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Acute Care Update: Causes,Consequences, and Strategies for
Managing Critical Bleeding
A podcast educational activity based on a live programconducted on December 8, 2008 in Orlando, Florida
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Acute Care Update: Causes, Consequences, and Strategiesfor Managing Critical Bleeding
P R O G R A M A G E N D A
Bleeding in Medical and Surgical Patients: Common Causes, Mechanisms, and
Treatment OptionsRobert MacLaren, Pharm.D., FCCP, FCCM
Patient case: Anticoagulant-associated Intracranial HemorrhageGretchen M. Brophy, Pharm.D., BCPS, FCCP, FCCM
Patient case: Surgery-associated BleedingJeremy D. Flynn, Pharm.D., BCPS
P R O G R A M F A C U L T Y
Robert MacLaren, Pharm.D., FCCP, FCCM, Program ChairAssociate ProfessorUniversity of Colorado School of PharmacyDenver, Colorado
Gretchen M. Brophy, Pharm.D., BCPS, FCCP, FCCMAssociate Professor of Pharmacy and NeurosurgeryVirginia Commonwealth UniversityMedical College of Virginia CampusRichmond, Virginia
Jeremy D. Flynn, Pharm.D., BCPSClinical Pharmacist SpecialistUK HealthCare-Pharmacy Services
Assistant ProfessorDepartment of Pharmacy Practice and ScienceUniversity of Kentucky College of PharmacyLexington, Kentucky
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Acute Care Update: Causes, Consequences, and Strategiesfor Managing Critical Bleeding
D I S C L O S U R E S T A T E M E N TIn accordance with the Accreditation Council for Continuing Medical Educations and the
Accreditation Council for Pharmacy Educations Standards for Commercial Support,ASHP Advantage requires that all individuals involved in the development of programcontent disclose their relevant financial relationships. A person has a relevant financialrelationship if the individual or his or her spouse/partner has a financial relationship (e.g.,employee, consultant, research grant recipient, speakers bureau, or stockholder) in anyamount occurring in the last 12 months with a commercial interest whose products orservices may be discussed in the CME activity content over which the individual hascontrol. The existence of these relationships is provided for the information ofparticipants and should not be assumed to have an adverse impact on presentations.
All faculty and planners for ASHP Advantage education activities are qualified andselected by ASHP Advantage and required to disclose any relevant financial
relationships with commercial interests. ASHP Advantage identifies and resolvesconflicts of interest prior to an individuals participation in development of content for aneducational activity.
The faculty and planners report the following relationships:
Robert MacLaren, Pharm.D., FCCP, FCCM, Program Chair
Dr. MacLaren reports that he has served as a consultant for Novo Nordisk.
Gretchen M. Brophy, Pharm.D., BCPS, FCCP, FCCM
Dr. Brophy reports that she has served as a consultant for and has received researchgrant funding from Novo Nordisk.
Jeremy D. Flynn, Pharm.D., BCPS
Dr. Flynn reports that he has served as a consultant for Novo Nordisk and TheMedicines Company.
Kristi Hofer, Pharm.D.
Dr. Hofer reports no relationships pertinent to this activity.
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Acute Care Update: Causes, Consequences, and Strategiesfor Managing Critical Bleeding
P R O G R A M O V E R V I E W
The clinical and economic consequences of serious bleeding in critically ill patients aresignificant. Uncontrolled hemorrhage is considered the leading cause of preventable
death in the United States. Because health system formularies include many agents topromote and inhibit blood coagulation, pharmacists need to know how to use themsafely and appropriately.
Transfusion of blood products is often required to manage serious bleeding in critically illpatients; however, there are significant risks associated with transfusion of bloodproducts. Consequently, pharmacologic strategies, including aminocaproic acid,tranexamic acid, desmopressin, and recombinant activated factor VIIa, are beinginvestigated for controlling bleeding and reducing the need for transfusions. Pharmacistspracticing in the acute care setting must keep abreast of this evolving body of knowledgeto ensure that these agents continue to be used appropriately. Pharmacists involved inmedication order review and approval, development and implementation of clinical
guidelines and protocols, and formulary decision-making, as well as clinical specialistspracticing in critical care, surgical, and emergency care settings need access to currentinformation on agents used to manage bleeding in critically ill patients.
This educational activity will examine conditions that may lead to bleeding and strategiesfor managing bleeding, including both conventional treatments and emerging therapeuticalternatives. Using patient case examples and an automated audience response system,faculty will engage participants in the clinical decision-making process involved inmanaging patients with critical bleeding.
L E A R N I N G O B J E C T I V E S
At the conclusion of this knowledge-based educational activity, participants should beable to:
List the most common causes of bleeding in hospitalized patients.
Analyze recently published data regarding the safety and efficacy of variousagents used to control bleeding in critically ill patients.
When presented with a patient case, suggest therapeutic options for managingbleeding in the perioperative and acute care settings.
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Acute Care Update: Causes, Consequences, and Strategiesfor Managing Critical Bleeding
C O N T I N U I N G E D U C A T I O N A C C R E D I T A T I O N
The American Society of Health-System Pharmacists is accredited by
the Accreditation Council for Pharmacy Education as a provider ofcontinuing pharmacy education. The program provides 2.0 hours (0.2CEUs) of continuing education credit (program number 204-000-08-455-H01P).
F O R M A T A N D M E T H O D S
This is an online activity consisting of audio for three presentations, a post-test, and anactivity evaluation tool. Participants must listen to all presentations, take the activitypost-test, and complete the course evaluation to receive continuing education credit. A
minimum score of 70% is required on the test for credit to be awarded, and participantsmay print their official statements of continuing education credit immediately. Theestimated time to complete this activity is two hours. This activity is provided free ofcharge.
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Acute Care Update: Causes, Consequences, and Strategiesfor Managing Critical Bleeding
INSTRUCTIONS FOR TAKING POST-TESTS AND
RECEIVING YOUR CE STATEMENTS ONLINE FOR PODCASTACTIVITIES
The online ASHP Learning Center allows participants to obtain their CE statements
conveniently and immediately using any computer with an Internet connection. To takethe posttest and obtain your CE statement for this ASHP Advantage Podcast activity,please follow these steps:
1. Type http://www.ashpadvantage.com/podcasts in your internet browser. Click on"Take Post Test" link under the name of the podcast.
2. Log in to the ASHP Learning Center using your e-mail address and password.
3. If you have not logged in to the new ASHP Learning Center (launched August2008) and are not a member of ASHP, you will need to set up an account byclicking on Become a user and following the instructions.
4. Click on the radio button next to the correct answer for each question. Once youare satisfied with your selections, click Grade Test to process your test andcomplete the remaining steps to complete the program evaluation and print yourCE statement.
If you have any problems processing your CE, contact ASHP Advantage atsupport@ashpadvantage.com.
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Acute Care Update: Causes, Consequences, and Strategiesfor Managing Critical Bleeding
Robert MacLaren, Pharm.D., FCCP, FCCM, Program ChairAssociate ProfessorUniversity of Colorado School of PharmacyDenver, Colorado
Robert MacLaren, Pharm.D., FCCP, FCCM, is Associate Professor in the Department ofClinical Pharmacy at the University of Colorado Denver School of Pharmacy in Aurora,Colorado. In addition, he is a clinical pharmacist in the medical intensive care unit at theUniversity of Colorado Hospital, which is also located on the Anschutz Medical Campusin Aurora. Dr. MacLaren also serves as co-director of the critical care residency at theUniversity of Colorado.
