Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial.

BACKGROUND: There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure. METHODS: TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761. FINDINGS: Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10). INTERPRETATION: Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy. FUNDING: National Institutes of Health.

Assessment of the Utilization of Validated Diagnostic Predictive Tools and D-Dimer in the Evaluation of Pulmonary Embolism: A Single-Center Retrospective Cohort Study from a Public Hospital in New York City.

INTRODUCTION: A significant increase in the use of computed tomography with pulmonary angiography (CTPA) for the diagnosis of pulmonary embolism (PE) has been observed in the past twenty years. We aimed to investigate whether the validated diagnostic predictive tools and D-dimers were adequately utilized in a large public hospital in New York City. METHODS: We conducted a retrospective review of patients who underwent CTPA for the specific indication of ruling out PE over a period of one year. Two independent reviewers, blinded to each other and to the CTPA and D-dimer results, estimated the clinical probability (CP) of PE using Well's score, the YEARS algorithm, and the revised Geneva score. Patients were classified based on the presence or absence of PE in the CTPA. RESULTS: A total of 917 patients were included in the analysis (median age: 57 years, female: 59%). The clinical probability of PE was considered low by both independent reviewers in 563 (61.4%), 487 (55%), and 184 (20.1%) patients based on Well's score, the YEARS algorithm, and the revised Geneva score, respectively. D-dimer testing was conducted in less than half of the patients who were deemed to have low CP for PE by both independent reviewers. Using a D-dimer cut-off of <500 ng/mL or the age-adjusted cut-off in patients with a low CP of PE would have missed only a small number of mainly subsegmental PE. All three tools, when combined with D-dimer < 500 ng/mL or 95%. CONCLUSION: All three validated diagnostic predictive tools were found to have significant diagnostic value in ruling out PE when combined with a D-dimer cut-off of <500 ng/mL or the age-adjusted cut-off. Excessive use of CTPA was likely secondary to suboptimal use of diagnostic predictive tools.

Diaphragmatic thickening fraction as a predictor for intubation in patients with COVID-19.

The diaphragm is the primary respiratory muscle, and its dysfunction predisposes patients to respiratory failure. Diaphragm function can be assessed by ultrasound measurement - Diaphragmatic Thickening Fraction (DTF). Respiratory viral infections (including SARS-CoV-2) can cause diaphragm dysfunction. Our case series follows three patients infected with COVID-19 pneumonia. Bedside diaphragmatic ultrasound assessments measuring DTF were trended over patient's hospital course until clinical improvement (i.e., off oxygen) or worsening (i.e., intubation). Our preliminary results suggest a correlation between DTF trends and respiratory status in patients requiring 100% oxygen. Further studies are required to assess DTF and its possible correlation to respiratory failure.

Symptomatic, clinical and biomarker associations for mortality in hospitalized COVID-19 patients enriched for African Americans.

BACKGROUND AND AIMS: Initial reports on US COVID-19 showed different outcomes in different races. In this study we use a diverse large cohort of hospitalized COVID-19 patients to determine predictors of mortality. METHODS: We analyzed data from hospitalized COVID-19 patients (n = 5852) between March 2020- August 2020 from 8 hospitals across the US. Demographics, comorbidities, symptoms and laboratory data were collected. RESULTS: The cohort contained 3,662 (61.7%) African Americans (AA), 286 (5%) American Latinx (LAT), 1,407 (23.9%), European Americans (EA), and 93 (1.5%) American Asians (AS). Survivors and non-survivors mean ages in years were 58 and 68 for AA, 58 and 77 for EA, 44 and 61 for LAT, and 51 and 63 for AS. Mortality rates for AA, LAT, EA and AS were 14.8, 7.3, 16.3 and 2.2%. Mortality increased among patients with the following characteristics: age, male gender, New York region, cardiac disease, COPD, diabetes mellitus, hypertension, history of cancer, immunosuppression, elevated lymphocytes, CRP, ferritin, D-Dimer, creatinine, troponin, and procalcitonin. Use of mechanical ventilation (p = 0.001), shortness of breath (SOB) (p < 0.01), fatigue (p = 0.04), diarrhea (p = 0.02), and increased AST (p < 0.01), significantly correlated with death in multivariate analysis. Male sex and EA and AA race/ethnicity had higher frequency of death. Diarrhea was among the most common GI symptom amongst AAs (6.8%). When adjusting for comorbidities, significant variables among the demographics of study population were age (over 45 years old), male sex, EA, and patients hospitalized in New York. When adjusting for disease severity, significant variables were age over 65 years old, male sex, EA as well as having SOB, elevated CRP and D-dimer. Glucocorticoid usage was associated with an increased risk of COVID-19 death in our cohort. CONCLUSION: Among this large cohort of hospitalized COVID-19 patients enriched for African Americans, our study findings may reflect the extent of systemic organ involvement by SARS-CoV-2 and subsequent progression to multi-system organ failure. High mortality in AA in comparison with LAT is likely related to high frequency of comorbidities and older age among AA. Glucocorticoids should be used carefully considering the poor outcomes associated with it. Special focus in treating patients with elevated liver enzymes and other inflammatory biomarkers such as CRP, troponin, ferritin, procalcitonin, and D-dimer are required to prevent poor outcomes.

