key: cord-0793986-gvbz3k0q authors: Seelhammer, Troy G.; Rowse, Phillip; Yalamuri, Suraj title: Bivalirudin for Maintenance Anticoagulation During Veno-Venous Extracorporeal Membrane Oxygenation for COVID-19 date: 2020-06-25 journal: J Cardiothorac Vasc Anesth DOI: 10.1053/j.jvca.2020.06.059 sha: d9d79b7c54a47f9640af83ecaf99535cb5271b8e doc_id: 793986 cord_uid: gvbz3k0q In its severe manifestation, COVID-19 compromises oxygenation in a manner that is refractory to maximal conventional support and requires escalation to extracorporeal membrane oxygenation (ECMO). Maintaining ECMO support for extended durations requires a delicately balanced anticoagulation strategy to maintain circuit viability by preventing thrombus deposition, while avoiding excessive anticoagulation yielding hemorrhage; a task that is complicated in COVID-19 secondary to an inherent hypercoagulable state. Bivalirudin, a member of the direct thrombin inhibitor drug class, offers potential advantages during ECMO including to its ability to exert its effect by directly attaching to and inhibiting freely circulating and fibrin-bound thrombin. Herein, we report the successful use of an anticoagulation strategy employing the off-label use of a continuous infusion of bivalirudin in a case of severe hypoxemic and hypercarbic respiratory failure caused by COVID-19 requiring VV-ECMO. Importantly, therapeutic anticoagulation intensity was rapidly achieved with stable pharmacokinetics and there was no need for any circuit interventions throughout the patient's 27 day ECMO course. In COVID-19, bivalirudin offers a potential option for maintaining systemic anticoagulation during ECMO in a manner that may mitigate the pro-thrombotic nature of the underlying pathophysiologic state. HIT, heparin-induced thrombocytopenia aPTT, activated partial thromboplastin time P:F, ratio of arterial oxygen partial pressure to fractional inspired oxygen mg/kg/hr, milligrams per kilogram per hour mg, milligrams mg/dL, milligrams per deciliter ng/mL, nanograms per milliliter OR, operating room CrCL, creatinine clearance ECT, ecarin clotting time PaO2, arterial oxygen partial pressure Abstract In its severe manifestation, COVID-19 compromises oxygenation in a manner that is refractory to maximal conventional support and requires escalation to extracorporeal membrane oxygenation (ECMO). Maintaining ECMO support for extended durations requires a delicately balanced anticoagulation strategy to maintain circuit viability by preventing thrombus deposition, while avoiding excessive anticoagulation yielding hemorrhage; a task that is complicated in COVID-19 secondary to an inherent hypercoagulable state. Bivalirudin, a member of the direct thrombin inhibitor drug class, offers potential advantages during ECMO including to its ability to exert its effect by directly attaching to and inhibiting freely circulating and fibrin-bound thrombin. Herein, we report the successful use of an anticoagulation strategy employing the off-label use of a continuous infusion of bivalirudin in a case of severe hypoxemic and hypercarbic respiratory failure caused by COVID-19 requiring VV-ECMO. Importantly, therapeutic anticoagulation intensity was rapidly achieved with stable pharmacokinetics and there was no need for any circuit interventions throughout the patient's 27 day ECMO course. In COVID-19, bivalirudin offers a potential option for maintaining systemic anticoagulation during ECMO in a manner that may mitigate the pro-thrombotic nature of the underlying pathophysiologic state. In 2019 a novel coronavirus, named SARS-CoV-2, was identified to cause the disease COVID-19. 1 Severe cases of COVID-19 result in profound hypoxemia that is refractory to maximal conventional ventilator therapy that requires escalation to extracorporeal membrane oxygenation (ECMO) in carefully selected individuals. Given the extended duration of COVID-19 symptoms, maintaining circuit integrity for that period requires a finely tuned anticoagulation strategy that balances the need for anticoagulation to prevent thrombus deposition while avoiding hemorrhage. Achieving this harmony is complicated in COVID-19 secondary to an inherent hypercoagulable state with elevated risk for both venous and arterial thromboembolic complications. [2] [3] [4] Most typically, unfractionated heparin is utilized on ECMO due to its rapid onset of action, widespread availability, and the ability to reverse its action with protamine. However, heparin carries inherent limitations that predispose to persistent fluctuations in dose sensitivity and heparin-induced thrombocytopenia (HIT). 5 Direct thrombin inhibitors, of which bivalirudin is a member, produce transient inhibition of thrombin to mitigate the cleavage of fibrinogen to its active form. Furthermore, it offers potential advantages during ECMO due to its ability to exert this effect by directly attaching to and inhibiting both freely circulating and fibrin-bound thrombin. Additionally, bivalirudin offers reliable pharmacokinetics owing to its largely organ independent clearance. 