Acute Traumatic coagulopathy

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Outline the implication of acute traumatic coagulopathy to massive transfusion protocol

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Acute Traumatic Coagulopathy Implication to Massive Transfusion Protocol for TraumaAnd Intensive Care Management : 

Acute Traumatic Coagulopathy Implication to Massive Transfusion Protocol for TraumaAnd Intensive Care Management Dr. Lai Kang Yiu Intensive Care Unit Queen Elizabeth Hospital

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2003 Transfusion Protocol for Trauma

Worldwide, 1 in 7 deaths is due to injury, and this is expected to rise to 1 in 5 in the next 15 years, despite advances in resuscitation, trauma surgery, and critical care. : 

Worldwide, 1 in 7 deaths is due to injury, and this is expected to rise to 1 in 5 in the next 15 years, despite advances in resuscitation, trauma surgery, and critical care. Injury Chart Book Geneva: World Health Organization 2003

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Haemorrhage is the major potentially treatable cause of death in the initial 24 hours Trimodal Death Distribution

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Massive blood transfusion (> 10U of PRBC w/i 24 hoursand not accounting for other blood component therapy), carries a mortality rate between 20-50%, with most patients dying within 6-12 hours of hospital arrival.

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Activation of the anticoagulant protein C pathway by elevated thrombomodulin Hyperfibrinolysis Massive Blood Loss Replacement of patient’s blood volume within 24 hours Transfusion of more than 10 units of red cells in 24 hours Replacement of more than 50% of the patient’s blood volume in 3 hours Blood loss more than 150 mL/ minute in an adult

American College of Surgeons Classification of Acute Hemorrhage : 

American College of Surgeons Classification of Acute Hemorrhage

Estimation of Blood Volume Deficit in Trauma : 

Estimation of Blood Volume Deficit in Trauma

ATLS Resuscitation ProtocolA standard since 1985 : 

ATLS Resuscitation ProtocolA standard since 1985 Start two large bore IVs Give 2 L of crystalloid if SBP < 100 Start RBC if SBP is still <100 Start RBC if SBP normalizes and falls again Start RBC if bleeding is > 100 mL/min Continue RBC as long as above Give fresh frozen plasma if INR > 1.5 Give platelets if < 50 x 109/L Give cryoprecipitate if fibrinogen < 1g/L

Transfusion guidelines : 

Transfusion guidelines In 1994, the College of American Pathologists (CAP) : keep the INR < 1.5 INR < 1.5 and of platelets 50 × 109/L in actively bleeding patients. JAMA. 1994;271:777-781 In 1996, the ASA recommended : keep the INR < 1.5 and platelets to maintain counts 50 × 109/L in hemodynamically normal but actively bleeding patients; platelet 100 × 109/L may be useful in multiply or massively injured patients. Approved by the House of Delegates on October 22, 1995 and last amended on October 25, 2005). In 2007,the European Task Force for Advanced Bleeding Care in Trauma (ABC-T): keep INR < 1.5 and platelet > 50 x 10 9/L Critical Care. 2007;11:1-22

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FAST USS Examination Control External Bleeding + Diagnostic Adjunct to locate source of internal bleeding F.A.S.T.

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Emergency Laparotomy Blush Steel coils External fixation Pelvic Selective Embolization

Transfusion Protocol : 

Transfusion Protocol Break the Lethal Triad

Clinical Strategies to Reduce Complications of Transfusion Therapy : 

Clinical Strategies to Reduce Complications of Transfusion Therapy

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Fresh frozen plasma should be given earlier to patients requiring massive transfusion GONZALEZ Ernest A. The Journal of trauma, injury, infection, and critical care   2007, vol. 62, no1, pp. 112-119

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Fresh frozen plasma should be given earlier to patients requiring massive transfusion GONZALEZ Ernest A. The Journal of trauma, injury, infection, and critical care   2007, vol. 62, no1, pp. 112-119

The Lethal Triad of Massive Blood Transfusion During Trauma : 

The Lethal Triad of Massive Blood Transfusion During Trauma Coagulopathy leads to further bleeding

The Lethal Triad : 

The Lethal Triad Hypothermia Acidosis Coagulopathy Death If this “lethal triad“ is present ..... surgical control of bleeding is unlikely to be successful!

