Transcript Slide 1

The Holy Grail of Trauma
Finding the key to improving survival
Publication Explosion
Trauma and Blood Transfusion – 1990 - 2010
Outline
Improving survivability in trauma
1
Magnitude of the improvement gap
2
Transfusion options
3
The evidence from these options
4
Goal-directed therapy
5
Summary
Evidence for these options
http://www.llf.org.uk/resource/llf_blood_transfusion_jpeg.jpg
How do we quantify the
potential improvement gap?
• Chart and autopsy studies
• Before and after implementation of trauma
systems
• Time to death
• Country comparisons
Preventable Deaths
Esposito TJ, et al. J Trauma. 1995 Nov;39(5):955-62
41 preventable
deaths in
Montana in
1990
Preventable Deaths
Esposito TJ, et al. J Trauma 2003; 54: 663-70
25 preventable
deaths in
Montana in 1998
Preventable Deaths
Davenport RA, et al. B J Surg 2010; 97: 109-117
• Preventable Deaths at Royal London Hospital
before & after implementation of a trauma system
Year
Percent
2004
Preventable
Deaths (P/P)
6
2005
2
0.24
2006
2
0.19
All
10
0.38
0.87
Trauma Systems
MacKenzie EJ, et al. N Engl J Med 2006; 354: 366-78
• Mortality outcomes in 18 trauma hospitals and
51 non-trauma centers in 14 states (18,198
patients)
– Mortality rates – Death in hospital (adjusted):
• 7.6% trauma centers
• 9.5% non-trauma
• Relative risk 0.80 (0.66-0.98)
1.9%
– Subgroup analysis suggested benefit restricted to
those under 55 years of age (or no improvement in
the ‘elderly’)
Survivability in Trauma
Twijnstra MJ, et al. Ann Surg 2010; 251: 339-43.
• Trauma patients treated in the Netherlands
before and after implementation of a trauma
system (n=68,041)
– Mortality rates – Death in hospital:
• 2.6% before
• 2.3% after
• Relative risk 0.89 (0.80-0.98)
0.3%
– Adjusted OR – 0.84 (0.76-0.94)
– Subgroup analysis – trauma system appeared to
assist the less severely injured and elderly patients
35% died in the 1st 15 min
When do patients die in the first 24 hrs?
Acousta JA, et al J Am Coll Surg 1998; 186: 528-533
Resuscitation Outcomes Consortium
Minei JP, et al. Ann Surg 2010; 252:149-157
10 of 437 (2.3%) deaths deemed preventable
Nothing at the scene has changed in 30 years
Baker CC, et al. Am J Surg 1980; 140:144-150
53%
Country comparisons
Christensen MC et al. J Trauma 2010; 69: 344-352
Bottom line?
0.3-6% of all trauma deaths
might be preventable
(and a subgroup of these might be
salvageable with transfusion strategies)
Incidence of Injury in USA
2009 CDC Statistics
• 36.8 million ‘injuries’ in 2009
– 122/1000 population
• 182,479 deaths
– 60.5/100,000
• If 1% preventable…
– And half of the deaths ‘transfusion-related’…
– 913 deaths might be preventable with better
transfusion support
Prevention – Seat Belts
Thoma T. Ann Emerg Med 2009; 54: 837-839
5,024 more lives
saved with 100%
coverage
1,652 more lives saved
with 90% coverage
15,147 lives saved in
2007 with use at 82%
22,523 gun licenses refused or revoked between 1999 and 2008 from
individuals deemed a potential risk to themselves or to others
Prevention – Gun control
People don’t kill people, guns kill people
1 in 100 U.S. Adults Behind Bars, New Study Says
NY Times Feb 28, 2008
Prevention – Gun control
Guns don’t kill people, people kill people
Outline
Improving survivability in trauma
✓
1
Magnitude of the improvement gap
2
Transfusion options
3
The evidence from these options
4
Goal-directed therapy (my option)
5
Summary
Evidence for these options
http://www.llf.org.uk/resource/llf_blood_transfusion_jpeg.jpg
Non-transfusion Options that work
Transfusion is not the only option
Scoop and Run
1
RCT published in the NEJM in 1994 showed a 8% absolute
increase in survival for penetrating traumas
Insurance
2
Insurance at the time of gunshot injury translates into a 3%
absolute decrease in mortality
Trauma Systems
3
The implementation of organized trauma systems translates
into a 1.9% absolute increase in survivability
Bickell et al. NEJM 1994; 331: 1105-9
Dozier KC, et al. J Am Coll Surg 2010; 210: 280-5.
