key: cord-0875468-oti3dlm9 authors: Kannapadi, Nivedha V.; Jami, Meghana; Premraj, Lavienraj; Etchill, Eric W.; Giuliano, Katherine; Bush, Errol L.; Kim, Bo Soo; Seal, Stella; Whitman, Glenn; Cho, Sung-Min title: Neurological Injury in COVID-19 Patients Who Receive VV-ECMO Therapy: A Cohort Study date: 2021-05-13 journal: J Cardiothorac Vasc Anesth DOI: 10.1053/j.jvca.2021.05.017 sha: 1772b184689704012106184ca88f5d09c9116670 doc_id: 875468 cord_uid: oti3dlm9 nan Both thrombotic and bleeding events have been implicated in the progression of Coronavirus disease 2019 (COVID-19). 1, 2 Such dysregulation of coagulation has been associated with poor prognosis. 3, 4 Neurologic sequelae, such as ischemic stroke and intracranial hemorrhage (ICH), have been reported in COVID-19 patients at rates of 0.9%-2.3% and 0.9%, respectively. 5, 6, 7, 8 Limited data exists on neurological events in COVID-19 patients in the intensive care unit (ICU) who require extracorporeal membrane oxygenation (ECMO) due to severe acute respiratory distress syndrome (ARDS). We retrospectively reviewed COVID-19 adult patients supported by ECMO at our tertiary care center. Inclusion criteria were (1) a positive polymerase chain reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and (2) cannulation for venovenous (VV) ECMO support. Patient demographics, past medical history, adverse events during hospitalization, laboratory values on day 1 of ECMO, ECMO variables, and outcomes were obtained through electronic medical records. Neurological events, such as ischemic stroke, hypoxic ischemic brain injury (HIBI), ICH, and cerebral microbleed (CMB), were identified based on computed tomography (CT) and magnetic resonance imaging (MRI) reports conducted anytime during ECMO support to 5 days after decannulation. ICHs were defined as any hemorrhages visualized on CT scan, and CMBs were defined as hemorrhages <5 mm, visualized on susceptibility weighted imaging (SWI) or gradient recalled echo (GRE) MRI. 9 Both CMBs and ICH were defined as hemorrhagic neurological events. Bleeding events were categorized as in gastrointestinal tract, at cannulation site, and at tracheostomy site. This study was approved by the institutional review board. All ECMO patients in our center receive neurocritical care consultation and standardized neuromonitoring protocol. 10 Figure 1 shows CT without contrast imaging for the three patients who experienced ICH. All three patients with ICHs were managed by discontinuing heparin upon CT detection of neurological event. These patients' laboratory values on the first day of ECMO are shown in Table 2 . The four patients that experienced neurological events during ECMO support were compared to those without to better understand the differences between the two groups ( Table 3) . Patients with neurological events tended to be older, albeit non-significantly, with a median age of 55.5 (IQR: 50-59) vs. 47 years (IQR: 36-54). Although not statistically significant, it is notable that patients with neurological events had more bleeding events while on ECMO (100% vs. 75%), compared to those without. These patients were also less likely to have received Remdesivir (0% vs. 42%), anti-IL6 mediations (25% vs. 75%), and steroids (0% vs. 33%). Ventilation and ECMO variables were similar between the groups. All 16 patients were proned, received neuromuscular blockade, and underwent mechanical ventilation. Not surprisingly, patients with neurological events had a longer hospital stay (55.5 vs. 41 days). Nineteen percent (3/16) died within 30 days, and this mortality rate was similar regardless of neurological event. Patients with neurological events were significantly more likely to have lower platelet count and higher D-dimer values vs. those without. While not statistically significant, neurological events were also associated with lower hemoglobin, hematocrit, and P a CO 2 values and higher creatinine, aspartate aminotransferase (AST), IL-6, lactate dehydrogenase (LDH), ferritin, Creactive protein (CRP), and apTT values. An increased SOFA score on ECMO day 1 (median 9.5 vs. 7) was significantly associated with neurological events. Our analysis provides several important findings. First, no patient had an ischemic stroke, and ICHs were common with a rate of 25%. We hypothesized that the prevalence of neurological events in COVID-19 ARDS patients with ECMO support would be similar to other ARDS patients with ECMO support. Several prior studies have reported that patients treated with VV-ECMO for non-COVID-19-related respiratory failure are at higher risk for ICH than ischemic stroke. 