VEGF-A plasma levels are associated with impaired DLCO and radiological sequelae in long COVID patients.

BACKGROUND: Long COVID, also known as post-acute sequelae of COVID-19 (PASC), is characterized by persistent clinical symptoms following COVID-19. OBJECTIVE: To correlate biomarkers of endothelial dysfunction with persistent clinical symptoms and pulmonary function defects at distance from COVID-19. METHODS: Consecutive patients with long COVID-19 suspicion were enrolled. A panel of endothelial biomarkers was measured in each patient during clinical evaluation and pulmonary function test (PFT). RESULTS: The study included 137 PASC patients, mostly male (68%), with a median age of 55 years. A total of 194 PFTs were performed between months 3 and 24 after an episode of SARS-CoV-2 infection. We compared biomarkers evaluated in PASC patients with 20 healthy volunteers (HVs) and acute hospitalized COVID-19 patients (n = 88). The study found that angiogenesis-related biomarkers and von Willebrand factor (VWF) levels were increased in PASC patients compared to HVs without increased inflammatory or platelet activation markers. Moreover, VEGF-A and VWF were associated with persistent lung CT scan lesions and impaired diffusing capacity of the lungs for carbon monoxide (DLCO) measurement. By employing a Cox proportional hazards model adjusted for age, sex, and body mass index, we further confirmed the accuracy of VEGF-A and VWF. Following adjustment, VEGF-A emerged as the most significant predictive factor associated with persistent lung CT scan lesions and impaired DLCO measurement. CONCLUSION: VEGF-A is a relevant predictive factor for DLCO impairment and radiological sequelae in PASC. Beyond being a biomarker, we hypothesize that the persistence of angiogenic disorders may contribute to long COVID symptoms.

Perceived Quality of Life in Intensive Care Medicine Physicians: A French National Survey.

Purpose: There is a growing interest in the quality of work life (QWL) of healthcare professionals and staff well-being. We decided to measure the perceived QWL of ICU physicians and the factors that could influence their perception. Methods: We performed a survey coordinated and executed by the French Trade Union of Intensive Care Physicians (SMR). QWL was assessed using the French version of the Work-Related Quality of Life (WRQoL) scale, perceived stress using the French version of 10 item-Perceived Stress Scale (PSS-10) and group functioning using the French version of the Reflexivity Scale, the Social Support at Work Questionnaire (QSSP-P). Results: 308 French-speaking ICU physicians participated. 40% perceived low WRQoL, mainly due to low general well-being, low satisfaction with working conditions and low possibility of managing the articulation between their private and professional lives. Decreased QWL was associated with being a woman (p = .002), having children (p = .022) and enduring many monthly shifts (p = .022). Conclusions: This work highlights the fact that ICU physicians feel a significant imbalance between the demands of their profession and the resources at their disposal. Communication and exchanges within a team and quality of social support appear to be positive elements to maintain and/or develop within our structures.

Increased levels of GM-CSF and CXCL10 and low CD8+ memory stem T Cell count are markers of immunosenescence and severe COVID-19 in older people.

BACKGROUND: Ageing leads to altered immune responses, resulting in higher susceptibility to certain infections in the elderly. Immune ageing is a heterogeneous process also associated with inflammaging, a low-grade chronic inflammation. Altered cytotoxic T cell responses and cytokine storm have previously been described in severe COVID-19 cases, however the parameters responsible for such immune response failures are not well known. The aim of our study was to characterize CD8+ T cells and cytokines associated with ageing, in a cohort of patients aged over 70 years stratified by COVID-19 severity. RESULTS: One hundred and four patients were included in the study. We found that, in older people, COVID-19 severity was associated with (i) higher level of GM-CSF, CXCL10 (IP-10), VEGF, IL-1ß, CCL2 (MCP-1) and the neutrophil to lymphocyte ratio (NLR), (ii) increased terminally differentiated CD8+T cells, and (ii) decreased early precursors CD8+ T stem cell-like memory cells (TSCM) and CD27+CD28+. The cytokines mentioned above were found at higher concentrations in the COVID-19+ older cohort compared to a younger cohort in which they were not associated with disease severity. CONCLUSIONS: Our results highlight the particular importance of the myeloid lineage in COVID-19 severity among older people. As GM-CSF and CXCL10 were not associated with COVID-19 severity in younger patients, they may represent disease severity specific markers of ageing and should be considered in older people care.

One-Year Outcomes in Patients With Acute Stroke Requiring Mechanical Ventilation.

