Assessment of Jordanian physicians' knowledge about venous thromboembolism risk and management among COVID-19 patients

Objectives: The aim of this study was to assess Jordanian physicians' awareness about venous thromboembolism (VTE) risk among COVID-19 patients and its treatment protocol. Method(s): This was a cross-sectional-based survey that was conducted in Jordan in 2020. During the study period, a convenience sample of physicians working in various Jordanian hospitals were invited to participate in this study. Physicians' knowledge was evaluated and physicians gained one point for each correct answer. Then, a knowledge score out of 23 was calculated for each. Key Findings: In this study, 102 physicians were recruited. Results from this study showed that most of the physicians realize that all COVID-19 patients need VTE risk assessment (n = 69, 67.6%). Regarding VTE prophylaxis, the majority of physicians (n = 91, 89.2%) agreed that low molecular weight heparin (LMWH) is the best prophylactic option for mild-moderate COVID-19 patients with high VTE risk. Regarding severe/critically ill COVID-19 patients, 75.5% of physicians (n = 77) recognized that LMWH is the correct prophylactic option in this case, while 80.4% of them (n = 82) knew that mechanical prevention is the preferred prophylactic option for severe/critically ill COVID-19 patients with high bleeding risk. Moreover, 77.5% of physicians (n = 79) knew that LMWH is the treatment of choice for COVID-19 patients diagnosed with VTE. Finally, linear regression analysis showed that consultants had an overall higher knowledge score about VTE prevention and treatment in COVID-19 patients compared with residents (P = 0.009). Conclusion(s): All physicians knew about VTE risk factors for COVID-19 patients. However, consultants showed better awareness of VTE prophylaxis and treatment compared with residents. We recommend educational workshops be conducted to enhance physicians' knowledge and awareness about VTE thromboprophylaxis and management in COVID-19 patients.Copyright © 2022 The Author(s). Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved.

Management of Acquired von Willebrand Syndrome During Prolonged VV-ECMO

Acquired von Willebrand syndrome (AVWS) contributes to bleeding during extracorporeal membrane oxygenation (ECMO) support. Although it is recognized that AVWS rapidly resolves after ECMO decannulation, this approach may often be clinically unsuitable. In such cases, optimal AVWS management during ECMO support is not well established. We report our approach to managing AVWS in a patient on veno-venous (VV) ECMO for 59 days. A 19-year-old male developed hypoxemic respiratory failure from SARS-CoV-2 pneumonia. Following intubation, he progressed to VV-ECMO support for refractory hypoxemia and was started on bivalirudin for systemic anticoagulation. Two days later, he developed refractory gastrointestinal and oro-nasopharyngeal bleeding despite blood product transfusions and discontinuing bivalirudin. He was started on pantoprazole along with infusions of octreotide and aminocaproic acid. Upper endoscopy on ECMO day 5 revealed an ulcerative bleeding vessel in the duodenum that was clipped. Recurrent mucosal bleeding precluded resumption of systemic anticoagulation. On ECMO day 23, AVWS was diagnosed based on elevated von Willebrand factor (VWF) activity (207%, normal 55-189%) and antigen (234%, normal 50-210%) levels with abnormally low VWF high-molecular-weight multimers. Factor VIII complex was administered twice over the following week. Between doses, the ECMO circuit was exchanged to empirically mitigate suspected shear-related VWF consumption from the fibrin burden, and a repeat endoscopy controlled additional intestinal bleeding with local hemostatic agents. He received 36 units of red blood cells, 2 units of platelets, 2 units of plasma, and 7 pooled units of cryoprecipitate over 31 days leading into these combined interventions. In the 28 days afterwards, he received 3 units of red blood cells, 3.5 pooled units of cryoprecipitate, and no additional platelets or plasma. Our patient was maintained off systemic anticoagulation for 54 of 59 days of VV-ECMO support without any thrombotic complications occurring. With no subsequent clinical evidence of bleeding, repeat VWF testing was done two months post-decannulation and showed near-normal VWF activity (54%) and normal multimer distribution. Our patient rehabilitated well without any neurologic deficits and on discharge was requiring supplemental oxygen with sleep and strenuous activity. Avoiding systemic anticoagulation, repleting VWF, maintaining circuit integrity, and providing local hemostasis, when possible, may be a safe and effective management strategy of AVWS on ECMO support when decannulation is not a viable option.

