Rationale: Excessive stress (distending pressure), strain (volume deformation), and drop in inspiratory alveolar pressure are proposed mechanisms for patient self-inflicted lung injury. Objectives: To dissect the influence of inspiratory effort, respiratory mechanics, and ventilation mode on lung stress, strain, and drop in inspiratory alveolar pressure; and explore their impact on oxygenation and lung compliance. Methods: International cohort study analyzing respiratory recordings (esophageal pressure) of patients with acute hypoxemic respiratory failure. Association between muscular pressure (Pmus), surrogates of stress (driving trans-alveolar pressure), strain (tidal volume), and inspiratory alveolar pressure relative to PEEP were explored with mixed-models, including interactions for ventilation mode, respiratory system elastance, and synchrony. Association between these and changes in oxygenation and lung compliance were explored. Measurements and main results: 60 patients from 15 centers represented 528 recordings (339,796 breaths). For each cmH(2)O Pmus increase there was an increase in driving trans-alveolar pressure (median[CI 95%] 0.28[0.27-0.29]cmH(2)O) and tidal volume (0.16[0.16-0.17]ml/kg of predicted body weight) and decrease in alveolar pressure (-0.25[0.24-0.6]cmH(2)O, p<0.001). Volume-control ventilation showed less increase in stress and strain surrogates than pressure-targeted modes, but more drop in alveolar pressure (p<0.001, Pmus:mode interaction). Breath-stacking was infrequent and associated with higher stress. Lower inspiratory alveolar pressure relative to PEEP was associated with subsequent worsening oxygenation (p=0.04) and higher stress with worsening lung compliance (p=0.023). Conclusion: Strong efforts are associated with high surrogates for lung stress, strain, and lower inspiratory alveolar pressure relative to PEEP, differently according to the mode of ventilation, being associated with subsequent worsening oxygenation and lung compliance.

OBJECTIVES:To explore how early mechanical reperfusion impacts outcomes in high-risk pulmonary embolism (PE) patients supported by venoarterial extracorporeal membrane oxygenation (VA-ECMO). METHODS:This retrospective international study included adult patients treated with VA-ECMO for high-risk PE at 39 ECMO centers (2014-2024). Early mechanical reperfusion was defined as catheter-directed therapy or surgical embolectomy within 48 hours of ECMO initiation. Patients dying within 12 hours or receiving delayed reperfusion were excluded. The primary outcome was 90-day mortality, assessed using propensity-matched groups. MEASUREMENTS AND MAIN RESULTS:Among 492 patients on VA-ECMO (median age, 53 years), 69% had cardiac arrest, and 28% received early mechanical reperfusion. After propensity matching, 137 patients were compared in each group. Ninety-day mortality was 32% with early mechanical reperfusion on ECMO versus 39% with ECMO stand-alone (HR, 0.68 [95% CI, 0.45-1.03]; P = .07). Overall, ECMO duration and weaning rates were similar; however, early mechanical reperfusion improved ECMO weaning in patients without prior thrombolysis (subdistribution HR, 1.56 [95% CI, 1.03-2.36]; P = .04). Bleeding occurred in 50% of patients, with no significant difference between groups. CONCLUSIONS:In this large international cohort of patients with high-risk PE on VA-ECMO, early mechanical reperfusion therapy was not associated with a reduction in 90-day mortality or ECMO duration. These findings may support a stepwise, individualized approach favoring initial ECMO stand-alone support, although a certain clinical benefit from early mechanical reperfusion in selected patients cannot be excluded.

RationaleCOVID-19-associated acute-respiratory distress syndrome (C-ARDS) results from a direct viral injury associated with host excessive innate immune response mainly affecting the lungs. However, cytokine profile in the lung compartment of C-ARDS patients has not been widely studied, nor compared to non-COVID related ARDS (NC-ARDS).ObjectivesTo evaluate caspase-1 activation, IL-1 signature, and other inflammatory cytokine pathways associated with tissue damage using post-mortem lung tissues, bronchoalveolar lavage fluids (BALF), and serum across the spectrum of COVID-19 severity.MethodsHistological features were described and activated-caspase-1 labeling was performed in 40 post-mortem biopsies. Inflammatory cytokines were quantified in BALF and serum from 19 steroid-treated-C-ARDSand compared to 19 NC-ARDS. Cytokine concentrations were also measured in serum from 128 COVID-19 patients at different severity stages.Measurements and main resultsTypical “diffuse alveolar damage” in lung biopsies were associated with activated caspase-1 expression and vascular lesions. Soluble Caspase-1p20, IL-1β, IL-1Ra, IL-6 and at lower level IFNγ and CXCL-10, were highly elevated in BALF from steroid-treated-C-ARDS as well as in NC-ARDS. IL-1β appeared concentrated in BALF, whereas circulating IL-6 and IL-1Ra concentrations were comparable to those in BALF and correlated with severity. TNFα, TNFR1 and CXCL8 however, were significantly higher in NC-ARDS compared to C-ARDS, treated by steroid.ConclusionsIn the lungs of C-ARDS, both caspase-1 activation with a predominant IL-1β/IL-6 signature and IFNγ -associated chemokines are elevated despite steroid treatment. These pathways may be specifically targeted in ARDS to improve response to treatment and to limit alveolar and vascular lung damage.

