CaseCase

28y male involved in an industrial 28y male involved in an industrial accidentaccident

Sustained significant injuries to right Sustained significant injuries to right lower leg, femur and ?hemipelvislower leg, femur and ?hemipelvis

Prolonged extrication “tons of blood” Prolonged extrication “tons of blood” at the sceneat the scene

Case 1Case 1

Looks very unwell with ++ ongoing Looks very unwell with ++ ongoing bleedingbleeding– GCS E3 V4 M5 (12)GCS E3 V4 M5 (12)– Temp 34.7Temp 34.7– HR 160HR 160– BP 77/50 manualBP 77/50 manual– RR 30RR 30– SaOSaO22 97% 10L by mask 97% 10L by mask

What is your initial management?What is your initial management?

CaseCase

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 30minSurgery and IR are held up for 30min

Is there anything else we can do?Is there anything else we can do?

Massive transfusion Massive transfusion (all bleeding stops…)(all bleeding stops…)

Grand RoundsGrand RoundsOct 2Oct 2ndnd 2008 2008

Kristian HechtKristian HechtPGY-3 CCFP-EMPGY-3 CCFP-EM

ObjectivesObjectives

Define massive transfusionDefine massive transfusion Review complications of massive Review complications of massive

transfusiontransfusion Review FMC’s Massive Transfusion Review FMC’s Massive Transfusion

ProtocolProtocol Review literature supporting the MTPReview literature supporting the MTP Review adjunctive therapies in Review adjunctive therapies in

massive hemorrhagemassive hemorrhage

BackgroundBackground First attempted blood transfusion First attempted blood transfusion

was in 1492 after Pope Innocent VIII was in 1492 after Pope Innocent VIII became comatosebecame comatose

Blood from 3 aides was instilled into Blood from 3 aides was instilled into the Pope’s mouththe Pope’s mouth

All 4 diedAll 4 died

BackgroundBackground

In 1600’s many animal-to-human In 1600’s many animal-to-human transfusions attemptedtransfusions attempted– These were later banned due to high These were later banned due to high

mortalitymortality The first documented successful The first documented successful

transfusion was between two dogs in transfusion was between two dogs in 16671667

The first documented human-to-The first documented human-to-human transfusion was in 1818 by Dr. human transfusion was in 1818 by Dr. James Blundell a British obstetricianJames Blundell a British obstetrician

BackgroundBackground Hemorrhage is the second leading Hemorrhage is the second leading

cause of death in traumacause of death in trauma

CNS injury is 1CNS injury is 1stst

May require massive transfusionMay require massive transfusion

BackgroundBackground Massive transfusion (MT):Massive transfusion (MT):

– >10U pRBC’s in 24h>10U pRBC’s in 24h– Replacement of 50% blood volume in 3hReplacement of 50% blood volume in 3h– 4U pRBC in 4h with ongoing major bleeding4U pRBC in 4h with ongoing major bleeding– Replacement with blood loss >150mL/minReplacement with blood loss >150mL/min

Required in only 1% of civilian trauma ptsRequired in only 1% of civilian trauma pts

Mortality rates are between 20 – 50% in Mortality rates are between 20 – 50% in those requiring massive transfusionthose requiring massive transfusion

Complications of MTComplications of MT

Acute hemolytic transfusion reactionsAcute hemolytic transfusion reactions Hyperkalemia Hyperkalemia Acidosis Acidosis HypothermiaHypothermia HypocalcemiaHypocalcemia CoagulopathyCoagulopathy All more common and/or severe with All more common and/or severe with

increasing number of units transfusedincreasing number of units transfused

Acute hemolytic reactionsAcute hemolytic reactions

Most often due to ABO incompatible Most often due to ABO incompatible RBC’s or plasma (clerical error, lab RBC’s or plasma (clerical error, lab error etc)error etc)

Rarely seen with unmatched O+ Rarely seen with unmatched O+ pRBC’spRBC’s

Occasionally with unmatched type Occasionally with unmatched type specific pRBC’sspecific pRBC’s

Commonly with unmatched type Commonly with unmatched type specific specific whole bloodwhole blood

HyperkalemiaHyperkalemia

Storage of pRBC’s results in cell lysis Storage of pRBC’s results in cell lysis and increased extracellular [Kand increased extracellular [K++]]

