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Background: This study aimed to assess whether a driving pressure-limiting strategy based on positive end-expiratory pressure (PEEP) titration according to best respiratory system compliance and tidal volume adjustment increases the number of ventilator-free days within 28 days in patients with moderate to severe acute respiratory distress syndrome (ARDS)., Methods: This is a multi-centre, randomised trial, enrolling adults with moderate to severe ARDS secondary to community-acquired pneumonia. Patients were randomised to a driving pressure-limiting strategy or low PEEP strategy based on a PEEP:FiO 2 table. All patients received volume assist-control mode until day 3 or when considered ready for spontaneous modes of ventilation. The primary outcome was ventilator-free days within 28 days. Secondary outcomes were in-hospital and intensive care unit mortality at 90 days., Results: The trial was stopped because of recruitment fatigue after 214 patients were randomised. In total, 198 patients (n=96 intervention group, n=102 control group) were available for analysis (median age 63 yr, [interquartile range 47-73 yr]; 36% were women). The mean difference in driving pressure up to day 3 between the intervention and control groups was -0.7 cm H 2 O (95% confidence interval -1.4 to -0.1 cm H 2 O). Mean ventilator-free days were 6 (sd 9) in the driving pressure-limiting strategy group and 7 (9) in the control group (proportional odds ratio 0.72, 95% confidence interval 0.39-1.32; P=0.28). There were no significant differences regarding secondary outcomes., Conclusions: In patients with moderate to severe ARDS secondary to community-acquired pneumonia, a driving pressure-limiting strategy did not increase the number of ventilator-free days compared with a standard low PEEP strategy within 28 days., Clinical Trial Registration: NCT04972318., Competing Interests: Declaration of interest The authors declare that they have no conflicts of interest., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Importance: High-flow nasal oxygen (HFNO) and noninvasive ventilation (NIV) are commonly used respiratory support therapies for patients with acute respiratory failure (ARF)., Objective: To assess whether HFNO is noninferior to NIV on the rates of endotracheal intubation or death at 7 days in 5 patient groups with ARF., Design, Setting, and Participants: This noninferiority, randomized clinical trial enrolled hospitalized adults (aged ≥18 years; classified as 5 patient groups with ARF: nonimmunocompromised with hypoxemia, immunocompromised with hypoxemia, chronic obstructive pulmonary disease [COPD] exacerbation with respiratory acidosis, acute cardiogenic pulmonary edema [ACPE], or hypoxemic COVID-19, which was added as a separate group on June 26, 2023) at 33 hospitals in Brazil between November 2019 and November 2023 (final follow-up: April 26, 2024)., Interventions: High-flow nasal oxygen (n = 883) or NIV (n = 883)., Main Outcomes and Measures: The primary outcome was endotracheal intubation or death within 7 days assessed using a bayesian hierarchical model with dynamic borrowing across patient groups. Noninferiority was defined by a posterior probability of 0.992 or greater for an odds ratio (OR) less than 1.55., Results: Among 1800 patients, 1766 completed the study (mean age, 64 [SD, 17] years; 707 [40%] were women). The primary outcome of endotracheal intubation or death at 7 days occurred in 39% (344/883) in the HFNO group vs 38% (336/883) in the NIV group. In the immunocompromised with hypoxemia patient group, the primary outcome occurred in 57.1% (16/28) in the HFNO group vs 36.4% (8/22) in the NIV group; enrollment was stopped for futility (final OR, 1.07; 95% credible interval [CrI], 0.81-1.39; noninferiority posterior probability [NPP], 0.989). In the nonimmunocompromised with hypoxemia group, the primary outcome occurred in 32.5% (81/249) in the HFNO group vs 33.1% (78/236) in the NIV group (OR, 1.02 [95% CrI, 0.81-1.26]; NPP, 0.999). In the ACPE group, the primary outcome occurred in 10.3% (14/136) in the HFNO group vs 21.3% (29/136) in the NIV group (OR, 0.97 [95% CrI, 0.73-1.23]; NPP, 0.997). In the hypoxemic COVID-19 group, the primary outcome occurred in 51.3% (223/435) in the HFNO group vs 47.0% (210/447) in the NIV group (OR, 1.13 [95% CrI, 0.94-1.38]; NPP, 0.997). In the COPD exacerbation with respiratory acidosis group, the primary outcome occurred in 28.6% (10/35) in the HFNO group vs 26.2% (11/42) in the NIV group (OR, 1.05 [95% CrI, 0.79-1.36]; NPP, 0.992). However, a post hoc analysis without dynamic borrowing across the 5 ARF patient groups revealed some qualitatively different results in patients with COPD, immunocompromised patients, and patients with ACPE. The incidence of serious adverse events was similar (9.4% of patients in HFNO group vs 9.9% in NIV group)., Conclusions and Relevance: Compared with NIV, HFNO met prespecified criteria for noninferiority for the primary outcome of endotracheal intubation or death within 7 days in 4 of the 5 patient groups with ARF. However, the small sample sizes in some patient groups and the sensitivity of the findings to the choice of analysis model suggests the need for further study in patients with COPD, immunocompromised patients, and patients with ACPE., Trial Registration: ClinicalTrials.gov Identifier: NCT03643939.

