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The main results of the present study are as follows: 1) breathing gas mixtures containing 2% or 4% CO2significantly attenuated bronchoconstrictor responses to methacholine, not differently in healthy subjects and subjects with mild asthma, and 2) the causal inhibitory effect of CO2was significantly mediated via an indirect effect of the increment of V̇e in response to intrapulmonary hypercapnia.

Objective To investigate whether the decrease in dyspnea in neuromuscular diseases after air stacking (AS) occurs mostly in patients with decreased inspiratory muscle force and ensuing chest wall restriction or heterogeneous ventilation across the lungs. Design Interventional, before-after study. Setting A neurorehabilitation inpatient and outpatient center. Participants Fifteen consecutive adult patients affected by neuromuscular diseases (N=15). Interventions AS treatment. Main Outcome Measures Patients had vital capacity (VC) and sniff nasal inspiratory pressure (SNIP) measured. We measured Borg score, oxygen saturation, and ventilation heterogeneity across the lung as estimated from the difference between respiratory resistance at 5 and 19 Hz (R5-19) with the forced oscillation technique before and 5, 30, 60, and 120 minutes after applying AS. Results Before AS, Borg score was significantly related to R5-19 (r2 0.46, P Conclusions These findings suggest that dyspnea in neuromuscular diseases is related to heterogeneous ventilation rather than inspiratory muscle force and/or lung volumes decrease. Restoring ventilation distribution across the lungs with AS appears to improve dyspnea.

Measurement of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) represents the most suitable first-line method to assess lung function in clinical practice (1). In COPD...

Background: In amyotrophic lateral sclerosis (ALS) deterioration of vital capacity (VC) is a marker of disease progression and a criterion to start non-invasive ventilation. Yet lack of mouth seal as a result of facial muscle weakness or inadequate patient cooperation may bias VC measurements. Aim: To test whether measurements of VC are affected by different oral interfaces and are repeatable over time. Methods: Ten ALS patients, four of whom with bulbar dysfunction, were enrolled in this QI project. In random order, three different interfaces currently used in pulmonary function tests labs (rigid cylindrical mouthpiece, flanged mouthpiece, and oronasal mask) were tested. Patients performed 3 to 8 VC maneuvers with each interface. Results: VC was greater with the flanged mouthpiece (2.52 ± 0.25 L) than with oronasal mask (2.30 ± 0.24 L) or with the rigid cylindrical mouthpiece (2.29 ± 0.24 L) (p Conclusion: In most patients with ALS, the use of a flanged mouthpiece yielded significantly greater VC values than oronasal mask or rigid mouthpiece. In addition, a second round of measurements a week later led to significantly higher value of VC. These findings have the potential to impact monitoring of disease progression and clinical decisions in patients with ALS. Support: Veterans Administration VAH Hines, USA; University of Milan, Italy; Casa di Cura del Policlinico, Milan, Italy.

Bronchial asthma is a chronic disease characterized by airway hyperresponsiveness, airway inflammation and remodelling. The hypothesis that the illness is inflammatory in nature has recently been challenged by studies showing that airway smooth muscle (ASM) plays a more important role than previously thought. For example, it is now known that in asthma patients, ASM proliferates more and faster than in healthy subjects, carries intrinsic defects and exhibits impaired relaxation, increased velocity of shortening, plastic adaptation to short length and perturbed equilibrium of actin-to-myosin during cycling. Similar conclusions can be drawn from studies on airway mechanics. For instance, in asthma, abnormal ASM contributes to limiting the response to deep lung stretching and accelerates the return of bronchial tone to baseline conditions, and contributes to increased airway stiffness. Upon stimulation, ASM causes airway narrowing that is heterogeneous across the lung and variable over time. This heterogeneity leads to patchy ventilation. Experimental studies have shown that patchy ventilation may precipitate an asthma attack, and inability to maintain bronchial tone control over time can predict the occurrence of bronchospastic attacks over a matter of a few days. To improve our knowledge on the pathogenesis of asthma, we believe that it is necessary to explore the disease within the framework of the topographical, volume and time domains of the lung that play an important role in setting the severity and progression of the disease. Application of the forced oscillation technique and multiple breath nitrogen washout may, alone or in combination, help address questions unsolvable until now.

Background and objective During forced expiration, alveolar pressure (PALV) increases and intrathoracic gas is compressed. Thus, 1-s forced expiratory volume measured by spirometry (FEV1-sp) is smaller than 1-s forced expiratory volume measured by plethysmography (FEV1-pl). Thoracic gas compression volume (TGCV) depends on the amount of gas within the lung when expiratory flow limitation occurs in the airways. We therefore tested the hypothesis that bronchoconstrictor and bronchodilator responses using FEV1-sp are biased by height and gender, which are major determinants of lung volume. Methods We studied 54 asthmatics during methacholine challenge and 55 subjects with airway obstruction (FEV1-sp increase >200 mL and >12% after salbutamol) measuring at the same time FEV1-sp or FEV1-pl. Results During methacholine challenge, TGCV increased more in males than females, correlated with PALV, total lung capacity (TLC) and height, and the provocative dose was lower using FEV1-sp than FEV1-pl. With salbutamol, FEV1-pl increased

