Özet

Background: In this study, we present our experience in treating patients receiving extracorporeal membrane oxygenation for novel coronavirus disease-2019 (COVID-19)-associated acute respiratory distress syndrome using a combined anticoagulant and antiaggregant treatment with intravenous infusion of bivalirudin and aspirin.

Methods: Between April 1st, 2020 and January 31st, 2022, a total of 52 adult patients (32 males, 20 females; mean age: 44.5±11.5 years; range, 21 to 71 years) who received extracorporeal membrane oxygenation due to COVID-19-associated acute respiratory distress syndrome and whose anticoagulant treatment consisted of bivalirudin plus aspirin were retrospectively analyzed. During the first 10 days of extracorporeal membrane oxygenation, bivalirudin dosing, activated partial thromboplastin time, and activated clotting time, as well as major bleeding events and patient and/or ECMO-circuit thromboses were recorded.

Results: The mean bivalirudin dose per day ranged from 0.03 to 0.04 mg/kg/h, with a mean overall dose of 0.036 mg/kg/h. The mean activated partial thromboplastin time was 49.1±6.9 sec throughout 10 days of the application. The percentage of time in the target range for activated partial thromboplastin time was 58.9±20.1% within 10 days of application, compared to 33.1±31.1% for the first 24 h. The mean daily activated clotting time was below the target range within the first three days, but it was consistently within the target range after Day 3. During the first 10 days of the application, no mortality occurred. Major bleeding occurred in 11 patients (21.1%) and circuit thrombosis occurred in three patients (5.8%).

Conclusion: In patients receiving extracorporeal membrane oxygenation for COVID-19-associated acute respiratory distress syndrome, an hourly bivalirudin dose of 0.03 to 0.04 mg/kg/h throughout the first 10 days of application was associated with the targeted anticoagulation profile of 45 to 60 sec. The combination was associated with a comparable rate of major bleeding, but a lower rate of circuit-thrombosis compared to the literature reports.

Coronavirus disease-2019 (COVID-19) affects multiple systems and is usually associated with hypercoagulation and formation of microthrombi, resulting in microvascular thrombosis, venous thromboembolism or acute arterial thrombosis.[1]

Patients with COVID-19 may require extracorporeal membrane oxygenation (ECMO) due to COVID-19-associated pneumonia and severe acute respiratory distress syndrome (ARDS). COVID-19 has also been associated with an increased pro-inflammatory response and pro-thrombotic potential.[2] In patients with COVID-19-associated ARDS, venovenous ECMO (vv-ECMO) is the last resort to keep the patient alive after unsuccessful attempts with less invasive therapeutic options, to allow cell/tissue regeneration or as a bridge to lung transplantation. However, ECMO may be complicated by multiple factors, in particular hypercoagulation and ECMO-circuit thrombosis, making anticoagulant treatment the mainstay in ECMO. Insufficient or excessive anticoagulation or possible complications of anticoagulants may disrupt the artificial circulation and cause failure of the ECMO system. Achievement of target anticoagulation parameters without causing bleeding or thrombosis is particularly challenging due to COVID-19-associated coagulopathy, adverse effects of ECMO or ensuing sepsis.[1]

Although heparin is the most common anticoagulant used in ECMO, it has several drawbacks such as the development of heparin resistance, heparin-induced thrombocytopenia and individual variations in anticoagulation response.[3,4]

Bivalirudin is a direct inhibitor of thrombin.[5] It binds to circulating thrombin, as well as to fibrin-bound thrombin, interfering with the transformation of fibrinogen to fibrin.[5,6] It has been shown to have stable pharmacokinetics, a rapid anticoagulant effect, easy dose titration, and no risks for thrombocytopenia,[5] rendering it advantageous over heparin.[7-9] As an anticoagulant, it has been reported to be as effective as or even safer than heparin in elective percutaneous coronary interventions (PCIs).[10] It has also become a preferred anticoagulant over heparin in some ECMO centers.[8] The use of bivalirudin has been reported in patients receiving ECMO for severe COVID-19-associated ARDS.[11-13] The use of antiplatelet agents including aspirin, ticagrelor or cangrelor has been reported in combination with heparin[14] or bivalirudin[15] to mitigate pro-thrombotic potential of various settings.