11 The Extracorporeal Life Support Organization (ELSO) registry study reports that the rates of infarct and ICH in 983 COVID-19 ECMO patients are 0.7% and 6% ICHs, respectively. 13 Our data shows an ICH rate much greater than that of non-COVID-19 ECMO patients. In addition, severity of illness and coagulopathy may be important risk factors in ECMOassociated ICH. While the pathophysiology of ICH in COVID-19 patients is likely multifactorial, one hypothesis is that the cytokine-induced endothelial damage and breakdown of the blood brain barrier in COVID-19 patients may increase risk of ICH. 14 Table 3) . Lastly, lower platelet count and higher aPTT values on ECMO day 1 were associated with neurological events, indicating anticoagulation is an important factor in ECMO-associated ICH in COVID-19 patients. Lower hemoglobin values in these patients may indicate worsening coagulopathy predisposing patients to bleeding events. Furthermore, ICHs may be related to an acquired von Willebrand syndrome due to the high sheer stress of the ECMO circuit. 16, 17 Caution should be taken in interpreting these findings, however, as this study has a small sample size, and our center has a rigorous standardized neuromonitoring protocol that may increase the sensitivity of detection neurological events. 10 Diagnosis of neurological event was only made upon imaging findings, and routine CT was not recommended without neurological symptoms due to limited resources and desire to avoid unnecessary exposures during the pandemic. Thus, only 12 of the 16 patients received a CT scan during ECMO, causing a selection bias. Although the absence of ischemic stroke is interesting, this diagnosis is more difficult to make than ICH due to poor sensitivity of CT scans for early ischemia. In the absence of comparative analysis with a control group, we cannot provide definitive evidence of COVID-19 infection conferring independent risk of neurological events during ECMO support. However, our study still provides valuable information suggesting an increased ICH risk in COVID-19 ECMO patients. Future research is warranted to corroborate our findings and describe the risk factors for this critically ill population. Given the devastating outcome of neurological events in COVID-19 ECMO patients, the utility of routine neuroimaging and re-evaluation of anticoagulation strategy should be further explored. COVID-19-Associated Coagulopathy and Inflammatory Response: What Do We Know Already and What Are the Knowledge Gaps? COVID-19 Associated Hypercoagulability: Manifestations, Mechanisms, and Management. [Internet]Shock [Internet] Publish Ahead of Print2020 The values of coagulation function in COVID-19 patients Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia Acute Cerebrovascular Events in Hospitalized COVID-19 Patients Neurological manifestations of pediatric multisystem inflammatory syndrome potentially associated with COVID-19 SARS-CoV-2 and Stroke in a New York Healthcare System Clinical Characteristics of Stroke with COVID-19: A Systematic Review and Meta-Analysis Clinically Silent Brain Injury and Perioperative Neurological Events in Patients With Left Ventricular Assist Device: A Brain Autopsy Study Noninvasive Neurological Monitoring in Extracorporeal Membrane Oxygenation Brain injury during venovenous extracorporeal membrane oxygenation Intracranial hemorrhage in adults on ECMO Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry Stroke in COVID-19: A systematic review and metaanalysis (11.2-14.9) 0.280 aPTT, s 48 ALT: alanine transferase; aPTT: activated partial thromboplastin time; AST: aspartate transferase; CRP: C-reactive protein; ECMO: extra-corporeal membrane oxygenation IL-6: interleukin 6; INR: international normalized ratio; LDH: lactate dehydrogenase; P:F: pressure of arterial oxygen to fraction of inspired oxygen; PT: prothrombin time; RESP: Respiratory ECMO Survival Predication; SOFA: sequential organ failure assessment; WBC: white blood cells *: Mann-Whitney and Fischer's exact tests