Massive Bleeding

A. Prof. Dr. Dietmar Fries

Clinical Division for General and Surgical Critical Care Medicine Medical University Innsbruck, Austria

international collaboration:
Tel HashomerMedical University of TelAviv, Israel US Army, Fort Sam Houston, Texas, USA Coalition Warefare Program - US Army Dept. of Bioengineering, Univ. of San Diego, USA

conflict of interest:
Astra Zeneca, Baxter, Braun, Biotest, CSL Behring, Delta Select, Dade Behring, Fresenius, Glaxo, Haemoscope, Hemogem, Lilly, LFB, Mitsubishi Pharma, NovoNordisk, Pentapharm

Definition: Massive Bleeding

Definitions include: ;Loss of 50% circulating volume in 3 hours ;Loss of greater than 150 ml min-1 ;Loss of whole blood volume within 24 hours NHS 2006

Vicious Circle
coagulopathy

blood loss

hypovolemia

Morbidity/Mortality

transfusion

dilution

Fluid therapy in haemorrhagic shock? Massive Transfusion Protocols Target Controlled Bleeding Management

Evidenced Based Literature (Cochrane Library)

Is the normalisation of blood pressure in bleeding trauma patients harmful ? Roberts I Lancet 2001 ...no evidence for effectivness ... ...resuscitation practice can at best be regarded as experimental Timing and volume of fluid administration for patients with bleeding following trauma. Kwan I 2003 ...uncertainity about the best fluid administration strategy in bleeding trauma patients ... Colloid solutions for fluid resuscitation. Bunn F 2003 ... no evidence that one colloid is more effective or safe than any other ... Hypertonic versus isotonic crystalloid fluid resuscitation in critically ill patients. Bunn F 2002 ...not enough data to be able to say whether hypertonic crystalloid is better than isotonic crystalloid ...

Immediate versus dalayed fluid resuscitation for hypotensive patients with penetrating torso injuries
Bickell W.H. et al. NEJM 1994; 331: 1105-9

n = 598 patients age: 31a 11 systolic blood pressure: 90 mmHg penetrating chest trauma immediate fluid resuscitation (n= 309): 62% survivors delayed fluid resuscitation (n=289): 70% survivors p=0.04 !!!

Statistics: Fisher Exact Test

Survivor
immediate fluid replacement

Non Survivor

193
1 patient

116 86

delayed fluid replacement

203

p=0.04

Statistik: Fisher Exact Test

Survivor
immediate fluid replacement

Non Survivor

193 202

116 87

delayed fluid replacement

p=0.057

Immediate versus dalayed fluid resuscitation for hypotensive patients with penetrating torso injuries
Bickell W.H. et al. NEJM 1994; 331: 1105-9

immediate fluid resuscitation (n= 309): 62% survivors delayed fluid resuscitation (n=289): 70% survivors p=0.04

but : ... 22 patients within the delayed group received fluid 70 patients died before surgery (41/29)

Hypotensive resuscitation during active Haemorrhage: impact on in hospital mortality

Dutton RP: J Trauma (2002) 6:1141
Patients (n=110) with haemorrhagic shock were randomized: 1. target SBP > 100 mm Hg 2. target SBP of 70 mm Hg Fluid therapy was titrated to this endpoint

SBP > 100 mmHg active bleeding (n.s.) death predicted survival actual survival 4 94% 92,7%

SBP = 70 mmHg 2,57 min (n.s.) (n.s.) (n.s.)

