Case 28y male involved in an industrial accident 28y male involved in an industrial accident Sustained significant injuries to right lower leg, femur and ?hemipelvis Sustained significant injuries to right lower leg, femur and ?hemipelvis Prolonged extrication “tons of blood” at the scene Prolonged extrication “tons of blood” at the scene

Case 1 Looks very unwell with ++ ongoing bleeding Looks very unwell with ++ ongoing bleeding –GCS E3 V4 M5 (12) –Temp 34.7 –HR 160 –BP 77/50 manual –RR 30 –SaO 2 97% 10L by mask What is your initial management? What is your initial management?

Case What other investigations? What other investigations? Who are you going to call? Who are you going to call? Surgery and IR are held up for 30min Surgery and IR are held up for 30min Is there anything else we can do? Is there anything else we can do?

Massive transfusion (all bleeding stops…) Grand Rounds Oct 2 nd 2008 Kristian Hecht PGY-3 CCFP-EM

Objectives Define massive transfusion Define massive transfusion Review complications of massive transfusion Review complications of massive transfusion Review FMC’s Massive Transfusion Protocol Review FMC’s Massive Transfusion Protocol Review literature supporting the MTP Review literature supporting the MTP Review adjunctive therapies in massive hemorrhage Review adjunctive therapies in massive hemorrhage

Background First attempted blood transfusion was in 1492 after Pope Innocent VIII became comatose First attempted blood transfusion was in 1492 after Pope Innocent VIII became comatose Blood from 3 aides was instilled into the Pope’s mouth Blood from 3 aides was instilled into the Pope’s mouth All 4 died All 4 died

Background In 1600’s many animal-to-human transfusions attempted In 1600’s many animal-to-human transfusions attempted –These were later banned due to high mortality The first documented successful transfusion was between two dogs in 1667 The first documented successful transfusion was between two dogs in 1667 The first documented human-to-human transfusion was in 1818 by Dr. James Blundell a British obstetrician The first documented human-to-human transfusion was in 1818 by Dr. James Blundell a British obstetrician

Background Hemorrhage is the second leading cause of death in trauma Hemorrhage is the second leading cause of death in trauma CNS injury is 1 st CNS injury is 1 st May require massive transfusion May require massive transfusion

Background Massive transfusion (MT): Massive transfusion (MT): – >10U pRBC’s in 24h –Replacement of 50% blood volume in 3h –4U pRBC in 4h with ongoing major bleeding –Replacement with blood loss >150mL/min Required in only 1% of civilian trauma pts Required in only 1% of civilian trauma pts Mortality rates are between 20 – 50% in those requiring massive transfusion Mortality rates are between 20 – 50% in those requiring massive transfusion

Complications of MT Acute hemolytic transfusion reactions Acute hemolytic transfusion reactions Hyperkalemia Hyperkalemia Acidosis Acidosis Hypothermia Hypothermia Hypocalcemia Hypocalcemia Coagulopathy Coagulopathy  All more common and/or severe with increasing number of units transfused

Acute hemolytic reactions Most often due to ABO incompatible RBC’s or plasma (clerical error, lab error etc) Most often due to ABO incompatible RBC’s or plasma (clerical error, lab error etc) Rarely seen with unmatched O+ pRBC’s Rarely seen with unmatched O+ pRBC’s Occasionally with unmatched type specific pRBC’s Occasionally with unmatched type specific pRBC’s Commonly with unmatched type specific whole blood Commonly with unmatched type specific whole blood

Hyperkalemia Storage of pRBC’s results in cell lysis and increased extracellular [K + ] Storage of pRBC’s results in cell lysis and increased extracellular [K + ] 12 mEq/L at 7d 12 mEq/L at 7d 32 mEq/L at 21d 32 mEq/L at 21d

Hyperkalemia Inconsequential if infused slowly Inconsequential if infused slowly K + is shifted to intracellular space and later eliminated K + is shifted to intracellular space and later eliminated If large amounts of pRBC’s infused through a central line a large amount of K + is delivered directly to the RA If large amounts of pRBC’s infused through a central line a large amount of K + is delivered directly to the RA –Potentially resulting in…

Hyperkalemia If encountered treat as per medical hyperkalemia If encountered treat as per medical hyperkalemia May be prevented by using peripheral venous access May be prevented by using peripheral venous access Use of fresh blood (<14d) may decrease incidence Use of fresh blood (<14d) may decrease incidence

