Abstract Background Randomized trials evaluating emergency treatments may be conducted with Exception from Informed Consent (EFIC) when informed consent is infeasible. In EFIC trials, a period of community consultation and public disclosure precedes initiation of enrollment. The Randomized Trial of Sedative Choice for Intubation (RSI) was a 2,365-patient randomized trial conducted with EFIC in 14 emergency departments and intensive care units across the United States. This manuscript reports the approach to community consultation and public disclosure in the RSI trial. Methods Community consultation and public disclosure were conducted locally in each region of enrolling sites. The coordinating center provided sites with templates and access to an engagement coordinator to assist with developing and executing site plans. Results Community consultation and public disclosure occurred at the coordinating center from February 2021-January 2022 and in the regions of the five additional enrolling sites from September 2023-June 2024. Community consultation included in-person surveys with 789 patients or family members in emergency department or intensive care unit waiting rooms and invitation of more than 200 local groups to town halls or Community Engagement Studios. Public disclosure included (i) social media advertisements viewed more than 1.2 million times, (ii) a trial website with more than 16,000 unique visitors, (iii) informational flyers in hospitals and public settings, and (iv) featured information in traditional media. Completing local community consultation and public disclosure required an average of 139 h of research personnel time and approximately $18,822 at each site, in addition to coordinating center effort and costs. Conclusions Pre-trial community consultation activities in the RSI trial engaged over 1,000 patients, families, and community members and public disclosure reached over 1.2 million community members. While the total cost and duration of activities at sites were substantially lower than reported in prior EFIC trials, these costs remained significant. Trial registration ClinicalTrials.gov; No.: NCT05277896; URL: www.clinicaltrials.gov

BACKGROUND: Laryngoscope blade size may affect successful intubation on the first attempt, but evidence to inform the optimal blade size for standard-geometry curved video laryngoscopes (VLs) in critically ill adults is limited. RESEARCH QUESTION: Does the use of a size 3 vs size 4 standard-geometry curved VL blade affect outcomes of tracheal intubation in critically ill adults? STUDY DESIGN AND METHODS: We performed a secondary analysis of data from 2 multicenter randomized trials conducted in ICUs and emergency departments (EDs) in the United States. We included adult patients who, on the first intubation attempt, received a standard-geometry curved VL blade of size 3 or 4. The primary outcome was the incidence of successful intubation on the first attempt. Secondary outcomes included the duration of the procedure, the lowest oxygen saturation, the incidence of severe hypoxemia, glottic view, and exploratory clinical outcomes. We used propensity score-based inverse probability of treatment weighting (IPTW) to adjust for baseline differences between groups. RESULTS: Of 1,220 patients, 517 patients (42%) were intubated with a size 3 blade and 703 patients (58%) were intubated with a size 4 blade. After IPTW adjustment, patients intubated with a size 3 blade and a size 4 blade did not differ regarding the incidence of successful intubation on the first attempt (84.6% vs 87.6%, respectively; adjusted OR, 0.78; 95% CI, 0.54-1.14). Procedure duration was similar (38.4 seconds vs 39.1 seconds; aHR, 0.97; 95% CI, 0.85-1.10). Complications and exploratory outcomes were comparable between groups. INTERPRETATION: Our results show that among critically ill adults undergoing emergency tracheal intubation with standard-geometry VLs, blade size (3 vs 4) was not associated with first-pass success or other major procedural and clinical outcomes.

