Blood Conservation Presentation 4pp - baptisthealth.net presentations... · Blood Conservation...

Pharmacologic Blood Conservation Agents: Pharmacologic Blood Conservation Agents: Clinically Supportive Data & Recommended Practices

Edwin G. Avery, IV, M.D., C.P.I.

Chief, Division of Cardiac Anesthesia

University Hospitals Case Medical Center

Case Western Reserve University School of Medicine

Cleveland, OH

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Disclosures:

Covidien: funded research, consultant, speaker’s bureau

CSL Behring: funded research

Overview:

Blood conservation drugs

AlternativeAlAlAlAlAlAlAl blood conservation adjuncts

Blood Conservation Drugs

Am

icar

TXA

Keyser Soze

Blood Conservation Drugs

Antifibrinolytics (Aminocaproic acid & Tranexamic acid)

Recombinant activated factor VII (NovoSevenÒ)

Desmopressin (DDAVP)

The usual suspects…

Blood Conservation Drugs: Antifibrinolytics

Old faithful…the lysine analogues

Antifibrinolytics (the lysine analogues)

e-Aminocaproic acid (ACA) is a synthetic

monoamino carboxylic acid derivative of the amino

acid lysine that is an indirect inhibitor of fibrinolysis;

it is synthesized via a chemical process§

It’s chemical composition and size make it unlikely to

induce an allergic reaction & it’s inexpensive

§ http://www.drugs.com/pro/amicar.html

Last accessed 4.17.2012

Blood Conservation Drugs: AntifibrinolyticsClinically Supportive Data

e-Aminocaproic acid (Amicar®, XanodyneÒ) Tranexamic Acid (CyklokapronÒ)

ACA & TXA work mainly by indirectly inhibiting

fibrinolysis; they act as a lysine analogue and occupy lysine

residue binding sites on plasminogen known to bind fibrin (a

cofactor required for tissue plasminogen activator [TPA] to

activate the plasminogen). With ACA/TXA occupying the

fibrin binding sites on plasminogen (the inactive zymogenic

form of plasmin) it cannot be readily converted to plasmin,

the enzyme which is directly responsible for fibrinolysis§

ACA is also a very weak inhibitor of plasmin§

§http://www.drugbank.ca/drugs/DB00513




ACA & TXA

ACA/TXA administration is indicated to promote

hemostasis when fibrinolysis is thought to be

contributing to hemorrhage (e.g., cardiac and hepatic

surgery, abruptio placentae, hepatic cirrhosis and

carcinoma of various organs) §

§ http://www.drugs.com/pro/amicar.html




Clinically Supportive Data - Primary Hyperfibrinolysis

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&frm=1&source=web&cd=1&ved=0CCQQFjAA&url=http%3A%2F%2Fdiablo

valleyperfusion.com%2Fmod%25206%2520fibrinolysis%2520core.ppt&ei=z9ONT43BBcfA0AHJ_J2oDw&usg=AFQjCNE-

qmdy2ehP2tNeG8fYV55B3uy-AQ Last accessed 4.17.2012

q Treat 1º fibrinolysis

w/ACA/TXA

q Treat 2º fibrinolysis

w/anticoagulation,

not ACA/TXA

Blood Conservation Drugs: gs: Antifibrinolytics

Clinically Supportive Data-Cardiac Surgery

The Lysine Analogues (ACA and TXA)

The Good

↓Incidence of blood transfusion by 68%

w/ACA M & 29% w/TXA M3

↓Magnitude of perioperative bleeding by

35% w/ACAM

Large RCT of high risk subjects

examining effect of aprotinin, TXA and

ACA did not reveal any significant safety

concerns to be associated with lysine

analogue use†

The Bad

No significant effect of ACA on reduced

transfusion in a meta-analysesM2

TXA /ACA use not associated with

¯incidence of surgical re-exploration

All of the performed studies appear

inhomogeneous and thus may not be

appropriate for meta-analysis M

Recent evidence suggests that the use of

TXA has a significant association with

postoperative seizure risk (OR 7.4; P<.001)§,‡

Incidence of renal insufficiency with ACA v

TXA (30% v 20%; P=0.005)‡

M1999 Ann Thorac Surg 68;1321-5 (meta-analysis)M21997 Anesth Analg 85;1258-67 (meta-analysis) M32001 Cochrane Database Syst Rev CD001886 (meta-analysis)

†2008 NEJM 358(22);2319-31 (RCT, n=2331)

M3

§Manji RA, et al. 2011 Can J Anesth.‡2011 JCTVA 25(1):20-5 (retrospective, n=604)

