management of post op bleeeding Flashcards
antifibrinolytic agents
Lysing Analogs › Aminocaproic Acid (ACA) / Amicar › Tranexamic Acid (TA)
Aprotinin
aminocaproic acid (ACA)/AMICAR
2 lysine molecules stuck together Competitively binds to lysine sites of
plasminogen/ plasmin
› Prevents Plasmin from binding to fibrinogen/fibrin
APROTININ
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.
LYSINE ANALOGS
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.
LYSINE ANALOGS PHARMOCOLOGY
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
LYSINE ANALOGS ELIMINATION
Renal excretion Half-life: 1-2 hours with IV administration
dosing protocols
***Varies widely for prophylaxis Loading dose pre-CPB over 1-15 min
followed by a continuous IV infusion. Sometimes a pump dose
DOSING ACA
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
TIMING OF DODING ACA
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
dosing of TA
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
LYSING ANALOGS SIDE EFFECTS
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.
APROTININ
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
APROTININ PHARMOCOLOGY
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
APROTININ ALLERGIC REACTIONS
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.
APROTININ ACTION
Non-specific serine protease inhibitor
Effects: › Trypsin
› Chymotrypsin › Plasmin › Kallikrein › Bradykinin
› TPA › Urokinase Plasminogen Activator › Complement
APROTININ HISTORY
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.
aprotinin dosing
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
aprotinin 1st 20 patients
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
aprotinin action 2
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
aprotininin efficacy
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
aprotinin issues patency
no difference in vein graft patency and all arterial grafts patent after 12 days
aprotinin neuroligical effects
has protective effect. no strokes in aprotinin group
aprotinin effect on dialysis
none
Normal GFR, 50% Normal GFR, <20% normal GFR
Low risk for dialysis, >20% risk for dialysis, 85% risk for dialysis
aprotinin and creatinine
Aprotinin competes with creatinine in the ascending Loop of Henle.
› Expect the rise in creatinine with Aprotinin Not necessarily indicator of renal damage
aprotinin renal events
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.
costs aprotinin
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
costs of recombinant factor,rbc,platelets,FFP
› Recombinant Factor VIIa - $5,000-$9,000 /
dose May require multiple doses
› RBC: $300-$500 › Platelets: $850 › FFP: $100
APROTININ DOWNFALL
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
APROTININ COMPLICATIONS
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
in conclusion ways to avoid post op bleeding
Rewarm the patient thoroughly Reverse Protamine Get all the surgical bleeders Be aware of hemodilution
Consider use of antifibrinolytic/ lysine analog