BACKGROUND:Two biological subphenotypes in acute respiratory distress syndrome (ARDS) have been identified in retrospective analyses, with differential clinical outcomes and post-hoc responses to investigational treatments. The ability to identify biological subphenotypes in real-time is unknown. We aimed to evaluate the feasibility of using the multisite ISPY COVID Network to prospectively evaluate biological subphenotypes in real-time. METHODS:This prospective, observational, cohort study enrolled patients with ARDS and severe acute hypoxaemic respiratory failure (AHRF) and assessed the feasibility of real-time stratification into biological subphenotypes using plasma concentrations of IL-6, soluble tumour necrosis factor-1 (TNFR1), and clinical variables. Participants were eligible if they were receiving mechanical ventilation, non-invasive positive pressure ventilation, or heated high flow nasal oxygen (at flow rates ≥30 L/min); had severe AHRF (defined by an SpO2 to FiO2 ratio ≤315, calculated with SpO2 ≤97%, or PaO2 to FiO2 ratio <300 if arterial blood gas was available); and the presence of these criteria for less than 48 h. Key exclusion criteria were being younger than 18 years, known pregnancy, being incarcerated, ARDS secondary to trauma, and rapidly improving hypoxaemia. Enrolled patients had to meet inclusion and exclusion criteria at the time of consent and blood draw. Enrolled patients were stratified into either a severe AHRF group (unilateral infiltrate) or an ARDS group (bilateral infiltrates) based on chest imaging at enrolment, determined by the study team. After enrolment, a blood sample (up to 6 mL) was collected and immediately taken to the local laboratory for plasma analysis. Following biomarker quantification participants were allocated to the hypoinflammatory or hyperinflammatory groups. Feasibility was defined a priori as successful real-time biological subphenotyping in greater than 75% of the final 100 enrolled participants. FINDINGS:From June 15, 2023, to Oct 31, 2024, 844 patients at 17 hospitals in the ISPY COVID Network across the USA were screened for the study. After 504 exclusions and two withdrawals of consent, 338 patients were enrolled. 124 (37%) of the enrolled cohort were classified as AHRF, and 214 (63%) were classified as ARDS. 199 (59%) of patients were male and 138 (41%) were female, and the median age at enrolment was 64 years (IQR 54-74). The majority of patients were white (239 [71%]). 250 (74%) of the enrolled cohort completed subphenotype assignment using fresh plasma and were defined as successfully subphenotyped. Successful real-time subphenotyping increased from 59 for the first 100 enrolled participants (59% [95% CI 49-69]) to 82 for the last 100 enrolled participants (82% [73-89]), meeting the predefined feasibility threshold. Median time to subphenotype assignment from blood collection in the overall cohort and the successfully subphenotyped subgroup was 2·2 h (IQR 1·5-19·8) and 1·9 h (1·3-2·3) from the time of blood collection, respectively. The hyperinflammatory subphenotype was identified in 61 (29%) of 214 participants with ARDS and 29 (23%) of the 124 participants with severe AHRF. Clinical outcomes including mortality, organ support-free days and ventilator-free days were worse in patients with hyperinflammatory ARDS compared with those with hypoinflammatory ARDS. INTERPRETATION:Rapid real-time biological subphenotyping for ARDS and severe AHRF in a multisite US hospital network is feasible; and successful real-time subphenotyping both improved over the study time-course and was completed within 2·2 h from study blood collection. These results support the feasibility of real-time precision trials of therapies targeting biological subphenotypes in ARDS. FUNDING:COVID R&D Consortium, Allergan, Amgen, Takeda Pharmaceutical Company, Ingenus Pharmaceuticals, Implicit Bioscience, Johnson & Johnson, Pfizer, Roche-Genentech, Apotex, FAST Grant from Emergent Venture George Mason University, and The Grove Foundation. This work was supported by the US Defense Threat Reduction Agency (MCDC-2013-001). This project has been funded in whole or in part with Federal funds from the US Department of Health and Human Services; Administration for Strategic Preparedness and Response; and Biomedical Advanced Research and Development Authority (MCDC-2014-001).

