: (1) the effect of the ratio at 24
hours on outcome and (2) the effect of the ratio on
outcome in a time-dependent analysis
Previous reports have been unable to perform such
an analysis because of the start time of transfusion
being absent in the trauma databases
Synder et al 2009
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Identified all trauma patients who received 10 or
more RBC in the first 24 hours
Physician reviewers “detectives” searched each
chart to find the start time of each component
We are not told the percentage of “missing” times
Start times were verified with issue times from the
blood bank information system
Synder et al 2009
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Divided patients into low ratio (<1:2) and high ratio
(≥1:2) groups at 12 periods for the first 24 hours
(every 30 mins for the first 2 hrs, hourly from 2-6
hrs, and every 6 hrs until 24 hrs)
Transfusion policy: blocks of 6 RBCs and 4 FFP,
although the FFP was not kept thawed in
anticipation of a trauma patient
Synder et al 2009
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Median time to the first RBC and first FFP was 18
and 93 minutes, respectively
The start times for the first FFP ranged from 24 to
350 minutes!
Using the ratio at 24 hrs as a fixed point, a high
ratio was associated with a statistically significant
risk reduction in death (odds ratio, 0.37;0.22-0.63)
In contrast, in their time-dependent analysis, a high
ratio was not associated with a reduction in
mortality (0.84, 0.47-1.50)
When do patients die in the first 24 hours?
Acousta JA, et al J Am Coll Surg 1998; 186: 528-533
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Synder et al 2009
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Synder et al 2009
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At 60 to 90 minutes into resuscitation: 83% of
patients were in the low ratio group
By 6 hours, 47% were in the high ratio group
What to look for in MTP papers
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Design
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Quality of data
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Inclusion criteria - % of total registry/database
Retrospective? – registry vs. single centre?
What variables are missing?
Where do the transfusion records come from?
Timing of the blood products – available?
Controlling for survivorship bias – time dependent?
Transfusion protocols – disclosed?
Control for changes in practice over time – is the date of
injury a variable?
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If you were going to design a
prospective randomized controlled
trial what would be the two arms?
Translation: Jeannie wants free advice!
Arm 1: Formula
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Ratio? 1:1 or 1:2
Include platelets as well in the formula? 1 pool per
4 RBCs?
Cell salvaged units: how does the blood bank adjust
the units they are releasing for salvaged RBCs? Or
just ignore them?
Thawed plasma vs. immediate thawing
Buy a microwave?
Arm 2: Control
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
Just issue what they ask for?
 What
about MDs that have already adopted 1:1
practice – risk of contamination

Issue 1:2 for FFP – ie. compare two set ratios
 Then
let them ask for ‘top-up’ FFP and platelets based
on laboratory results
Thanks!
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