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.

RATIONALE:Diaphragm dysfunction impedes weaning from mechanical ventilation. Transvenous diaphragm neurostimulation can increase diaphragm strength, but its impact on patient outcomes is uncertain. OBJECTIVES:To test the safety and effectiveness of transvenous diaphragm neurostimulation to increase successful weaning in patients with difficulty weaning from mechanical ventilation in comparison with standard of care. METHODS:This international, multicenter, open-label, randomized clinical trial (RESCUE-3) included adult patients requiring mechanical ventilation for ⩾96 hours who met readiness-to-wean criteria and failed two or more weaning attempts. Patients were randomized to twice-daily transvenous diaphragm neurostimulation (treatment) or standard of care (control). The primary outcome was successful weaning at Day 30. Secondary outcomes included duration of ventilation to Day 30 and mortality at Day 30. The prespecified primary analysis utilized a Bayesian approach with borrowing of prior information from a previous Phase-II randomized trial, downweighted to account for possible differences in trials. MEASUREMENTS AND MAIN RESULTS:Because of slow enrollment and financial considerations, the trial was halted at the first interim analysis after 200 patients were randomized. Overall, 216 patients were randomized in the modified intent-to-treat population (treatment group, n = 102; control group n = 114). At Day 30, 71 (70%) patients in the treatment group and 69 (61%) patients in the control group were successfully weaned (adjusted hazard ratio, 1.34; 95% credible interval = 1.01-1.78; posterior probability of superiority, 97.9%). Treatment reduced the duration of ventilation (adjusted difference, -2.5 d; 95% credible interval = -5.0 to 0.1; posterior probability of superiority, 97.1%). Serious adverse events were reported in 36% of patients in the treatment group and 24% of patients in the control group; 9.8% of patients in the treatment group and 10.5% of patients in the control group died (adjusted hazard ratio, 0.74; 95% credible interval = 0.37-1.46; posterior probability of superiority, 80.6%). CONCLUSIONS:Although the trial was stopped early because of slow enrollment, transvenous diaphragm neurostimulation showed a high probability of potential benefit for weaning success but with a possible increase in serious adverse events.

Liberation from mechanical ventilation (MV) remains challenging, particularly in difficult-to-wean patients. Weaning failure (i.e. inability to wean or post-extubation failure) and spontaneous breathing trial (SBT) failure are often grouped together despite distinct underlying mechanisms. Moreover, most studies have focused on a single physiological predictor of weaning success, although ventilator liberation is a complex, multiorgan process. We hypothesized that a multimodal, ultrasound-based assessment performed during SBT in difficult-to-wean patients would improve prediction of weaning outcomes compared with individual physiological parameters. In this single-center prospective observational study, adult difficult-to-wean patients (≥ 48 h of mechanical ventilation and failure of the first separation attempt) underwent a standardized SBT. A comprehensive assessment of diaphragmatic function, lung aeration, cardiac function, and peripheral muscle strength was performed. In addition, dyspnea assessment and clinical variables were recorded before and at the end of the SBT. An integrated predictive model was developed using clinical selection and Least Absolute Shrinkage and Selection Operator (LASSO) regression, and it was compared with individual predictors. The primary outcome was to predict weaning failure (inability to wean or post-extubation failure). SBT failure was evaluated as a secondary outcome and defined as the inability to successfully complete the SBT due to clinical signs of intolerance. Weaning failure occurred in 27

After cardiac surgery, patients are liberated from mechanical ventilation despite diaphragm dysfunction and atelectasis; understanding their breathing pattern can help interpreting conditions with diaphragm dysfunction and defining a tolerable range of effort under mechanical ventilation. Prospective physiological study describing the magnitude and pattern of breathing effort after cardiac surgery. Three spontaneous breathing trial modalities performed in random order, including two un-assisted (continuous positive airway pressure 0 cmH2O -CPAP0- and T-piece) and one assisted (pressure-support 5/PEEP 5 cmH2O- PS5PEEP5). Airway, esophageal, and gastric pressures were recorded and diaphragm ultrasound was performed. Airway occlusion pressure (P0.1) was also measured. Difference in magnitude of respiratory effort between conditions was explored through linear mixed-models with Tukey adjustment for pairwise comparisons. Association between pre-defined clinical variables (opioid dose, body mass index, and chest wall compliance) as well as measures of diaphragm function with expiratory muscle activity was explored through mixed-effects models. Thirty patients were included. Maximum inspiratory pressure during a Mueller maneuver was − 29.8 ± -12.6 cmH2O. Estimated mean (CI95