Hypothermia Traumatized pts are at risk for significant hypothermia due to environmental and surgical exposure Traumatized pts are at risk for significant hypothermia due to environmental and surgical exposure pRBC’s are stored at 4°C and will cause rapid hypothermia if not put through warmer pRBC’s are stored at 4°C and will cause rapid hypothermia if not put through warmer Hypothermia is an independent risk factor for mortality in trauma Hypothermia is an independent risk factor for mortality in trauma

Hypothermia Physiologic effects: Physiologic effects: –Decreased contractility –Cardiac dysrhythmia –Coagulopathy

Hypothermia Treatment Treatment –Drapes/blankets –Warmed IV fluids –Warm humidified O 2 –External rewaming (hot air blankets, etc) –Internal rewarming (peritoneal/pleural lavage)

QT c =510

Hypocalcemia Citrate is used as an anticoagulant in all blood products Citrate is used as an anticoagulant in all blood products Citrate binds ionized calcium and inhibits calcium-dependent coagulation Citrate binds ionized calcium and inhibits calcium-dependent coagulation Higher concentrations in FFP and Plts Higher concentrations in FFP and Plts Usually inconsequential due to rapid hepatic metabolism Usually inconsequential due to rapid hepatic metabolism May become significant with poor circulation and/or large amounts May become significant with poor circulation and/or large amounts

Hypocalcemia Tetany Tetany QT prolongation QT prolongation Decreased myocardial contractility Decreased myocardial contractility Hypotension Hypotension Exacerbation of concomitant hyperkalemia Exacerbation of concomitant hyperkalemia Coagulopathy (occurs at very low [Ca 2+ ]) Coagulopathy (occurs at very low [Ca 2+ ])

Hypocalcemia Treatment Treatment Correct shock Correct shock Decrease rate of blood product infusion Decrease rate of blood product infusion IV CaCl 2 1g slowly IV CaCl 2 1g slowly

Acidosis In hemorrhagic shock metabolic acidosis results from poor perfusion and subsequent lactate production In hemorrhagic shock metabolic acidosis results from poor perfusion and subsequent lactate production Stored pRBC’s pH 6.87 at 21d Stored pRBC’s pH 6.87 at 21d Metabolism of exogenous acid may be decreased due to poor circulation or rapid/large amount Metabolism of exogenous acid may be decreased due to poor circulation or rapid/large amount

Acidosis Causes other electrolyte disturbances (hyper K + ) Causes other electrolyte disturbances (hyper K + ) Independent risk factor for coagulopathy Independent risk factor for coagulopathy Activity of factor VIIa decreases by 90% when pH drops from 7.4 to 7.0 Activity of factor VIIa decreases by 90% when pH drops from 7.4 to 7.0

Acidosis Treatment Treatment –Correction of volume status and restoration of tissue perfusion –Use fresh blood products if possible –Addition of HCO 3 - is ineffective

Stored blood products pH 6.87 pH 6.87 [K + ] 32 mEq/L [K + ] 32 mEq/L 4°C 4°C citrate citrate

Coagulopathy Clinically Clinically –Oozing from IV sites, wounds and uninjured mucosa Lab values can correlate poorly with coagulopathy Lab values can correlate poorly with coagulopathy –PT abnormal in 97% –aPTT abnormal in 70%

Coagulopathy Often present on admission esp. with CNS and penetrating trauma Often present on admission esp. with CNS and penetrating trauma Correlated with increased mortality Correlated with increased mortality Often leads to further bleeding and ongoing need for volume resuscitation Often leads to further bleeding and ongoing need for volume resuscitation Leads to further worsening of physiologic derrangments Leads to further worsening of physiologic derrangments

Ongoing hemorrhage Shock acidosis Volume replacement Blood products Hyopthermia Hemodilution Coagulopathy Bloody vicious cycle

Coagulopathy Acidosis Deranged metabolism Consumptive coagulation HemodilutionHypothermia

Coagulopathy Acidosis Deranged metabolism Consumptive coagulation HemodilutionHypothermia

Normal clotting Local coagulation at wound Exposure of tissue factor Activation of clotting cascade Tissue injury

Consumptive and Intravascular Coagulation Systemic release of thromboplastin Systemic endothelial damage Widespread intravascular coagulation Massive soft tissue damage, long bone fractures, CNS injury