6 A growing body of evidence has emerged demonstrating the safety of bivalirudin during ECMO with some studies reporting a superior balance between thrombosis and hemorrhage. [7] [8] [9] We report the successful use of an anticoagulation strategy employing a continuous infusion of bivalirudin in a 65-year-old female with severe hypoxemic and hypercarbic respiratory failure caused by COVID-19 requiring veno-venous ECMO (VV-ECMO). A 65-year-old female with past medical history significant only for hypertension and hyperlipidemia was admitted to the hospital in hypoxemic and hypercarbic respiratory failure due to confirmed COVID-19 on a PCR assay. Following admission to an outside institution she was initially treated with non-invasive ventilation and self-proning. Due to progressive hypoxemia, she was intubated on hospital day (HD) 2, which was complicated by severe subcutaneous emphysema and pneumomediastinum concerning for tracheal injury. She was transferred to our institution for consideration of ECMO therapy. Important clinical events are summarized in Figure 1 . Initial arterial blood gas revealed a normal partial pressure of carbon dioxide, but a markedly depressed ratio of arterial oxygen partial pressure (PaO2) to fractional inspired oxygen being positive for lupus anticoagulant. 11 However, this has not been associated with a bleeding tendency and the lupus anticoagulant may, in fact, predispose to a thrombotic tendency resulting in suggestions that a prolonged aPTT not be cited as a barrier for the use of anticoagulation in patients with COVID-19. With these considerations in mind, recommendations have been published suggesting targeting higher than typical anticoagulation intensity with concurrent potential benefit from antiplatelet agents in ECMO patients with COVID-19. 3 To our knowledge, this is the first reported case of the use of direct thrombin inhibitors for maintenance anticoagulation during ECMO employed in the setting of COVID-19. There remains a relative dearth of published evidence for ECMO in the setting of COVID-19 with complete absence of reports of anticoagulation management in this population. Our center transitioned to a bivalirudin infusion as a first line anticoagulant for adult and pediatric ECMO in 2017. As such, employing bivalirudin in our patient was not a novel strategy chosen due to the pro-thrombotic nature of COVID-19. It is worth stating that heparin was not contraindicated in this patient and its use for the rapid obtainment of therapeutic anticoagulation at the time of ECMO initiation is standard practice at our institution with subsequent transition to bivalirudin for maintenance in all patients barring contraindications to its use (absolute or relative stasis due to rapid proteolysis of local stores of bivaluridin, antiphosholipid syndrome as the baseline aPTT may be falsely elevated, and allergy/intolerance). One potential hindrance with the use of bivalirudin is anticoagulation monitoring with various laboratory assays having been described including activating clotting time, ecarin clotting time (ECT), and chromogenic antifactor IIa assays; the most robust experience utilizes aPTT. [12] [13] [14] Although uncommon, bivalirudin resistance thought to be secondary to elevated Factor VIII or fibrinogen has been reported with recommendations to employ alternative assays (ECT or chromogenic antifactor IIa) if concern for inaccurate aPTT becomes present. 15 At our center, dosing adjustments rely on an ECMO patient derived algorithm that is adjusted for estimated creatinine clearance and guided by aPTT monitoring. In this patient, an elevated aPTT target of 60-80 seconds was utilized that differed significantly from non-COVID-19 VV-ECMO patients (typical targets at our center for VV-ECMO is 40-60 seconds and for VA-ECMO 60-80 seconds). The decision to select an elevated aPTT target was reinforced by the grossly elevated D-dimer of 1584 ng/ml which has been associated with thrombotic complications in COVID- 19. 4 Additionally, low dose ASA was added empirically once appropriate hemostasis and anticoagulant tolerance was demonstrated in an effort mitigate platelet activation. The clinical impact of its addition is unclear. ECMO circuits are complex systems of tubing built from foreign material and often coated with anticoagulant (heparin bonded) and include a membrane oxygenator with a large surface area. Unfractionated heparin remains the mainstay of continuous anticoagulation therapy in the patient on ECMO support due to its rapid onset of action, widespread availability, and the ability to reverse its action with protamine. 5 However, inherent limitations exist including the requirement of the cofactor antithrombin III through which its action is mediated, unpredictable kinetics requiring frequent dose adjustments, and the highly antigenic nature of heparin that may trigger HIT. 7 COVID-19 may exacerbate variations in heparin sensitivity secondary to reduced antithrombin III levels. 