MacKenzie et al. N Engl J Med 2006; 354: 366-78
Women
Rule
Bullard MK et al, Surgery. 2010 Jan;147(1):134-7.
“We propose that the administration of exogenous
estrogen will improve outcomes after injury and
hemorrhage”
“Imagine the …possible benefits to early estrogen
administration in a testosterone-laden biker,
screaming obscenities in your trauma bay.”
Non-transfusion options that don’t work
The senior surgeon
1
A study from Johns Hopkins Hospital found no improvement in
survival when they compared novice surgeons to experts
Transport speed
2
A study from 10 trauma hospitals in North America found no
improvement in survival with faster transport times
Resident working hours
3
Restriction of resident working hours did not improve outcomes
Haut ER, et al. Arch Surg 2009; 144: 759-64
Newgard CD, et al. Ann Emerg Med 2010; 55:235-46
Helling TS, et al. J Trauma. 2010: 69:607-12
Transfusion Options
What should you put in the box?
1
Recombinant factor VIIa
2
W
Formula resuscitation
3
Fresh blood
4
Fresh warm whole blood
5
6
ABO identical plasma
Fibrinogen concentrates
http://ecx.images-amazon.com/images/I/31H6wFfIl7L._SL500_AA300_.jpg
RESIDENT
ResidentGUIDANCE
guidance RECOMMENDED
suggested
FOR WACKY STATISTICAL METHODS
1st RCT rVIIa
• Conclusion: Recombinant FVIIa
resulted in a significant reduction in RBC
transfusion in severe blunt trauma. Similar
trends were observed in penetrating
trauma. The safety of rFVIIa was
established in these trauma populations
withinKDthe
investigated
dose
range.
Boffard,
B.Riou, B.Warren
et al. J.Trauma.
2005; 59:8-18
Boffard KD, et al. J Trauma. 2005;59:8-15
Trial Design
Boffard KD, et al. J Trauma. 2005;59:8-15
Arrival
Trauma at ER
Randomisation
8
Transfusion
(units RBC)
n=301
0
6
rFVIIa
Placebo
2 studies
(Blunt &
Penetrating)
200 ug/kg 0
100 ug/kg 1
100 ug/kg 3
No Effect on Transfusion Rate
Boffard KD, et al. J Trauma. 2005;59:8-15
RBC
Control
RBC
R7a
Blunt
7.2 u
7.8 u
Penetrating
4.8 u
4.0 u
* p=0.07
Exclude patients who bled to death in
the 1st 2 days?
Survival (not ITT)
Boffard KD, et al. J Trauma. 2005;59:8-15
Recombiant Factor VIIa - CONTROL
Hauser CJ, et al. J Trauma 2010; 69: 489-500
• Prospective, randomized, double-blinded,
multicenter trial (150 hospitals in 26
countries)
– 3 doses r7a 200/100/100 ug/kg - $30K
– Up to age 70
– Still bleeding with shock/hypotension/acidosis
after 4 units RBC
Recombinant Factor VIIa - CONTROL
Hauser CJ, et al. J Trauma 2010; 69: 489-500
• Powered to detect a 16.7% mortality
reduction assuming a 30% baseline mortality
• Planned interim analysis
• Stopped early due to high likelihood of futility
• 573 enrolled, 560 dosed, 554 in ITT
• No difference in mortality (11% vs 11%)
Recombinant Factor VIIa - CONTROL
Hauser CJ, et al. J Trauma 2010; 69: 489-500
• Does r7a prevents FFP transfusion
which prevents RBC transfusions?