Background:Emergency tracheal intubation is a common and high-risk procedure. Ketamine and etomidate are sedative medicines commonly used to induce anesthesia for emergency tracheal intubation, but whether the induction medication used affects patient outcomes is uncertain. Research Question:Does the use of ketamine for induction of anesthesia decrease the incidence of death among adults undergoing emergency tracheal intubation, compared to the use of etomidate? Study Design and Methods:The Randomized trial of Sedative choice for Intubation (RSI) is a pragmatic, multicenter, unblinded, parallel-group, randomized trial being conducted in 14 sites (6 emergency departments and 8 intensive care units) in the United States. The trial compares ketamine vs etomidate for induction of anesthesia among 2,364 critically ill adults undergoing emergency tracheal intubation. The primary outcome is all-cause, 28-day in-hospital mortality. The secondary outcome is the incidence of cardiovascular collapse during intubation, a composite of hypotension, receipt of vasopressors, and cardiac arrest. Enrollment began on April 6, 2022, and is expected to conclude in 2025. Interpretation:The RSI trial will provide important data on the effects of ketamine vs etomidate on death and other outcomes for critically ill adults undergoing emergency tracheal intubation. Specifying the protocol and statistical analysis plan before the conclusion of enrollment increases the rigor, reproducibility, and interpretability of the trial. Trial Registry:ClinicalTrials.gov ; No.: NCT05277896 ; URL: www.clinicaltrials.gov. Take-Home Points:Study Question: Does use of ketamine for induction of anesthesia during emergency tracheal intubation decrease the incidence of death, compared with use of etomidate?Results: This manuscript describes the protocol and statistical analysis plan for the Randomized trial of Sedative choice for Intubation (RSI) comparing ketamine vs etomidate for induction of anesthesia for emergency tracheal intubation.Interpretation: Prespecifying the full statistical analysis plan before completion of enrollment increases rigor, reproducibility, and transparency of the trial results.

BACKGROUND: Airway management is a critical component of the care of patients experiencing cardiac arrest, but data from randomized trials on the use of video vs direct laryngoscopy for intubation in the setting of cardiac arrest are limited. Current American Heart Association guidelines recommend placement of an endotracheal tube either during CPR or shortly after return of spontaneous circulation, but do not provide guidance around intubation methods, including the choice of laryngoscope. RESEARCH QUESTION: Does use of video laryngoscopy improve the incidence of successful intubation on the first attempt, compared with use of direct laryngoscopy, among adults undergoing tracheal intubation after experiencing cardiac arrest? STUDY DESIGN AND METHODS: This secondary analysis of the Direct vs Video Laryngoscope (DEVICE) trial compared video laryngoscopy vs direct laryngoscopy in the subgroup of patients who were intubated after cardiac arrest. The primary outcome was the incidence of successful intubation on the first attempt. Additional outcomes included the duration of laryngoscopy. RESULTS: Among the 1,417 patients in the DEVICE trial, 113 patients (7.9%) experienced cardiac arrest before intubation, of whom 48 patients were randomized to the video laryngoscopy group and 65 patients were randomized to the direct laryngoscopy group. Successful intubation on the first attempt occurred in 40 of 48 patients (83.3%) in the video laryngoscopy group and in 42 of 65 patients (64.6%) in the direct laryngoscopy group (absolute risk difference, 18.7 percentage points; 95% CI, 1.2-36.2 percentage points; P = .03). The mean duration of laryngoscopy was 48.0 seconds (SD, 37.3 seconds) in the video laryngoscope group and 98.0 seconds (SD, 122.4 seconds) in the direct laryngoscopy group (mean difference, -50.0 seconds; 95% CI, -86.8 to-13.3 seconds; P = .004). INTERPRETATION: Among adults undergoing tracheal intubation after experiencing cardiac arrest, use of video laryngoscopy was associated with increased incidence of successful intubation on the first attempt and shortened duration of laryngoscopy, compared with use of direct laryngoscopy.

