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.

Mapping the correlations between bandgap, HOMO, and LUMO trends for meta substituted Zn-MOFs.

Bandgap is a key property that determines electrical and optical properties in materials. Modulating the bandgap thus is critical in developing novel materials particularly semiconductors with improved features. This study examines the bandgap, highest occupied molecular orbital (HOMO), and lowest unoccupied molecular orbital (LUMO) energy level trends in a metal organic framework, metal-organic framework 5 (MOF-5), as a function of Hammett substituent effect (with the constant σm in the meta-position of the benzene ring) and solvent dielectric effect (with the constant ε). Specifically, experimental design and response surface methodologies helped to assess the significance of trends and correlations between these molecular properties with σm and ε. While the HOMO and LUMO decrease with increasing σm, the LUMO exhibits greater sensitivity to the substituent's electron withdrawing capability. The relative difference in these trends helps to explain why the bandgap tends to decrease with increasing σm.

Characteristics and Outcomes of Prolonged Venoarterial Extracorporeal Membrane Oxygenation After Cardiac Surgery: The Post-Cardiotomy Extracorporeal Life Support (PELS-1) Cohort Study.

OBJECTIVES: Most post-cardiotomy (PC) extracorporeal membrane oxygenation (ECMO) runs last less than 7 days. Studies on the outcomes of longer runs have provided conflicting results. This study investigates patient characteristics and short- and long-term outcomes in relation to PC ECMO duration, with a focus on prolonged (> 7 d) ECMO. DESIGN: Retrospective observational cohort study. SETTING: Thirty-four centers from 16 countries between January 2000 and December 2020. PATIENTS: Adults requiring post PC ECMO between 2000 and 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Characteristics, in-hospital, and post-discharge outcomes were compared among patients categorized by ECMO duration. Survivors and nonsurvivors were compared in the subgroup of patients with ECMO duration greater than 7 days. The primary outcome was in-hospital mortality. Two thousand twenty-one patients were included who required PC ECMO for 0-3 days ( n = 649 [32.1%]), 4-7 days ( n = 776 [38.3%]), 8-10 days ( n = 263 [13.0%]), and greater than 10 days ( n = 333 [16.5%]). There were no major differences in the investigated preoperative and procedural characteristics among ECMO duration groups. However, the longer ECMO duration category was associated with multiple complications including bleeding, acute kidney injury, arrhythmias, and sepsis. Hospital mortality followed a U-shape curve, with lowest mortality in patients with ECMO duration of 4-7 days ( n = 394, 50.8%) and highest in patients with greater than 10 days ECMO support ( n = 242, 72.7%). There was no significant difference in post-discharge survival between ECMO duration groups. In patients with ECMO duration greater than 7 days, age, comorbidities, valvular diseases, and complex procedures were associated with nonsurvival. CONCLUSIONS: Nearly 30% of PC ECMO patients were supported for greater than 7 days. In-hospital mortality increased after 7 days of support, especially in patients undergoing valvular and complex surgery, or who had complications, although the long-term post-discharge prognosis was comparable to PC ECMO patients with shorter support duration.

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.

Neurologic complications in patients receiving aortic versus subclavian versus femoral arterial cannulation for post-cardiotomy extracorporeal life support: results of the PELS observational multicenter study.