Dilutional Coagulopathy Results from loss of whole blood and replacement of factor and platelet-poor fluids Results from loss of whole blood and replacement of factor and platelet-poor fluids ATLS 3:1 replacement of blood loss with crystalloid ATLS 3:1 replacement of blood loss with crystalloid Also in shock, fluid shifts from the extracellular to vascular space, worsening hemodilution Also in shock, fluid shifts from the extracellular to vascular space, worsening hemodilution

Dilutional Coagulopathy First described in 1954 First described in 1954 Commonly occurred in those receiving >10U of stored whole blood (up to 78%) Commonly occurred in those receiving >10U of stored whole blood (up to 78%) –Related to stored platelet dysfunction and factor V and VIII deficiency 1970’s: modified whole blood 1970’s: modified whole blood –Platelets removed –Thromobcytopenia related coagulopathy

Dilutional Coagulopathy 1980’s: fractionated component transfusion 1980’s: fractionated component transfusion –Implemented to reduce infectious disease transmission and conserve scarce blood products Diluted coagulation factors Diluted coagulation factors Transfusion of components based on Transfusion of components based on lab parameters (hgb>70, plt >30, INR>1.5)

Dilutional Coagulopathy Traditionally FFP transfusion started after 1 blood volume and/or INR>1.5 Traditionally FFP transfusion started after 1 blood volume and/or INR>1.5 Recommendations based on mathematical models in elective surgical patients Recommendations based on mathematical models in elective surgical patients Drawbacks to previous recommendations Drawbacks to previous recommendations –Mathematical models invalid in trauma pts –Relied on lab studies  Difficult to use clinically –Inadequate response

FFP One unit contains: One unit contains: –0.5g fibrinogen –All other coagulation factors in physiologic concentrations –Will raise factors by 3–5%  Contains the most citrate of all blood products

Slow paradigm shift to factor replacement before the development of coagulopathy Slow paradigm shift to factor replacement before the development of coagulopathy Now trending to replacement of RBC:plasma:platelets at 1:1:1 ratios Now trending to replacement of RBC:plasma:platelets at 1:1:1 ratios

Crystalloid Blood products Bloody vicious cycle

Massive Transfusion Protocol Implemented in June 2008 as a pilot Implemented in June 2008 as a pilot Developed by Trauma Services in conjunction with ER, ICU, OR, Transfusion Medicine and Canadian Blood services Developed by Trauma Services in conjunction with ER, ICU, OR, Transfusion Medicine and Canadian Blood services

Massive Transfusion Protocol Has been activated ~40 times Has been activated ~40 times –Mostly trauma pts –Some OR cases and GI bleeds –Currently in a ‘trial phase’ Currently evaluating: time to MTP pack arrival, trauma severity score, type of injury and final ratio of blood products Currently evaluating: time to MTP pack arrival, trauma severity score, type of injury and final ratio of blood products

2 Protocol based on varying levels of evidence and expert consensus

MTP Cinat et al. examined FFP:RBC ratios in civilian trauma Arch Surg 1999; 134: Cinat et al. examined FFP:RBC ratios in civilian trauma Arch Surg 1999; 134: Survivors had avg ratio 1:1.8 Survivors had avg ratio 1:1.8 Nonsurvivors had avg ratio 1:2.5 Nonsurvivors had avg ratio 1:2.5

Retropsective study involving 246 combat- related trauma patients in Iraq requiring >10U pRBC’s between 2003 and 2005 Retropsective study involving 246 combat- related trauma patients in Iraq requiring >10U pRBC’s between 2003 and 2005 Compared mortality relative to the ratio of plasma:RBC transfused Compared mortality relative to the ratio of plasma:RBC transfused

Limitations Retrospective study Retrospective study Young healthy patient population Young healthy patient population Mostly penetrating trauma Mostly penetrating trauma Unclear how groups were allocated to receive different ratios Unclear how groups were allocated to receive different ratios Low ratio group were slightly sicker at presentation Low ratio group were slightly sicker at presentation

Recommended anticipating transfusion needs of severely injured trauma pts Recommended anticipating transfusion needs of severely injured trauma pts Emphasized preventing coagulopathy with early* FFP, cryoprecipitate and platelets Emphasized preventing coagulopathy with early* FFP, cryoprecipitate and platelets * before 1 blood volume and/or signs of coagulopathy