The Lethal Triad of CoagulopathyAfter Massive Transfusion : 

The Lethal Triad of CoagulopathyAfter Massive Transfusion Critical dilution for coagulation factors :after the loss of 1.2 blood volumes and for platelets at 2 blood volumes. Acidosis: reduce the activity of the Xa-Va prothrombinase complex by 50% at pH 7.2, 70% at pH 7, and 90% at pH 6.8 Hypothermia :by preventing the activation of platelets by traction on the glycoprotein Ib, IX, V complex by von Willebrand factor(VWF). Sheardependent platelet activation↓ 50% function at 30ºC. DIC: head, bones, and gravid uterus

Acidosis : 

Acidosis Base deficit (BD) ≥ 6 identifies patients that require early transfusion, increased ICU days and risk for ARDS and MOF BD of ≥ 6 is strongly associated with the need for MT and mortality in both civilian and military trauma. Patients have an elevated BD before their blood pressure drops to classic “hypotension” levels. Acidosis contributes more to coagulopathy more than hypothermia (not reversible) Xa-Va complex activity reduced: pH: 7.2 50% 7.o 70% 6.8 90%

Temperature : 

Temperature A temperature < 96°F or 35°C is associated with an increase in mortality. Trauma patients that are hypothermic are not perfusing their tissue The coagulation cascade is an enzymatic pathway that degrades with temperature and ceases at 92 F (33.3C) Reduces activity of clotting factors by 50% at 34 C Platelet activation almost eliminated at 30 C

Rate of Heat TransferGentilello LM. In: Maull KI, et al, eds. Advances in Trauma and Critical Care. Vol 9. St Louis, MO: Mosby; 1994:39-79. : 

Rate of Heat TransferGentilello LM. In: Maull KI, et al, eds. Advances in Trauma and Critical Care. Vol 9. St Louis, MO: Mosby; 1994:39-79. Q=mc(T2 - T1)

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Prevention Is Better Than Cure Sherry Porter Biddy Chang Sunnybrook Health Sciences Centre

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Prevention Is Better Than Cure Sherry Porter Biddy Chang Sunnybrook Health Sciences Centre

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Prevention Is Better Than Cure Sherry Porter Biddy Chang Sunnybrook Health Sciences Centre

Coagulopathy and Trauma : 

Coagulopathy and Trauma Derangements in coagulation occur rapidly after trauma By the time of arrival at the ED, 28% (2,994 of 10,790) of trauma patients had a detectable coagulopathy that was associated with poor outcome Acute Trauma Coagulopathy is the Natural Body Defence Against DIC !

Coagulopathy of Trauma : 

Coagulopathy of Trauma

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The generation or exposure of TF at the wound site, and its interaction with factor VII, is the PRIMARY physiologic event in initiating clotting. The components of the intrinsic pathway (ie, factors VIII, IX, XI) are responsible for AMPLIFICATION of this process only after a small initial amount of thrombin has been generated through the extrinsic pathway.

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Action of rFVIIa

rFVIIa : 

rFVIIa Function of rFVIIa Linear increase in factor Xa independently of TF Dose-response thrombin generation even in the absence of F VIII & F IX Direct activation of F IX on activated platelets in the absence of TF Localization to site of bleeding on activated platelets Inhibition of fibrinolysis (TAFI) Enhancement of thrombin generation on platelet surface Formation of stable (fibrinolysis-resistant) fibrin clot

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Potential Role of FVIIa in Acute Traumatic Coagulopathy FVIIa Inhibit Fibrinolysis Direct thrombin generation even in the absence of FVIII and FIX Increase Xa Direct activate IX on activated platelet

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Activated protein C pathway Thrombin binds Thrombomodulin The complex Thrombin- Thrombomodulin activates Protein C APC decreases FVIIIa and FVa and induces D-dimers production

In 2007,the European Task Force for Advanced Bleeding Care in Trauma(Spahn et al., Crit Care 2007; 11:R17) : 

In 2007,the European Task Force for Advanced Bleeding Care in Trauma(Spahn et al., Crit Care 2007; 11:R17) We suggest that the use of rFVIIa be considered if major bleeding in blunt trauma persists despite standard attempts to control bleeding an best practice use of blood components. We suggest an initial dose of 200 microgramm/kg followed by two 100 microgramm/kg doses administered at 1 and 3 hours following the first dose. (Grade 2C)

Israel Defense Forces NovoSeven Treatment Guideline for TraumaJ. Thromb Haemost 2005; 3: 640-8 : 

Israel Defense Forces NovoSeven Treatment Guideline for TraumaJ. Thromb Haemost 2005; 3: 640-8 Massive bleeding: Loss of entire blood volume in 24h (10U PRBC in 70kg) Loss of 50% blood in 3h Blood loss rate 150mL/min Blood loss rate 1.5mL/kg for over 20 min Failure to arrest hemorrhage despite: FFP: 10-15mL/kg (4-6U for 70kg) Cryo: 1-2U/10kg (10-15U for 70kg) Platelets: 1-2U/10kg (10-15U for 70kg) Correction of acidosis: pH7.2 Warming of hypothermic patients (recommended, not mandatory for rFVIIa)