Safety Profile n= 4119
Levi M, et al. NEJM 2010; 363: 1791-1800.
• Arterial TE events were more common in
r7a treated patients OR 1.68 (1.2-2.4,
p=0.003)
– Risk attributed to patients over 65 years
– 65-74 yrs – OR 2.12 (0.95-4.71, p=0.07)
– >75 yrs – OR 3.02 (1.22-7.48, p=0.02)
What about formula driven
resuscitation or 1:1:1 or DCR?
Iraq 2003-2005
Borgman et al. J Trauma 2007; 63: 805-813.
• >10 units of blood (RBC/whole blood) in 24 hrs
– This type of trial design may excluded severely injured patients
who died before #10
• Divided patients into 3 groups based on similar ratios of
FFP:RBC and mortality
• Analyzed to determine the effect of the FFP:RBC ratio on
mortality
• Transfusion protocol not disclosed
• Between 2003-05 – 5,293 admitted of whom 246 (4.6%)
were included
• 95% penetrating trauma
Not much
Medium
Lots (1:1.4)
N=31
N=53
N=162
Thorax injury
26%
9%
7%
Hemoglobin
94
108
109
Base deficit
13
9
8
Heart rate
122
118
111
sBP
90
98
97
Crystalloid
1.8 L/hr
0.6
0.5
RBC
4 units/hr
0.9
0.8
Plasma
2
6
12
Plasma
0.1 unit/hr
0.3
0.6
Factor 7a
16%
26%
36%
Variable
Outcomes
Borgman et al. J Trauma 2007; 63: 805-813.
Variable
Not much
Medium
Lots
n
31
53
162
Mortality
65%
34%
19%
4 hrs (2-16)
1.6 days (4 hours
– 6.5 days)
18
31
Median time 2 hrs (1-4)
to death
Number of 20
deaths
Their conclusion
Borgman et al. J Trauma 2007; 63: 805-813.
• High FFP:RBC ratio results in a 55% absolute
risk reduction in mortality!
– High FFP:RBC ratio decreased the hourly transfusion
rate
QUOTABLE
“If you want to get people
to believe something
really, really stupid, just
stick a number on it.”
Author Charles Seife
Proofiness: The Dark Arts of
Mathematical Deception
Other Retros
Study
Duchesne
n
135
Highest FFP
26%
Lowest FFP
88%
Maegele
Holcomb
Scalea
713
466
250
24%
40%
No difference
46%
60%
Kashuk
Sperry
Teixeira
Zink
133
415
383
466
8%
28%
26%
26%
40%
35%
90%
55%
55%
Median 26%
Delta 29%!
Of course, same goes for platelets
Inaba K, et al. J Am Coll Surg 2010; 211: 573-9.
Different patients:
Total
Low
Med
High
V High
sBP<90
31%
40%
19%
33%
25%
GCS<8
31%
45%
27%
28%
26%
Different outcomes:
Snyder – Confirms survivorship bias
J Trauma 66:358-364, 2009
• 2 way analysis:
(1)the effect of the ratio at 24 hours on outcome
(2)the effect of the ratio on outcome in a timedependent analysis
• 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!
Snyder - Alabama
J Trauma 66:358-364, 2009
0.37;0.22-0.63
0.84, 0.47-1.50
Indication Creep
Mell MW, et al. Surg 2010; 148: 955-62.