In this study, we aimed to present our experience in treating patients receiving ECMO for COVID-19-associated ARDS with a combined anticoagulant and antiaggregant treatment with intravenous infusion of bivalirudin and aspirin during ECMO applications.

Yöntem

This single-center, retrospective study was conducted at the ICU of Koşuyolu High Specialization Training and Research Hospital between April 1st, 2020 and January 31st, 2022. We reviewed electronic medical records and patients" charts to identify patients who were admitted to the intensive care unit (ICU) with COVID-19-associated ARDS and received vv-ECMO. During the pandemic, our 58-bed cardiovascular ICU served as a member of the Extracorporeal Lung Support Organization (ELSO) not only to patients who were admitted to the ICU, but also to those who were transferred to our center after initiation of ECMO. All patients received anticoagulant treatment with intravenous infusion of bivalirudin combined with 150 mg of daily aspirin. During the pandemic period, none of the patients admitted for COVID-19 received heparin for anticoagulation while on ECMO.

Exclusion criteria included the presence of any of the following conditions: non-COVID-19-associated ARDS, use of left ventricular assist device, use of ECMO for less than 10 days, viral infections other than COVID-19, or intracranial hemorrhage. Data of one patient was unavailable, also requiring exclusion. A total of 52 patients (32 males, 20 females; mean age: 44.5±11.5 years; range, 21 to 71 years) were included. Data included patients" demographic characteristics (age, sex), body weight, coexisting renal replacement therapy, and blood transfusions. All ECMO applications for COVID-19-associated ARDS were managed and supervised by a dedicated ICU team involving cardiovascular surgeons and ICU physicians.

Definitions
COVID-19-associated ARDS was diagnosed based on the Berlin criteria.[16] Obesity was defined as having a body mass index (BMI) of greater than 30 kg/m². Chronic respiratory disease was defined as the presence of chronic obstructive pulmonary disease, asthma or any respiratory insufficiency requiring oxygen support.

Laboratory parameters
For anticoagulation, intravenous infusion of bivalirudin was initiated in combination with aspirin on the first ECMO day. Coagulation parameters monitored throughout the first 10 days of ECMO included activated partial thromboplastin time (aPTT) measured on a Stago STA-R Evolution® analyzer (Diagnostica Stago, NJ, USA) every 4 h within the first 24 h and subsequently every 6 h; activated clotting time (ACT) measured using an i-STAT Kaolin ACT c artridge ( Abbott, I L, USA) on an i -STAT 1 analyzer 300-G (Abbott, IL, USA) every 2 h within the first 24 h and subsequently every 4 h; international normalized ratio (INR) measured (Diagnostica Stago) every 4 h within the first 24 h and subsequently every 6 h. Platelet counts were obtained daily. D-dimer and fibrinogen levels were also monitored every two days. Data on hourly bivalirudin doses for each patient and routine ACT monitoring were recorded manually.

Based on the institutional practice, the main target for aPTT was 45 to 60 sec (reference range, 26-35 sec). The target ACT was 170 to 200 sec. The bivalirudin dose was hourly recorded and adjusted, when necessary, mainly based on aPTT, also taking ACT, INR, and the platelet count into consideration; therefore, for each increase of 10 sec in the target aPTT, a corresponding decrease (10 to 25%) in the bivalirudin dose. The percentage of time at which aPTT remained at the target range and the percentage of time at which aPTT was below 45 sec and exceeded 60 sec were calculated for each patient and overall means were obtained for the first 10 days of ECMO. The percentage of time at which aPTT remained at the target range was also calculated for the first 24 h. In the presence of major bleeding accompanied by a platelet count of <50,000 cells, platelets were transfused. In the presence of ongoing bleeding and an INR of >1.5, fresh frozen plasma and/or vitamin K were administered; in the presence of a low fibrinogen level (<1.5 mg/dL), human fibrinogen concentrate was administered. In the presence of persistent bleeding, the bivalirudin dose was consistently reduced in a range of 20%.