Obesity is associated with important decrements in lung volumes. Despite this, ventilation remains normally or near normally distributed at least for moderate decrements in functional residual capacity (FRC). We tested the hypothesis that this is because maximum flow increases presumably as a result of an increased lung elastic recoil. Forced expiratory flows corrected for thoracic gas compression volume, lung volumes, and forced oscillation technique at 5–11–19 Hz were measured in 133 healthy subjects with a body mass index (BMI) ranging from 18 to 50 kg/m2. Short-term temporal variability of ventilation heterogeneity was estimated from the interquartile range of the frequency distribution of the difference in inspiratory resistance between 5 and 19 Hz (R5–19_IQR). FRC % predicted negatively correlated with BMI ( r = −0.72, P < 0.001) and with an increase in slope of either maximal ( r = −0.34, P < 0.01) or partial flow-volume curves ( r = −0.30, P < 0.01). Together with a slight decrease in residual volume, this suggests an increased lung elastic recoil. Regression analysis of R5–19_IQRagainst FRC % predicted and expiratory reserve volume (ERV) yielded significantly higher correlation coefficients by nonlinear than linear fitting models ( r2= 0.40 vs. 0.30 for FRC % predicted and r2= 0.28 vs. 0.19 for ERV). In conclusion, temporal variability of ventilation heterogeneities increases in obesity only when FRC falls approximately below 65% of predicted or ERV below 0.6 liters. Above these thresholds distribution is quite well preserved presumably as a result of an increase in lung recoil.

Lung diffusing capacity for CO (DLCO) is compromised in haematopoietic stem-cell transplantation (HSCT) recipients. We derived alveolar-capillary membrane conductance (DM,CO) and pulmonary capillary volume (VC) from DLCO and diffusing capacity for NO (DLNO). Forty patients were studied before and 6 weeks after HSCT. Before HSCT, DLNO and DLCO were significantly lower than in 30 healthy controls. DM,CO was ∼40% lower in patients than in controls (p0.001), whereas VC did not differ significantly. After HSCT, DLNO and DM,CO further decreased, the latter by ∼22% from before HSCT (p0.01) while VC did not change significantly. Lung density, serum CRP and reactive oxygen metabolites were significantly increased, with the latter being correlated (R2=0.71, p0.001) with the decrement in DLNO. We conclude that DLNO and, to a lesser extent, DLCO are compromised before HSCT mainly due to a DM,CO reduction. A further reduction of DM,CO without VC loss occurs after HSCT, possibly related to development of oedema, or interstitial fibrosis, or both.

Inspiratory resistance (RINSP) and reactance (XINSP) were measured for 7 min at 5 Hz in 10 subjects with mild asymptomatic asthma and 9 healthy subjects to assess the effects of airway smooth muscle (ASM) activation by methacholine (MCh) and unloading by chest wall strapping (CWS) on the variability of lung function and the effects of deep inspiration (DI). Subjects were studied at control conditions, after MCh, with CWS, and after MCh with CWS. In all experimental conditions XINSP was significantly more negative in subjects with asthma than in healthy subjects, suggesting greater inhomogeneity in the former. However, the variability in both RINSP and XINSP was increased by either ASM activation or CWS, without significant difference between groups. DI significantly reversed MCh-induced changes in RINSP both in subjects with asthma and healthy subjects, but XINSP in the former only. This effect was impaired by CWS more in subjects with asthma than in healthy subjects. The velocity of RINSP and XINSP recovery after DI was faster in subjects with asthma than healthy subjects. In conclusion, these results support the opinion that the short-term variability in respiratory impedance is related to ASM tone or operating length, rather than to the disease. Nevertheless, ASM in individuals with asthma differs from that in healthy individuals in an increased velocity of shortening and a reduced sensitivity to mechanical stress when strain is reduced.

Background Even after publication of the 2011 update of GOLD report, some fundamental questions in the management of COPD are still open and this may weaken the applicability of these guidelines in everyday clinical practice. Objective To assess the level of consensus amongst Italian respirologists on different topics related to diagnosis, monitoring and role of bronchodilator therapy in COPD, by using the Delphi technique. Methods A Delphi study was undertaken between July and November 2011, when two questionnaires were consecutively sent to a panel of experts to be answered anonymously. After each round, the data were aggregated at group level of question topics and structured feedback was given to the panel. Results A first-round questionnaire was sent to 208 pulmonologists randomly selected from different Italian regions. The 132 respondents (63% of those initially selected) were from northern (53%), central (19%) and southern (28%) Italy. A second-round questionnaire was sent to all the first-round respondents, and a response was received from 110 of them (83%). The main topics that reached the pre-defined cut off for consensus (67% or more) were: a) bronchodilator therapy with long-acting bronchodilators could be beneficial in patients with airflow limitation even in the absence of symptoms, b) in patients not fully controlled with one long-acting bronchodilator, maximizing bronchodilation (i.e. adding another bronchodilator with a different mechanism of action) is the preferable option; and c) the use of inhaled corticosteroids (ICSs) as add on therapy should be considered in severe patients with frequent exacerbations. Conclusions Italian specialists agree on several aspects of the diagnosis and treatment of COPD and expert opinion could support everyday decision process in the management of COPD.