12 mEq/L at 7d12 mEq/L at 7d

32 mEq/L at 21d32 mEq/L at 21d

HyperkalemiaHyperkalemia

Inconsequential if infused slowlyInconsequential if infused slowly KK++ is shifted to intracellular space is shifted to intracellular space

and later eliminatedand later eliminated If large amounts of pRBC’s infused If large amounts of pRBC’s infused

through a central line a large amount through a central line a large amount of Kof K++ is delivered directly to the RA is delivered directly to the RA– Potentially resulting in…Potentially resulting in…

HyperkalemiaHyperkalemia

If encountered treat as per medical If encountered treat as per medical hyperkalemiahyperkalemia

May be prevented by using May be prevented by using peripheral venous accessperipheral venous access

Use of fresh blood (<14d) may Use of fresh blood (<14d) may decrease incidencedecrease incidence

HypothermiaHypothermia

Traumatized pts are at risk for Traumatized pts are at risk for significant hypothermia due to significant hypothermia due to environmental and surgical exposureenvironmental and surgical exposure

pRBC’s are stored at 4pRBC’s are stored at 4°°C and will C and will cause rapid hypothermia if not put cause rapid hypothermia if not put through warmerthrough warmer

Hypothermia is an independent risk Hypothermia is an independent risk factor for mortality in traumafactor for mortality in trauma

HypothermiaHypothermia

Physiologic effects:Physiologic effects:– Decreased contractilityDecreased contractility– Cardiac dysrhythmia Cardiac dysrhythmia – CoagulopathyCoagulopathy

HypothermiaHypothermia

TreatmentTreatment– Drapes/blanketsDrapes/blankets– Warmed IV fluidsWarmed IV fluids

– Warm humidified OWarm humidified O22

– External rewaming (hot air blankets, External rewaming (hot air blankets, etc)etc)

– Internal rewarming (peritoneal/pleural Internal rewarming (peritoneal/pleural lavage)lavage)

QTc

=510

HypocalcemiaHypocalcemia

Citrate is used as an anticoagulant in Citrate is used as an anticoagulant in all blood productsall blood products

Citrate binds ionized calcium and Citrate binds ionized calcium and inhibits calcium-dependent inhibits calcium-dependent coagulationcoagulation

Higher concentrations in FFP and PltsHigher concentrations in FFP and Plts Usually inconsequential due to rapid Usually inconsequential due to rapid

hepatic metabolismhepatic metabolism May become significant with poor May become significant with poor

circulation and/or large amountscirculation and/or large amounts

HypocalcemiaHypocalcemia

TetanyTetany QT prolongationQT prolongation Decreased myocardial contractilityDecreased myocardial contractility HypotensionHypotension Exacerbation of concomitant Exacerbation of concomitant

hyperkalemiahyperkalemia Coagulopathy (occurs at very low Coagulopathy (occurs at very low

[Ca[Ca2+2+])])

HypocalcemiaHypocalcemia

TreatmentTreatment Correct shockCorrect shock

Decrease rate of blood product Decrease rate of blood product infusioninfusion

IV CaClIV CaCl2 2 1g slowly1g slowly

AcidosisAcidosis

In hemorrhagic shock metabolic In hemorrhagic shock metabolic acidosis results from poor perfusion acidosis results from poor perfusion and subsequent lactate productionand subsequent lactate production

Stored pRBC’s pH Stored pRBC’s pH 6.876.87 at 21dat 21d

Metabolism of exogenous acid may Metabolism of exogenous acid may be decreased due to poor circulation be decreased due to poor circulation or rapid/large amountor rapid/large amount

AcidosisAcidosis

Causes other electrolyte Causes other electrolyte disturbances (hyper Kdisturbances (hyper K++))

Independent risk factor for Independent risk factor for coagulopathycoagulopathy

Activity of factor VIIa decreases by Activity of factor VIIa decreases by 90%90% when pH drops from 7.4 to 7.0 when pH drops from 7.4 to 7.0

AcidosisAcidosis

TreatmentTreatment

– Correction of volume status and Correction of volume status and restoration of tissue perfusion restoration of tissue perfusion

