the role of aprotinin in cardiac surgery
TRANSCRIPT
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The Role of Aprotinin in Cardiac Surgery
Mike Poullis
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What is it?• A Kunitz non specific serine protease inhibitor
• 6,500 Da cationic protein
• Inhibits trypsin, plasmin, kallikrein, and elastase in a dose-dependent manner
• Originally isolated from Bovine lung tissue
• The role of aprotinin in the lung, which is present in a number of species, remains unexplained.
• Found in Mast cells
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OverviewBasic Science
• Heparin
• Thrombin
• Platelets
• Kallikrein-Kinnin system
• Neutrophils
• Fibrinolysis
Clinical
• Dosage• Adverse affects• Routine CABG• Redo CABG• Endocarditis• Hypothermic circulatory arrest• Cardiac Transplantation• Factor V Leiden• HIT, HITT• Bleeding post CPB in ITU• Pulmonary dysfunction• Cerebral dysfunction• Cost
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Basic Science
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Heparin and Aprotinin
• Usually monitor ACT
• Need to monitor KCT
• More heparin needed
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Heparin and Aprotinin II
CLOT
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Thrombin
Extrinsic VIIIntrinsic
Endothelium
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Thrombin and Aprotinin
• Aprotinin inhibits the effects of thrombin
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Platelets
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Platelets• Cellular constituent of coagulation system• Number can be normal but don’t work
• Platelet Agonists (Afferent)
• Agonist Receptor
• Adrenaline alpha• Collagen VLA• ADP ADP• Thrombin PAR I and IV
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Platelet
Platelet
Microaggregationand Macroaggregation
PAR-1 (Thrombin receptor)
PAR-4
ADP
Adrenaline Collagen
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Mechanism of G protein receptor activation by soluble ligand eg ADP
Cell Membrane
G protein
Soluble ligand(Reversible)
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Protease Activated Receptors (PAR)
• Thrombin is the classic
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Mechanism of G protein receptor activation by protease eg Thrombin
Cell Membrane
G protein
Protease eg thrombin(Irreversible)
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(cont)
Cell Membrane
G protein
(Irreversible)Tethered ligand
Activation
Peptide
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PAR activating peptides
Cell Membrane
G protein
(reversible)PAR activating peptide
Activation
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Actions proteolytic inhibitors eg Aprotinin
Cell Membrane
G protein
Protease eg thrombinAprotinin
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Platelets and Aprotinin
• Aprotinin inhibits thrombin induced platelet aggregation but not adrenaline, collagen, and ADP induced aggregation
• Neutrophil enzymes can cleave PAR receptor and make it functionless
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PAR deactivation
Cell Membrane
G protein
Protease eg thrombin
(Irreversible)
Deactivator eg elastase
aa 41/42
NH2
aa 43/44 & 55/56
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Kallikrein-Kinnin system
• Activated by contact with foreign surfaces liberates factor XII
• Factor XII and prekallikrein drive the process
• Kallikrein directly activates neutrophils• Kallikrein activates complement• Kallikrein helps form bradykinin• Kallikrein activates factor XII
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Kallikrein-Kinnin system and Aprotinin
• High-dose aprotinin inhibits the kallikrein-C1-INH complex formation.
• Low dose aprotinin significantly, but incompletely inhibits the increase in kallikrein-C1-INH complex levels.
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Neutrophils
• Activated during CPB directly and indirectly
• Release neutrophil elastase, cathepsin G, lysozymes, and myeloperoxidase
• Main target of anti inflammatory treatment
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Neutrophils and Aprotinin
• Low-dose and pump prime only aprotinin treatments blunt CPB-induced CD11b upregulation.
• High-dose aprotinin significantly decreases CD11b/CD18 up regulation following CPB onset.
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Fibrinolysis
• Natural mechanism to prevent uncontrolled coagulation
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Fibrinolysis and Aprotinin
• D-dimer levels reduced by aprotinin
• Direct effect on plasmin
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Clinical•Dosage•Adverse affects•Routine CABG•Redo CABG•Endocarditis•Hypothermic circulatory arrest•Cardiac Transplantation•Factor V Leiden•HIT, HITT•Bleeding post CPB in ITU•Pulmonary dysfunction•Cerebral dysfunction•Cost
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Dosages of Aprotinin• High dose
– Initial bolus of 2*106 KIU (280 mg)– Infusion of 70 mg/h (5*105 KIU),– addition of 280 mg to the pump prime fluid.
