activation pathway’s contributions to a pro-inammatory response, the immune sys­tem’s complement pathway is activated through exposure to the foreign material of the circuit [98]. Activated complement, tissue necrosis factor-α (TNF-α), and inter­leukin- 6 (IL-6), in turn, can induce the expression of tissue factor, triggering a fur­ther coagulation response [98]. Finally, acquired antithrombin III deciency is relatively common during ECMO, seen in approximately 50% of individuals, and thought to be due to the use of heparin for anticoagulation [116].

safe for VV-ECMO [92]. There are no established, standardized dosing and moni­toring protocols for anticoagulation for several reasons. First, ECMO technology continues to evolve, with older circuits requiring greater anticoagulation intensity compared to contemporary circuits [47]. Data regarding optimal monitoring using the anti-factor Xa assay (anti-Xa) or activated partial thromboplastin time (aPTT) varies, and therefore, different centers prefer different monitoring and targets (see Sect. 9.4.4). Centers also vary in the level of anticoagulation intensity targeted, which differs based on patient risk factors for bleeding versus thrombosis. The ret­rospective nature of currently published literature makes it difcult to control for these various risk factors and how they impact optimal management [47].

In a minority of ECMO centers or in situations where heparin is contraindicated (e.g., HIT), direct thrombin inhibitors (DTIs) are used as either the primary or the secondary choice of anticoagulation, respectively. As the name implies, DTIs bind directly to thrombin, inhibiting the conversion of brin to brinogen and the activa­tion of factors V, VIII, and XI [24]. The DTIs most used in ECMO are argatroban and bivalirudin, and they have several advantages over heparin, including a predict­able anticoagulant effect independent of antithrombin III and no risk for HIT (Table9.1) [24]. Additionally, bivalirudin and argatroban bind circulating and clot­bound thrombin, suggesting that they may be more effective than heparin, which only binds circulating thrombin [24]. Argatroban and bivalirudin are monitored with aPTT or ACT and can markedly increase the INR disproportionate to their actual anticoagulant effects [24]. Despite these advantages, there are limitations that exist within the class and each specic agent. Unlike heparin, DTIs do not have a reversal agent and have considerations in organ dysfunction [24]. Bivalirudin has a short half-life (25 minutes), but is renally cleared, and requires signicant dose reductions in renal dysfunction [24]. Argatroban is hepatically metabolized, and dose reductions are necessary with hepatic dysfunction; argatroban has demon­strated a prolonged half-life in critical illness and should be dose adjusted accord­ingly [24]. Bivalirudin is unique in that it is locally metabolized by proteases and therefore can disassociate from thrombin in static blood, increasing the risk of clot­ting, which can be of concern in low-ow ECMO states or in areas of the circuit where blood may pool (e.g., the oxygenator) [24]. Finally, DTIs are signicantly more expensive than heparin; for a 70kg patient receiving starting dose infusions of heparin, argatroban, and bivalirudin at wholesale acquisition pricing, the cost per day would be $12.50, $800, and $2200, respectively [6, 14].

As mentioned previously, there are no standardized protocols regarding dosing and monitoring of anticoagulation in ECMO.Monitoring of heparin can be done utiliz­ing aPTT, ACT, or anti-Xa, and DTIs can be monitored with aPTT or ACT. The ELSO guidelines make no recommendations as to the preferred laboratory monitor­ing parameter for heparin or DTIs, and note that each method has its advantages and disadvantages (Table9.2) [92]. In addition to considering the various pros and cons of each method, patient factors also play a role in deciding the optimal method to choose including the patient’s age, comorbidities, and other coagulation decien­cies the patient may have [29]. It is important to note that while these methods as a whole help to guide the clinician in determining the patient’s response to anticoagu­lation, their results do not always correlate to outcomes; bleeding and thrombotic events can happen at subtherapeutic, therapeutic, or supratherapeutic levels [29]. In addition, these methods do not give a full picture of what is going on within the coagulation cascade and platelet activation, as they are only able to measure pieces of this very complex system [29].

cardiopulmonary bypass targets high ranges of 400–800seconds, for ECMO, tar­gets are much lower at 180–200seconds [29]. Studies have shown that there can be discordance between ACT and anti-Xa, particularly in patients with hemorrhagic complications, where ACT was <180seconds but anti-Xa was >0.7IU/mL [13, 84]. Other studies have shown poor correlation between the ACT result and the heparin dosing [7].

As previously mentioned, the ECMO circuit is composed of cannulas, tubing, oxy­genator, heat exchanger, and blood pump. These components have undergone sev­eral technologic improvements since their inception to improve efcacy as well as temper potential complications. These changes include heparin-coated polyvinyl chloride tubing and cannulas to reduce drug adsorption and inammatory response, silicone-based oxygenators replaced with polymethylpentene oxygenators with integrated heat exchangers for increased durability and reduced circuit changes, and conversion from roller to centrifugal pumps to decrease shear stress and hemolysis [26]. Despite these improvements, the ECMO circuit provides physical and chemi­cal changes to drug distribution, which can result in profound therapeutic alterations.