Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor-Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials.

Importance: Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology. Objective: To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II. Design, Setting, and Participants: Two randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022. Interventions: A 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo. Main Outcomes and Measures: The primary outcome was oxygen-free days, an ordinal outcome that classifies a patient's status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension. Results: Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, -2.3 [95% CrI, -4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, -2.4 [95% CrI, -5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo. Conclusions and Relevance: In adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04924660.

Inhaled Nitric Oxide for Clinical Management of COVID-19: A Systematic Review and Meta-Analysis.

BACKGROUND: Severe COVID-19 is associated with hypoxemia and acute respiratory distress syndrome (ARDS), which may predispose multiorgan failure and death. Inhaled nitric oxide (iNO) is a clinical vasodilator used in the management of acute respiratory distress syndrome (ARDS). This study evaluated the response rate to iNO in patients with COVID-19-ARDS. METHOD: We searched Medline and Embase databases in May 2022, and data on the use of iNO in the treatment of ARDS in COVID-19 patients were synthesized from studies that satisfied predefined inclusion criteria. A systematic synthesis of data was performed followed by meta-analysis. We performed the funnel plot and leave-one-out sensitivity test on the included studies to assess publication bias and possible exaggerated effect size. We compared the effect size of the studies from the Unites States with those from other countries and performed meta-regression to assess the effect of age, year of publication, and concomitant vasodilator use on the effect size. RESULTS: A total of 17 studies (including 712 COVID-19 patients) were included in this systematic review of which 8 studies (involving 265 COVID-19 patients) were subjected to meta-analysis. The overall response rate was 66% (95% CI, 47-84%) with significantly high between-studies heterogeneity (I2 = 94%, p < 0.001). The funnel plot showed publication bias, although the sensitivity test using leave-one-out analysis showed that removing any of the study does not remove the significance of the result. The response rate was higher in the Unites States, and meta-regression showed that age, year of publication, and use of concomitant vasodilators did not influence the response rate to iNO. CONCLUSION: iNO therapy is valuable in the treatment of hypoxemia in COVID-19 patients and may improve systemic oxygenation in patients with COVID-19-ARDS. Future studies should investigate the mechanism of the activity of iNO in COVID-19 patients to provide insight into the unexplored potential of iNO in general ARDS.

Inhaled Pulmonary Vasodilators in COVID-19 Infection: A Systematic Review and Meta-Analysis.

Introduction: Inhaled pulmonary vasodilators (IPVD) have been previously studied in patients with non-coronavirus disease-19 (COVID-19) related acute respiratory distress syndrome (ARDS). The use of IPVD has been shown to improve the partial pressure of oxygen in arterial blood (PaO2), reduce fraction of inspired oxygen (FiO2) requirements, and ultimately increase PaO2/FiO2 (P/F) ratios in ARDS patients. However, the role of IPVD in COVID-19 ARDS is still unclear. Therefore, we performed this meta-analysis to evaluate the role of IPVD in COVID-19 patients. Methods: Comprehensive literature search of PubMed, Embase, Web of Science and Cochrane Library databases from inception through April 22, 2022 was performed for all published studies that utilized IPVD in COVID-19 ARDS patients. The single arm studies and case series were combined for a 1-arm meta-analysis, and the 2-arm studies were combined for a 2-arm meta-analysis. Primary outcomes for the 1-arm and 2-arm meta-analyzes were change in pre- and post-IPVD P/F ratios and mortality, respectively. Secondary outcomes for the 1-arm meta-analysis were change in pre- and post-IPVD positive end-expiratory pressure (PEEP) and lung compliance, and for the 2-arm meta-analysis the secondary outcomes were need for endotracheal intubation and hospital length of stay (LOS). Results: 13 single arm retrospective studies and 5 case series involving 613 patients were included in the 1-arm meta-analysis. 3 studies involving 640 patients were included in the 2-arm meta-analysis. The pre-IPVD P/F ratios were significantly lower compared to post-IPVD, but there was no significant difference between pre- and post-IPVD PEEP and lung compliance. The mortality rates, need for endotracheal intubation, and hospital LOS were similar between the IPVD and standard therapy groups. Conclusion: Although IPVD may improve oxygenation, our investigation showed no benefits in terms of mortality compared to standard therapy alone. However, randomized controlled trials are warranted to validate our findings.

Nitric oxide versus epoprostenol for refractory hypoxemia in Covid-19.