Rationale: It is known that day-to-day variability of lung function is increased in asthma but it is also increased in COPD (Timmins et al. 2012). Objectives: To identify possible FOT parameter and time window for calculating the day-to-day variability of airway obstruction and compare its accuracy, sensitivity and specificity for identifying asthma from healthy and COPD. Methods: Daily home FOT measurements were collected from 47 mild-to-moderate asthmatics, 20 moderate-to-severe COPD patients and 35 healthy controls. The mean and day-to-day variability (standard deviation, SD, or coefficient of variation, CV) of FOT time-series were then calculated over multiple time windows. PEF variability was calculated as per current recommendations. Measurements and Main Results: A two-week day-to-day variability of inspiratory resistance (CV 14 R insp ) allowed an optimal and significant separation of the asthma from the healthy and COPD groups (p 2 = 0.49, p 2 = 0.44, p 2 = 0.30, p 14 R insp was significantly higher in asthma (0.14±0.05) than both in the healthy (0.07±0.02, p 14 R insp for separating asthmatics from healthy subjects was significantly greater than PEF (91% vs. 57%, p Conclusions: CV 14 R insp is a sensitive and specific marker of asthma.

We investigated whether obesity is associated with airway hyperresponsiveness in otherwise healthy humans and, if so, whether this correlates with a restrictive lung function pattern or a decreased number of sighs at rest and/or during walking. Lung function was studied before and after inhaling methacholine (MCh) in 41 healthy subjects with body mass index ranging from 20 to 56. Breathing pattern was assessed during a 60-min rest period and a 30-min walk. The dose of MCh that produced a 50% decrease in the maximum expiratory flow measured in a body plethysmograph (PD50MCh) was inversely correlated with body mass index ( r2 = 0.32, P < 0.001) and waist circumference ( r2 = 0.25, P < 0.001). Significant correlations with body mass index were also found with the maximum changes in respiratory resistance ( r2 = 0.19, P < 0.001) and reactance ( r2 = 0.40, P < 0.001) measured at 5 Hz. PD50MCh was also positively correlated with functional residual capacity ( r2 = 0.56, P < 0.001) and total lung capacity ( r2 = 0.59, P < 0.001) in men, but not in women. Neither PD50MCh nor body mass index correlated with number of sighs, average tidal volume, ventilation, or breathing frequency. In this study, airway hyperresponsiveness was significantly associated with obesity in otherwise healthy subjects. In obese men, but not in women, airway hyperresponsiveness was associated with the decreases in lung volumes.

Background Traditionally, ventilatory limitation to exercise is assessed by measuring the breathing reserve (BRR) [ ie , the difference between minute ventilation at peak exercise and maximum voluntary ventilation measured at rest]. Recent studies have however, documented important abnormalities in ventilatory adaptation with a remarkable potential to limit exercise even in the presence of a normal BRR. Among these abnormalities is lung hyperinflation and expiratory flow limitation. This was documented by comparing tidal to maximum flow-volume loops (FVLs) collected throughout the test. In the present study, we wondered whether the advantages of using such a technique within the classic cardiopulmonary exercise test (CPET) might be obscured by the maneuvers interfering with the main functional parameters of the test, and eventually with interpretation of the CPET. Methods We studied 18 healthy subjects, 19 patients affected by COPD, and 19 patients with chronic heart failure during a maximum exercise test on three different study days in a random order. On one occasion, the CPET was conducted with no FVLs (control test [CTRL]), whereas on the other occasions FVLs were incorporated every 1 min during exercise (FVL 1 -min) or every 2 min during exercise (FVL 2 -min). Results None of the classic cardiovascular parameters recorded at ventilatory anaerobic threshold or at peak exercise differed between the study days (by analysis of variance). Furthermore, the coefficients of variation of the main parameters between FVL 1 -min and FVL 2 -min days vs CTRL day were well within the natural variability thresholds reported in the literature. Conclusions The FVLs appear to not interfere with the main functional parameters used for the interpretation of CPET.

The recent definition that chronic obstructive pulmonary disease (COPD) is a "preventable and treatable dis- ease state characterized by airflow limitation that is not fully reversible" reminds that the respiratory functional evaluation is an integral part in the diagnostic and follow-up process in this disease. This review has the scope to focus on some of the most debated pathophysiological and functional issues. One of these is how airflow obstruction occurs and progresses. To this aim, we will discuss the functional role of mucus, increased thickness of the submucosa and adventitia, airway smooth muscle, site of airway narrowing, collapsibility of the central airways, and loss of lung elastic recoil in decreasing flow. Then, we will present a functional clinical approach to the disease that covers the most important features of the dis- ease, such as diagnosis, follow-up, severity assessment, lung hyperinflation, and bronchodilator response.

