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CARDIOVASCULAR ANESTHESIOLOGY

Extracorporeal Membrane Oxygenation with Danaparoid Sodium After Massive Pulmonary Embolism

Christian Bauer, MD^*, Zuzana Vichova, MD^*, Patrick Ffrench, MD^*, Christiane Hercule, MD^*, Olivier Jegaden, PhD^*, Olivier Bastien, PhD^*, and Jean-Jacques Lehot, PhD^*

From *Université Claude Bernard Lyon 1, France; and Hemostasis Laboratory, Department of Cardiovascular Surgery, and Anesthesiology and Intensive Care Unit, Hospices Civils de Lyon, Hopital Cardiovasculaire et Pneumologique Louis Pradel, Bron, France.

Address correspondence to Christian Bauer, MD, Hospices Civils Lyon, Hopital Cardiovasculaire et Pneumologique Louis Pradel, Anesthesiology and Intensive Care Unit, Bron, F-69677, France. Address e-mail to christian.bauer{at}chu-lyon.fr.

Abstract

During extracorporeal membrane oxygenation, anticoagulation therapy is usually achieved with unfractionated heparin. We report on an extracorporeal membrane oxygenation with danaparoid sodium for a patient with severe respiratory failure due to massive pulmonary embolism and suspected type 2 heparin-induced thrombocytopenia. Danaparoid, a low molecular weight heparinoid, is an alternative to heparin for patients who develop type 2 heparin-induced thrombocytopenia. Danaparoid was given at 400 IU/h with an objective of antifactor Xa activity of 0.6–0.8 U/mL, which was monitored twice a day. No excessive bleeding or clotting of the circuit was noted. The patient was weaned from extracorporeal membrane oxygenation after 9 days of treatment.

In cases of acute massive pulmonary embolism, pulmonary embolectomy or thrombolytic therapy are considered effective treatments. Extracorporeal membrane oxygenation (ECMO) may be used for cardiopulmonary support, either as a bridge to surgical embolectomy1 or as a destination therapy until functional cardiopulmonary recovery.2,3 If an ECMO is used, anticoagulation is routinely achieved with unfractionated heparin. However, a possible adverse effect of heparin is heparin-induced thrombocytopenia (HIT), often accompanied by arterial and venous thrombosis and resulting in frequent morbidity and mortality.4 This requires immediate discontinuation of heparin and initiation of an alternative anticoagulation. In this study, danaparoid was chosen to substitute for heparin. Danaparoid and direct thrombin inhibitors have been evaluated as substitutes for heparin but, unlike cardiopulmonary bypass (CPB) for cardiac surgery,5–16 little information on the use of danaparoid in ECMO has been published. The use of danaparoid, with its prolonged half-life, for long-term ECMO could be a challenge. We report a successful ECMO management with danaparoid of a patient with suspected type 2 HIT.

CASE DESCRIPTION

A 30-yr-old man was admitted to hospital with epigastric and chest pain. A computed tomography scan revealed a massive bilateral pulmonary embolism with an extending thrombus starting in the right pulmonary artery and a thrombus in the left posterobasal pulmonary artery. Transthoracic echocardiography showed normal left ventricular systolic function and a slightly dilated right ventricle without acute cor pulmonale. The abdominal Doppler examination revealed portal vein and left iliac vein thrombosis. Full anticoagulation was started immediately with 500 IU/kg/24 h of unfractionated heparin to obtain plasma heparin levels of 0.2–03 U/mL. After 3 days of heparin therapy, the platelet count decreased from 214 x 10⁹/L to 74 x 10⁹/L and type 2 HIT was suspected. Therefore, the heparin therapy was stopped, and anticoagulation with danaparoid was started at 400 IU/h for 4 h, then at 300 IU/h to obtain an antifactor Xa activity of 0.5–0.8 U/mL. Thirty-six hours after heparin withdrawal, the platelet count increased to 130 x 10⁹/L.

His respiratory status dramatically worsened with acute chest pain, hypoxemia (Sao₂ <70%), and mechanical ventilation with nitric oxide at 10 ppm in 100% oxygen was initiated. Pao₂ decreased to 33.5 mm Hg and bradycardia at 50 bpm occurred. Venoarterial ECMO, via a surgical cannulation of the femoral vessels (pump Medtronic® Bio-Medicus® 550 Bio-Console®, oxygenator Medos® Hollow Fiber Oxygenator Hilite® 7000 LT), was initiated in this hemodynamically unstable patient who was not transportable to an operating room. The ECMO blood flow was set at 80 mL · kg^–1 · min^–1. Sao₂ improved and the ventilator settings were gradually reduced to obtain end-inspiratory pressure below 20 cm H₂O and Fio₂ of 40%. The danaparoid dose was increased to 400 IU/h to reach an antifactor Xa level of 0.6–0.8 U/mL. Antifactor Xa activity was monitored twice a day and the administration of danaparoid was modified accordingly (Fig. 1). Activated partial thrombin time was monitored in the same way and varied between 35 and 42 s, without any correlation between antifactor Xa activity and, thus, the anticoagulant effect of danaparoid. Nine units of packed red blood cells were transfused during the first 3 days of ECMO therapy. Two more units were needed from that point until termination of the ECMO. The patient was successfully weaned from ECMO after 9 days of treatment.