After completing his undergraduate degree in pharmacy at the University of BritishColumbia in Vancouver, Canada, Dr. MacLaren earned his Doctor of Pharmacy degree
at the University of Utah in Salt Lake City and completed a critical care specialtyresidency in Memphis at the University of Tennessee and Baptist Memorial Hospital. Heworked for two years as a critical care specialist at the Queen Elizabeth II HealthSciences Centre in Halifax, Canada, before joining the faculty at the University ofColorado.
Dr. MacLaren is a fellow of the American College of Clinical Pharmacy and the Societyof Critical Care Medicine. His clinical research interests include gastrointestinal motilitydysfunction associated with critical illness and the use of intravenous glutamine as asupplement to parenteral nutrition. He conducts animal studies of acetaminophentoxicity and has been involved with outcomes research of pharmacologic therapies andthe impact of pharmacists in the intensive care unit. He has authored several articles
relating to the pharmacologic and nutritional therapies of critically ill patients and hasbeen an invited speaker at national and international meetings.
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Bleeding in Medical and SurgicalPatients: Common Causes,Mechanisms, and Treatment
Robert MacLaren, Pharm.D., FCCM, FCCP
Associate Professor
University of Colorado School of Pharmacy
Denver, Colorado
Case Scenario Jill is a 58-y.o. woman admitted with septic shock
and oliguria. Her PMH is significant for PE 2 yearsago (no longer requiring anticoagulation, but shetakes aspirin 325 mg daily)
Baseline labs show platelets 37 x 109/L, Hct 24%(for which 2 units of RBCs are administered for earlygoal directed therapy of Hct >30%), INR 1.7, aPTT48 seconds, BUN 85 mg/dL, ALT 2200 IU/L, and
AST 3450 IU/L
APACHE II score >25, so activated protein C isstarted
She receives 8 L normal saline and norepinephrine0.3 mcg/kg/min, is intubated, and renal support isstarted
What risk factors does Jill have forhemorrhage?
A. Anticoagulant use
(activated protein C,
aspirin)
B. Baseline coagulopathy
C. Thrombocytopenia
D. Liver and renal
dysfunction
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Reasons to Transfuse
0
25
50
75
100
LowHg
Bleed
LowBP
Surgery
Ischemia
Othe
r
25-30% of all transfusions are in the ICU
Corwin HLet al. Crit Care Med. 2004;32:39-52.
N=4892
patients from284 ICUs
Causes of Critical Bleeding
Thrombocytopenia (
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Coagulopathy Reflected by prolonged prothrombin time (PT) or
activated partial thromboplastin time (aPTT) of
1.5 times the upper limit of the normal range
General causes:
Test Result Likely Causes
PT prolonged, aPTT normal Factor VII deficiency, mild vitamin K
deficiency, mild liver dysfunction, vitamin K
antagonists
PT normal, aPTT prolonged Factor VIII, IX, XI deficiency, unfractionated
heparin, antiphospholipid antibody
Both prolonged Factor II, V, X defi ciency, severe vitamin K
deficiency, global clotting factor deficiency
(lack of synthesis = liver failure, loss =
massive bleeding, consumption = DIC)
Levi Met al. Crit Care. 2006; 10:222.
Thrombocytopenia/CoagulopathyDiagnosis in the ICU
Platelet count: 50 x109/L in 24 hours
Normal Prolonged
Present: DIC
Absent: Sepsis
Liver failure
HIT antibody present withheparin exposure
PT?
D-dimer/ fibrindegradation products?
Schistocytes present, thenthrombotic microangiopathy
Antiplatelet antibodies or
medications
Bone marrow suppression
Levi Met al. Crit Care. 2006; 10:222.
(Collagen)
XII XIIa
XI XIa
IX Ca++
X
IXaPF 3
Ca++VIII
XaCa++PF 3V
X
Factor IIICa++
VIIa VII
XIII
Fibrin(monomer/polymer)
ThrombinProthrombin(II)
Fibrinogen(I)
XIIIa
StableFibrin
Polymer
Monitored byProthrombin Time
(PT, INR)Measures
VII, X, V, II, I
Monitored byActivated PartialThromboplastin
Time(aPTT)
MeasuresXII, XI, X, IX, VIII,
V, II, I
EXTRINSIC SYSTEMINTRINSIC SYSTEM
(Tissue Factor)
The Clotting Cascade
Adapted from Hirsh Jet al. Circulation. 2007; 116:552-60.
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Factors Contributing to AbnormalCoagulation
Hypocalcemia
Dilution
Hypothermia
Limits platelet activation
and clotting factor function
Mortality OR = 1.2
Dilution and
hypothermia
Hypothermia
Acidosis Reduces clotting factor function (e.g., VII activity reduced
90% at pH of 7.20) due to altered protease activity andlimited anion exposure of phospholipids
Cohort analysis of recombinant factor VIIa showed pH
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DIC Common causes
Sepsis, trauma/surgery/burns, malignancy (solid tumors,
myeloproliferative, or lymphoproliferative), immunologic reactions
(transplant rejection, transfusion, snake bites), obstetrical calamities,
severe liver failure, pancreatitis, vascular abnormalities, cardio-
pulmonary bypass Underlying themes = systemic inflammatory response and TF exposure
Diagnos is
Laboratory Test 0 Points 1 Point 2 Points 3 Points
Platelet count
(x 109/L)
>100 50-100 100
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The Importance of Exposed Tissue Factor
Adapted from Levi M. Crit Care Med. 2007; 35:2191-5.
Massive Blood Loss/Transfusion
Defined as hemorrhage requiring 10 units of
RBCs in 24 hours
Bleed causes loss and consumption of
clotting factors, platelets, fibrinogen, etc.
Hemodilution from saline resuscitation (room
temperature and chloride-induced acidosis)
Blood transfusions contain citrate, which
binds calcium, and are acidic (pH 6.3-7)
Napolitano LMet al. Crit Care Clin. 2004; 20:255-68.Hardy JF et al. Can J Anaesth. 2006; 53(6 Suppl):S40-58.
Spahn DRet al. Br J Anaesth. 2005; 95:130-9.
Storage of donor blood causes biochemical and corpuscularchanges to RBC: Depletion of adenosine triphosphate and 2,3-DPG
Activate platelets via thromboxane A2 and adenosine diphosphate
Membrane vesiculation and phospholipid exposure to activatethrombin
Loss of cell deformability to induce endothelial damage and
margination of platelets Increased time for pro-inflammatory cytokine production
pH of stored blood ~ 6.3
Old Blood
Napolitano LMet al. Crit Care Clin. 2004; 20:255-68. Hardy JF et al. Can J Anaesth. 2006; 53(6 Suppl):S40-58.Spahn DRet al. Br J Anaesth. 2005; 95:130-9.
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Platelet Dysfunction
Drugs: aspirin, NSAIDs, dipyridamole,clopidogrel, ticlopidine, glycoprotein IIb/IIIainhibitors
Microangiopathy TTP due to deficiency of protease that cleaves vWf to
cause ultra-large vWf multimers that readily attach toendothelium and platelets
HUS typical of E. coli O157:H7 that releases cytotoxinresponsible for endothelial and platelet activation
Immune-mediated HIT, drug- and non-drug-induced immune-mediated
mechanisms
Zimmerman LH. Pharmacotherapy. 2007; 27(9 Pt 2):45S-56S.Jaffer AK. J Thromb Thrombolysis. 2008; 25:85-90.