– Use fresh blood products if possibleUse fresh blood products if possible

– Addition of HCOAddition of HCO33-- is ineffective is ineffective

Stored blood productsStored blood products

pH 6.87pH 6.87 [K[K++] 32 mEq/L] 32 mEq/L 44°C°C citratecitrate

CoagulopathyCoagulopathy

ClinicallyClinically– Oozing from IV sites, wounds and Oozing from IV sites, wounds and

uninjured mucosauninjured mucosa

Lab values can correlate poorly with Lab values can correlate poorly with coagulopathycoagulopathy– PT abnormal in 97%PT abnormal in 97%– aPTT abnormal in 70%aPTT abnormal in 70%

CoagulopathyCoagulopathy

Often present on admission esp. with Often present on admission esp. with CNS and penetrating traumaCNS and penetrating trauma

Correlated with increased mortalityCorrelated with increased mortality Often leads to further bleeding and Often leads to further bleeding and

ongoing need for volume ongoing need for volume resuscitationresuscitation

Leads to further worsening of Leads to further worsening of physiologic derrangmentsphysiologic derrangments

Ongoing hemorrhage

Volume replacement

Blood products

Shock acidosis

Coagulopathy

Hyopthermia Hemodilution

Bloody vicious cycle

Hypothermia

HemodilutionConsumptivecoagulation

Derangedmetabolism

Acidosis

Coagulopathy

Hypothermia

HemodilutionConsumptivecoagulation

Derangedmetabolism

Acidosis

Coagulopathy

Normal clottingNormal clotting

Local coagulation at wound

Exposure of tissue factor

Activation of clotting cascade

Tissue injury

Consumptive and Intravascular Consumptive and Intravascular CoagulationCoagulation

Systemic release of thromboplastin

Systemic endothelial damage

Widespread intravascular coagulation

Massive soft tissue damage, long bone fractures, CNS injury

Dilutional CoagulopathyDilutional Coagulopathy

Results from loss of whole blood and Results from loss of whole blood and replacement of factor and platelet-replacement of factor and platelet-poor fluidspoor fluids

ATLS 3:1 replacement of blood loss ATLS 3:1 replacement of blood loss with crystalloidwith crystalloid

Also in shock, fluid shifts from the Also in shock, fluid shifts from the extracellular to vascular space, extracellular to vascular space, worsening hemodilutionworsening hemodilution

Dilutional CoagulopathyDilutional Coagulopathy

First described in 1954First described in 1954 Commonly occurred in those receiving Commonly occurred in those receiving

>10U of stored whole blood (up to >10U of stored whole blood (up to 78%)78%)– Related to stored platelet dysfunction and Related to stored platelet dysfunction and

factor V and VIII deficiencyfactor V and VIII deficiency

1970’s: modified whole blood1970’s: modified whole blood– Platelets removedPlatelets removed– Thromobcytopenia related coagulopathyThromobcytopenia related coagulopathy

Dilutional CoagulopathyDilutional Coagulopathy

1980’s: fractionated component 1980’s: fractionated component transfusiontransfusion– Implemented to reduce infectious disease Implemented to reduce infectious disease

transmission and conserve scarce blood transmission and conserve scarce blood productsproducts

Diluted coagulation factorsDiluted coagulation factors Transfusion of components based on Transfusion of components based on

lab parameterslab parameters (hgb>70, plt >30, (hgb>70, plt >30, INR>1.5)INR>1.5)

Dilutional CoagulopathyDilutional Coagulopathy Traditionally FFP transfusion started after Traditionally FFP transfusion started after

1 blood volume and/or INR>1.51 blood volume and/or INR>1.5

Recommendations based on mathematical Recommendations based on mathematical models in elective surgical patientsmodels in elective surgical patients

Drawbacks to previous recommendationsDrawbacks to previous recommendations– Mathematical models invalid in trauma ptsMathematical models invalid in trauma pts– Relied on lab studiesRelied on lab studies

Difficult to use clinicallyDifficult to use clinically– Inadequate responseInadequate response

FFPFFP

One unit contains:One unit contains:– 0.5g fibrinogen0.5g fibrinogen– All other coagulation factors in All other coagulation factors in

physiologic concentrationsphysiologic concentrations– Will raise factors by 3–5%Will raise factors by 3–5%Contains the most citrate of all blood Contains the most citrate of all blood

productsproducts

Slow paradigm shift to factor Slow paradigm shift to factor replacement replacement beforebefore the development of the development of coagulopathycoagulopathy

