Best Practice & Research Clinical Anaesthesiology 29 (2015) 189e202

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Anticoagulation management associated with extracorporeal circulation Roman M. Sniecinski, MD, Associate Professor of Anesthesiology, Cardiothoracic Anesthesia Fellowship Director a, *, Jerrold H. Levy, MD, Professor of Anesthesiology/Associate Professor of Surgery, CoDirector Cardiothoracic ICU b, 1 a

Emory University School of Medicine, Department of Anesthesiology, 1364 Clifton Rd, NE, Atlanta, GA 30322, USA b Cardiothoracic Anesthesia and Critical Care, Duke University Medical Center, 2301 Erwin Road, 5691H HAFS, Durham, NC 27710, USA

Keywords: cardiopulmonary bypass unfractionated heparin whole-blood-activated coagulation time heparin resistance antithrombin III

The use of extracorporeal circulation requires anticoagulation to maintain blood fluidity throughout the circuit, and to prevent thrombotic complications. Additionally, adequate suppression of hemostatic activation avoids the unnecessary consumption of coagulation factors caused by the contact of blood with foreign surfaces. Cardiopulmonary bypass represents the greatest challenge in this regard, necessitating profound levels of anticoagulation during its conduct, but also quick, efficient reversal of this state once the surgical procedure is completed. Although extracorporeal circulation has been around for more than half a century, many questions remain regarding how to best achieve anticoagulation for it. Although unfractionated heparin is the predominant agent used for cardiopulmonary bypass, the amount required and how best to monitor its effects are still unresolved. This review discusses the use of heparin, novel anticoagulants, and the monitoring of anticoagulation during the conduct of cardiopulmonary bypass. © 2015 Elsevier Ltd. All rights reserved.

* Corresponding author. Tel.: þ1 404 558 7307; Fax: þ1 678 620 2634. E-mail addresses: [email protected] (R.M. Sniecinski), [email protected] (J.H. Levy). 1 Tel.: þ1 919 684 0862. http://dx.doi.org/10.1016/j.bpa.2015.03.005 1521-6896/© 2015 Elsevier Ltd. All rights reserved.

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The development of anticoagulation for cardiopulmonary bypass While the birth of cardiopulmonary bypass (CPB) is widely celebrated as 6 May 1953, when Dr. John Gibbon successfully utilized it during the closure of an atrial septal defect, it is less appreciated that extracorporeal circulation for organs was actually conceived >100 years earlier by the French physiologist Julien-Jean Cesar le Gallois [1]. One of the greatest obstacles faced by le Gallois and other early developers of CPB was the profound activation of the coagulation system, resulting in clotting of circuits and thrombosis of vessels. Defibrinated blood was used in conjunction with bubble-type oxygenators as early as 1856, but reliable systemic anticoagulation remained elusive [2]. It was not until the discovery of heparin by Howell and McLean in 1916, and really only following the development of high-yield manufacturing processes in the late 1930s, that anticoagulation for CPB became feasible [3]. Early protocols for heparin administration were simply weight-based with little attempt at monitoring its effects. In 1957, the Mayo Clinic described “prevention of the coagulation of blood” for the Gibbon-type pump oxygenator, prescribing 3 mg of heparin (i.e., 300 units) per kilogram of patient bodyweight [4]. The activated clotting time (ACT) of whole blood was reported by Hattersley in 1966 [5], and this eventually led to a practical point-of-care testing that could be imported into the operating room for monitoring the effects of heparin. Bull et al. popularized the concept of the “safe zone” for anticoagulation during CPB in the mid-1970s, defining this as an ACT between 300 and 600 s [6]. It is intuitively evident that clot formation in CPB circuits can lead to devastating complications, but preventing thrombi is actually only one of the goals of anticoagulation. A variety of mechanisms lead to thrombin production during CPB, which can activate and consume critical hemostatic components including platelets, fibrinogen, and other coagulation factors [7]. Somewhat paradoxically, inadequate anticoagulation on CPB can lead to a profound coagulopathy, likely due to disseminated intravascular coagulation (DIC), upon its termination. This review attempts to summarize the knowledge gained over the past 40 years, and to guide clinicians with respect to the practice of anticoagulation for adults on CPB. Anticoagulation agents Despite its age, which is older than the US Food and Drug Administration (FDA), heparin remains the anticoagulant of choice for extracorporeal circulation. It can achieve profound levels of anticoagulation, is inexpensive, and it has a readily available antidote in protamine. Unfortunately, it also has significant limitations that have led to the search for alternate agents. Clinicians today are faced with an increasing array of choices for providing anticoagulation for CPB. While most are reserved for situations where heparin cannot be used, it is important to understand their potential benefits and limitations. Table 1 summarizes the dosing information of the below agents that have been used in the setting of CPB. Unfractionated heparin Unfractionated heparin (UFH) is a heterogenous mixture of sulfated polysaccharides prepared from animal tissues. The primary source has changed over the years from canine liver to bovine lung, and it is now predominantly porcine intestine. The extraction and purification processes result in a mixture of polysaccharide chains of 5e30 kDa in weight, of which 20e50% contain the specific pentasaccharidebinding site for the protein antithrombin (AT) [8]. The primary mechanism of UFH's anticoagulant effect is largely indirect, in that it accelerates AT's endogenous inhibition of factor IIa (thrombin) and factor Xa by >1000-fold each. The ratio of thrombin to Xa inhibition for UFH is assumed to be 1:1. Importantly, the neutralization of thrombin by AT requires heparin chains of higher molecular weight, containing at least 18 saccharide units. Low molecular weight heparins (LMWHs), provided they contain the specific pentasaccharide sequence, can still bind to AT and accelerate its inhibition of Xa, but inhibition of thrombin is severely reduced [8]. Factors IXa, XIa, and XIIa are also inactivated by the heparineAT complex, although to a much lesser degree [9]. Once AT binds to the coagulation factor, the heparin molecule is released and available to bind to other targets.