OBJECTIVE: To compare the efficacy and outcomes with inhaled nitric oxide (iNO) and inhaled epoprostenol (iEPO) in patients with refractory hypoxemia due to COVID-19. DESIGN: Retrospective Cohort Study. SETTING: Single health system multicenter academic teaching hospitals. PATIENTS OR SUBJECTS: Age group of 18-80 years admitted to the medical ICU. INTERVENTIONS: Mechanically ventilated patients with COVID-19 infection, who received either iNO or iEPO between March 1st, 2020, and June 30th, 2020. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the change in the PaO2/FiO2 (P/F) ratio 1 hour after initiation of pulmonary vasodilator therapy. Secondary outcomes include P/F ratios on days 1-3 after initiation, positive response in P/F ratio (increase of at least 20% in PaO2), total days of treatment, rebound hypoxemia (if there was a drop in oxygen saturation after treatment was stopped), ventilator free days (if any patient was extubated), days in ICU, days to extubation, days to tracheostomy, mortality days after intubation, 30-day survival and mortality. 183 patients were excluded, as they received both iNO and iEPO. Of the remaining 103 patients, 62 received iEPO and 41 received iNO. The severity of ARDS was similar in both groups. Change in P/F ratio at one hour was 116 (70.3) with iNO and 107 (57.6) with iEPO (Mean/SD). Twenty-two (53.7%) patients in the iNO group and 25 (40.3%) in the iEPO group were responders to pulmonary vasodilators n(%)(p = 0.152) (more than 20% increase in partial pressure of oxygen, Pao2), and 18 (43.9%) and 31 (50%) patients in the iNO and iEPO group (p = 0.685), respectively, had rebound hypoxemia. Only 7 patients in the cohort achieved ventilator free days (3 in the iEPO group and 4 in iNO group). CONCLUSIONS: We found no significant difference between iNO and iEPO in terms of change in P/F ratio, duration of mechanical ventilation, ICU, in-hospital mortality in this cohort of mechanically ventilated patients with COVID-19. Larger, prospective studies are necessary to validate these results.

Compassionate use of Pulmonary Vasodilators in Acute Severe Hypoxic Respiratory Failure due to COVID-19.

BACKGROUND: There have been over 200 million cases and 4.4 million deaths from COVID-19 worldwide. Despite the lack of robust evidence one potential treatment for COVID-19 associated severe hypoxaemia is inhaled pulmonary vasodilator (IPVD) therapy, using either nitric oxide (iNO) or prostaglandins. We describe the implementation of, and outcomes from, a protocol using IPVDs in a cohort of patients with severe COVID-19 associated respiratory failure receiving maximal conventional support. METHODS: Prospectively collected data from adult patients with SARS-CoV-2 admitted to the intensive care unit (ICU) at a large teaching hospital were analysed for the period 14th March 2020 - 11th February 2021. An IPVD was considered if the PaO2/FiO2 (PF) ratio was less than 13.3kPa despite maximal conventional therapy. Nitric oxide was commenced at 20ppm and titrated to response. If oxygenation improved Iloprost nebulisers were commenced and iNO weaned. The primary outcome was percentage changes in PF ratio and Alveolar-arterial (A-a) gradient. RESULTS: Fifty-nine patients received IPVD therapy during the study period. The median PF ratio before IPVD therapy was commenced was 11.33kPa (9.93-12.91). Patients receiving an IPVD had a lower PF ratio (14.37 vs. 16.37kPa, p = 0.002) and higher APACHE-II score (17 vs. 13, p = 0.028) at ICU admission. At 72 hours after initiating an IPVD the median improvement in PF ratio was 33.9% (-4.3-84.1). At 72 hours changes in PF ratio (70.8 vs. -4.1%, p < 0.001) and reduction in A-a gradient (44.7 vs. 14.8%, p < 0.001) differed significantly between survivors (n = 33) and non-survivors (n = 26). CONCLUSIONS: The response to IPVDs in patients with COVID-19 associated acute hypoxic respiratory failure differed significantly between survivors and non-survivors. Both iNO and prostaglandins may offer therapeutic options for patients with severe refractory hypoxaemia due to COVID-19. The use of inhaled prostaglandins, and iNO where feasible, should be studied in adequately powered prospective randomised trials.

Inhaled pulmonary vasodilators are not associated with improved gas exchange in mechanically ventilated patients with COVID-19: A retrospective cohort study.

