SARS-CoV-2 infection and persistence in the human body and brain at autopsy.

Coronavirus disease 2019 (COVID-19) is known to cause multi-organ dysfunction1-3 during acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some patients experiencing prolonged symptoms, termed post-acute sequelae of SARS-CoV-2 (refs. 4,5). However, the burden of infection outside the respiratory tract and time to viral clearance are not well characterized, particularly in the brain3,6-14. Here we carried out complete autopsies on 44 patients who died with COVID-19, with extensive sampling of the central nervous system in 11 of these patients, to map and quantify the distribution, replication and cell-type specificity of SARS-CoV-2 across the human body, including the brain, from acute infection to more than seven months following symptom onset. We show that SARS-CoV-2 is widely distributed, predominantly among patients who died with severe COVID-19, and that virus replication is present in multiple respiratory and non-respiratory tissues, including the brain, early in infection. Further, we detected persistent SARS-CoV-2 RNA in multiple anatomic sites, including throughout the brain, as late as 230 days following symptom onset in one case. Despite extensive distribution of SARS-CoV-2 RNA throughout the body, we observed little evidence of inflammation or direct viral cytopathology outside the respiratory tract. Our data indicate that in some patients SARS-CoV-2 can cause systemic infection and persist in the body for months.

Histopathology and SARS-CoV-2 Cellular Localization in Eye Tissues of COVID-19 Autopsies.

Ophthalmic manifestations and tissue tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported in association with coronavirus disease 2019 (COVID-19), but the pathology and cellular localization of SARS-CoV-2 are not well characterized. The objective of this study was to evaluate macroscopic and microscopic changes and investigate cellular localization of SARS-CoV-2 across ocular tissues at autopsy. Ocular tissues were obtained from 25 patients with COVID-19 at autopsy. SARS-CoV-2 nucleocapsid gene RNA was previously quantified by droplet digital PCR from one eye. Herein, contralateral eyes from 21 patients were fixed in formalin and subject to histopathologic examination. Sections of the droplet digital PCR-positive eyes from four other patients were evaluated by in situ hybridization to determine the cellular localization of SARS-CoV-2 spike gene RNA. Histopathologic abnormalities, including cytoid bodies, vascular changes, and retinal edema, with minimal or no inflammation in ocular tissues were observed in all 21 cases evaluated. In situ hybridization localized SARS-CoV-2 RNA to neuronal cells of the retinal inner and outer layers, ganglion cells, corneal epithelia, scleral fibroblasts, and oligodendrocytes of the optic nerve. In conclusion, a range of common histopathologic alterations were identified within ocular tissue, and SARS-CoV-2 RNA was localized to multiple cell types. Further studies will be required to determine whether the alterations observed were caused by SARS-CoV-2 infection, the host immune response, and/or preexisting comorbidities.

Flow-Sizing Critical Care Resources.

OBJECTIVES: To describe the factors affecting critical care capacity and how critical care organizations (CCOs) within academic centers in the U.S. flow-size critical care resources under normal operations, strain, and surge conditions. DATA SOURCES: PubMed, federal agency and American Hospital Association reports, and previous CCO survey results were reviewed. STUDY SELECTION: Studies and reports of critical care bed capacity and utilization within CCOs and in the United States were selected. DATA EXTRACTION: The Academic Leaders in the Critical Care Medicine Task Force established regular conference calls to reach a consensus on the approach of CCOs to "flow-sizing" critical care services. DATA SYNTHESIS: The approach of CCOs to "flow-sizing" critical care is outlined. The vertical (relation to institutional resources, e.g., space allocation, equipment, personnel redistribution) and horizontal (interdepartmental, e.g., emergency department, operating room, inpatient floors) integration of critical care delivery (ICUs, rapid response) for healthcare organizations and the methods by which CCOs flow-size critical care during normal operations, strain, and surge conditions are described. The advantages, barriers, and recommendations for the rapid and efficient scaling of critical care operations via a CCO structure are explained. Comprehensive guidance and resources for the development of "flow-sizing" capability by a CCO within a healthcare organization are provided. CONCLUSIONS: We identified and summarized the fundamental principles affecting critical care capacity. The taskforce highlighted the advantages of the CCO governance model to achieve rapid and cost-effective "flow-sizing" of critical care services and provide recommendations and resources to facilitate this capability. The relevance of a comprehensive approach to "flow-sizing" has become particularly relevant in the wake of the latest COVID-19 pandemic. In light of the growing risks of another extreme epidemic, planning for adequate capacity to confront the next critical care crisis is urgent.