ECMO management
All cannulations were performed percutaneously using the right internal jugular vein and the right or left femoral vein. Heparin-coated ECMO systems were used; i.e., LivaNova (LivaNova - Sorin Group Italia s.r.l., Mirandola, Italy) and or Maquet (Getinge Group, Göteborg, Sweden). During the first 10 days of ECMO, only the LivaNova system was used. The size of the cannulas was determined according to the ELSO guidelines. During ECMO, flow and fresh-gas-flow parameters were recorded every hour. For maintenance, each ECMO oxygenator was insufflated with a sweep gas flow at a rate of 10 L/min two times daily. Morning and evening partial oxygen pressures were checked in blood gas samples obtained from the ECMO outflow circuit. The only indication for device-oxygenator replacement was ECMO-circuit thrombosis, defined by any decrease in the partial oxygen pressure below 200 mmHg, while the fraction of inspired oxygen (FiO2) was 100% in the outflow circuit on two successive measurements. Spare oxygenators were always kept available for the possibility of ECMO thrombosis.

Despite the ECMO duration ranged from 11 to 99 days, the duration for data analysis was set as the first 10 days of ECMO due to the fact that extension of ECMO support beyond 10 days would have caused decreases in the number of patients enrolled.

Weaning from ventilator
During the ECMO support, patients received pressure-controlled ventilation. Following discontinuation of ECMO support and sedatives, patients whose spontaneous respiration was restored continued to have mechanical ventilation in the continuous positive airway pressure (CPAP) mode and, then, were weaned successfully.

Complications
Major bleeding was defined as a decreased hemoglobin level by >2 g/dL due to gastrointestinal or bronchial bleeding, hematuria or intrathoracic hemorrhage detected on chest radiography or computed tomography (CT) or intracranial hemorrhage detected by CT.16 Any condition indicative of major bleeding was dealt with by adjustment for bivalirudin dosing combined with the use of hemostatic agents or packed red cell transfusions (>1 U) or any intervention to prevent bleeding. Thromboembolic events included ECMO-circuit thrombosis, cerebrovascular ischemia and venous thrombosis confirmed by Doppler ultrasonography.

Statistical analysis
Statistical analysis was performed using the SPSS version 28.0 software (IBM Corp., Armonk, NY, USA). Descriptive data were expressed in mean ± standard deviation (SD), median and interquartile range (IQR), or number and frequency. All parameters were first calculated per day for each patient as means and, then, an overall mean was calculated for the relevant variable. Percentage of aPTT in therapeutic range was calculated by the number of aPTT tests within the therapeutic range divided by the number of total aPTT test, multiplied by 100. Normality of the variables was tested using the Kolmogorov-Smirnov test. Quantitative independent variables were compared using the independent samples t-test and Mann-Whitney U test. Qualitative independent variables were compared using the chi-squared test or Fisher exact test. In very few cases with missing variables, the pertinent data was removed. A p value of <0.05 was considered statistically significant.

Bulgular

Of a total of 52 patients, except for one patient, all patients were transferred to our center after initiation of ECMO at another center, with clinical and radiological findings of and a positive polymerase chain reaction (PCR) test for COVID-19. At the time of ICU admission, ACT was in a range of 150 to 170 sec in all patients. Demographic and clinical characteristics of the patients are summarized in Table 1.

Table 1. Demographic, clinical and laboratory characteristics of 52 patients

The mean daily bivalirudin doses and corresponding coagulation parameters recorded during the first 10 days of ECMO are presented in Table 2. The mean bivalirudin doses per day ranged from 0.03 to 0.04 mg/kg/h. The overall mean bivalirudin dose was 0.036 mg/kg/h.

Table 2. Daily bivalirudin doses and coagulation parameters

The mean aPTT was 49.1±6.9 sec throughout 10 days of ECMO. While the mean percentage of time at which aPTT was within the target range was considerably low (33.1±31.1%) for the first 24 h of ECMO, it almost doubled to 58.9±20.1% throughout 10 days of ECMO. The mean percentages of time at which aPTT was below or over the target range were 30.1±23.8% and 10.6±16.6%, respectively. The mean ACT per day was consistently within the target range after Day 3. The mean INR ranged from 1.4 to 1.6. The lowest platelet count was 78x10³ cells/µL. The mean 10-day D-dimer level was 7.6±4.6 ng/mL.

