American journal of respiratory and critical care medicine最新文献

Rationale: There is no broadly accessible treatment for patients with refractory chronic cough, a disease characterized by chronic cough that persists despite treatment for other cough-related etiologies or has no identified underlying cause. Objectives: SOOTHE (NCT04678206), a Phase 2b, randomized, placebo-controlled trial, evaluated the efficacy and safety of P2X3 antagonist camlipixant in adults with refractory chronic cough (cough duration ≥1 year; baseline awake cough frequency ≥25 coughs/hour). Methods: After a single-blind, 16-day placebo run-in, patients were randomized (1:1:1:1) to receive camlipixant 12.5, 50, or 200 mg twice-daily, or placebo for 4 weeks. The primary endpoint was change from baseline to Day 28 in objective 24-hour cough frequency. Secondary endpoints included cough severity and cough-related quality of life. Measurements and Main Results: Overall, 310 patients were randomized. A statistically significant reduction in placebo-adjusted 24-hour cough frequency was seen in the 50 mg (-34.4%; 95% confidence interval: -50.5 to -13.3; P=0.0033) and 200 mg (-34.2%; 95% confidence interval: -50.7 to -12.2; P=0.0047) camlipixant arms. All camlipixant arms showed a trend for greater improvement in Cough Severity Visual Analog Scale and Leicester Cough Questionnaire over placebo. Camlipixant was well tolerated with no serious treatment emergent adverse events reported. Taste alteration occurred in 4.8-6.5% of patients in camlipixant arms (vs. 0% with placebo); these were usually mild-moderate. Conclusions: Camlipixant treatment reduced cough frequency and improved patient reported outcomes in patients with refractory chronic cough, with an acceptable safety profile. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT04678206.

Rationale: Recovery from chronic obstructive pulmonary disease (COPD) exacerbations is heterogeneous and has a profound impact on disease trajectories. Resolution of airway inflammation is an active process which may be driven by Specialized Pro-resolving Mediators (SPMs).

Objectives: To characterize the temporal change in SPMs in the sputum of COPD patients during COPD exacerbations, their association with exacerbation triggers and exacerbation recovery.

Methods: Participants were recruited from the London COPD Exacerbation Cohort between 01/11/2016 and 01/04/2018. Participants were reviewed at baseline, exacerbation onset, 1 week, 2 weeks and 6 weeks during their exacerbation recovery. Sputum, nasopharyngeal swabs, phlebotomy, quality of life questionnaires and spirometry were performed at each visit. SPMs were measured in sputum by liquid chromatography tandem mass spectrometry. Respiratory viruses were measured by quantitative PCR and bacteria by microbiological culture.

Measurements and main results: There were 68 exacerbations during the study period. Median time to symptomatic recovery was 21 days for viral exacerbations compared to 13 days in non-viral exacerbations (P<0.001). There was a significant increase in Resolvin D1 (RvD1) at exacerbation onset in bacterial exacerbations but not viral exacerbations. Lower levels of RvD1 were associated with prolonged respiratory symptoms during the 1-week and 2-week recovery time points. Exogenous RvD1 significantly reduced IL-6 and CXCL8 response to rhinovirus infection in COPD bronchial epithelial cells.

Conclusions: There is a dynamic temporal change in airway SPMs during COPD exacerbations. Reduced levels of RvD1 were associated with prolonged respiratory symptoms. SPMs may be a potential therapeutic approach to promote exacerbation recovery.

Rationale: Diaphragm inactivity during invasive mechanical ventilation may predispose the lung and diaphragm to injury, and is associated with adverse clinical outcomes.

Objectives: Assess the feasibility of continuous on-demand diaphragm neurostimulation-assisted mechanical ventilation to maintain diaphragm activity in the absence of respiratory drive for at least 24 hours of mechanical ventilation.

Methods: In a single center phase 1 clinical trial, patients receiving invasive mechanical ventilation for acute hypoxemic respiratory failure or after thoracic surgery underwent transvenous diaphragm neurostimulation delivered in synchrony with mechanical ventilation. Diaphragm neurostimulation was delivered when breaths were initiated by the ventilator and not by the patient until a successful spontaneous breathing trial was performed or for up to seven days. The co-primary outcomes were safety and feasibility of maintaining diaphragm activity over the first 24 hours of intervention.

Measurements and main results: Twenty participants were enrolled and 19 underwent study procedures. Diaphragm neurostimulation was successfully initiated in all 19 patients (100%) and on-target diaphragm activity was maintained for ≥50% of hours of passive mechanical ventilation over the initial 24-hour period in 18/19 (95%) patients. Diaphragm neurostimulation was well-tolerated; one pneumothorax unrelated to device occurred following subclavian catheter placement prior to surgery. Over the 7-day study period, diaphragm activity was maintained during a median of 100% (IQR 95-100%) hours with absent respiratory drive.

Conclusions: Continuous on-demand diaphragm neurostimulation-assisted mechanical ventilation is feasible and can prevent diaphragm inactivity during mechanical ventilation. Clinical trial registration available at www.

Clinicaltrials: gov, ID: NCT05465083.

