Book Text

Anticoagulation for CPB

Heparin remains the only drug available for anticoagulation of patients for CPB. Commercially available heparin is extracted from either bovine lung or porcine intestine.

1973

It is a negatively charged mucopolysaccharide that contains a specific pentasaccharide sequence that binds antithrombin III (AT-III). Heparin alone has no anticoagulant effect. Its effects are mediated by potentiating AT-III. It is not a uniform compound, and individual heparin molecules can have molecular weights ranging from 10,000 to 30,000 daltons. Heparin's efficacy in potentiating AT-III is, to some extent, inversely related to its molecular weight, with smaller fractions being more effective. The differential anticoagulant effects of heparin molecules reflect the presence or absence of the pentasaccharide binding sequence for AT-III. Porcine intestine heparin (sometimes referred to as mucosal heparin) tends to have a lower molecular weight and, thus, more potent anticoagulant activity. However, smaller fragments are also more difficult to reverse with protamine. AT-III binds thrombin, and the complex is rapidly removed from the circulation. AT-III also binds other factors in the coagulation cascade, such as factors Xa, IXa, XIa, and XIIa, but the potentiating effect of heparin on these factors is much less potent (10- to 100-fold) than that on the AT-III/thrombin reaction.

As one would predict for a molecule with variable molecular weight, its physiologic effects are also variable. Effort has been made by the U.S. Pharmacopoeia to standardize lots whereby 1 U of heparin is that which is able to keep 1 mL of sheep's blood liquid for 1 hour. However, even such standardization is not perfect in that the same dose of heparin may still evoke different levels of anticoagulation in different patients because of the inherent variability in sheep's blood across batches, the fact that sheep's blood is not identical to human blood, and the fact that humans differ from one another in levels of AT-III and other coagulation factors present in their serum. Moreover, levels of AT-III in the same patient may change over time, in the presence of disease, and in the presence of medications, including heparin itself.

AT-III is produced by the liver. However, the liver does not possess the ability to acutely increase AT-III production in response to a stimulus. Thus, plasma AT-III levels (measured as a percentage of normal activity) will decrease when production is decreased, when removal is increased, or when plasma is diluted. Liver dysfunction can result in decreased production. Heparin therapy leads to increased removal because the AT-III-heparin-thrombin complex is rapidly cleared from the circulation. Heparin therapy for as little as 24 to 48 hours can decrease AT-III activity to 60% to 70% of normal. Thrombin generation, as occurs with hematomas, can exacerbate this decrement. CPB-associated hemodilution will decrease AT-III levels. AT-III levels can be supplemented in patients in whom heparin fails to achieve adequate anticoagulation pre-CPB by administering fresh frozen plasma or AT-III concentrate. Disadvantages of fresh frozen plasma include the time required to thaw and administer and the risk of transmission of infection. AT-III concentrate is expensive, and recombinant AT-III is not currently commercially available.

The variable anticoagulant response to heparin implies that a specific dose of heparin will evoke different anticoagulant effects across patients. Even so, most institutions use 300 to 400 IU of heparin per kilogram pre-CPB. Heparin is effective within one circulation time because it rapidly binds AT-III. Though uncommon, heparin can cause serious, acute side effects, including allergic reactions, histamine release, and calcium chelation. Allergic reactions probably reflect the source of heparin (bovine or porcine) and the extraction process, which does not necessarily remove all nonheparin molecules.

The anticoagulant effects of heparin can be monitored by using the activated clotting time (ACT), the Lee-White whole blood clotting time, and the activated partial thromboplastin time (aPTT). As illustrated in Figure 50-32 , the Lee-White clotting time is directly related to the heparin dose, but the time frame to achieve an end point with high doses of heparin renders it impractical. The aPTT reaches infinity above intermediate doses of heparin. The ACT uses diatomaceous earth (celite) or aluminum silicate (kaolin) to activate the intrinsic cascade. Bull and colleagues' seminal work in the 1970s illustrated the linear relationship between heparin dose and the ACT (at least up to 600 seconds) and recommended what the authors considered minimum target ACT values for the safe conduct of CPB ( Fig. 50-33 ). ^[195] No universal agreement has been reached regarding the minimum ACT required before initiating CPB. Most institutions view ACT values of 400 to 450 seconds as acceptable. Celite-based ACT measurements can be prolonged by aprotinin. The kaolin-based ACT, which is not modified by aprotinin because aluminum silicate rapidly absorbs aprotinin, should be used to monitor anticoagulation when aprotinin is being administered.