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Table 1 Summary of anticoagulants for cardiopulmonary bypass. Agent

Dosing

Monitoring

Comments

Unfractionated heparin

Bolus: 300e500 U/kg CPB Prime: up to 10,000 units

Wide variety of dosing and monitoring used

Danaparoid (27)

Bolus: 125 U/kg CPB Prime: 3 U/ml of priming fluid Infusion: 7 U/kg/h Bolus: 0.25 mg/kg CPB Prime: 0.2 mg/kg in priming fluid Infusion: 0.5 mg/min Bolus: 1 mg/kg CPB Prime: 50 mg in priming fluid Infusion: 2.5 mg/kg/h Bolus: 0.1 mg/kg Infusion: 5 mg/kg/min

ACT Heparin concentration (Hepcon) High-dose thrombin time Anti-Xa activity

Lepirudin (32)

Bivalirudin (35)

Argatroban (38)

Lower incidence of HIT cross-reactivity Bleeding complications due to long T1/2 Not recommended if other alternates available

ECT

No longer manufactured Desirudin similar, but CPB data not available

ECT ACT

ACT target 2.5 times baseline measurement Additional boluses 0.1e0.5 mg/kg as needed Hemoconcentration reduces drug levels on CPB

ACT ECT

Infusion adjusted to keep ACT >400 s Extensive blood product use when ACT > 600 s

ACT, activated clotting time; HIT, heparin-induced thrombocytopenia; ECT, ecarin clotting time.