BACKGROUND:Mechanical insufflation-exsufflation (MI-E) improves tracheal secretion clearance in patients with neuromuscular disease. Whether it could mitigate the need for tracheal suctioning without altering comfort and safety in intubated patients free of neuromuscular disease admitted in the ICU is unknown. METHODS:Prospective, randomized, crossover open-label study. Intubated patients without preexisting neuromuscular diseases were included. Two tracheal suctioning strategies were compared: suctioning with prior use of MI-E versus standard suctioning. The primary outcome was the number of tracheal suctioning procedures over a 24-h period. Secondary outcomes included sputum volume collected, blood gas, pain, and adverse events related to suctioning. RESULTS:The study enrolled 40 subjects over a 2-year period. Out of the 201 tracheal suctioning procedures performed during the 24-h MI-E period, 130 (65%) were actually preceded by the use of MI-E. The number of tracheal suctioning procedures was 5 [3-8] during the 24-h MI-E period and 5 [4-8] during the 24-h standard suctioning period (P = .99). There was no difference between MI-E and the standard suctioning 24-h study periods in terms of the volume of secretions suctioned (10 [5-20] mL vs 15 [5-28] mL, P = .81) and behavioral pain scale (4 [3-4] vs 4 [3-5], P = .51). There was no difference in terms of blood gas, arterial desaturation, or any adverse events. No pneumothoraces were observed. CONCLUSION:In subjects intubated in the ICU, the systematic use of MI-E before tracheal suctioning did not reduce the number of suctioning procedures but was not associated with a higher prevalence of adverse events.

Lung-protective ventilation is the current standard for mechanical ventilation of patients with acute respiratory distress syndrome (ARDS). Traditionally, this approach has focused on the controlled phase of mechanical ventilation, but emerging data suggest that how patients are managed during assisted ventilation may also impact clinical outcomes. Experimental and observational clinical data indicate that excessive respiratory effort may further damage already injured lungs and may also lead to diaphragm myotrauma. Conversely, insufficient effort and prolonged passive ventilation are associated with diaphragm atrophy and dysfunction. Recent non-invasive techniques to monitor respiratory drive and effort at the bedside have facilitated the development of a new strategy to protect both the lungs and the diaphragm. The lung- and diaphragm-protective (LDP) ventilation framework highlights the need to better integrate ventilation and sedation strategies to facilitate timely and safe spontaneous breathing. This new paradigm has driven the development of emerging supportive and therapeutic modalities, such as diaphragm neurostimulation and partial neuromuscular blockade. Clinical trials are needed to evaluate the impact of LDP strategies on patient-centered outcomes, using designs that account for the possibility of heterogeneity of treatment effect in the ARDS population. In this review, we summarize the physiological background for the LDP framework, as well as the current clinical evidence evaluating this strategy.