BACKGROUND: Long-term outcomes of patients with severe stroke remain poorly documented. We aimed to characterize one-year outcomes of patients with stroke requiring mechanical ventilation in the intensive care unit (ICU). METHODS: We conducted a prospective multicenter cohort study in 33 ICUs in France (2017-2019) on patients with consecutive strokes requiring mechanical ventilation for at least 24 hours. Outcomes were collected via telephone interviews by an independent research assistant. The primary end point was poor functional outcome, defined by a modified Rankin Scale score of 4 to 6 at 1 year. Multivariable mixed models investigated variables associated with the primary end point. Secondary end points included quality of life, activities of daily living, and anxiety and depression in 1-year survivors. RESULTS: Among the 364 patients included, 244 patients (66.5% [95% CI, 61.7%-71.3%]) had a poor functional outcome, including 190 deaths (52.2%). After adjustment for non-neurological organ failure, age ≥70 years (odds ratio [OR], 2.38 [95% CI, 1.26-4.49]), Charlson comorbidity index ≥2 (OR, 2.01 [95% CI, 1.16-3.49]), a score on the Glasgow Coma Scale <8 at ICU admission (OR, 3.43 [95% CI, 1.98-5.96]), stroke subtype (intracerebral hemorrhage: OR, 2.44 [95% CI, 1.29-4.63] versus ischemic stroke: OR, 2.06 [95% CI, 1.06-4.00] versus subarachnoid hemorrhage: reference) remained independently associated with poor functional outcome. In contrast, a time between stroke diagnosis and initiation of mechanical ventilation >1 day was protective (OR, 0.56 [95% CI, 0.33-0.94]). A sensitivity analysis conducted after exclusion of patients with early decisions of withholding/withdrawal of care yielded similar results. We observed persistent physical and psychological problems at 1 year in >50% of survivors. CONCLUSIONS: In patients with severe stroke requiring mechanical ventilation, several ICU admission variables may inform caregivers, patients, and their families on post-ICU trajectories and functional outcomes. The burden of persistent sequelae at 1 year reinforces the need for a personalized, multi-disciplinary, prolonged follow-up of these patients after ICU discharge. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03335995.

Cumulative dose of epinephrine and mode of death after non-shockable out-of-hospital cardiac arrest: a registry-based study.

BACKGROUND: Epinephrine increases the chances of return of spontaneous circulation (ROSC) in out-of-hospital cardiac arrest (OHCA), especially when the initial rhythm is non-shockable. However, this drug could also worsen the post-resuscitation syndrome (PRS). We assessed the association between epinephrine use during cardiopulmonary resuscitation (CPR) and subsequent intensive care unit (ICU) mortality in patients with ROSC after non-shockable OHCA. METHODS: We used data prospectively collected in the Sudden Death Expertise Center (SDEC) registry (capturing OHCA data located in the Greater Paris area, France) between May 2011 and December 2021. All adults with ROSC after medical, cardiac and non-cardiac causes, non-shockable OHCA admitted to an ICU were included. The mode of death in the ICU was categorized as cardiocirculatory, neurological, or other. RESULTS: Of the 2,792 patients analyzed, there were 242 (8.7%) survivors at hospital discharge, 1,004 (35.9%) deaths from cardiocirculatory causes, 1,233 (44.2%) deaths from neurological causes, and 313 (11.2%) deaths from other etiologies. The cardiocirculatory death group received more epinephrine (4.6 ± 3.8 mg versus 1.7 ± 2.8 mg, 3.2 ± 2.6 mg, and 3.5 ± 3.6 mg for survivors, neurological deaths, and other deaths, respectively; p < 0.001). The proportion of cardiocirculatory death increased linearly (R2 = 0.92, p < 0.001) with cumulative epinephrine doses during CPR (17.7% in subjects who did not receive epinephrine and 62.5% in those who received > 10 mg). In multivariable analysis, a cumulative dose of epinephrine was strongly associated with cardiocirculatory death (adjusted odds ratio of 3.45, 95% CI [2.01-5.92] for 1 mg of epinephrine; 12.28, 95% CI [7.52-20.06] for 2-5 mg; and 23.71, 95% CI [11.02-50.97] for > 5 mg; reference 0 mg; population reference: alive at hospital discharge), even after adjustment on duration of resuscitation. The other modes of death (neurological and other causes) were also associated with epinephrine use, but to a lesser extent. CONCLUSIONS: In non-shockable OHCA with ROSC, the dose of epinephrine used during CPR is strongly associated with early cardiocirculatory death. Further clinical studies aimed at limiting the dose of epinephrine during CPR seem warranted. Moreover, strategies for the prevention and management of PRS should take this dose of epinephrine into consideration for future trials.