Israel Defense Forces NovoSeven Treatment Guideline for TraumaJ. Thromb Haemost 2005; 3: 640-8 : 

Israel Defense Forces NovoSeven Treatment Guideline for TraumaJ. Thromb Haemost 2005; 3: 640-8 Preconditions Fibrinogen 50 mg/dL (100 mg/dL preferred) Platelet 50000*109/L (100000 *109/L preferred) pH 7.2 Treatment Initial 100~140 (120) g/kg IV bolus, 15 to 20 min. Repeat 100 g/kg IV Total dose > 200 g/kg, check and correct preconditions. If correction not feasible, give FFP 10-15mL/kg or 4-6 U/70kg Cryo 1-2 U/10kg or 10-15 U/70kg Platelet 1-2 U/10kg or 10-15 U/70kg Correct pH and calcium Third dose 100 g/kg IV

Safety: Shock Trauma CenterThomas, GOR et al. J Trauma 62, 2007 : 

Safety: Shock Trauma CenterThomas, GOR et al. J Trauma 62, 2007 9% thromboembolic complications Mesenteric ischemia Cerebral ischemia Myocardial ischemia Other arterial / venous thrombosis 3% highly associated with FVIIa 1% serious and highly associated

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? The Role of Prothrombin Complex Concentrate

Fibrinogen Content in Various Blood Products (mg) : 

Fibrinogen Content in Various Blood Products (mg)

Haemodilution markedly prolonged prothrombin time and reduced peak thrombin generation. Prothrombin complex concentrate(25 IU/kg) but not FFP (15 ml/Kg), fully reversed those effects. : 

Haemodilution markedly prolonged prothrombin time and reduced peak thrombin generation. Prothrombin complex concentrate(25 IU/kg) but not FFP (15 ml/Kg), fully reversed those effects. Conclusions: PCC was effective in correcting dilutional coagulopathy and controlling bleeding in an in vivo large-animal trauma model. In light of its suitability for more rapid administration than FFP, PCC merits further investigation as a therapy for dilutional coagulopathy in trauma and surgery. Prothrombin complex concentrate vs fresh frozen plasma for reversal of dilutional coagulopathy in a porcine trauma model G. Dickneite ,* and I. Pragst BJA Advance Access published online on January 24, 2009

Administration of fibrinogen (200 mg/ kg) and PCC (35 IU/Kg) was able to reduce mortality and bleeding in a porcine liver laceration model to induce uncontrolled haemorrhage although APTT remain unchanged. : 

Administration of fibrinogen (200 mg/ kg) and PCC (35 IU/Kg) was able to reduce mortality and bleeding in a porcine liver laceration model to induce uncontrolled haemorrhage although APTT remain unchanged. Blood loss after liver injury was significantly less in the treatment group as compared with placebo: 240 ml (50–830) vs 1800 ml (1500–2500) (P<0.0001). All treated animals survived, whereas 80% of the placebo group died (P<0.0001). Efficacy of fibrinogen and prothrombin complex concentrate used to reverse dilutional coagulopathy—a porcine model D. Fries1 et al BJA Advance Access originally published online on August 1, 2006

Prothrombin Complex Concentrate (PCC) : 

Prothrombin Complex Concentrate (PCC) 43 PCC: Clotting factors (II, VII, IX, and X) that can be used to reverse coagulopathy PCC: Effects are fast and long acting PCC: Use in trauma patients appears safe and beneficial in critically injured population Associated with thrombogenicity Kalina M, et al. Am Surg. 2008;74:858-861; Köhler M. Thromb Res. 1999;95(4 suppl):S13-S17; Riess HB, et al. Thromb Res. 2007;121:9-16.

No Consensus on Use of PCC : 

No Consensus on Use of PCC Risk of PCC Thrombotic complication It contains heparin 200 IU/500 Unit vial No FVII in HA CSL’s brand The European guideline on the Management of bleeding following major trauma: a European guideline 2007 recommend the use of PCC according to the manufacturer's instructions only for the emergency reversal of vitamin K-dependent oral anticoagulants.

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If this “lethal triad“ is present ..... surgical control of bleeding is unlikely to be successful!

Damage Control Resuscitation : 

Damage Control Resuscitation New Diagnostic Criteria Acidosis- Base Deficit > - 6 Coagulopathy – INR > 1.5 Hypotension – Systolic BP < 90 mmHg Hemoglobin - < 11 g/dL Temperature - < 96. 5 F (35.8C) Pattern recognition Weak or absent radial pulse Abnormal mental status Severe Traumatic Injury DCR Within 5 minutes Identify patients in trouble Identify patients with increased mortality Identify patients with increased probability of massive transfusion May not be able to identify patient at risk of massive transfusion.

