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Anthony Holley, a world famous transfusion and coagulation guru, draws on his military, ED and ICU experience and talks about the most recent blood transfusion guidelines. They are a great resource and can be downloaded here. This talk is different to the last one he gave at Bedside Critical Care 2012!
Citation preview
Bedside Critical Care 2012
Reconsidering Coagulopathy and it’s Management ?
Anthony HolleyIntensivist
Royal Brisbane & Women’s Hospital
Bedside Critical Care 2012
http://www.nba.gov.au/guidelines/order/index.htmlhttp://www.nba.gov.au/guidelines/review.html
Exsanguination
Bedside Critical Care 2012
Haemorrhage remains a major and potentially reversible cause of all trauma deaths.
More pronounced in the setting of penetrating trauma.
Current literature from the Afghanistan and Iraq conflicts report that as many as 15% of casualties require massive transfusions
Mortality in this group is 20-50%
Bedside Critical Care 2012
Coagulopathy
Acidosis Hypothermia
Bleeding
Kashuk JL, Moore EE, Millikan JS, Moore JB. Major abdominal vasculartrauma—a unified approach. J Trauma 1982; 22:672-679.
Classically Trauma-induced Coagulopathy
TOWARDS A DEFINITION, CLINICAL AND LABORATORY CRITERIA, AND A SCORING SYSTEM FOR DISSEMINATED INTRAVASCULAR COAGULATION
The consensual definition of DIC as proposed by the ISTH
“DIC is an acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes. It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction”
Fletcher B. Taylor et al on behalf of the Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH) 2001
Bedside Critical Care 2012
Diagnostic algorithm for the diagnosis of overt DIC
1.Risk assessment: Does the patient have a underlying disorder known to be associated with overt DIC? If yes: proceed; If no: do not use this algorithm;
2. Order global coagulation tests (platelet count, prothrombin time (PT), fibrinogen, soluble fibrin monomers or fibrin degradation products)
3. Score global coagulation test resultsplatelet count (>100 = 0; <100 = 1; <50= 2)elevated fibrin-related marker (e.g. soluble fibrin monomers/fibrin degradation products) (no increase: 0; moderate increase: 2; strong increase: 3)prolonged prothrombin time (< 3 sec.= 0; > 3 sec. but < 6 sec.= 1; > 6 sec. = 2)fibrinogen level (> 1.0 gram/l = 0; < 1.0 gram/l = 1)
4. Calculate score
5. If > 5: compatible with overt DIC; repeat scoring dailyIf < 5: suggestive (not affirmative) for non-overt DIC; repeat next 1-2 days
Bedside Critical Care 2012
Clinical conditions that may be associated with overt DIC
1.sepsis/severe infection (any micro-organism)2.trauma (e.g. polytrauma, neurotrauma, fat embolism)3.organ destruction (e.g. severe pancreatitis)4.malignancy- solid tumors- myeloproliferative/lymphoproliferative malignancies5.obstetrical calamities- amniotic fluid embolism- abruptio placentae6.vascular abnormalities- Kasabach-Merrit Syndrome- large vascular aneurysms 7.severe hepatic failure8.severe toxic or immunologic reactions- snake bites- recreational drugs- transfusion reactions- transplant rejection
Bedside Critical Care 2012
Diagnostic algorithm for the diagnosis of overt DIC
2. Order global coagulation tests (platelet count, prothrombin time (PT), fibrinogen, soluble fibrin monomers or fibrin degradation products)
3. Score global coagulation test results
platelet count (>100 = 0; <100 = 1; <50= 2)
elevated fibrin-related marker (e.g. soluble fibrin monomers/fibrin degradation products) (no increase: 0; moderate increase: 2; strong increase: 3)
prolonged prothrombin time (< 3 sec.= 0; > 3 sec. but < 6 sec.= 1; > 6 sec. = 2)fibrinogen level (> 1.0 gram/l = 0; < 1.0 gram/l = 1)
4. Calculate score
5. If > 5: compatible with overt DIC; repeat scoring dailyIf < 5: suggestive (not affirmative) for non-overt DIC; repeat next 1-2 days
A Time to Consider
1.Mechanism of coagulopathy2.Tranexamic acid3.Product ratios 4.Activated factor VII5.Best modality to assess coagulopathy
Bedside Critical Care 2012
Dilution?