Enteral citrulline supplementation versus placebo on SOFA score on day 7 in mechanically ventilated critically ill patients: the IMMUNOCITRE randomized clinical trial.

BACKGROUND: Restoring plasma arginine levels through enteral administration of L-citrulline in critically ill patients may improve outcomes. We aimed to evaluate whether enteral L-citrulline administration reduced organ dysfunction based on the Sequential Organ Failure Assessment (SOFA) score and affected selected immune parameters in mechanically ventilated medical intensive care unit (ICU) patients. METHODS: A randomized, double-blind, multicenter clinical trial of enteral administration of L-citrulline versus placebo for critically ill adult patients under invasive mechanical ventilation without sepsis or septic shock was conducted in four ICUs in France between September 2016 and February 2019. Patients were randomly assigned to receive enteral L-citrulline (5 g) every 12 h for 5 days or isonitrogenous, isocaloric placebo. The primary outcome was the SOFA score on day 7. Secondary outcomes included SOFA score improvement (defined as a decrease in total SOFA score by 2 points or more between day 1 and day 7), secondary infection acquisition, ICU length of stay, plasma amino acid levels, and immune biomarkers on day 3 and day 7 (HLA-DR expression on monocytes and interleukin-6). RESULTS: Of 120 randomized patients (mean age, 60 ± 17 years; 44 [36.7%] women; ICU stay 10 days [IQR, 7-16]; incidence of secondary infections 25 patients (20.8%)), 60 were allocated to L-citrulline and 60 were allocated to placebo. Overall, there was no significant difference in organ dysfunction as assessed by the SOFA score on day 7 after enrollment (4 [IQR, 2-6] in the L-citrulline group vs. 4 [IQR, 2-7] in the placebo group; Mann‒Whitney U test, p = 0.9). Plasma arginine was significantly increased on day 3 in the treatment group, while immune parameters remained unaffected. CONCLUSION: Among mechanically ventilated ICU patients without sepsis or septic shock, enteral L-citrulline administration did not result in a significant difference in SOFA score on day 7 compared to placebo. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02864017 (date of registration: 11 August 2016).

Circulating Ubiquitous RNA, A Highly Predictive and Prognostic Biomarker in Hospitalized Coronavirus Disease 2019 (COVID-19) Patients.

BACKGROUND: Approximately 15-30% of hospitalized coronavirus disease 2019 (COVID-19) patients develop acute respiratory distress syndrome, systemic tissue injury, and/or multi-organ failure leading to death in around 45% of cases. There is a clear need for biomarkers that quantify tissue injury, predict clinical outcomes, and guide the clinical management of hospitalized COVID-19 patients. METHODS: We herein report the quantification by droplet-based digital polymerase chain reaction (ddPCR) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNAemia and the plasmatic release of a ubiquitous human intracellular marker, the ribonuclease P (RNase P) in order to evaluate tissue injury and cell lysis in the plasma of 139 COVID-19 hospitalized patients at admission. RESULTS: We confirmed that SARS-CoV-2 RNAemia was associated with clinical severity of COVID-19 patients. In addition, we showed that plasmatic RNase P RNAemia at admission was also highly correlated with disease severity (P < .001) and invasive mechanical ventilation status (P < .001) but not with pulmonary severity. Altogether, these results indicate a consequent cell lysis process in severe and critical patients but not systematically due to lung cell death. Finally, the plasmatic RNase P RNA value was also significantly associated with overall survival. CONCLUSIONS: Viral and ubiquitous blood biomarkers monitored by ddPCR could be useful for the clinical monitoring and the management of hospitalized COVID-19 patients. Moreover, these results could pave the way for new and more personalized circulating biomarkers in COVID-19, and more generally in infectious diseases, specific from each patient organ injury profile.

Prevention of Early Ventilator-Associated Pneumonia after Cardiac Arrest.