Aim of this paper was to evaluate the effects of changes in obesity status on lung function decline over an 8-year follow-up. Adults over 24 years (n=1212) from the general population, who participated in both Po River Delta first (PD1, 1980-1982) and second (PD2, 1988-1991) epidemiological surveys, were stratified as "never obese" (BMI30 Kg/m(2) at both PD1 and PD2), "becoming obese" (BMI30 Kg/m(2) at PD1 andor = 30 Kg/m(2) at PD2), "always obese" (BMIor = 30 Kg/m(2) at both PD1 and PD2), and "becoming non-obese" (BMIor = 30 Kg/m(2) at PD1 and30Kg/m(2) at PD2). Linear regression models for changes in FEV(1), FVC, and VC (computed as absolute differences between the values at PD2 and those at PD1) with longitudinal categories of obesity, gender, age, and baseline smoking habits as covariates were applied. The "becoming obese" and "always obese" categories had a significantly greater decline of lung function than "never obese" group; in the "always obese" group, this was true for vital capacities but not FEV(1). Conversely, in the "becoming non-obese" group lung function was at PD2 improved with respect to PD1. Compared with "Never obese" the mean increase in lung function was of 93, 180, and 48 mL for FEV(1), FVC, and VC, respectively. In this general population sample, remaining or becoming obese increases the decline in lung function over 8 years, while becoming non-obese decreases it.

Definitions et subdivisions du volume pulmonaire 17S48 Preparation du patient 17S49 Determination des subdivisions pulmonaires ........ 17S49 Mesure de la CRF par plethysmographie corporelle 17S50 Introduction et theorie 17S50 Materiel 17S50 Technique de mesure 17S50 Controle qualite 17S51 Calculs 17S52 Mesure de la CRF par rincage de l’azote 17S52 Introduction et theorie 17S52 Materiel 17S52 Technique de mesure 17S53 Controle qualite 17S53 Calculs 17S54 Mesure de la Crf par dilution de l’helium 17S54 Introduction et theorie 17S54 Materiel 17S54 Technique de mesure 17S55 Controle qualite 17S56 Calculs 17S56 Mesure des volumes pulmonaires par des techniques d’imagerie 17S56 Radiographies conventionnelles 17S57 Tomodensitometrie 17S57 Imagerie par resonance magnetique 17S57 Controverses et questions critiques 17S57 Valeurs de reference 17S58 Prevention des infections 17S58 Abreviations 17S58

Generalites 17S80 Spirometrie 17S81 Volumes pulmonaires 17S83 Capacite de diffusion du monoxyde de carbone 17S85 Les differents types d’anomalies respiratoires 17S86

Udgivelsesdato: 2007-Mar

We examined the effects of chest wall strapping (CWS) on the response to inhaled methacholine (MCh) and the effects of deep inspiration (DI). Eight subjects were studied on 1 day with MCh inhaled without CWS (CTRL), 1 day with MCh inhaled during CWS (CWSon/on), and 1 day with MCh inhaled during temporary removal of CWS (CWSoff/on). On the CWSon/on day, MCh caused greater increases in pulmonary resistance, upstream resistance, dynamic elastance, residual volume, and greater decreases in maximal expiratory flow than on the CTRL day. On the CWSoff/on day, the changes in these parameters with MCh were not different from the CTRL day. Six of the subjects were again studied using the same protocol on CTRL and CWSon/on days, except that, on a third day, MCh was given after applying the CWS, but the measurements before and after the inhalation were made without CWS (CWSon/off). The latter sequence was associated with more severe airflow obstruction than during CTRL, but less than with CWSon/on. The bronchodilator effects of a DI were blunted when CWS was applied during measurements (CWSon/on and CWSoff/on) but not after it was removed (CWSon/off). We conclude that CWS is capable of increasing airway responsiveness only when it is applied during the inhalation of the constrictor agent. We speculate that breathing at low lung volumes induced by CWS enhances airway narrowing because the airway smooth muscle is adapted at a length at which the contractile apparatus is able to generate a force greater than normal.

[⇓][1] SERIES “ATS/ERS TASK FORCE: STANDARDISATION OF LUNG FUNCTION TESTING” Edited by V. Brusasco, R. Crapo and G. Viegi Number 4 in this Series [1]: #F4

Contains fulltext : 47552.pdf (Publisher’s version ) (Closed access) BACKGROUND: Increased oxidative stress is important in the pathogenesis of chronic obstructive pulmonary disease (COPD). We postulated that treatment with the antioxidant N-acetylcysteine would reduce the rate of lung-function decline, reduce yearly exacerbation rate, and improve outcomes. METHODS: In a randomised placebo-controlled study in 50 centres, 523 patients with COPD were randomly assigned to 600 mg daily N-acetylcysteine or placebo. Patients were followed for 3 years. Primary outcomes were yearly reduction in forced expiratory volume in 1 s (FEV1) and the number of exacerbations per year. Analysis was by intention to treat. FINDINGS: The yearly rate of decline in FEV1 did not differ between patients assigned N-acetylcysteine and those assigned placebo (54 mL [SE 6] vs 47 mL [6]; difference in slope between groups 8 mL [9]; 95% CI -25 to 10). The number of exacerbations per year did not differ between groups (1.25 [SD 1.35] vs 1.29 [SD 1.46]; hazard ratio 0.99 [95% CI 0.89-1.10, p=0.85]). Subgroup analysis suggested that the exacerbation rate might be reduced with N acetylcysteine in patients not treated with inhaled corticosteroids and secondary analysis was suggestive of an effect on hyperinflation. INTERPRETATION: N-acetylcysteine is ineffective at prevention of deterioration in lung function and prevention of exacerbations in patients with COPD.