Spinal Cord Infarction With Prolonged Femoral Venoarterial Extracorporeal Membrane Oxygenation.

OBJECTIVES: There have been sporadic reports of ischemic spinal cord injury (SCI) during venoarterial extracorporeal membrane oxygenation (VA-ECMO) support. The authors observed a troubling pattern of this catastrophic complication and evaluated the potential mechanisms of SCI related to ECMO. DESIGN: This study was a case series. SETTING: This study was performed at a single institution in a University setting. PARTICIPANTS: Patients requiring prolonged VA-ECMO were included. INTERVENTIONS: No interventions were done. This was an observational study. MEASUREMENTS AND MAIN RESULTS: Four hypotheses of etiology were considered: (1) hypercoagulable state/thromboembolism, (2) regional hypoxia/hypocarbia, (3) hyperperfusion and spinal cord edema, and (4) mechanical coverage of spinal arteries. The SCI involved the lower thoracic (T7-T12 level) spinal cord to the cauda equina in all patients. Seven out of 132 (5.3%) patients with prolonged VA-ECMO support developed SCI. The median time from ECMO cannulation to SCI was 7 (range: 6-17) days.There was no evidence of embolic SCI or extended regional hypoxia or hypocarbia. A unilateral, internal iliac artery was covered by the arterial cannula in 6/7 86%) patients, but flow into the internal iliac was demonstrated on imaging in all available patients. The median total flow (ECMO + intrinsic cardiac output) was 8.5 L/min (LPM), and indexed flow was 4.1 LPM/m2. The median central venous oxygen saturation was 88%, and intracranial pressure was measured at 30 mmHg in one patient, suggestive of hyperperfusion and spinal cord edema. CONCLUSIONS: An SCI is a serious complication of extended peripheral VA-ECMO support. Its etiology remains uncertain, but the authors' preliminary data suggested that spinal cord edema from hyperperfusion or venous congestion could contribute.

Regionalization of Critical Care in the United States: Current State and Proposed Framework From the Academic Leaders in Critical Care Medicine Task Force of the Society of Critical Care Medicine.

OBJECTIVES: The Society of Critical Care Medicine convened its Academic Leaders in Critical Care Medicine taskforce on February 22, 2016, during the 45th Critical Care Congress to develop a series of consensus papers with toolkits for advancing critical care organizations in North America. The goal of this article is to propose a framework based on the expert opinions of critical care organization leaders and their responses to a survey, for current and future critical care organizations, and their leadership in the health system to design and implement successful regionalization for critical care in their regions. DATA SOURCES AND STUDY SELECTION: Members of the workgroup convened monthly via teleconference with the following objectives: to 1) develop and analyze a regionalization survey tool for 23 identified critical care organizations in the United States, 2) assemble relevant medical literature accessed using Medline search, 3) use a consensus of expert opinions to propose the framework, and 4) create groups to write the subsections and assemble the final product. DATA EXTRACTION AND SYNTHESIS: The most prevalent challenges for regionalization in critical care organizations remain a lack of a strong central authority to regulate and manage the system as well as a lack of necessary infrastructure, as described more than a decade ago. We provide a framework and outline a nontechnical approach that the health system and their critical care medicine leadership can adopt after considering their own structure, complexity, business operations, culture, and the relationships among their individual hospitals. Transforming the current state of regionalization into a coordinated, accountable system requires a critical assessment of administrative and clinical challenges and barriers. Systems thinking, business planning and control, and essential infrastructure development are critical for assisting critical care organizations. CONCLUSIONS: Under the value-based paradigm, the goals are operational efficiency and patient outcomes. Health systems that can align strategy and operations to assist the referral hospitals with implementing regionalization will be better positioned to regionalize critical care effectively.