BACKGROUND: Cerebral perfusion may change depending on arterial cannulation site and may affect the incidence of neurologic adverse events in post-cardiotomy extracorporeal life support (ECLS). The current study compares patients' neurologic outcomes with three commonly used arterial cannulation strategies (aortic vs. subclavian/axillary vs. femoral artery) to evaluate if each ECLS configuration is associated with different rates of neurologic complications. METHODS: This retrospective, multicenter (34 centers), observational study included adults requiring post-cardiotomy ECLS between January 2000 and December 2020 present in the Post-Cardiotomy Extracorporeal Life Support (PELS) Study database. Patients with Aortic, Subclavian/Axillary and Femoral cannulation were compared on the incidence of a composite neurological end-point (ischemic stroke, cerebral hemorrhage, brain edema). Secondary outcomes were overall in-hospital mortality, neurologic complications as cause of in-hospital death, and post-operative minor neurologic complications (seizures). Association between cannulation and neurological outcomes were investigated through linear mixed-effects models. RESULTS: This study included 1897 patients comprising 26.5% Aortic (n = 503), 20.9% Subclavian/Axillary (n = 397) and 52.6% Femoral (n = 997) cannulations. The Subclavian/Axillary group featured a more frequent history of hypertension, smoking, diabetes, previous myocardial infarction, dialysis, peripheral artery disease and previous stroke. Neuro-monitoring was used infrequently in all groups. Major neurologic complications were more frequent in Subclavian/Axillary (Aortic: n = 79, 15.8%; Subclavian/Axillary: n = 78, 19.6%; Femoral: n = 118, 11.9%; p < 0.001) also after mixed-effects model adjustment (OR 1.53 [95% CI 1.02-2.31], p = 0.041). Seizures were more common in Subclavian/Axillary (n = 13, 3.4%) than Aortic (n = 9, 1.8%) and Femoral cannulation (n = 12, 1.3%, p = 0.036). In-hospital mortality was higher after Aortic cannulation (Aortic: n = 344, 68.4%, Subclavian/Axillary: n = 223, 56.2%, Femoral: n = 587, 58.9%, p < 0.001), as shown by Kaplan-Meier curves. Anyhow, neurologic cause of death (Aortic: n = 12, 3.9%, Subclavian/Axillary: n = 14, 6.6%, Femoral: n = 28, 5.0%, p = 0.433) was similar. CONCLUSIONS: In this analysis of the PELS Study, Subclavian/Axillary cannulation was associated with higher rates of major neurologic complications and seizures. In-hospital mortality was higher after Aortic cannulation, despite no significant differences in incidence of neurological cause of death in these patients. These results encourage vigilance for neurologic complications and neuromonitoring use in patients on ECLS, especially with Subclavian/Axillary cannulation.

Outcomes after definitive radiation therapy for localized prostate cancer in a national health care delivery system.

PURPOSE: Accurate information regarding real-world outcomes after contemporary radiation therapy for localized prostate cancer is important for shared decision-making. Clinically relevant end points at 10 years among men treated within a national health care delivery system were examined. METHODS: National administrative, cancer registry, and electronic health record data were used for patients undergoing definitive radiation therapy with or without concurrent androgen deprivation therapy within the Veterans Health Administration from 2005 to 2015. National Death Index data were used through 2019 for overall and prostate cancer-specific survival and identified date of incident metastatic prostate cancer using a validated natural language processing algorithm. Metastasis-free, prostate cancer-specific, and overall survival using Kaplan-Meier methods were estimated. RESULTS: Among 41,735 men treated with definitive radiation therapy, the median age at diagnosis was 65 years and median follow-up was 8.7 years. Most had intermediate (42%) and high-risk (33%) disease, with 40% receiving androgen deprivation therapy as part of initial therapy. Unadjusted 10-year metastasis-free survival was 96%, 92%, and 80% for low-, intermediate-, and high-risk disease. Similarly, unadjusted 10-year prostate cancer-specific survival was 98%, 97%, and 90% for low-, intermediate-, and high-risk disease. The unadjusted overall survival was lower across increasing disease risk categories at 77%, 71%, and 62% for low-, intermediate-, and high-risk disease (p < .001). CONCLUSIONS: These data provide population-based 10-year benchmarks for clinically relevant end points, including metastasis-free survival, among patients with localized prostate cancer undergoing radiation therapy using contemporary techniques. The survival rates for high-risk disease in particular suggest that outcomes have recently improved.

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.

A descriptive evaluation of causes of death in venovenous extracorporeal membrane oxygenation.

Veno-venous extracorporeal membrane oxygenation (VV ECMO) has become an important support modality for patients with acute respiratory failure refractory to optimal medical therapy, such as low tidal volume mechanical ventilator support, early paralytic infusion, and early prone positioning. The objective of this cohort study was to investigate the causes and timing of in-hospital mortality in patients on VV ECMO. All patients, excluding trauma and bridge to lung transplant, admitted 8/2014-6/2019 to a specialty ICU for VV ECMO were reviewed. Two hundred twenty-five patients were included. In-hospital mortality was 24.4% (n = 55). Most non-survivors (46/55, 84%) died prior to lung recovery and decannulation from VV ECMO. Most common cause of death (COD) for patients who died on VV ECMO was removal of life sustaining therapy (LST) in setting of multisystem organ failure (MSOF) (n = 24). Nine patients died a median of 9 days [6, 11] after decannulation. Most common COD in these patients was palliative withdrawal of LST due to poor prognosis (n = 3). Non-survivors were older and had worse predictive mortality scores than survivors. We found that death in patients supported with VV ECMO in our study most often occurs prior to decannulation and lung recovery. This study demonstrated that the most common cause of death in patients supported with VV ECMO was removal of LST due MSOF. Acute hemorrhage (systemic or intracranial) was not found to be a common cause of death in our patient population.