2,97 min 4 90% 92,7%

infusion - why?
MAP = CO x SVR DO2: CO x CaO2 CaO2: (Hb x SaO2 x 1,34) + (pO2 x 0,003) improvement of perfusion and peripheral oxygenation

Hypovolemia
blood volume CO and DO2 macrocirculation

septic shock

800 1.000 mL

50 400 mL 500 5.000 mL

vasoconstriction perfusion microcirculation

Endotoxemia
300 2.000 mL

100 1.000 mL

ischemia

MOF

gut, kidney,

increased pT and apTT due to increased BE Increased BE: high thrombomodulin and decreased protein C

Protein C activation due to shock, hypoperfusion

Independent HR for mortality

Early vasopressor

12 h 24 h

Aggressive volume therapy 12 h

24 h
0,5 1,0 5

Independant HR for mortality (95% CI)

Sperry J: J Trauma 2008;64:9

Fluid Compartments and Resuscitation

Compartment Glucose 5% intravascular interstitial intracellular Crystalloid Colloid

Na Plasma 0,9% Saline Ringers Lactate 141 154 131

Cl 103 154 111

K 4-5 2

Ca 5 3

Buffer Bicarb Lactate

pH 7.4 5.7 6.4

British Consensus guideline on Intravenous Fluid Therapy for Adult surgical Patients

Morbidity and survival vs time to correct occult hypoperfusion

100 90 80 70 60 50 40 30 20 10 0 0-6h 7 - 12h 13 - 24h > 24h
Laktatclearance

survival Resp. Kompl MOF

acidosis is associated: cardiac failure, higher morbidity and mortality. Persistent OH is associated higher rates of RC, MSOF, and death. Blow O: J Trauma (1999) 47:964

Fluid therapy in haemorrhagic shock? Yes! Massive Transfusion Protocols Target Controlled Bleeding Management

Bleeding and Coagulation Disorders in Critical Care

1. Massive bleeding consumption coagulopathy 2. Dilutional coagulopathy: - interaction: colloids coagulation fibrinpolymerisation disturbance 3. Hyperfibrinolysis 4. Hypothermia 5. Acidosis 6. Anaemia 7. Thrombocytopenia/-pathia 8. Electrolyte disturbances 9. Drug induced coagulopathy 10. DIC 11. Extracorporeal devices 12. Liver failure 13. .

Fresh Frozen Plasma - Basics

Used for volume replacement since 1941. 25-30% of all ICU patients receive FFP, 50% without reason. retrospective studies: RBC: FFP in a ratio of 1:1 improved survival (?).

Fresh Frozen Plasma

In which indication/situation? How much? 10 15 ml/kg FFP after the 4th RBC 1 : 1 1 : 1 ratio ???
... not evidence based ...!!!

Pro A retrospective analysis from the Trauma Registry of the Deutsche Gesellschaft fr Unfallchirurgie M. Maegele et al. Vox Sanguis 2008
retrospective analysis German Trauma Registry ISS > 16 >10 RBC (ER ICU) n = 484 mean age 40,1 years mean ISS 41

RBC:FFP = 1:1 Sepsis, MOF RBC:FFP < 1:1 ventilator days, ICU- and hospital stay

Ambiguous Crude Complication Rate Comparison for Patients Who Received a High FFP vs. a Low FFP: Transfusion Ratio
70 60 50 40 30 20 10 0 FFP 1 : RBC 1 FFP : RBC<1:1
Sperry J: J Trauma 2008;65:986 p = 0,085 p = 0,008 p = 0,001 p = 0,2
Mortality (%) MOF (%) Nosoc. inf (%) ARDS (%)

Con The Relationship of Blood Product Ratio to Mortality: Survival Benefit or Survival Bias?

retrospective analysis in 134 patients the first unit PRBC: median 18 minutes (1 348 min) the first unit of FFP: median 93 minutes (24 350 min)

Snyder C: J Trauma 2009;66 358

Therefore, it could be concluded that the nonsurvivors in our study population did not die because they got a lower FFP:PRBC ratio; they got a lower ratio because they died
Snyder C: J Trauma 2009;66 358

American Society of Anesthesiologists: Newsletter July 2009

1:1:1 ratio needs more studies there is significant survivor bias use of POC monitoring avoids unnecessary transfusion 1:1:1 ignores the risk of allogenic transfusion known to be dose dependent

optimal ratio of RBC:FFP

Pro 1:1

Ambiguous
Duchesne et al. J Trauma
2008; 65:2726

Con 1:1
Scalea et al. Ann Surg 2008; 248:57884 Kashuk et al. J Trauma 2008; 65:26170 Snyder C J Trauma 2009; 66:35862