(Collagen)
XII XIIa
XI XIa
IX Ca++
X
IXaPF 3
Ca++VIII
XaCa++PF 3V
X
Factor IIICa++
VIIa VII
XIII
Fibrin(monomer/polymer)
ThrombinProthrombin(II)
Fibrinogen(I)
XIIIa
StableFibrin
Polymer
EXTRINSIC SYSTEMINTRINSIC SYSTEM
(Tissue Factor)
Mechanisms of Anticoagulants
Adapted from Hirsh J et al. Circulation.2007; 116:552-60.
Heparin
Fondaparinux
DTI
LMWH
APC
Fibrinolytics
Goals of Therapy
Stop or control hemorrhage
Minimize blood product use
Minimize adverse events
Hgb of 7-8 g/dL, Hct of 21-24%
INR
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Therapeutic Options Treat the etiology!
Blood products Red blood cells (RBCs)
Whole blood
Platelets (plts) Fresh frozen plasma (FFP)
Prothrombin complex concentrate (PCC)
Cryoprecipitate
Cryosupernatant
Pharmacologic agents Local hemostatic agents/sealants
Vitamin K
Recombinant activated factor VII (rFVIIa)
Desmopressin (DDAVP)
Conjugated estrogens
Anti-fibrinolytic agents (aprotinin, aminocaproic acid, tranexamic acid)
Others: recombinant activated factor VIII (rFVIIIa), recombinantactivated factor IX (rFIXa), recombinant activated factor XI (rFXIa), vWfconcentrate
Shander A et al. Pharmacotherapy. 2007; 27(9 Pt 2):57S-68S.Voils S. Pharmacotherapy. 2007; 27(9 Pt 2):69S-84S.
Blood ProductsProduct Contents Indications and Dose Concerns*
P la tel et s T hro mb ocy tes in pl as ma P l ts
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Managing Anticoagulant-InducedHemorrhage
Anticoagulant Reversing Strategy
Warfarin Vitamin K + FFP or PPC r FVIIa (low dose)
Heparin Protamine
Low molecular weight
heparin
Protamine (anti-IIa, ~60% anti-Xa)
Fondaparinux, direct
thrombin inhibitors
PCC rFVIIa
Fibr inolyt ics Anti fibr inolyt ics + FFP or PCC rFVIIa
Activated protein C FFP or PCC rFVIIa
Antiplatelet agents Platelets + desmopressin
Zimmerman LH. Pharmacotherapy. 2007; 27(9 Pt 2):45S-56S.Jaffer AK. J Thromb Thrombolysis. 2008; 25:85-90.
Protocols and Targeted Therapy
Several institution-specific protocols andguidelines directing therapy show similarpatient outcomes while minimizing bloodproduct use
Targeted therapy based on point-of-caretesting (PT, aPTT, plts fibrinogen thromboelastography) reducesprocoagulant and blood product use whileimproving patient outcomes (shorter
surgical time)Rebuck JA. Pharmacotherapy. 2007; 27(9 Pt 2):103S-9S.Despotis G et al. Transfusion. 2008; 48(1 Suppl):2S-30S.
Thromboelastography
Parame ter Interpretat ion Th erap y
r (15-23
min)
Quantity of
clotting factors
FFP
K (5-10
min)
Rate of clot
formation
Fibrinogen
(cryoprecipitate)
(22-38) Rate of clot
formation
Fibrinogen
(cryoprecipitate)
MA (47-58mm)
Strength ofclot and
platelet
activation
Platelets desmopressin
rFVIIa
A60 (>
90%)
Fibrinolysis Antifibrinolytics
MacLaren R. Pharmacotherapy. 2007; 27(9 Pt 2):93S-102S.
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Case Scenario Jill is a 58-y.o. woman admitted with septic shock and
oliguria. Her PMH is significant for PE 2 years ago (no
longer requiring anticoagulation, but she takes aspirin
325 mg daily) Baseline labs show platelets 37 x 109/L, Hct 24% (for
which 2 units of RBCs are administered for EGT of Hct
>30%), INR 1.7, aPTT 48 seconds, BUN 45 mg/dL, ALT
2200 IU/L, and AST 3450 IU/L
APACHE II score >25, so activated protein C is started
She receives 8 L normal saline and norepinephrine 0.3
mcg/kg/min, is intubated, and renal support is started
What additional information would youlike to know to minimize Jills risk of
hemorrhage?
A. pH
B. Fibrinogen
C. Temperature
D. Ionized calcium
What additional information would youlike to know to minimize Jills risk of
hemorrhage?
pH
Fibrin
ogen
Tem
perature
Ionizedcalcium
41%
30%
7%
22%
A. pH
B. Fibrinogen
C. Temperature
D. Ionized calcium
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Case Scenario The next day, Jills Hct and Hgb drop substantially. A
retroperitoneal hematoma is suspected. Her blood
pressure is tenuous and she is too unstable to go to the
OR. Labs show platelets 24 x 109/L, Hct 19% (for which2 units of RBCs are administered), INR 2.2, aPTT 52
seconds, and fibrinogen 85 mg/dL
Activated protein C is stopped
Which of the following could beetiologies of Jills hemorrhage?
A. Anticoagulant use
(activated protein C,
aspirin)
B. Massive blood loss
C. DIC
D. Liver and renal
dysfunction
Which of the following could beetiologies of Jills hemorrhage?
Anticoagulant
use
(ac...
Massiv
ebloo
dloss
DIC
Live
rand
renald
ysfu
...
0%
20%20%
60%A. Anticoagulant use
(activated protein C,
aspirin)
B. Massive blood lossC. DIC
D. Liver and renal
dysfunction
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In addition to RBCs, what therapy wouldyou recommend to treat Jills bleed?
A. FFP for activated protein C
use, liver dysfunction, andDIC
B. Platelets for
thrombocytopenia and aspirin
use
C. Cryoprecipitate for low
fibrinogen
D. Desmopressin for aspirin use
E. rFVIIa for ???
In addition to RBCs, what therapy wouldyou recommend to treat Jills bleed?
FFP
forac
tivated
prote..
Platelets
forthr
ombo
...
Cryoprec
ipita
teforlow
...
Desmopr
essin
forasp
...
rFVIIa
for?
??
57%
20%
6%8%9%
A. FFP for activated protein C
use, liver dysfunction, and
DIC
B. Platelets for
thrombocytopenia and aspirin
use
C. Cryoprecipitate for low
fibrinogen
D. Desmopressin for aspirin use
E. rFVIIa for ???
You, the pharmacist, may help by?
A. Correcting factors (e.g., pH,
calcium) to maximize
coagulation
B. Realizing the benefits and
limitations of procoagulantagents to optimize therapy
C. Targeting therapy based on
point-of-care testing
D. Understanding the
concerns associated with
therapy to minimize
adverse events
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You, the pharmacist, may help by?
Correctingfactors(e....
Realizingtheb
enefit.
..
Targetingtherapyba
s..
Understanding
thec...
19%
27%
18%
36%
A. Correcting factors (e.g., pH,
calcium) to maximize
coagulation
B. Realizing the benefits and
limitations of procoagulant
agents to optimize therapy
C. Targeting therapy based on
point-of-care testing
D. Understanding the
concerns associated with
therapy to minimize
adverse events
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Acute Care Update: Causes, Consequences, and Strategiesfor Managing Critical Bleeding
SE L E C T E D R E F E R E N C E S- Presentation 1
Caldwell SH, Hoffman M, Lisman T et al. Coagulation disorders and hemostasis in liverdisease: pathophysiology and critical assessment of current management. Hepatology.
