key: cord-0853639-9v2bmbod
authors: Guo, Zhen; Sun, Lin; Li, Bailing; Tian, Rui; Zhang, Xiaolin; Zhang, Zhongwei; Clifford, Sean P.; Liu, Yuan; Huang, Jiapeng; Li, Xin
title: Anticoagulation Management in Severe COVID-19 Patients on Extracorporeal Membrane Oxygenation
date: 2020-09-04
journal: J Cardiothorac Vasc Anesth
DOI: 10.1053/j.jvca.2020.08.067
sha: 577dbba3b54bc35bb1f0054eaaa1f747421f10a1
doc_id: 853639
cord_uid: 9v2bmbod

OBJECTIVE: To explore special coagulation characteristics and anticoagulation management in extracorporeal membrane oxygenation assisted patients with coronavirus disease 2019. DESIGN: This study is single center retrospective observation of a series of patients. PARTICIPANTS: Laboratory-confirmed severe COVID-19 patients who received venovenous ECMO support from January 20(th) to May 20(th), 2020. INTERVENTIONS: This study analyzed the anticoagulation management and monitoring strategies, bleeding complications, and thrombotic events during ECMO support. RESULTS: Eight of 667 confirmed COVID-19 patients received venovenous ECMO and had an elevated D-dimer before and during ECMO support. An ECMO circuit pack (oxygenator and tubing) was replaced a total of 13 times in all eight patients and coagulation related complications included oxygenator thrombosis (7/8), tracheal hemorrhage (5/8), oronasal hemorrhage (3/8), thoracic hemorrhage (3/8), bleeding at puncture sites (4/8), and cannulation site hemorrhage (2/8). CONCLUSIONS: Hypercoagulability and secondary hyperfibrinolysis during ECMO support in COVID-19 patients are common and possibly increase the propensity for thrombotic events and failure of the oxygenator. Currently there is not enough evidence to support a more aggressive anticoagulation strategy.

Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spread rapidly in China and across the world causing a global pandemic, due to its strong transmissibility and virulence 1, 2 .

A majority of coronavirus disease 2019 (COVID-19) patients have mild symptoms and recover completely; however, approximately 5-14% become severely or critically ill with acute respiratory distress syndrome (ARDS) requiring intensive care unit (ICU) admission 3 .

Rates of invasive mechanical ventilation among patients admitted to ICU ranged from 29% to 91% and the mortality rate was about 80% among patients on mechanical ventilation 4, 5 .

Extracorporeal membrane oxygenation (ECMO) could offer life-saving rescue therapy when mechanical ventilation fails to maintain adequate oxygenation in COVID-19 patients. ECMO has been used successfully to manage severe respiratory failure in patients with H1N1 influenza A, H7N9 avian influenza, and Middle East respiratory syndrome [6] [7] [8] [9] .

However, there are not many reports describing ECMO support for COVID-19 patients, and littles is still known about the coagulation characteristics of these patients while on ECMO support. Inflamed lung connective tissue and pulmonary endothelial cells may result in microthrombi formation and contribute to the high incidence of thrombotic complications in severe COVID-19 10, 11 . ECMO could also aggravate the activation of coagulation cascade and consumption of clotting factors causing further coagulation abnormalities. This study aims to summarize the coagulation characteristics, anticoagulation management, and complications of COVID-19 patients who received ECMO support in Shanghai, China.

All adult patients diagnosed with COVID-19 were admitted to Shanghai Public Health Clinical Center, a designated hospital for COVID-19 treatment in Shanghai and patients were treated by multidisciplinary teams including ECMO experts from different hospitals 12 12, 13 . The diagnosis of ARDS was defined with the Berlin definition (three categories of ARDS were proposed based on the PaO 2 /FiO 2 ratio) 14 . Patients were admitted to the ICU if PaO 2 /FiO 2 <100 mmHg with high-flow nasal cannula (FiO 2 100%, 30L/min).

We conducted a retrospective study of eight COVID-19 patients who received venovenous ECMO. The demographics, comorbidities, laboratory results, ECMO-related data and coagulation parameters from the medical records were collected. If there were more than one laboratory tests in the same day, we used the most aberrant values. All the medical data of this study were retrieved from the Shanghai Public Health Clinical Center and used with permission.

Standard COVID-19 treatment included protective lung ventilation strategy, optimal PEEP, sedation, lung recruitment, prone positioning, neuromuscular blockade, and volume optimalization 15 . In cases where a patient showed no substantial improvement, ECMO was initiated according to the protocol at our institution ( Figure 1 ). The decision to provide ECMO support should be individualized and based on the risk and benefit assessment for the patient, but there were some absolute contraindications. According to the exclusion criteria used in the ECMO to Rescue Lung Injury in Severe ARDS (EOLIA Trial) and ELSO Guideline for COVID-19 16, 17 , absolute contraindications for venovenous ECMO in our center included: prolonged high ventilatory pressures (i.e. end inspiratory plateau pressures > 30 cmH 2 O for longer than 7 days), an expected difficulty in obtaining vascular access, severe coagulopathy, and any condition or organ dysfunction that would limit the likelihood of overall benefit from ECMO ( disseminated malignancy, severe multiple organ failure and uncontrolled bleeding).