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.

Peripheral cannulation for extracorporeal membrane oxygenation yields superior neurologic outcomes in adult patients who experienced cardiac arrest following cardiac surgery.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) for refractory cardiac arrest has improved mortality in post-cardiac surgery patients; however, loss of neurologic function remains one of the main and devastating complications. We reviewed our experience with ECPR and investigated the effect of cannulation strategy on neurologic outcome in adult patients who experienced cardiac arrest following cardiac surgery that was managed with ECPR. METHODS: Patients were categorized by central versus percutaneous peripheral VA-extracorporeal membrane oxygenation (ECMO) cannulation strategy. We reviewed patient records and evaluated in-hospital mortality, cause of death, and neurologic status 72 hours after cannulation. RESULTS: From January 2010 to September 2019, 44 patients underwent post-cardiac surgery ECPR for cardiac arrest. Twenty-six patients received central cannulation; 18 patients received peripheral cannulation. Mean post-operative day of the cardiac arrest was 3 and 9 days (p = 0.006), and mean time between initiation of CPR and ECMO was 40 ± 24 and 28 ± 22 minutes for central and peripheral cannulation, respectively. After 72 hours of VA-ECMO support, 30% of centrally cannulated patients versus 72% of peripherally cannulated patients attained cerebral performance status 1-2 (p = 0.01). Anoxic brain injury was the cause of death in 26.9% of centrally cannulated and 11.1% of peripherally cannulated patients. Survival to discharge was 31% and 39% for central and peripheral cannulation, respectively. CONCLUSIONS: Peripheral VA-ECMO allows for continuous CPR and systemic perfusion while obtaining vascular access. Compared to central cannulation, a peripheral cannulation strategy is associated with improved neurologic outcomes and decreased likelihood of anoxic brain death.

Neurological complications during veno-venous extracorporeal membrane oxygenation: Does the configuration matter? A retrospective analysis of the ELSO database.

BACKGROUND: Single- (SL) and double-lumen (DL) catheters are used in clinical practice for veno-venous extracorporeal membrane oxygenation (V-V ECMO) therapy. However, information is lacking regarding the effects of the cannulation on neurological complications. METHODS: A retrospective observational study based on data from the Extracorporeal Life Support Organization (ELSO) registry. All adult patients included in the ELSO registry from 2011 to 2018 submitted to a single run of V-V ECMO were analyzed. Propensity score (PS) inverse probability of treatment weighting estimation for multiple treatments was used. The average treatment effect (ATE) was chosen as the causal effect estimate of outcome. The aim of the study was to evaluate differences in the occurrence and the type of neurological complications in adult patients undergoing V-V ECMO when treated with SL or DL cannulas. RESULTS: From a population of 6834 patients, the weighted propensity score matching included 6245 patients (i.e., 91% of the total cohort; 4175 with SL and 20,270 with DL cannulation). The proportion of patients with at least one neurological complication was similar in the SL (306, 7.2%) and DL (189, 7.7%; odds ratio 1.10 [95% confidence intervals 0.91-1.32]; p = 0.33). After weighted propensity score, the ATE for the occurrence of least one neurological complication was 0.005 (95% CI - 0.009 to 0.018; p = 0.50). Also, the occurrence of specific neurological complications, including intracerebral hemorrhage, acute ischemic stroke, seizures or brain death, was similar between groups. Overall mortality was similar between patients with neurological complications in the two groups. CONCLUSIONS: In this large registry, the occurrence of neurological complications was not related to the type of cannulation in patients undergoing V-V ECMO.

Clinical Outcomes of Pregnant and Postpartum Extracorporeal Membrane Oxygenation Patients.