Purpose: To assess the effect of antisense therapy to block kallikrein-kinin pathway in COVID-19 patients., Material and Methods: Randomized, placebo-controlled, double blind, controlled trial enrolling hospitalized COVID-19 patients that required supplementary oxygen to sustain peripheral oxygen saturation. Key exclusion criteria included use of mechanical ventilation or vasopressors, and patients with more than 10 days since symptom onset or more than 48 h of oxygen use. Patients were randomized to either one subcutaneous dose of ISIS721744, an antisense that blocks prekallikrein, or placebo. The primary outcome was the number of days alive and free of oxygen support up to 15 days (DAFOR15). Secondary endpoints included organ failure score, need and duration of mechanical ventilation up to 15 days, and all-cause mortality at 30 days. Exploratory endpoints included physiological parameters, biomarkers, and quality of life., Results: From October 10, 2020, to December 09, 2020, 111 patients were randomized at thirteen sites in Brazil (56 to treatment and 55 to control group). Average age was 57.5 years, and most patients were male (68.5%). There were no significant differences in DAFOR15 between groups (5.9 ± 5.2 days for the intervention arm and 7.7 ± 5.1 for the control group; mean difference - 0.65, 95% confidence intervals from -2.95 to 1.36, p = 0.520)., Conclusion: Antisense therapy designed to block the kallikrein-kinin pathway did not demonstrate clinical benefits in increasing days-alive without respiratory support at 15 days in patients with COVID-19 during the first wave in 2020., Gov Identifier: NCT04549922., Competing Interests: Declaration of competing interest None. This study was funded by Ionis Pharmaceutical, US, through a grant provided to HCor. The sponsor reviewed and agreed with the protocol, but had no role in any other aspect of the trial execution. MJ and GB were Ionis employees at the time this study was designed and provided relevant feedback on design of the trial and reviewed the final manuscript for intellectually relevant content. FGZ has received consulting fees from Baxter, unrelated to the scope of this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Critically ill patients are at increased risk of health care-associated infections due to various devices (central line-associated bloodstream infection, catheter-associated urinary tract infection, and ventilator-associated pneumonia), which pose a significant threat to this population. Among several strategies, daily bathing with chlorhexidine digluconate, a water-soluble antiseptic, has been studied as an intervention to decrease the incidence of health care-associated infections in the intensive care unit; however, its ability to reduce all health care-associated infections due to various devices is unclear. We designed the Daily Chlorhexidine Bath for Health Care Associated Infection Prevention (CLEAN-IT) trial to assess whether daily chlorhexidine digluconate bathing reduces the incidence of health care-associated infections in critically ill patients compared with soap and water bathing., Methods: The CLEAN-IT trial is a multicenter, open-label, cluster randomized crossover clinical trial. All adult patients admitted to the participating intensive care units will be included in the trial. Each cluster (intensive care unit) will be randomized to perform either initial chlorhexidine digluconate bathing or soap and water bathing with crossover for a period of 3 to 6 months, depending on the time of each center's entrance to the study, with a 1-month washout period between chlorhexidine digluconate bathing and soap and water bathing transitions. The primary outcome is the incidence of health care-associated infections due to devices. The secondary outcomes are the incidence of each specific health care-associated infection, rates of microbiological cultures positive for multidrug-resistant pathogens, antibiotic use, intensive care unit and hospital length of stay, and intensive care unit and hospital mortality., Conclusion: The CLEAN-IT trial will be used to study feasible and affordable interventions that might reduce the health care-associated infection burden in critically ill patients.