BACKGROUND: Patients who are treated with targeted temperature management after out-of-hospital cardiac arrest with shockable rhythm are at increased risk for ventilator-associated pneumonia. The benefit of preventive short-term antibiotic therapy has not been shown. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving adult patients (>18 years of age) in intensive care units (ICUs) who were being mechanically ventilated after out-of-hospital cardiac arrest related to initial shockable rhythm and treated with targeted temperature management at 32 to 34°C. Patients with ongoing antibiotic therapy, chronic colonization with multidrug-resistant bacteria, or moribund status were excluded. Either intravenous amoxicillin-clavulanate (at doses of 1 g and 200 mg, respectively) or placebo was administered three times a day for 2 days, starting less than 6 hours after the cardiac arrest. The primary outcome was early ventilator-associated pneumonia (during the first 7 days of hospitalization). An independent adjudication committee determined diagnoses of ventilator-associated pneumonia. RESULTS: A total of 198 patients underwent randomization, and 194 were included in the analysis. After adjudication, 60 cases of ventilator-associated pneumonia were confirmed, including 51 of early ventilator-associated pneumonia. The incidence of early ventilator-associated pneumonia was lower with antibiotic prophylaxis than with placebo (19 patients [19%] vs. 32 [34%]; hazard ratio, 0.53; 95% confidence interval, 0.31 to 0.92; P = 0.03). No significant differences between the antibiotic group and the control group were observed with respect to the incidence of late ventilator-associated pneumonia (4% and 5%, respectively), the number of ventilator-free days (21 days and 19 days), ICU length of stay (5 days and 8 days if patients were discharged and 7 days and 7 days if patients had died), and mortality at day 28 (41% and 37%). At day 7, no increase in resistant bacteria was identified. Serious adverse events did not differ significantly between the two groups. CONCLUSIONS: A 2-day course of antibiotic therapy with amoxicillin-clavulanate in patients receiving a 32-to-34°C targeted temperature management strategy after out-of-hospital cardiac arrest with initial shockable rhythm resulted in a lower incidence of early ventilator-associated pneumonia than placebo. No significant between-group differences were observed for other key clinical variables, such as ventilator-free days and mortality at day 28. (Funded by the French Ministry of Health; ANTHARTIC ClinicalTrials.gov number, NCT02186951.).

Early Clinical and Electrophysiological Brain Dysfunction Is Associated With ICU Outcomes in COVID-19 Critically Ill Patients With Acute Respiratory Distress Syndrome: A Prospective Bicentric Observational Study.

OBJECTIVES: Describe the prevalence of acute cerebral dysfunction and assess the prognostic value of an early clinical and electroencephalography (EEG) assessment in ICU COVID-19 patients. DESIGN: Prospective observational study. SETTING: Two tertiary critical care units in Paris, France, between April and December 2020. PATIENTS: Adult critically ill patients with COVID-19 acute respiratory distress syndrome. INTERVENTIONS: Neurologic examination and EEG at two time points during the ICU stay, first under sedation and second 4-7 days after sedation discontinuation. MEASUREMENTS AND MAIN RESULTS: Association of EEG abnormalities (background reactivity, continuity, dominant frequency, and presence of paroxystic discharges) with day-28 mortality and neurologic outcomes (coma and delirium recovery). Fifty-two patients were included, mostly male (81%), median (interquartile range) age 68 years (56-74 yr). Delayed awakening was present in 68% of patients (median awakening time of 5 d [2-16 d]) and delirium in 74% of patients who awoke from coma (62% of mixed delirium, median duration of 5 d [3-8 d]). First, EEG background was slowed in the theta-delta range in 48 (93%) patients, discontinuous in 25 patients (48%), and nonreactive in 17 patients (33%). Bifrontal slow waves were observed in 17 patients (33%). Early nonreactive EEG was associated with lower day-28 ventilator-free days (0 vs 16; p = 0.025), coma-free days (6 vs 22; p = 0.006), delirium-free days (0 vs 17; p = 0.006), and higher mortality (41% vs 11%; p = 0.027), whereas discontinuous background was associated with lower ventilator-free days (0 vs 17; p = 0.010), coma-free days (1 vs 22; p < 0.001), delirium-free days (0 vs 17; p = 0.001), and higher mortality (40% vs 4%; p = 0.001), independently of sedation and analgesia. CONCLUSIONS: Clinical and neurophysiologic cerebral dysfunction is frequent in COVID-19 ARDS patients. Early severe EEG abnormalities with nonreactive and/or discontinuous background activity are associated with delayed awakening, delirium, and day-28 mortality.

Treatment of COVID-19-associated ARDS with mesenchymal stromal cells: a multicenter randomized double-blind trial.