OBJECTIVES:Our study aimed to investigate the effects of sevoflurane inhalation on mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistances (PVRs) in acute respiratory distress syndrome (ARDS) patients during lung protective ventilation. DESIGN:Prospective cohort study. SETTING:Medical ICU of a university teaching hospital. PATIENTS:Deeply sedated, intubated adult patients with moderate to severe ARDS with Pa o2 /F io2 less than 150 mm Hg, with a positive end-expiratory pressure of greater than or equal to 5 cm H 2 O and septic shock monitored with a pulmonary arterial catheter. INTERVENTIONS:Sedation was switched from IV midazolam to sevoflurane inhalation. MEASUREMENTS AND MAIN RESULTS:Main objective was the change in mPAP between before (T0) and 1 hour (H + 1) after sevoflurane inhalation. Main secondary outcomes were mPAP 12-18 hours (H + 12-18) after inclusion, PVR indexed (PVRI), cardiac index, Pa o2 /F io2 , pulmonary shunt at H + 1, and H + 12-18 after inclusion. The H + 12-18 measurements were performed either in supine position (SP) or in prone position (PP), if Pa o2 /F io2 ratio was less than 150 mm Hg at H + 1. Fifteen patients were included in interim analysis. mPAP was 24 ± 4 mm Hg at inclusion and remained unchanged after 1 hour (24 ± 5 mm Hg) and 12-18 hours (23 ± 6 mm Hg) of sevoflurane inhalation. The mean expired fraction of sevoflurane was 0.75% ± 0.25% at H + 1 and 0.71% ± 0.25% at H + 12-18. No significant variations in PVRI, cardiac index, mean arterial pressure, pulmonary shunt were observed at H + 1 and H + 12-18. An improvement of Pa o2 /F io2 was observed at H + 12-18 in patients who remained in SP (from 158 ± 49 to 249 ± 86 mm Hg; p = 0.015) and in those turned prone (from 134 ± 36 to 241 ± 109 mm Hg; p = 0.018). CONCLUSIONS:In mechanically ventilated moderate to severe ARDS patients receiving lung protective ventilation, sevoflurane inhalation was not associated with decreases in mPAPs and PVRs. However, the smaller than planned sample size does not allow definitive conclusions.

Background/Objectives: International guidelines recommend the use of antibiotic prophylaxis for lung transplantation (LT). Although multiplex PCR (mPCR) has been shown to hasten antibiotic adaptation during pneumonia, its use to guide antibiotic prophylaxis in patients undergoing LT has not been described. We aimed to determine whether mPCR in bronchoalveolar lavage (BAL) in donor and recipient allows the early adaptation of antibiotic prophylaxis during LT. Methods: a retrospective, single-center study to evaluate the proportion of patients for whom mPCR (FilmArray Pneumonia Plus Panel®, Biomérieux (FAPP)) in the donor and recipient BAL resulted in an early modification of antibiotic prophylaxis. We also compared the time to results using mPCR and standard microbiology and the time spent with inadequate antibiotic prophylaxis. Results: Forty-one patients were included. Donor and recipient mPCR resulted in the early adaptation of antibiotic prophylaxis in 10 (24%) patients. Standard microbiology confirmed the results of mPCR in 90% of them. FAPP resulted in an antibiotic escalation based on donor (9/10) or recipient (1/10) BAL identification, mainly Group 3 Enterobacterales and non-fermenting Gram-negative bacilli. The time to results was 1.7 (1.5–2.4) h for mPCR vs. 74.3 (41.5–92.7) h for standard microbiology (p < 0.001) on donor BAL and 1.7 (1.5–2.4) h vs. 92.8 (48.4–112.9) h (p < 0.001) on recipient BAL. Patients with mPCR-based adaptation had a 71.9 (30.7–92.1) h reduction in the duration of inadequate antibiotic prophylaxis. Conclusions: mPCR in donor and recipient BAL during LT might lead to faster adaptation and a reduction in the time spent with inadequate antibiotic prophylaxis.

