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.

High-Flow Nasal Oxygen for Severe Hypoxemia: Oxygenation Response and Outcome in Patients with COVID-19.

Rationale: The "Berlin definition" of acute respiratory distress syndrome (ARDS) does not allow inclusion of patients receiving high-flow nasal oxygen (HFNO). However, several articles have proposed that criteria for defining ARDS should be broadened to allow inclusion of patients receiving HFNO. Objectives: To compare the proportion of patients fulfilling ARDS criteria during HFNO and soon after intubation, and 28-day mortality between patients treated exclusively with HFNO and patients transitioned from HFNO to invasive mechanical ventilation (IMV). Methods: From previously published studies, we analyzed patients with coronavirus disease (COVID-19) who had PaO2/FiO2 of ⩽300 while treated with ⩾40 L/min HFNO, or noninvasive ventilation (NIV) with positive end-expiratory pressure of ⩾5 cm H2O (comparator). In patients transitioned from HFNO/NIV to invasive mechanical ventilation (IMV), we compared ARDS severity during HFNO/NIV and soon after IMV. We compared 28-day mortality in patients treated exclusively with HFNO/NIV versus patients transitioned to IMV. Measurements and Main Results: We analyzed 184 and 131 patients receiving HFNO or NIV, respectively. A total of 112 HFNO and 69 NIV patients transitioned to IMV. Of those, 104 (92.9%) patients on HFNO and 66 (95.7%) on NIV continued to have PaO2/FiO2 ⩽300 under IMV. Twenty-eight-day mortality in patients who remained on HFNO was 4.2% (3/72), whereas in patients transitioned from HFNO to IMV, it was 28.6% (32/112) (P < 0.001). Twenty-eight-day mortality in patients who remained on NIV was 1.6% (1/62), whereas in patients who transitioned from NIV to IMV, it was 44.9% (31/69) (P < 0.001). Overall mortality was 19.0% (35/184) and 24.4% (32/131) for HFNO and NIV, respectively (P = 0.2479). Conclusions: Broadening the ARDS definition to include patients on HFNO with PaO2/FiO2 ⩽300 may identify patients at earlier stages of disease but with lower mortality.

Plasma endostatin correlates with hypoxia and mortality in COVID-19-associated acute respiratory failure.

Background: The contribution of endothelial injury in the pathogenesis of COVID-19-associated acute respiratory distress syndrome (ARDS) and resulting respiratory failure remains unclear. Plasma endostatin, an endogenous inhibitor of angiogenesis and endothelial dysfunction is upregulated during hypoxia, inflammation and progress of pulmonary disease. Aim: To investigate if plasma endostatin is associated to hypoxia, inflammation and 30-day mortality in patients with severe COVID-19 infection. Method: Samples for blood analysis and plasma endostatin quantification were collected from adult patients with ongoing COVID-19 (n = 109) on admission to intensive care unit (day 1). Demographic characteristics and 30-day mortality data were extracted from medical records. The ability of endostatin to predict mortality was analyzed using receiving operating characteristics and Kaplan-Meier analysis with a cutoff at 46.2 ng/ml was used to analyze the association to survival. Results: Plasma endostatin levels correlated with; PaO2/FiO2 (r = -0.3, p < 0.001), arterial oxygen tension (r = -0.2, p = 0.01), lactate (r = 0.2, p = 0.04), C-reactive protein (r = 0.2, p = 0.04), ferritin (r = 0.2, p = 0.09), D-dimer (r = 0.2, p = 0.08) and IL-6 (r = 0.4, p < 0.001). Nonsurvivors at 30 days had higher plasma endostatin levels than survivors (72 ± 26 vs 56 ± 16 ng/ml, p = 0.01). Receiving operating characteristic curve (area under the curve 0.7) showed that plasma endostatin >46.2 ng/ml predicts mortality with a sensitivity of 92% and specificity of 71%. In patients with plasma endostatin >46.2 ng/ml probability of survival was lower (p = 0.02) in comparison to those with endostatin <46.2 ng/ml. Conclusion: Our results suggest that plasma endostatin is an early biomarker for disease severity in COVID-19.

Timing and causes of death in severe COVID-19 patients.

BACKGROUND: Previous studies reporting the causes of death in patients with severe COVID-19 have provided conflicting results. The objective of this study was to describe the causes and timing of death in patients with severe COVID-19 admitted to the intensive care unit (ICU). METHODS: We performed a retrospective study in eight ICUs across seven French hospitals. All consecutive adult patients (aged ≥ 18 years) admitted to the ICU with PCR-confirmed SARS-CoV-2 infection and acute respiratory failure were included in the analysis. The causes and timing of ICU deaths were reported based on medical records. RESULTS: From March 1, 2020, to April 28, 287 patients were admitted to the ICU for SARS-CoV-2 related acute respiratory failure. Among them, 93 patients died in the ICU (32%). COVID-19-related multiple organ dysfunction syndrome (MODS) was the leading cause of death (37%). Secondary infection-related MODS accounted for 26% of ICU deaths, with a majority of ventilator-associated pneumonia. Refractory hypoxemia/pulmonary fibrosis was responsible for death in 19% of the cases. Fatal ischemic events (venous or arterial) occurred in 13% of the cases. The median time from ICU admission to death was 15 days (25th-75th IQR, 7-27 days). COVID-19-related MODS had a median time from ICU admission to death of 14 days (25th-75th IQR: 7-19 days), while only one death had occurred during the first 3 days since ICU admission. CONCLUSIONS: In our multicenter observational study, COVID-19-related MODS and secondary infections were the two leading causes of death, among severe COVID-19 patients admitted to the ICU.