Multisystem Inflammatory Syndrome in Children Requiring ECMO: Anticoagulation strategies and Lessons Learned

Intro: Multisystem Inflammatory Syndrome in Children (MIS-C) is a post-infectious inflammatory response after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which can cause acute cardiac dysfunction requiring mechanical circulatory support (MCS). MCS utilization for MIS-C is complicated by a propensity for thrombosis, which threatens circuit integrity. This study describes a cohort of MIS-C patients requiring MCS, their outcomes, and the anticoagulation strategies utilized. Method(s): A retrospective case series of patients diagnosed with MIS-C needing veno-arterial extracorporeal membrane oxygenation (VA-ECMO) at Children's Healthcare of Atlanta from March 1, 2020 to June 30, 2022. VA-ECMO variables, laboratory data, complications, and outcomes were collected. Result(s): Seven patients (all male) with severe MIS-C required VA-ECMO for acute cardiac dysfunction. Median age was 13 years (range 4-15 years). Median ICU stay was 13 days (range 6-17 days) with a median ECMO duration of 7 days (IQR 3-8 days) and median mechanical ventilation duration of 8 days (IQR 5-11 days). All seven patients survived to hospital discharge with good neurologic outcomes. Median time to qualitatively normal ventricular function by echocardiogram was 9.5 days (IQR 3-21 days). Heparin was initially used in 6 patients, bivalrudin initially used in 1 patient, and 1 patient converted from heparin to bivalirudin for refractory systemic thrombosis. Median heparin dose was 206u/kg/d (IQR 192-276u/kg/d) with median anti-Xa levels of 0.75 (IQR 0.1-1.1) and median daily PTT 102 seconds (IQR 83-107 seconds). Median daily PTT of patients receiving bivalirudin was 86 seconds (80-93 seconds). Median R-values by thromboelastography were 38 seconds (IQR 25-55 seconds). Two patients required catheter directed thrombolysis with tissue plasminogen activator (t-PA) for refractory intracardiac thrombi, both were initially started on heparin. Significant cannula thrombosis occurred in 2 patients, 1 initially started on heparin and 1 initially on bivalrudin. Bleeding resulting in compartment syndrome occurred in one patient on heparin requiring fasciotomy of the upper extremities, this patient was not receiving t-PA. Conclusion(s): Anticoagulation management for MIS-C patients requiring ECMO is fraught with challenges. A successful management strategy may necessitate higher heparin assay levels, the use of direct thrombin inhibitors for refractory thrombosis, and the deployment of catheter directed thrombolysis. In this case series, CDT was safely and successfully used in two patients. Further studies are required to understand the optimal anticoagulation strategy for these patients to minimize complications.

Complications Of A Severe Case Of Multisystem Inflammatory Syndrome In Children

Case Presentation: A 10 year old male with prior COVID-19 exposure presented with 7 days of fever, rash, cough, vomiting, and hypotension. Laboratory evaluation was notable for SARS-CoV2 antibodies, elevated cardiac enzymes, BNP, and inflammatory markers. Initial echocardiogram showed normal cardiac function and a small LAD coronary aneurysm. He was diagnosed with Multisystemic Inflammatory Syndrome in Children (MIS-C) and given methylprednisolone and IVIG. Within 24 hours, he developed severe LV dysfunction and progressive cardiorespiratory failure requiring VA-ECMO cannulation and anticoagulation with bivalirudin. Cardiac biopsy demonstrated lymphocytic infiltration consistent with myocarditis. On VA-ECMO, he had transient periods of complete AV block. With immunomodulator treatment (anakinra, infliximab) and 5 days of plasmapheresis, inflammatory symptoms and cardiac function improved. He weaned off ECMO, and anticoagulation was transitioned to enoxaparin. He had left sided weakness 5 days later, and brain MRI revealed an MCA infarct. Ten days later, he had focal right sided weakness and repeat MRI showed multiple hemorrhagic cortical lesions, thought to be thromboembolic with hemorrhagic conversion secondary to an exaggerated inflammatory response to an MSSA bacteremia in the setting of MIS-C. Enoxaparin was discontinued. After continued recovery and a slow anakinra and steroid wean, he has normal coronary arteries, cardiac function, and baseline ECG but requires ongoing neurorehabilitation. Discussion(s): COVID-19 infection in children is often mild, but MIS-C is an evolving entity that can present with a wide range of features and severity. This case highlights two concepts. While first degree AV block is often reported in MIS-C, there is potential for progression to advanced AV block. Close telemetry monitoring is critical, especially if there is evidence of myocarditis. MIS-C shares features with Kawasaki disease, with a notable difference being a higher likelihood of shock and cardiac dysfunction in MIS-C. In MIS-C patients with cardiovascular collapse requiring ECMO, there is a risk for stroke. There should be a low threshold for neuroimaging and multidisciplinary effort to guide anticoagulation in these complex cases.

