Modulation of airway caliber by deep inhalation in children.

To elucidate whether deep inhalation (DI) modulates changes in airway caliber in childhood, we measured the effect of DI on respiratory impedance before and after inhaled methacholine or salbutamol in 4- to 7-yr-old children (n = 15) suffering from recurrent wheezing. In all children, the real part of impedance between 12 and 16 Hz (Re[Z](12-16)) increased after methacholine from 5.6 +/- 1.2 to 8.2 +/- 1.6 cmH(2)O. l(-1). s (P < 0.001) and resonance frequency from 18 +/- 3 to 25 +/- 5 Hz (P < 0.001). These changes were partially reversed by DI: Re[Z](12-16) decreased to 7.2 +/- 1.2 cmH(2)O. l(-1). s (P < 0.01) and resonance frequency to 19 +/- 5 Hz (P < 0.001). In nine children, on a separate occasion, Re[Z](12-16) decreased after salbutamol from 8.3 +/- 1.9 to 5.1 +/- 0.9 cmH(2)O. l(-1). s (P < 0.001) and resonance frequency from 21 +/- 6 to 15 +/- 3 Hz (P < 0.05). The decrease of Re[Z](12-16) was partially reversed by DI (to 6.2 +/- 1.4 cmH(2)O. l(-1). s, P < 0. 01), but resonance frequency did not change significantly (P = 0.75). We conclude that in 4- to 7-yr-old children pharmacologically induced changes in airway caliber are modulated by DI. These findings suggest that airway-to-parenchyma interdependence is operative in this age range.     

Effects of rapid saline infusion on lung mechanics and airway responsiveness in humans.

Lung mechanics and airway responsiveness to methacholine (MCh) were studied in seven volunteers before and after a 20-min intravenous infusion of saline. Data were compared with those of a time point-matched control study. The following parameters were measured: 1-s forced expiratory volume, forced vital capacity, flows at 40% of control forced vital capacity on maximal (Vm(40)) and partial (Vp(40)) forced expiratory maneuvers, lung volumes, lung elastic recoil, lung resistance (Rl), dynamic elastance (Edyn), and within-breath resistance of respiratory system (Rrs). Rl and Edyn were measured during tidal breathing before and for 2 min after a deep inhalation and also at different lung volumes above and below functional residual capacity. Rrs was measured at functional residual capacity and at total lung capacity. Before MCh, saline infusion caused significant decrements of forced expiratory volume in 1 s, Vm(40), and Vp(40), but insignificantly affected lung volumes, elastic recoil, Rl, Edyn, and Rrs at any lung volume. Furthermore, saline infusion was associated with an increased response to MCh, which was not associated with significant changes in the ratio of Vm(40) to Vp(40). In conclusion, mild airflow obstruction and enhanced airway responsiveness were observed after saline, but this was not apparently due to altered elastic properties of the lung or inability of the airways to dilate with deep inhalation. It is speculated that it was likely the result of airway wall edema encroaching on the bronchial lumen.     

On the functional consequences of bronchial basement membrane thickening.

Reticular basement membrane (RBM) thickness and airway responses to inhaled methacholine (MCh) were studied in perennial allergic asthma (n = 11), perennial allergic rhinitis (n = 8), seasonal allergic rhinitis (n = 5), and chronic obstructive pulmonary disease (COPD, n = 9). RBM was significantly thicker in asthma (10.1 +/- 3.7 microm) and perennial rhinitis (11.2 +/- 4.2 microm) than in seasonal rhinitis (4.7 +/- 0.7 microm) and COPD (5.2 +/- 0.7 microm). The dose (geometric mean) of MCh causing a 20% decrease of 1-s forced expiratory volume (FEV(1)) was significantly higher in perennial rhinitis (1,073 microg) than in asthma (106 microg). In COPD, the slope of the linear regression of all values of forced vital capacity plotted against FEV(1) during the challenge was higher, and the intercept less, than in other groups, suggesting enhanced airway closure. In asthma, RBM thickness was positively correlated (r = 0.77) with the dose (geometric mean) of MCh causing a 20% decrease of FEV(1) and negatively correlated (r = -0.73) with the forced vital capacity vs. FEV(1) slope. We conclude that 1) RBM thickening is not unique to bronchial asthma, and 2) when present, it may protect against airway narrowing and air trapping. These findings support the opinion that RBM thickening represents an additional load on airway smooth muscle.     