Hirshberg et al. J Trauma 2003; 54:45463 Ho et al. Am J Surg 2005; 190:47984 Gonzalez et al. J Trauma 2007; 62:1129 Borgman et al. J Trauma 2007; 63:805 13 Gunter et al. J Trauma 2008; 65:52734 Maegele M Vox Sang 2008; 95:1129 Cotton et al. J Trauma. 2008;64:117782

Sperry et al. J Trauma

2008; 65:98693

Volume expansion and plasma protein clearance during intravenous infusion of 5% albumin and autologous plasma.
Hedin A and Hahn G. Clinical Science 2005;10:217-224

10mL/kg 5% Albumin versus FFP

Albumin PV + 17% Fib -12% AT -16% Plt - 7% PT aPTT FFP PV + 21% Fib + 6% AT + 3% Plt -10% PT aPTT

FFP causes volume expansion and dilution no relevant increase in clotting factor concentrations

Efficacy of standard dose and 30ml/kg FFP in critically ill patients

22 ICU patients with increased apTT, pT FFP 12.2ml/kg vs 33.5ml/kg Clotting factor concentrations before and after administration of FFP in 50%: no therapy necessary 12mL/kg: effect in 20% 30mL/kg FFP: effect in 100%

Chowdhury P. British J Haematol 2004;125:69

Standard coagulation tests and standardized administration of FFP: futile

FFP- effective ?
Is FFP clinically effective? A systematic review of randomized trials. 57 studies: only 5 studies with possible benefit Stanworth SJ BJH 2004 The role of prophylactic FFP in decreasing blood loss and correcting coagulopathy in cardiac surgery A systematic review 6 studies: no effect on blood loss Casbard AC Anaesthesia 2004

Coagulation management with FFP and clotting factor concentrates in severe traumatized patient: CT scan at admission to trauma centre

Coagulation management with FFP and clotting factor concentrates in severe traumatized patient

12 RBC 1 TK 15 FFP FibTEM MCF: 6 mm exTEM MCF: Fibrinogen: 48 mm 232 mg/dL 10 g Fibrinogen 3 mm 27 mm 60 mg/dL 27 mm 61 mm 285 mg/dL

3-fold increase!

Transfusion of FFP Gabe was associated with: VAP with (RR 5.42) and without shock (RR 1.97) septic shock with positive blood culture (RR 3.35) non specified septic shock (RR 3.22) RR for transfusion of FFP and all infections: 2.99 Crit Care Med. 2008 Apr;36(4):1114-1118

Conclusion: no difference in new bleeding episodes new onset acute lung injury was more frequent in the transfused group (18% vs. 4%, p =.021). risk-benefit ratio of FFP transfusion in critically ill medical patients with coagulopathy may not be favorable. Crit Care Med. 2005; 33(11):2667-2671

Each unit of FFP was independently associated with a 2.1% higher risk of MOF and a 2.5% higher risk of ARDS.

Treatment - FFP

Fluid therapy in haemorrhagic shock: Yes! Massive Transfusion Protocols: better than nothing! Target Controlled Bleeding Management?

sequence of critical of clotting factor concentrations :

1. Fibrinogen 2. Prothrombin 3. Factor V 4. Factor VII 5. Platelets Hiippala ST Anesth Analg 1995

critical level of fibrinogen in clinical practice? Charbit B et al.: fibrinogen as an early predictor for severe PPH.
J Thromb Haemost (2007) Gerlach R et al.: postoperative haemorrhage after intracranial surgery and fibrinogen. Stroke (2002) Blome M et al.: fibrinogen and postoperative bleeding in CABG. Thromb Haemost (2005) Ucar HI et al.: Preoperative fibrinogen and postoperative bleeding after open heart surgery. Heart Surg Forum (2007) Karlsson H et al.: plasma fibrinogen level and CABG. Transfusion (2008) Stinger H et al.: high ratio of FI:transfused RBC improved mortality in combat causuality and massive transfusion. J Trauma (2008)

increased bleeding tendency, if fibrinogen level is below 1.5 2.0 g/dL

Critical blood loss - fibrinogen baseline concentration

Singbartl K et al. Anest&Analg 2003
1 0 0 0 0

Maximal Allowable Blood Loss (ml)