2006; 44:1039-46.
Corwin HL, Gettinger A, Pearl RG et al. The CRIT Study: anemia and blood transfusionin the critically ill--current clinical practice in the United States. Crit Care Med.2004;32:39-52.
Despotis G, Eby C, Lublin DM. A review of transfusion risks and optimal management ofperioperative bleeding with cardiac surgery. Transfusion.2008; 48(1 Suppl):2S-30S.
Dutton RP. Goals of therapy in common bleeding emergencies. Pharmacotherapy.2007;27(9 Pt 2):85S-92S.
Hardy JF, de Moerloose P, Samama CM et al. Massive transfusion and coagulopathy:pathophysiology and implications for clinical management. Can J Anaesth.2006; 53(6Suppl):S40-58.
Hirsh J, ODonnell M, Eikelboom JW. Beyond unfractionated heparin and warfarin:current and future advances. Circulation.2007; 116:552-60.
Jaffer AK. Managing anticoagulant related coagulopathy. J Thromb Thrombolysis.2008;25:85-90.
Levi M. Disseminated intravascular coagulation. Crit Care Med.2007; 35:2191-5.
Levi M, Opal SM. Coagulation abnormalities in critically ill patients. Crit Care.2006;10:222.
Lisman T, Leebeek FW. Hemostatic alterations in liver disease: a review onpathophysiology, clinical consequences, and treatment. Dig Surg.2007; 24:250-8.
MacLaren R, Weber LA, Brake H et al. A multicenter assessment of recombinant factorVIIa off-label usage: clinical experiences and associated outcomes. Transfusion.2005;45:1434-42.
MacLaren R. Key concepts in the management of difficult hemorrhagic cases.Pharmacotherapy.2007; 27(9 Pt 2):93S-102S.
Mannucci PM, Levi M. Prevention and treatment of major blood loss. N Engl J Med.2007; 356:2301-11.
Mercer KW, Gail Macik B, Williams ME. Hematologic disorders in critically ill patients.Semin Respir Crit Care Med.2006; 27:286-96.
Napolitano LM, Corwin HL. Efficacy of red blood cell transfusion in the critically ill. CritCare Clin.2004; 20:255-68.
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Acute Care Update: Causes, Consequences, and Strategiesfor Managing Critical Bleeding
Rebuck JA. Practical considerations when developing guidelines for managing criticalbleeding.Pharmacotherapy.2007; 27(9 Pt 2):103S-9S.
Schreiber MA. Coagulopathy in the trauma patient. Curr Opin Crit Care.2005; 11:590-7.
Shander A, Goodnough LT. Update on transfusion medicine. Pharmacotherapy.2007;27(9 Pt 2):57S-68S.
Spahn DR, Rossaint R. Coagulopathy and blood component transfusion in trauma. Br JAnaesth.2005; 95:130-9.
Trotter JF. Coagulation abnormalities in patients who have liver disease. Clin Liver Dis.2006; 10:665-78.
Voils S. Pharmacologic interventions for the management of critical bleeding.Pharmacotherapy.2007; 27(9 Pt 2):69S-84S.
Zimmerman LH. Causes and consequences of critical bleeding and mechanisms ofblood coagulation. Pharmacotherapy.2007; 27(9 Pt 2):45S-56S.
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Acute Care Update: Causes, Consequences, and Strategiesfor Managing Critical Bleeding
Gretchen M. Brophy, Pharm.D., BCPS, FCCP, FCCMAssociate Professor of Pharmacy and NeurosurgeryVirginia Commonwealth UniversityMedical College of Virginia CampusRichmond, Virginia
Gretchen M. Brophy Pharm.D., BCPS, FCCP, FCCM, is Associate Professor ofPharmacy and Neurosurgery at Virginia Commonwealth University (VCU) in Richmond,Virginia. In addition, she is the critical care pharmacist in the Neuroscience IntensiveCare Unit (NSICU) at VCU Health System, Medical College of Virginia Campus.
After earning her Doctor of Pharmacy degree at the University of Arizona, Dr. Brophycompleted pharmacy practice and critical care residencies at the University of Kentucky.She is a Board Certified Pharmacotherapy Specialist and fellow of the American Collegeof Critical Care Medicine and the American College of Clinical Pharmacy.
Dr. Brophy is currently a co-investigator in traumatic brain injury biomarker studiessponsored by the National Institutes of Health and Department of Defense. Herresearch interests include neuroprotection, intracranial hemorrhage, acute ischemicstroke, and biokinetics.
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Anticoagulant-Associated
Intracerebral Hemorrhage:Conventional and EmergingTherapeutic Strategies
Gretchen M. Brophy, Pharm.D., BCPS, FCCP, FCCMAssociate Professor of Pharmacy and NeurosurgeryVirginia Commonwealth UniversityMedical College of VirginiaRichmond, Virginia
Objectives
Identify pharmacologic options for hemostasis in thepatient with intracerebral hemorrhage (ICH)
Review the evidence for use of hemostatic agents inpatients with anticoagulant-associated ICH
Discuss strategies and guidelines for treatment of life-threatening ICH
Determine the best therapeutic strategy for a patient whopresents with anticoagulant-associated ICH
Clinical Case JC is a 72-y.o. African American man who
presents with ICH HPI: he was found down by his wife after she made a 5-
minute trip to the mailbox He is currently unconscious, and was intubated for airway
protection
CT scan: left-sided ICH and subdural hematoma Vitals: BP 184/89 mm Hg; HR 99 bpm; temp 99.8F; height
61; weight 87 kg Neuro: Glasgow coma scale score of 6 PMH: atrial fibrillation, hypertension, hypercholesterolemia Home meds: warfarin 5 mg daily, amlodipine 10 mg daily,
atorvastatin 20 mg daily at bedtime Labs: INR 3.1 JC was admitted to the neuroscience ICU 2 hours after
symptom onset and needs emergent neurosurgicalintervention
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Anticoagulant-AssociatedIntracerebral Hemorrhage (ICH)
ICH accounts for 10-15% of all strokes, andanticoagulant-associated ICH accounts for ~20% of all
ICH1,2
Hematoma expansion is an independent risk factor forpoor outcomes and high mortality3
Warfarin use is a risk factor for hematoma expansionand almost doubles ICH mortality2,4
Rapid INR reversal decreases the risk of hematomagrowth and may decrease time to emergent surgery
1Flaherty ML et al. Neurology. 2006; 66:1182-6. 3Davis SM et al. Neurology. 2006; 66:1175-81.2Rosand J et al.Arch Intern Med.2004;164:880-4. 4Flibotte JJ et al. Neurology. 2004; 63:1059-64.
What pharmacologic treatment options doesJC have for anticoagulant-associated ICH?
Vitamin K Promotes liver synthesis of clotting factors: II, VII, IX, X
Fresh frozen plasma (FFP) Coagulation factors and fibrinogen in variable amounts
Prothrombin complex concentrate (PCC) Factors II, VII, IX, and X and prothrombin, proteins C, S, & Z in
variable amounts
Recombinant activated factor VII (rFVIIa)
rFVIIa only
Liu-DeRyke X et al. Pharmacotherapy. 2008;28:485-95.