The fibroproliferative stage and persistent inflammation of acute respiratory distress syndrome (ARDS) are key factors leading to either the resolution of the syndrome or fibrosis. Previous studies suggest that a corticosteroid therapy promotes the evolution of ARDS toward an adapted repair process whereas others suggest that this therapy increases the risk of death if it starts more than 14 days after ARDS onset. Since the efficacy and safety of delayed 2 mg/kg methylprednisolone therapy in patients with ARDS is a matter of debate, we performed this observational multicentric retrospective study. We analysed the data of 392 patients with ARDS who received 2 mg/kg methylprednisolone therapy. The primary endpoint was mortality six months after 2 mg/kg methylprednisolone therapy was started. The secondary endpoints included mortality 60 days after the corticosteroid therapy initiation and the number of ventilator-free days (VFDs) and intensive care unit (ICU)-free days. We investigated the occurrence of complications such as ventilator-acquired pneumonia (VAP), septic shock and gastrointestinal bleeding arising after the start of the protocol. A total of 189 (48.2%) patients received 2 mg/kg methylprednisolone therapy within the first 14 days of ARDS onset. A total of 203 (51.8%) patients received it more than 14 days included post-ARDS-onset. The mortality rate six months after the initiation of 2 mg/kg methylprednisolone therapy was 51.9% in the early initiation group and 52.2% in the late initiation group (p = 0.942). The mortality rate 60 days after the initiation of 2 mg/kg methylprednisolone therapy was 47.1% in the early group and 47.3% in the late group (p = 0.968). There was no significant difference in the number of VFDs (p = 0.336) or ICU-free days (p = 0.175) 60 days after the start of the 2 mg/kg protocol. Initiating the protocol 14 days after the onset of ARDS seemed to be associated with more complications (p < 0.001). Late initiation was associated with greater occurrence of VAP (p = 0.018) or gastrointestinal bleeding (p = 0.012). These results suggest that an initiation of 2 mg/kg methylprednisolone therapy after 14 days from ARDS onset is not associated with an increased risk of death as compared with initiation prior to day 14. Delayed 2 mg/kg methylprednisolone therapy in patients with persistent ARDS should be considered.

Background/Objectives: Sepsis remains one of the leading causes of mortality worldwide, characterized by a complex and heterogeneous clinical presentation. Despite advances in patient monitoring and biomarkers, early detection of sepsis in the intensive care unit (ICU) is often hampered by incomplete data and diagnostic uncertainty. In recent years, machine learning models have been proposed as predictive tools, but many function as opaque “black boxes”, meaning that humans are unable to understand algorithmic reasoning, poorly suited to the uncertainty-laden clinical environment of critical care. Even when post-hoc interpretability methods are available for these algorithms, their explanations often remain difficult for non-expert clinicians to understand. Methods: In this clinical perspective, we explore the specific advantages of probabilistic graphical models, particularly Bayesian Networks (BNs) and their dynamic counterparts (DBNs), for sepsis prediction. Results: Recent applications of AI models in sepsis prediction have demonstrated encouraging results, such as DBNs achieving an AUROC of 0.94 in early detection, or causal probabilistic models in hospital admissions (AUROC 0.95). These models explicitly represent clinical reasoning under uncertainty, handle missing data natively, and offer interpretable, transparent decision paths. Drawing on recent studies, including real-time sepsis alert systems and treatment-effect modeling, we highlight concrete clinical applications and their current limitations. Conclusions: We argue that BNs present a great opportunity to bridge the gap between artificial intelligence and bedside care through human-in-the-loop collaboration, transparent inference, and integration into clinical information systems. As critical care continues to move toward data-driven decision-making, Bayesian models may offer not only technical performance but also the epistemic humility needed to support clinicians facing uncertain, high-stakes decisions.