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced acute respiratory distress syndrome (ARDS) causes high mortality. Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) have potentially relevant immune-modulatory properties, whose place in ARDS treatment is not established. This phase 2b trial was undertaken to assess the efficacy of UC-MSCs in patients with SARS-CoV-2-induced ARDS. METHODS: This multicentre, double-blind, randomized, placebo-controlled trial (STROMA-CoV-2) recruited adults (≥ 18 years) with SARS-CoV-2-induced early (< 96 h) mild-to-severe ARDS in 10 French centres. Patients were randomly assigned to receive three intravenous infusions of 106 UC-MSCs/kg or placebo (0.9% NaCl) over 5 days after recruitment. For the modified intention-to-treat population, the primary endpoint was the partial pressure of oxygen to fractional inspired oxygen (PaO2/FiO2)-ratio change between baseline (day (D) 0) and D7. RESULTS: Among the 107 patients screened for eligibility from April 6, 2020, to October 29, 2020, 45 were enrolled, randomized and analyzed. PaO2/FiO2 changes between D0 and D7 did not differ significantly between the UC-MSCs and placebo groups (medians [IQR] 54.3 [- 15.5 to 93.3] vs 25.3 [- 33.3 to 104.6], respectively; ANCOVA estimated treatment effect 7.4, 95% CI - 44.7 to 59.7; P = 0.77). Six (28.6%) of the 21 UC-MSCs recipients and six of 24 (25%) placebo-group patients experienced serious adverse events, none of which were related to UC-MSCs treatment. CONCLUSIONS: D0-to-D7 PaO2/FiO2 changes for intravenous UC-MSCs-versus placebo-treated adults with SARS-CoV-2-induced ARDS did not differ significantly. Repeated UC-MSCs infusions were not associated with any serious adverse events during treatment or thereafter (until D28). Larger trials enrolling patients earlier during the course of their ARDS are needed to further assess UC-MSCs efficacy in this context. TRIAL REGISTRATION: NCT04333368. Registered 01 April 2020, https://clinicaltrials.gov/ct2/history/NCT04333368 .

Von Willebrand factor collagen-binding capacity predicts in-hospital mortality in COVID-19 patients: insight from VWF/ADAMTS13 ratio imbalance.

BACKGROUND: Microthrombosis is a hallmark of COVID-19. We previously described von willebrand factor (VWF) and their high molecular weight multimers (HMWMs) as potential trigger of microthrombosis. OBJECTIVES: Investigate VWF activity with collagen-binding assay and ADAMTS13 in COVID-19. METHODS AND RESULTS: Our study enrolled 77 hospitalized COVID-19 patients including 37 suffering from a non-critical form and 40 with critical form. Plasma levels of VWF collagen-binding ability (VWF:CB) and ADAMTS13 activity (ADAMTS13:Act) were measured in the first 48 hours following admission. VWF:CB was increased in critical (631% IQR [460-704]) patients compared to non-critical patients (259% [235-330], p < 0.005). VWF:CB was significantly associated (r = 0.564, p < 0.001) with HMWMs. Moreover, median ADAMTS13:Act was lower in critical (64.8 IU/dL IQR 50.0-77.7) than non-critical patients (85.0 IU/dL IQR 75.8-94.7, p < 0.001), even if no patients displayed majors deficits. VWF:Ag-to-ADAMTS13:Act ratio was highly associated with VWF:CB (r = 0.916, p < 0.001). Moreover, VWF:CB level was highly predictive of COVID-19 in-hospital mortality as shown by the ROC curve analysis (AUC = 0.92, p < 0.0001) in which we identified a VWF:CB cut-off of 446% as providing the best predictor sensitivity-specificity balance. We confirmed this cut-off thanks to a Kaplan-Meier estimator analysis (log-rank p < 0.001) and a Cox-proportional Hazard model (HR = 49.1, 95% CI 1.81-1328.2, p = 0.021) adjusted on, BMI, C-reactive protein, and D-dimer levels. CONCLUSION: VWF:CB levels could summarize both VWF increased levels and hyper-reactivity subsequent to ADAMTS13 overflow and, therefore, be a valuable and easy to perform clinical biomarker of microthrombosis and COVID-19 severity.

COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is presenting as a systemic disease associated with vascular inflammation and endothelial injury. Severe forms of SARS-CoV-2 infection induce acute respiratory distress syndrome (ARDS) and there is still an ongoing debate on whether COVID-19 ARDS and its perfusion defect differs from ARDS induced by other causes. Beside pro-inflammatory cytokines (such as interleukin-1 ß [IL-1ß] or IL-6), several main pathological phenomena have been seen because of endothelial cell (EC) dysfunction: hypercoagulation reflected by fibrin degradation products called D-dimers, micro- and macrothrombosis and pathological angiogenesis. Direct endothelial infection by SARS-CoV-2 is not likely to occur and ACE-2 expression by EC is a matter of debate. Indeed, endothelial damage reported in severely ill patients with COVID-19 could be more likely secondary to infection of neighboring cells and/or a consequence of inflammation. Endotheliopathy could give rise to hypercoagulation by alteration in the levels of different factors such as von Willebrand factor. Other than thrombotic events, pathological angiogenesis is among the recent findings. Overexpression of different proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) or placental growth factors (PlGF) have been found in plasma or lung biopsies of COVID-19 patients. Finally, SARS-CoV-2 infection induces an emergency myelopoiesis associated to deregulated immunity and mobilization of endothelial progenitor cells, leading to features of acquired hematological malignancies or cardiovascular disease, which are discussed in this review. Altogether, this review will try to elucidate the pathophysiology of thrombotic complications, pathological angiogenesis and EC dysfunction, allowing better insight in new targets and antithrombotic protocols to better address vascular system dysfunction. Since treating SARS-CoV-2 infection and its potential long-term effects involves targeting the vascular compartment and/or mobilization of immature immune cells, we propose to define COVID-19 and its complications as a systemic vascular acquired hemopathy.

