The use of extracorporeal membrane oxygenation (ECMO) is increasing globally due to simplified equipment and increased demand during the COVID-19 pandemic, while bleeding and thrombotic events remain a significant challenge. An analysis of the Extracorporeal Life Support Organization (ELSO) database of 7579 patients with veno-venous ECMO (VV-ECMO) between 2010 and 2017 showed that 40.2% of patients experienced one or more bleeding or thrombotic events, of which 54.9% Circuit thrombosis was the most common event in the event. In contrast, an analysis of 11,984 veno-arterial (VA-ECMO) patients from the same database reported 8,457 events, 62.1% of which were bleeding events. Balancing anticoagulation to prevent thrombotic complications and bleeding in these complex critically ill patients is an ongoing challenge for clinicians during ECMO. In this practical update, we review the management of anticoagulation in ECMO.
Anticoagulation Monitoring: Laboratory Testing
< span>Laboratory testing is used to balance thrombosis versus bleeding in ECMO and to optimize patient management, not just treatment of major critical illnesses requiring extracorporeal life support (ECLS), including acute lung injury and/or shock. In addition to standardized tests such as hemoglobin, platelet count, and antithrombin (AT) levels, Figure 1 and Table 1 list specific anticoagulation management strategies, including activated clotting time (ACT), activated Partial thromboplastin time (aPTT) and anti-factor Xa (anti-Xa). The level of anticoagulation required for VV and VA-ECMO may vary, depending on the underlying disease, risk of thrombosis, and factors that determine the severity of the patient’s disease.
Figure 1. The optimal anticoagulation target in ECMO patients is currently unknown and may be determined by underlying disease, patient comorbidities, and thrombotic/bleeding risk /event varies.
Ab, antibody: aPTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulopathy; ECMO, extracorporeal membrane oxygenation; GI, gastrointestinal tract; HIT, heparin-induced Thrombocytopenia; PF4, platelet factor 4; VWS, von Willebrand’s syndrome
Table 1. Venous Anticoagulation
Features | Unfractionated heparin | Argatroban | Bivalirudin |
structure | Glycosaminoglycans | Chemical Synthesis< /span> | peptide |
Molecular weight (Daltons) | 3000–30,000 | 508 | 2180 |
Suppress target | Factor Xa, Factor IIa (thrombin) | Factor IIa (thrombin) | Factor IIa (thrombin) |
Cofactor | Antithrombin | none | none |
half-life | about 1 hour may increase with high doses | 25min | |
Metabolism | reticuloendothelial tissue | liver | kidney |
Route of Administration | Veins | Vins | Monitoring | aPTT, anti-Xa level, (ACT) 1 < /td> | aPTT, Dilute Thrombin Time, (ACT)1 Ecarin Clotting Time (ECT) | < p>aPTT, diluted thrombin time, (ACT) 1 Ecarin Clotting Time (ECT) |
reversible/ antagonists | yes < p>protamine | no | no |
Target Range2 | aPTT 40-80s2 anti-Xa 0.2–0.5(-0.7) IU/mL3 | aPTT 40-80s2 blood clot 0.6-0.8 μg/mL4 ECT 1.5–2.0-fold extension 5 | aPTT 40-80s< sup>2 blood clot 0.6-0.8μg/mL4 < span>ECT 1.5–2.0-fold extension 5 |
1It is no longer recommended as a first-choice proprietary trial due to its poor correlation with heparin dose
2The target range is empirical and based on the provider’s assessment of bleeding/thrombotic risk (eg, an empirical aPTT range of 40-60 is typically used initially) em>
4Experimental (clot determination based on diluted thrombin time)
5< /sup> was linearly related to DTI concentration, with no saturation effect during 70-80 years compared with aPTT, but no data available for ECMO patients.
Abbreviations: aPTT, activated partial thromboplastin time; ECT, ecarin clotting time; DTI, direct thrombin Inhibitors (argatroban and bivalirudin);
activated clotting time (ACT) span>
ACT is a whole blood test to assess the effect of heparin or direct thrombin inhibitor (DTI) on contact activation/intrinsic coagulation inhibition . Factors that prolong ACT include hypothermia, platelet function/number, and coagulation factor levels. The recommended ACT range for ECMO is 180–200 seconds. However, ACT was often inconsistently correlated with other coagulation tests, including anti-Xa/heparin levels and aPTT.