Now trending to replacement of Now trending to replacement of RBC:plasma:platelets at 1:1:1 ratiosRBC:plasma:platelets at 1:1:1 ratios

Ongoing hemorrhage

Shock acidosis

Coagulopathy

Hyopthermia Hemodilution

CrystalloidBlood

products

Bloody vicious cycle

Massive Transfusion Massive Transfusion ProtocolProtocol

Implemented in June 2008 as a pilotImplemented in June 2008 as a pilot

Developed by Trauma Services in Developed by Trauma Services in conjunction with ER, ICU, OR, conjunction with ER, ICU, OR, Transfusion Medicine and Canadian Transfusion Medicine and Canadian Blood servicesBlood services

Massive Transfusion Massive Transfusion ProtocolProtocol

Has been activated ~40 timesHas been activated ~40 times– Mostly trauma ptsMostly trauma pts– Some OR cases and GI bleeds Some OR cases and GI bleeds – Currently in a ‘trial phase’Currently in a ‘trial phase’

Currently evaluating: time to MTP Currently evaluating: time to MTP pack arrival, trauma severity score, pack arrival, trauma severity score, type of injury and final ratio of blood type of injury and final ratio of blood productsproducts

2 Protocol based on varying levels of evidence and expert consensus

MTPMTP

Cinat et al. examined FFP:RBC ratios Cinat et al. examined FFP:RBC ratios in civilian trauma in civilian trauma Arch Surg 1999; 134:964-968Arch Surg 1999; 134:964-968

Survivors had avg ratio 1:1.8Survivors had avg ratio 1:1.8

Nonsurvivors had avg ratio 1:2.5Nonsurvivors had avg ratio 1:2.5

Retropsective study involving 246 Retropsective study involving 246 combat-related trauma patients in Iraq combat-related trauma patients in Iraq requiring >10U pRBC’s between 2003 requiring >10U pRBC’s between 2003 and 2005and 2005

Compared mortality relative to the ratio Compared mortality relative to the ratio of plasma:RBC transfusedof plasma:RBC transfused

LimitationsLimitations

Retrospective study Retrospective study Young healthy patient populationYoung healthy patient population Mostly penetrating traumaMostly penetrating trauma Unclear how groups were allocated Unclear how groups were allocated

to receive different ratiosto receive different ratios Low ratio group were slightly sicker Low ratio group were slightly sicker

at presentationat presentation

Recommended anticipating transfusion Recommended anticipating transfusion needs of severely injured trauma ptsneeds of severely injured trauma pts

Emphasized preventing coagulopathy Emphasized preventing coagulopathy with early* FFP, cryoprecipitate and with early* FFP, cryoprecipitate and plateletsplatelets

**before 1 blood volume and/or signs of before 1 blood volume and/or signs of coagulopathycoagulopathy

MTPMTP

May have implications on blood May have implications on blood supplysupply

Will necessitate the availability of Will necessitate the availability of FFP on relatively short noticeFFP on relatively short notice– Some blood banks in trauma centers Some blood banks in trauma centers

keep stock of thawed FFP, refrigerated keep stock of thawed FFP, refrigerated for 5dfor 5d

– This fresh refrigerated plasma has 20% This fresh refrigerated plasma has 20% less factor activityless factor activity

PlateletsPlatelets

PlateletsPlatelets

Traditionally transfused if <50x10Traditionally transfused if <50x1099/L/L Johansson et alJohansson et al. . showed increased showed increased

survival in AAA patients who received survival in AAA patients who received platelet transfusions to keep platelet transfusions to keep >100x10>100x1099/L /L

Cosgriff et al. MT patientsCosgriff et al. MT patients– Survivors had plt:RBC of 1:1.3Survivors had plt:RBC of 1:1.3– Non-survivors had plt:RBC of 1:2Non-survivors had plt:RBC of 1:2

MTPMTP

Transfusion of pRBC’s, plasma and Transfusion of pRBC’s, plasma and platelets in a 1:1:1 ratio results in a platelets in a 1:1:1 ratio results in a solution that has:solution that has:– Hematocrit 30%Hematocrit 30%– Coagulation factors 60%Coagulation factors 60%– Platelets 80 x10Platelets 80 x1099/L/L

