Tidal Volume

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvβ6) integrin inhibitor, in participants with IPF.MethodsThis was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvβ6-specific ligand, [18F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (VT), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in VT > 0%) of ≥80%.ResultsEight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected VT at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI: - 9 to 42%). The posterior probability that the true % reduction in VT > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination.ConclusionsThis study demonstrated engagement of the αvβ6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug.Trial registrationclinicaltrials.gov: NCT03069989; date of registration: 3 March 2017.

Normal human breathing exhibits complex variability in both respiratory rhythm and volume. Analyzing such nonlinear fluctuations may provide clinically relevant information in patients with complex illnesses such as asthma. We compared the cycle-by-cycle fluctuations of inter-breath interval (IBI) and lung volume (LV) among healthy volunteers and patients with various types of asthma. Continuous respiratory datasets were collected from forty age-matched men including 10 healthy volunteers, 10 patients with controlled atopic asthma, 10 patients with uncontrolled atopic asthma, and 10 patients with uncontrolled non-atopic asthma during 60 min spontaneous breathing. Complexity of breathing pattern was quantified by calculating detrended fluctuation analysis, largest Lyapunov exponents, sample entropy, and cross-sample entropy. The IBI as well as LV fluctuations showed decreased long-range correlation, increased regularity and reduced sensitivity to initial conditions in patients with asthma, particularly in uncontrolled state. Our results also showed a strong synchronization between the IBI and LV in patients with uncontrolled asthma. Receiver operating characteristic (ROC) curve analysis showed that nonlinear analysis of breathing pattern has a diagnostic value in asthma and can be used in differentiating uncontrolled from controlled and non-atopic from atopic asthma. We suggest that complexity analysis of breathing dynamics may represent a novel physiologic marker to facilitate diagnosis and management of patients with asthma. However, future studies are needed to increase the validity of the study and to improve these novel methods for better patient management.

BackgroundIn patients with acute respiratory distress syndrome (ARDS), low tidal volume ventilation has been associated with reduced mortality. Driving pressure (tidal volume normalized to respiratory system compliance) may be an even stronger predictor of ARDS survival than tidal volume. We sought to study whether these associations hold true in acute respiratory failure patients without ARDS.MethodsThis is a retrospectively cohort analysis of mechanically ventilated adult patients admitted to ICUs from 12 hospitals over 2 years. We used natural language processing of chest radiograph reports and data from the electronic medical record to identify patients who had ARDS. We used multivariable logistic regression and generalized linear models to estimate associations between tidal volume, driving pressure, and respiratory system compliance with adjusted 30-day mortality using covariates of Acute Physiology Score (APS), Charlson Comorbidity Index (CCI), age, and PaO2/FiO2 ratio.ResultsWe studied 2641 patients; 48% had ARDS (n = 1273). Patients with ARDS had higher mean APS (25 vs. 23, p ConclusionsIn a large retrospective analysis of critically ill non-ARDS patients receiving mechanical ventilation, we found that tidal volume was associated with 30-day mortality, while driving pressure was not.

Recent advances in depth camera technology enable precise quantification of shape changes of the human torso during breathing and therefore predict respiratory volumes. The aim of this study was to investigate the potential of estimating tidal volumes during relaxed breathing from two depth cameras. Data were analysed from 21 healthy participants. For each participant, a set of 30 physical markers were placed across the torso and tracked using two depth cameras. Marker positions were mapped to 3D coordinates and used as inputs for a volume algorithm that estimated respiratory volumes. A breath-by-breath analysis was then conducted to compare estimated volumes with spirometry measurements. The camera-derived volumes were strongly correlated with spirometry (marginal R2 = 0.941) and showed excellent agreement with a mean (SD) absolute difference of 78.0 (34.8) mL. Bland-Altman analysis showed a bias of -4.6 mL and 95% limits of agreement of -192.3 to 183 mL. The reduced 17-marker configuration also showed a strong correlation with spirometry (marginal R2 = 0.918) but reduced agreement, with a mean (SD) absolute difference of 107.4 (58.2) mL and a Bland-Altman bias of -76.4 mL (95% limits of agreement: -298.1 to 145.3 mL). This is the first study to use a marker-based system to estimate respiratory volumes from two facing depth cameras. The use of markers allows for segmentation of the torso and therefore offers the potential to characterise breathing without the need for an expensive laboratory motion capture system.