PURPOSE: Measure the effect of inhaled pulmonary vasodilators on gas exchange in mechanically ventilated patients with COVID-19. METHODS: A retrospective observational cohort study at three New York University Hospitals was performed including eighty-four mechanically ventilated SARS Cov-2 nasopharyngeal PCR positive patients, sixty nine treated with inhaled nitric oxide (iNO) and fifteen with inhaled epoprostenol (iEPO). The primary outcomes were change in PAO2:FIO2 ratio, oxygenation Index (OI), and ventilatory ratio (VR) after initiation of inhaled pulmonary vasodilators. RESULTS: There was no significant change in PAO2:FIO2ratio after initiation of iNO (mean - 4.1, 95% CI -17.3-9.0, P = 0.54) or iEPO (mean - 3.4, 95% CI -19.7-12.9, P = 0.66), in OI after initiation of iNO (mean 2.1, 95% CI-0.04-4.2, P = 0.054) or iEPO (mean - 3.4, 95% CI -19.7-12.9, P = 0.75), or in VR after initiation of iNO (mean 0.17, 95% CI -0.03-0.36, P = 0.25) or iEPO (mean 0.33, 95% CI -0.0847-0.74, P = 0.11). PAO2:FIO2, OI and VR did not significantly change over a five day period starting the day prior to drug initiation in patients who received either iNO or iEPO assessed with a fixed effects model. CONCLUSION: Inhaled pulmonary vasodilators were not associated with significant improvement in gas exchange in mechanically ventilated patients with COVID-19.

Nitric oxide: Clinical applications in critically ill patients.

Inhaled nitric oxide (iNO) acts as a selective pulmonary vasodilator and it is currently approved by the FDA for the treatment of persistent pulmonary hypertension of the newborn. iNO has been demonstrated to effectively decrease pulmonary artery pressure and improve oxygenation, while decreasing extracorporeal life support use in hypoxic newborns affected by persistent pulmonary hypertension. Also, iNO seems a safe treatment with limited side effects. Despite the promising beneficial effects of NO in the preclinical literature, there is still a lack of high quality evidence for the use of iNO in clinical settings. A variety of clinical applications have been suggested in and out of the critical care environment, aiming to use iNO in respiratory failure and pulmonary hypertension of adults or as a preventative measure of hemolysis-induced vasoconstriction, ischemia/reperfusion injury and as a potential treatment of renal failure associated with cardiopulmonary bypass. In this narrative review we aim to present a comprehensive summary of the potential use of iNO in several clinical conditions with its suggested benefits, including its recent application in the scenario of the COVID-19 pandemic. Randomized controlled trials, meta-analyses, guidelines, observational studies and case-series were reported and the main findings summarized. Furthermore, we will describe the toxicity profile of NO and discuss an innovative proposed strategy to produce iNO. Overall, iNO exhibits a wide range of potential clinical benefits, that certainly warrants further efforts with randomized clinical trials to determine specific therapeutic roles of iNO.

Identification of hub genes associated with COVID-19 and idiopathic pulmonary fibrosis by integrated bioinformatics analysis.

INTRODUCTION: The coronavirus disease 2019 (COVID-19), emerged in late 2019, was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The risk factors for idiopathic pulmonary fibrosis (IPF) and COVID-19 are reported to be common. This study aimed to determine the potential role of differentially expressed genes (DEGs) common in IPF and COVID-19. MATERIALS AND METHODS: Based on GEO database, we obtained DEGs from one SARS-CoV-2 dataset and five IPF datasets. A series of enrichment analysis were performed to identify the function of upregulated and downregulated DEGs, respectively. Two plugins in Cytoscape, Cytohubba and MCODE, were utilized to identify hub genes after a protein-protein interaction (PPI) network. Finally, candidate drugs were predicted to target the upregulated DEGs. RESULTS: A total of 188 DEGs were found between COVID-19 and IPF, out of which 117 were upregulated and 71 were downregulated. The upregulated DEGs were involved in cytokine function, while downregulated DEGs were associated with extracellular matrix disassembly. Twenty-two hub genes were upregulated in COVID-19 and IPF, for which 155 candidate drugs were predicted (adj.P.value < 0.01). CONCLUSION: Identifying the hub genes aberrantly regulated in both COVID-19 and IPF may enable development of molecules, encoded by those genes, as therapeutic targets for preventing IPF progression and SARS-CoV-2 infections.

Digital Tracking of Physical Activity, Heart Rate, and Inhalation Behavior in Patients With Pulmonary Arterial Hypertension Treated With Inhaled Iloprost: Observational Study (VENTASTEP).

