acute care update causes

8/12/2019 Acute Care Update Causes

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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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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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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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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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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 [email protected].

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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


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


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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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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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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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

26


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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?


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%


B. Restart warfarin therapy

todayC. Consider restarting warfarin

in 1 week

D. Insert an inferior vena cavafilter

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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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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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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)



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)



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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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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Acute Care Update: Causes, Consequences, and Strategies

for Managing Critical Bleeding

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 (

acute care update causes

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