The use of oxygen hoods in patients failing on conventional high-flow oxygen delivery systems, the effects on oxygenation, mechanical ventilation and mortality rates in hypoxic patients with COVID-19. A Prospective Controlled Cohort Study.

INTRODUCTION: Efforts to meet increased oxygen demands in COVID-19 patients are a priority in averting mechanical ventilation (MV), associated with high mortality approaching 76.4-97.2%. Novel methods of oxygen delivery could mitigate that risk. Oxygen hoods/helmets may improve: O2-saturation (SaO2), reduce in-hospital mechanical ventilation and mortality rates, and reduce length of hospitalization in hypoxic Covid-19 patients failing on conventional high-flow oxygen delivery systems. METHODS: DesignProspective Controlled Cohort Study. SettingSingle Center. ParticipantsAll patients admitted with a diagnosis of COVID-19 were reviewed and 136/347 patients met inclusion criteria. Study period3/6/2020 to 5/1/2020. 136 participants completed the study with known status for all outcome measures. Intervention or exposureOxygen hoods/helmets as compared to conventional high-flow oxygen delivery systems. MAIN OUTCOME(S) AND MEASURE(S): 1) Pre and post change in oxygen saturation (SaO2). 2) In-hospital Mechanical Ventilation (MV). 3) In-hospital Mortality. 4) Length of hospitalization. RESULTS: 136 patients including 58-intervention and 78-control patients were studied. Age, gender, and other demographics/prognostic indicators were comparable between cohorts. Oxygen hoods averted imminent or immediate intubation/MV in all 58 COVID-19 patients failing on conventional high-flow oxygen delivery systems with a mean improvement in SaO2 of 8.8%, p < 0.001. MV rates were observed to be higher in the control 37/78 (47.4%) as compared to the intervention cohort 23/58 (39.7%), a difference of 7.7%, a 27% risk reduction, not statistically significant, OR 95%CI 0.73 (0.37-1.5). Mortality rates were observed higher in the control 54/78 (69.2%) as compared to the intervention cohort 36/58 (62.1%), a difference of 7.1%, a 27% risk reduction, not statistically significant OR 95%CI 0.73 (0.36-1.5). CONCLUSION: Oxygen hoods demonstrate improvement in SaO2 for patients failing on conventional high-flow oxygen-delivery systems and prevented imminent mechanical ventilation. In-hospital mechanical ventilation and mortality rates were reduced with the use of oxygen hoods but not found to be statistically significant. The oxygen hood is a safe, effective oxygen-delivery system which may reduce intubation/MV and mortality rates. Their use should be considered in treating hypoxic COVID-19 patients. Further research is warranted. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04407260.

Derivation of a Clinical Risk Score to Predict 14-Day Occurrence of Hypoxia, ICU Admission, and Death Among Patients with Coronavirus Disease 2019.

BACKGROUND: Uncertainty surrounding COVID-19 regarding rapid progression to acute respiratory distress syndrome and unusual clinical characteristics make discharge from a monitored setting challenging. A clinical risk score to predict 14-day occurrence of hypoxia, ICU admission, and death is unavailable. OBJECTIVE: Derive and validate a risk score to predict suitability for discharge from a monitored setting among an early cohort of patients with COVID-19. DESIGN: Model derivation and validation in a retrospective cohort. We built a manual forward stepwise logistic regression model to identify variables associated with suitability for discharge and assigned points to each variable. Event-free patients were included after at least 14 days of follow-up. PARTICIPANTS: All adult patients with a COVID-19 diagnosis between March 1, 2020, and April 12, 2020, in 10 hospitals in Massachusetts, USA. MAIN MEASURES: Fourteen-day composite predicting hypoxia, ICU admission, and death. We calculated a risk score for each patient as a predictor of suitability for discharge evaluated by area under the curve. KEY RESULTS: Of 2059 patients with COVID-19, 1326 met inclusion. The 1014-patient training cohort had a mean age of 58 years, was 56% female, and 65% had at least one comorbidity. A total of 255 (25%) patients were suitable for discharge. Variables associated with suitability for discharge were age, oxygen saturation, and albumin level, yielding a risk score between 0 and 55. At a cut point of 30, the score had a sensitivity of 83% and specificity of 82%. The respective c-statistic for the derivation and validation cohorts were 0.8939 (95% CI, 0.8687 to 0.9192) and 0.8685 (95% CI, 0.8095 to 0.9275). The score performed similarly for inpatients and emergency department patients. CONCLUSIONS: A 3-item risk score for patients with COVID-19 consisting of age, oxygen saturation, and an acute phase reactant (albumin) using point of care data predicts suitability for discharge and may optimize scarce resources.