Circulating Von Willebrand factor and high molecular weight multimers as markers of endothelial injury predict COVID-19 in-hospital mortality.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a respiratory disease associated with endotheliitis and microthrombosis. OBJECTIVES: To correlate endothelial dysfunction to in-hospital mortality in a bi-centric cohort of COVID-19 adult patients. METHODS: Consecutive ambulatory and hospitalized patients with laboratory-confirmed COVID-19 were enrolled. A panel of endothelial biomarkers and von Willebrand factor (VWF) multimers were measured in each patient ≤ 48 h following admission. RESULTS: Study enrolled 208 COVID-19 patients of whom 23 were mild outpatients and 189 patients hospitalized after admission. Most of endothelial biomarkers tested were found increased in the 89 critical patients transferred to intensive care unit. However, only von Willebrand factor antigen (VWF:Ag) scaled according to clinical severity, with levels significantly higher in critical patients (median 507%, IQR 428-596) compared to non-critical patients (288%, 230-350, p < 0.0001) or COVID-19 outpatients (144%, 133-198, p = 0.007). Moreover, VWF high molecular weight multimers (HMWM) were significantly higher in critical patients (median ratio 1.18, IQR 0.86-1.09) compared to non-critical patients (0.96, 1.04-1.39, p < 0.001). Among all endothelial biomarkers measured, ROC curve analysis identified a VWF:Ag cut-off of 423% as the best predictor for in-hospital mortality. The accuracy of VWF:Ag was further confirmed in a Kaplan-Meier estimator analysis and a Cox proportional Hazard model adjusted on age, BMI, C-reactive protein and D-dimer levels. CONCLUSION: VWF:Ag is a relevant predictive factor for in-hospital mortality in COVID-19 patients. More than a biomarker, we hypothesize that VWF, including excess of HMWM forms, drives microthrombosis in COVID-19.

Epidemiology and Predictors of Long-Stays in Medical ICU: A Retrospective Cohort Study.

INTRODUCTION: Prolonged stays in ICU have been associated with overconsumption of resources but little is known about their epidemiology. We aimed to identify predictors and prognostic factors of extended stays, studying a long-stay population. METHODS: We present a retrospective cohort study between July 2000 and December 2013 comparing patients hospitalized in a medical ICU for ≥30 days (long-stay patients-LSP) with patients hospitalized for <30 days (short-stay patients-SSP). Admission characteristics were collected from the local database for every patient and evolution during the ICU stay was retrieved from LSP files. RESULTS: Among 8906 patients hospitalized in the ICU, 417 (4.7%) were LSP. At admission, male sex (adjusted odds-ratio (aOR) 1.4 [1.1; 1.7]), inpatient (aOR 2.0 [1.6; 2.4]) and in-ICU hospitalizations for respiratory (aOR 2.9 [1.6; 3.5]) or infectious diseases (aOR 1.6 [1.1; 2.5]) were all independently associated with a long stay in the ICU, while hospitalizations for metabolic (aOR 0.2 [0.1; 0.5]) or cardiovascular diseases (aOR 0.3 [0.2; 0.5]) were in favor of a short stay. In-ICU and in-hospital LSP mortality were 38.8% and 48.2%. Age (aOR 1.02 [1.00-1.04]), catecholamines (aOR 3.9 [1.9; 8.5]), renal replacement therapy (aOR 2.4 [1.3; 4.3]), primary disease-related complications (aOR 2.5 [1.4; 4.6]) and nosocomial infections (aOR 4.1 [1.8; 10.1]) were independently associated with mortality in LSP. CONCLUSION: LSP were highly comorbid patients mainly hospitalized for respiratory diseases. Their mortality was mostly related to nosocomial infections but the majority were discharged alive from the hospital.

Angiopoietin-2 as a marker of endothelial activation is a good predictor factor for intensive care unit admission of COVID-19 patients.