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 (∼1 min) after methacholine (MCh) inhalation was varied from spontaneous tidal volume to lung volumes terminating at ∼80, ∼90, and 100% of total lung capacity (TLC). Partial forced expiratory flow at 40% of control forced vital capacity (V̇part) and residual volume (RV) were measured at control and again at 2, 7, and 11 min after MCh. The decrease in V̇partand 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 V̇part( 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 V̇part, likely due to the different mechanisms that regulate airway closure and expiratory flow limitation.

Patients with chronic heart failure have an abnormal pattern of exercise ventilation (V̇e), characterized by small tidal volumes (Vt), increased alveolar ventilation, and elevated physiological dead space (Vd/Vt). To investigate whether increased lung water in isolation could reproduce this pattern of exercise ventilation, 30 ml/kg of saline were rapidly infused into nine normal subjects, immediately before a symptom-limited incremental exercise test. Saline infusion significantly reduced forced vital capacity, 1-s forced expiratory volume, and alveolar volume ( P < 0.01 for all). After saline, exercise ventilation assessed by the V̇e/V̇co2 slope increased from 24.9 ± 2.4 to 28.0 ± 2.9 l/l, ( P < 0.0002), associated with a small decrease in arterial Pco2, but without changes in Vt, Vd/Vt, or alveolar-arterial O2 difference. A reduction in maximal O2 uptake of 175 ± 184 ml/min ( P < 0.02) was observed in the postsaline infusion exercise studies, associated with a consistent reduction in maximal exercise heart rate (8.1 ± 5.9 beats/min, P < 0.01), but without a change in the O2 pulse. Therefore, infusion of saline to normal subjects before exercise failed to reproduce either the increase in Vd/Vt or the smaller exercise Vt described in heart failure patients. The observed increase in V̇e can be attributed to dilution acidosis from infusion of the bicarbonate-free fluid and/or to afferent signals from lung and exercising muscles. The reduction in maximal power output, maximal O2 uptake, and heart rate after saline infusion may be linked to accumulation of edema fluid in exercising muscle, impairing the diffusion of O2 to muscle mitochondria.

Objectives A combination of functional measurements reflecting a decrease in maximum flow, a degree of lung hyperinflation, the relationship between maximum inspiratory and expiratory flows, bronchodilator response, and diffusing capacity of the lung for carbon monoxide (Dlco) was used to quantify the extent of emphysema, as assessed by high-resolution CT (HRCT) scanning. Design Forced inspiratory and expiratory spirometry, lung volumes, reversibility test, and single-breath diffusing capacity were assessed before and after inhaling albuterol, 200 μg. Relationships between lung function variables and emphysema extent, as determined by HRCT scanning, were tested by univariate and multivariate analyses. Subjects Thirty-nine COPD outpatients with moderate-to-severe obstruction. Measurements and results Emphysema extent, as assessed by HRCT scanning, ranged from 18 to 70%. All of the lung function parameters that were studied, except for the change in FEV1 percent predicted after salbutamol inhalation, correlated significantly with the extent of emphysema (r2 range, 0.19 to 0.44). Functional residual capacity, forced expiratory flow at 50% of FVC/forced inspiratory flow at 50% of FVC, Dlco/alveolar volume ratio, and bronchodilator-induced change in FEV1/FVC ratio were the only variables retained by stepwise multiple regression analysis. The multiple regression model explained 71% of the variability of emphysema extent measured by HRCT scanning. Conclusions The combination of lung function measurements reflecting lung hyperinflation, bronchial collapsibility, lung diffusing capacity, and bronchodilator response provides a good estimate of the extent of emphysema, as evaluated by HRCT scanning. These data suggest that pulmonary function tests are useful in assessing and monitoring parenchymal damage in COPD patients.

In vivo, the airway response to constrictor stimuli is the net result of a complex array of factors, some facilitating and some opposing airway narrowing, which makes the interpretation of bronchial challenges far from being straightforward. This review begins with a short description of the complex mechanisms of airway smooth muscle activation and force generation as the starting events for airway narrowing. It then focuses on gain factors modulating airway smooth muscle shortening and on the geometric factors determining the magnitude of reduction in airway caliber in vivo. Finally, in light of the evidence that mechanical modulation of airway smooth muscle tone and airway narrowing is at least as important as the inflammatory contractile mediators in the pathogenesis of airway hyper-responsiveness, the implications for the interpretation of bronchial challenges in clinical settings are discussed.