Attenuation of induced bronchoconstriction in healthy subjects: effects of breathing depth.

The effects of breathing depth in attenuating induced bronchoconstriction were studied in 12 healthy subjects. On four separate, randomized occasions, the depth of a series of five breaths taken soon (approximately 1 min) after methacholine (MCh) inhalation was varied from spontaneous tidal volume to lung volumes terminating at approximately 80, approximately 90, and 100% of total lung capacity (TLC). Partial forced expiratory flow at 40% of control forced vital capacity (V(part)) and residual volume (RV) were measured at control and again at 2, 7, and 11 min after MCh. The decrease in V(part) and the increase in RV were significantly less when the depth of the five-breath series was progressively increased (P < 0.001), with a linear relationship. The attenuating effects of deep breaths of any amplitude were significantly greater on RV than V(part) (P < 0.01) and lasted as long as 11 min, despite a slight decrease with time when the end-inspiratory lung volume was 100% of TLC. In conclusion, in healthy subjects exposed to MCh, a series of breaths of different depth up to TLC caused a progressive and sustained attenuation of bronchoconstriction. The effects of the depth of the five-breath series were more evident on the RV than on V(part), likely due to the different mechanisms that regulate airway closure and expiratory flow limitation.     

Gas exchange and intrapulmonary distribution of ventilation during continuous-flow ventilation

In 12 anesthetized paralyzed dogs, pulmonary gas exchange and intrapulmonary inspired gas distribution were compared between continuous-flow ventilation (CFV) and conventional mechanical ventilation (CMV). Nine dogs were studied while they were lying supine, and three dogs were studied while they were lying prone. A single-lumen catheter for tracheal insufflation and a double-lumen catheter for bilateral endobronchial insufflation [inspired O2 fraction = 0.4; inspired minute ventilation = 1.7 +/- 0.3 (SD) 1.kg-1.min-1] were evaluated. Intrapulmonary gas distribution was assessed from regional 133Xe clearances. In dogs lying supine, CO2 elimination was more efficient with endobronchial insufflation than with tracheal insufflation, but the alveolar-arterial O2 partial pressure difference was larger during CFV than during CMV, regardless of the type of insufflation. By contrast, endobronchial insufflation maintained both arterial PCO2 and alveolar-arterial O2 partial pressure difference at significantly lower levels in dogs lying prone than in dogs lying supine. In dogs lying supine, the dependent lung was preferentially ventilated during CMV but not during CFV. In dogs lying prone, gas distribution was uniform with both modes of ventilation. The alveolar-arterial O2 partial pressure difference during CFV in dogs lying supine was negatively correlated with the reduced ventilation of the dependent lung, which suggests that increased ventilation-perfusion mismatching was responsible for the increase in alveolar-arterial O2 partial pressure difference. The more efficient oxygenation during CFV in dogs lying prone suggests a more efficient matching of ventilation to perfusion, presumably because the distribution of blood flow is also nearly uniform.     

Gas transport during high-frequency ventilation

During high-frequency small-volume ventilation (HFV), the transport rate of gas from the mouth to a lung region is a function of two conductances (conductance is the transfer rate of a gas divided by its partial pressure difference): regional longitudinal gas conductance along the airways (Grlongi) and gas conductance between lung regions (Ginter). Grlongi per unit regional lung (gas) volume [Grlongi/(Vr beta g)] was determined during HFV in 11 anesthetized paralyzed dogs lying supine. The distribution of Grlongi/(Vr beta g) was nearly uniform during HFV when stroke volumes were less than approximately two-thirds of the Fowler dead-space volume. By contrast, the distribution of Grlongi/(Vr beta g) was nonuniform when the stroke volume exceeded approximately two-thirds of the Fowler dead-space volume and the oscillation frequency was 5 Hz. Gas conductance along the airways per unit lung gas volume [average Glongi/(V beta g)], for the entire lung, increased with stroke volume at all frequencies, but for a given product of oscillation frequency and stroke volume, the average Glongi/(V beta g) was greater when stroke volume was large and oscillation frequency was low. The average Glongi/(V beta g) increased with frequency up to a maximal value; the frequency at which the maximum occurred depended on the kinematic viscosity of the inspired gas mixture.     