Background: Driving pressure has been suggested to be the main driver of ventilator-induced lung injury and mortality in observational studies of acute respiratory distress syndrome. Whether a driving pressure-limiting strategy can improve clinical outcomes is unclear., Objective: To describe the protocol and statistical analysis plan that will be used to test whether a driving pressure-limiting strategy including positive end-expiratory pressure titration according to the best respiratory compliance and reduction in tidal volume is superior to a standard strategy involving the use of the ARDSNet low-positive end-expiratory pressure table in terms of increasing the number of ventilator-free days in patients with acute respiratory distress syndrome due to community-acquired pneumonia., Methods: The ventilator STrAtegy for coMmunIty acquired pNeumoniA (STAMINA) study is a randomized, multicenter, open-label trial that compares a driving pressure-limiting strategy to the ARDSnet low-positive end-expiratory pressure table in patients with moderate-to-severe acute respiratory distress syndrome due to community-acquired pneumonia admitted to intensive care units. We expect to recruit 500 patients from 20 Brazilian and 2 Colombian intensive care units. They will be randomized to a driving pressure-limiting strategy group or to a standard strategy using the ARDSNet low-positive end-expiratory pressure table. In the driving pressure-limiting strategy group, positive end-expiratory pressure will be titrated according to the best respiratory system compliance., Outcomes: The primary outcome is the number of ventilator-free days within 28 days. The secondary outcomes are in-hospital and intensive care unit mortality and the need for rescue therapies such as extracorporeal life support, recruitment maneuvers and inhaled nitric oxide., Conclusion: STAMINA is designed to provide evidence on whether a driving pressure-limiting strategy is superior to the ARDSNet low-positive end-expiratory pressure table strategy for increasing the number of ventilator-free days within 28 days in patients with moderate-to-severe acute respiratory distress syndrome. Here, we describe the rationale, design and status of the trial.

Background: Halofuginone (PJS-539) is an oral prolyl-tRNA synthetase inhibitor that has a potent in vitro activity against SARS-CoV-2 virus. The safety and efficacy of halofuginone in Covid-19 patients has not been studied., Methods: We conducted a phase II, randomized, double-blind, placebo-controlled, dose ranging, safety and tolerability trial of halofuginone in symptomatic (≤ 7 days), mostly vaccinated, non-hospitalized adults with mild to moderate Covid-19. Patients were randomized in a 1:1:1 ratio to receive halofuginone 0.5mg, 1mg or placebo orally once daily for 10 days. The primary outcome was the decay rate of the SARS-CoV-2 viral load logarithmic curve within 10 days after randomization., Results: From September 25, 2021, to February 3, 2022, 153 patients were randomized. The mean decay rate in SARS-CoV-2 viral load log10 within 10 days was -3.75 (95% CI, -4.11; -3.19) in the placebo group, -3.83 (95% CI, -4.40; -2.27) in the halofuginone 0.5mg group and -4.13 (95% CI, -4.69; -3.57) in the halofuginone 1mg group, with no statistically significant difference in between placebo vs. halofuginone 0.5mg (mean difference -0.08; 95% CI -0.82 to 0.66, p = 0.96) and between placebo vs. halofuginone 1mg (mean difference -0.38; 95% CI, -1.11; 0.36, p = 0.41). There was no difference on bleeding episodes or serious adverse events at 28 days., Conclusions: Among non-hospitalized adults with mild to moderate Covid-19 halofuginone treatment was safe and well tolerated but did not decrease SARS-CoV-2 viral load decay rate within 10 days., Competing Interests: S.T is a co-inventor and receives royalties from patents owned by University of California San Diego (UCSD) and is a co-founder and has an equity interest in Oxitope, LLC and its affiliates, Kleanthi Diagnostics, LLC and Covicept Therapeutics, Inc and has a dual appointment at UCSD and Ionis Pharmaceuticals; A.F.C has received contract payments from Nurix Therapeutics, Inc. and has options in Covicept Therapeutics; J.D.E is a cofounder, consultant and shareholder in Covicept Therapeutics (San Diego, CA) and TEGA Therapeutics (La Jolla, CA); P.L.S.M.G. is a cofounder, consultant and shareholder in Covicept Therapeutics (San Diego, CA). All remaining authors: No conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials, although some restrictions might apply as stated in the submission., (Copyright: © 2024 Tomazini et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Repurposed drugs for treatment of new onset disease may be an effective therapeutic shortcut. We aimed to evaluate the efficacy of repurposed antivirals compared to placebo in lowering SARS-CoV2 viral load of COVID-19 patients., Methods: REVOLUTIOn is a randomised, parallel, blinded, multistage, superiority and placebo controlled randomised trial conducted in 35 centres in Brazil. We include patients aged 18 years or older admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, symptoms onset 9 days or less and SpO 2 94% or lower at room air were eligible. All participants were randomly allocated to receive either atazanavir, daclatasvir or sofosbuvir/daclatasvir or placebo for 10 days. The primary outcome was the decay rate (slope) of the SARS-CoV-2 viral load logarithm assessed in the modified intention to-treat population. This trial was registered with ClinicalTrials.gov, number NCT04468087., Findings: Between February 09, 2021, and August 04, 2021, 255 participants were enrolled and randomly assigned to atazanavir (n = 64), daclatasvir (n = 66), sofosbuvir/daclatasvir (n = 67) or placebo (n = 58). Compared to placebo group, the change from baseline to day 10 in log viral load was not significantly different for any of the treatment groups (0.05 [95% CI, -0.03 to 0.12], -0.02 [95% CI, -0.09 to 0.06], and -0.03 [95% CI, -0.11 to 0.04] for atazanavir, daclatasvir and sofosbuvir/daclatasvir groups respectively). There was no significant difference in the occurrence of serious adverse events between treatment groups., Interpretation: No significant reduction in viral load was observed from the use of atazanavir, daclatasvir or sofosbuvir/daclatasvir compared to placebo in hospitalised COVID-19 patients who need oxygen support with symptoms onset 9 days or less., Funding: Ministério da Ciência, Tecnologia e Inovação (MCTI) - Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ); Cia Latino-Americana de Medicamentos (Clamed); Cia Industrial H. Carlos Schneider (Ciser); Hospital Research Foundation Incorporation, Australia, HCor São Paulo; Blanver Farmoquímica; Instituto de Tecnologia em Fármacos (Farmanguinhos) da Fundação Oswaldo Cruz (Fiocruz); Coordenação Geral de Planejamento Estratégico (Cogeplan)/Fiocruz; and Fundação de apoio a Fiocruz (Fiotec, VPGDI-054-FIO-20-2-13)., Competing Interests: ISM reports devices supply from Fisher & Paykel outside the submitted work; ISM and ABC reports funding paid to HCor by Ministerio da Ciência, Tecnologia e Inovação (MCTIC)/Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ), Cia Latino Americana de Medicamentos (Clamed); Cia Industrial H. Carlos Schneider (Ciser); Hospital Research Foundation Incorporation, Australia, HCor São Paulo; Blanver Farmoquímica; Instituto de Tecnologia em Fármacos (Farmanguinhos) da Fundação Oswaldo Cruz (Fiocruz); Coordenação Geral de Planejamento Estratégico (Cogeplan)/Fiocruz; and Fundação de apoio a Fiocruz; LPD reports personal statistical Consulting fees from Servier Laboratories, Aché Laboratory and Astra Zeneca; FGZ reports grants for investigator initiated trials paid to his institution from Bactiguard, Ionis Pharmaceuticals and statistical Consulting from Bactiguard; RGR reported research grants from Pfizer and Brazilian Ministry of Health-PROADI-SUS; LCPA reported participation on advisory board of COVID-19 drugs for MSD; OB reported grants or contracts from: AstraZeneca, Amgen, Bayer, Pfizer, BMS Servier, Novartis Boehringer-Ingelheim, RDL reports grants or contracts from Bristol-Myers Squibb, Glaxo Smith Kline, Medtronic, Pfizer, Sanofi with payments to his institution, payment or honoraria for lectures, presentations, speakers, manuscript writing from Pfizer, Participation on a Data Safety Monitoring Board or Advisory Board of Glaxo Smith Kline and Consulting fees from Bayer, Boehringer Ingleheim, Bristol-Myers Squibb, Daiichi Sankyo, Glaxo Smith Kline, Medtronic, Merck, Pfizer, Portola and Sanofi; AA reports grants form Population Health Research Institute, EMS and Bayer as funding to his institution, payment for lectures for EMS and Bayer. All other authors declare no competing interests., (© 2023 The Authors.)