During the first 10 days of ECMO, no mortality occurred. Major bleeding occurred in 11 patients (21.1%) of bronchial (n=3), bronchial + nasal (n=1), anal fissure (n=1), gastrointestinal (n=3), nasopharyngeal (n=3) source. Major bleeding lasted one day in seven patients, two days in three patients, and five days in one patient.

Extracorporeal membrane oxygenation-circuit thrombosis occurred in three patients (5.8%) (Table 1), on Day 5 (n=1) and on Day 8 (n=2). Two incidences of ECMO-circuit thrombosis coincided with increased administration of blood products due to major bleeding.

Comparison of patients with and without major bleeding showed only INR and D-dimer being significantly higher in patients with major bleeding (Table 3). The percentages of aPTT within, below or over the target range during 10 days of ECMO were similar in the two groups.

Table 3. Inter-group comparisons of patients with and without major bleeding

The overall mean ICU stay was 64.2±32.2 (range, 17 to 156) days, of which a mean of 45.1±22.4 (range, 11 to 99) days was spent on ECMO (Table 1). The overall mortality rate during hospitalization was 42.3%.

Tartışma

In the current study, in which bivalirudin in combination with aspirin was used in place of heparin to manage anticoagulation during vv-ECMO in patients with COVID-19-associated ARDS, an hourly bivalirudin dose of 0.03 to 0.04 mg/kg/h throughout the first 10 days of ECMO was associated with the targeted anticoagulation profile of 45 to 60 sec, yielding a mean aPTT of 49.1±6.9 sec. The percentage of time in the target range for aPTT was 58.9±20.1% within 10 days of ECMO, compared to 33.1±31.1% for the first 24 h. Bivalirudin and aspirin were used together to obtain both anticoagulant and antiplatelet effects, respectively. Adverse events included major bleeding (21.1%) and ECMO-circuit thrombosis (5.8%).

Due to the known drawbacks of heparin during ECMO,[4,17] interest is growing in the use of bivalirudin as an alternative in either dedicated ECMO centers[18] or sporadically.[19] To date, only a single center has reported a dosing protocol for anticoagulation with bivalirudin to monitor and guide coagulation parameters.[20] There has been a growing number of reports on the use of bivalirudin, with varying target anticoagulation parameters and ensuing complications in patients with or without COVID-19-associated ARDS.[11,21] In another study comparing bivalirudin and heparin in critically ill patients with severe COVID-19, bivalirudin displayed similar rates of hospital mortality and thromboembolic complications.[22]

In the current study, we aimed to provide a 10-day dosing picture for bivalirudin, with corresponding target anticoagulation parameters. Our target aPTT was relatively lower than rates reported in the literature. Trigonis et al.[11] achieved a target aPTT of 60 to 80 sec with a median bivalirudin dose of 0.18 mg/kg/h in 19 patients receiving ECMO for COVID-19-associated ARDS. In another report of 33 COVID-19 patients on ECMO, a starting bivalirudin dose of 0.2 mg/kg/h provided a therapeutic range of 60 to 80 sec for aPTT within an average of 20 h.[21] Seelhammer et al.[ reported a 27-day course of ECMO in a patient with COVID-19, during which a target aPTT range of 60 to 80 sec was achieved with a bivalirudin dose of 0.15 to 0.25 mg/kg/h, with no occurrence of ECMO-circuit thrombosis. Our target anticoagulation parameters, particularly aPTT, and the bivalirudin doses were lower than those reported for ECMO applications both in COVID-19 and non-COVID-19 patients.[7,11] Aspirin may have had a role in reducing bivalirudin doses.

Patients with and without major bleeding differed significantly in only two laboratory parameters; i.e., INR and D-dimer being higher in the former group. In case of a higher INR (≥1.5), we administered fresh frozen plasma and/or vitamin K. We could not explain why the D-dimer levels were significantly higher in patients with major bleeding, for which no literature data could be found in patients with COVID-19.