Aspirin Use Is Associated With Decreased Mechanical Ventilation, Intensive Care Unit Admission, and In-Hospital Mortality in Hospitalized Patients With Coronavirus Disease 2019.

BACKGROUND: Coronavirus disease-2019 (COVID-19) is associated with hypercoagulability and increased thrombotic risk in critically ill patients. To our knowledge, no studies have evaluated whether aspirin use is associated with reduced risk of mechanical ventilation, intensive care unit (ICU) admission, and in-hospital mortality. METHODS: A retrospective, observational cohort study of adult patients admitted with COVID-19 to multiple hospitals in the United States between March 2020 and July 2020 was performed. The primary outcome was the need for mechanical ventilation. Secondary outcomes were ICU admission and in-hospital mortality. Adjusted hazard ratios (HRs) for study outcomes were calculated using Cox-proportional hazards models after adjustment for the effects of demographics and comorbid conditions. RESULTS: Four hundred twelve patients were included in the study. Three hundred fourteen patients (76.3%) did not receive aspirin, while 98 patients (23.7%) received aspirin within 24 hours of admission or 7 days before admission. Aspirin use had a crude association with less mechanical ventilation (35.7% aspirin versus 48.4% nonaspirin, P = .03) and ICU admission (38.8% aspirin versus 51.0% nonaspirin, P = .04), but no crude association with in-hospital mortality (26.5% aspirin versus 23.2% nonaspirin, P = .51). After adjusting for 8 confounding variables, aspirin use was independently associated with decreased risk of mechanical ventilation (adjusted HR, 0.56, 95% confidence interval [CI], 0.37-0.85, P = .007), ICU admission (adjusted HR, 0.57, 95% CI, 0.38-0.85, P = .005), and in-hospital mortality (adjusted HR, 0.53, 95% CI, 0.31-0.90, P = .02). There were no differences in major bleeding (P = .69) or overt thrombosis (P = .82) between aspirin users and nonaspirin users. CONCLUSIONS: Aspirin use may be associated with improved outcomes in hospitalized COVID-19 patients. However, a sufficiently powered randomized controlled trial is needed to assess whether a causal relationship exists between aspirin use and reduced lung injury and mortality in COVID-19 patients.

Ultrasound-assisted catheter directed thrombolysis for pulmonary embolus during extracorporeal membrane oxygenation.

BACKGROUND: Acute pulmonary embolism (PE) is the third most common cause of cardiovascular death. For patients who are hemodynamically unstable, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support has been shown to provide hemodynamic stability, and allow time for definitive treatment and recovery. Ultrasound-assisted catheter directed thrombolysis (USAT) has the potential to be a safe adjunct and expedite right ventricular (RV) recovery for patients requiring VA-ECMO for PE. METHODS: A review of all VA-ECMO patients from January 2017 to September 2019 was performed. A total of 49 of these patients were cannulated due to a PE. USAT therapy was used as an adjunct in 6 (12%) of these patients. These 6 patients were given standardized USAT therapy with EKOs catheters at 1 mg/h of tissue plasminogen activator with an unfractionated heparin infusion for additional systemic anticoagulation. Outcomes, including in-hospital death, 90-day survival, RV recovery, and complications, were examined in the cohort of patients that received USAT as an adjunct to ECMO. RESULTS: Median age was 54 years old. Five of the six patients presented with a massive PE and had a PE severity score of Class V. One patient presented with a submassive PE with a Bova score of 2, but was cannulated to VA-ECMO in the setting of worsening RV function. All patients demonstrated recovery of RV function, were free from in-hospital death, and were alive at 90-day follow-up. CONCLUSION: Ekosonic endovascular system therapy may be a safe and feasible adjunct for patients on VA-ECMO for PE, and allow for survival with RV recovery with minimal complications.

Intoxication and overdose should not preclude veno-venous extracorporeal membrane oxygenation.

