METHODS AND TECHNIQUES TO REDUCE THE USE OF BLOOD COMPONENTS. - Aprotinin. Andre Luiz Tyszka, MD. Cardiac Surgeon Maringa - Brazil

1. INTRODUCTION

Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) are at serious hazard for significant postoperative bleeding. This bleeding trend is due to the surgical procedure itself involving major vascular structures, plus the deleterious effect of extracorporeal circulation over the hemostatic mechanisms.

The postoperative bleeding is one of the major complications of open heart surgery. The incidence of life-threatening bleeding is somewhat between 5 to 25%. Patients undergoing isolated coronary artery graft surgery (CABG), 2 to 5% of them have postoperative hemorrhage leading to reexploration. In these patients, in-hospital mortality is nearly 3 times higher and average length of stay from surgery to discharge is significantly longer (2).

The blood transfusion itself has several risks. The most common are infectious disease transmission and transfusion reactions (hemolytic, non-hemolytic, graft-versus-host disease, anaphylactic reaction). Even though the risk of transfusion have considerably diminished with the routine use of sensitive assays for viral detection, the cost of transfusion and limitations in the supply of blanked blood have generate further interest in reducing transfusion requirements during cardiac surgical procedures.

To assess mortality and risk factors associated with reexploration for hemorrhage in patients undergoing coronary artery bypass grafting (CABG), Dacey and cols. studied a consecutive cohort of 8586 patients undergoing isolated CABG, between 1992 and 1995 (2). The higher rates of reexploration for hemorrhage were observed in patients with prolonged (> 150 minutes) cardiopulmonary bypass and in those requiring an intra-aortic balloon pump intraoperatively. In multivariate analysis, older age, smaller body surface area, prolonged cardiopulmonary bypass, and number of distal anastomoses were associated with increased bleeding risks.

2. THE DELETERIOUS EFFECTS OF CPB ON HEMOSTATIC SYSTEM

The heparin prevents clotting by activating the natural plasma protein, antithrombin (AT), therefore acts at the end of the coagulation cascade. Standard heparin preparations vary in anticoagulant effectiveness, and the coagulation effect is influenced by concentrations of plasma antithrombin. The CPB-related bleeding problems associated with heparin include platelet abnormalities, heparin resistance, heparin rebound, and heparin-induced thrombocytopenia. (3)

Exposure of the heparinized blood to the wound and to the synthetic surfaces of the extracorporeal perfusion circuit stimulates thrombosis and partially activates coagulation proteins, fibrinolytic proteins, platelets, and blood cells compromising wound hemostasis. Both pathways are activated during cardiac surgery with CPB. The intrinsic pathway involves factor XII, prekalikrein, kininogen, and factor XI (collectively termed "contact protein") is activated by exposure of the blood to synthetic surfaces. The wound provides powerful thrombotic stimulus by activating the extrinsic pathway. Even though the pericardium do not express tissue factor, others tissue as epicardium, fat, subcutaneous tissue, skeletal muscle cells, and adventitia of the great vessels do. The tissue factor is a specific protein bound to cellular membranes, initiates the extrinsic coagulation pathway by activating factor VII in the presence of calcium.

Cardiopulmonary bypass routinely increase bleeding times because of platelet dysfunction for several hours afterward. Platelet dysfunction is caused by decrease in its number or function deficiency. It is one of the major causes of postoperative bleeding. Thrombocytopenia is produced by dilution with prime, platelet adhesion to circuit surfaces, platelet aggregation, and activation and removal of damaged platelets by the reticulo-endothelial system.

Heparin fails to completely suppress thrombin formation, which converts fibrinogen to fibrin. The fibrin, therefore, is lysed by plasmin, and lysis of the bound fibrin increases bleeding, destroying formed hemostatic clots. Fibrinolysis begins with the surgical incision and progressively increases during CPB. Fibrinolytic activity is very high in blood aspirated from the wound.

3. STRATEGIES TO REDUCE THE NEED FOR TRANSFUSION

The modern cardiac surgery uses several different means to reduce postoperative anemia and the need for blood-product transfusion (1).

3.1. Surgical technique: In approximately two-thirds of patients a surgical bleeding source is found. Common sites of ongoing hemorrhage include side branches of the internal mammary artery and saphenous vein grafts, mammary arterial harvest sites, graft anastomoses, cannulation sites, insertion sites of pacing wires, and around sternal closure wires. Meticulous surgical hemostasis is the basis of any blood conservation program. Careful hemostasis before heparinization and CPB is as important as after administration of protamine (4).