• Low dose– Initial bolus of 1*106 KIU (140 mg) – Infusion of 35 mg/h (2.5*105 KIU)
• 50 ml/hr
• Remember high ACTs or use KCT
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Adverse effects
• Anaphylactic reaction
• Graft occlusion
• Renal impairment
• Microvascular occlusion
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Uses for aprotinin
• Routine CABG• Redo CABG• Endocarditis• Hypothermic circulatory arrest• Cardiac Transplantation• Factor V Leiden• HIT, HITT• Bleeding post CPB in ITU• Pulmonary dysfunction• Cerebral dysfunction• Cost
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Routine CABG
Analyses of coronary graft patency after aprotinin use: results from the International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial.
Alderman EL, et al.J Thorac Cardiovasc Surg 1998 Nov;116(5):716-30
13 international sites were randomized to receive intraoperative aprotinin (n = 436) or placebo (n = 434).
Probability of early vein graft occlusion was increased by aprotinin, but this outcome was promoted by multiple risk factors for graft occlusion.
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Redo CABGEffect of aprotinin on need for blood transfusion after repeat open-heart surgery.
Royston D, Bidstrup BP, Taylor KM, Sapsford RN. Lancet 1987 Dec 5;2(8571):1289-91
22 patients undergoing repeat open-heart surgery through a previous median sternotomy wound
11 received high dose aprotinin
Their mean blood loss was 286 ml compared with 1509 ml in the 11 control patients
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Endocarditis
Effect of aprotinin on need for blood transfusion in patients with septic endocarditis having open-heart surgery.
Bidstrup BP, Royston D, Taylor KM, Sapsford RN.Lancet 1988 Feb 13;1(8581):366-7
Improved outcome for seriously ill open heart surgery patients: focus on reoperation and endocarditis.
Taylor KM.J Heart Lung Transplant 1993 Jan-Feb;12(1 Pt 1):S14-8
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Hypothermic circulatory arrest
• Stasis
• Renal Failure
• Bleeding
• ???Inflammation
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Hypothermic circulatory arrest
Pro: aprotinin should be used in patients undergoing hypothermic circulatory arrest.
Royston D.J Cardiothorac Vasc Anesth 2001 Feb;15(1):121-5
Con: aprotinin should not be used in patients undergoing hypothermic circulatory arrest.
Gravlee GP.J Cardiothorac Vasc Anesth 2001 Feb;15(1):126-8
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Cardiac TransplantationDefining the role of aprotinin in heart transplantation.
Prendergast TW, et al.Ann Thorac Surg 1996 Sep;62(3):670-4
Risk of anaphylaxis from aprotinin re-exposure during LVAD removal and heart transplantation.
Milano CA, Patel VS, Smith PK, Smith MS.J Heart Lung Transplant 2002 Oct;21(10):1127-30
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Factor V Leiden
Aprotinin, cardiac surgery, and factor V Leiden.
Sweeney JD, et al.
Transfusion 1997 Nov-Dec;37(11-12):1173-8
Protein C inhibition by aprotinin
10 % of cardiac surgery population are Factor V Leiden +Ve
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HIT, HITT, CPB and Aprotinin• PF-4 and heparin antibody
• Clinical suspicion• Immunoassay• Bioassay
• How do you develop HIT?– Tissues and blood cell activation– Heparin exposure– Antibody formation– Antibody has to have a functional Fc
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PAF
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Drugs to treat HIT
• LMW
• Ancrod
• Aprotinin
• Thrombin antagonists Hirudin
• Ancrod - aprotinin interaction is important
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Bleeding Post CPB in ITU
• No real evidence, all anecdotal
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Pulmonary Dysfunction
The effect of aprotinin on ischemia-reperfusion injury in an in situ normothermic ischemic lung model.
Eren S, et al.
Eur J Cardiothorac Surg 2003 Jan;23(1):60-5
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Cerebral dysfunction
Etiology and incidence of brain dysfunction after cardiac surgery.
Murkin JM.
J Cardiothorac Vasc Anesth 1999 Aug;13(4 Suppl 1):12-7;
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Cost
A model of the direct and indirect effects of aprotinin administration on the overall costs of coronary revascularization surgery in a university teaching hospital cardiothoracic unit.
Robinson D, Bliss E.
Clin Ther 2002 Oct;24(10):1677-89
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Personal Arrogant Opinion
• Acute endocarditis
• Hypothermic circulatory arrest
– Neither of the above for bleeding
• Excessive fibrinolysis ? As dictated by TEG
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Remember
“If intravenous aprotinin does not stop the bleeding, try putting the bottles in the holes”
Mike Desmond, CTC
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