The effects of inhaled bronchodilators at rest and during exercise were studied in 15 subjects with chronic obstructive pulmonary disease. In a crossover study against placebo, albuterol caused a significant increase in expiratory flow and reduced lung hyperinflation and dyspnea at rest, but this was not associated with differences in symptoms with exercise or any relevant parameter of physical performance. Dynamic hyperinflation occurred during exercise similarly after placebo or albuterol and was associated with a reduction of forced expiratory flows. This, in turn, was correlated with the bronchoconstrictor effect of deep inhalation determined at rest. In a parallel group study, expiratory flow was increased by 3-wk treatment with salmeterol ( n = 9) but not with placebo ( n = 6). However, in neither group was the response to exercise different from baseline. These results suggest that in chronic obstructive pulmonary disease effective pharmacological bronchodilation at rest may not be predictive of benefits of exercise tolerance. This may be related to the occurrence of airway narrowing during exercise, particularly when a deep inhalation at rest is followed by a decrease in expiratory flow.

Deep breaths taken before inhalation of methacholine attenuate the decrease in forced expiratory volume in 1 s and forced vital capacity in healthy but not in asthmatic subjects. We investigated whether this difference also exists by using measurements not preceded by full inflation, i.e., airway conductance, functional residual capacity, as well as flow and residual volume from partial forced expiration. We found that five deep breaths preceding a single dose of methacholine 1) transiently attenuated the decrements in forced expiratory volume in 1 s and forced vital capacity in healthy ( n = 8) but not in mild asthmatic ( n = 10) subjects and 2) increased the areas under the curve of changes in parameters not preceded by a full inflation over 40 min, during which further deep breaths were prohibited, without significant difference between healthy ( n = 6) and mild asthmatic ( n = 16) subjects. In conclusion, a series of deep breaths preceding methacholine inhalation significantly enhances bronchoconstrictor response similarly in mild asthmatic and healthy subjects but facilitates bronchodilatation on further full inflation in the latter.

We studied whether bronchodilatation occurs with exercise during the late asthmatic reaction (LAR) to allergen ( group 1, n = 13) or natural asthma (NA; group 2, n = 8) and whether this is sufficient to preserve maximum ventilation (V˙e max), oxygen consumption (V˙o 2 max), and exercise performance (W˙max ). In group 1, partial forced expiratory flow at 30% of resting forced vital capacity increased during exercise, both at control and LAR. W˙max was slightly reduced at LAR, whereasV˙e max, tidal volume, breathing frequency, and V˙o 2 max were preserved. Functional residual capacity and end-inspiratory lung volume were significantly larger at LAR than at control. In group 2, partial forced expiratory flow at 30% of resting forced vital capacity increased greatly with exercise during NA but did not attain control values after appropriate therapy. Compared with control, W˙max was slightly less during NA, whereas V˙o 2 maxand V˙e max were similar. Functional residual capacity, but not end-inspiratory lung volume at maximum load, was significantly greater than at control, whereas tidal volume decreased and breathing frequency increased. In conclusion, remarkable exercise bronchodilation occurs during either LAR or NA and allowsV˙e max andV˙o 2 max to be preserved with small changes in breathing pattern and a slight reduction inW˙max.

The changes in breathing pattern and lung mechanics in response to incremental exercise were compared in 14 subjects with chronic heart failure and 15 normal subjects. In chronic heart failure subjects, exercise hyperpnea was achieved by increasing breathing frequency more than tidal volume. The rate of increase in breathing frequency with carbon dioxide output was inversely correlated ( r = −0.61, P< 0.05) with dynamic lung compliance measured at rest, but not with static lung compliance either at rest or at maximum exercise. Although decrease in expiratory flow reserve near functional residual capacity in chronic heart failure occurred earlier with exercise than in the normal subjects ( P < 0.01), it was not correlated with changes in breathing pattern or occurrence of tachypnea. Tachypnea was achieved in chronic heart failure subjects with an increase in duty cycle because of a greater than normal decrease in expiratory time with exercise. We conclude that in chronic heart failure preexisting increase in lung stiffness plays a significant role in causing tachypnea during exercise. The results of the present study do not support the hypothesis that dynamic compression of the airways downstream from the flow-limiting segment occurring during exercise contributes to hyperpnea.

Current guidelines recommend severity of chronic obstructive pulmonary disease be graded by using forced expiratory volume in 1 s (FEV1). But this measurement is biased by thoracic gas compression depending on lung volume and airflow resistance. The aim of this study was to test the hypothesis that the effect of thoracic gas compression on FEV1 is greater in emphysema than chronic bronchitis because of larger lung volumes, and this influences severity classification and prognosis. FEV1 was simultaneously measured by spirometry and body plethysmography (FEV1-pl) in 47 subjects with dominant emphysema and 51 with dominant chronic bronchitis. Subjects with dominant emphysema had larger lung volumes, lower diffusion capacity, and lower FEV1 than those with dominant chronic bronchitis. However, FEV1-pl, patient-centered variables (dyspnea, quality of life, exercise tolerance, exacerbation frequency), arterial blood gases, and respiratory impedance were not significantly different between groups. Using FEV1-pl instead of FEV1 shifted severity distribution toward less severe classes in dominant emphysema more than chronic bronchitis. The body mass, obstruction, dyspnea, and exercise (BODE) index was significantly higher in dominant emphysema than chronic bronchitis, but this difference significantly decreased when FEV1-pl was substituted for FEV1. In conclusion, the FEV1 is biased by thoracic gas compression more in subjects with dominant emphysema than in those with chronic bronchitis. This variably and significantly affects the severity grading systems currently recommended.