INTRODUCTION: Acute intoxication (AI) related morbidity and mortality are increasing in the United States. For patients with severe respiratory failure in the setting of an acute ingestion, veno-venous extracorporeal membrane oxygenation (VV ECMO) can provide salvage therapy. The purpose of this study was to evaluate outcomes in patients with overdose-related need for VV ECMO. METHODS: We performed a retrospective review of all patients admitted to a specialty VV ECMO unit between August 2014 and August 2018. Patients were stratified by those whose indication for VV ECMO was directly related to an acute ingestion (alcohol, illicit drug, or prescription drug overdose) and those with unrelated diagnoses. Demographics, pre-cannulation clinical characteristics, ECMO parameters, and outcomes data was collected and analyzed with parametric and non-parametric statistics as indicated. RESULTS: 189 patients were enrolled with 27 (14%) diagnosed with AI. Patients requiring VV ECMO for an AI were younger, had lower median BMI and PaO2/FiO2, and higher RESP scores than non-AI patients (p = 0.002, 0.01, 0.03 and 0.01). There was no difference in pre-cannulation pH, lactate, or SOFA scores between the two groups (p = 0.24, 0.5, 0.6). There was no difference in survival to discharge (p = 0.95). Among survivors, there was no difference in ECMO time or hospital stay (p = 0.24, 0.07). CONCLUSION: We demonstrate no survival difference for patients with and without an AI-related need for VV ECMO. AI patients should be supported with VV ECMO when traditional therapies fail despite potential stigma against acceptance on referral.

Methylprednisolone may be associated with improved lung compliance in acute respiratory distress syndrome patients on veno-venous extracorporeal membrane oxygenation.

INTRODUCTION: Methylprednisolone has been used for acute respiratory distress syndrome with variable results. Veno-venous extracorporeal membrane oxygenation use in acute respiratory distress syndrome has increased. Occasionally, both are used. We hypothesized that methylprednisolone could improve lung compliance and ease weaning from extracorporeal membrane oxygenation in acute respiratory distress syndrome patients. METHODS: We retrospectively reviewed all patients in our veno-venous extracorporeal membrane oxygenation unit treated with methylprednisolone over a 20 month period. Methylprednisolone was initiated for inability to wean off veno-venous extracorporeal membrane oxygenation. Dynamic compliance (Cdyn) was calculated at cannulation, methylprednisolone initiation, and decannulation. Demographics, extracorporeal membrane oxygenation-specific data, and ventilator data were collected. Wilcoxon rank-sum test was used to test for differences in dynamic compliance. RESULTS: A total of 12 veno-venous extracorporeal membrane oxygenation patients received methylprednisolone. Mean age was 50 (±15) years. Seven had influenza. Methylprednisolone was started on median Day 16 (interquartile range: 11-22) of veno-venous extracorporeal membrane oxygenation. In total, 10 patients had veno-venous extracorporeal membrane oxygenation decannulation on median Day 12 (7-22) after methylprednisolone initiation. Two patients died before decannulation. The 10 decannulated patients had initial median dynamic compliance (mL × cm H2O-1) of 12 (7-23), then 16 (10-24) at methylprednisolone initiation, and then 44 (34-60) at decannulation. Dynamic compliance was higher at decannulation than methylprednisolone initiation (p = 0.002), and unchanged from cannulation to methylprednisolone initiation for all patients (p = 0.97). A total of 10 patients had significant infections. None had significant gastrointestinal bleed or wound healing issues. CONCLUSION: Methylprednisolone may be associated with improved compliance in acute respiratory distress syndrome allowing for decannulation from veno-venous extracorporeal membrane oxygenation. High rates of infection are associated with methylprednisolone use in veno-venous extracorporeal membrane oxygenation. Further studies are required to identify appropriate patient selection for methylprednisolone use in patients on veno-venous extracorporeal membrane oxygenation.

High-efficiency, high-flux in-line hemofiltration using a high blood flow extracorporeal circuit.