Bedside Critical Care 2012
Little or no dilutional effect of crystalloid therapy on the standard tests of coagulation either in vitro or in healthy volunteers
Colloid vs CrystalloidCoagulopathy was present in 10% of
patients who received less than 500 ml of fluid
? Alternative mechanism
Bedside Critical Care 2012
Moderate/severe hypothermia present < 9% of trauma patients
Relationship between hypothermia, shock and injury severity is a weak independent predictor of mortality (OR 1.19)
Very little effect of moderate hypothermia on coagulation proteases.
Significant effects on function and clinical bleeding only at temperatures < 33°C.
Hypothermia?
Bedside Critical Care 2012
Effects of IV HCL acid on human volunteers.
Definite dose–response of acidaemia on clotting function by thromboelastometry.
Little clinically significant effect on protease function down to a pH of 7.2 in in-vitro studies
Animal studies: pH of 7.1 produces only a 20% prolongation of the PT & APTT.
Acidaemia?
Bedside Critical Care 2012
Consumption regarded as a primary cause of traumatic coagulopathy
Little evidence for consumption of clotting factors as a relevant mechanism
In patients without shock coagulation times are never prolonged, regardless of the amount of thrombin generated
Consumption?
Time to Challenge the Dogma?
Bedside Critical Care 2012
“None of these appears to be responsible for acute coagulopathy, and it appears that shock is the prime initiator of the process!"
Bedside Critical Care 2012
Coagulopathy
Acidosis Hypothermia
Bleeding
Inju
ry
Hyperfibrinolysis
Classically Trauma-induced Coagulopathy
APC
Bedside Critical Care 2012
Shock and systemic hypoperfusion?Dose-dependent prolongation of clotting
times with increasing systemic hypoperfusion.
Base deficit (BD) as a surrogate for perfusion
2% of patients with a BD < 6 mEq/l had prolonged clotting times
20% of patients with a BD > 6 mEq/l.
Drivers of Traumatic Coagulopathy?
Bedside Critical Care 2012
Acute coagulopathy in massive transfusion appears to be due to activation of anticoagulant and fibrinolytic pathways.
Thrombomodulin–protein C pathway is implicated.
Mechanism of Acute Traumatic Coagulopathy
Bedside Critical Care 2012
Normal
Haemostasis
Procoagulant
Activity
Antifibrinolytic activity
AnticoagulantActivity
fibrinolytic activity
Thrombus
Bleeding
Bedside Critical Care 2012
With tissue hypoperfusion the endothelium expresses thrombomodulin which complexes with thrombin.
Less thrombin is available to cleave fibrinogen
Thrombin complexed to thrombomodulin activates protein C, which inhibits cofactors V and VIII
Protein C Activation
Protein C Anticoagulant Pathway
Bedside Critical Care 2012
Biological Response Pathological in Shock
Bedside Critical Care 2012
Tissues subjected to low-flow states generate an anticoagulant milieu
Avoids thrombosis of vascular beds.
Bedside Critical Care 2012
Trauma is associated with increased fibrinolytic activity.
Tissue plasminogen activator (tPA) is released from the endothelium following injury and ischaemia.
Local control mechanism to reduce propagation of clot to normal vasculature
Hyperfibrinolysis
Hyperfibrinolysis
Reduction in plasminogen activator inhibitor-1 (PAI-1) levels in tissue hypoperfusion
APC
A new understanding of coagulopathy in trauma: potential therapeutic implications. 2012 Yearbook of Intensive Care and Emergency Medicine. Edited J.-L. Vincent. Springer. Read M, Holley A
Bedside Critical Care 2012
CRASH-2 trial collaborators. The Lancet. 2010;376:23-32
Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with
significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial
Tranexamic acid
Bedside Critical Care 2012
ACEM ASM 2010
Plasminogen activator
PlasminPlasminogen
Blockade Blockade
Tranexamic AcidTranexamic AcidTranexamic AcidTranexamic AcidF
ibrin
olysis
Bedside Critical Care 2012
Bedside Critical Care 2012
The Study
Prospective double blind274 hospitals40 countriesn=20211Tranexamic (n=10 060) acid vs
placebo (10115)1 g over 10 minutes then 1 g over 8
hoursPrimary outcome: in hospital four week
mortality
Bedside Critical Care 2012
Tranexamic AcidTranexamic Acid
Bedside Critical Care 2012
Tranexamic AcidTranexamic Acid
Bedside Critical Care 2012
But............