Background Human herpesvirus-6 (HHV-6) DNAemia is not rare in intensive care unit (ICU) patients. However, evidence for a causal association of HHV-6 DNAemia with organ disease and with mortality is limited in this setting. In ICU patients with HHV-6 DNAemia, we sought to (1) assess the prevalence of HHV-6 disease, (2) identify risk factors for HHV-6 disease, and (3) investigate its association with mortality. Methods This was a retrospective multicenter case-matched study in 3 ICUs from January 2011 to January 2022 of patients with HHV-6 viral load in whole blood (genome equivalent copies/106 cells) detected during the ICU stay. Results A total of 168 patients were included. Seventeen (10%) were classified as having HHV-6 disease (ie, HHV-6 DNAemia with attributable end-organ disease) and 151 (90%) as HHV-6 reactivation (ie, HHV-6 DNAemia without any attributable end-organ disease). Immunosuppression was significantly more frequent in patients with HHV-6 (100% vs 48%; P < .001). Eleven (65%) patients with HHV-6 disease received hematopoietic stem cell transplantation (HSCT). End-organ diseases were encephalitis (n = 10) and pneumonia (n = 7). ICU mortality was 32% (n = 53). In multivariate analysis, HHV-6 disease remained independently associated with ICU (odds ratio [OR]: 4.90) and 90-day (hazard ratio: 2.25) mortality. Mortality remained significantly higher in the HHV-6 disease group (OR: 4.30) compared with matched ICU patients without HHV-6 DNAemia. Conclusions Our analysis suggests that HHV-6 disease develops in 10% of patients with HHV-6 detection in the ICU, mostly in the setting of allogeneic HSCT, and is independently associated with ICU and 90-day mortality.

Safe and long-lasting separation from invasive mechanical ventilation (MV) is a critical aspect of care provision in the intensive care unit (ICU), yet it remains a complex and heterogeneously applied process. Current weaning strategies often rely on fragmented assessments, personal judgment, and poorly integrated decision milestones that individually and collectively may contribute to delayed attempts, weaning and extubation failure. In this How I Do It article, we propose a comprehensive framework based on seven hallmarks, organized into three sequential and interrelated phases (3S framework): screening, separating, and securing. The screening phase includes sedation management, the facilitation phase (maintaining limb and respiratory muscles strength and functionality, as well as cardiac function) and the transition phase (which involves switching from controlled to partial support mode and the stepwise reduction of ventilatory support). The separating phase includes the assessment of readiness for spontaneous breathing trial (SBT), SBT conduct, and extubation risk assessment and decision-making. The securing phase focuses on post-extubation management and includes strategies to prevent respiratory failure. Rather than focusing on isolated physiological parameters or scores, this framework highlights the dynamic, staged, and integrative nature of the weaning process. By structuring current evidence around these hallmarks, we aim to provide both a patient-centered approach to ventilator liberation and a conceptual foundation for future research, protocol development, and clinical decision-making.

Objective To understand the differences in the weaning process and outcomes in men and women enrolled in the WorldwidE AssessmeNt of Separation of pAtients From ventilatory assistancE (WEAN SAFE) study. Methods We analysed patients in the WEAN SAFE cohort who commenced weaning from invasive ventilation, stratified by biological sex. The primary outcome was the effect of sex on delayed weaning and failed weaning from invasive mechanical ventilation. Secondary outcomes included the influence of sex on ventilatory management, ICU/hospital survival and decisions to limit life-sustaining interventions. Results Of 4,523 patients who entered the weaning process, 1,754 (38.8%) were women and 2,769 (61.2%) were men. Women were shorter, had higher P/F ratios, and received higher tidal volumes and lower PEEP than men. Women on controlled ventilation received higher driving pressures, while women on assisted ventilation received higher inspiratory pressures than men. Both female sex and shorter stature were independently associated with higher tidal volume ventilation, with shorter females at particular risk. In univariate analyses, women were less likely to successfully wean from invasive ventilation. When adjusted for factors such as height, age, and frailty profile, there was no independent association between sex and weaning success. In patients with more severe respiratory failure (P/F ratios <200), there were no sex differences in ventilatory support, weaning management and outcomes. Conclusions Women weaning from ventilation were shorter and had less severe respiratory failure but received less protective lung ventilation and more frequent ventilatory over-assistance. When adjusted for height and age, female sex was not independently associated with failed weaning from invasive ventilation. Trial registration ClinicalTrials.gov, NCT03255109.