Blood Conservation Drugs: gs: Antifibrinolytics

Clinically Supportive Data-Hepatic Surgery

The Lysine Analogs (ACA and TXA)

The Good

↓Magnitude of TEG assessed fibrinolysis

w/ACA in Orthotopic liver transplant

surgery†

Transfusion free hepatic tumor resection

surgery has been described with TXA‡

The Bad

Few data support the use of

antifibrinolytics in hepatic surgery

No published dosing recommendations

exist in the peer reviewed literature

†1987 Anesth 66; 766-73‡2006 Ann Surg 243(2);173-80

e-Aminocaproic acid and Tranexamic acid

Prophylactic antifibrinolytic therapy is often indicated in surgical

procedures in which fibrinolysis is common (e.g., cardiac

surgery)§

Class I recommendation – Level of Evidence A

Antifibrinolytic therapy is never 100% routine as individuals with

known thrombophilias or hypercoagulable states may be at ↑risk

for thrombotic complications if treated with these agents

Renal dosage adjustment is needed in patients with compromised

renal function†

Alternatively, rescue lysine analog administration† can be

executed with the knowledge that there is little data supporting

this approach

§ 2007 Ann Thor Surg 83;S27-86

Blood Conservation Drugs: AntifibrinolyticsRecommended Treatment

† http://www.casecag.com/Amicar_Clin_Prot_12-05-2010.pdf

e-Aminocaproic acid and Tranexamic acid

Dosing regimens vary significantly across clinical venues

Cardiac surgical regimens tend to be much higher than those in

orthopedic or hepatic surgery§,†,‡

No specific society generated dosing guidelines exist for either of

the lysine analogs

§http://www.casecag.com/Amicar_Clin_Prot_12-05-2010.pdf†1987 Anesth 66; 766-73‡2006 Ann Surg 243(2);173-80

Blood Conservation Drugs: AntifibrinolyticsRecommended Treatment – Dosing Regimens

†2012 Canad J Anesth 59(1);6-13§ 2007 Ann Thorac Surg;83: S27-86

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Blood Conservation Drugs: AntifibrinolyticsRecommended Treatment – Dosing Regimens

Antifibrinolytics (pre-CPB vs. Rescue)

e-Aminocaproic acid§

Tranexamic acid (seizure risk OR 7.4, P<0.001)-consider waiting on

extubation as propofol gtt likely mitigates seizure occurrence†

www.casecag.comBlood Conservation Drugs: NovoSeven

Blood Conservation Drugs: NovoSeven

Recombinant activated factor VII (Novo SevenÒ)

A recombinant protein derived from baby hamster

kidney cells that is similar to human factor VIIa but in

fact no human serum or proteins are used in the

production or formulation of this product §

Clinically Supportive Data

§NovoSeven Package Insert (09-2009)


rVIIaIt works by activating the

extrinsic coagulation

pathway which occurs

when rVIIa combines with

Tissue Factor to activate

factor X→Xa and

IX→IXa which ultimately

results in thrombin

generation and clotting at

the site of vessel injury§


§NovoSeven Package Insert (09-2009)

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Recombinant activated factor VII

use for refractory life threatening

bleeding (unrelated to factor VII, VIII, or IX

deficiency)

Has been observed to be an effective blood

conservation adjunct in a number of trials in various

clinical settings (few exist in cardiac surgery)

Does appear to have some safety issues associated with

its use




J Obstet Gynaecol Res.

37(7):901-7, 2011 Jul

Neurocirugia (Asturias, Spain).

22(3):209-23, 2011 Jun.

J Trauma 2005;59:8-18

Ann Emerg Med 2009;54:737-44

2011 J Cardiothorac Vasc Anes 25(5): 804-10

2009 Circulation 120;21-7

2007 Ann Thor Surg 83;S27-86


Clinically Supportive Data-Cardiac Surgery


The Good

↓Incidence of reoperation for bleeding

(P=0.03)† and NS(13% v 42%)M

↓Transfusion requirement (P=0.01)†

↓Rate of mediastinal drainage (24 mLs/° v

51 mLs/°); P=0.018†

No difference in the death rate M

The Bad

↑Incidence of critical SAEs (NS)†

↑Incidence stroke (4.7% v 0.9%); [OR

3.69 (1.1-12.38)]; P=0.03M

↑Perioperative thrombotic events (7.5% v

5.6%); [OR 1.84(0.82-4.89)]; P=0.14M

Pilot dose escalating study stopped early

at recommendation of DSMB and 140

μg/kg dose not tested

Few studies

M2011 J Cardiothorac Vasc Anes 25(5): 804-10 (6 trials/2 RPCT; n=470)†2009 Circulation 120;21-7 (pilot P-II ICU only, n=172)