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• The TASH score is a simple method for quickly predicting need of mass transfusion • It can be calculated within the first 10 minutes after admission Trauma Associated Severe Hemorrhage (TASH)-Score: probability of mass transfusion as surrogate for life threatening hemorrhage after multiple trauma.Yücel N, J Trauma. 2006 Jun;60(6):1228-36; discussion 1236-7.

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Probability PMT for Mass derived from TASH

ABC (Assessment of Blood Composition) Score for Risk of Massive Transfusion : 

ABC (Assessment of Blood Composition) Score for Risk of Massive Transfusion

Major Shift In Trauma Care : 

Major Shift In Trauma Care “Damage Control Resuscitation represents the most important advance in trauma care for hospitalized civilian and military casualties from this war.” Cordts, Brosch and Holcomb, J Trauma, 2008

Damage Control ResuscitationCotton BA, et al. J Trauma. 2008;64:1177-1183 : 

Damage Control ResuscitationCotton BA, et al. J Trauma. 2008;64:1177-1183 Damage control hematology: the impact of a trauma exsanguination protocol on survival and blood product utilization (Cotton et al. Journal of Trauma, 2008) Three components Hematologic Limited crystalloid Permissive hypotension

Damage Control ResuscitationCotton BA, et al. J Trauma. 2008;64:1177-1183 : 

Damage Control ResuscitationCotton BA, et al. J Trauma. 2008;64:1177-1183 74% reduction in the odds of mortality Increase in unexpected survivors Decrease in unexpected deaths Less intraoperative crystalloid; fewer postoperative blood products

Damage Control Surgery : 

Damage Control Surgery Performed in the setting of massive transfusion, refractory shock, hypothermia, & coagulopathy Stop hemorrhage Control contamination Temporary abdominal closure Return patient to ICU for correction of shock, coagulopathy, & hypothermia Re-exploration for definitive repair when stable (12-48 hrs)

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Arrest of Haemorrhage Provide volume that also restores the haemostatic cascade Minimize crystalloid Permissive hypotension Small volume resuscitation Stop the bleeding Stay out of trouble

Permissive HypotensionRediscovered : 

Permissive HypotensionRediscovered “If the pressure is raised before the surgeon is ready to check any bleeding that may take place, blood that is sorely needed may be lost.” The Preventative Treatment of Wound Shock Cannon W, Fraser J, Cowell E JAMA 1918:618-621

Permissive Hypotension : 

Permissive Hypotension ATLS and others: 15-20 years of ‘high volume’ fluid resuscitation Chasing the tachycardia Crystalloid versus colloid NO TRUE EVIDENCE OF IMPROVED SURVIVAL Current UK consensus guidelines Permissive hypotension: avoid ‘popping the clot’ Radial or femoral pulse Systolic 70-80mmHg ‘Small volume’ resuscitation Hypertonic + colloid

Permissive hypotension: theory : 

Permissive hypotension: theory Decrease in vasoconstriction Earlier dislocation of the thrombus Increased blood loss Dilution coagulopathy Decrease oxygen transport capacity Metabolic acidosis Hypothermia

Permissive hypotension: Clinical : 

Permissive hypotension: Clinical

Ineffectiveness of On-Site Intravenous Lines: Is prehospital time the culprit?Sampalis JS et al. J Trauma 1997 Oct;43(4):608-617 : 

Ineffectiveness of On-Site Intravenous Lines: Is prehospital time the culprit?Sampalis JS et al. J Trauma 1997 Oct;43(4):608-617 217 patients on-site intravenous fluid replacement (IV group) with patients for whom this intervention was not performed (no-IV group). The mortality rates for the IV and no-IV groups were 23 and 6% (p < 0.001) Use of on-site intravenous fluid replacement was associated with a significant increase in the risk of mortality (adjusted odds ratio = 2.3; p = 0.04)

Immediate versus delayed fluid resuscitation forhypotensive patients with penetrating torso injuriesBickell WH et al Engl J Med 1994 Oct 27; 331:1105-9 : 

Immediate versus delayed fluid resuscitation forhypotensive patients with penetrating torso injuriesBickell WH et al Engl J Med 1994 Oct 27; 331:1105-9 Prospective, randomized pre-hospital trial 598 patients with penetrating torso trauma and systolic BP < 90 mmHg Initial BP averaged 72 mmHg in ‘limited’ resusc, 78mmHg in ‘standard’ Standard resuscitation vs Limited resuscitation (until surgical intervention) 2480 mls vs 375 mls IV fluids Limited resuscitation : 30% mortality and 23% complication rate Standard Resuscitation : 38% mortality (p=0.04) and 30% complication rate

Hypotensive resuscitation during active hemorrhage: Impact on in-hospital mortalityDutton RP et al J Trauma 2002 June;52(6):1141-1146 : 

