Elevation in lung volume and preventing catastrophic airway closure in asthmatics during bronchoconstriction.

BACKGROUND: Asthma exacerbations cause lung hyperinflation, elevation in load to inspiratory muscles, and decreased breathing capacity that, in severe cases, may lead to inspiratory muscle fatigue and respiratory failure. Hyperinflation has been attributed to a passive mechanical origin; a respiratory system time-constant too long for full exhalation. However, because the increase in volume is also concurrent with activation of inspiratory muscles during exhalation it is unclear whether hyperinflation in broncho-constriction is a passive phenomenon or is actively controlled to avoid airway closure. METHODS: Using CT scanning, we measured the distensibility of individual segmental airways relative to that of their surrounding parenchyma in seven subjects with asthma and nine healthy controls. With this data we tested whether the elevation of lung volume measured after methacholine (MCh) provocation was associated with airway narrowing, or to the volume required to preventing airway closure. We also tested whether the reduction in FVC post-MCh could be attributed to gas trapped behind closed segmental airways. FINDINGS: The changes in lung volume by MCh in subjects with and without asthma were inversely associated with their reduction in average airway lumen. This finding would be inconsistent with hyperinflation by passive elevation of airway resistance. In contrast, the change in volume of each subject was associated with the lung volume estimated to cause the closure of the least stable segmental airway of his/her lungs. In addition, the measured drop in FVC post MCh was associated with the estimated volume of gas trapped behind closed segmental airways at RV. CONCLUSIONS: Our data supports the concept that hyperinflation caused by MCh-induced bronchoconstriction is the result of an actively controlled process where parenchymal distending forces on airways are increased to counteract their closure. To our knowledge, this is the first imaging-based study that associates inter-subject differences in whole lung behavior with the interdependence between individual airways and their surrounding parenchyma.

18F-FDG uptake rate is a biomarker of eosinophilic inflammation and airway response in asthma.

UNLABELLED: In asthma, the relationship among airway inflammation, airway hyperresponsiveness, and lung function is poorly understood. Methods to noninvasively assess these relationships in human subjects are needed. We sought to determine whether (18)F-FDG uptake rate (K(i), min(-1)) could serve as a biomarker of eosinophilic inflammation and local lung function. METHODS: We used PET/CT to assess regional pulmonary perfusion (Q), specific ventilation per unit volume (sV(A)), fractional gas content (Fgas), airway wall thickness, and regional K(i) 10 h after segmental allergen challenge to the right middle lobe in 6 asthmatic subjects with demonstrated atopy. Q, sV(A), and Fgas in the allergen-challenged lobe were compared with the right upper lobe, where diluent was applied as a control. The airway wall thickness aspect ratio (ω) of the allergen-challenged airway was compared with those of similarly sized airways from unaffected areas of the lung. Differences in K(i) between allergen and diluent segments were compared with those in cell counts obtained 24 h after the allergen challenge by a bronchoalveolar lavage of the respective segments. RESULTS: We found systematic reductions in regional Q, sV(A), and Fgas and increased ω in all subjects. The ratio of eosinophil count (allergen to diluent) was linearly related (R(2) = 0.9917, P < 0.001) to the ratio of K(i). CONCLUSION: Regional K(i) measured with PET is a noninvasive and highly predictive biomarker of eosinophilic airway inflammation and its functional effects. This method may serve to help in the understanding of allergic inflammation and test the therapeutic effectiveness of novel drugs or treatments.

Dynamics of tidal volume and ventilation heterogeneity under pressure-controlled ventilation during bronchoconstriction: a simulation study.

The difference in effectiveness between volume-controlled ventilation (VCV) and pressure-controlled ventilation (PCV) on mechanically ventilated patients during bronchoconstriction is not totally clear. PCV is thought to deliver a more uniform distribution of ventilation than VCV, but the delivered tidal volume could be unstable and affected by changes in the degree of constriction. To explore the magnitude of these effects, we ran numerical simulations with both modes of ventilation in a network model of the lung in which we incorporated not only the pressure and flow dynamics along the airways but also the effect of cycling pressures and tissue tethering forces during breathing on the dynamic equilibrium of the airway smooth muscle (ASM) (Venegas et al., Nature 434: 777-782). These simulations provided an illustration of changes in airway radii, the total delivered tidal volume stability, and distribution of ventilation following a transition from VCV to PCV and during progressively increasing ASM activation level. These simulations yielded three major results. First, the ventilation heterogeneity and patchiness in ventilation during steady-state VCV were substantially reduced after the transition to PCV. Second, airway radius, tidal volume, and the distribution of ventilation under severe bronchoconstriction were highly sensitive to the setting of inspiratory pressure selected for PCV and to the degree of activation of the ASM. Third, the dynamic equilibrium of active ASM exposed to cycling forces is the major contributor to these effects. These insights may provide a theoretical framework to guide the selection of ventilation mode, the adjustment of ventilator settings, and the interpretation of clinical observations in mechanically ventilated asthmatic patients.