Clinically Supportive Data-Trauma/ER

The Good

↓Incidence of RBC transfusion by 2.6

units in rVIIa treated blunt trauma (BT)

subjects (P=0.02)†

↓Incidence of RBC transfusion by 1.0 unit

in rVIIa treated penetrating trauma (PT)

subjects (NS)†

↓Need for massive transfusion (>20 units)

in BT 14% v 33% (P=0.03)†

↓Need for massive transfusion (>20 units)

in PT 7% v 19% (NS)†

Trend towards ↓mortality and critical

complications

The Bad

No difference in death rate between rVIIa

and placebo treated subjects

†J Trauma 2005;59:8-18 (RPCT; n=301)


Clinically Supportive Data-Neurosurgery

† Neurocirugia (Astur). 22(3):209-23, 2011 Jun

The Good The Bad

Systematic administration of rVIIa is not

recommended for spontaneous intracranial

hemorrhage†

Limited data consisting of retrospective

studies and case reports provide minimal

support to the practice of treating other

neurosurgical bleeds with rVIIa†Crickets chirping…


Clinically Supportive Data - Post-partum hemorrhage

The Good

75% incidence (6/8) of good bleeding

control (↓hemorrhage within 15 minutes

of dosing)

No serious adverse events were observed

The authors suggest that based on their

results rVIIa should be considered prior to

hysterectomy in this clinical setting

The Bad

Limited data consisting of a single

retrospective case series (n=8) study

which provides minimal support to the

practice of treating other post-partum

hemorrhage with rVIIa†

No consistent dose regimen (55-105

μg/kg) examined thus no single treatment

dose can be recommended based upon this

work

† J Obstet Gynaecol Res. 37(7):901-7, 2011 Jul

rVIIa is a largely nonvalidated OFF-LABEL

treatment that presently should be considered a

***

p y

**Salvage Therapy***

in severely hemorrhaging patients regardless

of the clinical venue.

Recommended PracticesRecommended Practices


No published guidelines exist to direct dosing therapy with this agent in the U.S.

In all but the most dire clinical circumstances physicians should first administer algorithm guided hemostatic blood products prior to treatment with rVIIa

rVIIa Doses of 40 μg/kg to 90 μg/kg have undergone limited investigation in cardiac surgery and safety issues have been noted to

be associated with its use; thus, a starting dose of 35-40 μg/kg is recommended with the option to repeat the dose at 40-50 μg/kg one hour later+ if bleeding is responsive to this treatment, but persistent

It may he helpful to use point-of-care and/or central lab testing to assess the effect of initial treatment

Recommended PracticesRecommended Practices


Clinical Case

Clinical Case 64 YOM w/severe AI secondary to paravalvular leak

of bioprostheticAV, 2v CAD, ̄ LVEF, mild pulmonary

HTN, DM type II, HTN, cholesterolemia

Redo-sternotomy, CABG x2 and AVR

(Edwards PerimountÒ bovine pericardial 23

mm) AXC 2:44

Noted tear in left pulmonary artery, re-AXC 1:03

Repair pulmonary artery

Off CPB 6:43

Clinical Case

Left heart failure/cardiogenic shock® Inotropes + IABP

D 20 min®Right heart failure/cardiogenic shock

Off CPB 7:46 total

Back on CPB, RVAD (Abiomed AB5000)

Clinical Case The surgical team assesses the bleeding as severe following protamine

administration of 0.7 mg per 100 IU Heparin. Next steps…?

Clinical Case

Clinical Case se –– TEG #1

FFP

Clinical Case se –– TEG #1 Heparinase


4710.3

s/p 70% Protamine

3 doses Plts

4 units FFP

1150mg RIASTAP

2 RBC

4.9Heparinase


s/p 50 mg Protamine

2 doses Plts (total 5)

2 units FFP (total 6)

1150mg RIASTAP (total 2300)

2 RBC (total 4)

11.8 4.7 38 56.7Heparinase

Clinical Case se –– TEG #3 Heparinases/p 50 mg Protamine

rVIIa 35 mg/kg

3 units FFP (total 9)

1150mg RIASTAP (total 3450)