View larger version (15K): [in this window] [in a new window]   Figure 1. Monitoring of antifactor Xa activity with corresponding dosage of danaparoid sodium. Arrows indicate the course of extracorporeal membrane oxygenation (ECMO) therapy. D0: day 0. D1: day 1.

Although the HIT assay result was negative 12 h after initiation of ECMO by both heparin-induced platelet aggregation assay and by the absence of anti-PF4/heparin antibodies in the PF4-dependent enzyme-linked immunosorbent assay, because the patient was stable, treatment with danaparoid was continued until the end of ECMO.

Prothrombotic risk factors were evaluated, and heterozygosity for the mutation G20210A in the prothrombin gene was detected. This mutation is associated with increased plasma prothrombin concentrations and is an independent risk factor for pulmonary embolism.17 Other inherited risk factors were not found (deficiencies in antithrombin, protein C or protein S, hyperhomocysteinemia, lupus anticoagulant antibodies, anticardiolipid antibodies, factor V Leiden mutation). A possible additional, acquired risk factor for thromboembolism may have been due to a 20-h air flight the patient took 2 mo before.18

DISCUSSION

For patients with HIT who require extracorporeal circulation, including ECMO, alternative anticoagulant options include using heparin with a platelet inhibitor (epoprostenol, tirofiban), using a direct thrombin inhibitor (lepirudin, bivalirudin, or argatroban) or using a low-molecular weight heparinoid, such as danaparoid sodium. There is no evidence-based data to suggest what the best choice might be. However, factors to consider include renal function, the physician's experience, the availability of a particular drug, and the published literature supporting its use, since these are off-label uses. In France, of the direct thrombin inhibitors, only lepirudin and danaparoid are approved for treating HIT-associated thrombosis.

Studies on the use of danaparoid with CPB for cardiac surgery show varying results, including clots in the bypass circuit5–8 and in the operative field,9 or major postoperative bleeding.10–12 In a large retrospective study, the use of danaparoid in cardiac surgery with CPB was associated, in 42% of patients, with major bleeding, defined by fatal or life-threatening hemorrhage, the necessity for reoperation or the transfusion of more than 2 U of blood or other blood product. These adverse events were possibly dose-related.13 However, other studies reported no complications.14–16

Danaparoid has a long elimination half-life time (19–25 h), no antidote, and a possibility of cross-reactivity with anti-PF4/heparin antibodies.19,20 However, danaparoid is one of the drugs recommended for the treatment of HIT based on current published guidelines.4 In renal failure, danaparoid accumulates in the blood and prolongs the anticoagulant effect. Activated clotting time and activated partial thromboplastin time cannot monitor the anticoagulant effect of danaparoid14,21 or any other factor Xa inhibitor; rather anti-Xa activity must be measured.22

In our case, despite subsequent negative laboratory tests supporting our initial diagnosis of HIT, we decided not to switch back to heparin before cessation of ECMO because the patient was stable. As a consequence of the different pharmacokinetic properties of danaparoid, maintaining adequate anti-Xa activity while switching from danaparoid to heparin is unknown. Danaparoid and heparin anticoagulant activities are both monitored by anti-Xa activity, aiming at different levels (0.6–0.8 U/mL and 0.3–0.6 U/mL, respectively). Although high levels of antifactor Xa activity (1.5 ± 0.3 U/mL)23 have to be maintained during CPB, the target in the setting of ECMO is lower to keep the antifactor Xa activity level 0.6–0.8 U/mL.

Another option would have been the use of recombinant hirudin (lepirudin). Although there is no antidote for lepirudin, the short half-life time of 60–90 min in patients with normal renal function24 and the absence of cross-reactivity to heparin-induced antibodies make this drug a potential alternative.25 The anticoagulant effect of lepirudin can be measured by ecarin clotting time (ECT) on whole blood samples. The ECT assay requires some modifications when high doses of lepirudin are used23 and quality assessment of this modified assay is lacking.26 Because of difficulties with ECT in this setting, we decided not to use lepirudin.

Our extracorporeal circuits for ECMO are all coated with Carmeda® BioActive Surface, where heparin is covalently bound to the artificial surface. Although this type of coating does not encourage the occurrence of anti-PF4/heparin antibodies in patients with ventricular assist devices,27 we still should have used a noncoated device in this patient to avoid any heparin exposure.

The patient experienced some bleeding with a mean red blood cell requirement of 1.2 U/d. This amount was less than that recorded in other studies with ECMO support.28 Most of the units (9/11) were transfused during the first 3 days of treatment. Blood loss had several origins: hemodilution that occurs at initiation of ECMO, bleeding at the cannula insertion site, platelet dysfunction by circuit activation,29 and hemolysis due to the centrifugal pump. The removal of the cannulae was performed without excessive bleeding while the antifactor Xa activity was within therapeutic levels. Neither clotting of the circuit nor new thrombotic complications or thrombosis extension occurred.

In summary, danaparoid was administered as an alternative during femoral venoarterial ECMO with daily monitoring of anti-Xa activity. Further experience with danaparoid in this setting is needed.

Footnotes

Accepted for publication December 11, 2007.

Reprints will not be available from the author.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bauer, C. Articles by Lehot, J.-J. Search for Related Content PubMed PubMed Citation Articles by Bauer, C. Articles by Lehot, J.-J. Related Collections Cardiovascular Complications Monitoring (Cardiac) Coagulation