Warfarin Reversal Studies and Case Reports
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Guidelines for Managing Elevated INR or Bleedingin Patients Receiving Warfarin
Condition Intervention
Serious bleeding at any elevation of
INR
Withhold warfarin therapyand give vitamin K (10mg by slow IV infusion), supplemented with FFP,
PCC, or rFVIIa, depending on the urgency of thesituation; vitamin K can be repeated every 12 hr(Grade 1C)
Life-threatening bleedingWithhold warfarin therapyand give FFP, PCC, orrFVIIa supplemented with vitamin K (10 mg byslow IV infusion). Repeat, if necessary, dependingon INR (Grade 1C)
Warfarin-associated ICHVitamin K IV + clotting factor replacement (ClassI, B). PCC, rFVIIa, factor IX complex concentrateto normalize INR very rapidly with smallervolumes than FFP but risk of thromboembolismFFP is a potential choice but requires largevolumes and much longer infusion times (ClassIIb, B)
Ansell J et al Chest. 2008; 133(6Suppl):160S-98S.
Ansell J et al. Chest. 2008; 133(6Suppl):160S-98S.
Broderick J et al.Stroke.
2007; 38:2001-23.
Which of the following is the best initialtreatment option for JC after stopping
warfarin?
A. Vitamin K and FFP
B. FFP and PCC
C. PCC and vitamin K
D. Vitamin K, FFP, andrFVIIa
Which of the following is the best initialtreatment option for JC after stopping
warfarin?
Vitamin
Kand
FFP
FFP
andPC
C
PCC
and
vitamin
K
Vitamin
K,FFP
,and
r...
52%
32%
12%
3%
A. Vitamin K and FFP
B. FFP and PCC
C. PCC and vitamin K
D. Vitamin K, FFP, andrFVIIa
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Emergency Management ofCoagulopathic ICH Patients
Scenario Agent Dose Comments
Warfarin FFP
or
PCC
and
Vitamin K
15 mL/kg IV
1530 IU/kg IV
10 mg IV
Typically 4-6 units(200 mL) given
Faster than FFP
1 mg/min max
Warfarin andemergencyneurosurgicalintervention
Above PLUS
rFVIIa 20-80 mcg/kg IV
Contraindicated inacutethromboembolicdisease
Mayer SA et al. Lancet Neurol. 2005; 4:662-72.
Which agent has the fastesttime to INR reversal?
A. Vitamin K
B. FFP
C. PCC
D. rFVIIa
Which agent has the fastesttime to INR reversal?
Vitamin
KFFP
PCC
rFVIIa
7%
66%
13%13%
A. Vitamin K
B. FFP
C. PCCD. rFVIIa
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Time to Reversal
Aguilar MI et al. Mayo Clin Proc. 2007; 82:82-92.Mathews M et al. Neurocrit Care. 2006; 5:141-52
Rapid
Rapid
Fast
Prompt
Slow
Huttner HB et al. Stroke. 2006; 37:1465-70.
PCC Usual dose: 15-50 IU/kg
Dosed based on factor IX content
Individualize therapy based on INR levels: Dose = actual body weight (kg) X (target % plasma activity
current % plasma activity)
Yasaka M et al. Thromb Res. 2005; 115:455-9. Aguilar MI et al. Mayo Clin Proc. 2007; 82:82-92.MacLaren R.Pharmacotherapy.2007; 27(9 Pt 2):93S-102S. Preston FE et al. Br J Haematol. 2002; 116:619-24.
Infusion rate: 2 mL/min (Bebulin VH); 3-10 mL/min (Profilnine SD) Reports of infusions as short as 2-10 minutes for Profilnine SD
Expensive
INR Target < 1.3
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PCC
Aguilar MI et al. Mayo Clin Proc. 2007; 82:82-92.
Factor VIIa: Mechanism of Action
1. INITIATION: TissueFactor/FVIIa interactionleads to thrombingeneration
2. AMPLIFICATION/PROPAGATION:
rFVIIa activates factor Xon the surface ofactivated platelets,leading to an enhancedthrombin burst at thesite of injury
3. FIBRIN CLOTFORMATION:Thrombin convertsfibrinogen into fibrin,producing a stable clot
Hoffman M et al. Thromb Haemost. 2001;85:958-65.
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Clinical Case
Repeat CT scan 2 hours after admission showsno further growth of ICH
INR is now 1.4
JC was rushed to surgery for evacuation of thehematoma and is doing well postoperatively
Repeat CT at 24 hours shows no hematomagrowth
On day 2, you notice JC has a right facial droopand right-sided weakness
He is diagnosed with acute ischemic stroke(AIS)
What should be recommendedat this time?
A. Consider t-PA treatmentfor the AIS
B. Consider rFVIIa andPCC as a potentialcause of the AIS
C. Consider further INRcorrections with vitaminK and FFP
D. Consider starting
heparin anticoagulation
What should be recommendedat this time?
Consider
t-PA
treatm
e..
ConsiderrFVIIa
and
P..
Considerfurther
INR
...
Considerstarting
hep...
20% 24%
3%
53%
A. Consider t-PA treatmentfor the AIS
B. Consider rFVIIa and
PCC as a potentialcause of the AIS
C. Consider further INRcorrections with vitaminK and FFP
D. Consider startingheparin anticoagulation
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Treatment Overview Vitamin K
Delayed onset: 1-2 hours
Correction of INR: 6-24 hours (INR
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What is the best recommendation regardingJCs home warfarin therapy?
Donotrestartwarfari...
Restartwarfarin
ther...
Considerrestarting
w...
Changeto
antiplatelet..
.
5%
40%
35%
21%
A. Do not restart warfarin in JC
B. Restart warfarin therapytoday
C. Consider restarting warfarinin 1 week
D. Change to antiplatelettherapy
What if JC was receiving warfarin for deep veinthrombosis treatment (week 8) instead of for
atrial fibrillation?
A. Do not restart warfarin in JC
B. Restart warfarin therapytoday
C. Consider restarting warfarinin 1 week
D. Insert an inferior vena cavafilter
What if JC was receiving warfarin for deep veinthrombosis treatment (week 8) instead of for
atrial fibrillation?
Donot restart warfari...
Restart warfarin
ther...
Considerrestarting
...
Insert an
inferiorven...
8%
57%
24%
11%
A. Do not restart warfarin in JC
B. Restart warfarin therapy
todayC. Consider restarting warfarin
in 1 week
D. Insert an inferior vena cavafilter
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Acute Care Update: Causes, Consequences, and Strategiesfor Managing Critical Bleeding
S E L E C T E D R E F E R E N C E S - Presentation 2
Aguilar MI, Hart RG, Kase CS et al. Treatment of warfarin-associated intracerebralhemorrhage: literature review and expert opinion. Mayo Clin Proc.2007; 82:82-92.
Ansell J, Hirsh J, Hylek E et al. Pharmacology and management of the vitamin Kantagonists: American College of Chest Physicians evidence-based clinical practiceguidelines (8th edition). Chest.2008; 133(6 Suppl):160S-98S.
Broderick J, Connolly S, Feldmann E et al. Guidelines for the management ofspontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from theAmerican Heart Association/American Stroke Association Stroke Council, High BloodPressure Research Council, and the Quality of Care and Outcomes in ResearchInterdisciplinary Working Group. Stroke.2007; 38:2001-23.
Davis SM, Broderick J, Hennerici M et al. Hematoma growth is a determinant of mortality
and poor outcome after intracerebral hemorrhage. Neurology.2006; 66:1175-81.
Dutton RP, McCunn M, Hyder M et al. Factor VIIa for correction of traumaticcoagulopathy. J Trauma.2004; 57:709-18.