Background: Emergency tracheal intubation is a common and high-risk procedure. Ketamine and etomidate are medicines commonly used to induce anesthesia for emergency tracheal intubation, but whether the induction medication used affects patient outcomes is uncertain. Research Question: Does the use of ketamine for induction of anesthesia decrease the incidence of death among adults undergoing emergency tracheal intubation compared with the use of etomidate? Study Design and Methods: The Randomized Trial of Sedative Choice for Intubation (RSI) is a pragmatic, multicenter, unmasked, parallel-group randomized trial being conducted at 14 sites (6 emergency departments and 8 ICUs) in the United States. The trial compares ketamine vs etomidate for induction of anesthesia among 2,364 critically ill adults undergoing emergency tracheal intubation. The primary outcome is all-cause 28-day in-hospital mortality. The secondary outcome is the incidence of cardiovascular collapse during intubation, a composite of hypotension, receipt of vasopressors, and cardiac arrest. Results: Enrollment began on April 6, 2022, and is expected to conclude in 2025. Interpretation: The RSI will provide important data on the effects of ketamine vs etomidate on death and other outcomes for critically ill adults undergoing emergency tracheal intubation. Specifying the protocol and statistical analysis plan before the conclusion of enrollment increases the rigor, reproducibility, and transparency of the trial. Clinical Trial Registration: ClinicalTrials.gov; No.: NCT05277896; URL: www.clinicaltrials.gov

Background Airway management is a critical component of the care of patients experiencing cardiac arrest, but data from randomized trials on the use of video vs direct laryngoscopy for intubation in the setting of cardiac arrest are limited. Current AHA guidelines recommend placement of an endotracheal tube either during CPR or shortly after return of spontaneous circulation but do not provide guidance around intubation methods, including the choice of laryngoscope. Research question Does use of video laryngoscopy improve the incidence of successful intubation on the first attempt, compared to use of direct laryngoscopy, among adults undergoing tracheal intubation after experiencing cardiac arrest? Study Design and Methods This secondary analysis of the Direct versus Video Laryngoscope (DEVICE) trial compared video laryngoscopy versus direct laryngoscopy in the subgroup of patients who were intubated following cardiac arrest. The primary outcome was the incidence of successful intubation on the first attempt. Additional outcomes included the duration of laryngoscopy. Results Among the 1,417 patients in the DEVICE trial, 113 (7.9%) had experienced cardiac arrest prior to intubation, of whom 48 were randomized to the video laryngoscopy group and 65 to the direct laryngoscopy group. Successful intubation on the first attempt occurred in 40 of 48 patients (83.3%) in the video laryngoscopy group and 42 of 65 patients (64.6%) in the direct laryngoscopy group (absolute risk difference, 18.7 percentage points; 95% confidence interval [CI], 1.2 to 36.2; P = 0.03). The mean duration of laryngoscopy was 48.0 seconds (standard deviation [SD], 37.3 seconds) in the video laryngoscope group and 98.0 seconds (SD, 122.4) in the direct laryngoscopy group (mean difference, -50.0; 95% CI, -86.8 to -13.3, P = 0.004). Interpretation Among adults undergoing tracheal intubation after experiencing cardiac arrest, use of video laryngoscopy was associated with increased incidence of successful intubation on the first attempt and shortened duration of laryngoscopy, compared to use of direct laryngoscopy.