In the current study, aspirin was used to mitigate the potential pro-thrombotic effect of COVID-19.[2] The use of aspirin with bivalirudin was also reported in patients with or without COVID-19 during ECMO, albeit in a small proportion of patients (11%).[11] A systematic review and meta-analysis that compared bivalirudin or argatroban with heparin in patients on ECMO reported significantly lower rates of in-hospital mortality, major bleeding and pump-related thrombosis and higher time percentages within the therapeutic range with bivalirudin or argatroban.[23] In our study, during the first 10 days of ECMO, no patients developed venous or arterial thrombosis, and ECMO-circuit thrombosis was detected on three devices. The absence of venous or arterial thrombosis in our study with bivalirudin plus aspirin is in contrast with the findings of Trigonis et al.[11] who reported deep venous thrombosis in 57.9% of COVID-19 patients receiving ECMO for a median of 11 days and who reported no data on the replacement of oxygenators or occurrence of ECMO-circuit thrombosis. In our study, all ECMO oxygenators were used beyond the validation period indicated by the manufacturer as five days, until the occurrence of ECMO-circuit thrombosis. Thus, the three incidences of ECMO-circuit thrombosis occurred on Day 5 (n=1) and Day 8 (n=2), which coincided with increased administration of blood products due to major bleeding in two patients. Our combination strategy might have led to a lower rate of ECMO-circuit thrombosis (5.8%) over the first 10 days of ECMO compared to 26.3% within seven days of ECMO[24] and 17.3% in a study that used bivalirudin alone.[25]

The use of an antiplatelet agent in combination with anticoagulant treatment has rarely been reported, the results of which have been comparable to anticoagulant treatment alone or even better with the combination. Bein et al.[14] compared heparin-receiving patients with and without low-dose aspirin during pumpless extracorporeal lung assist for an average of 6.6 days. The addition of aspirin did not increase bleeding events or the need for transfusion. In another study, Baldetti et al.[15] used cangrelor in combination with bivalirudin during venoarterial ECMO in patients undergoing PCI. During a mean of five days of combined anticoagulation treatment, a thrombotic event occurred in 14%, and major bleeding occurred in 21% patients.

The main limitation to our study is its retrospective design and lack of a comparison group; therefore, it may only provide limited evidence about the use of bivalirudin plus aspirin for anticoagulation. Another limitation is that we could not evaluate the effect of aspirin on thrombocyte function due to the unavailability of tests to monitor platelet function, such as bedside thromboelastography. Activated clotting time monitoring was performed using the i-STAT ACT test, which is less sensitive to low-dose heparin than the Hemochron low-range ACT (ACT-LR) test.

In conclusion, in patients receiving extracorporeal membrane oxygenation for COVID-19-associated acute respiratory distress syndrome, an hourly bivalirudin dose of 0.03 to 0.04 mg/kg/h throughout the first 10 days of extracorporeal membrane oxygenation was associated with the targeted anticoagulation profile of 45 to 60 sec. In addition, the combination was associated with a comparable rate of major bleeding and a lower rate of circuit-thrombosis as compared with the literature reports.

Ethics Committee Approval: The study protocol was approved by the Kartal Kosuyolu High Specialization Training and Research Hospital Ethics Committee (date: 09.08.2022, no: 2022/11/601). The study was conducted in accordance with the principles of the Declaration of Helsinki.

Data Sharing Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author Contributions: Conception, design, collection and analysis of data, drafting, revising, approval: H.O.; Analysis of data, approval of the final form: A.E.A., H.H., M.M.Ö., M.Ş., Ş.M., M.E.G.; Conception , design, and analysis of data, approval of the final form: M.K.K.

Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding: The authors received no financial support for the research and/or authorship of this article.

Kaynaklar

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11) Trigonis R, Smith N, Porter S, Anderson E, Jennings M, Kapoor R, et al. Efficacy of bivalirudin for therapeutic anticoagulation in COVID-19 patients requiring ECMO support. J Cardiothorac Vasc Anesth 2022;36:414-8. doi:10.1053/j.jvca.2021.10.026.

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25) Rivosecchi RM, Arakelians AR, Ryan J, Murray H, Ramanan R, Gomez H, et al. Comparison of anticoagulation strategies in patients requiring venovenous extracorporeal membrane oxygenation: Heparin versus bivalirudin. Crit Care Med 2021;49:1129-36. doi: 10.1097/CCM.0000000000004944.