Variations in end-of-life practices in intensive care units worldwide (Ethicus-2): a prospective observational study.

BACKGROUND: End-of-life practices vary among intensive care units (ICUs) worldwide. Differences can result in variable use of disproportionate or non-beneficial life-sustaining interventions across diverse world regions. This study investigated global disparities in end-of-life practices. METHODS: In this prospective, multinational, observational study, consecutive adult ICU patients who died or had a limitation of life-sustaining treatment (withholding or withdrawing life-sustaining therapy and active shortening of the dying process) during a 6-month period between Sept 1, 2015, and Sept 30, 2016, were recruited from 199 ICUs in 36 countries. The primary outcome was the end-of-life practice as defined by the end-of-life categories: withholding or withdrawing life-sustaining therapy, active shortening of the dying process, or failed cardiopulmonary resuscitation (CPR). Patients with brain death were included in a separate predefined end-of-life category. Data collection included patient characteristics, diagnoses, end-of-life decisions and their timing related to admission and discharge, or death, with comparisons across different regions. Patients were studied until death or 2 months from the first limitation decision. FINDINGS: Of 87 951 patients admitted to ICU, 12 850 (14·6%) were included in the study population. The number of patients categorised into each of the different end-of-life categories were significantly different for each region (p<0·001). Limitation of life-sustaining treatment occurred in 10 401 patients (11·8% of 87 951 ICU admissions and 80·9% of 12 850 in the study population). The most common limitation was withholding life-sustaining treatment (5661 [44·1%]), followed by withdrawing life-sustaining treatment (4680 [36·4%]). More treatment withdrawing was observed in Northern Europe (1217 [52·8%] of 2305) and Australia/New Zealand (247 [45·7%] of 541) than in Latin America (33 [5·8%] of 571) and Africa (21 [13·0%] of 162). Shortening of the dying process was uncommon across all regions (60 [0·5%]). One in five patients with treatment limitations survived hospitalisation. Death due to failed CPR occurred in 1799 (14%) of the study population, and brain death occurred in 650 (5·1%). Failure of CPR occurred less frequently in Northern Europe (85 [3·7%] of 2305), Australia/New Zealand (23 [4·3%] of 541), and North America (78 [8·5%] of 918) than in Africa (106 [65·4%] of 162), Latin America (160 [28·0%] of 571), and Southern Europe (590 [22·5%] of 2622). Factors associated with treatment limitations were region, age, and diagnoses (acute and chronic), and country end-of-life legislation. INTERPRETATION: Limitation of life-sustaining therapies is common worldwide with regional variability. Withholding treatment is more common than withdrawing treatment. Variations in type, frequency, and timing of end-of-life decisions were observed. Recognising regional differences and the reasons behind these differences might help improve end-of-life care worldwide. FUNDING: None.

Assessment of the Association of COPD and Asthma with In-Hospital Mortality in Patients with COVID-19. A Systematic Review, Meta-Analysis, and Meta-Regression Analysis.

Together, chronic obstructive pulmonary disease (COPD) and asthma account for the most common non-infectious respiratory pathologies. Conflicting preliminary studies have shown varied effect for COPD and asthma as prognostic factors for mortality in coronavirus disease 2019 (COVID-19). The aim of this study was to explore the association of COPD and asthma with in-hospital mortality in patients with COVID-19 by systematically reviewing and synthesizing with a meta-analysis the available observational studies. MEDLINE, Scopus, and medRxiv databases were reviewed. A random-effects model meta-analysis was used, and I-square was utilized to assess for heterogeneity. In-hospital mortality was defined as the primary endpoint. Sensitivity and meta-regression analyses were performed. Thirty studies with 21,309 patients were included in this meta-analysis (1465 with COPD and 633 with asthma). Hospitalized COVID-19 patients with COPD had higher risk of death compared to those without COPD (OR: 2.29; 95% CI: 1.79-2.93; I2 59.6%). No significant difference in in-hospital mortality was seen in patients with and without asthma (OR: 0.87; 95% CI: 0.68-1.10; I2 0.0%). The likelihood of death was significantly higher in patients with COPD that were hospitalized with COVID-19 compared to patients without COPD. Further studies are needed to assess whether this association is independent or not. No significant difference was demonstrated in COVID-19-related mortality between patients with and without asthma.