RATIONALE: Hypoxemia is a common and life-threatening complication of emergency tracheal intubation. Preoxygenation with supplemental oxygen prior to induction of anesthesia decreases the risk of hypoxemia during intubation. An oxygen mask is the most common method of preoxygenation used in current clinical care. While preoxygenation using noninvasive ventilation has been shown to reduce hypoxemia during intubation compared to preoxygenation with an oxygen mask, noninvasive ventilation may not be suitable for all patients or settings. When an oxygen mask is used, whether the type of mask affects the incidence of hypoxemia is not known.METHODS: We conducted a secondary analysis of the Pragmatic Trial Examining Oxygenation Prior to Intubation (PREOXI) and Direct vs Video Laryngoscope (DEVICE) randomized controlled trials. We compared the incidence of hypoxemia, defined as a peripheral oxygen saturation <85% between induction and 2 minutes after tracheal intubation, between participants preoxygenated with facemask oxygen (either a nonrebreather or facemask without oxygen reservoir) versus a bag-mask device without manual ventilation. The primary analysis was a propensity weighted multivariate logistic regression adjusting for body mass index (BMI), APACHE II score, intubation location (ICU vs ED) and hypoxemic respiratory failure prior to intubation as covariates.RESULTS: Of the 2440 participants enrolled in the PREOXI and DEVICE trials, 1077 were preoxygenated using facemask oxygen and 148 were preoxygenated using a bag-mask device without manual ventilation. The median highest Fraction of Inspired Oxygen (FiO2) prior to intubation was 0.3 (interquartile range [IQR] 0.21 to 0.66) in both the facemask oxygen and bag-mask device groups. A total of 168/1077 (16%) of participants in the facemask oxygen group and 28/148 (19%) of participants in the bag-mask device groups received heated high flow nasal cannula oxygen in the hour prior to intubation. Hypoxemia occurred in 156/1034 (15.1%) participants in the facemask oxygen group and 20/139 (14.4%) participants in the bag-mask device group. In the multivariate analysis, participants preoxygenated with facemask oxygen had similar odds of hypoxemia to those preoxygenated with a bag-mask device (aOR:1.21, 95%CI:[0.70,2.09]). The median lowest oxygen saturation between induction and 2 minutes after tracheal intubation was 97 (IQR 91 to 100) in the facemask oxygen group and 98 (IQR 93 to 100), P=0.33 in the bag-mask device group.CONCLUSIONS: In this secondary analysis of two trials which enrolled critically ill adults undergoing emergency tracheal intubation, preoxygenation with facemask oxygen was not associated with decreased incidence of hypoxemia compared to preoxygenation with a bag-mask device.

STUDY OBJECTIVES:Complications are common during emergency tracheal intubation. Although graduate medical education in emergency medicine and critical care mandate competency in this procedure, thresholds for proficiency are poorly defined. We evaluated the relationship between the operator performing intubation and complications of emergency tracheal intubation. METHODS:We performed a secondary analysis of data from 8 multicenter randomized trials of critically ill adults undergoing emergency tracheal intubation in an emergency department or ICU in the United States. We examined the relationship between an operator's prior intubating experience and procedural outcomes, including successful intubation on the first attempt and lowest oxygen saturation. RESULTS:Among 2,839 intubations with data on prior intubating experience of the operator, 1,863 (65.6%) were by critical care medicine clinicians and 739 (26.0%) by emergency medicine clinicians. The median number of reported previous intubations by clinicians was 56.0 (interquartile range, 32 to 100). Greater intubation experience was associated with an increased odds of successful intubation on the first attempt (odds ratio [OR], 1.75; 95% confidence interval [CI], 1.30 to 2.36; P<.001) and increased lowest oxygen saturation (OR 1.45; 95% CI, 1.21 to 1.73; P<.001). Learning curves suggested a plateau effect between 35 and 50 intubations. CONCLUSION:For tracheal intubations performed in an emergency department or ICU, intubating experience is associated with improved procedural outcomes, reaching a plateau outcome after a mean 35 to 50 previous intubations.

Background:Ensitrelvir is an antiviral agent against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with associated drug-drug interactions (DDIs) through CYP3A, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporter-3 (OAT-3) inhibition. We present the development and implementation of an online DDI screener to assess interactions during the STRIVE ensitrelvir trial. Methods:The STRIVE Network is conducting a randomized, double-blind, placebo-controlled trial evaluating ensitrelvir's efficacy and safety in hospitalized adults with coronavirus disease 2019 (COVID-19) and lower respiratory tract involvement. DDI guidance was compiled into a database accessed via a web portal where a multidisciplinary team categorized medications as permitted, prohibited, or conditionally permitted. For prohibited medications, washout periods and start/restart criteria were provided with alternative medication suggestions. Sites could request new medications for addition. After 18 months, a survey was conducted to assess the tool's usefulness. Results:Version 1 of the DDI screener launched in December 2022 with 615 medications, expanding to 1182 through 6 updates by version 7. In 11 cases, prohibited medications were revised to conditionally permit enrollment after dosage adjustments (antihypertensives, anti-infectives, and psychiatric medications). Anticoagulants, immunosuppressants, and emergency use medications posed the greatest challenges due to trial blinding. With 334 participants enrolled across 150 sites in 13 countries, 117192 screener searches were completed by May 2024. The most searched medication classes were antihypertensive, antibiotics, corticosteroids, and anticoagulants. Sites found the DDI screener most helpful during screening/enrollment and valued the washout guidance. Conclusions:DDI resources for investigational medications like ensitrelvir, with high DDI potential, are crucial for safe conduct of clinical trials. Effective implementation requires a multidisciplinary, iterative approach that incorporates real-time feedback from trial sites.