Activated partial thromboplastin time (aPTT)
aPTT assesses contact-activated/intrinsic coagulation and is usedto monitor heparin and DTIs, a test to assess thrombosis. The recommended treatment target is initially 40-50 seconds, then titrated to 60-80 seconds based on bleeding and/or thrombotic risk. The activator used is a phospholipid (ellagic acid) and clot formation is determined by mechanical or optical clot detection. aPTT assay is affected by antithrombin, factor VIII, factor XII and fibrinogen levels. For heparin monitoring, aPTTOften inconsistent with anti-Xa monitoring. aPTT was also used to assess DTIs (argatroban and bivalirudin). Variability and extent of treatment vary by clinical condition and should be individualized.
anti-factor Xa levels
For unfractionated heparin (UFH) therapy, anti-Xa levels are increasingly used, and anti-Xa levels correlate better with UFH levels than aPTT. The recommended ECMO target level range is 0.3-0.7 IU/mL; However, anti-Xa levels cannot assess thrombosis. Tests may be affected by the patient’s AT deficiency, hyperlipidemia, coagulation factor levels and hemolysis, and plasma hemoglobin and/or hyperbilirubinemia.
Viscoelasticity Test< span>
Viscoelasticity tests evaluate clot-based assays using specific activators (eg, tissue factor, ellagic acid, kaolin) to assess whole blood clot formation, commonly used in Bleeding management assessment, not anticoagulation monitoring.
Antithrombin (AT)
< /span>AT is essential for the effectiveness of heparin. However, levels decrease during ECMO due to consumptive coagulation and other reasons. Despite use of the drug, there are no data to support improved outcomes after supplementation in ECMO patients.
Anticoagulation
< strong>Unfractionated heparin (heparin)
Unfractionated heparin (heparin) is therapeutic because of its titration, reversibility, and short duration of action (about 1 hour). main drug. Despite increasing use, anti-Xa monitoring does not provide information on thrombosis or other factors affecting the balance of hemostasis. In an era of goal-directed therapy, there are no data to suggest that maintenance of specific anti-Xa concentrations is associated with improved outcomes, as diseases requiring ECMO inherently affect morbidity and mortality. Heparin resistanceHeparin resistance is poorly defined as the current definition is >35000 units/day, there is no specific weight-based dose, and A clot aggregation test based on the high influence of hypercoagulability and thrombocytosis. When high-dose heparin fails to achieve the desired aPTT or ACT values, checking anti-Xa levels can aid in the diagnosis. The benefit and risk considerations of DTI for heparin resistance should be carefully evaluated. ArgatrobanArgatroban is a synthetic approximately 500 Dalton L-arginine Acid derivatives that reversibly inhibit thrombin by monovalent binding to thrombin. Argatroban may be the DTI of choice for the treatment of renal failure due to hepatic clearance (half-life = 40–50 minutes) and has been studied in intensive care unit (ICU) and ECMO populations. BivalirudinBivalirudin is a small peptide (approximately 2400 Daltons) DTI that Reversibly binds thrombin and inhibits its activity. Half-life is 20-30 minutes, but extends to 240 minutes in renal failure. Bivalirudin is widely used as a heparin substitute in the cath lab and has been reported for ECMO. heparin-induced thrombocytopenia
DTIs argatroban and bivalirudin for diagnosis or suspected need for ECMO and other indications of patients. In ICU and ECMO patients, thrombocytopenia has multiple causes, often making diagnosis challenging.
In conclusion, since different anticoagulation trials, different anticoagulation regimens and ECMO outcomes depend on the patient’s underlying disease process, optimizing anticoagulation practice Still improving. In addition, the new simplified ECMO circuit has greatly facilitated its worldwide application.
Heparin is the mainstay of ECMO anticoagulation and can be administered through a variety of laboratory tests. When routinely monitored using clot-based assays (aPTT or ACT), anti-Xa levels help determine whether heparin target levels are being achieved. Viscoelasticity testing can be used to help identify hemorrhagic coagulation defects. In heparin-resistant patients, weight-based dosing should be considered, and anti-Xa levels should be assessed and titrated accordingly. Alternatively, switch to DTI or supplemental AT, which are potential options.
There is no uniform ECMO anticoagulation practice because there is no evidence-based consensus to guide anticoagulation medication, monitoring, treatment goals, optimal levels, and Management of complications and outcomes. Much research is still needed on one mode in use since the 1980s, and further research is needed to identify appropriate targets. A potential flow of clinical management is shown in Figure 1.
Source:Intensive Care Med
https://doi.org/10.1007/ s00134-022-06723-z
Disclaimer: This article is reproduced in the world of acute and critical illness, the author Yang Tianzhen, only for learning and communication, the copyright belongs to the original author.
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