BACKGROUND: Coronavirus disease-2019 (COVID-19), a respiratory disease has been associated with ischemic complications, coagulation disorders, and an endotheliitis. OBJECTIVES: To explore endothelial damage and activation-related biomarkers in COVID-19 patients with criteria of hospitalization for referral to intensive care unit (ICU) and/or respiratory worsening. METHODS: Analysis of endothelial and angiogenic soluble markers in plasma from patients at admission. RESULTS: Study enrolled 40 consecutive COVID-19 patients admitted to emergency department that fulfilled criteria for hospitalization. Half of them were admitted in conventional wards without any ICU transfer during hospitalization; whereas the 20 others were directly transferred to ICU. Patients transferred in ICU were more likely to have lymphopenia, decreased SpO2 and increased D-dimer, CRP and creatinine levels. In those patients, soluble E-selectin and angiopoietin-2 were significantly increased (p value at 0.009 and 0.003, respectively). Increase in SELE gene expression (gene coding for E-selectin protein) was confirmed in an independent cohort of 32 patients using a whole blood gene expression profile analysis. In plasma, we found a strong association between angiopoetin-2 and CRP, creatinine and D-dimers (with p value at 0.001, 0.001 and 0.003, respectively). ROC curve analysis identified an Angiopoietin-2 cut-off of 5000 pg/mL as the best predictor for ICU outcome (Se = 80.1%, Sp = 70%, PPV = 72.7%, NPV = 77%), further confirmed in multivariate analysis after adjustment for creatinine, CRP or D-dimers. CONCLUSION: Angiopoietin-2 is a relevant predictive factor for ICU direct admission in COVID-19 patients. This result showing an endothelial activation reinforces the hypothesis of a COVID-19-associated microvascular dysfunction.

Immune Alterations in a Patient with SARS-CoV-2-Related Acute Respiratory Distress Syndrome.

We report a longitudinal analysis of the immune response associated with a fatal case of COVID-19 in Europe. This patient exhibited a rapid evolution towards multiorgan failure. SARS-CoV-2 was detected in multiple nasopharyngeal, blood, and pleural samples, despite antiviral and immunomodulator treatment. Clinical evolution in the blood was marked by an increase (2-3-fold) in differentiated effector T cells expressing exhaustion (PD-1) and senescence (CD57) markers, an expansion of antibody-secreting cells, a 15-fold increase in γδ T cell and proliferating NK-cell populations, and the total disappearance of monocytes, suggesting lung trafficking. In the serum, waves of a pro-inflammatory cytokine storm, Th1 and Th2 activation, and markers of T cell exhaustion, apoptosis, cell cytotoxicity, and endothelial activation were observed until the fatal outcome. This case underscores the need for well-designed studies to investigate complementary approaches to control viral replication, the source of the hyperinflammatory status, and immunomodulation to target the pathophysiological response. The investigation was conducted as part of an overall French clinical cohort assessing patients with COVID-19 and registered in clinicaltrials.gov under the following number: NCT04262921.

EMERGEncy versus delayed coronary angiogram in survivors of out-of-hospital cardiac arrest with no obvious non-cardiac cause of arrest: Design of the EMERGE trial.

BACKGROUND: In adults, the most common cause of out-of-hospital cardiac arrests (OHCA) is acute coronary artery occlusion. If an immediate coronary angiogram (CAG) is recommended for survivors presenting a ST segment elevation on the electrocardiogram (ECG) performed after resuscitation, there is still a debate regarding the best strategy in patients without ST segment elevation. HYPOTHESIS: Performing an immediate CAG after an OHCA without ST segment elevation on the post-resuscitation ECG and no obvious non-cardiac cause of arrest could lead to a better 180-day survival rate with no or minimal neurological sequel as compared with a delayed CAG performed 48 to 96 hours after the arrest. DESIGN: The EMERGE trial is a prospective national, randomized, open and parallel group trial, in which 970 survivors of OHCA will be randomized (1:1) to either immediate (as soon as possible after return of spontaneous circulation) or delayed (48 to 96 h) CAG. Participants will be OHCA patients with no ST segment elevation on the post resuscitation ECG and no obvious non-cardiac cause of arrest. The primary endpoint of the study is the 180-day survival rate with no or minimal neurological sequel corresponding to Cerebral Performance Category (CPC) 1 or 2. The secondary endpoints are: occurrence of shock during the first 48 hours, ventricular tachycardia and/or fibrillation during the first 48 hours, change in left ventricular ejection fraction between baseline and 180 days assessed by echocardiogram, neurological status evaluated by the CPC score at intensive care unit (ICU) discharge and day 90 neurological status assessed by the Glasgow Outcome Scale Extended score (GOSE) at 90 and 180 days, overall survival rate, and hospital length of stay. SUMMARY: The EMERGE trial is a prospective, multicenter, randomized, controlled trial that will assess the 180-day survival rate with no or minimal neurologic sequel in patients resuscitated from an OHCA without ST segment elevation and who will be managed with either immediate or delayed CAG.