• Ruptured AAAs between 1987 and 2007
(note: pre 1:1 paper by Borgman)
• Includes 128 patients transfused >10 units
• Transfusion at the discretion of the MDs
• Volume of FFP did not impact survivability
• In multivariate analysis, ratio of FFP (<1:2)
resulted in a 4-fold increased risk of death
• Only possible mathematical conclusion –
more RBCs = more deaths
FFP
RBC
http://www.learningradiology.com/caseofweek/caseoftheweekpix/aneurysmrupture2.jpg
The pre- and post-MTP studies
• Another way to look for effects on outcomes
• Unfortunately:
– Selection bias results in different patients
between the two groups
– Not the same time period – other changes to
care have occurred
Military Before, After
Simmons JW, et al. J Trauma 2010; 69: S75-80.
• They were able to change transfusion practice
Military Before, After
Simmons JW, et al. J Trauma 2010; 69: S75-80.
• Formula-driven resuscitation was associated
with an increased risk of MT despite no
differences in baseline characteristics
Military Before, After
Simmons JW, et al. J Trauma 2010; 69: S75-80.
• They successfully managed patients “better”
–
–
–
–
–
–
–
–
Warmer on arrival (96.5 to 98.2°F)
Less crystalloid exposure in first 12 hours (14 vs. 9 L)
More FFP (8 to 14 U)
More platelets (1 to 2 U)
“Better” ratio (0.54 to 0.76)
Faster transport
CAT-tourniquet for every soldier
New medic resuscitation guidelines
Miltary Before, After (n=777)
Simmons JW, et al. J Trauma 2010; 69: S75-80.
P=0.12
TRFL – Pilot Feasibility Study
35 patients - 16 months
3 excluded
32 patients
1:1:1 = 18 patients
Lab = 14 patients
1:1:1 in 75%
ratio 1.2:1:1
17% death
Lab q2h in 100%
ratio 2:1:0.6
14% death (24h)
Fresher Blood in Trauma
Spinella et al. Crit Care. 2009;13(5):R151.
• Retrospective cohort 2004-07 of trauma
pts admitted to ICU, civilian
• Patients transfused ≥5 RBC units during
admission
– Compared: <27 days vs. >28 days
• Matched by RBC Tx (+/- 1 unit)
• Primary outcomes were deep vein
thrombosis and in-hospital mortality (?)
Fresher Blood in Trauma
Spinella et al. Crit Care. 2009;13(5):R151. Epub 2009 Sep 22.
• 270 patients identified of whom only 202
(75%) could be matched
– Patients receiving ‘older’ blood were more
likely to have blunt injury (96 vs. 89%)
• RBC storage age:
– Maximum -19 vs. 34 days
– Median - 14 vs. 20 days
Fresher Blood in Trauma
Spinella et al. Crit Care. 2009;13(5):R151. Epub 2009 Sep 22.
Survived (%)
(n=161)
Died (%)
(n=41)
78%
(56/72)
22%
(16/72)
79%
(30/38)
21%
(8/38)
83%
(10/12)
17%
(2/12)
81%
(65/80)
19%
(15/80)
Fresher Blood in Trauma
Spinella et al. Crit Care. 2009;13(5):R151. Epub 2009 Sep 22.
12.8%
Fresher Blood in Trauma
Spinella et al. Crit Care. 2009;13(5):R151. Epub 2009 Sep 22.
Young vs. Old
Weinberg JA, et al. J Trauma 2008; 65: 794-798.
• 430 transfused trauma patients over 7 years
• ‘amount’ of young vs old (>14 days) RBC
comparison
Warm fresh whole blood
Why might WFWB be better?
Spinella PC, et al. J Trauma 2009; 66: S69-76.
Spinella PC. Crit Care Med 2008; 36: S340-45.
• Reduce storage lesion
• Improves cardiac
output
• Improves
microcirculatory
hemodynamics
• Improves O2
consumption
• Already in ‘right’ ratio
•
•
•
•
•
•
Warmer
More concentrated
More ‘functional’
Less additives
Less anticoagulants
Corrects
coagulopathy more
efficiently
• Decreases mortality
Warm Fresh Whole Blood
Morel N, et al. J Trauma 2010; 68: 1266-7.