3.2. Individualized dosing of heparin: It is recommended to improve control of the heparin dosage and to prevent prolonged activated clotting times that may occur if a standard dose is given routinely. Heparin titration has so far shown efficacy in reducing blood loss after bypass in comparison with standard heparin anticoagulation.

3.3. Hemodilution: Patients readily tolerate hemodilution during cardiopulmonary bypass without long-term sequelae. Autologous blood donation for postoperative reinfusion is recommended for reducing homologous blood usage.

Autologous blood transfusion can be obtained either preoperatively or before bypass. Predonation, when collected several days before surgery, it is special helpful for patients with unusual serum antibodies, and can be stimulated with erytropoietin. Intraoperative collection is much more common, either before the CPB institution or in the very early phases of the bypass process. The donated blood volume (500 to 1,000ml) is replaced with isotonic intravenous fluid. The level of acceptance of relative anemia both during the operation and into the postoperative period remains controversial. For most patients the hematocrit of 20% is safe, during cardiopulmonary bypass time. By the reinfusion of the freshly collected autologous blood, a reduction in total operative blood requirement could be realized (3).

3.4. Autotransfusion: The blood is collect from surgical field using a suction -based aspiration device that anticoagulates the blood as it is collected. Then, the blood collected is filtered and stored for reinfusion. This technique is extremely simple and inexpensive, but the blood recovered is rich in activates plasma proteins (17).

3.5. Cell Savers: Before or after systemic heparinization, blood is recovered from the surgical field and immediately heparin is added; the blood the passes through a 20um filter to a reservoir, where the red cells are washed with saline solution and concentrated by centrifugation. Cell savers devices scavenge red cells with minimal plasma constituents. The final blood collected with this system can have a hematocrit as high as 70%.

3.6. Heparin-treated circuits: Heparin is an imperfect anticoagulant that permits the formation of microthrombi in the pump-oxigenator. Effort continues to be made to make the artificial surfaces biocompatible. The most common method involving bonding heparin to the surfaces. Heparin's strong acidity makes it possible to bind it ionically or covalently to plastic surfaces, and this has been shown to decrease thrombus formation and platelet adhesion upon artificial surfaces. The commercially available Carmeda (Medtronic Cardiopulmonary, Anaheim, California, USA) is covalently bind and in the Duraflo (Baxter Healthcare Corporation, Irvine, California, USA) ionically binds heparin. Both systems are used with reduced doses of systemic heparin. Postoperative blood loss is reduced by 4.5-24.0%, and postoperative transfusion requirements are slightly less. (12,15)

3.7. Platelet Plasmapheresis: when it done intraoperatively remove a large aliquot of platelets from the perfusate and it prepare a platelet rich plasma. This method is not cost effective for routine open-heart patients but may be useful in high-risk patients who require prolonged CPB or reoperations.

3.8. Pharmacological Approach: Prevention of transfusion has become possible by manipulation of the control of coagulation and inflammatory processes and by the introduction of pharmacologic agents.

Desmopressin acetate: (DDAVP) is an analogue of vasopressin that transiently raises plasma concentrations of von Willebrand's factor and factor VIII from endogenous sources. Erythropoietin: can increase red cell production in patients with renal failure, those who wish donate autologous blood, and Jehovah's Witnesses. The rate of increase in red cell mass varies among patients. The therapy is effective over a period of weeks but may not be helpful within only a few days.

Antifibrinolytics: prophylactic administration of the synthetic antifibrinolytics decreases blood loss and transfusion requirement. Epsilon-aminocaproic acid is given in a 5-10g loading dose, followed by an infusion of 1-1.5g/hour for 5-10 hours. Tranexamic acid is given in a 10mg/kg as a bolus after heparinization followed by a continuous intravenous infusion of 1mg/kg over 10 hours (18).

Reversible Platelet Inhibitors: Strategies to prevent the platelet activation during CPB. Experimentally, some reversible inhibitors that are rapidly removed to restore normal platelet function after CPB, but this has not yet been made clinically practicable. Aprotinin is widely used and has proven efficacy in the management of excess bleeding. It is a serine protease inhibitor and has several possible mechanisms of action, including inhibition of the plasma enzyme systems activated by contact with the foreign surface of the bypass circuit and preservation of platelet function.

4. APROTININ

Aprotinin is a single-chain polypeptide with a molecular weight of 6,512 Daltons. Aprotinin is a potent natural inhibitor of plasma protease obtained from bovine lung tissue. It inhibits trypsin, plasmin, urokinase, and tissue and plasma kallikrein.