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) as a rescue therapy for cardiopulmonary failure is expanding in critical care medicine. In this case series, we describe the clinical outcomes of 21 consecutive pregnant or postpartum patients that required venovenous (VV) or venoarterial (VA) ECMO. Our objective was to characterize maternal and fetal survival in peripartum ECMO and better understand ECMO-related complications that occur in this unique patient population. METHODS: Between January 2009 and June 2019, all pregnant and postpartum patients treated with ECMO for respiratory or circulatory failure at a single quaternary referral center were identified. For all patients, indications for ECMO, maternal and neonatal outcomes, details of ECMO support, and anticoagulation and bleeding complications were collected. RESULTS: Twenty-one obstetric patients were treated with ECMO over 10 years. Thirteen patients were treated with VV ECMO and 8 patients were treated with VA ECMO. Six patients were pregnant at the time of cannulation and 3 patients delivered while on ECMO; all 6 maternal and infant dyads survived to hospital discharge. The median gestational age at cannulation was 28 weeks (interquartile range [IQR], 24-31). In the postpartum cohort, ECMO initiation ranged from immediately after delivery up to 46 days postpartum. Fifteen women survived (72%). Major bleeding complications requiring surgical intervention were observed in 7 patients (33.3%). Two patients on VV ECMO required bilateral orthotopic lung transplantation and 1 patient on VA ECMO required orthotopic heart transplantation to wean from ECMO. CONCLUSIONS: Survival for mother and neonate are excellent with peripartum ECMO in a high-volume ECMO center. Neonatal and maternal survival was 100% when ECMO was used in the late second or early third trimester. Based on these results, ECMO remains an important treatment option for peripartum patients with cardiopulmonary failure.

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.

Von Willebrand Factor Concentrate Administration for Acquired Von Willebrand Syndrome- Related Bleeding During Adult Extracorporeal Membrane Oxygenation.

OBJECTIVE: To review the use of Von Willebrand Factor (VWF) concentrate for treatment of acquired Von Willebrand syndrome (VWS)-related bleeding in adult extracorporeal membrane oxygenation (ECMO) patients and determine if it was associated with improved VWF laboratory parameters. DESIGN: Retrospective observational cohort study. SETTING: Tertiary care academic medical center. PARTICIPANTS: Adult ECMO patients who received VWF concentrate for treatment of acquired VWS- related bleeding. INTERVENTIONS: None, observational study. MEASUREMENTS AND MAIN RESULTS: Ten adult ECMO patients received VWF concentrate for treatment of bleeding with evidence of acquired VWS over a 15-month period. Six patients were on veno-arterial ECMO and 4 were on veno-venous ECMO. The most common site of bleeding was airway or tracheal bleeding. The mean dose of VWF concentrate was 41 IU/kg. Mean VWF antigen was 263 ± 93 IU/dL before treatment and 394 ± 54 after treatment. Mean ristocetin cofactor activity was 127 ± 47 IU/dL before treatment and 240 ± 33 after treatment. The mean VWF ristocetin cofactor activity antigen ratio increased from 0.52 ± 0.14 before treatment to 0.62 ± 0.04 after treatment. Four of 10 patients had complete resolution of their bleeding within 24 hours, and 6 of 10 had complete resolution of their bleeding within 2- to- 4 days. There were 3 patients who had thrombotic events potentially related to VWF concentrate administration. No patient had an arterial thrombosis, stroke, or myocardial infarction. CONCLUSIONS: VWF concentrate administration increases VWF function in adult ECMO patients, but also may be associated with increased thrombotic risk. Larger studies are needed to determine VWF concentrate's safety, efficacy, and optimal dosing in adult ECMO 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.

Platelet factor-4 concentration in adult veno-arterial ECMO patients.

BACKGROUND: Heparin induced thrombocytopenia (HIT) is reported at a variable rate in extracorporeal membrane oxygenation (ECMO) patients. A critical factor impacting platelet factor-4 (PF4)-heparin antibody formation is plasma PF4 concentration. We hypothesized that PF4 concentration would be increased during veno-arterial (VA) ECMO. METHODS: Plasma PF4 concentration was measured during the first 5 ECMO days in 20 VA ECMO patients and 10 control plasma samples. PF4-heparin ratios were estimated using an assumed heparin concentration of 0.4 IU/mL. This correlates with an activated partial thromboplastin time of 60 to 80 seconds, which is the anticoagulation target in our center. RESULTS: Twenty VA ECMO patients were enrolled, 10 of which had pulmonary embolism. Median PF4 concentration was 0.03 µg/mL [0.01, 0.13] in control plasma. Median PF4 concentration was 0.21 µg/mL [0.12, 0.34] on ECMO day 1 or 2, 0.16 µg/mL [0.09, 0.25] on ECMO day 3, and 0.12 µg/mL [0.09, 0.22] on ECMO day 5. Estimated median PF4-heparin ratios were 0.04, 0.03, and 0.02 respectively. Two patients (10%) developed HIT that was confirmed by serotonin release assay. PF4 concentration did not differ significantly in these patients compared to non-HIT patients (p = 0.37). No patient had an estimated PF4-heparin ratio between 0.7 and 1.4, which is the reported optimal range for PF4-heparin antibody formation. CONCLUSION: Our data suggest that PF4 concentration is mildly elevated during VA ECMO compared to control plasma. Estimated PF4-heparin ratios were not optimal for HIT antibody formation. These data support epidemiologic studies where HIT incidence is low during VA ECMO.