• Damage control resuscitation using warm
fresh whole blood: a paramount role for
leukocytes and derived microparticles in the
prevention of coagulation abnormalites
• Transfusing functional white blood cells is
one of the singularities of WFWB!!
Warm Fresh Whole Blood
Spinella PC et al. J Trauma 2009; 66 (4 Suppl): S69-S76
• Jan 2004-October 2007, retrospective
– WFWB + RBC, FFP (but not PLT)
– vs. components only
• Outcome – 24 hr and 30 day mortality
• Well matched – except WFWB patients
were colder on arrival (earlier cohort)
• Use of WFWB decreased over time – why?
Warm Fresh Whole Blood
Spinella PC et al. J Trauma 2009; 66 (4 Suppl): S69-S76
Spinella PC. Crit Care Med 2008; 36: S340-45
• Missing whole blood unit recipients
– This paper: 100 patients x 5 Units (median)
= about 500 units
• 2008 review by same author quotes
more than 6000 units transfused
• Who got the other 5500 units?
Warm Fresh Whole Blood
Spinella PC et al. J Trauma 2009; 66 (4 Suppl): S69-S76
Fresh Warm Whole Blood
Spinella PC et al. J Trauma 2009; 66 (4 Suppl): S69-S76
Key words in the discussion on the
limitations of the study…
“…because of the time required to initiate
and collect WFWB…”
ABO-identical plasma saves lives
Inaba K, et al. Arch Surg 2010; 145: 899-906
• Retrospective analysis of transfused
trauma patients, 2000-2008
– Between 2000 and 2008, the use of ABO-nonidentical plasma increased 200%
– Propensity matching required
• 10 units of group O plasma, 8 units of
group A plasma, and 8 units of group B
plasma thawed at all times
ABO-identical plasma saves lives
Inaba K, et al. Arch Surg 2010; 145: 899-906
ABO Group (%)
• A
• B
• O
ISS Score
AIS >2 (%)
• Chest
• Abdomen
ABO-Compat
ABO-Identical
12
4
84
26
35
14
52
23
48
44
38
35
Whatever it was, it was not random!
ABO-identical plasma saves lives
Inaba K, et al. Arch Surg 2010; 145: 899-906
• Why would any group O patient ever get
non-identical plasma at their center?
1) Early in the time period there was no thawed
plasma and rapidly bleeding patients were
transfused a few units of AB plasma until the
blood group was processed (sicker & earlier
time period)
2) These patients were bleeding so fast that
they depleted the group O inventory (sicker)
ABO-non-identical plasma harms 1 in 8!
ABO-identical plasma saves lives
Inaba K, et al. Arch Surg 2010; 145: 899-906
Same patients as Borgman paper…same number…same time…same place
Fibrinogen:RBC Ratio
Stinger HK, et al. J Trauma 2008; 64: S79-85
Variable
Low F:R (52)
High F:R (200)
F:R ratio (g/unit)
RBC
FWB
Cryoprecipitate
FFP
Mortality
Death from Bleed
0.1
16
0.6
0.8
3.5
52% (27)
85%
0.5
16
3
9
11
24% (42)
44%
Fibrinogen Concentrates
The next trend?
16 grams
9 grams
12 grams
Acta Anaesthesiol Scand. 2010;54:111-7. Epub 2009 Oct 26
Anaesthesia. 2010;65:199-203. Epub 2009 Nov 30
Scand J Clin Lab Invest. 2010;70:453-7
Fibrinogen as per FIBTEM
Schochl H et al. Critical Care 2010; 14: R55
• Retrospective analysis of trauma patients
transfused >5 u/24 hours
• They use ROTEM to decide what to give
– Increased FIBTEM MCF – 2-4 g fibrinogen
– Increased EXTEM MCF– Platelets
– Increased EXTEM CT – PCC 1000-1500 IU
– When do they give FFP?