Background:Evidence comparing high-flow nasal cannula (HFNC) and non-invasive ventilation (NIV) in acute hypercapnic respiratory failure remains controversial. We compared their short-term effects on breathing effort, ventilation, CO2 clearance, and preference. Methods:A randomized, crossover, non-inferiority trial was conducted in patients with stabilized hypercapnic exacerbation requiring NIV or HFNC. Baseline oxygen therapy was followed by a randomized sequence of NIV and HFNC at 30 and 50 L.min-1. The primary endpoint was to assess non-inferiority of HFNC 50 L.min-1 compared to NIV. Diaphragm, parasternal intercostal, and transversus abdominis muscle activity were assessed using thickening fraction (TF) and the product of TF and respiratory rate (TF•RR). Ventilation was evaluated using electrical impedance tomography and transcutaneous partial pressure of carbon dioxide (tcCO2). Results:21 patients (mean ± SD age 69 ± 11 years, 82% COPD) were enrolled. In 17, diaphragm thickening fraction (TFdi) was available: HFNC 50 L.min-1 was non-inferior to NIV in reducing TFdi (p = 0.122, 95% CI: -19.1-3.4), as was HFNC at 30 L.min-1 (p = 0.413, 95% CI: -17.0-5.7). Only HFNC 50 L.min-1 reduced TFdi•RR (p = 0.036) and respiratory rate compared to baseline (p = 0.001). HFNC at 50 L.min-1 decreased the baseline TFdi by 18% ± 36% (p = 0.033), whereas NIV did not decrease it. HFNC and NIV reduced tcCO₂ compared to baseline. Minute ventilation and the estimated ventilatory ratio were lower with HFNC than NIV (p < 0.01). HFNC was the preferred strategy by the patients. Conclusions:In stabilized hypercapnic exacerbation, HFNC and NIV reduced tcCO₂, but only HFNC lowered ventilatory ratio and minute ventilation. HFNC at 50 L.min-1 reduced diaphragm activity and was non-inferior to NIV in this regard, while being preferred by patients.

Diagnostic certainty criteria for ICI-myocarditis

Methods concerning Immune-checkpoint proteins profiling on peripheral blood mononuclear cells and Circulating immune checkpoint agents drug monitoring

Introduction P0.1 and inspiratory occlusion pressure (ΔPocc) have been suggested as therapeutic goals of lung and diaphragm protective mechanical ventilation. This study sought 1) to describe P0.1 and ΔPocc measurements during the four first days after intubation, 2) to determine which proportion of patients are within predefined “safe” ranges and 3) to explore their association with outcomes. Methods Intubated patients with a planned duration of mechanical ventilation of more than 24 hours and able to trigger ventilator were included. From inclusion (day 1) to day 4 and during the first spontaneous breathing trial (SBT), P0.1 and ΔPocc were collected. Data related to the patient's outcome were collected up to day-28. Results 101 patients were enrolled. Median P0.1 and ΔPocc values over time were 2 cmH2O [1; 3] and 11 cmH2O [6; 18] respectively and increase during the first 4 days. Eighty one percent of P0.1 measurements and 36% of ΔPocc measurements were in safe ranges i.e. ≤ 3.5 cmH2O and 7 cmH2O ≤ ΔPocc ≤ 15 cmH2O respectively. At day 4, ΔPocc within safe ranges was associated with higher ventilator-free days 23 days [17; 45] versus 20 days [2.5; 23] (p = 0.04). Two minutes after the SBT onset, patients with SBT failure had a higher P0.1 as compared to patients with SBT success: 4 cmH2O [2; 6] vs. 6 cmH2O [4; 8] (p = 0,02) respectively. Conclusion P0.1 was low in a majority of patients and was not associated with clinical outcomes. By contrast, ΔPocc was within safe ranges in a quarter of the patients and was associated with more ventilator-free days at day 4

Delay between presentation for ICI myocarditis, appearance of life-threatening myotoxicity criteria (severity grade 4, Supplementary Table 5 for details concerning grading) and start of the immunosuppressive treatments (with dose) in severe ICI-myocarditis patients requiring abatacept.

Treatment modalities and reported adverse events by quartile of period of inclusion.