The ability of current renal replacement therapy modalities to achieve rapid solute removal is limited by membrane surface area and blood flow rate. Extracorporeal membrane oxygenation offers high blood flow and hemodynamic support that may be harnessed to overcome limitations in traditional renal replacement therapy. Using an extracorporeal membrane oxygenation circuit, we describe a high blood flow, high-efficiency hemofiltration technique using in-line hemofilters (hemoconcentrators) and standard replacement fluid to enhance solute clearance. Using this approach and a total of 5 L of replacement volume per treatment, creatinine (Cr) clearances of 8.3 L/hour and 11.2 L/hour using one and two hemoconcentrators, respectively, were achieved. With use of a high blood flow rate of up to 5 L/min, this hemofiltration technique can potentially offer clearance of 30 times that of continuous renal replacement therapy and of 6 times that of hemodialysis which may expand the ability to remove substances traditionally not considered removable via existing extracorporeal therapies.

Pilot study evaluating a non-titrating, weight-based anticoagulation scheme for patients on veno-venous extracorporeal membrane oxygenation.

OBJECTIVE: There is no universally accepted algorithm for anticoagulation in patients on veno-venous extracorporeal membrane oxygenation. The purpose of this pilot study was to compare a non-titrating weight-based heparin infusion to that of a standard titration algorithm. METHODS: We performed a prospective randomized non-blinded study of patients: Arm 1-standard practice of titrating heparin to activated partial thromboplastin times goal of 45-55 seconds, and Arm 2-a non-titrating weight-based (10 units/kg/h) infusion. Primary outcome was need for oxygenator/circuit changes. Secondary outcomes included differences in hemolysis and bleeding episodes. Descriptive statistics were performed for the continuous data, and primary and secondary outcomes were compared using Fisher's exact test as appropriate. RESULTS: Six patients were randomized to Arm 1 and four to Arm 2. There was no difference in age, pH, PaO2/FiO2 ratio, peak inspiratory pressure, positive end expiratory pressure, mean airway pressure at time of cannulation, time on extracorporeal membrane oxygenation, or survival to hospital discharge in the two arms. Arm 1 had a statistically higher median activated partial thromboplastin times (48 (43, 52) vs 38 (35, 42), p < 0.008) and lower LDH (808 units/L (727, 1112) vs 940 units/L (809, 1137), p = 0.02) than Arm 2. There was no difference in plasma hemoglobin (4.3 (2.5, 8.7) vs 4.3 (3.0, 7.3), p = 0.65) between the two arms. There was no difference in mean oxygenator/circuit change, transfused packed red blood cell, or documented bleeding complications per patient in each arm (p = 0.56, 0.43, 0.77, respectively). CONCLUSION: In this pilot study, a non-titrating, weight-based heparin infusion appears safe and as effective in preventing veno-venous extracorporeal membrane oxygenation circuit thrombotic complications as compared to a titration algorithm. Larger studies are needed to confirm these preliminary findings.

Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit.

OBJECTIVE: To revise the "Clinical Practice Guidelines for the Sustained Use of Sedatives and Analgesics in the Critically Ill Adult" published in Critical Care Medicine in 2002. METHODS: The American College of Critical Care Medicine assembled a 20-person, multidisciplinary, multi-institutional task force with expertise in guideline development, pain, agitation and sedation, delirium management, and associated outcomes in adult critically ill patients. The task force, divided into four subcommittees, collaborated over 6 yr in person, via teleconferences, and via electronic communication. Subcommittees were responsible for developing relevant clinical questions, using the Grading of Recommendations Assessment, Development and Evaluation method (http://www.gradeworkinggroup.org) to review, evaluate, and summarize the literature, and to develop clinical statements (descriptive) and recommendations (actionable). With the help of a professional librarian and Refworks database software, they developed a Web-based electronic database of over 19,000 references extracted from eight clinical search engines, related to pain and analgesia, agitation and sedation, delirium, and related clinical outcomes in adult ICU patients. The group also used psychometric analyses to evaluate and compare pain, agitation/sedation, and delirium assessment tools. All task force members were allowed to review the literature supporting each statement and recommendation and provided feedback to the subcommittees. Group consensus was achieved for all statements and recommendations using the nominal group technique and the modified Delphi method, with anonymous voting by all task force members using E-Survey (http://www.esurvey.com). All voting was completed in December 2010. Relevant studies published after this date and prior to publication of these guidelines were referenced in the text. The quality of evidence for each statement and recommendation was ranked as high (A), moderate (B), or low/very low (C). The strength of recommendations was ranked as strong (1) or weak (2), and either in favor of (+) or against (-) an intervention. A strong recommendation (either for or against) indicated that the intervention's desirable effects either clearly outweighed its undesirable effects (risks, burdens, and costs) or it did not. For all strong recommendations, the phrase "We recommend …" is used throughout. A weak recommendation, either for or against an intervention, indicated that the trade-off between desirable and undesirable effects was less clear. For all weak recommendations, the phrase "We suggest …" is used throughout. In the absence of sufficient evidence, or when group consensus could not be achieved, no recommendation (0) was made. Consensus based on expert opinion was not used as a substitute for a lack of evidence. A consistent method for addressing potential conflict of interest was followed if task force members were coauthors of related research. The development of this guideline was independent of any industry funding. CONCLUSION: These guidelines provide a roadmap for developing integrated, evidence-based, and patient-centered protocols for preventing and treating pain, agitation, and delirium in critically ill patients.