7 5 0 0

F iFb i Ib N IN T F iFb i Ib N IN T F iFb i Ib N IN T F iFb i Ib N IN T

I4 T I4 T

54 05 m 0 gm/ dgl / d (H l c ( tH t I4 I N cI T N 54 0 5m 0 gm/ dgl / (dH l c ( tH t I4 I N cI T N 3 0 0 m g / d l ( H c t 4 3 0 0 m g / d l ( H c t I N I T IT IN

5 I T% 4) 5 % ) 0 I T% 4) 0 % ) 5 I T% 4) 5 % ) 2 0 0 m g / d l ( H c t 4 5 2 0 0 m g / d l ( H c t I N I T IT I N I T% 4) 5 % )

5 0 0 0

BL 3.750 ml
2 5 0 0

>2000ml

BL 1.900 ml BL 750 ml
4 0 04 0 0

0 0

1 10 00 0

2 0 2 00 0

3 0 0 3 0 0

F F i ib b P PL LA AS

( M M A A - M- M IN IN S

m g /g d /l d ) l) (m

FI 150 mg/dL: 750 ml or 3.750 ml Critical FI levels may be reached before the need of RBCs!!!

Efficacy of fibrinogen concentrate Author

Danes et al. 2008

Methods
Observational study in 69 patients Retrospective analysis of 9 children with aquired fibrinogen deficiency Retrospective analysis of 43 patients with aquired fibrinogen deficiency Prospective controlled randomized study in 20 patients Controlled prospective randomized study in 20 patients Controlled prospective randomized study in 18 patients Controlled prospective randomized study in 18 patients

Results
Normalisation of coagulation following fibrinogen concentrate Normalisation of coagulation following fibrinogen concentrate

Haas et al. 2008

Fenger-Eriksen et al. 2008

Normalisation of coagulation and reduced transfusion rate following fibrinogen concentrate Normalisation of coagulation and reduced transfusion rate following fibrinogen concentrate reduced blood loss and transfusion rate following fibrinogen concentrate

Fenger-Eriksen et al. 2008

Karlsson M et al. 2008

Rahe-Meyer N et al. 2008 Rahe-Meyer N et al. 2008

reduced blood loss and transfusion rate following fibrinogen concentrate reduced blood loss and transfusion rate following fibrinogen concentrate

recommendation 28: we recommend treatment with FI if significant bleeding is accompanied by TEG signs of functional fibrinogen deficit or a plasma FI level of less than 1.5 2.0 g/l (Grade 1C). We suggest an initial fibrinogen concentrate dose of 3-4g or 50mg/kg. Repeated doses may be guided by TEG monitoring and laboratory assessment (Grade 2C).

With brain injury

Without brain injury

Coagulation Management in traumatized and massiv bleeding patients Task Force for perioperative Coagulation (AGPG) of the Austrian Society for Anaesthesia, Critical Care Medicine and Emergency Medicine (GARI)
1. anaemie: 8 9 (10) g/dL. 2. avoid hypothermia, warm infusion solutions, active warming if possible 3. acidosis: buffer therapy, if coagulation therapy is indicated 2. hyperfibrinolysis: consider the use of tranexamic acid in all kind of massive transfusion 3. platelets: > 50.000 100.000 x103l 4. FFP: patients with severe trauma and coagulopathy will not recover from FFP alone; targeted administration of clotting factors is favorable. 5. fibrinogen: > 1,5 g/dL 2,0 g/dL 6. rFVIIa: if surgery, interventional radiology, packing, etc. fails and only after appropriate coagulation therapy. 7. local hemostyptic wound deressings: QuickClot, Hemcon, Combat Gauze, etc. are much more effective than standard gauze dressing