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.

Mechanical Ventilation Management during Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome. An International Multicenter Prospective Cohort.

Rationale: Current practices regarding mechanical ventilation in patients treated with extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome are unknown.Objectives: To report current practices regarding mechanical ventilation in patients treated with ECMO for severe acute respiratory distress syndrome (ARDS) and their association with 6-month outcomes.Methods: This was an international, multicenter, prospective cohort study of patients undergoing ECMO for ARDS during a 1-year period in 23 international ICUs.Measurements and Main Results: We collected demographics, daily pre- and per-ECMO mechanical ventilation settings and use of adjunctive therapies, ICU, and 6-month outcome data for 350 patients (mean ± SD pre-ECMO PaO2/FiO2 71 ± 34 mm Hg). Pre-ECMO use of prone positioning and neuromuscular blockers were 26% and 62%, respectively. Vt (6.4 ± 2.0 vs. 3.7 ± 2.0 ml/kg), plateau pressure (32 ± 7 vs. 24 ± 7 cm H2O), driving pressure (20 ± 7 vs. 14 ± 4 cm H2O), respiratory rate (26 ± 8 vs. 14 ± 6 breaths/min), and mechanical power (26.1 ± 12.7 vs. 6.6 ± 4.8 J/min) were markedly reduced after ECMO initiation. Six-month survival was 61%. No association was found between ventilator settings during the first 2 days of ECMO and survival in multivariable analysis. A time-varying Cox model retained older age, higher fluid balance, higher lactate, and more need for renal-replacement therapy along the ECMO course as being independently associated with 6-month mortality. A higher Vt and lower driving pressure (likely markers of static compliance improvement) across the ECMO course were also associated with better outcomes.Conclusions: Ultraprotective lung ventilation on ECMO was largely adopted across medium- to high-case volume ECMO centers. In contrast with previous observations, mechanical ventilation settings during ECMO did not impact patients' prognosis in this context.

Characterization of Postoperative Infection Risk in Cardiac Surgery Patients With Delayed Sternal Closure.

OBJECTIVES: To compare the incidence of postoperative infection in cardiac surgery patients who had delayed sternal closure (DSC) with those who had primary sternal closure (PSC) and evaluate the effectiveness of antibiotic prophylaxis in DSC patients. DESIGN: Retrospective, observational cohort study with propensity score matching. SETTING: Single academic medical center. PARTICIPANTS: Cardiothoracic surgery patients, excluding transplantation patients, from a single academic medical center who had DSC or PSC between November 2015 and November 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 2,685 patients who had cardiac surgery with cardiopulmonary bypass, 99 had DSC. Fifty-nine DSC patients met study inclusion criteria, and the final propensity score matched cohort included 57 patients with DSC and 57 patients with PSC. Propensity score matching reduced bias but was unable to balance all covariates. The most common indication for DSC was coagulopathy in 32 of the 57 patients. All patients in the PSC group received routine antibiotic prophylaxis for 48 hours after surgery. Patients in the DSC group received prolonged broadened prophylaxis until 48 hours after sternal closure. Despite prolonged broadened antibiotic prophylaxis, the DSC group had a higher rate of postoperative infection (31.6% v 3.5%; p < 0.005), mainly pneumonia (19.3% v 1.8%; p < 0.005), in the first 30 days after surgery. There was no difference in the incidence of sepsis (5.3% v 0%; p = 0.24), superficial skin and soft tissue infection (1.8% v 1.8%; p = 1), or mediastinitis/deep tissue infection (5.3% v 0%; p = 0.24) in patients with DSC. Seventy-seven percent of causative organisms for infection were Gram-negative bacteria in the matched cohort. CONCLUSION: The incidence of postoperative infection, particularly pneumonia, is high in cardiothoracic surgery patients with DSC, even with prolonged broadened antibiotic prophylaxis, but the rate of mediastinitis/deep tissue infection did not appear to be greater with DSC. Additional research is needed into optimal antibiotic prophylaxis in this high-risk group of patients.