Current opinion is that a vagal stimulation is beneficial for the cardiovascular apparatus but also causes airflow obstruction. The aim of this study was to examine this paradox. By using the within-breath Forced Oscillation Technique, inspiratory resistance and reactance at 5 Hz (R5 and X5, respectively) and cardio-vascular activity can be simultaneously measured humans at baseline and during baroreceptors stimulation by neck suction, allowing the study of the correlation between the parasympathetic activation and airway caliber. Correlation between changes in lung function and neck suction at 0.1Hz was tested in 15 volunteers using the cross-spectrum between either R5 or X5 and the stimulating waveform. Baroreceptors stimulation induced cardiovascular changes compatible with parasympathetic activation. The magnitude of the cross-spectrum between the pressure swings applied to the neck and both R5 and X5 presented a peak at 0.1 Hz with a higher coherence for R5 than X5. On average, R5 slightly but significantly increased compared to baseline, while changes in X5 were negligible. The response to the stimulation was highly variable among subjects.

Bronchial asthma is a chronic disease characterized by airway hyperresponsiveness, airway inflammation and remodelling. The hypothesis that the illness is inflammatory in nature has recently been challenged by studies showing that airway smooth muscle (ASM) plays a more important role than previously thought. For example, it is now known that in asthma patients, ASM proliferates more and faster than in healthy subjects, carries intrinsic defects and exhibits impaired relaxation, increased velocity of shortening, plastic adaptation to short length and perturbed equilibrium of actin-to-myosin during cycling. Similar conclusions can be drawn from studies on airway mechanics. For instance, in asthma, abnormal ASM contributes to limiting the response to deep lung stretching and accelerates the return of bronchial tone to baseline conditions, and contributes to increased airway stiffness. Upon stimulation, ASM causes airway narrowing that is heterogeneous across the lung and variable over time. This heterogeneity leads to patchy ventilation. Experimental studies have shown that patchy ventilation may precipitate an asthma attack, and inability to maintain bronchial tone control over time can predict the occurrence of bronchospastic attacks over a matter of a few days. To improve our knowledge on the pathogenesis of asthma, we believe that it is necessary to explore the disease within the framework of the topographical, volume and time domains of the lung that play an important role in setting the severity and progression of the disease. Application of the forced oscillation technique and multiple breath nitrogen washout may, alone or in combination, help address questions unsolvable until now.

During forced expiration, alveolar pressure (PALV ) increases and intrathoracic gas is compressed. Thus, 1-s forced expiratory volume measured by spirometry (FEV1-sp ) is smaller than 1-s forced expiratory volume measured by plethysmography (FEV1-pl ). Thoracic gas compression volume (TGCV) depends on the amount of gas within the lung when expiratory flow limitation occurs in the airways. We therefore tested the hypothesis that bronchoconstrictor and bronchodilator responses using FEV1-sp are biased by height and gender, which are major determinants of lung volume.We studied 54 asthmatics during methacholine challenge and 55 subjects with airway obstruction (FEV1-sp increase200 mL and12% after salbutamol) measuring at the same time FEV1-sp or FEV1-pl .During methacholine challenge, TGCV increased more in males than females, correlated with PALV , total lung capacity (TLC) and height, and the provocative dose was lower using FEV1-sp than FEV1-pl . With salbutamol, FEV1-pl increased200 mL and12% in 28 subjects, predominantly tall males, with larger TLC, TGCV and PALV .Bronchoconstrictor and bronchodilator responses are overestimated by standard spirometry in subjects with larger lungs because of TGCV.

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.

Lung and chest wall mechanics were studied during fits of laughter in 11 normal subjects. Laughing was naturally induced by showing clips of the funniest scenes from a movie by Roberto Benigni. Chest wall volume was measured by using a three-dimensional optoelectronic plethysmography and was partitioned into upper thorax, lower thorax, and abdominal compartments. Esophageal (Pes) and gastric (Pga) pressures were measured in seven subjects. All fits of laughter were characterized by a sudden occurrence of repetitive expiratory efforts at an average frequency of 4.6 ± 1.1 Hz, which led to a final drop in functional residual capacity (FRC) by 1.55 ± 0.40 liter ( P < 0.001). All compartments similarly contributed to the decrease of lung volumes. The average duration of the fits of laughter was 3.7 ± 2.2 s. Most of the events were associated with sudden increase in Pes well beyond the critical pressure necessary to generate maximum expiratory flow at a given lung volume. Pga increased more than Pes at the end of the expiratory efforts by an average of 27 ± 7 cmH2O. Transdiaphragmatic pressure (Pdi) at FRC and at 10% and 20% control forced vital capacity below FRC was significantly higher than Pdi at the same absolute lung volumes during a relaxed maneuver at rest ( P < 0.001). We conclude that fits of laughter consistently lead to sudden and substantial decrease in lung volume in all respiratory compartments and remarkable dynamic compression of the airways. Further mechanical stress would have applied to all the organs located in the thoracic cavity if the diaphragm had not actively prevented part of the increase in abdominal pressure from being transmitted to the chest wall cavity.