Acute Massive Thrombus Following Fontan Procedure

Background Patients with hypoplastic left heart syndrome (HLHS) undergo a Fontan procedure as part of single ventricle surgical palliation. Post-Fontan, sluggish blood flow and an imbalance in coagulant factor proteins may predispose to thrombus formation. Other risk factors may include chylothorax as well as acute and chronic inflammation. Currently, there is no standardized surveillance strategy to detect thrombus in Fontan patients. Case A 34-month old male with HLHS underwent an extracardiac non-fenestrated Fontan complicated by chylothorax treated with 5 days of IV steroids and diuretics. He was on therapeutic aspirin. After progressive worsening of right pleural effusion, a chest tube was placed three weeks post-Fontan with continued chylous output. Stool alpha 1 antitrypsin was negative. Decision-making Given persistent chylothorax, a repeat echocardiogram was performed revealing a large mass in the Fontan circuit less than one month post-op. Cardiac CT showed occlusive thrombus filling the entirety of the Fontan conduit extending into hepatic veins and bilateral pulmonary arteries. He underwent extensive surgical thrombectomy and Fontan conduit revision. Hypercoagulable work-up revealed elevated factor 8 and von Willebrand factor activity which persisted more than one month post-op. Patient's history was also significant for COVID-19 infection 6 months prior. He was initially anticoagulated with bivalirudin with tirofiban initiated for antiplatelet therapy. He was ultimately transitioned to rivaroxaban, pentoxifylline and aspirin with chylothorax resolution over one month without thrombus recurrence. Conclusion Development of risk stratification tools to identify patients at higher risk for thrombi formation post-Fontan may facilitate patient selection for more aggressive anticoagulation. Consideration of elevated factor 8 as well as persistent or recurrent chylothorax may be beneficial, as increased thrombosis risk has been reported for both conditions in Fontan patients.Copyright © 2023 American College of Cardiology Foundation

Heparin-based versus bivalirudin-based anticoagulation in pediatric extracorporeal membrane oxygenation: A systematic review.

Introduction: Optimal anticoagulation therapy is essential for the prevention of thrombotic and hemorrhagic complications in pediatric patients supported with extracorporeal membrane oxygenation (ECMO). Recent data have demonstrated bivalirudin has the potential to surpass and replace heparin as the anticoagulant of choice. Methods: We conducted a systematic review comparing the outcomes of heparin-based versus bivalirudin-based anticoagulation in pediatric patients supported on ECMO to identify the preferred anticoagulant to minimize bleeding events, thrombotic complications, and associated mortality. We referenced the PubMed, Cochrane Library, and Embase databases. These databases were searched from inception through October 2022. Our initial search identified 422 studies. All records were screened by two independent reviewers using the Covidence software for adherence to our inclusion criteria, and seven retrospective cohort studies were identified as appropriate for inclusion. Results: In total, 196 pediatric patients were anticoagulated with heparin and 117 were anticoagulated with bivalirudin while on ECMO. Across the included studies, it was found that for patients treated with bivalirudin, trends were noted toward lower rates of bleeding, transfusion requirements, and thrombosis with no difference in mortality. Overall costs associated with bivalirudin therapy were lower. Time to therapeutic anticoagulation varied between studies though institutions had different anticoagulation targets. Conclusion: Bivalirudin may be a safe, cost-effective alternative to heparin in achieving anticoagulation in pediatric ECMO patients. Prospective multicenter studies and randomized control trials with standard anticoagulation targets are needed to accurately compare outcomes associated with heparin versus bivalirudin in pediatric ECMO patients.

Correlation between partial thromboplastin time and thromboelastography in adult critically ill patients requiring bivalirudin for extracorporeal membrane oxygenation.

STUDY OBJECTIVE: Thromboelastography (TEG) offers a more dynamic assessment of hemostasis over activated partial thromboplastin time (aPTT). However, the clinical utility of TEG in monitoring bivalirudin during extracorporeal membrane oxygenation (ECMO) remains unknown. The purpose of this study was to evaluate the correlation between aPTT and TEG in adult ECMO patients anticoagulated with bivalirudin. DESIGN: Multicenter, retrospective, cohort study conducted over a 2-year period. SETTING: Two academic university medical centers (Banner University Medical Center) in Phoenix and Tucson, AZ. PATIENTS: Adult patients requiring ECMO and bivalirudin therapy with ≥1 corresponding standard TEG and aPTT plasma samples drawn ≤4 h of each other were included. The primary endpoint was to determine the correlation coefficient between the standard TEG reaction (R) time and bivalirudin aPTT serum concentrations. MEASUREMENTS AND MAIN RESULTS: A total of 104 patients consisting of 848 concurrent laboratory assessments of R time and aPTT were included. A moderate correlation between TEG R time and aPTT was demonstrated in the study population (r = 0.41; p < 0.001). Overall, 502 (59.2%) concurrent assessments of TEG R time and aPTT values showed agreement on whether they were sub-, supra-, or therapeutic according to the institution's classification for bivalirudin. The 42.2% (n = 271/642) discordant TEG R times among "therapeutic" aPTT were almost equally distributed between subtherapeutic and supratherapeutic categories. CONCLUSIONS: Moderate correlation was found between TEG R time and aPTT associated with bivalirudin during ECMO in critically ill adults. Further research is warranted to address the optimal test to guide clinical decision-making for anticoagulation dosing in ECMO patients.

Bivalirudin vs. Enoxaparin in Intubated COVID-19 Patients: A Pilot Multicenter Randomized Controlled Trial.