Entrance criteria soft (HR>110 bpm, SBP<90 mmHg)
70% of patients SBP > 90 mmHgOnly 16% of patients SBP <75 mmHgNo reduction in blood transfusion observedMedian no. of RBC units transfused = 3 in
both groupsNeeds to be given within three hours of
injury
Bedside Critical Care 2012
Tranexamic acid safely reduces the risk of death in bleeding trauma patients!
Bedside Critical Care 2012
Ratios
Bedside Critical Care 2012
Ratios
Bedside Critical Care 2012
Holcomb JB, Wade CE, Michalek JE, Chisholm GB, Zarzabal LA, Schreiber MA, Gonzalez EA, Pomper GJ, Perkins JG, Spinella PC, Williams KL, Park MS. Increased plasma and platelet to red blood cell ratios improves outcome in 466massively transfused civilian trauma patients. Ann Surg 2008; 248:447-458.
Product Ratios
Bedside Critical Care 2012
Massive data base ~ 25 00016% transfused 11.4% received massive transfusionsLogistic regression identified the ratio
of FFP to PRBC use as an independent predictor of survival.
Higher the ratio of FFP:PRBC the greater probability of survival.
The optimal ratio in this analysis was an FFP:PRBC ratio of 1:3 or less.
Teixeira PG, Inaba K, Shulman I, Salim A, Demetriades D, Brown C,Browder T, Green D, Rhee P. Impact of plasma transfusion in massively transfused trauma patients. J Trauma 2009; 66:693-697.
Practice Point
In patients with critical bleeding requiring massive transfusion, insufficient evidence was identified to support or refute the use of specific ratios of RBCs to blood components.
Bedside Critical Care 2012
Bedside Critical Care 2012
Bedside Critical Care 2012
Activated Factor VIIActivated Factor VII
301 trauma patients were enrolled. 143 blunt, 137 penetrating.
Hauser et al. J Trauma. 2010
Sep;69(3):489-500 Bedside Critical Care 2012
Randomized prospective trial573 patients No effect on mortalityNo effect on thrombotic eventsTrial stopped early for lack of efficacy!
Bedside Critical Care 2012
Bedside Critical Care 2012
Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2010;363:1791-1800.
Bedside Critical Care 2012
Bedside Critical Care 2012
Recommendation 2
The routine use of rFVIIa in trauma patients with critical bleeding requiring massive transfusion is not recommended because of its lack of effect on mortality (Grade B) and variable effect on morbidity (Grade C).
Practice Point1. An MTP should include advice on the
administration of rFVIIa when conventional measures – including surgical haemostasis and component therapy – have failed to control critical bleeding.
2. NB: rFVIIa is not licensed for this use. Its use should only be considered in exceptional circumstances where survival is considered a credible outcome
3. When rFVIIa is administered to patients with critical bleeding requiring massive transfusion, an initial dose of 90 μg/kg is reasonable.
Bedside Critical Care 2012
SummaryMore to coagulopathy than acidosis, hypothermia
and dilution.Almost certainly hypoperfusion is the principle
driver.Acidosis, hypothermia and dilution certainly
contribute.Despite advances in our understanding we haven’t
yet found the magic bullet.We will have to wait for the definitive word on
product ratios.Tranexamic acid given early seems to be safe and
effective and we are unlikely to get better evidence than CRASH2
Bedside Critical Care 2012
Bedside Critical Care 2012
Thank YouThank You