BACKGROUND: Pulmonary arterial hypertension restricts the ability of patients to perform routine physical activities. As part of pulmonary arterial hypertension treatment, inhaled iloprost can be administered via a nebulizer that tracks inhalation behavior. Pulmonary arterial hypertension treatment is guided by intermittent clinical measurements, such as 6-minute walk distance, assessed during regular physician visits. Continuous digital monitoring of physical activity may facilitate more complete assessment of the impact of pulmonary arterial hypertension on daily life. Physical activity tracking with a wearable has not yet been assessed with simultaneous tracking of pulmonary arterial hypertension medication intake. OBJECTIVE: We aimed to digitally track the physical parameters of patients with pulmonary arterial hypertension who were starting treatment with iloprost using a Breelib nebulizer. The primary objective was to investigate correlations between changes in digital physical activity measures and changes in traditional clinical measures and health-related quality of life over 3 months. Secondary objectives were to evaluate inhalation behavior, adverse events, and changes in heart rate and sleep quality. METHODS: We conducted a prospective, multicenter observational study of adults with pulmonary arterial hypertension in World Health Organization functional class III who were adding inhaled iloprost to existing pulmonary arterial hypertension therapy. Daily distance walked, step count, number of standing-up events, heart rate, and 6-minute walk distance were digitally captured using smartwatch (Apple Watch Series 2) and smartphone (iPhone 6S) apps during a 3-month observation period (which began when iloprost treatment began). Before and at the end of the observation period (within 2 weeks), we also evaluated 6-minute walk distance, Borg dyspnea, functional class, B-type natriuretic peptide (or N-terminal pro-B-type natriuretic peptide) levels, health-related quality of life (EQ-5D questionnaire), and sleep quality (Pittsburgh Sleep Quality Index). RESULTS: Of 31 patients, 18 were included in the full analysis (observation period: median 91.5 days, IQR 88.0 to 92.0). Changes from baseline in traditional and digital 6-minute walk distance were moderately correlated (r=0.57). Physical activity (daily distance walked: median 0.4 km, IQR -0.2 to 1.9; daily step count: median 591, IQR -509 to 2413) and clinical measures (traditional 6-minute walk distance: median 26 m, IQR 0 to 40) changed concordantly from baseline to the end of the observation period. Health-related quality of life showed little change. Total sleep score and resting heart rate slightly decreased. Distance walked and step count showed short-term increases after each iloprost inhalation. No new safety signals were identified (safety analysis set: n=30). CONCLUSIONS: Our results suggest that despite challenges, parallel monitoring of physical activity, heart rate, and iloprost inhalation is feasible in patients with pulmonary arterial hypertension and may complement traditional measures in guiding treatment; however, the sample size of this study limits generalizability. TRIAL REGISTRATION: ClinicalTrials.gov NCT03293407; https://clinicaltrials.gov/ct2/show/NCT03293407. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/12144.

Acute kidney injury: Incidence, risk factors, and outcomes in severe COVID-19 patients.

BACKGROUND: COVID-19 is a multisystemic disorder that frequently causes acute kidney injury (AKI). However, the precise clinical and biochemical variables associated with AKI progression in patients with severe COVID-19 remain unclear. METHODS: We performed a retrospective study on 278 hospitalized patients who were admitted to the ward and intensive care unit (ICU) with COVID-19 between March 2020 and June 2020, at the University Hospital, São Paulo, Brazil. Patients aged ≥ 18 years with COVID-19 confirmed on RT-PCR were included. AKI was defined according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria. We evaluated the incidence of AKI, several clinical variables, medicines used, and outcomes in two sub-groups: COVID-19 patients with AKI (Cov-AKI), and COVID-19 patients without AKI (non-AKI). Univariate and multivariate analyses were performed. RESULTS: First, an elevated incidence of AKI (71.2%) was identified, distributed across different stages of the KDIGO criteria. We further observed higher levels of creatinine, C-reactive protein (CRP), leukocytes, neutrophils, monocytes, and neutrophil-to-lymphocyte ratio (NLR) in the Cov-AKI group than in the non-AKI group, at hospital admission. On univariate analysis, Cov-AKI was associated with older age (>62 years), hypertension, CRP, MCV, leucocytes, neutrophils, NLR, combined hydroxychloroquine and azithromycin treatment, use of mechanical ventilation, and vasoactive drugs. Multivariate analysis showed that hypertension and the use of vasoactive drugs were independently associated with a risk of higher AKI in COVID-19 patients. Finally, we preferentially found an altered erythrocyte and leukocyte cellular profile in the Cov-AKI group compared to the non-AKI group, at hospital discharge. CONCLUSIONS: In our study, the development of AKI in patients with severe COVID-19 was related to inflammatory blood markers and therapy with hydroxychloroquine/azithromycin, with vasopressor requirement and hypertension considered potential risk factors. Thus, attention to the protocol, hypertension, and some blood markers may help assist doctors with decision-making for the management of COVID-19 patients with AKI.