Although the majority of UFH's anticoagulation effect comes from its interaction with AT, there are some AT-independent effects as well. These interactions are particularly important with respect to clotbound thrombin, as AT-mediated inhibition is severely reduced when thrombin is attached to a fibrin molecule [10]. This is the primary reason that low-dose heparin infusions fail to stop the propagation of venous clot. In 1981, Tollefsen et al. isolated a second heparin-dependent thrombin inhibitor that, since AT was occasionally referred to as heparin cofactor, they termed heparin cofactor II (HCII) [11]. The exact function of HCII remains largely unknown, although it has been postulated to play a role in hemostasis during pregnancy [12]. The dermatan sulfate Intimatan, an HCII agonist, has been shown to provide anticoagulation independent of AT [13], but clinical studies in the setting of CPB are lacking. Heparin has also been shown to induce endothelial cells to secrete tissue factor pathway inhibitor (TFPI) [14]. TFPI inhibits tissue factorefactor VIIa complexes formed as part of the extrinsic pathway. The majority of TFPI becomes bound to plasma proteins, and its significance in cardiac surgery is unclear. The mechanisms of UFH's inhibitory actions against thrombin are summarized in Fig. 1. The pharmacokinetics of UFH is complex and nonlinear [15]. There are two mechanisms for its elimination: one is quick, but saturable, and the other is non-saturable, but prolonged. Following an intravenous (IV) bolus, a portion of UFH binds to various plasma proteins, is taken up by macrophages, and is internalized by endothelial cells. This represents the rapid clearance of the drug, but it is overwhelmed by doses exceeding 100 U/kg [16,17]. Renal elimination is the non-saturable pathway, with larger molecular weight chains filtered more quickly than smaller ones. IV administration of a bolus of UFH results in peak onset of anticoagulant effects within 2e3 min [18], and the half-life increases significantly with larger doses. A dose of 100 U/kg has a half-life of approximately 1 h, whereas a 400 U/kg dose has one of 2.5 h [19]. In addition to anticoagulant effects on thrombin, heparin is also well known for activating platelets. The most feared complication of this is heparin-induced thrombocytopenia (HIT), which has been extensively reviewed elsewhere [20,21]. Briefly, the disorder is a result of antibody production against heparin complexed to platelet factor 4 (PF4) on the surface of platelets. These antibodies then crosslink platelets via the Fc receptor, activate them, and begin the coagulation process. However, not all heparin effects on platelets are immune-mediated, but rather caused by the heparin molecule's negative charge. Nonimmune interactions (the so-called HIT type I) are thought to occur via platelet IIb/IIIa receptors, decreasing the platelet's threshold for activation [22,23]. This often results in a small decrease in platelet count during the first few days of an infusion of UFH, which is not typically clinically relevant. As the doses of UFH used for CPB are significantly higher, it is possible that these

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Fig. 1. Anticoagulant effects of UFH. This figure shows a condensed version of the coagulation cascade, including the tissue factor (TF) pathway (i.e., extrinsic pathway) and the contact activation pathway (i.e., intrinsic pathway). The major actions of UFH consist of forming a complex with antithrombin (AT) to inhibit factor Xa and factor IIa (thrombin) as denoted by the large dotted lines. The smaller dashed lines indicate other anticoagulant effects including heparineAT complex inhibition of factors IXa, XIa and XIIa. UFH effects independent of AT include complexing with heparin cofactor II (HCII) to inhibit IIa, as well as promoting the release of tissue factor pathway inhibitor (TFPI) from the endothelium. HMWK, high molecular weight kininogen.

nonimmune interactions could contribute to coagulopathy seen following cardiac surgery. However, given that the conduct of CPB itself causes platelet dysfunction, it is difficult to isolate these effects in the operating room.

Low molecular weight heparins As their name suggests, LWMHs include the smaller chains of UFH e typically 24 h. A potential advantage of danaparoid is that it has a much lower, although not zero, cross-reactivity with HIT antibodies compared to LMWHs [26]. As such, in the past it was used in patients with HIT for anticoagulation on CPB. However, since it is not neutralized with protamine and has a long half-life, the incidence of major postoperative bleeding complications approaches 50% [27]. Danaparoid is no longer available in most countries. Fondaparinux (pentasaccharides) Unlike UFH, LMWHs, or heparinoid compounds, fondaparinux (Arixtra®, GlaxcoSmithKline, NC, USA) is a completely homogenous mixture of an oligosaccharide [28]. It contains the same critical pentasaccharide sequence as heparin which interacts with AT and produces only anti-Xa inhibition. Although fondaparinux can initiate the formation of anti-PF4 antibodies, it does not seem to support platelet activation [29]. Despite this, its long half-life (~20 h) and the inability to be neutralized by protamine preclude it from being useful for anticoagulation for CPB. However, its use has been reported in a patient on postoperative extracorporeal membrane oxygenation (ECMO) [30]. Direct thrombin inhibitors Hirudin is a small (

Anticoagulation management associated with extracorporeal circulation.

The use of extracorporeal circulation requires anticoagulation to maintain blood fluidity throughout the circuit, and to prevent thrombotic complicati...
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