Venovenous ECMO was adopted as the chosen mode to improve oxygen supply and carbon dioxide elimination using the Rotaflow ® system (Getinge, Rastatt, Germany) equipped with a Quadrox ® oxygenator (Getinge, Antalya, Turkey). Ultrasound-guided Seldinger technique was used for cannulation of the femoral vein as drainage site and the internal jugular vein as perfusion site. The tip of the internal jugular vein cannula (outflow cannula) was positioned at the junction between right atrium and superior vena cava. The tip of the femoral vein cannula (inflow cannula) was advanced into the right atrium approximately one centimeter beyond the inferior vena cava/right atrium junction and cautions were taken to avoid cannula tip contacting the interatrial septum under echocardiographic guidance. The blood flow (50-70ml/kg) and oxygen flow were set according to the pulse oxygen saturation and blood gas results to maintain PaO 2 60-80 mmHg and PaCO 2 35-45 mmHg. Point of care ultrasonography for the lungs, heart, abdomen, vasculature and chest X-ray were performed on a daily basis. Protective lung ventilation strategy was adopted after ECMO initiation (FiO 2 <40%, tidal volume 2-4 ml/kg, plateau pressure <25 cmH 2 O, and respiratory rate 8-10 times/minute). Ventilator parameters and electrical impedance tomography were closely monitored. When necessary, continuous renal replacement therapy (CRRT) was performed using the port on the ECMO oxygenator. After March 2 nd , 2020, antithrombin (AT) activity monitoring was added, and thromboelastography was used whenever necessary to assess coagulopathy status. When the heparin dose exceeded 20 U/kg/Hr, the possibility of heparin resistance was considered. Due to the lack of commercial antithrombin agents in China, fresh frozen plasma was supplemented at the dose of 200-400 mL/d according to volume status when antithrombin activity was lower than 70%. Platelets were infused when platelet count was less than 80×10 9 /L. If there was significant drop in platelet counts after continuous heparin infusion, heparin-induced thrombocytopenia was highly suspected. After confirmed by 4T score and anti-PF4/heparin antibody test, argatroban was used at a dose of 0.2-0.7 μg/kg/min, and the target of ACT and aPTT was the same as that of heparin.

When there was significant thrombosis within the oxygenator, accompanied by D-dimer>10 μg/mL, fibrinogen<1.5 g/L, and a sustained decrease in platelet count, we replaced the entire ECMO circuit pack ( oxygenator and tubing ) despite satisfactory gas exchange function. In the context of bleeding, secondary hyperfibrinolysis and fibrinogen consumption, tranexamic acid (10-20 mg/kg via slow injection; followed by a dose of 1,000 mg/d at the rate of 1-2 mg/kg/hr for 2-3 days) and fibrinogen (at 1-2 g/d until fibrinogen >1.5 g/L) were infused. If there was significant bleeding or need for invasive procedures, heparin was reduced or suspended for a short period of time until ACT fell below 150s and we transfused blood products if necessary.

As described in our previous study, weaning of ECMO was started when improvements were observed on chest X-ray/CT, arterial blood gas, respiratory mechanics, and other indicators 18 .

The sweep to flow ratio was maintained at 1:1 and ECMO flow was gradually reduced to 2.5 L/min while continuing the same mechanical ventilation parameters. With the ECMO flow maintained at 2.5 L/min, the ECMO sweep was gradually reduced until there was complete cessation of the sweep. In order to take patients off ECMO, the following criteria were maintained for 24-48 hours at ECMO flow rates of 2.5L/min without sweep: ① stable hemodynamics; ② significant improvements in ventilation and gas exchange functions, as evident by chest X-ray, CT, electrical impedance tomography and pulmonary ultrasound; ③ PaO 2 /FiO 2 ＞150 mmHg, PCO 2 ≤50 mmHg, RR ≤20; ④ body temperature＜38℃; ⑤ Murray Index＜3; ⑥ HCT>35%. Table 1 summarized the outcomes of eight ECMO supported patients included in this analysis.

Patient 7 received ECMO initially on January 30 th , 2020 for eight days and was weaned off.

His condition deteriorated on February 12 th , 2020 and ECMO had to be restarted again. He died of a pneumothorax and severe bleeding complications ten days after the reintroduction of ECMO support. Three other patients died of persistent worsening lung consolidation, which was difficult to reverse, and suffered secondary lung infections with multiple drug-resistant bacteria. Patient 1, 3, and 5 were successfully weaned off ECMO upon meeting the weaning criteria after 40 days, 47 days, and 22 days respectively and they were discharged by 20 th May 2020. Patient 8 was successfully weaned off ECMO and still on rehabilitation treatment. Of the eight patients, six developed acute kidney injury and required CRRT.

The ages of patients ranged from 25-81 years, and the body mass index ranged from 20.8-24.5. Prior to ECMO, mechanical ventilation duration was between 5 hours to 21 days, and the PaO 2 /FiO 2 ratio was less than 80 (54-76) for all patients. Our previous report 18 and Table   1 provide detailed clinical data of demographics, laboratory results, ventilator parameters and ECMO-related data for each patient. All patients were sedated and provided with analgesics (RASS <-3) during ECMO.