Eckman MH, Rosand J, Knudsen KA et al. Can patients be anticoagulated afterintracerebral hemorrhage? A decision analysis. Stroke.2003; 34:1710-6.
Erhardtsen E, Nony P, Dechavanne M et al. The effect of recombinant factor VIIa(NovoSeven) in healthy volunteers receiving acenocoumarol to an internationalnormalized ratio above 2.0. Blood Coagul Fibrinolysis.1998; 9:741-8.
Flaherty ML, Haverbusch M, Sekar P et al. Long-term mortality after intracerebralhemorrhage. Neurology.2006; 66:1182-6.
Flibotte JJ, Hagan N, ODonnell J et al. Warfarin, hematoma expansion, and outcome ofintracerebral hemorrhage. Neurology.2004; 63:1059-64.
Hoffman M, Monroe DM 3rd. A cell-based model of hemostasis. Thromb Haemost.2001;85:958-65.
Huttner HB, Schellinger PD, Hartmann M et al. Hematoma growth and outcome intreated neurocritical care patients with intracerebral hemorrhage related to oralanticoagulant therapy: comparison of acute treatment strategies using vitamin K, freshfrozen plasma, and prothrombin complex concentrates. Stroke.2006; 37:1465-70.
Kawaguchi C, Takahashi Y, Hanesaka Y et al. The in vitro analysis of the coagulationmechanism of activated factor VII using thrombelastogram. Thromb Haemost.2002;88:768-72.
Liu-DeRyke X, Rhoney D. Hemostatic therapy for the treatment of intracranialhemorrhage. Pharmacotherapy.2008; 28:485-95.
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Acute Care Update: Causes, Consequences, and Strategiesfor Managing Critical Bleeding
MacLaren R. Key concepts in the management of difficult hemorrhagic cases.Pharmacotherapy.2007; 27(9 Pt 2):93S-102S.
Mathews M, Newman R, Chappell ET. Management of coagulopathy in the setting ofacute neurosurgical disease and injury. Neurocrit Care.2006; 5:141-52.
Mayer SA, Brun NC, Begtrup K et al. Recombinant activated factor VII for acuteintracerebral hemorrhage. N Engl J Med.2005; 352:777-85.
Mayer SA, Rincon F. Treatment of intracerebral haemorrhage. Lancet Neurol.2005;4:662-72.
Mayer SA, Brun NC, Begtrup K et al. Efficacy and safety of recombinant activated factorVII for acute intracerebral hemorrhage. N Engl J Med.2008; 358: 2127-37.
NovoSeven prescribing information. Novo Nordisk Inc: Princeton, NJ; 2008.
Preston FE, Laidlaw ST, Sampson B et al. Rapid reversal of oral anticoagulation withwarfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42patients. Br J Haematol.2002; 116:619-24.
Rosand J, Eckman MH, Knudsen KA et al. The effect of warfarin and intensity ofanticoagulation on outcome of intracerebral hemorrhage.Arch Intern Med.2004;164:880-4.
Yasaka M, Sakata T, Naritomi H et al. Optimal dose of prothrombin complex concentratefor acute reversal of oral anticoagulation. Thromb Res.2005; 115:455-9.
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Acute Care Update: Causes, Consequences, and Strategiesfor Managing Critical Bleeding
Jeremy D. Flynn, Pharm.D., BCPSClinical Pharmacist SpecialistUK HealthCare-Pharmacy Services
Assistant ProfessorDepartment of Pharmacy Practice and ScienceUniversity of Kentucky College of PharmacyLexington, Kentucky
Jeremy D. Flynn, Pharm.D., BCPS, is Assistant Adjunct Professor of Pharmacy at theUniversity of Kentucky (UK) College of Pharmacy Department of Pharmacy Practice inLexington, Kentucky. He is also Assistant Adjunct Professor of Surgery at the UKCollege of Medicine. Dr. Flynn is a clinical pharmacy specialist in cardiothoracic surgeryand critical care at the University of Kentucky Chandler Medical Center. He is activelyinvolved with the critical care residency program at UKHealthcare.
Following completion of pharmacy practice and critical care residencies at UK, Dr. Flynncompleted an ACCP Critical Care fellowship under the guidance of W. Scott Akers.Dr. Flynn has been active in the field of cardiovascular and critical carepharmacotherapy. His teaching, research, and patient care activities focus on thepharmacotherapeutic management of the cardiothoracic surgery and heart / lungtransplant populations. Recent areas of research include an evaluation of antifibrinolytictherapy in cardiac surgery patients and the treatment and prevention of atrialarrhythmias following thoracic surgery. Dr. Flynn serves as a journal referee forPharmacotherapy, The Annals of Pharmacotherapy, and Critical Care Medicine.
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Surgery-Associated Bleeding:A Cardiac Surgery Case
Jeremy Flynn, Pharm.D., BCPSClinical Pharmacist Specialist, Cardiothoracic SurgeryAssistant ProfessorUniversity of Kentucky College of PharmacyDepartment of Pharmacy Practice and ScienceLexington, Kentucky
Objectives List the most common risk factors for bleeding
associated with cardiac surgery
Describe the preoperative interventions commonlyemployed to reduce bleeding, including the availablepharmacologic agents for prophylaxis
Explain the therapeutic options available for thetreatment of bleeding in the cardiac surgical patient
Apply the information discussed to a patient case andselect appropriate therapy
Patient Case AB is a 70-y.o. woman who presents with chest
pain (found to be NSTEMI) and is taken for PCI UFH started, 600-mg clopidogrel loading dose given
before catheterization (ACC/AHA Class IArecommendation)
Catheterization shows 3-vessel CAD w/60% left
main coronary artery occlusion Lesions not amenable to angioplasty/stenting
Ongoing chest pain not relieved by IABP (Intra-aortic balloon pump)
PMH: CAD, HTN, chronic renal insufficiency (SCr 2.0 mg/dL),
DM, aortic valve replacement in 1998
Hct 34%; BSA 1.5 m2
It is determined that the patient will need CABGAnderson JL et al. J Am Coll Cardiol. 2007; 50:e1-157.
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Which of the following is NOT a risk factorassociated with increased bleeding with
cardiac surgery?
A. Advanced ageB. Urgent/emergent
operation
C. Obesity
D. Use of antiplatelet/
antithrombotic agents
E. Redo sternotomy
Which of the following is NOT a risk factorassociated with increased bleeding with
cardiac surgery?
Adva
nced
age
Urg
ent/e
merge
ntop
e...
Obe
sity
Use
ofantipl
atelet
/an..
.
Redo
stern
otom
y
3%
23%
16%
2%
55%A. Advanced age
B. Urgent/emergent
operation
C. Obesity
D. Use of antiplatelet/
antithrombotic agents
E. Redo sternotomy
Predictors of Postoperative Bleeding
1) Advanced age
2) Small body size or preoperative anemia (lowRBC volume)
3) Prolonged operation (cardiopulmonary bypasstime) high correlation with type of surgery
4) Emergency operation5) Other comorbidities (e.g., CHF, COPD, HTN,
peripheral vascular disease, renal failure)
6) Use of antiplatelet & antithrombotic drugs Redo sternotomy can also increase risk
Ferraris VA et al.Ann Thorac Surg. 2007; 83(5 Suppl):S27-86. Ferraris VA et al.Ann Surg. 2002; 235:820-7.
10-20% of patients consume 80% of blood products
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Critical Stages of Cardiac Surgery
Preoperative
Risk factor assessment
Medications
Prophylaxis strategy
Intraoperative Type and length of procedure
Cardiopulmonary bypass (CPB)
Anticoagulation strategy
Postoperative Monitoring
Coagulopathy
What do we need to know to continually assess bleeding risk, severityof bleed, and/or treatment options?