Hypotensive resuscitation during active hemorrhage: Impact on in-hospital mortalityDutton RP et al J Trauma 2002 June;52(6):1141-1146 Patients in hemorrhagic shock randomized to target BP of 70mmHg or 100mmHg Fluid administered to this endpoint until hemorrhage control 114 mm Hg vs. 100 mm Hg, p < 0.001 No difference in mortality

Haemostatic Resuscitation : 

Haemostatic Resuscitation Damage control philosophy can be extended to hemostatic resuscitation restoring normal coagulation minimizing crystalloid Traditional resuscitation strategies dilute the already deficient coagulation factors and increase multiple organ failure The aggressive haemostatic resuscitation should be combined with equally aggressive control of bleeding

Hemostatic Resuscitation : 

Hemostatic Resuscitation Early Dx in ED 1:1 ratio (PRBC to FFP) ED use of rFVIIa Call for Fresh Whole Blood from the ED Frequent cryoprecipitate and platelets Repeated doses of rFVIIa in OR and ICU as required Minimal crystalloid

Fresh Frozen Plasma : 

Fresh Frozen Plasma Fresh frozen plasma should be used as a primary resuscitative fluid. This product should be present upon arrival of the casualty in the ED This approach not only addresses the metabolic abnormality of shock, but initiates reversal of the coagulopathy present.

Fresh Whole Blood : 

Fresh Whole Blood Fresh whole blood (FWB) must be called for early after ED arrival, takes 60 minutes Injury Pattern recognition Fresh whole blood is the optimal resuscitation fluid for severely injured casualties. Fresh whole blood is the best fluid for hypotensive resuscitation for hemorrhagic shock.

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The Ratio of Blood Products Transfused Affects Mortality in Patients Receiving Massive Transfusions at a Combat Support HospitalBorgman MA, Spinella PC, Perkins JG J Trauma vol. 63, 805 - 813, 2007

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The Ratio of Blood Products Transfused Affects Mortality in Patients Receiving Massive Transfusions at a Combat Support HospitalBorgman MA, Spinella PC, Perkins JG J Trauma vol. 63, 805 - 813, 2007

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Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Holcomb JB et al: Ann Surg 248:447, 2008 High plasma + high platelet to RBC ratios associated with ↓ truncal hemorrhage ↓ ICU, vent days + LOS ↑ survival

The ratio of fibrinogen to red cells transfused affects survival in casualties receiving massive transfusions at an Army combat surgical hospital. Stinger HK et al: J Trauma 2008; 64: S79-85. : 

The ratio of fibrinogen to red cells transfused affects survival in casualties receiving massive transfusions at an Army combat surgical hospital. Stinger HK et al: J Trauma 2008; 64: S79-85.

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The ratio of fibrinogen to red cells transfused affects survival in casualties receiving massive transfusions at an Army combat surgical hospital. Stinger HK et al: J Trauma 2008; 64: S79-85.

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Are We Ready For The Change ? Systolic BP < 90 mmHg BE > - 6 mmol/L INR > 1.5 T < 96 °F (35.6 °C) Hb < 11 g/dL

Development of Resuscitation ProtocolFor Major Haemorrhagic Shock : 

Development of Resuscitation ProtocolFor Major Haemorrhagic Shock World War II Mid 70’ - 2003 2008 - Chimerism Acute coagulopathy of trauma Fresh Whole Blood Saves Life Crystalloid Colloid Packed cells

Component Therapy vs Fresh Whole Blood : 

Component Therapy vs Fresh Whole Blood So Component Therapy Gives You 1U PRBC + 1U PLT + 1U FFP + 10 pk Cryo = 660 COLD mL Hct 29% Plt 87K Coag activity 65% 750 mg fibrinogen 500 mL Warm Hct: 38-50% Plt: 150-400K Coags: 100% 1500 mg Fibrinogen

Best option – your own blood! : 

Best option – your own blood! Minimise loss as much as possible Circulation preservation Urgent transfer to theatre More effectively carries oxygen Fresh vs stored blood No Allograft transfusion problems Antigens White cells Transfusion complications

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Management of Trauma Patient Requring Massive Transfusion Role of ICU (OT) Ambulance & A&E Department

Conclusion (I) : 

Conclusion (I) Data are starting to support changes in transfusion approaches and policy: Trauma is a leading case of death worldwide and 30-40% of trauma patients die secondary to bleeding and coagulopathy Early trauma induced coagulopathy occurs in ~25% of trauma patients and predicts four fold increased in mortality Implementation of a MTP with aggressive use of plasma/cryoprecipitate/platelets may reduce mortality and may reduce blood product usage. Increased amount of coagulation products relative to RBC products transfused improves mortality Until results from prospective trials, current data support a target ratio of plasma:red blood cell:platelet transfusions of 1:1:1. during massive blood loss