7.1 2.8 54.4 63.1Heparinase

Clinical Case

Clinical Case

Hemostasis achieved

Massive inflammatory tissue injury including lung injury (TRALI)

with copious edema and blood from ETT for 3-4 hours

Oxygenation OK with recruitment maneuvers every 5-10 minutes

but PaCO2 > 120 mmHg & pH 6.5

Bleeding restarted, loss of vascular tone, worsening left heart failure

all unresponsive to medications and finally death

Blood Conservation Drugs: DDAVP

§2007 Ann Thorac Surg;83: S27-86



http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMe

etingMaterials/PediatricAdvisoryCommittee/UCM215090.pdf

Desmopressin (DDAVP) [1-deamino-8-d-arginine vasopressin]†

DDAVP is a chemically synthesized derivative of human

antidiuretic hormone (ADH) (a.k.a. 8-arginine vasopressin)

Indicated as antidiuretic replacement therapy for central

diabetes insipidis and for management of temporary polyuria

and polydipsia associated with head trauma or surgery in the

pituitary region

Desmopressin (DDAVP)§,†

Stimulates the release of factor VIII precursors, von

Willebrand factor and tissue type plasminogen activator from

vascular endothelium

Has the potential to improve platelet function through its

pharmacodynamics in certain clinical scenarios

Its use to promote blood conservation through its effect on

platelet function is OFF-LABEL

†Klick JC. Avery EG. Anesthesiology 2nd ed. 2012; Chap 16; 196-217





Has been well tested as a blood conservation adjunct in a

number of cardiac surgical trials

Class IIb recommendation –Level of Evidence B§

It does not reduce bleeding after cardiac surgery

when administered prophylactically

Class III recommendation –Level of Evidence A§

Patients with lab-based testing proven platelet defects have

been observed to benefit from DDAVP in this setting†, ‡

†1999 Lancet 354;106-10

‡1992 Anesth 77;38-46



Clinically Supportive Data – Cardiac Surgery


Has been demonstrated to be effective in improving platelet

function in patients with uremia induced platelet dysfunction

as well as in those with Type I von Willebrand’sdisease§



Clinically Supportive Data – Cardiac Surgery


Dose at 0.3 mg/kg (slow IV infusion to avoid ̄ BP)§

Redose at 12+ hr intervals or greater

More effective in the setting of lab/POCT based

demonstration of platelet dysfunction (e.g., TEG, ROTEM,

PFA-100)

Not recommended for routine use




Recommended Practice – Cardiac Surgery

Alternativeve Blood Conservation Drugs

Fibrinogen concentrate (RiastapÒ)

Prothrombin complex concentrates (KonyneÒ,

ProfilnineÒ or KCentraÒ)

Whole blood?

Fib i

Alternative

t t (Ri t Ò)

ve Blood Conservation Drugs

Treatment of Cardiac Surgical Bleeding

Fibrinogen concentrate (RIASTAP) l

Indicated in treatment of afibrinogenemia

Fibrinogen is the precursor to fibrin which serves as the proteinaceous

scaffolding of a blood clot and promotes platelet aggregation

Recent appreciation has been made of the potential contributions of

fibrinogen in the treatment of severe hemorrhage§, †

Pharmacologic Adjuncts


§2012 Anes Analg;114: 261-274

l2009 Expert Opin Biol Ther. 9:1325-1333.

Treatment of Cardiac Surgical Bleeding

Prothrombin complex concentrates (PCCs)Originally intended as a treatment for Hemophilia B (Christmas disease)

Contains Factors II, VII, IX, and X (in varying amounts depending on manufacturer)†

Has been described as a rescue bleeding agent in cardiac surgery§ and is a

standard rescue therapy in some large academic medical centers

Limited safety data available at present –not for routine use

Pharmacologic Adjuncts


§2008 Crit Care 12;R105

2010 Vox Sang. 99(3):251-60

2006 Crit Care Resusc. 8(2):141-5

Alternative Drug Adjunctsct -tssssssssss---Whole Blood

Acute Normovolemic Hemodilution

ANH Tips

A-line collection

1:1 Colloid replacement

Short large gacatheter

Use a scale

Agitate bag frequently

Baseline (sec): 136

On CPB: 619

Post-protamine: 193

Final ACT: 141

Alternative Drug Adjunctsct -tssssssss---Whole Blood

Alternative Drug Adjunctsct -tssssssss---Whole Blood

Rewarming on CPB after deep hypothermic circulatory arrest

(AVR + Hemiarch)

Alternative Drug Adjunctsct -tssssssssss-Whole Blood

Post 1 unit of whole blood (~400 mLs)

The End nd –– Thank Youwww.casecag.com

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