16 Direct thrombin inhibitors have numerous pharmacokinetic and pharmacodynamic advantages versus heparin. Bivalirudin is a member of the direct thrombin inhibitor drug class and is FDA approved for the short term use (up to 4 hours post-procedure) in adult patients undergoing percutaneous coronary intervention. 17 It is a semisynthetic bivalent inhibitor of thrombin that produces transient inhibition of thrombin. This action at the terminal step in the cleavage of fibrinogen to its active form establishes the foundation for its potential role in interrupting an important humoral regulatory process that is deranged in acute inflammatory states. Owing in part to its largely organ independent metabolism, bivalirudin has a short half-life of 25 minutes in patients with normal renal function. 6, 18 Other reported benefits of this drug class, when compared to heparin, include the ability to inhibit circulating and clot-bound thrombin and the absence of association with HIT. 18 Sepsis and ARDS, including COVID-19, are characterized by a pro-coagulant state that results in a massive production of thrombin. 19 In addition to direct effects on the endothelial barrier by thrombin, the subsequent cleavage of fibrinogen to fibrin results in diffuse alveolar and interstitial fibrin deposition yielding the formation of microthrombi. 19 An important interplay between the innate immune system and platelets occur at the site of endothelial lesions in a mechanism that is upregulated by the effect of thrombin. This mechanistic description underscores an additional potential clinical advantage of direct thrombin inhibitors in ECMO patients afflicted with COVID-19. Over the last decade, an expanding body of evidence has established the safety of bivalirudin in mechanical circulatory support with emerging data demonstrating superior balance between thrombosis and hemorrhage. [7] [8] [9] Ranucci et al identified a reduction of aPTT variations, blood loss, and transfusion requirements with bivalirudin based anticoagulation in a population of post-cardiotomy veno-arterial ECMO (VA-ECMO) patients. 9 Pieri et al again found a reduction in dose adjustment requirements and a reduced incidence of supra-therapeutic aPTT with bivalirudin in 5 VV and 5 VA-ECMO patients. 8 In a retrospective study of 32 pediatric patients ECMO patients, Hamzah et al reported a reduction in bleeding events in patients anticoagulated with bivalirudin. 7 Importantly, bivalirudin was more cost effective despite higher drug acquisition costs. In a cohort of 44 shock patients (92% VA-ECMO), Berei et al found no difference in thrombotic events or mortality but suggested bivalirudin as a viable alternative to heparin based protocols. 20 Our COVID-19 positive patient on ECMO anticoagulated with bivalirudin demonstrated excellent stability in aPTT with minimal requirements for dose adjustments. Importantly, anticoagulant intensity was achieved rapidly and sustained with only a single supra-therapeutic aPTT assay occurring in the setting of enterococcus bacteremia. Hemostasis was appropriate with no blood product transfusion requirement and the patient was successfully separated from ECMO without hematologic complications. Furthermore, the absence of thrombotic, embolic, and circuit complications was encouraging. This is reinforced when considering the entrainment of additional thrombotic risk associated with COVID-19. With the growing evidence of its safety as well as the superiority described in several recent publications, bivalirudin should be considered for maintenance of anticoagulation for COVID-19 patients requiring ECMO. Bivalirudin, a member of the direct thrombin inhibitor drug class, offers potential advantages during ECMO due to its ability to exert its effect by directly attaching to and inhibiting both freely circulating and fibrin-bound thrombin as well as reliable pharmacokinetics owing to its largely organ independent clearance. In our COVID-19 positive patient, we successfully used a continuous infusion of bivalirudin in a case of severe hypoxemic and hypercarbic respiratory requiring VV-ECMO. We demonstrated a rapid achievement of therapeutic anticoagulation, stable pharmacokinetics, and relative ease of dose titration. Importantly, there was no need for any circuit interventions, including oxygenator exchange or thrombus excision, throughout her 27 day ECMO course. 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A Report of Thromboelastography Findings and other Parameters of Hemostasis Angiomax (bivalirudin) for injection, for intravenous use Anticoagulation with direct thrombin inhibitors during extracorporeal membrane oxygenation Immunothrombosis in Acute Respiratory Distress Syndrome: Cross Talks between Inflammation and Coagulation Evaluation of Systemic Heparin Versus Bivalirudin in Adult Patients Supported by Extracorporeal Membrane Oxygenation The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.