Objectives: To evaluate the effect of genetic variant status on sotatercept efficacy and effect of sotatercept treatment on biomarkers in pulmonary arterial hypertension Methods: PULSAR (NCT03496207) was a phase 2, randomized, controlled study of sotatercept vs placebo added to background therapy for pulmonary arterial hypertension. Participants had DNA sequencing done at baseline to detect genetic variants in disease-associated genes (ACVRL1, BMPR2, CAV1, EIF2AK4, ENG, KCNA3, KCNK3, and SMAD9). Safety (adverse events) and efficacy (pulmonary vascular resistance, 6-minute walk distance) were assessed by variant status and treatment at 24 weeks. Serum levels of BMPR2 mRNA and N-terminal pro-hormone B-type natriuretic peptide were assessed at baseline and 24 weeks by treatment and variant status. Analysis of covariance was used to compare the change from baseline by treatment and variant status.

Results: Of 76 participants included, 25 had pathogenic variants detected (23 BMPR2; 2 other) and 51 had no variants or variants of uncertain significance. BMPR2 mutation carriers were younger and more frequently on triple therapy but had less severe clinical characteristics at baseline. Changes at 24 weeks in pulmonary vascular resistance and 6-minute walk distance did not differ by variant status. BMPR2 gene expression varied less than twofold from baseline over time, irrespective of treatment or variant status. The adverse events profile was generally consistent with that seen in the parent PULSAR study.

Conclusions: These results suggest consistent safety and clinical efficacy of sotatercept for treatment of pulmonary arterial hypertension, irrespective of BMPR2 variant status. Clinical trial registration available at www.

Clinicaltrials: gov, ID: NCT03496207.

Rationale: No systematic investigation into dyspnea in patients receiving prolonged ventilation (>21 d) after recovering from critical illness has been published. Objectives: We sought to determine the magnitude, nature, and pathophysiological basis of dyspnea during an unassisted-breathing trial in patients receiving prolonged ventilation. Methods: Dyspnea intensity and descriptor selection were investigated in 27 patients receiving prolonged ventilation during a 60-minute unassisted-breathing trial. Pressure-time product, respiratory mechanics, and Ptc_CO2 were also measured. Measurements and Main Results: Of 10 patients who reported dyspnea during assist-control ventilation, 9 (90.0%) selected "Not getting enough air" to characterize dyspnea. Vt setting was lower in dyspneic than in nondyspneic patients (480.0 vs. 559.4 ml), P < 0.046. During the unassisted-breathing trial (n = 26), patients developed increases in dyspnea (P < 0.01) and Ptc_CO2 (P < 0.01) but no change in [Formula: see text]e. Dyspnea score was strongly linked to Ptc_CO2 (P < 0.012) and airway resistance (P < 0.013) but not respiratory work (although pressure-time product was almost three times higher than normal). At 60 minutes into the trial, 83.3% of patients selected "Not getting enough air" on its own or in combination with "Too much effort" to describe discomfort, whereas only 16.7% selected "Too much effort" on its own (P < 0.001). Across the dyspnea spectrum, patients chose "Not getting enough air" overwhelmingly over other descriptor options (P < 0.001). Conclusions: Patients developed increases in dyspnea and Ptc_CO2 but unchanged [Formula: see text]e and work of breathing during an unassisted-breathing trial; patients selected air-hunger descriptors overwhelmingly over excessive effort. The observations support the belief that air hunger results from heightened respiratory center stimulation combined with the incapacity to increase [Formula: see text]e.

Rationale: Individuals acting as surrogate decision-makers for critically ill patients frequently struggle in this role and experience high levels of long-term psychological distress. Prior interventions that were designed solely to improve information sharing between clinicians and family members have been ineffective. Objectives: We sought to examine the impact of a multicomponent family support intervention on patient and family outcomes. Methods: We conducted a patient-level randomized clinical trial at six ICUs in a healthcare system in Pennsylvania. An external interventionist interacted daily with surrogate decision-makers for incapacitated, critically ill patients at high risk of death or severe long-term functional impairment to deliver four types of protocolized support during the ICU stay: emotional support; communication support; decisional support; and, if indicated, anticipatory grief support. The control condition involved usual care plus two brief education sessions about critical illness. Measurements and Main Results: Primary outcome was the surrogates' scores on the Hospital Anxiety and Depression Scale at 6 months (range = 0-42). A total of 444 surrogates of 291 patients were enrolled (233 surrogates in intervention and 211 in control). The Four Supports intervention was delivered with high fidelity (frequency of per protocol delivery of key intervention elements, 97.1%; quality rating of intervention delivery, 2.9 ± 0.2 on a scale ranging from 1 to 3, with higher scores indicating higher quality of intervention delivery). There was no intervention effect on the primary outcome, surrogates' Hospital Anxiety and Depression Scale total scores at 6-month follow-up (β = 0.06; 95% confidence interval, -0.07 to 0.19; P = 0.35), or the prespecified secondary outcomes. Conclusions: Among critically ill patients at high risk of death or functional impairment, a family support intervention delivered by an external interventionist did not reduce surrogates' long-term psychological symptom burden.Clinical trial registered with www.clinicaltrials.gov (NCT01982877).