American journal of respiratory and critical care medicine最新文献

Rationale: Variability in the outcomes of mobilization interventions is expected due to their complexity, and one of the post-hoc hypotheses for the findings of the TEAM trial is the impact of 'dosage' of mobilization on clinical outcomes.

Objective: The aim of the present study is to understand the impact of the 'dose' of mobilization on 28-day mortality of patients included in TEAM trial.

Methods: A target trial emulation estimating the per-protocol effect, which is the effect had all patients in the trial adhered to strategies with different 'doses' and timing, was used. All patients included in TEAM trial (adult in the ICU who were undergoing invasive mechanical ventilation) were included and the primary outcome was 28-day mortality. Simulated interventions combining different thresholds of duration of mobilization and different thresholds of highest ICU mobility scale achieved in each day were assessed using g-formulas considering baseline and time-varying confounders.

Measurements and main results: Overall, 741 patients were included, with a median age of 62 (51-71) years and 37% females. Prolonged mobilization time carried worse outcomes when lower levels of mobility were achieved (risk ratio [RR], 1.33 [95% confidence interval [CI], 1.10 to 1.63] for mobilization time ≤ 20 minutes and mobility scale of 2). When an ICU mobility scale greater than 4 was achieved on a given day, prolonged duration of mobilization did not increase mortality compared to natural course (RR, 1.13 [95%CI, 0.96 to 1.46] for mobilization time ≤ 20 minutes and IMS of 4).

Conclusions: Prolonged mobilization when only lower ICU mobility scale levels could be achieved were associated with increased 28-day mortality.

Rationale: Elexacaftor/tezacaftor/ivacaftor, a CF transmembrane conductance regulator (CFTR) modulator, stabilizes and restores F508del-CFTR function, which is the most common CFTR variant. In multiple clinical and real-world studies, elexacaftor/tezacaftor/ivacaftor was shown to be safe and highly effective in people with CF carrying at least one F508del-CFTR (∼80% of people with CF).

Objectives: To characterize the response of rare, non-F508del CFTR variants to elexacaftor/tezacaftor/ivacaftor in vitro, and in clinical and real-world studies.

Methods: We engineered Fischer rat thyroid (FRT) cells each of which express one of 620 rare exonic CFTR variants present in public databases and evaluated their in vitro response to elexacaftor/tezacaftor/ivacaftor. We evaluated efficacy and safety of elexacaftor/tezacaftor/ivacaftor in a 24-week randomized, placebo-controlled, Phase 3 trial (445-124) in participants with 1 of 18 rare variants and no F508del and in a real-world study (CFD-016) in people carrying 82 rare variants and no F508del.

Measurements and main results: In FRT cells, 518 of 620 (84%) rare variants responded to elexacaftor/tezacaftor/ivacaftor. In 445-124, mean improvements were seen in the primary endpoint of percent predicted FEV1 (9.2 percentage points [95%CI:7.2,11.3;P<0.0001]), and secondary endpoints of sweat chloride (-28.3mmol/L [95%CI:-32.1,-24.5mmol/L;P<0.0001]) and CFQ-R RD (19.5points [95%CI:15.5,23.5;P<0.0001]). In CFD-016, improvements in lung function were seen after treatment initiation.

Conclusions: In vitro, clinical, and real-world data support elexacaftor/tezacaftor/ivacaftor treatment in people carrying a range of CFTR variants and no F508del. The response of 84% of rare CFTR variants that produce protein to protein-stabilizing therapy suggests variants in many regions of the protein causes disease via protein destabilization.

Rationale: Conventional monitoring of acute respiratory distress syndrome (ARDS) relies on global parameters, e.g., tidal volume, airway pressure, and driving pressure. These parameters do not capture regional stress heterogeneity within the lung.

Objectives: To develop and validate a novel technique, lung stress mapping visualizing regional lung stress throughout the lung, and to evaluate its biological and clinical relevance.

Methods: Lung stress mapping combines esophageal pressure and plateau pressure with CT-derived pleural pressure gradients to generate spatially resolved maps of inspiratory transpulmonary pressure. Accuracy was tested in pigs by surgically inserted pleural sensors. Biological relevance was assessed in rabbits by correlating lung stress mapping-derived parameters with regional proinflammatory cytokine expression. Clinical feasibility and associations with outcome were evaluated in 20 consecutive ARDS patients enrolled in a prospective study.

Measurements and main results: Good correlation and agreement between sensor-derived and mapping-derived lung stress were confirmed. In rabbits, lung inflammation predominantly occurred in nondependent lung regions where lung stress was higher, and overall inflammation correlated with lung stress mapping-derived parameters. In ARDS patients, all received lung-protective ventilation. Non-survivors had significantly higher lung stress mapping-derived maximum and mean lung stress than survivors, despite similar global ventilatory parameters. Exploratory ROC analyses showed stronger associations of lung stress mapping-derived parameters with 90-day mortality than driving pressure.

Conclusions: Lung stress mapping accurately quantified regional transpulmonary stress and revealed biologically and clinically meaningful heterogeneity. This technique may help identify patients with ARDS at increased risk of ventilator-induced lung injury who would not be recognized through conventional respiratory monitoring.