Aprotinin was initially used for treatment of acute pancreatitis. Its ability to diminish the negative effects of cardiopulmonary bypass was studied in early 60s, with inconstant results. In the end of 80's Bidstrup and Royston reported remarkable reductions in postoperative bleeding and blood use after many forms of operations performed with CPB with high-dose aprotinin (14). This and other studies throughout Europe, where it was first approved for clinical usage, has shown blood loss reduction of the order of 40% to 50% and reductions in blood use of 40% to 80% (5).

The exact mechanism by which aprotinin achieves its hemostatic effects is multiple and still the subject of much debate. Although the mechanism of action is not clearly, it known that aprotinin inhibits serine proteases and preserves platelet function. This was suggested because patients who received aprotinin have shorter bleeding times than placebo-treated-patients.

Aprotinin strongly inhibits plasmin formation, and only partially inhibits kallikrein activation. Plasmin is an active proteolitic enzyme from fibrinolytic system, so aprotinin inhibits the fibrinolysis and reduces thrombin formation. By inhibiting kallikrein, the intrinsic pathway, complement, and neutrophils are inactivated. Aprotinin may block the conversion of kininogen to the inflammatory mediator bradykinin, as well as inhibit the activation of C1 of the complement system, and the whole body inflammatory response is attenuated (6).

4.1. Aprotinin dose:

Aprotinin have been administered in various dosages within the scope of bypass surgery. It has a half-life time of approximately 5 hours and is metabolized by the proximal tubules of the kidney. The most common protocol for aprotinin dosage is the "Hammersmith dose". This high dose consisting of 2,000,000 KIU aprotinin loading dose, immediately after anesthetic induction 2,000,000 KIU added to CPB circuit prime, and a continuous infusion of 500,000 KIU during surgery, until closing the chest. Other services have been adopted the "low dose" protocol consisting of half dose of the full high-dose. Studies from Cosgrove (7), Liu (8) and Misfeld (9) found that the low-dose is as effective as high dose aprotinin in decrease blood loss and blood requirement, but not in anti-inflammatory activity (6)

4.2. Laboratory monitoring of anticoagulation during CPB with aprotinin:

In the presence of aprotinin, prolongation of the ACT is dependent of the type of the test employed. Aprotinin prolongs the celite activated ACT by different mechanism of heparin, and may lead to an overestimation of the degree of anticoagulation. It is recommended for celite-ACT greater than 750 seconds during CPB. Kaolin absorbs aprotinin and minimizes its effects on the ACT, so kaolin activated ACT is less affected by aprotinin and is preferred for anticoagulation management (5). Heparin titration is an alternative, and additional heparin must be administered to patients during surgery to maintain their heparin concentration over to 2.7U/mL (16).

4.3 Adverse Effects of Aprotinin

One potential adverse effect of aprotinin could be postoperative graft occlusion. Bidstrup BP (10) and Alderman (11) analyzed coronary graft patency after aprotinin use. These studies documented no statistically significant increase in the prevalence of myocardial infarction. These results support the concept that aprotinin achieves improved hemostasis by allowing hemostatic mechanisms to function normally at the end of bypass, rather than by creating a hypercoagulable state.

Since aprotinin is excreted in the renal tubular epithelium, it might be expected to have adverse effects on renal function. Even though, there are no indications that aprotinin is associated with clinically significant postoperative renal insufficiency or failure (13).

Allergic reactions: Aprotinin is a bovine protein, and it may cause anaphylactic reactions in approximately 0.5% of patients. These reactions can be more frequent with drug re-exposure, but due to a decrease of antibody titers with time, after 5 years, the incidence of anaphylactic reaction may be similar with the first time. All patients' candidates to aprotinin protocol should receive a test dose (1ml), 10 minutes before the loading dose or immediately after anesthetic induction. In case of re-exposure, the risk:benefit must be weighted carefully. One option is delay the loading dose until the CPB can be possible, if the patient has a cardiovascular collapse after aprotinin. The efficacy of pre-treatment with steroids and histamine blockers is not proven.

5. CONCLUSIONS

Hemorrhage requiring surgical reexploration after CABG is associated with markedly increased mortality and length of stay. When administered profilatically to patients undergoing to open heart surgery, aprotinin is consistently associated with decreased fibrynolisis and reduced bleeding in the perioperative period. Patients predicted to have increased risks of bleeding might benefit from prophylactic use of aprotinin. The need to re-explore to stop non-surgical bleeding is diminished without any increased risk of mortality or myocardial infarction, and reduces the need for blood transfusion. Aprotinin is generally well tolerated, anaphylactic reaction are possible but are rare.

6. REFERENCES

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