BACKGROUND:For critically ill adults undergoing tracheal intubation, observational studies suggest that the use of etomidate to induce anesthesia may increase the risk of death. Whether the use of ketamine rather than etomidate decreases the risk of death is uncertain. METHODS:In a randomized trial conducted in 14 emergency departments and intensive care units in the United States, we randomly assigned critically ill adults who were undergoing tracheal intubation to receive ketamine or etomidate for the induction of anesthesia. The primary outcome was in-hospital death from any cause by day 28. The secondary outcome was cardiovascular collapse during intubation, defined by the occurrence of a systolic blood pressure below 65 mm Hg, receipt of a new or increased dose of vasopressors, or cardiac arrest. RESULTS:A total of 2365 patients underwent randomization and were included in the trial population; 1176 were assigned to the ketamine group and 1189 to the etomidate group. In-hospital death by day 28 occurred in 330 of 1173 patients (28.1%) in the ketamine group and in 345 of 1186 patients (29.1%) in the etomidate group (risk difference adjusted for trial site, -0.8 percentage points; 95% confidence interval [CI], -4.5 to 2.9; P = 0.65). Cardiovascular collapse during intubation occurred in 260 of 1176 patients (22.1%) in the ketamine group and in 202 of 1189 patients (17.0%) in the etomidate group (risk difference, 5.1 percentage points; 95% CI, 1.9 to 8.3). Prespecified safety outcomes were similar in the two groups. CONCLUSIONS:Among critically ill adults undergoing tracheal intubation, the use of ketamine to induce anesthesia did not result in a significantly lower incidence of in-hospital death by day 28 than etomidate. (Funded by the Patient-Centered Outcomes Research Institute and others; RSI ClinicalTrials.gov number, NCT05277896.).

The COVID-19 pandemic gave rise to clinical trials focused on systematic, accurate primary data capture, and reduced reliance on source data verification (SDV). Here, we report on a natural experiment that allowed us to assess the quality, cost, and impact of this approach compared to traditional SDV. The I-SPY COVID trial (NCT04488081) was a multicenter, open-label, platform trial that employed a streamlined daily checklist, daily capture of labs and medications, and centralized monitoring to ensure accurate data collection in lieu of SDV. The trial enrolled 1,111 patients in 11 drug arms with severe COVID-19. After the trial arms were closed, extensive retrospective SDV was performed on 333 (30.0 https://clinicaltrials.gov/study/NCT04488081

OBJECTIVES:Diabetes mellitus has been associated with greater difficulty of tracheal intubation in the operating room. This relationship has not been examined for tracheal intubation of critically ill adults. We examined whether diabetes mellitus was independently associated with the time from induction of anesthesia to intubation of the trachea among critically ill adults.DESIGN:A secondary analysis of data from five randomized trials completed by the Pragmatic Critical Care Research Group (PCCRG).SETTING:Emergency departments (EDs) or ICUs at 11 centers across the United States that enrolled in randomized trials of a pre-intubation checklist, fluid bolus administration, bag-mask ventilation between induction and laryngoscopy, and intubation using a bougie vs. stylet.PATIENTS:Critically ill adults undergoing tracheal intubation with a laryngoscope in an ED or an ICU.INTERVENTIONS:None.MEASUREMENTS AND MAIN RESULTS:A total of 2654 patients were included in this analysis, of whom 638 (24.0%) had diabetes mellitus. The mean time from induction of anesthesia to intubation of the trachea was 169 seconds (sd, 137s). Complications occurred during intubation in 1007 patients (37.9%). Diabetes mellitus was not associated with the time from induction of anesthesia to intubation of the trachea (-4.4 s compared with nondiabetes; 95% CI, -17.2 to 8.3 s; p = 0.50). Use of a video vs. direct laryngoscope did not modify the association between diabetes mellitus and the time from induction to intubation (p for interaction = 0.064). Diabetes mellitus was not associated with the probability of successful intubation on the first attempt (85.6% vs. 84.3%; p = 0.46) or complications during intubation (39.8% vs. 37.4%; p = 0.52).CONCLUSIONS:Among 2654 critically ill patients undergoing tracheal intubation in an ED or an ICU, diabetes mellitus was not independently associated with the time from induction to intubation, the probability of successful intubation on the first attempt, or the rate of complications during intubation.