Fibrinogen as per FIBTEM
Schochl H et al. Critical Care 2010; 14: R55
• N=149 patients over 4 years RBC>5/24
– Excluded 15 that died in <60 min and 3 that got
nothing but RBC
– Severely injured – mean ISS 38
– Median 10 RBC/24 hours
– Only 3/131 did NOT get fibrinogen concentrates!
(median 7 g/24 hours) – 0.8g:RBC
– 30 treated with PCC, 21 FFP, 29 platelets!
– Predicted mortality 34%, observed 24%
Theusinger OM et al. Curr Opin Anesth 2009; 22: 305-12.
Outline
Improving survivability in trauma
✓
✓
✓
1
Magnitude of the improvement gap
2
Transfusion options
3
The evidence from these options
4
Goal-directed therapy
5
Summary
Evidence for these options
http://www.llf.org.uk/resource/llf_blood_transfusion_jpeg.jpg
Goal Directed Therapy
The individualized approach
A
B
ONLY RBCS
CBC, INR, fibrinogen q1h
RBCs <10 and surgical
control planned
CBC, INR, fibrinogen q1h
LAB DRIVEN
CBC, INR, fibrinogen q1h
C E=mc2
E=mc2
No bleeding =
No components
Predicting who will need massive transfusion
Cotton BA, et al. J Trauma 2010; 69: S33-9.
• ABC Score >2 = 85% chance of MT
Variable
Yes
Penetrating
SBP<90
HR>120
+FAST
✓
✓
✓
3
No
X
TASH-score updated
Maegele M, et al. Vox Sang 2010; Aug 24: epub
Unmatched RBC predicts
Nunez TC, et al. Transfusion 2010; 50: 1914-20
Inaba K et al. J Trauma 2008; 65: 1222-6
• Independent predictor of MT
1. 27.8% of patients receiving unmatched went
on to receive 10 U or more in the first 6
hours (vs. 5.3% of those that did not)
2. 29.3% of patients receiving unmatched went
on to receive 10 U or more in the first 12
hours (vs. 1.8% of those that did not)
3. My hospital – 26% vs. 1.8%
Harm to patients who do not require
massive transfusion
• 1,685 trauma patients transfused <10 RBC
– 30.6% received plasma in first 12 hours
– Half had an ISS>25
• 284 matched pairs identified
– 2.9 U RBC over first 12 hours
– 3.0 U FFP for the plasma group
– Groups were well matched
Inaba K, et al. J Am Coll Surg 2010; 210: 957-65.
Number Needed to Harm = 12
Collateral Damage
Harm to patients who do not require massive transfusion
Inaba K, et al. J Am Coll Surg 2010; 210: 957-65.
My favorite quote
Morley SL. Arch Dis Child Educ Pract Ed 2010; epub
“Until more data are available, caution
should be exercised in using fixed ratios of
blood components for all except early
resuscitation of the most severe trauma
cases as all blood products carry risk that
may outweigh therapeutic benefit if used in
excess”
My favorite quote
Morley SL. Arch Dis Child Educ Pract Ed 2010; epub
“Such strategies should also be regarded as
‘resuscitation’ in the most acute sense and
as soon as hemorrhage is controlled and
the patient’s clinical status has stabilised,
then titration of products based on blood
testing should be re-instituted to reduce
the risk of overtransfusion.”
Summary
Lots of great ideas, lots of hype,
but no clear winners in this quest
• 0.3-6% of all trauma deaths may be preventable
(some with transfusion)
– We might be at the end of the journey for improving
survival in trauma
• No clear successes to date: rVIIa, 1:1:1, fresh
blood, WFWB, ABO-identical or fibrinogen
concentrates
• Stick with an individualized goal-directed
approach until RCTs show us a better way