(1) Background: In COVID-19 patients, the occurrence of thromboembolic complications contributes to disease progression and mortality. In patients at increased risk for thrombotic complications, therapeutic enoxaparin should be considered. However, critically ill COVID-19 patients could develop resistance to enoxaparin. Bivalirudin, a thrombin inhibitor, may be an alternative. This pilot multicenter randomized controlled trial aims to ascertain if bivalirudin may reduce the time spent under invasive mechanical ventilation, as compared to enoxaparin. (2) Methods: Intubated COVID-19 patients at risk for thrombo-embolic complications were randomized to receive therapeutic doses of enoxaparin or bivalirudin. We ascertained the time spent under invasive mechanical ventilation during the first 28 days from Intensive Care Unit (ICU) admission. A standardized weaning protocol was implemented in all centers. In addition, we assessed the occurrence of thromboembolic complications, the number of patients requiring percutaneous tracheostomy, the gas exchange, the reintubation rate, the ICU length of stay, the ICU and 28-days mortalities. (3) Results: We enrolled 58 consecutive patients. Bivalirudin did not reduce the time spent under invasive mechanical ventilation as compared to enoxaparin (12 [8; 13] vs. 13 [10; 15] days, respectively; p = 0.078). Thrombotic (p = 0.056) and embolic (p = 0.423) complications, need for tracheostomy (p = 0.423) or reintubation (p = 0.999), the ICU length of stay (p = 0.076) and mortality (p = 0.777) were also similar between treatments. Patients randomized to bivalirudin showed a higher oxygenation at day 7 and 15 after randomization, when compared to enoxaparin group. (4) Conclusions: In intubated COVID-19 patients at increased risk for thromboembolic complications, bivalirudin did not reduce the time spent under invasive mechanical ventilation, nor improved any other clinical outcomes.

SUCCESSFUL USE OF BIVALIRUDIN DURING THE THIRD TRIMESTER OF PREGNANCY WHILE ON EXTRACORPOREAL MEMBRANE OXYGENATION

SESSION TITLE: Close Critical Care Calls SESSION TYPE: Case Reports PRESENTED ON: 10/18/2022 11:15 am - 12:15 pm INTRODUCTION: Heparin is the preferred anticoagulant for use in pregnancy while on extracorporeal membrane oxygenation (ECMO) (1). Alternatives to heparin in this patient population are not well studied as heparin-induced thrombocytopenia is rare in pregnancy. Parenteral non-heparin anticoagulants available in the United States include the direct thrombin inhibitors argatroban and bivalirudin, both of which are utilized in ECMO. Guidelines recommend avoidance of these agents in pregnancy if at all possible (2). Whereas case reports support the safe use of argatroban in pregnancy, to our knowledge, there are no known documented reports of bivalirudin use in this patient population (3). Here we describe the successful use of bivalirudin during pregnancy. CASE PRESENTATION: A 25 year old G2P1 was transferred to our institution at 28 weeks gestation for further management of acute hypoxic respiratory failure secondary to COVID-19. On hospital day 2 the patient was urgently placed on venovenous (VV) ECMO for refractory hypoxemia, high dead space with acidosis, and the inability to provide adequate gas exchange and lung protection with mechanical ventilation alone. Following ECMO cannulation with a 25f cannula in the right femoral vein and a 21f cannula in the right internal jugular vein, she was anticoagulated with heparin at a rate of 12 units/kg/hr. This was titrated to target a PTT goal of 60-80 seconds. On ECMO day 2, the TEG demonstrated a markedly hypocoagulable state, and the heparin nomogram called for increasing heparin dosing based on PTT. Given the already high dose of heparin that the patient was on (32.9 units/kg/hr), the decision was made to switch from heparin to bivalirudin to prevent over anticoagulation and reduce bleeding risk. Bivalirudin was titrated to a goal PTT of 50-60 seconds, with an initial rate of 0.15 mg/kg/hr (dose range 0.15-0.22 mg/kg/hr). Therapy was continued and on ECMO day 11, at 29w6d the patient delivered via cesarean section. Bivalirudin was discontinued 2.5 hours prior to the surgical procedure which resulted with no fetal bleeding complications. The patient was decannulated from ECMO on day 20 and was later discharged from the hospital. The newborn is developing well and meeting age adjusted milestones. DISCUSSION: Bivalirudin was selected based on institutional experience and the pharmacokinetic properties of the drug (half-life of 25 minutes) as we considered a situation where an emergent delivery may be indicated. Bivalirudin successfully prevented clotting of the circuit with no maternal or fetal bleeding complications during its use. CONCLUSIONS: Our case report describes a multidisciplinary approach to managing a pregnant patient on ECMO requiring anticoagulation using an alternative medication to heparin. This is the first documented use of bivalirudin in pregnancy. Reference #1: ELSO Guidelines for Cardiopulmonary Extracorporeal Life Support Extracorporeal Life Support Organization, Version 1.4 August 2017. Ann Arbor, MI, USA www.elso.org. Reference #2: Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(Suppl): e691S–736S Reference #3: Young SK, Al-Mondhiry HA, Vaida SJ, et al. Successful use of argatroban during the third trimester of pregnancy: case report and review of the literature. Pharmacotherapy 2008;28: 1531–6. DISCLOSURES: No relevant relationships by Jacqueline Finger No relevant relationships by Caitlin Gluck No relevant relationships by Cameron Hypes No relevant relationships by John Rathbun