What is the best option for prophylaxisto minimize the bleeding risk for this patient?
A. Aprotinin loading dose
and infusion
B. Wait 5 days prior to
proceeding with CABG
C. Give platelet
transfusion prior to
surgery
D. -aminocaproic acid
(EACA)
E. Desmopressin
(DDAVP)
What is the best option for prophylaxisto minimize the bleeding risk for this patient?
Apr
otini
nloa
dingd
os...
Wait
5da
ysprior
to...
Give
plate
lettran
sfus..
.
Des
mopr
essin
(DDA
VP)
12%
16%19%18%
34%A. Aprotinin loading dose
and infusion
B. Wait 5 days prior to
proceeding with CABG
C. Give platelet
transfusion prior to
surgery
D. -aminocaproic acid
(EACA)
E. Desmopressin
(DDAVP)
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Preoperative/Prophylactic Treatment
Anticoagulation discontinuation/reversal
Heparin, LMWH, warfarin, fondaparinux
Blood products Platelet transfusions for clopidogrel exposure?
Antifibrinolytics
Lysine analogues
-aminocaproic acid (EACA)
Tranexamic acid (TXA)
Aprotinin
No longer available in U.S. due to safety concerns
Antifibrinolytic DataMeta-Analysis Total of 19 trials randomizing 2430 subjects
10 aprotinin vs. TXA -- 3 TXA vs. EACA
6 aprotinin vs. EACA
Aprotinin vs. TXA(1707 patients)
Aprotinin vs. EACA(399 patients)
Blood Loss Aprotinin superior106 mL (37-176)
Aprotinin superior184 mL (134-235)
Transfusion(rate and total)
ND ND
Re-operationND Insufficient data
Mortality, MI, and stroke No trends observed favoring any of the agents
No differences found between TXA and EACA
Carless PA et al. BMC Cardiovasc Disord. 2005; 5:19.
Blood Conservation Using Antifibrinolyticsin a Randomized Trial (BART) Study
Compared the three antifibrinolytic products
Similar demographics, risk profiles, and operative data
Modest reduction in massive bleeding with aprotinin
Mortality?
Fergusson DAet al. N Engl J Med. 2008; 358:2319-31.
Number needed to
harm: 50 patients
Doubling of death from
cardiac causes
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BART Study - Efficacy
Aprotinin(%)
TXA(%)
EACA(%)
Aprotinin vs.
TXA(RR 95% CI)
Aprotinin
vs. EACA(RR 95% CI)
Bleeding from chest
tubes 5.3 7.5 8.3
0.70
(0.47-1.03)
0.63
(0.43-0.92)
Massive transfusion 2.1 2.2 2.80.93
(0.47-1.83)
0.73
(0.38-1.37)
Death due to
hemorrhage1.4 1.0 0.5
1.36
(0.55-3.36)
2.75
(0.88-8.60)
Re-operation 5.5 8.1 8.20.68
(0.47-1.00)
0.67
(0.46-0.98)
Any massive
bleeding9.5 12.1 12.1
0.79
(0.59-1.05)
0.79
(0.59-1.05)
Fergusson DA et al. N Engl J Med. 2008; 358:2319-31.
No differences identified in major adverse effects:
Stroke, MI, DVT, PE, or renal failure
AB proceeded to urgent CABG and was given appropriatedoses of -aminocaproic acid for prophylaxis.
Patient Case
The patient experienced significant generalized oozing afterseparation from CPB and reversal of heparin, leading tosignificant blood loss and pooling of blood in the thoracic cavity
Unable to close until bleeding is corrected
Time on CPB
X-clamp time
220 minutes
160 minutes
Anticoagulation
Monitoring
Reversal
Heparin 300 units/kg bolus
ACT (POC) Goal >550 sec
Protamine 3 mg/kg
Total dose
550 units/kg
Packed RBC (PRBC)
transfusions
Total of 4 units through the
case to maintain Hct 26-28%
What is the first intervention you wouldmake to correct the bleeding?
A. Send coagulation labsand hemogram
B. Transfuse blood products(e.g., packed RBCs,
platelets, fresh frozenplasma, fibrinogen)
C. Check activated clottingtime (ACT)/point-of-care(POC) testing
D. Give desmopressin
E. Give recombinant factorVIIa (rFVIIa)
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What is the first intervention you wouldmake to correct the bleeding?
Sen
dcoa
gulat
ionlab..
.
Tran
sfuse
bloo
dpro
...
Che
ckac
tivate
dclot
ti..
Give
desm
opre
ssin
Give
reco
mbina
ntfa
ct..
11%
30%
31%
11%
17%
A. Send coagulation labsand hemogram
B. Transfuse blood products(e.g., packed RBCs,platelets, fresh frozenplasma, fibrinogen)
C. Check activated clottingtime (ACT)/point-of-care(POC) testing
D. Give desmopressin
E. Give recombinant factorVIIa (rFVIIa)
Bleeding and Cardiac Surgery Surgically correctable (200 mL/hr)
Normal coagulation studies
Clotting in mediastinal drainage tubes
Coagulopathy related (generalized oozing)
Common occurrence after exposure to extracorporeal
circulation (severity related to duration of CPB)
Related to abnormal:
Clotting parameters Platelet quantity and quality
Fibrinogen levels Residual drug effect
Sabiston DC Jr, Spencer F, eds. Surgery of the chest. 6 th ed. Philadelphia, PA: W.B. Saunders; 1995.
Evidence from Randomized Trials for MassiveHemorrhage in the Cardiac Surgery Patient
Some of the issues are addressed in the clinical practice guideline from theSociety of Thoracic Surgeons and Society of Cardiovascular Anesthesiologists:Perioperative Blood Transfusion and Blood Conservation in Cardiac Surgery
Ferraris VA et al. Ann Thorac Surg. 2007; 83(5 Suppl):S27-86.
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Key Points to Consider
Planning is essential
Identify high-risk patients
Have treatment options immediately available
Protocols
Massive transfusion protocol or service-specific
bleeding protocol
Monitoring strategy
Anticoagulation strategy
Complete reversal of heparin
Residual heparin or rebound effect
Goals of Therapy
Stop or control hemorrhage
Minimize blood product use
Minimize adverse events
Correct coagulation tests and blood counts
pH 7.20, temperature 35C, normal
ionized calcium
Avoid re-exploration for bleeding
Ferraris VA et al.Ann Thorac Surg. 2007; 83(5 Suppl):S27-86.Dutton RP. Pharmacotherapy. 2007; 27(9 Pt 2):85S-92S.
Monitoring
Point-of-care vs. central laboratory?
Point-of-care preferred
ACT monitoring
Platelet function
Thromboelastography (TEG)
Timing of treatment
Do NOT wait for test results from lab
Use visual cues in the OR
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Transfusion Therapy Primary means of treating/controlling acute
intraoperative bleeding
Product Contents Indications and Dose Concerns
PRBC Maintain target Hgb/Hct
Platelets Thrombocytes in
plasma
Plts
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Desmopressin Use of desmopressin acetate (DDAVP) is not unreasonable
to attenuate excessive bleeding and transfusion in certain
patients with demonstrable and specific platelet dysfunction
known to respond to this agent(Class IIb, Level of evidence B)
Uremic or CPB-induced platelet dysfunction
Type I von Willebrand disease
Not shown to be effective as prophylaxis
Typical dose 0.3 mcg/kg IV
Laupacis Aet al.Anesth Analg. 1997; 85:1258-67.