Background: Ventilator-associated pneumonia (VAP) is a common and serious ICU complication, affecting up to 40% of mechanically ventilated patients. The diagnosis of VAP currently relies on retrospective clinical, radiological, and microbiological criteria, which often delays targeted treatment and promotes the overuse of broad-spectrum antibiotics. The early prediction of VAP is crucial to improve outcomes and guide antimicrobial use related to this disease. This study aimed to develop and validate PREDICT (Pneumonia Risk Evaluation and Diagnostic Intelligence via Computational Technology), a deep learning algorithm for early VAP prediction that is based solely on vital signs. Methods: We conducted a retrospective cohort study using the MIMIC-IV database, which includes ICU patients who were ventilated for at least 48 h. Five vital signs (respiratory rate, SpO2, heart rate, temperature, and mean arterial pressure) were structured into 24 h temporal windows. The PREDICT model, based on a long short-term memory neural network, was trained to predict the onset of VAP 6, 12, and 24 h in the future. Its performance was compared to that of conventional machine learning models (random forest, XGBoost, logistic regression) using their AUPRC, sensitivity, specificity, and predictive values. Results: PREDICT achieved high predictive accuracy with AUPRC values of 96.0%, 94.1%, and 94.7% at 6, 12, and 24 h before the onset of VAP, respectively. Its sensitivity and positive predictive values exceeded 85% across all horizons. Traditional ML models showed a drop in performance over longer timeframes. Analysis of the model’s explainability highlighted the respiratory rate, SpO2, and temperature as key predictive features. Conclusions: PREDICT is the first deep learning model specifically designed for early VAP prediction in ICUs. It represents a promising tool for timely clinical decision-making and improved antibiotic stewardship.

Background: Few data are available concerning the outcome of patients denied venovenous extracorporeal membrane oxygenation (VV-ECMO) relative to severe acute respiratory distress syndrome (ARDS) due to COVID-19. Methods: We compared the 90-day survival rate of consecutive adult patients for whom our center was contacted to discuss VV-ECMO indication. Three groups of patients were created: patients for whom VV-ECMO was immediately indicated (ECMO-indicated group), patients for whom VV-ECMO was not indicated at the time of the call (ECMO-not-indicated group), and patients for whom ECMO was definitely contraindicated (ECMO-contraindicated group). Results: In total, 104 patients were referred for VV-ECMO support due to severe COVID-19 ARDS. Among them, 32 patients had immediate VV-ECMO implantation, 28 patients had no VV-ECMO indication, but 1 was assisted thereafter, and 44 patients were denied VV-ECMO for contraindication. Among the 44 patients denied, 30 were denied for advanced age, 24 for excessive prior duration of mechanical ventilation, and 16 for SOFA score >8. The 90-day survival rate was similar for the ECMO-indicated group and the ECMO-not-indicated group at 62.1 and 61.9%, respectively, whereas it was significantly lower (20.5%) for the ECMO-contraindicated group. Conclusions: Despite a low survival rate, 50% of patients were at home 3 months after being denied for VV-ECMO for severe ARDS due to COVID-19.

IntroductionDuring COVID-19, renal impairment is the most frequent after lung impairment and is associated with poor prognosis particularly in intensive care unit (ICU). We aimed to assess the existence and incidence of early renal dysfunction and its prognostic value in patients with COVID-19-related acute respiratory distress syndrome (ARDS).MethodsIn this prospective multicenter study, patients aged over 18 years with invasive mechanical ventilation for ARDS were enrolled in 3 ICUs. Precise evaluation of renal dysfunction markers including urinary proteins electrophoresis (UPE) and quantification, was performed within 24 hours after mechanical ventilation onset.ResultsFrom March 2020 to December 2021, 135 patients were enrolled: 100 COVID-19 ARDS and 35 non-COVID-19 ARDS. UPE found more tubular dysfunction in COVID-19 patients (68% vs. 21.4%, p<0.0001) and more normal profiles in non-COVID-19 patients (65.0% vs. 11.2%, p=0.0003). COVID-19 patients significantly displayed early urinary leakage of tubular proteins like beta-2-microglobulin and free-light chains, tended to display more frequently acute kidney injury (AKI) (51.0% vs 34.3%, p=0.088), had longer mechanical ventilation (20 vs. 9 days, p<0.0001) and longer ICU stay (26 vs. 15 days, p<0.0001). In COVID-19 ARDS, leakage of free lambda light chain was associated with the onset of KDIGO ≥2 AKI (OR: 1.014, 95%CI [1.003-1.025], p=0.011).ConclusionsPatients with COVID-19-related ARDS display a proximal tubular dysfunction, prior to the onset of AKI, which predicts AKI. Proximal tubular damage seems an important mechanism of COVID-19-induced nephropathy. Analysis of urinary proteins is a reliable non-invasive tool to assess proximal tubular dysfunction in the ICU.

