management of post op bleeeding

Question 1

antifibrinolytic agents

Answer 1

 Lysing Analogs › Aminocaproic Acid (ACA) / Amicar › Tranexamic Acid (TA)
 Aprotinin

Question 2

aminocaproic acid (ACA)/AMICAR

Answer 2

 2 lysine molecules stuck together  Competitively binds to lysine sites of
plasminogen/ plasmin
› Prevents Plasmin from binding to fibrinogen/fibrin

Question 3

APROTININ

Answer 3

 58 amino acid polypeptide  Single Lysine
› High affinity for plasmin at this site
 Non-specific serine protease inhibitor
› Has other actions
› Catalyzes multiple reactions of inflammation, coagulation, and other cellular attack mechanisms.

Question 4

LYSINE ANALOGS

Answer 4

 ACA and TA › 2 commercially available › Clinically available for 40+ years
 Prophylactic use in cardiac surgery dates back to 1960s. Primarily thought to use after CPB
 1989 – Del Rossi, et al.
› Large Placebo controlled group (350pts)
› Pre-CPB administration of ACA decreased post operative chest tube drainage and transfusion without inducing thrombotic complications.
 Showed effective in decreasing blood loss.

Question 5

LYSINE ANALOGS PHARMOCOLOGY

Answer 5

 IV Administration  Uptake is immediate  Small, water-soluble molecules
 Distributed readily into extravascular water spaced before being taken up into various cells and tissues.
 NOTE: TA – Weak protein-bound › Crosses BBB and Placenta

Question 6

LYSINE ANALOGS ELIMINATION

Answer 6

Renal excretion  Half-life: 1-2 hours with IV administration

Question 7

dosing protocols

Answer 7

 ***Varies widely for prophylaxis  Loading dose pre-CPB over 1-15 min
followed by a continuous IV infusion.  Sometimes a pump dose

Question 8

DOSING ACA

Answer 8

 Loading Dose: 75-150mg/kg (5-10gm in adults)
 IV Infusion: 10-15mg/kg/hr › Continues until end of CPB or until Protamine
is given
 Pump Dose: 2-2.5g/L
› Some add/ some don’t
› Makes sense to add b/c of added plasma volume on pump
Daily, et al Protocol (aka: “10-10-10”) › 10g given as slow bolus (5-10min) pre-CPB › 10g in CPB prime › 10g after CPB
 Pt with kidney disease
› Normal/reduced LD
› Reduced continuous infusion rate  ACA: 5mg/kg/hr  TA: 0.5mg/kg/hr

Question 9

TIMING OF DODING ACA

Answer 9

Initial Dose › As early as induction and incision
 Reports of clot formation on PA Catheter and EKG ST- segment changes
› Await full anticoagulation with heparin prior to administration
 Kluger et al. Study › 90 primary CABG pts › Given ACA pre-incision, after heparin, and placebo › Both ACA protocols decreased chest tube drainage › No difference between ACA groups
› Therefore, acceptable to give prior to CPB, but after heparin

Question 10

dosing of TA

Answer 10

 1/7 to 1/10th of ACA  Loading Dose: 10-15mg/kg over 10-

15min  Infusion: 1-1.5mg/kg/hr  Pump: 2-2.5mg/L

Question 11

LYSING ANALOGS SIDE EFFECTS

Answer 11

 In DIC Patients › Intravascular Clots
 Thromboembolic Complications › Reduced Graft Patency › DVT › PE
› Stroke
› MI
› **All theoretically possible after heparin neutralization, but no association has been found.
 Something to consider –
› Patients at low risk for transfusion (despite CPB) may not benefit from prophylactic anti- fibrinolytics. But may help tip the scales between transfusion or not if they are on the fence.

Question 12

APROTININ

Answer 12

 58 amino acid polypeptide  Found in all mammalian lung tissue  Isolated from bovine lung
 Activated Sites
› Contains single lysine
› Binding site for most serine proteases it inhibits

Question 13

APROTININ PHARMOCOLOGY

Answer 13

 Full Hammersmith Regimen (Most common) › 2 million KIU in pump › 2 million KIU to pt over 30-60 minutes › 500,000 KIU/hr infusion for pump run
› T1/2= 5 hours with this regimen › Renal excretion

Question 14

APROTININ ALLERGIC REACTIONS

Answer 14

 Foreign protein from bovine source
 Size similar to protamine
 1st time exposure reaction rare
 Test dose of 1mL given prior to loading dose
 Wait about 10 min after test dose before starting loading dose
 Found reaction in kids with less than 6 months between exposures
› FDA revised advisory to put 12 months between exposures.

