ImportancePreclinical 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.ObjectiveTo 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 ParticipantsTwo 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.InterventionsA 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 MeasuresThe 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.ResultsBoth 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 RelevanceIn 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 RegistrationClinicalTrials.gov Identifier: NCT04924660

Few studies have reported the complications and outcomes of patients with Legionella pneumonia requiring ICU admission. The objective of our study is to report the clinical course, complications, and 30-day mortality of patients with Legionella pneumonia admitted to the critical care units at our medical center over a 10-year period.

Background: While numerous investigations have described worse outcomes for patients undergoing emergent procedures at night, few studies have investigated the impact of nighttime on the outcomes of emergent endotracheal intubation (EEI). We hypothesized that for patients requiring EEI at night, the outcome of first pass success would be lower as compared to during the day. Methods: We performed a retrospective cohort study of all patients admitted to our institution between January 1st, 2016 and July 17st, 2019 who underwent EEI outside of an emergency department or operating room. Nighttime was defined as between 7:00 pm and 6:59 am. The primary outcome was the rate of first pass success. Logistic regression was utilized with adjustment for demographic, morbidity and procedure related covariables. Results: The final examined cohort included 1,674 EEI during the day and 1,229 EEI at night. The unadjusted rate of first pass success was not different between the day and night (77.5% vs. 74.6%, unadjusted odds ratio (OR): 0.85; 95% confidence interval (CI): 0.72, 1.0; P = 0.073 though following adjustment for prespecified covariables the odds of first pass success was lower at night (adjusted OR: 0.83, 95% CI: 0.69, 0.99; P = 0.042. Obesity was found to be an effect modifier on first pass success rate for day vs. night intubations. In obese patients, nighttime intubations had significantly lower odds of first pass success (adjusted OR: 0.71, 95% CI: 0.52, 0.98; P = 0.037). Discussion: After adjustment for patient and procedure related factors, we have found that the odds of first pass success is lower at night as compared to the day. This finding was, to some degree, driven by obesity which was found to be a significant effect modifier in this relationship.

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Background Investigations into the use of low tidal volume ventilation (LTVV) have been performed for patients in emergency departments (EDs) or intensive care units (ICUs). Practice differences between the ICU and non-ICU care areas have not been described. We hypothesized that the initial implementation of LTVV would be better inside ICUs than outside. Methods: This is a retrospective observational study of patients initiated on invasive mechanical ventilation (IMV) between January 1, 2016, and July 17, 2019. Initial recorded tidal volumes after intubation were used to compare the use of LTVV between care areas. Low tidal volume was considered 6.5 cc/kg of ideal body weight (IBW) or less. The primary outcome was the initiation of low tidal volume. Sensitivity analyses used a tidal volume of 8 cc/kg of IBW or less, and direct comparisons were performed between the ICU, ED, and wards. Results: There were 6392 initiations of IMV: 2217 (34.7%) in the ICU and 4175 (65.3%) outside. LTVV was more likely to be initiated in the ICU than outside (46.5% vs 34.2%; adjusted odds ratio [aOR] 0.62, 95% confidence interval [CI] 0.56-0.71, P < .01). The ICU also had more implementation when PaO2/FiO2 ratio was less than 300, (48.0% vs 34.6%; aOR 0.59, 95% CI 0.48-0.71, P < .01). When comparing individual locations, wards had lower odds of LTVV than the ICU (aOR 0.82, 95% CI 0.70-0.96, P  =  .02), the ED had lower odds than the ICU (aOR 0.55, 95% CI 0.48-0.63, P < .01), and the ED had lower odds than the wards (aOR 0.66, 95% CI 0.56-0.77, P < .01). Interpretation: Initial low tidal volumes were more likely to be initiated in the ICU than outside. This finding remained when examining only patients with a PaO2/FiO2 ratio less than 300. Care areas outside of the ICU do not employ LTVV as often as ICUs and are, therefore, a possible target for process improvement.