L’assistance respiratoire extracorporelle veino-veineuse (Extracorporeal Membrane Oxygenation (ECMO-VV)) s’est imposée comme un traitement de recours dans les cas de syndrome de détresse respiratoire aiguë (SDRA) les plus sévères malgré le positionnement en décubitus ventral (DV). La question de l’intérêt et de la faisabilité de la poursuite du DV chez les patients sous ECMO-VV est importante compte tenu d’une part du bénéfice attendu mais aussi d’autre part, de la difficulté technique à sa mise en œuvre chez ces patients. La majorité des études observationnelles montre une amélioration supplémentaire de l’oxygénation en DV et parfois après DV chez les patients sous ECMO-VV. De plus, plusieurs méta-analyses d’études comparatives non randomisées suggèrent une diminution de la mortalité avec l’utilisation du DV, plutôt précoce et prolongée. Des études cliniques randomisées sont toutefois nécessaires afin d’en préciser les indications et les modalités. Dans cette mise au point, nous abordons tout d’abord le rationnel physiopathologique relatif à l’utilisation de cette technique chez les patients sous ECMO-VV puis nous discutons ses éventuelles indications et sa faisabilité. Enfin, nous évoquons ses aspects pratiques.

To report the outcomes of patients with severe tuberculosis (TB)-related acute respiratory distress syndrome (ARDS) on extracorporeal membrane oxygenation (ECMO), including predictors of 90-day mortality and associated complications. An international multicenter retrospective study was conducted in 20 ECMO centers across 13 countries between 2002 and 2022. We collected demographic data, clinical details, ECMO-related complications, and 90-day survival status for 79 patients (median APACHE II score of 20 [25th to 75th percentile, 16 to 28], median age 39 [28 to 48] years, PaO2/FiO2 ratio of 69 [55 to 82] mmHg before ECMO) who met the inclusion criteria. Thoracic computed tomography showed that 61 patients (77

Background To inform future research and practice, we aimed to investigate the outcomes of patients who received extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS) due to different variants of SARS-CoV-2. Methods This retrospective study included consecutive adult patients with laboratory-confirmed SARS-CoV-2 infection who received ECMO for ARDS in 21 experienced ECMO centres in eight European countries (Austria, Belgium, England, France, Germany, Italy, Portugal, and Spain) between Jan 1, 2020, and Sept 30, 2021. We collected data on patient characteristics, clinical status, and management before and after the initiation of ECMO. Participants were grouped according to SARS-CoV-2 variant (wild type, alpha, delta, or other) and period of the pandemic (first [Jan 1-June 30] and second [July 1-Dec 31] semesters of 2020, and first [Jan 1-June 30] and second [July 1-Sept 30] semesters of 2021). Descriptive statistics and Kaplan-Meier survival curves were used to analyse evolving characteristics, management, and patient outcomes over the first 2 years of the pandemic, and independent risk factors of mortality were determined using multivariable Cox regression models. The primary outcome was mortality 90 days after the initiation of ECMO, with follow-up to Dec 30, 2021. Findings ECMO was initiated in 1345 patients. Patient characteristics and management were similar for the groups of patients infected with different variants, except that those with the delta variant had a younger median age and less hypertension and diabetes. 90-day mortality was 42% (569 of 1345 patients died) overall, and 43% (297/686) in patients infected with wild-type SARS-CoV-2, 39% (152/391) in those with the alpha variant, 40% (78/195) in those with the delta variant, and 58% (42/73) in patients infected with other variants (mainly beta and gamma). Mortality was 10% higher (50%) in the second semester of 2020, when the wild-type variant was still prevailing, than in other semesters (40%). Independent predictors of mortality were age, immunocompromised status, a longer time from intensive care unit admission to intubation, need for renal replacement therapy, and higher Sequential Organ Failure Assessment haemodynamic component score, partial pressure of arterial carbon dioxide, and lactate concentration before ECMO. After adjusting for these variables, mortality was significantly higher with the delta variant than with the other variants, the wild-type strain being the reference. Interpretation Although crude mortality did not differ between variants, adjusted risk of death was highest for patients treated with ECMO infected with the delta variant of SARS-CoV-2. The higher virulence and poorer outcomes associated with the delta strain might relate to higher viral load and increased inflammatory response syndrome in infected patients, reinforcing the need for a higher rate of vaccination in the population and updated selection criteria for ECMO, should a new and highly virulent strain of SARS-CoV-2 emerge in the future. Mortality was noticeably lower than in other large, multicentre series of patients who received ECMO for COVID-19, highlighting the need to concentrate resources at experienced centres. Copyright (c) 2023 Elsevier Ltd. All rights reserved.