Question 15

APROTININ ACTION

Answer 15

 Non-specific serine protease inhibitor
 Effects: › Trypsin
› Chymotrypsin › Plasmin › Kallikrein › Bradykinin
› TPA › Urokinase Plasminogen Activator › Complement

Question 16

APROTININ HISTORY

Answer 16

Used/known since 1960s
 1980s – collaboration of 2 cardiac surgeons: Ben Bidstrup and Kenneth Taylor and an anesthesiologist, David Royston.
› Hammersmith Hospital, London.
Wanted to see if Aprotinin could decrease the frequency and severity of post-op lung dysfunction after CPB.
› Thought inflammatory mediation through a kallikrein-initiated cascade might be the trigger for post-CPB pulmonary dysfunction.

Question 17

aprotinin dosing

Answer 17

 Came up with a formula they thought would drastically inhibit kallikrein production
› 2 million KIU pre-CPB
› 2 million KIU in pump
› 500,000 KIU/hr to cover metabolism/ clearance

Question 18

aprotinin 1st 20 patients

Answer 18

No effect on Pulmonary gas exchange and
post op lung dysfunction › BUT! The surgical field was dramatically DRY.
› Lead to the early publications of transfusion- sparing and decrease chest tube drainage associated with Aprotinin.
 Example of blood loss data:  Aprotinin patients: 245mL  Placebo patients: 1979mL

Question 19

aprotinin action 2

Answer 19

 Decreasing Kallikrein › Decrease inflammation
 Kallikrein doesn’t affect bleeding › DOES activate intrinsic cascade › Activation of coagulation precursor proteins › Activates pro-inflammatory WBCs › Inhibits Platelet-WBC Interactions
 Inflammatory down regulation
› Protects platelets  GPIb and IIb/IIIa receptors are better preserved

Question 20

aprotininin efficacy

Answer 20

 Decreased chest tube output in re- operation cases, complex CABG, CABG with ASA/Platelet-Inhibitors on board
 40-80% reduction in chest tube output compared to placebo

Question 21

aprotinin issues patency

Answer 21

no difference in vein graft patency and all arterial grafts patent after 12 days

Question 22

aprotinin neuroligical effects

Answer 22

has protective effect. no strokes in aprotinin group

Question 23

aprotinin effect on dialysis

Answer 23

none

Question 24

Normal GFR, 50% Normal GFR, <20% normal GFR

Answer 24

Low risk for dialysis, >20% risk for dialysis, 85% risk for dialysis

Question 25

aprotinin and creatinine

Answer 25

 Aprotinin competes with creatinine in the ascending Loop of Henle.
› Expect the rise in creatinine with Aprotinin  Not necessarily indicator of renal damage

Question 26

aprotinin renal events

Answer 26

Found that the use of Aprotinin was associated with an increased risk of renal and non-renal events compared to ACA, TA, and no antifibrinolytic
 Renal events: › Aprotinin: 5.5% › No Antifibrinolytic: 1.8%
 Dose dependent › Risk increases as the dose increases
 Aprotinin patients may have been sicker on average, and thus were getting Aprotinin b/c they were sicker.

Question 27

costs aprotinin

Answer 27

 ACA – generic › $1.50-$10 per 5gm vial › Case: $5-$30
 TA – generic › Case: $20-$300
 Aprotinin – off patent, but costly to extract
› $300-$450 per bottle › Case: $1000-$1500

Question 28

costs of recombinant factor,rbc,platelets,FFP

Answer 28

› Recombinant Factor VIIa - $5,000-$9,000 /
dose  May require multiple doses
› RBC: $300-$500 › Platelets: $850 › FFP: $100

Question 29

APROTININ DOWNFALL

Answer 29

 December 2006 – FDA Revised labeling
› Don’t give w/in 12 mo of prior exposure
› Only for patients who are at increased risk for blood loss and blood transfusion associated with CPB in the course of a CABG
› NOTE: TA, ACA are not FDA approved for prophylactic use in cardiac surgery.
 2007 – Temporarily withdrawn from the market worldwide
 5/2008 permanently withdrawn from the market
› Use is limited to very select research

Question 30

APROTININ COMPLICATIONS

Answer 30

 Complications have been seen with both lysine analogs and Aprotinin
› Intravascular Thrombis
› Aprotinin increases serum creatinine transiently
› Retrospective studies associate Aprotinin with:
 Renal Failure  Stroke  MI  Increased Mortality  **NOT seen with Lysine Analogs

Question 31

in conclusion ways to avoid post op bleeding

Answer 31

 Rewarm the patient thoroughly  Reverse Protamine  Get all the surgical bleeders  Be aware of hemodilution
 Consider use of antifibrinolytic/ lysine analog