Conclusions (II)Goal for Resuscitation - Early : 

Conclusions (II)Goal for Resuscitation - Early Change in triage criteria for early identification of trauma patient at risk of massive blood transfusion Expedite control of hemorrhage with damage control surgery Maintain blood pressure 80-100 mmHg systolic before definitive surgery! Limit crystalloid infusion and consider vasopressors early! Give blood products early and often: pRBC: FFP:Platelet at 1:1:1 ratio Frequent laboratory studies! Early consideration of rFVII at A&E Department and operation theatre

Conclusions (III)Key Goals for the Management of critical bleeding inthe Trauma Patient : 8 Steps to Support Coagulation : 

Conclusions (III)Key Goals for the Management of critical bleeding inthe Trauma Patient : 8 Steps to Support Coagulation Achieve normothermia Achieve normal pH Achieve normal Ca2++ Treat with FFP, if PT or aPTT abnormal Treat with platelets, if < 80 x 109 Treat with Fibrinogen, if < 1g/l Treat with Antifibrinolytics,if hyperfibrinolysis Treat with rFVIIa, if all else fails Plt > 50x109, Fg > 1g/l, Hct >24, pH > 7,2 Modified from Spahn D, Roissaint R, Br J Anaesth 2005; 95(2): 130-139

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2003 Acute Coagulopathy of Trauma

One quarter of major trauma patients has acute coagulopathy on arrival to A&E Department : 

One quarter of major trauma patients has acute coagulopathy on arrival to A&E Department Patients arriving with a coagulopathy were 4 times more likely to die than those with normal coagulation. This effect was independent of injury severity. Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. Brohi K, Cohen MJ, Ganter MT, Schultz MJ, Levi M, Mackersie RC, Pittet JF 1: J Trauma. 2008 May;64(5):1211-7

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Acute coagulopathy of trauma: mechanism, identification and effect Karim Brohia, Mitchell J. Cohenb and Ross A. Davenport Curr Opin Crit Care 13:680–685. Royal London Hospital Median time Incident – Hospital Admission: 72 minutes

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Derangements in coagulation occur rapidly after trauma and are related to the injury severity score (ISS) By the time of arrival at the ED, 1/4 of trauma patients had a coagulopathy associated with a poor outcome Acute Traumatic Coagulopathy Brohi, Karim BSc, FRCS, FRCA; Singh, Jasmin MB, BS, BSc; Heron, Mischa MRCP, FFAEM; Coats, Timothy MD, FRCS, FFAEM The Journal of Trauma: Injury, Infection, and Critical Care: June 2003 - Volume 54 - Issue 6 - pp 1127-1130

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Retrospective analysis of 5000 Patients European Collaborative Study

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Retrospective analysis of 5000 Patients European Collaborative Study

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Retrospective analysis of 5000 Patients European Collaborative Study

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Retrospective analysis of 5000 Patients European Collaborative Study

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Injury Shock Retrospective analysis of 5000 Patients European Collaborative Study

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Retrospective analysis of 5000 Patients European Collaborative Study

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Coagulation Cascade

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Acute Traumatic Coagulopathy: Initiated by Hypoperfusion Modulated Through the Protein C Pathway? Karim Brohi, FRCS, FRCA,* Mitchell J. Cohen, MD,* Michael T. Ganter, MD,† Michael A. Matthay, MD,‡ Robert C. Mackersie, MD,* and Jean-François Pittet, MD†‡ Ann Surg. 2007 May; 245(5): 812–818. Admission plasma thrombomodulin and protein C levels are predictive of clinical outcomes following major trauma.

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High thrombomodulin and low protein C levels were significantly associated with increased mortality, blood transfusion requirements, acute renal injury, and reduced ventilator-free days. Acute Traumatic Coagulopathy: Initiated by Hypoperfusion Modulated Through the Protein C Pathway? Karim Brohi, FRCS, FRCA,* Mitchell J. Cohen, MD,* Michael T. Ganter, MD,† Michael A. Matthay, MD,‡ Robert C. Mackersie, MD,* and Jean-François Pittet, MD†‡ Ann Surg. 2007 May; 245(5): 812–818.