Challenges and Strategies for Veno Venous (VV) Extracorporeal Membrane Oxygenation (ECMO) in COVID-19 Acute Respiratory Distress Syndrome (ARDS) During Second Wave of Pandemic: A Case Series

Case series: Extracorporeal membrane oxygenation (ECMO) use for severe acute respiratory distress syndrome due to coronavirus disease 2019 (COVID-19) patients has increased during the second wave of the pandemic. However, there are many complications associated with the management of ECMO in critically ill COVID- 19 patients. We report a case series of challenges and strategies for managing critically ill COVID-19 patients on ECMO support for severe ARDS. Seven COVID-19 patients required VV ECMO of which three were women and four were men of median age of 43 years. Among seven, three cases (42%) recovered. We experienced multiple challenges and complications in the management of the patients, being a non-ECMO centre with limited resources, in heavy workload during the second wave of the pandemic. All the patients required multiple invasive procedures like placement of invasive lines, frequent bronchoscopies for bronchial toileting. Displacement of both ECMO cannulas required repositioning under ultrasound guidance, four patients underwent percutaneous tracheostomy on ECMO. Three patients had ECMO-oxygenator failure that required the exchange of a new ECMO circuit. ACT was monitored for the management of anticoagulation. A challenging task is to achieve a balance between bleeding and thrombotic events, for which anticoagulation had to be stopped for the acceptable ACT, required transfusion of multiple blood products for correcting coagulopathy. One patient developed HIT antibodies and managed with bivalirudin for the management of anticoagulation which was challenging in titrating the drug dose and ACT. Two patients had an intracranial haemorrhage on ECMO support, managed conservatively despite anticoagulation. Pseudoaneurysm of femoral vein diagnosed and managed with ultrasound-guided thrombin injection. Four patients got decannulated from ECMO. One patient had unexplained severe haemolysis immediately after initiation of ECMO, unfortunately, he could not recover. Management of VV ECMO in resource-limited, non-ECMO centre in a pandemic is challenging. Mortality depends on various factors, despite expertise, advanced critical care management in COVID- 19 ARDS and ECMO. Increased use of VV ECMO during the second wave of pandemic reported significant changes in strategies for management of challenges, though further studies are still required for the best outcome.

Prolonged ECMO Support of an Adult with SARS-CoV-2 ARDS and Right Heart Failure in a Children's Hospital

ECMO has become a widely recognized support modality for patients with severe cardiac or respiratory failure, and has been increasingly utilized in the ongoing severe acute respiratory syndrome due to coronavirus-2 (SARS-CoV-2) pandemic. Long-term support on ECMO for acute respiratory distress syndrome (ARDS) is also becoming more commonplace with eventual lung recovery, obviating the need for lung transplantation. However, long-term ECMO support has not been well studied for SARS-CoV-2 ARDS patients. We report the case of a 39-year-old female with severe SARS-CoV-2-induced ARDS successfully supported on venovenous ECMO (V-V ECMO) for 5,208 hours (217 days) in a high ECMO-volume, quaternary care children's hospital in 2021. At the time of this writing, this is the longest reported patient successfully supported on ECMO for SARS-CoV-2 ARDS. Our patient was initially cannulated at our children's hospital with dual-site V-V ECMO, via the right internal jugular vein (RIJ) and right common femoral vein. Bedside tracheostomy was performed on ECMO day 40, for early mobility, oral feeding, interaction, and pulmonary rehabilitation planning. Unfortunately, during her course she suffered multiple complications including bacterial co-infections, bleeding requiring anticoagulant changes from unfractionated heparin (UFH) to bivalirudin, multiple ECMO circuit changes due to blood product consumption and coagulopathy, and pneumothoraces requiring thoracostomy tube placements. Approximately 1.5 months into her ECMO course, she suffered acute hypoxemia and echocardiography revealed indirect evidence of pulmonary hypertension with right heart failure. Initial right heart catheterization while on V-V ECMO revealed elevated right ventricular end-diastolic pressure (RVEDP=15-20 mmHg) and severe systemic desaturation with main pulmonary artery (MPA) pressure of 30 mmHg. Pulmonary hypertension and right heart support was initiated in the form of inhaled nitric oxide (iNO), inotropes, phosphodiesterase inhibitors, nitrates, angiotensin-converting enzyme inhibitors, and diuresis. Ultimately, due to necessity of right-heart decompression and support, on ECMO day 86 she was transitioned to single-site V-V ECMO utilizing a 31 Fr dual-lumen venovenous cannula (ProtekDuo (LivaNova, UK)) placed via her RIJ through her right atrium (RA) into the MPA in the cardiac catheterization laboratory. Subsequent heart catheterization more than 2 months later revealed severe right ventricular (RV) diastolic dysfunction (RVEDP=35 mmHg) and moderate left ventricular (LV) diastolic dysfunction (pulmonary capillary wedge pressure (PCWP=24 mmHg)). During her course, multiple trials off ECMO were attempted with varying lengths of time off ECMO support, but ultimately required ongoing ECMO support. She developed evidence of end-organ dysfunction from her cor pulmonale, including oliguric renal failure requiring renal replacement therapy (RRT), hepatic injury with elevated transaminases and hyperammonemia leading to depressed mental state, feeding intolerance, and coagulopathy. Additionally, due to long-term nasogastric enteral tube placement for caloric supplementation and enteral medication administration, she developed concerns for invasive sinusitis with erosion into ethmoid and maxillary sinuses. As she was an adult patient being cared for in a free-standing academic children's hospital, multiple adult medicine consultants were involved in her care. Specifically, adult nephrology, cardiology, cardiothoracic surgery (for ProtekDuo cannula placement), and gastroenterology/ hepatology were integral into her care, along with our pediatric critical care medicine and ECMO teams. Notably, this was the first patient supported on ECMO to receive tracheostomy, RA-MPA dual-lumen VV cannula, and full autonomous mobility outside of the ICU at our well-established ECMO program, which has served as the index patient leading to future advances in the care of our ECMO patients. Over time and with multiple therapies to alleviate her cor pulmonale, the patient's echocardiograms evealed improved, half-systemic right-sided cardiac pressures. She was ultimately decannulated from ECMO at our center before being transferred back to the referring adult facility, and discharged to home 8 months after her initial presentation with acute respiratory failure.