BACKGROUND: Severe COVID-19 has been associated with hypercoagulability and platelet activation, which is known to result in excessive accumulation of serotonin. However, few studies have evaluated whether serotonergic blockade may improve clinical outcomes among those with COVID-19. RESEARCH QUESTION: Does cyproheptadine, an antiserotonergic drug most commonly used to treat serotonin syndrome, improve time to clinical recovery in patients with severe COVID-19? STUDY DESIGN AND METHODS: The Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis in COVID (I-SPY COVID) study is a phase 2, multicenter, adaptive, open-label randomized controlled trial designed to screen potential therapeutic agents rapidly to identify those with a high probability of improving outcomes for hospitalized critically ill patients with COVID-19. For this report, participants randomized to receive cyproheptadine 8 mg enterally every 8 hours for 10 days or until hospital discharge were compared with concurrently enrolled control patients who were treated with the standard of care regimen of dexamethasone and remdesivir and did not receive an investigational agent. Bayesian survival regression models were used to model the hazard functions for the 2 events of interest: (1) recovery (treating death as a competing event) and (2) overall death as a function of randomization arm and baseline COVID-19 level. RESULTS: From September through December 2021, 35 participants were randomized and consented to receive cyproheptadine and 61 concurrent control patients were eligible for analysis. At that point, futility criteria were met and the data monitoring committee halted further enrollment into the cyproheptadine arm. The posterior probability that cyproheptadine would increase the rate of recovery was 0.1% and the posterior probability that cyproheptadine would improve survival was 16.3%. INTERPRETATION: In an open-label phase 2 trial of adults critically ill with severe COVID-19, cyproheptadine did not improve recovery or survival compared with the standard of care. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04488081; URL: www. clinicaltrials.gov CHEST Critical Care 2025; 3(4):100201

RATIONALE Mounting evidence demonstrates a role for extracellular vesicles (EVs) in driving lung disorders, such as COPD. While cigarette smoke (CS) is the primary risk factor for COPD, a link between CS and the EVs that could lead to COPD is unknown. OBJECTIVE To ascertain whether exposure to CS elicits a proteolytic EV signature capable of driving disease pathogenesis. METHODS Protease expression and enzymatic activity was measured in EVs harvested from the BAL fluid of smoke-exposed mice and otherwise healthy human smokers. Pathogenicity of EVs was examined using pathological tissue scoring following EV transfer into naïve recipient mice. MEASUREMENTS & MAIN RESULTS Our analyses reveal a unique EV profile defined by neutrophil and macrophage-derived EVs. These EVs are characterized by abundant surface expression of neutrophil elastase (NE) and matrix metalloproteinase (MMP-12), respectively. CS-induced mouse or human-derived airway EVs had a robust capacity to elicit rapid lung damage in naïve recipient mice, with an additive effect of NE and MMP-12-expressing EVs. CONCLUSIONS These studies demonstrate the capacity of CS to drive the generation of unique EV populations containing NE and MMP-12. The coordinated action of these EVs is completely sufficient to drive emphysematous disease, and their presence could operate as a prognostic indicator for COPD development. Furthermore, given the robust capacity of these EVs to elicit emphysema in naïve mice, they provide a novel model to facilitate pre-clinical COPD research. Indeed, the development of this model has led to the discovery of a previously unrecognized CS-induced protective mechanism against EV-mediated damage.