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Acute coagulopathy of trauma: mechanism, identification and effect Karim Brohia, Mitchell J. Cohenb and Ross A. Davenport Curr Opin Crit Care 13:680–685. Only 2% of patients with a base deficit under 6mEq/l had prolonged clotting times, compared with 20% of patients with a base deficit over 6mEq/l. Not reversed with pH neutralization

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Acute coagulopathy of trauma: mechanism, identification and effect Karim Brohia, Mitchell J. Cohenb and Ross A. Davenport Curr Opin Crit Care 13:680–685. Trauma + Shock

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Trauma, induces the initiation of coagulation Tissue factor (TF) is exposed and binds to FVIIa or FVII which is subsequently converted to FVIIa The complex between TF and FVIIa activates FIX and FX FXa binds to FVa on the cell surface Normal Haemostasis: Initiation Phase

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Normal Haemostasis: Amplification phase The FXa/FVa complex converts small amounts of prothrombin into thrombin The small amount of thrombin generated activates FVIII, FV, FXI and platelets locally. FXIa converts FIX to FIXa Activated platelets bind FVa, FVIIIa and FIXa

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Normal Haemostasis : Propagation Phase The FVIIIa/FIXa Complex activates FX on the surfaces of activated platelets FXa in association with FVa converts large amounts of prothrombin into thrombin creating a “thrombin burst”. The “thrombin burst” leads to the formation of a stable fibrin clot.

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Thrombin is generated primarily via the ‘extrinsic’ pathway with multiple feed-forward loops. When thrombomodulin (TM) is presented by the endothelium, it complexes thrombin which is no longer available to cleave fibrinogen. This anticoagulant thrombin activates protein C which reduces further thrombin generation through inhibition of cofactors V and VIII. Anticoagulation

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Activated protein C pathway Thrombin binds Thrombomodulin The complex Thrombin- Thrombomodulin activates Protein C APC decreases FVIIIa and FVa and induces D-dimers production

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Tissue plasminogen activator (tPA) is released from the endothelium by injury and hypoperfusion and cleaves plasminogen to initiate fibrinolysis. Activated protein C (aPC) consumes plasminogen activator inhibitor-1 (PAI-1) when present in excess, and reduced PAI-1 leads to increased tPA activity and hyperfibrinolysis. Hyperfibrinolysis

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Potential Role of FVIIa in Acute Traumatic Coagulopathy FVIIa Inhibit Fibrinolysis Direct thrombin generation even in the absence of F VIII & F IX Increase Xa Direct activate IX on activated platelet

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Early Use of Blood Product Give products in a ratio of PRBC:FFP:platelets 1:1:1 Early use of Novo VII Traditionally, FFP & platelet concentrates are given as “needed”

What is the Natural Role of aPC in Acute Traumatic Injury ? : 

What is the Natural Role of aPC in Acute Traumatic Injury ?

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Jean-Francois Pittet Cardiovascular Research Institute University of California San Francisco

Slide 112: 

Jean-Francois Pittet Cardiovascular Research Institute University of California San Francisco

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Jean-Francois Pittet Cardiovascular Research Institute University of California San Francisco

Slide 114: 

Jean-Francois Pittet Cardiovascular Research Institute University of California San Francisco

Slide 115: 

Jean-Francois Pittet Cardiovascular Research Institute University of California San Francisco

Summary : 

Summary First Animal Model of Acute Traumatic Coagulopathy Mimics human response to trauma/hypoperfusion Role of Activated Protein C in Trauma/ Hypoperfusion Jean-Francois Pittet Cardiovascular Research Institute University of California San Francisco

Clinical Implications : 

Clinical Implications Inhibition of anticoagulant function of Protein C could become a NEW, mechanistic treatment for Acute Traumatic Coagulopathy in trauma patients. Role of protein C in organ dysfunction in traumatic shock: recombinant mutant non-anticoagulant protein C…potential treatment in humans ? Jean-Francois Pittet Cardiovascular Research Institute University of California San Francisco

Evidence-based monitoring on the efficacy of massive transfusion protocol : 

Evidence-based monitoring on the efficacy of massive transfusion protocol Dr. Lai Kang Yiu Intensive Care Unit Queen Elizabeth Hospital

The TEG assays can assess coagulopathy, platelet dysfunction, and hyperfibrinolysis at an early stage posttrauma and suggest more effective interventions. : 

The TEG assays can assess coagulopathy, platelet dysfunction, and hyperfibrinolysis at an early stage posttrauma and suggest more effective interventions. Platelet Mapping assays correlated with the need for blood transfusion. The abnormal TEG System parameters correlated with fatality. These coagulopathies were already evident on site. Early evaluation of acute traumatic coagulopathy by thrombelastography Carroll RC, Craft RM, Langdon RJ Transl Res CCM vol. 154, 34 - 39, 2009

PlateletMapping showed lower platelet adenosine diphosphate (ADP) responsiveness in patients who needed transfusions (MA=22.7±17.1 vs MA=35.7±19.3, P=0.004) and a correlation of fibrinogen<100mg/dL with fatalities (P=0.013). : 

