the role of aprotinin in cardiac surgery l.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
The Role of Aprotinin in Cardiac Surgery PowerPoint Presentation
Download Presentation
The Role of Aprotinin in Cardiac Surgery

Loading in 2 Seconds...

play fullscreen
1 / 49

The Role of Aprotinin in Cardiac Surgery - PowerPoint PPT Presentation


  • 190 Views
  • Uploaded on

The Role of Aprotinin in Cardiac Surgery. Mike Poullis. 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

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

The Role of Aprotinin in Cardiac Surgery


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
what is it
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
overview
Basic 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

Overview
heparin and aprotinin
Heparin and Aprotinin
  • Usually monitor ACT
  • Need to monitor KCT
  • More heparin needed
thrombin
Thrombin

Intrinsic

Extrinsic VII

Endothelium

thrombin and aprotinin
Thrombin and Aprotinin
  • Aprotinin inhibits the effects of thrombin
platelets10
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
platelet
Platelet

PAR-1 (Thrombin receptor)

PAR-4

Platelet

ADP

Microaggregation

and

Macroaggregation

Collagen

Adrenaline

mechanism of g protein receptor activation by soluble ligand eg adp
Mechanism of G protein receptor activation by soluble ligand eg ADP

Soluble ligand

(Reversible)

Cell Membrane

G protein

protease activated receptors par
Protease Activated Receptors (PAR)
  • Thrombin is the classic
mechanism of g protein receptor activation by protease eg thrombin
Mechanism of G protein receptor activation by protease eg Thrombin

Protease eg thrombin

(Irreversible)

Cell Membrane

G protein

slide15
(cont)

Tethered ligand

(Irreversible)

Peptide

Cell Membrane

G protein

Activation

par activating peptides
PAR activating peptides

PAR activating peptide

(reversible)

Cell Membrane

G protein

Activation

actions proteolytic inhibitors eg aprotinin
Actions proteolytic inhibitors eg Aprotinin

Protease eg thrombin

Aprotinin

Cell Membrane

G protein

platelets and aprotinin
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
par deactivation
PAR deactivation

Protease eg thrombin

Deactivator eg elastase

aa 43/44 & 55/56

aa 41/42

(Irreversible)

NH2

Cell Membrane

G protein

kallikrein kinnin system
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
kallikrein kinnin system and aprotinin
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.
neutrophils
Neutrophils
  • Activated during CPB directly and indirectly
  • Release neutrophil elastase, cathepsin G, lysozymes, and myeloperoxidase
  • Main target of anti inflammatory treatment
neutrophils and aprotinin
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.
fibrinolysis
Fibrinolysis
  • Natural mechanism to prevent uncontrolled coagulation
fibrinolysis and aprotinin
Fibrinolysis and Aprotinin
  • D-dimer levels reduced by aprotinin
  • Direct effect on plasmin
clinical
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
dosages of aprotinin
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
adverse effects
Adverse effects
  • Anaphylactic reaction
  • Graft occlusion
  • Renal impairment
  • Microvascular occlusion
uses for aprotinin
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
routine cabg
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.

redo cabg
Redo CABG

Effect 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

endocarditis
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

hypothermic circulatory arrest
Hypothermic circulatory arrest
  • Stasis
  • Renal Failure
  • Bleeding
  • ???Inflammation
hypothermic circulatory arrest36
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

cardiac transplantation
Cardiac Transplantation

Defining 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

factor v leiden
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

hit hitt cpb and aprotinin
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
drugs to treat hit
Drugs to treat HIT
  • LMW
  • Ancrod
  • Aprotinin
  • Thrombin antagonists Hirudin
  • Ancrod - aprotinin interaction is important
bleeding post cpb in itu
Bleeding Post CPB in ITU
  • No real evidence, all anecdotal
pulmonary dysfunction
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

cerebral dysfunction
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;

slide46
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

personal arrogant opinion
Personal Arrogant Opinion
  • Acute endocarditis
  • Hypothermic circulatory arrest
    • Neither of the above for bleeding
  • Excessive fibrinolysis ? As dictated by TEG
remember
Remember

“If intravenous aprotinin does not stop the bleeding, try putting the bottles in the holes”

Mike Desmond, CTC

hot dates
Hot dates
  • Monday Teaching 7.30am start
  • Friday 13th Audit