Ferraris VAet al.Ann Thorac Surg.2007; 83(5 Suppl):S27-86.
Recombinant Factor VIIa Use of recombinant factor VIIa concentrate is not
unreasonable for the management of intractable nonsurgical
bleeding that is unresponsive to routine hemostatic therapy
after cardiac procedures using CPB (Class IIb, level of evidenceB)
Issues to consider pH, temperature, platelet count
Place in therapy? Early, prerequisite blood products, salvage
Patient-specific risk CVA, PVD, PE, mechanical valve, VAD, etc.
Dose? Round to nearest vial size, dose cap,
multiple doses?
Ferraris VA et al.Ann Thorac Surg. 2007; 83(5 Suppl):S27-86.
VAD = ventricular assist device
The team has decided to give AB rFVIIa after aninadequate response to blood products (8 PRBCs,
6 FFP, 4 Plts, and 1 Cryo)
What is the most appropriate dose?
A. 1 mg
B. 30 mcg/kgC. 90 mcg/kg
D. 120 mcg/kg
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The team has decided to give AB rFVIIa after aninadequate response to blood products (8 PRBCs,
6 FFP, 4 Plts, and 1 Cryo)
What is the most appropriate dose?
1mg
30mc
g/kg
90mc
g/kg
120m
cg/kg
43%
3%
24%
30%
A. 1 mg
B. 30 mcg/kg
C. 90 mcg/kg
D. 120 mcg/kg
rFVIIa Dosing No published randomized, controlled trials to guide
dosing
Should consider
Severity of bleeding (urgency)
Patient risk factors
Ease of evaluating response
Doses reported in the literature for cardiac surgery
11 to 180 mcg/kg
Trend toward smaller doses
Warren O et al.Ann Thorac Surg.2007; 83:707-15.
Karkouti K et al. Can J Anaesth. 2007; 54:573-82.
The Safety and Efficacy of Recombinant Factor VII for theTreatment of Bleeding following Cardiac Surgery: AMultinational, Randomized, Placebo-controlled Trial
172 patients randomized to 1 of 3 groups (single bolus in ICU)
Placebo (n=68)
rFVIIa 40 mcg/kg (n=35)
rFVIIa 80 mcg/kg (n=69)
Primary Outcome
Critical serious adverse events at 30 days
Death
Acute MI
Cerebral infarction
Clinical symptomatic PE or other thromboembolic events
Secondary endpoints
Rates of re-operation, blood loss volumes, and transfusionClinicalTrials.gov Identifier: NCT00154427;
Ravi G et al. Presented at AHA Scientific Sessions. New Orleans, LA; 2008 Nov 9.
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Authors cautiously concluded that rFVIIa is probably safe and
may be beneficial to treat bleeding after cardiac surgery.
Outcome PlaceborFVIIa
40 mcg/kg
rFVIIa80 mcg/kg
Critical Serious
Adverse Events 7% 14%(p=0.25) 12%(p=0.43)
Re-operation 25% 14%(p=0.21)
12%(p=0.04)
Allogeneic Blood
Transfusion volumes825 ml 640 ml
(p=0.047)
500 ml(p=0.042)
Median Drainage Rate(4 hours after drug)
51 ml/hr 35 ml/hr(p=0.763)
24 ml/hr(p=0.018)
Age, CPB time, and type of surgery (emergent/urgent) predicted cSAEs
(critical, serious adverse events)
The Safety and Efficacy of Recombinant Factor VII for theTreatment of Bleeding following Cardiac Surgery: AMultinational, Randomized, Placebo-controlled Trial
Ravi G et al. Presented at AHA Scientific Sessions. New Orleans, LA; 2008 Nov 9.
Authors cautiously concluded that rFVIIa is probably safe andmay be beneficial to treat bleeding after cardiac surgery.
Outcome PlaceborFVIIa
40 mcg/kg
rFVIIa80 mcg/kg
Critical Serious
Adverse Events7% 14%
(p=0.25)
12%(p=0.43)
Re-operation 25% 14%(p=0.21)
12%(p=0.04)
Allogeneic Blood
Transfusion volumes825 ml 640 ml
(p=0.047)
500 ml(p=0.042)
Median Drainage Rate(4 hours after drug)
51 ml/hr 35 ml/hr(p=0.763)
24 ml/hr(p=0.018)
Age, CPB time, and type of surgery (emergent/urgent) predicted cSAEs
(critical, serious adverse events)
The Safety and Efficacy of Recombinant Factor VII for theTreatment of Bleeding following Cardiac Surgery: AMultinational, Randomized, Placebo-controlled Trial
Ravi G et al. Presented at AHA Scientific Sessions. New Orleans, LA; 2008 Nov 9.
ICU Management of Hemorrhagefollowing Cardiac Surgery
Patient evaluation
Hemodynamically stable or not
Surgical bleed or generalized oozing
Rebound of anticoagulation (heparin)
Monitoring?
Chest tube drainage
Lab values (CBC, PT/INR, aPTT, fibrinogen, etc)
Treatment strategies?
Return to OR (if unstable or unresponsive to treatment)
Directed by lab values for stable patients
Correct coagulopathy (blood products and drugs)
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What If Scenarios What if AB had a recent history of HIT and was
anticoagulated for CPB with bivalirudin?
What if the hospital routinely used TEG monitoringfor cardiac surgery and the tracing suggested?
Abnormal TEG
Segment
Blood Product
Indicated
Increased r-time(start of clot formation) FFP
Decreased MA(overall clot strength)
Platelets
Decreased angle(speed of clot formation) Cryoprecipitate
Luddington RJ. Clin Lab Haematol. 2005; 27:81-90.
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Acute Care Update: Causes, Consequences, and Strategiesfor Managing Critical Bleeding
Voils S. Pharmacologic interventions for the management of critical bleeding.Pharmacotherapy.2007; 27(9 Pt 2):69S-84S.
Warren O, Mandal K, Hadjianastassiou V et al. Recombinant activated factor VII incardiac surgery: a systematic review.Ann Thorac Surg.2007; 83:707-14.
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Acute Care Update: Causes, Consequences, and Strategies
for Managing Critical Bleeding
Table 1. Blood ProductsProduct Contents Indications and Dose Concerns*
Platelets Thrombocytes in plasma Plts
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Table 2. Pharmacologic AgentsProduct Contents or MOA Indications and Dose Concerns
Local
hemostatics
A. Cellulose-based
B. Fibrin (human or bovine) fibrinolytic inhibitor aprotonin
thrombin
C. Thrombin (human or bovine)D. Zeolite that causes exothermic reaction
E. Chitason (chitin) that activates platelets and electrophysiologic
endothelial attraction of RBCs
F. Synthetics (PEGs or collagen-fibrin)
A. May not adhere
B. Immune reaction, infection
transmission, aprotonin
C. Immune reactionD. Heat-induced tissue damage
E. May not adhere
F. Immune reaction, costly
Vitamin K Cofactor for activation of
factors II, VII, IX, K
INR 1.5
0.5-20 mg IV or PO
Slow acting
Variable SC absorption
IV requires slow administration
rFVIIa Activates platelets to
augment thrombin burst
Anticoagulant-induced hemorrhage,
ICH, refractory hemorrhage (surgery,
trauma)
10-90 mcg/kg IV
Short-acting
Thrombosis (
Recommended