Evaluation and treatment of pain in critically ill adults.

Pain is experienced by the overwhelming majority of patients during their intensive care unit stay, but it remains an underappreciated problem. To effectively treat pain, it must be detected and quantified using a validated assessment tool. It is acknowledged that optimal pain relief may be difficult to achieve given the complex interplay of coexisting medical conditions and the environment in which care is provided. Nonetheless, by following structured approaches to pain, resource consumption may be reduced, and even improved survival may be realized. This review covers practices and techniques specific to addressing and treating pain in the adult intensive care environment. Traditional pharmacological approaches including opiate and nonopiate medications are reviewed, as are regional anesthetic techniques and nonpharmacological approaches used for controlling pain.

Maternal transfer of IgA and IgG SARS-CoV-2 specific antibodies transplacentally and via breast milk feeding.

BACKGROUND: Although there have been many studies on antibody responses to SARS-CoV-2 in breast milk, very few have looked at the fate of these in the infant, and whether they are delivered to immunologically relevant sites in infants. METHODS: Mother/infant pairs (mothers who breast milk fed and who were SARS-CoV-2 vaccinated before or after delivery) were recruited for this cross-sectional study. Mother blood, mother breast milk, infant blood, infant nasal specimen, and infant stool was tested for IgA and IgG antibodies against SARS-CoV-2 spike trimer. RESULTS: Thirty-one mother/infant pairs were recruited. Breast milk fed infants acquired systemic anti-spike IgG antibodies only if their mothers were vaccinated antepartum (100% Antepartum; 0% Postpartum; P<0.0001). Breast milk fed infants acquired mucosal anti-spike IgG antibodies (in the nose) only if their mothers were vaccinated antepartum (89% Antepartum; 0% Postpartum; P<0.0001). None of the infants in either group had anti-spike IgA in the blood. Surprisingly, 33% of the infants whose mothers were vaccinated antepartum had high titer anti-spike IgA in the nose (33% Antepartum; 0% Postpartum; P = 0.03). Half-life of maternally transferred plasma IgG antibodies in the Antepartum infant cohort was ~70 days. CONCLUSION: Vaccination antepartum followed by breast milk feeding appears to be the best way to provide systemic and local anti-SARS-CoV-2 antibodies for infants. The presence of high titer SARS-CoV-2-specific IgA in the nose of infants points to the potential importance of breast milk feeding early in life for maternal transfer of mucosal IgA antibodies. Expectant mothers should consider becoming vaccinated antepartum and consider breast milk feeding for optimal transfer of systemic and mucosal antibodies to their infants.

Neurologic Outcomes After Extracorporeal Cardiopulmonary Resuscitation: Recent Experience at a Single High-Volume Center.