PlateletMapping showed lower platelet adenosine diphosphate (ADP) responsiveness in patients who needed transfusions (MA=22.7±17.1 vs MA=35.7±19.3, P=0.004) and a correlation of fibrinogen<100mg/dL with fatalities (P=0.013). For the 14 fatalities, thrombelastography (TEG) reaction (R) time was 3703±11,618 versus 270±393s (P=<0.001), and maximal amplitude (MA, a evaluation of clot strength) was 46.4±22.4 versus 64.7±9.8mm (P<0.001). Hyperfibrinolysis (percent fibrinolysis after 60min [LY60] >15%) was observed in 3 patients in the ED with a 67% fatality rate (P=<0.001 by chi-square testing). Early evaluation of acute traumatic coagulopathy by thrombelastography Carroll RC, Craft RM, Langdon RJ Transl Res CCM vol. 154, 34 - 39, 2009

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Standard TEG parameters (Haemoscope Corporation). Reaction (R) time, clot formation (K) time, clotting rate (angle=α), strength of clot (maximal amplitude [MA]), and percent fibrinolysis at 30min (A30) and at 60min (LY60) not shown. (Reprinted from Carroll RC, Craft RM, Langdon RJ, et al. Early evaluation of acute traumatic coagulopathy by thrombelastography. Transl Res. 2009;154:34-39,Elsevier.)

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The most common coagulopathy was a prolonged R, which could reflect a systemic loss of factor V and VIII. Normal values: R= 78–198 s, K= 48–168 s, Angle= 57–78, MA= 55–75 mm, and LY60 15%).

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Low MA is indicative of platelet dysfunction Prolonged LY60 is indicative of hypefrinolyis

Conclusion (I) : 

Conclusion (I) Data are starting to support changes in transfusion approaches and policy: Trauma is a leading case of death worldwide and 30-40% of trauma patients die secondary to bleeding and coagulopathy Early trauma induced coagulopathy occurs in ~25% of trauma patients and predicts four fold increased in mortality Implementation of a MTP with aggressive use of plasma/cryoprecipitate/platelets may reduce mortality and may reduce blood product usage. Increased amount of coagulation products relative to RBC products transfused improves mortality Until results from prospective trials, current data support a target ratio of plasma:red blood cell:platelet transfusions of 1:1:1. during massive blood loss

Conclusions (II)Goal for Resuscitation - Early : 

Conclusions (II)Goal for Resuscitation - Early Expedite control of hemorrhage with damage control surgery Maintain blood pressure 80-100 mmHg systolic! Limit crystalloid infusion and consider vasopressors early! Give blood products early and often: pRBC: FFP:Platelet at 1:1:1 ratio Frequent laboratory studies!

Conclusions (III)Key Goals for the Management of critical bleeding inthe Trauma Patient : 8 Steps to Support Coagulation : 

Conclusions (III)Key Goals for the Management of critical bleeding inthe Trauma Patient : 8 Steps to Support Coagulation Achieve normothermia Achieve normal pH Achieve normal Ca2++ Treat with FFP, if PT or aPTT abnormal Treat with platelets, if < 80 x 109 Treat with Fibrinogen, if < 1g/l Treat with Antifibrinolytics,if hyperfibrinolysis Treat with rFVIIa, if all else fails Plt > 50x109, Fg > 1g/l, Hct >24, pH > 7,2 Modified from Spahn D, Roissaint R, Br J Anaesth 2005; 95(2): 130-139

End : 

End ‘Blood is thicker than water’ - Preserve rather than replace Acute Traumatic Coagulopathy

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Any Questions ?

Risk of Transfusion : 

Risk of Transfusion Dr. Lai Kang Yiu Intensive Care Unit Queen Elizabeth Hospital

Risks of Transfusions(Dzieczkowski and Anderson) : 

Risks of Transfusions(Dzieczkowski and Anderson) Reactions (Frequency: unit) Febrile (FNHTR) 1–4:100 Allergic 1–4:100 Delayed hemolytic 1:1,500 Acute hemolytic 1:12,000 Fatal hemolytic 1:100,000 Anaphylactic 1:150,000 TRALI: 1:5000 Miscellaneous RBC allosensitization 1:100 HLA allosensitization 1:10 Graft vs. host disease Rare Infections CMV 3-12:100 Hepatitis C 1:103,000 Hepatitis B 1:200,000 HIV-1 1:490,000 HIV-2 Unknown HTLV-I (II) 1:641,000 Malaria 1:4,000,000 Immunomodulation Postoperative sepsis Tumour relapse

Possible Mechanisms of Transfusion-Associated Immunomodulation : 

Possible Mechanisms of Transfusion-Associated Immunomodulation Anergy Tolerance Cytokines released during blood storage Iron-mediated immune suppression Suppressor cell network inhibition Anti-idiotypic and anti-clonotypic antibodies Clonal deletion

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Any Questions ?