Safe and effective administration of multiple recombinant factors on VA-ECMO via post-oxygenator pigtail during acute massive pulmonary hemorrhage

Introduction: Massive bleeding on extracorporeal membrane oxygenation (ECMO) is associated with multiple coagulation defects, including depletion of coagulation factors and development of acquired von Willebrand syndrome (AVWS). The use of recombinant factors, in particular recombinant activated factor VII (rFVIIa, Novoseven), to treat severe refractory hemorrhage in ECMO has been described. However, the use of multiple recombinant factors has been avoided in large part due to concern for circuit complications and thrombosis. Here, we describe the safe and effective administration of rFVIIa and recombinant von Willebrand factor complex (vWF/ FVIII, Humate-P) via post-oxygenator pigtail catheter on VA-ECMO for the treatment of massive pulmonary hemorrhage. Case Description: A 21-month-old (13.4 kg) girl with a recent history of COVID-19 infection presented to an outside hospital with parainfluenza bronchiolitis resulting in acute refractory hypoxemic respiratory failure (oxygenation index 58), refractory septic shock, and myocardial dysfunction. She was cannulated to VA-ECMO and subsequently diagnosed with necrotizing pneumonia from Pseudomonas and herpes simplex infections. Her course was complicated by a large left-sided pneumatocele and bronchopleural fistula requiring multiple chest tubes. She also had right mainstem bronchus obstruction from necrotic airway debris and complete right lung atelectasis. She was noted to have prolonged episodes of mucosal and cutaneous bleeding (oropharynx, chest tube insertion sites, peripheral IV insertion sites) associated with absent high molecular weight von Willebrand multimers consistent with AVWS. Tranexamic acid infusion was initiated and bivalirudin anticoagulation was discontinued. VA-ECMO flows were escalated to 140-160 ml/kg/min to maintain circuit integrity and meet high patient metabolic demand in the absence of anticoagulation. On ECMO day 26, she underwent bronchoscopy to clear necrotic debris from her airway to assist with lung recruitment. The procedure was notable for mucosal bleeding requiring topical epinephrine and rFVIIa. Post-procedure, she developed acute hemorrhage from her right mainstem bronchus, resulting in significant hemothorax (estimated 950 ml) with mediastinal shift, increased venous pressures, desaturation and decreased ECMO blood flow rate, necessitating massive transfusion of 2,050 ml (150 ml/kg) of packed red blood cells, platelets, plasma and cryoprecipitate. An airway blocker was placed in the mid-trachea to control bleeding. In addition to transfusion of appropriate blood products and continuation of tranexamic acid infusion, she was given both rFVIIa (100mcg/kg) and vWF-FVIII (70 units vWF/kg loading dose on the day of hemorrhage, followed by 40 units vWF/kg every 12 hours for 3 additional doses). Both products were administered over 10 minutes through a post-oxygenator pigtail to allow the product to circulate throughout the patient prior to entering the ECMO circuit. The circuit was closely monitored during administration and no changes to circuit integrity were noted in the subsequent hours while hemostasis was achieved. The ECMO circuit remained without thrombosis for 9 days after the bleeding event. Discussion: Balancing anticoagulation and hemostasis is a central challenge in maintaining ECMO support, especially given the prevalence of acquired coagulopathies such as AVWS. For our patient, AVWS contributed to mucosal bleeding necessitating cessation of anticoagulation and utilization of a high ECMO blood flow strategy to minimize circuit clot burden. This was further complicated by absent native lung function and minimal myocardial function, resulting in complete dependence on ECMO. An acute massive pulmonary hemorrhage was treated with multiple recombinant factors (rFVIIa and vWF/FVIII), that are often avoided on ECMO. To minimize clotting risk to the circuit and to maximize transit of these factors to our patient, we added a post-oxygenator pigtail for administration. While this approach was the result of extreme circumstances, th use of a post-oxygenator pigtail for administration of recombinant factors may represent a viable strategy for refractory hemorrhage while on ECMO.