Objective: To evaluate the effectiveness of the Welch Allyn Connex® Spot Monitor/Hillrom Connecta™ solution in activating the rapid response team in a timely manner compared to manual activation., Methods: The Hillrom study is a single-center, open-label, superiority, cluster-randomized, parallel-group (1:1 allocation ratio) clinical trial that will be conducted in a tertiary hospital. Two sets of three wards with 28 beds will be included (one as the intervention cluster and the other as the control). The wards will be randomly assigned to use the Welch Allyn Connex® Spot Monitor/Hillrom Connecta™ automated solution (intervention cluster) or to maintain the usual routine (control cluster) regarding rapid response team activation. The primary outcome will be the absolute number of episodes of rapid response team triggering in an appropriate time; as secondary outcomes, clinical features (mortality, cardiac arrest, need for intensive care unit admission and duration of hospitalization) will be assessed according to clusters in an exploratory way. A sample size of 216 rapid response team activations was estimated to identify a possible difference between the groups. The protocol has been approved by the institutional Research Ethics Committee., Expected Results: The Welch Allyn Connex® Spot Monitor/Hillrom Connecta™ automated solution is expected to be more effective in triggering the nurse call system to activate the rapid response team in a timely and adequate manner compared to manual triggering (usual practice)., Clinicaltrials.gov: NCT04648579.

Objective: To describe the IMPACTO-MR, a Brazilian nationwide intensive care unit platform study focused on the impact of health care-associated infections due to multidrug-resistant bacteria., Methods: We described the IMPACTO-MR platform, its development, criteria for intensive care unit selection, characterization of core data collection, objectives, and future research projects to be held within the platform., Results: The core data were collected using the Epimed Monitor System® and consisted of demographic data, comorbidity data, functional status, clinical scores, admission diagnosis and secondary diagnoses, laboratory, clinical, and microbiological data, and organ support during intensive care unit stay, among others. From October 2019 to December 2020, 33,983 patients from 51 intensive care units were included in the core database., Conclusion: The IMPACTO-MR platform is a nationwide Brazilian intensive care unit clinical database focused on researching the impact of health care-associated infections due to multidrug-resistant bacteria. This platform provides data for individual intensive care unit development and research and multicenter observational and prospective trials.

Repurposed drugs are important in resource-limited settings because the interventions are more rapidly available, have already been tested safely in other populations and are inexpensive. Repurposed drugs are an effective solution, especially for emerging diseases such as COVID-19. The REVOLUTIOn trial has the objective of evaluating three repurposed antiviral drugs, atazanavir, daclatasvir and sofosbuvir, already used for HIV- and hepatitis C virus-infected patients in a randomized, placebo-controlled, adaptive, multiarm, multistage study. The drugs will be tested simultaneously in a Phase II trial to first identify whether any of these drugs alone or in combination reduce the viral load. If they do, a Phase III trial will be initiated to investigate if these medications are capable of increasing the number of days free respiratory support. Participants must be hospitalized adults aged ≥ 18 years with initiation of symptoms ≤ 9 days and SpO2 ≤ 94% in room air or a need for supplemental oxygen to maintain an SpO2 > 94%. The expected total sample size ranges from 252 to 1,005 participants, depending on the number of stages that will be completed in the study. Hence, the protocol is described here in detail together with the statistical analysis plan. In conclusion, the REVOLUTIOn trial is designed to provide evidence on whether atazanavir, daclatasvir or sofosbuvir decrease the SARS-CoV-2 load in patients with COVID-19 and increase the number of days patients are free of respiratory support. In this protocol paper, we describe the rationale, design, and status of the trial. ClinicalTrials.gov identifier: NCT04468087.