Background: For moderate to severe acute respiratory distress syndrome (ARDS), lung-protective ventilation combined with prolonged and repeated prone position (PP) is recommended. For the most severe patients for whom this strategy failed, venovenous extracorporeal membrane oxygenation (vv-ECMO) allows a reduction in ventilation-induced lung injury and improves survival. Some aggregated data have suggested a benefit regarding survival in pursuing PP during vv-ECMO. The combination of PP and vv-ECMO has been also documented in COVID-19 studies, although there is scarce evidence concerning respiratory mechanics and gas exchange response. The main objective was to compare the physiological response of the first PP during vv-ECMO in two cohorts of patients (COVID-19-related ARDS and non-COVID-19 ARDS) regarding respiratory system compliance (CRS) and oxygenation changes. Methods: This was a single-center, retrospective, and ambispective cohort study in the ECMO center of Marseille, France. ECMO was indicated according to the EOLIA trial criteria. Results: A total of 85 patients were included, 60 in the non-COVID-19 ARDS group and 25 in the COVID-19-related ARDS group. Lung injuries of the COVID-19 cohort exhibited significantly higher severity with a lower CRS at baseline. Concerning the main objective, the first PP during vv-ECMO was not associated with a change in CRS or other variation in respiratory mechanic variables in both cohorts. By contrast, oxygenation was improved only in the non-COVID-19 ARDS group after a return to the supine position. Mean arterial pressure was higher during PP as compared with a return to the supine position in the COVID-19 group. Conclusion: We found distinct physiological responses to the first PP in vv-ECMO-supported ARDS patients according to the COVID-19 etiology. This could be due to higher severity at baseline or specificity of the disease. Further investigations are warranted.

Importance Prone positioning may improve outcomes in patients with severe acute respiratory distress syndrome (ARDS), but it is unknown whether prone positioning improves clinical outcomes among patients with ARDS who are undergoing venovenous extracorporeal membrane oxygenation (VV-ECMO) compared with supine positioning. Objective To test whether prone positioning vs supine positioning decreases the time to successful ECMO weaning in patients with severe ARDS supported by VV-ECMO. Design, Setting, and Participants Randomized clinical trial of patients with severe ARDS undergoing VV-ECMO for less than 48 hours at 14 intensive care units (ICUs) in France between March 3, 2021, and December 7, 2021. Interventions Patients were randomized 1:1 to prone positioning (at least 4 sessions of 16 hours) (n = 86) or to supine positioning (n = 84). Main Outcomes and Measures The primary outcome was time to successful ECMO weaning within 60 days following randomization. Secondary outcomes included ECMO and mechanical ventilation-free days, ICU and hospital length of stay, skin pressure injury, serious adverse events, and all-cause mortality at 90-day follow-up. Results Among 170 randomized patients (median age, 51 [IQR, 43-59] years; n = 60 women [35%]), median respiratory system compliance was 15.0 (IQR, 10.7-20.6) mL/cm H2O; 159 patients (94%) had COVID-19-related ARDS; and 164 (96%) were in prone position before ECMO initiation. Within 60 days of enrollment, 38 of 86 patients (44%) had successful ECMO weaning in the prone ECMO group compared with 37 of 84 (44%) in the supine ECMO group (risk difference, 0.1% [95% CI, -14.9% to 15.2%]; subdistribution hazard ratio, 1.11 [95% CI, 0.71-1.75]; P = .64). Within 90 days, no significant difference was observed in ECMO duration (28 vs 32 days; difference, -4.9 [95% CI, -11.2 to 1.5] days; P = .13), ICU length of stay, or 90-day mortality (51% vs 48%; risk difference, 2.4% [95% CI, -13.9% to 18.6%]; P = .62). No serious adverse events were reported during the prone position procedure. Conclusions and Relevance Among patients with severe ARDS supported by VV-ECMO, prone positioning compared with supine positioning did not significantly reduce time to successful weaning of ECMO. Trial Registration ClinicalTrials.gov Identifier: NCT04607551.