Anticoagulation Strategies in Critically Ill Patients With SARS-CoV-2 Infection: The Role of Direct Thrombin Inhibitors.

OBJECTIVES: To compare heparin-based anticoagulation and bivalirudin-based anticoagulation within the context of critically ill patients with a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. DESIGN: An observational study. SETTING: At the intensive care unit of a university hospital. PARTICIPANTS AND INTERVENTIONS: Critically ill patients with a SARS-CoV-2 infection receiving full anticoagulation with heparin or bivalirudin. MEASUREMENTS AND MAIN RESULTS: Twenty-three patients received full anticoagulation with bivalirudin and 60 with heparin. Despite patients in the bivalirudin group having higher mortality risk scores (SAPS II 60 ± 16 v 39 ±7, p < 0.001) and a higher need for extracorporeal support compared to the heparin group, hospital mortality was comparable (57% v 45, p = 0.3). No difference in thromboembolic complications was observed, and bleeding events were more frequent in patients treated with bivalirudin (65% v 40%, p = 0.01). Similar results were confirmed in the subgroup analysis of patients undergoing intravenous anticoagulation; in addition to comparable thrombotic complications occurrence and thrombocytopenia rate, however, no difference in the bleeding rate was observed (65% v 35%, p = 0.08). CONCLUSIONS: Although heparin is the most used anticoagulant in the intensive care setting, bivalirudin-based anticoagulation was safe and effective in a cohort of critically ill patients with SARS-CoV-2. Bivalirudin may be given full consideration as an anticoagulation strategy for critically ill patients with SARS-CoV-2, especially in those with thrombocytopenia and on extracorporeal support.

A journey through anticoagulant therapies in the treatment of left ventricular thrombus in post-COVID-19 heparin-induced thrombocytopenia: a case report.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction associated with thrombosis. Clinical scoring systems and the presence of anti-platelet factor 4 (anti-PF4)/heparin antibodies determine the diagnosis. CASE PRESENTATION: A 57-year-old man who was treated with acenocoumarol due to a chronic left ventricular thrombus was admitted to the hospital for severe SARS-CoV-2 pneumonia and pulmonary embolism. The patient was started on bemiparin and discharged. Left lower limb acute arterial ischemia and thrombocytopenia were diagnosed 18 days later. Computed tomography angiography revealed a large left ventricular thrombus and multiple arterial thrombi. Left femoral-popliteal thromboembolectomy was performed. Anti-PF4/heparin antibodies confirmed an HIT diagnosis. Fondaparinux (7.5 mg/24 h) was initiated, but cardiac surgery was necessary. Bivalirudin was used during surgery, with an initial load (1.25 mg/kg) and maintenance infusion (2.5 mg/kg/h). The cardiac thrombus was extracted, but the patient experienced a postsurgical myocardial infarction. Percutaneous cardiovascular intervention (PCI) required a bivalirudin load (0.75 mg/kg) and maintenance infusion (1.75 mg/kg/h). No coronary lesions were detected, and argatroban was started afterwards (0.5 µg/kg/min). When the platelet count exceeded 100 × 109/L, acenocoumarol was initiated. Thereupon, acetylsalicylic acid (100 mg/24 h) was added. No other complications have been reported to date. CONCLUSION: The clinical presentation of intraventricular and multiple arterial thrombi is remarkable. SARS-CoV-2 infection likely contributed to a hypercoagulable state. The management of patients with HIT undergoing cardiac surgery is challenging. If surgery cannot be delayed, then treatment with bivalirudin is recommended. Additionally, this drug is recommended for PCI. Bivalirudin is safe and well-tolerated in both procedures.

CHARACTERIZATION OF BIVALIRUDIN USE IN COVID-19 EXTRACORPOREAL MEMBRANE OXYGENATION PATIENTS

B Introduction: b The Extracorporeal Life Support Organization (ELSO) recommends that patients requiring extracorporeal membrane oxygenation (ECMO) receive systemic anticoagulation to mitigate the thrombotic potential of the extracorporeal device. B Methods: b This retrospective cohort study included patients with COVID-19 requiring ECMO who received bivalirudin for anticoagulation from April 1, 2020 to April 19, 2021. [Extracted from the article] Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

EVALUATION OF ECMO BIVALIRUDIN PROTOCOL

Patients with COVID-19 on ECMO took longer to reach two consecutive aPTTs within therapeutic range. A medication use evaluation of all ECMO patients who received bivalirudin was previously conducted at Carilion, which resulted in a P&T approved addition of an ECMO Addendum in the pharmacy-directed DTI Protocol. In a subgroup analysis of patients with and without COVID-19 in the post-group, the primary outcome was higher in patients with COVID-19 (26.5 vs. 14.2 hours, p=0.018). [Extracted from the article] Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Early experience utilizing bivalirudin as anticoagulation in extracorporeal membrane oxygen in coronavirus disease 2019