As indicated by the coagulation parameters in Table 2 , most patients had an elevated D-dimer Following an expert consensus statement and guideline from Shanghai and the United States, our center has provided venovenous ECMO support to eight patients as of May 20 th , 2020 9,21 .

Traditional ECMO indications might lead to prolonged hypoxia and multiple organ failure in COVID-19 patients. Therefore, we adopted early ECMO support when mechanical ventilation was insufficient to correct hypoxia in these patients 18 . In this study we found that the clinical characteristics of COVID-19 patients were different from those of other viral pneumonia patients in terms of ECMO anticoagulation management and coagulation-related complications.

Severe COVID-19 patients manifested abnormal inflammatory responses and immune system damages, characterized by the rise of IL-6 levels and the decline in lymphocyte count, which is correlated with the severity of the pneumonia. 22, 23 . All eight critically ill patients on ECMO in our study exhibited a cytokine storm syndrome with high IL-6 levels. As other reports described, the inflammatory storm could activate the coagulation cascade and cause secondary hyperfibrinolysis, or disseminated intravascular coagulation (DIC) in severe COVID-19 patients [24] [25] [26] . It has become evident from published evidence that SARS-CoV-2 infection itself promotes immunological response, unseen with seasonal influenza 27 In addition, supra-physiological shear stress and interactions between foreign material and blood components during ECMO cause systemic activation of coagulation and inflammation pathways that, in extreme conditions, may lead to thrombosis and DIC 34 Figure 3 . Shortly after replacement, oxygenator thrombus was observed again in most patients and often accompanied by D-dimer and FDP near limit values (FDP>150 μg/mL and D-dimer level>20 μg/mL, respectively). In a standardized anticoagulation regimen with ACT maintained at around 200s, frequent oxygenator thrombosis events and hyperfibrinolysis were rarely seen in previous ECMO-supported patients 35 . In a retrospective study of 201 COVID-19 patients, Wu et al. found that the rise of D-dimer level was an independent risk factor of death 36 . In another multicenter retrospective cohort study, elevated D-dimer levels were strongly associated with in-hospital death, even after multivariable adjustment 37 .

However, whether or not this is associated with poor prognosis in ECMO supported COVID-19 patients still needs further research. According to Granja T et al., activation of GPIIb/IIIa and increased release of platelet microparticles in venovenous ECMO suggested that ARDS-related inflammatory responses may lead to activation of platelets and enhancement of fibrin polymerization, which may promote thrombosis 38 . Consumption of coagulation factors following thrombosis events was obvious. The need for fresh frozen plasma at the dose of 200-400 mL/day and platelets at an average of 0.8 U/day to restore coagulation function was necessary in our patients.

In cases of oxygenator thrombosis with D-dimer >10 μg/mL, fibrinogen <1g/L, and a drop in platelet count, the entire ECMO circuit pack should be replaced regardless of gas exchange function. In addition to aggressive ECMO circuit pack replacement, we also moderately increased the intensity of anticoagulation and corrected the deficiency of platelets and fibrinogen. If there was only hyperfibrinolysis or DIC (International Society on Thrombosis and Haemostasis Score >5 39 ) without oxygenator thrombosis, we moderately enhanced the coagulation pathway, and provided tranexamic acid therapy. Although ELSO does not recommend conventional antifibrinolytic therapy, we believe it is beneficial for blood protection in hypercoagulation status 39 Antithrombin plays an important role in the continuous endothelial activation because it is more exposed on the endothelium when the cells are activated, and it is more released in the blood with consequent rapid consumption with the use of high dose heparin 28 . In ECMO patients, acquired antithrombin deficiency is a result of hemodilution, initiation of coagulation cascade, and consumption due to the use of heparin. Antithrombin supplementation is necessary to restore adequate anticoagulation. Criteria for antithrombin supplementation in adult ECMO patients are not well defined. While antithrombin is frequently exogenously supplemented to restore therapeutic anticoagulation, when antithrombin activity is deficient, this practice varies widely among institutions. One concern about supplementing antithrombin in the presence of large doses of heparin was increased risk of bleeding 42 . After March 2 nd , 2020, antithrombin activity level was obtained in our center and antithrombin supplementation using continuous infusion plasma was recommended due to the lack of commercial antithrombin recombinant product in China. The effect of plasma therapy was unsatisfactory at 200-400 mL/d, and most patients had a low antithrombin level during ECMO support. Our goal for antithrombin was at least 70% of normal values.

This study is a single-center study based on a small number of cases. The coagulation properties of ECMO support in this cohort may not be representative, so more comprehensive clinical studies are needed to confirm these findings. In summary, hypercoagulability and secondary hyperfibrinolysis during ECMO support in COVID-19 patients were common and possibly increased the propensity for thrombotic events and oxygenator membrane failure.

Careful management of the anticoagulation regimen, along with the recruitment of highly experienced teams is necessary. There is insufficient evidence to support a more aggressive anticoagulation regimen currently for COVID-19 patients on ECMO support.

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.

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. 

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