AVANCOS no TRATAMENTO da HEMORRAGIA MACICA

AVANCOS no TRATAMENTO da
HEMORRAGIA MACICA
Sandro Rizoli, MD PhD FRCSC FACS
Professor Associado Cirurgia & Medicina Intensiva
De Souza Trauma Research Chair
Chefe Regiao XII Comite de Trauma
Colegio Americano Cirurgioes
Toronto – Canada
Imigrantes
4 milhoes
6,500 Brasileiros
Bleeding Common Cause of Death
6,000 trauma deaths/year Canada
1% Other
4%
CNS +
Exsanguination
4%Organ Failure
40%
CNS
51%
Exsanguination
& Coagulopathy
Sauaia et al J Trauma 1995;38:185
Trauma Bleeding is Common
Sunnybrook – 1100 traumas/year
30% transfused RBC
4% massive transfusion (50-60 patients)
>50% 3,000U FFP
90% 772U cryo
Massive Bleeding
Familiar to most surgeons
Trauma surgeon – 1ary responsibility
Novel management trauma
UGI bleed – NEJM 2008; 358:178
Post-operative bleeding
Critical Care bleedings
Mediastinal
hematoma
Publication Explosion
Trauma and Blood Transfusion – 1990 - 2010
Avancos Tratamento Hemorragia Macica
1.
2.
3.
4.
Ressuscitacao com formula 1:1:1
Fibrinogenio ao inves de plasma
Protocolos para transfusao macica
Anti fibrinoliticos
Formula driven resuscitation or
1:1:1 – damage control resuscitation
Current Resuscitation - Massive Bleeding
Crystalloid-based resuscitation
Directed by lab
Hg
>70g/L
FFP INR<1.5
Plat >50x109/L
Cryo fibrinogen>1g/L
Limitations
Lack evidence
Treat coagulopathy late
Patients coagulopathic
Poor results (1st cause death)
Damage control resuscitation
FFP 1:1 RBC
Massive bleeding
• Start with blood RBC 1:1 FFP:1 platelet
• Thawed plasma 24/7
• Treat coagulopathy from start
Evidence on FFP 1:1 RBC
Borgman (J.Trauma 2007;63:805)
•
•
•
Retrospective
246 US Military
≥10U RBC/24h (including whole blood)
FFP:RBC
1:8
1:2
1:1
mortality
65%
34%
19%
death by exsanguination
92%
78%
37%
Evidence on FFP 1:1 RBC
Problems
1. Too good to be true: drop mortality 50%
Borgman (J.Trauma 2007;63:805)
• Data quality (retrospective)
• Survivorship bias
FFP:RBC
mortality
1:8
1:1
65%
19%
time to death
2h
38h
Evidence on FFP 1:1 RBC
Problems
1. Too good to be true: bias
Snyder (J.Trauma 2009;66:358)
•
•
Retrospective; 134 patients; ≥10U/24h
Ratio at 24h vs. time-dependent variable
Does 1:1 really
improve survival?
Damage Control Resuscitation
• Initial report = drop mortality
1:1:1
Conventional
Duschene
26%
88%
Maegele
24%
46%
Holcomb
40%
60%
Kashuk
8%
40%
Scalea
No difference
Teixeira
26%
90%
Zink
26%
55%
Median
26%
55% ∆=29%
• USA trauma centers adopted DCR
Evidence on FFP 1:1 RBC
Problems
2. FFP to wrong patients: collateral damage
Inaba K, J Am Coll Surg 2010; 210: 957-65.
1,685 trauma patients given <10 RBC
– 30.6% FFP in 12h
284 matched pairs
2.9U RBC
3.0U FFP
Number needed to harm
12
Sunnybrook Trial
1:1:1 vs. laboratory-guided
Trauma Formula-Driven vs. Lab-Guided
Transfusion Study - TRFL
Jeannie Callum
Barto Nascimento
TRFL – Preliminary Results
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
MT = 40%
17% death
Lab q2h in 100%
ratio 2:1:0.6
MT = 83%
14% death (24h)
Avancos Tratamento Hemorragia Macica
CONCLUSOES:
• Ressuscitacao com formula 1:1:1
Nao descongele plasma por enquanto!
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
– Increase 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%
Avancos Tratamento Hemorragia Macica
CONCLUSOES
• Ressuscitacao com formula 1:1:1
• Fibrinogenio ao inves de plasma
Mesmo grau evidencia que 1:1:1
The pre- and post-MTP studies
Riskin DJ et al Am Coll Surg. 2009 Aug;209(2):198-205.
• Most Centers North America have MTP
• Goal: provide 1:1:1
• Group: Blood Banks + surgeons + OR + ER
• Review 2y before/after MTP implementation
• 4,223 vs. 4,414 patients (>10U RBC)
• 1:1.8 vs. 1:1.8 BUT 45% vs. 19% mortality
• Conclusion: MTP reduces mortality (????)
Military Before, After
Simmons JW, et al. J Trauma 2010; 69: S75-80.
• They were able to change transfusion practice
Miltary Before, After (n=777)
Simmons JW, et al. J Trauma 2010; 69: S75-80.
Militaries successfully managed patients “better”
BUT
P=0.12
Avancos Tratamento Hemorragia Macica
CONCLUSOES
• Resuscitacao com formula 1:1:1
• Fibrinogenio ao inves de plasma
• Protocolos para ressuscitacao
Protocolo nao; prepar reduz mortalidade!
Anti fibrinolytic reduces mortality
CRASH 2 Lancet 2010; 376(9734): 23-32
•
•
•
•
•
20.211 patients in 40 countries
Risk of significant bleeding
1g in 10min + 1g in 8h
4w mortality = 14.5% vs. 16%
Mortality bleeding = 4.9% vs. 5.7%
• Tranexamic acid reduces risk of death
Avancos Tratamento Hemorragia Macica
•
•
•
•
CONCLUSOES
Ressuscitacao com formula 1:1:1
Fibrinogenio ao inves de plasma
Protocolos para transfusao macica
Anti fibrinoliticos
T.A. bom, bonito e barato = vale a pena
Summary
Lots of great ideas, lots of hype,
but no clear winners
• 1:1:1 ou DCR: individualize + goal directed
– Requer plasma descongelado
– Transfunde quem nao precisa
• Fibrinogenio: cedo para mudar
• Protocolos: otima ideia
– Protocolo nao reduz mortalidade
– Preparacao e o mais importante
• Tranexamic: barato, seguro, reduz morte
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
Boffard,
B.Riou, B.Warren
et al. range.
J.Trauma.
2005; 59:8-18
Boffard KD, et al. J Trauma. 2005;59:8-15
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?
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 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%)
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)