Background: Extracorporeal membrane oxygenation (ECMO) is utilized as rescue therapy in patients diagnosed with coronavirus disease 2019 (COVID-19) with refractory respiratory or cardiogenic failure. Systemic anticoagulation with heparin remains the initial choice for thromboembolism prophylaxis in ECMO-treated patients. However, heparin carries the risk of severe complications, such as heparin-induced thrombocytopenia (HIT), and acquired antithrombin deficiency. Bivalirudin has been suggested as an alternative anticoagulant since it neither requires anti-thrombin III monitoring nor triggers HIT. Purpose: There is very limited data on the utilization of bivalirudin in patients with COVID-19 treated with ECMO. We report the clinical safety and efficacy of using bivalirudin at our institution. Methods: We retrospectively reviewed 17 patients diagnosed with COVID-19, who were treated with ECMO from 7/31/2020 to 12/20/2020. All patients received bivalirudin for thromboprophylaxis while on ECMO support. Results: The mean age of our study cohort was forty-five years. Thirteen patients (76.4%) were of either Hispanic or African American descent. Of the seventeen patients, six (35.3%) patients developed deep venous thrombosis and one (5.9%) patient developed pulmonary embolism. Two (11.8%) patients developed a clotted circuit that required exchange. Fifteen (88.2%) patients had hemorrhage requiring transfusion with the gastrointestinal tract as the most common bleeding site. Nine (52.9%) patients developed thrombocytopenia. Six (35.3%) patients were discharged home or to a long-term acute care center;eleven (64.7%) patients died. The average length of stay was thirty-seven days. Conclusion: In our small case series, the rates of complications and mortality remained high while using bivalirudin as anticoagulation of choice in patients diagnosed with COVID-19 and treated with ECMO. Further studies are needed to investigate the optimal anticoagulant in this population.

Efficacy of Bivalirudin for Therapeutic Anticoagulation in COVID-19 Patients Requiring ECMO Support.

OBJECTIVES: The Coronavirus Disease 2019 (COVID-19) pandemic has been associated with cases of refractory acute respiratory distress syndrome (ARDS) sometimes requiring support with extracorporeal membrane oxygenation (ECMO). Bivalirudin can be used for anticoagulation in patients on ECMO support, but its efficacy and safety in patients with COVID-19 is unknown. The authors set out to compare the pharmacologic characteristics and dosing requirements of bivalirudin in patients requiring ECMO support for ARDS due to COVID-19 versus ARDS from other etiologies. DESIGN AND SETTING: This retrospective case-control study was performed at Indiana University Health Methodist Hospital in Indianapolis, Indiana. PARTICIPANTS: Patients were included if they were on venovenous ECMO support between June 2019 and June 2020, and divided into two groups: ARDS secondary to COVID-19 and those with ARDS from another etiology (Non-COVID). INTERVENTIONS: Patient demographics, such as age, sex, weight, chronic comorbid conditions, baseline antiplatelet and anticoagulant use, antiplatelet use during ECMO, and need for renal replacement therapy were collected, and compared between groups. Time to activated partial thromboplastin time (aPTT) goal, percentage of time at aPTT goal, bivalirudin rates, total bivalirudin requirements, total duration on bivalirudin, total duration on ECMO, mortality, and complications associated with ECMO were collected and compared between groups. MEASUREMENTS AND MAIN RESULTS: A total of 42 patients met inclusion criteria (n = 19 COVID-19, n = 23 non-COVID). However, percentages of aPTTs at goal were maintained more consistently in patients with COVID-19 versus non-COVID (86% v 74%: p < 0.01). Higher median (IQR) daily rates (3.1 µg/kg/min [2.3-5.2] v 2.4 µg/kg/min [1.7-3.3]: p = 0.05) and higher median (IQR) maximum rates of bivalirudin (5 µg/kg/min [3.7-7.5] v 3.8 µg/kg/min [2.5-5]: p = 0.03) were required in the COVID-19 group versus the non-COVID group. Time to goal aPTT was similar between groups. There were no differences in complications associated with anticoagulation, as demonstrated by similar rates of bleeding and thrombosis between both groups. CONCLUSIONS: Patients on ECMO with ARDS from COVID-19 require more bivalirudin overall and higher rates of bivalirudin to maintain goal aPTTs compared with patients without COVID-19. However, COVID-19 patients more consistently maintain goal aPTT. Future randomized trials are needed to support efficacy and safety of bivalirudin for anticoagulation of COVID-19 patients on ECMO.

Bivalirudin for Maintenance Anticoagulation During Venovenous Extracorporeal Membrane Oxygenation for COVID-19.

In its severe manifestation, coronavirus disease 2019 (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, the successful use of an anticoagulation strategy using 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 venovenous ECMO is reported. Importantly, therapeutic anticoagulation intensity was achieved rapidly 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 prothrombotic nature of the underlying pathophysiologic state.