Although frequently erroneously viewed as such, the ACT is not necessarily a specific test for heparin. The ACT can be prolonged (in effect, impaired coagulation) by many factors other than heparin. Many of these factors

Figure 50-32 Graph illustrating the difference between heparin dose-response curves using the partial thromboplastin time (PTT, solid line), the whole blood coagulation time (WBCT), and the activated coagulation time (ACT, dashed line). The disadvantage of the PTT for measuring heparin effect is the exponential dose-response relationship. The advantage of ACT is that a straight line dose-response relationship exists that is similar to the WBCT, but the time is measured in seconds rather than minutes. Heparin half-life can be measured from both the WBCT and ACT, but not from the PTT. (From Young JA: Coagulation abnormalities with cardiopulmonary bypass. In Utley JR [ed]: Pathophysiology and Techniques of Cardiopulmonary Bypass. Baltimore, Williams & Wilkins, 1983.)

1974

Figure 50-33 A, The pioneering work of Bull and colleagues showing a dose-response curve wherein a patient's baseline activated coagulation time (ACT) is demonstrated at point A. Initial heparin dosing of 200 IU produced an ACT of greater than 350 seconds, and the dose-response curve was drawn with an intersection at 400 (A) and 480 seconds (B). From these intersects one can determine what further dose to administer to patients. Although this represents the classic method described by Bull and colleagues, few centers have the time or patience to wait for multiple doses of heparin to slowly creep up to the acceptable ACT for bypass. B, The right side of the illustration demonstrates the response of a population to a two-stage dosing planned to give an ACT of 480 seconds. Note some significant scatter around the 480-second number. (From Bull BS, Huse WM, Brauer FS, Korpman RA: Heparin therapy during extracorporeal circulation: II. The use of a dose-response curve to individualize heparin and protamine dosage. J Thorac Cardiovasc Surg 69:685–689, 1975.)

occur intraoperatively and include hemodilution, hypothermia, platelet dysfunction, and low fibrinogen levels. Indeed, any circumstance that decreases the concentration of the essential components of thrombus formation (e.g., hemodilution, decreased fibrinogen levels) or decreases the activity of these components (e.g., hypothermia, platelet dysfunction) will prolong the ACT. Heparin- and non-heparin-induced ACT prolongation can be discriminated by measuring heparin concentrations in plasma. The chromogenic heparin assay, the gold standard, is expensive and time consuming and thus impractical. However, the Hepcon analyzer device is widely available. In effect, this device uses ACT measurements in a series of blood samples to which varying doses of protamine have been added. Because protamine binds heparin stoichiometrically, the concentration of heparin present can be deduced by determining which sample has the shortest ACT. If no heparin is present, the sample without protamine should have the shortest or at least have the same ACT as those that contain protamine. If it is prolonged, a cause other than heparin is indicated.

Heparin remains the only approved drug for anticoagulation for CPB. Contraindications to heparin are relatively rare but include true allergy and type II heparin-induced thrombocytopenia. These contraindications have stimulated a search to identify alternatives to heparin. Ancrod, a snake venom, lyses fibrinogen, decreases fibrinogen levels, and has been used for CPB.^[196] ^[197] It is not routinely available but can be obtained with Food and Drug Administration (FDA) approval and clearly requires advanced planning. Hirudin, which inhibits thrombin and the final common pathway, is not readily monitored during CPB and is not currently available. Heparinoids are inadequate anticoagulants for CPB,^[198] and the prostacyclin analog iloprost (a potent but reversible platelet inhibitor) is inadequate on its own as an anticoagulant for CPB.