To the Editors: A few questions have been raised following the publication in 2005 of the joint American Thoracic Society (ATS)/European Respiratory Society (ERS) series of documents on standardising lung function testing and these are answered below. The following questions and answers pertain to the standardisation document for spirometry 1. ### Start of test criteria Should blows be rejected solely on the basis of a poor back extrapolated volume (EV)? #### Reply Usually. The forced vital capacity (FVC) may be usable, but the forced expiratory volume in 1 s (FEV1) is likely to be falsely high or low. #### Rationale The acceptability criteria for spirometry were designed to help technologists improve the subject’s technique in order to get the best and most reliable result. EV is important for determining that a fast start to the blow was achieved and this is crucial for getting the best values for FEV1 and peak expiratory flow (PEF). ### End of test criteria In the original document, there was an error in table 5. #### Reply In table 5, the within-manoeuvre criteria for a satisfactory completion of a blow should have read “Duration of ≥6 s (3 s for children) and a plateau in the volume–time curve, or if the subject cannot or should not continue to exhale.” The original table had “or” in twice, whereas the accompanying text was correct, as above. #### Rationale The end of test (EOT) criteria are applied in order to ensure that efforts are made to achieve the best estimate of FVC. When a subject cannot meet the plateau criterion (

According to a recent hypothesis, airway smooth muscle regulates airway calibre mostly at high lung volume, whereas the mucosa and adventitia dimensions dominate at low lung volumes. It was thought that if inhaled steroids decrease the thickness of airway wall in asthma, then forced vital capacity (FVC), which reflects the functional changes at low lung volume, should decrease less during induced bronchoconstriction than flow at high volume. The study was conducted in 31 mild asthmatics under control conditions and during a methacholine challenge before and after 4-weeks treatment with inhaled fluticasone dipropionate (1.5 mg daily, 16 patients) or placebo (15 patients). After fluticasone dipropionate treatment, control forced expiratory volume in one second (FEV1), and maximal flow at 50% of control FVC during forced expiration after a maximal (V'max,50) and a partial inspiration (V'p,50) significantly increased. During methacholine challenge, FVC decreased less than did FEV1 or V'max,50, and so did inspiratory vital capacity compared to V'p,50. Both the provocative dose of methacholine causing a 20% fall in FEV1 and the bronchodilator effect of deep inhalation significantly increased. The latter was assessed by means of the regression coefficient of all V'max,50 plotted against V'p,50. No significant changes in these parameters occurred after placebo. These data show that inhaled steroids remarkably blunt the occurrence of gas trapping during induced bronchoconstriction in mild bronchial asthma, possibly due to their effect on airway wall remodelling.

In this study we explored the effects of physical training on the response of the respiratory system to exercise. Eight subjects with irreversible mild-to-moderate airflow obstruction [forced expiratory volume in 1 s of 85 ± 14 (SD) % of predicted and ratio of forced expiratory volume in 1 s to forced vital capacity of 68 ± 5%] and six normal subjects with similar anthropometric characteristics underwent a 2-mo physical training period on a cycle ergometer three times a week for 31 min at an intensity of ∼80% of maximum heart rate. At this work intensity, tidal expiratory flow exceeded maximal flow at control functional residual capacity [FRC; expiratory flow limitation (EFL)] in the obstructed but not in the normal subjects. An incremental maximum exercise test was performed on a cycle ergometer before and after training. Training improved exercise capacity in all subjects, as documented by a significant increase in maximum work rate in both groups ( P < 0.001). In the obstructed subjects at the same level of ventilation at high workloads, FRC was greater after than before training, and this was associated with an increase in breathing frequency and a tendency to decrease tidal volume. In contrast, in the normal subjects at the same level of ventilation at high workloads, FRC was lower after than before training, so that tidal volume increased and breathing frequency decreased. These findings suggest that adaptation to breathing under EFL conditions does not occur during exercise in humans, in that obstructed subjects tend to increase FRC during exercise after experiencing EFL during a 2-mo strenuous physical training period.

During dynamic hyperinflation with induced bronchoconstriction, there is a reduction in lung elastic recoil at constant lung volume (R. Pellegrino, O. Wilson, G. Jenouri, and J. R. Rodarte. J. Appl. Physiol. 81: 964–975, 1996). In the present study, lung elastic recoil at control end inspiration was measured in normal subjects in a volume displacement plethysmograph before and after voluntary increases in mean lung volume, which were achieved by one tidal volume increase in functional residual capacity (FRC) with constant tidal volume and by doubling tidal volume with constant FRC. Lung elastic recoil at control end inspiration was significantly decreased by ∼10% within four breaths of increasing FRC. When tidal volume was doubled, the decrease in computed lung recoil at control end inspiration was not significant. Because voluntary increases of lung volume should not produce airway closure, we conclude that stress relaxation was responsible for the decrease in lung recoil.