MTP May have implications on blood supply May have implications on blood supply Will necessitate the availability of FFP on relatively short notice Will necessitate the availability of FFP on relatively short notice –Some blood banks in trauma centers keep stock of thawed FFP, refrigerated for 5d –This fresh refrigerated plasma has 20% less factor activity

Platelets

Platelets Traditionally transfused if <50x10 9 /L Traditionally transfused if <50x10 9 /L Johansson et al. showed increased survival in AAA patients who received platelet transfusions to keep >100x10 9 /L Johansson et al. showed increased survival in AAA patients who received platelet transfusions to keep >100x10 9 /L Cosgriff et al. MT patients Cosgriff et al. MT patients –Survivors had plt:RBC of 1:1.3 –Non-survivors had plt:RBC of 1:2

MTP Transfusion of pRBC’s, plasma and platelets in a 1:1:1 ratio results in a solution that has: Transfusion of pRBC’s, plasma and platelets in a 1:1:1 ratio results in a solution that has: –Hematocrit 30% –Coagulation factors 60% –Platelets 80 x10 9 /L Mimics whole blood proportions Mimics whole blood proportions Whole blood out  whole blood in Whole blood out  whole blood in

Other therapies Cryoprecipitate 15mL/U Cryoprecipitate 15mL/U –100U factor VIII –250mg fibrinogen –Also vWF, factor XIII and fibronectin Given in doses of 6-10U Given in doses of 6-10U Indicated when fibrinogen <1g/L with ongoing bleeding Indicated when fibrinogen <1g/L with ongoing bleeding Not currently indicated during early transfusion Not currently indicated during early transfusion

Recombinant factor VIIa Potent procoagulant Potent procoagulant Showed great promise in treatment of refractory massive hemorrhage Showed great promise in treatment of refractory massive hemorrhage Decreased transfusion utilization and improved outcome associated with the use of recombinant factor viia as an adjunct in trauma Kenneth D. Boffard, Brian Warren, Philip Iau, et al

rFVIIa Now emerging literature has made this “last ditch” treatment more controversial Now emerging literature has made this “last ditch” treatment more controversial May not be any added survival benefit May not be any added survival benefit May have increased thrombosis risk May have increased thrombosis risk Thomas et al. J Trauma 2007 – –thrombosis risk of 9.4% in pts receiving rFVIIa

Efficacy and Safety of Recombinant Activated Factor VII to Control Bleeding in Nonhemophiliac Patients: A Review of 17 Randomized Controlled Trials Ann Thorac Surg 2008;86: “generalized use of rFVIIa to prevent or to control bleeding in nonhemophiliac patients can not be recommended” Comprehensive Canadian Review of the Off-Label Use of Recombinant Activated Factor VII in Cardiac Surgery Circulation 2008; 118: “ rFVIIa is associated with reduced blood product transfusions and … does not appear to be associated with increased or decreased complication rates ”

Fibrinolytics Hyperfibrinolysis contributes to coagulopathy Hyperfibrinolysis contributes to coagulopathy Antifibrinolytics bind plasminogen/tPA and reduce fibrinolysis Antifibrinolytics bind plasminogen/tPA and reduce fibrinolysis –Aprotinin – Serine protease –Aminocaproic acid –Tranexamic acid Lysine proteases

Aprotinin Aprotinin –Cochrane review showed no evidence supporting routine use Tranexamic acid Tranexamic acid Aminocaproic acid Aminocaproic acid –Cochrane: no adequate studies to assess benefit in trauma CRASH-2: tranexamic acid Vs. Placebo CRASH-2: tranexamic acid Vs. Placebo Fibrinolytics

Summary Massive transfusion is uncommon in civilian trauma Massive transfusion is uncommon in civilian trauma MT has several preventable complications MT has several preventable complications “Early” coagulation factor replacement with FFP may result in lower mortality due to ongoing hemorrhage “Early” coagulation factor replacement with FFP may result in lower mortality due to ongoing hemorrhage No current indications for factor VIIa No current indications for factor VIIa No current indications for antifibrinolytics No current indications for antifibrinolytics

References Massive transfusion and nonsurgical hemostatic agents Crit Care Med 2008 Vol. 36, No. 7 (Suppl.) Black Hawk Down: The evolution of resuscitation strategies in massive traumatic hemorrhage Critical care :305 Rosen Tintinalli

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