Prevalence of Complete Airway Closure According to Body Mass Index in Acute Respiratory Distress Syndrome.

BACKGROUND: Complete airway closure during expiration may underestimate alveolar pressure. It has been reported in cases of acute respiratory distress syndrome (ARDS), as well as in morbidly obese patients with healthy lungs. The authors hypothesized that complete airway closure was highly prevalent in obese ARDS and influenced the calculation of respiratory mechanics. METHODS: In a post hoc pooled analysis of two cohorts, ARDS patients were classified according to body mass index (BMI) terciles. Low-flow inflation pressure-volume curve and partitioned respiratory mechanics using esophageal manometry were recorded. The authors' primary aim was to compare the prevalence of complete airway closure according to BMI terciles. Secondary aims were to compare (1) respiratory system mechanics considering or not considering complete airway closure in their calculation, and (2) and partitioned respiratory mechanics according to BMI. RESULTS: Among the 51 patients analyzed, BMI was less than 30 kg/m2 in 18, from 30 to less than 40 in 16, and greater than or equal to 40 in 17. Prevalence of complete airway closure was 41% overall (95% CI, 28 to 55; 21 of 51 patients), and was lower in the lowest (22% [3 to 41]; 4 of 18 patients) than in the highest BMI tercile (65% [42 to 87]; 11 of 17 patients). Driving pressure and elastances of the respiratory system and of the lung were higher when complete airway closure was not taken into account in their calculation. End-expiratory esophageal pressure (ρ = 0.69 [95% CI, 0.48 to 0.82]; P < 0.001), but not chest wall elastance, was associated with BMI, whereas elastance of the lung was negatively correlated with BMI (ρ = -0.27 [95% CI, -0.56 to -0.10]; P = 0.014). CONCLUSIONS: Prevalence of complete airway closure was high in ARDS and should be taken into account when calculating respiratory mechanics, especially in the most morbidly obese patients.

A Multicenter Randomized Trial Assessing the Efficacy of Helium/Oxygen in Severe Exacerbations of Chronic Obstructive Pulmonary Disease.

RATIONALE: During noninvasive ventilation (NIV) for chronic obstructive pulmonary disease (COPD) exacerbations, helium/oxygen (heliox) reduces the work of breathing and hypercapnia more than air/O2, but its impact on clinical outcomes remains unknown. OBJECTIVES: To determine whether continuous administration of heliox for 72 hours, during and in-between NIV sessions, was superior to air/O2 in reducing NIV failure (25-15%) in severe hypercapnic COPD exacerbations. METHODS: This was a prospective, randomized, open-label trial in 16 intensive care units (ICUs) and 6 countries. Inclusion criteria were COPD exacerbations with PaCO2 ≥ 45 mm Hg, pH ≤ 7.35, and at least one of the following: respiratory rate ≥ 25/min, PaO2 ≤ 50 mm Hg, and oxygen saturation (arterial [SaO2] or measured by pulse oximetry [SpO2]) ≤ 90%. A 6-month follow-up was performed. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was NIV failure (intubation or death without intubation in the ICU). The secondary endpoints were physiological parameters, duration of ventilation, duration of ICU and hospital stay, 6-month recurrence, and rehospitalization rates. The trial was stopped prematurely (445 randomized patients) because of a low global failure rate (NIV failure: air/O2 14.5% [n = 32]; heliox 14.7% [n = 33]; P = 0.97, and time to NIV failure: heliox group 93 hours [n = 33], air/O2 group 52 hours [n = 32]; P = 0.12). Respiratory rate, pH, PaCO2, and encephalopathy score improved significantly faster with heliox. ICU stay was comparable between the groups. In patients intubated after NIV failed, patients on heliox had a shorter ventilation duration (7.4 ± 7.6 d vs. 13.6 ± 12.6 d; P = 0.02) and a shorter ICU stay (15.8 ± 10.9 d vs. 26.7 ± 21.0 d; P = 0.01). No difference was observed in ICU and 6-month mortality. CONCLUSIONS: Heliox improves respiratory acidosis, encephalopathy, and the respiratory rate more quickly than air/O2 but does not prevent NIV failure. Overall, the rate of NIV failure was low. Clinical trial registered with www.clinicaltrials.gov (NCT 01155310).