Background: Assessing the neuromechanical coupling of inspiratory muscles during mechanical ventilation (MV) could reveal the physiological mechanism of MV failure. This study examined the respiratory neuromechanical characteristics between MV liberation success and failure. Methods: This is an observational prospective study that included patients during their ventilator liberation process. Assessment of surface electromyography (sEMG) of inspiratory muscles, including the diaphragm and extra-diaphragmatic (scalene, sternocleidomastoid, and parasternal) muscles, was performed 15 minutes after the initiation of spontaneous breathing trials. Neuromechanical efficiency of the diaphragm (NMEDia) and extra-diaphragmatic muscles (NMEExtra) were compared in patients who were successfully liberated from MV with those who failed MV liberation within 72 hours after extubation. Results: A total of 45 patients were enrolled and 28 were female (67%). The sample median age was 63 (IQR 47, 69) years old. One-third of patients failed MV liberation within 72 hours of their spontaneous breathing trials (SBTs). NMEDia was significantly lower in patients who failed MV liberation with a root mean square of (M 0.27), (IQR 0.21, 0.37) compared with (M 0.371), (IQR 0.3, 0.631) for the success group (p=0.0222). The area under the curve for NMEDia was lower in the failure group (M 0.270), (IQR 0.160, 0.370) and (M 0.485), (IQR 0.280, 0.683) for the success group (p=0.024). However, NMEExtra was not statistically different between the two groups. Conclusion: Reduced NMEDia is a predictor of MV liberation failure. NMEExtra was not a major contributor to MV liberation outcomes. Further studies should assess the performance of inspiratory muscles NME indices to predict MV liberation outcomes.

The enzyme leukotriene A4 hydrolase (LTA4H) is classically known for its epoxide hydrolase activity that converts leukotriene A4 (LTA4) to the neutrophil chemoattractant LTB4 [1]. In 2010, our group published a study in Science which demonstrated that during an influenza model of acute airway inflammation, LTA4H was released from cells to degrade proline-glycine-proline (PGP), a non-canonical CXCR1 and −2 agonist of polymorphonuclear neutrophil (PMN) recruitment and activation [2], thereby attenuating PMN inflammation [3]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of Interest: Jonathan Grigg reports lecture honoraria from GSK; outside the submitted work. Conflict of interest: None to disclose

Background Among critically ill adults undergoing tracheal intubation, hypoxemia increases the risk of cardiac arrest and death. The effect of preoxygenation with noninvasive ventilation, as compared with preoxygenation with an oxygen mask, on the incidence of hypoxemia during tracheal intubation is uncertain. Methods In a multicenter, randomized trial conducted at 24 emergency departments and intensive care units in the United States, we randomly assigned critically ill adults (age, >= 18 years) undergoing tracheal intubation to receive preoxygenation with either noninvasive ventilation or an oxygen mask. The primary outcome was hypoxemia during intubation, defined by an oxygen saturation of less than 85% during the interval between induction of anesthesia and 2 minutes after tracheal intubation. Results Among the 1301 patients enrolled, hypoxemia occurred in 57 of 624 patients (9.1%) in the noninvasive-ventilation group and in 118 of 637 patients (18.5%) in the oxygen-mask group (difference, -9.4 percentage points; 95% confidence interval [CI], -13.2 to -5.6; P<0.001). Cardiac arrest occurred in 1 patient (0.2%) in the noninvasive-ventilation group and in 7 patients (1.1%) in the oxygen-mask group (difference, -0.9 percentage points; 95% CI, -1.8 to -0.1). Aspiration occurred in 6 patients (0.9%) in the noninvasive-ventilation group and in 9 patients (1.4%) in the oxygen-mask group (difference, -0.4 percentage points; 95% CI, -1.6 to 0.7). Conclusions Among critically ill adults undergoing tracheal intubation, preoxygenation with noninvasive ventilation resulted in a lower incidence of hypoxemia during intubation than preoxygenation with an oxygen mask.