Regional expiratory flow limitation studied with Technegas in asthma.

Regional expiratory flow limitation (EFL) may occur during tidal breathing without being detected by measurements of flow at the mouth. We tested this hypothesis by using Technegas to reveal sites of EFL. A first study (study 1) was undertaken to determine whether deposition of Technegas during tidal breathing reveals the occurrence of regional EFL in induced bronchoconstriction. Time-activity curves of Technegas inhaled during 12 tidal breaths were measured in four asthmatic subjects at control conditions and after exposure to inhaled methacholine at a dose sufficient to abolish expiratory flow reserve near functional residual capacity. A second study (study 2) was conducted in seven asthmatic subjects at control and after three increasing doses of methacholine to compare the pattern of Technegas deposition in the lung with the occurrence of EFL. The latter was assessed at the mouth by comparing tidal with forced expiratory flow or with the flow generated on application of a negative pressure. Study 1 documented enhanced and spotty deposition of Technegas in the central lung regions with increasing radioactivity during tidal expiration. This is consistent with increased impaction of Technegas on the airway wall downstream from the flow-limiting segment. Study 2 showed that both methods based on analysis of flow at the mouth failed to detect EFL at the time spotty deposition of Technegas occurred. We conclude that regional EFL occurs asynchronously across the lung and that methods based on mouth flow measurements are insensitive to it.     

Beclomethasone rapidly ablates allergen-induced beta 2-adrenoceptor pathway dysfunction in human isolated bronchi

Bronchial rings from nonatopic humans were passively sensitized with serum from allergic subjects. Allergen challenge significantly reduced the relaxant effect of salbutamol on carbachol-induced contractions, suggesting beta(2)-adrenoceptor (beta(2)-AR) pathway dysfunction. Incubation of challenged rings for 3 h with 3 x 10(-6) M beclomethasone dipropionate (BDP) restored the relaxant effect, suggesting reversal of beta(2)-AR pathway dysfunction. Incubation with the G(s)alpha protein-stimulating cholera toxin attenuated contractile responses to carbachol significantly less in challenged than in unchallenged rings. Treatment of challenged rings with BDP resulted in an inhibitory effect of cholera toxin that was similar to the effect in unchallenged rings. G(s)alpha protein expression was not significantly altered by BDP, suggesting that the activity of G(s)alpha protein was increased. Relaxation of challenged rings by forskolin was not significantly affected by BDP, suggesting that beta(2)-AR pathway dysfunction was proximal to the adenylyl cyclase. In conclusion, short-term (3-h) treatment with BDP after allergen challenge ablated beta(2)-AR pathway dysfunction by increasing the activity of the G(s)alpha protein in human isolated bronchi.     

Measurement of pulmonary resistance and dynamic compliance with airway obstruction

We compared four algorithms by using leastsquares regression for determination of pulmonary resistance anddynamic elastance in subjects with emphysema, normal subjects, andsubjects with asthma before and after bronchoconstriction. The fourmethods evaluated include 1) asingle resistance and elastance, 2)separate resistances and elastances for each half breath,3) separate inspiratory andexpiratory resistances with a single elastance, and4) separate inspiratory andexpiratory resistances, an expiratory volume interaction term, and asingle elastance. All methods gave comparable results in normal andasthmatic subjects. We found expiratory resistance was larger thaninspiratory resistance in normal and asthmatic subjects during controlconditions, but inspiratory resistance was higher than expiratoryresistance in subjects who experienced severe bronchoconstriction inresponse to methacholine. In subjects who are flow limited,method 2 gives a higher inspiratoryresistance than would be computed by assuming that the elasticpressure-volume curve passes through the zero-flow points.Methods 1 and3 overestimate dynamic elastance andinspiratory resistance. Method 4 appears to identify flow limitation and dynamic hyperinflation andgives a good measure of inspiratory resistance and dynamic elastance.