Extracorporeal cardiopulmonary resuscitation (ECPR)-veno-arterial extracorporeal membrane oxygenation (ECMO) for refractory cardiac arrest-has grown rapidly, but its widespread adoption has been limited by frequent neurologic complications. With individual centers developing best practices, utilization may be increasing with an uncertain effect on outcomes. This study describes the recent ECPR experience at the University of Maryland Medical Center from 2016 through 2018, with attention to neurologic outcomes and predictors thereof. The primary outcome was dichotomized Cerebral Performance Category (≤2) at hospital discharge; secondary outcomes included rates of specific neurologic complications. From 429 ECMO runs over 3 years, 57 ECPR patients were identified, representing an increase in ECPR utilization compared with 41 cases over the previous 6 years. Fifty-two (91%) suffered in-hospital cardiac arrest, and 36 (63%) had an initial nonshockable rhythm. Median low-flow time was 31 minutes. Overall, 26 (46%) survived hospitalization and 23 (88% of survivors, 40% overall) had a favorable discharge outcome. Factors independently associated with good neurologic outcome included lower peak lactate, initial shockable rhythm, and higher initial ECMO mean arterial pressure. Neurologic complications occurred in 18 patients (32%), including brain death in 6 (11%), hypoxic-ischemic brain injury in 11 (19%), ischemic stroke in 6 (11%), intracerebral hemorrhage in 1 (2%), and seizure in 4 (7%). We conclude that good neurologic outcomes are possible for well-selected ECPR patients in a high-volume program with increasing utilization and evolving practices. Markers of adequate peri-resuscitation tissue perfusion were associated with better outcomes, suggesting their importance in neuroprognostication.

Brain Histopathology of Adult Decedents After Extracorporeal Membrane Oxygenation.

OBJECTIVE: To test the hypothesis that brain injury is more common and varied in patients receiving extracorporeal membrane oxygenation (ECMO) than radiographically observed, we described neuropathology findings of ECMO decedents and associated clinical factors from 3 institutions. METHODS: We conducted a retrospective multicenter observational study of brain autopsies from adult ECMO recipients. Pathology findings were examined for correlation with demographics, clinical data, ECMO characteristics, and outcomes. RESULTS: Forty-three decedents (n = 13 female, median age 47 years) received autopsies after undergoing ECMO for acute respiratory distress syndrome (n = 14), cardiogenic shock (n = 14), and cardiac arrest (n = 15). Median duration of ECMO was 140 hours, most decedents (n = 40) received anticoagulants; 60% (n = 26) underwent venoarterial ECMO, and 40% (n = 17) underwent venovenous ECMO. Neuropathology was found in 35 decedents (81%), including microhemorrhages (37%), macrohemorrhages (35%), infarctions (47%), and hypoxic-ischemic brain injury (n = 17, 40%). Most pathology occurred in frontal neocortices (n = 43 occurrences), basal ganglia (n = 33), and cerebellum (n = 26). Decedents with hemorrhage were older (median age 57 vs 38 years, p = 0.01); those with hypoxic brain injury had higher Sequential Organ Failure Assessment scores (8.0 vs 2.0, p = 0.04); and those with infarction had lower peak Paco2 (53 vs 61 mm Hg, p = 0.04). Six of 9 patients with normal neuroimaging results were found to have pathology on autopsy. The majority underwent withdrawal of life-sustaining therapy (n = 32, 74%), and 2 of 8 patients with normal brain autopsy underwent withdrawal of life-sustaining therapy for suspected neurologic injury. CONCLUSION: Neuropathological findings after ECMO are common, varied, and associated with various clinical factors. Further study on underlying mechanisms is warranted and may guide ECMO management.

Breathing Life Back Into the Kidney-Continuous Renal Replacement Therapy and Veno-Venous Extracorporeal Membrane Oxygenation.