Mimics whole blood proportionsMimics whole blood proportions Whole blood out Whole blood out whole blood in whole blood in

Other therapiesOther therapies

Cryoprecipitate 15mL/UCryoprecipitate 15mL/U– 100U factor VIII100U factor VIII– 250mg fibrinogen250mg fibrinogen– Also vWF, factor XIII and fibronectinAlso vWF, factor XIII and fibronectin

Given in doses of 6-10UGiven in doses of 6-10U Indicated when fibrinogen <1g/L with Indicated when fibrinogen <1g/L with

ongoing bleedingongoing bleeding Not currently indicated during early Not currently indicated during early

transfusiontransfusion

Recombinant factor VIIaRecombinant factor VIIa

Potent procoagulantPotent procoagulant Showed great promise in treatment Showed great promise in treatment

of refractory massive hemorrhageof refractory massive hemorrhageDecreased transfusion utilization and improved Decreased transfusion utilization and improved outcome associated with the use of recombinant outcome associated with the use of recombinant factor viia as an adjunct in trauma factor viia as an adjunct in trauma

Kenneth D. Boffard, Brian Warren, Philip Iau, et alKenneth D. Boffard, Brian Warren, Philip Iau, et al

rFVIIarFVIIa

Now emerging literature has made this Now emerging literature has made this “last ditch” treatment more controversial“last ditch” treatment more controversial

May not be any added survival benefitMay not be any added survival benefit

May have increased thrombosis riskMay 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 Efficacy and Safety of Recombinant Activated Factor VII to Control Bleeding in Nonhemophiliac Patients: A VII to Control Bleeding in Nonhemophiliac Patients: A Review of 17 Randomized Controlled Trials Review of 17 Randomized Controlled Trials

Ann Thorac SurgAnn Thorac Surg 2008;86:1038-1048 2008;86:1038-1048

““generalized use of rFVIIa to prevent or to control bleeding generalized use of rFVIIa to prevent or to control bleeding in in nonhemophiliac patients can not be recommended” nonhemophiliac patients can not be recommended”

Comprehensive Canadian Review of the Off-Label Use Comprehensive Canadian Review of the Off-Label Use of Recombinant Activated Factor VII in Cardiac Surgeryof Recombinant Activated Factor VII in Cardiac Surgery

Circulation 2008; 118:331-338Circulation 2008; 118:331-338

““rFVIIa is associated with reduced blood product rFVIIa is associated with reduced blood product transfusions transfusions and … does not appear to be associated with and … does not appear to be associated with increased or increased or decreased complication ratesdecreased complication rates””

FibrinolyticsFibrinolytics

Hyperfibrinolysis contributes to Hyperfibrinolysis contributes to coagulopathycoagulopathy

Antifibrinolytics bind Antifibrinolytics bind plasminogen/tPA and reduce plasminogen/tPA and reduce fibrinolysisfibrinolysis– Aprotinin Aprotinin – Serine protease– Serine protease

– Aminocaproic acidAminocaproic acid– Tranexamic acidTranexamic acid

Lysine proteases

AprotininAprotinin– Cochrane review showed no evidence Cochrane review showed no evidence

supporting routine usesupporting routine use

Tranexamic acidTranexamic acid Aminocaproic acidAminocaproic acid

– Cochrane: no adequate studies to assess Cochrane: no adequate studies to assess benefit in traumabenefit in trauma

CRASH-2: tranexamic acid Vs. PlaceboCRASH-2: tranexamic acid Vs. Placebo

FibrinolyticsFibrinolytics

SummarySummary

Massive transfusion is uncommon in Massive transfusion is uncommon in civilian traumacivilian trauma

MT has several preventable complicationsMT has several preventable complications ““Early” coagulation factor replacement Early” coagulation factor replacement

with FFP may result in lower mortality due with FFP may result in lower mortality due to ongoing hemorrhageto ongoing hemorrhage

No current indications for factor VIIaNo current indications for factor VIIa No current indications for antifibrinolyticsNo current indications for antifibrinolytics

ReferencesReferences

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 2008 12:305

Rosen Tintinalli

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