[Recommendations of the Committee of Andrology and Sexual Medicine of the AFU concerning the management of andrological and sexual medicine pathologies during the COVID-19 crisis]. / Recommandations du Comité d'andrologie et de médecine sexuelle de l'AFU concernant la prise en charge andrologique et en médecine sexuelle en contexte et en sortie de crise sanitaire liée au COVID-19.

OBJECTIVE: To assist urologists in the management of andrological and sexual medicine pathologies during the COVID-19 crisis. MATERIAL AND METHOD: Use of the formalized consensus method. RESULTS: The medical and surgical management of patients in andrology and sexual medicine must be adapted. Consultations should, as far as possible, be carried out by tele-consultation. For operative procedures, the delay between the operative decision and the date of (re)scheduling of the procedure will depend on: (1) the level of criticality of the clinical situation; (2) the type of intervention; (3) the functional and psychological repercussions, including quality of life while waiting for the procedure; (4) the notion of losing the chance of having an optimal outcome; (5) the risk of potential complications from delaying a procedure for too long; and (6) taking into account the patient's risk factors for severe forms of COVID-19. The protection of urologists from COVID-19 should be considered. Each urologist must make the best decision for the patient, taking into account the acceptable time frame and quality of life impact before surgical management, the COVID risk parameters, the technical and anesthetic feasibility and the structural possibility of the health care institution to ensure a specific dedicated pathway during the COVID-19 health crisis. CONCLUSION: The management of andrological and sexual medicine pathologies must be adapted to the COVID-19 crisis context. Some patients may require surgery, including in emergency. These recommendations are transitional and will end with the COVID-19 crisis.

COVID-19 Associated Reversible Cerebral Vasoconstriction Syndrome Successfully Treated with Nimodipine and Aspirin.

There have been limited cases linking SARS-CoV-2 infection with the development of reversible cerebral vasoconstriction syndrome (RCVS). We hereby report a rare case of RCVS in the setting of mild SARS-CoV-2 respiratory infection successfully treated with nimodipine and aspirin. SARS-CoV-2 attacks the ACE2-receptors, which are expressed in various body organs including the lungs, kidneys, and blood vessels. Vasoconstriction can result from down-regulation of the ACE2-receptors that can lead to sympathetic hypertonia of the cerebral blood vessel walls and/or over-activation of the renin-angiotensin axis.

Treating Acute Decompensated Heart Failure in Patients with COVID-19 Using Intravenous Nitroglycerin in 5% Glutathione.

The purpose of this current opinion article is to illustrate a novel approach to the treatment of acute decompensated heart failure (ADHF) in coronavirus disease 2019 (COVID-19) patients. The approach described herein relies on a reformulation of intravenous nitroglycerin in 5% glutathione, itself novel, and is felt to have the potential to not only improve the rate of resolution of ADHF, but also reduce the risk of complications of heart failure seen in patients with COVID-19.

Responsiveness of Inhaled Epoprostenol in Respiratory Failure due to COVID-19.

BACKGROUND: Inhaled pulmonary vasodilators are used as adjunctive therapies for the treatment of refractory hypoxemia. Available evidence suggest they improve oxygenation in a subset of patients without changing long-term trajectory. Given the differences in respiratory failure due to COVID-19 and "traditional" ARDS, we sought to identify their physiologic impact. METHODS: This is a retrospective observational study of patients mechanically ventilated for COVID-19, from the ICUs of 2 tertiary care centers, who received inhaled epoprostenol (iEpo) for the management of hypoxemia. The primary outcome is change in PaO2/FiO2. Additionally, we measured several patient level features to predict iEpo responsiveness (or lack thereof). RESULTS: Eighty patients with laboratory confirmed SARS-CoV2 received iEpo while mechanically ventilated and had PaO2/FiO2 measured before and after. The median PaO2/FiO2 prior to receiving iEpo was 92 mmHg and interquartile range (74 - 122). The median change in PaO2/FiO2 was 9 mmHg (-9 - 37) corresponding to a 10% improvement (-8 - 41). Fifty-percent (40 / 80) met our a priori definition of a clinically significant improvement in PaO2/FiO2 (increase in 10% from the baseline value). Prone position and lower PaO2/FiO2 when iEpo was started predicted a more robust response, which held after multivariate adjustment. For proned individuals, improvement in PaO2/FiO2 was 14 mmHg (-6 to 45) vs. 3 mmHg (-11 - 20), p = 0.04 for supine individuals; for those with severe ARDS (PaO2/FiO2 < 100, n = 49) the median improvement was 16 mmHg (-2 - 46). CONCLUSION: Fifty percent of patients have a clinically significant improvement in PaO2/FiO2 after the initiation of iEpo. This suggests it is worth trying as a rescue therapy; although generally the benefit was modest with a wide variability. Those who were prone and had lower PaO2/FiO2 were more likely to respond.

Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation.

The core pathology of coronavirus disease 2019 (COVID-19) is infection of airway cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that results in excessive inflammation and respiratory disease, with cytokine storm and acute respiratory distress syndrome implicated in the most severe cases. Thrombotic complications are a major cause of morbidity and mortality in patients with COVID-19. Patients with pre-existing cardiovascular disease and/or traditional cardiovascular risk factors, including obesity, diabetes mellitus, hypertension and advanced age, are at the highest risk of death from COVID-19. In this Review, we summarize new lines of evidence that point to both platelet and endothelial dysfunction as essential components of COVID-19 pathology and describe the mechanisms that might account for the contribution of cardiovascular risk factors to the most severe outcomes in COVID-19. We highlight the distinct contributions of coagulopathy, thrombocytopathy and endotheliopathy to the pathogenesis of COVID-19 and discuss potential therapeutic strategies in the management of patients with COVD-19. Harnessing the expertise of the biomedical and clinical communities is imperative to expand the available therapeutics beyond anticoagulants and to target both thrombocytopathy and endotheliopathy. Only with such collaborative efforts can we better prepare for further waves and for future coronavirus-related pandemics.

Characteristics of clinical trials evaluating cardiovascular therapies for Coronavirus Disease 2019 Registered on ClinicalTrials.gov: a cross sectional analysis.

Morbidity and mortality associated with COVID-19 has increased exponentially, and patients with cardiovascular (CV) disease are at risk for poor outcomes. Several lines of evidence suggest a potential role for CV therapies in COVID-19 treatment. Characteristics of clinical trials of CV therapies related to COVID-19 registered on ClinicalTrials.gov have not been described. METHODS: ClinicalTrials.gov was queried on August 7, 2020 for COVID-19 related trials. Studies evaluating established CV drugs, other fibrinolytics (defibrotide), and extracorporeal membrane oxygenation were included. Studies evaluating anti-microbial, convalescent plasma, non-colchicine anti-inflammatory, and other therapies were excluded. Trial characteristics were tabulated from study-specific entries. RESULTS: A total of 2,935 studies related to COVID-19 were registered as of August 7, 2020. Of these, 1,645 were interventional studies, and the final analytic cohort consisted of 114 studies evaluating 10 CV therapeutic categories. Antithrombotics (32.5%; n = 37) were most commonly evaluated, followed by pulmonary vasodilators (14.0%; n = 16), renin-angiotensin-aldosterone system-related therapies (12.3%; n = 14), and colchicine (8.8%; n = 10). Trials evaluating multiple CV therapy categories and CV therapies in combination with non-CV therapies encompassed 4.4% (n = 5) and 9.6% (n = 11) of studies, respectively. Most studies were designed for randomized allocation (87.7%; n = 100), enrollment of less than 1000 participants (86.8%; n = 99), single site implementation (55.3%; n = 63), and had a primary outcome of mortality or a composite including mortality (56.1%; n = 64). Most study populations consisted of patients hospitalized with COVID-19 (81.6%; n = 93). At the time of database query, 28.9% (n = 33) of studies were not yet recruiting and the majority were estimated to be completed after December 2020 (67.8%; n = 78). Most lead sponsors were located in North America (43.9%; n = 50) or Europe (36.0%; n = 41). CONCLUSIONS: A minority (7%) of clinical trials related to COVID-19 registered on ClinicalTrials.gov plan to evaluate CV therapies. Of CV therapy studies, most were planned to be single center, enroll less than 1000 inpatients, sponsored by European or North American academic institutions, and estimated to complete after December 2020. Collectively, these findings underscore the need for a network of sites with a platform protocol for rapid evaluation of multiple therapies and generalizability to inform clinical care and health policy for COVID-19 moving forward.