The purpose of this study was to evaluate the incidence of continuous renal replacement therapy (CRRT) in patients supported with veno-venous extracorporeal membrane oxygenation (VV ECMO). Secondary outcomes included mortality and the need for hemodialysis on hospital discharge. We performed a retrospective cohort study of all patients admitted to a specialty unit on VV ECMO between August 2014 and August 2018. Trauma and bridge to lung transplant patients were excluded. Demographics, comorbidities, pre-ECMO, ECMO, and renal replacement therapy outcome data were collected and analyzed with parametric and nonparametric statistics as appropriate. One hundred eighty-seven patients were enrolled. Median age was 45 (32, 55) years; precannulation pH, 7.21 (7.12, 7.30); PaO2/FiO2 ratio, 69 (56, 86); respiratory ECMO survival prediction score, 3 (0, 5); sequential organ failure assessment score, 12 (10, 14); and creatinine, 1.45 (0.93, 2.35) mg/dL. Overall survival to hospital discharge was 74.6%. Ninety-four (50.3%) patients had CRRT while on VV ECMO. Median time on CRRT was 14 (7, 21) days with 59 (61.4%) of these patients surviving to hospital discharge. Four (6.8%) patients, none with documented preexisting renal disease, required hemodialysis on discharge. CRRT patients had a statistically higher precannulation sequential organ failure assessment score, creatinine, total bilirubin and lower precannulation pH, respiratory ECMO survival prediction score, and platelet count compared with non-CRRT patients. Survival was 61.4% vs. 88.1% (p < 0.001). More than half of our patients received CRRT while on VV ECMO. CRRT was used in a more critically ill patient population and was associated with higher in-hospital mortality. However, for patients who survived to hospital discharge, the majority have full renal recovery.

Mortality Risk Assessment in COVID-19 Venovenous Extracorporeal Membrane Oxygenation.

BACKGROUND: A life-threatening complication of coronavirus disease 2019 (COVID-19) is acute respiratory distress syndrome (ARDS) refractory to conventional management. Venovenous (VV) extracorporeal membrane oxygenation (ECMO) (VV-ECMO) is used to support patients with ARDS in whom conventional management fails. Scoring systems to predict mortality in VV-ECMO remain unvalidated in COVID-19 ARDS. This report describes a large single-center experience with VV-ECMO in COVID-19 and assesses the utility of standard risk calculators. METHODS: A retrospective review of a prospective database of all patients with COVID-19 who underwent VV-ECMO cannulation between March 15 and June 27, 2020 at a single academic center was performed. Demographic, clinical, and ECMO characteristics were collected. The primary outcome was in-hospital mortality; survivor and nonsurvivor cohorts were compared by using univariate and bivariate analyses. RESULTS: Forty patients who had COVID-19 and underwent ECMO were identified. Of the 33 patients (82.5%) in whom ECMO had been discontinued at the time of analysis, 18 patients (54.5%) survived to hospital discharge, and 15 (45.5%) died during ECMO. Nonsurvivors presented with a statistically significant higher Prediction of Survival on ECMO Therapy (PRESET)-Score (mean ± SD, 8.33 ± 0.8 vs 6.17 ± 1.8; P = .001). The PRESET score demonstrated accurate mortality prediction. All patients with a PRESET-Score of 6 or lowers survived, and a score of 7 or higher was associated with a dramatic increase in mortality. CONCLUSIONS: These results suggest that favorable outcomes are possible in patients with COVID-19 who undergo ECMO at high-volume centers. This study demonstrated an association between the PRESET-Score and survival in patients with COVID-19 who underwent VV-ECMO. Standard risk calculators may aid in appropriate selection of patients with COVID-19 ARDS for ECMO.

Evidence of SARS-CoV-2-Specific T-Cell-Mediated Myocarditis in a MIS-A Case.

A 26-year-old otherwise healthy man died of fulminant myocarditis. Nasopharyngeal specimens collected premortem tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Histopathological evaluation of the heart showed myocardial necrosis surrounded by cytotoxic T-cells and tissue-repair macrophages. Myocardial T-cell receptor (TCR) sequencing revealed hyper-dominant clones with highly similar sequences to TCRs that are specific for SARS-CoV-2 epitopes. SARS-CoV-2 RNA was detected in the gut, supporting a diagnosis of multisystem inflammatory syndrome in adults (MIS-A). Molecular targets of MIS-associated inflammation are not known. Our data indicate that SARS-CoV-2 antigens selected high-frequency T-cell clones that mediated fatal myocarditis.