Dependence of bronchoconstrictor and bronchodilator responses on thoracic gas compression volume.

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 <200 mL and <12% in 28 subjects, predominantly tall males, with larger TLC, TGCV and PALV . CONCLUSIONS: Bronchoconstrictor and bronchodilator responses are overestimated by standard spirometry in subjects with larger lungs because of TGCV.

Role of hyperpnea in the relaxant effect of inspired CO2 on methacholine-induced bronchoconstriction.

Inhaling carbon dioxide (CO2) in humans is known to cause inconsistent effects on airway function. These could be due to direct effects of CO2 on airway smooth muscle or to changes in minute ventilation (V̇e). To address this issue, we examined the responses of the respiratory system to inhaled methacholine in healthy subjects and subjects with mild asthma while breathing air or gas mixtures containing 2% or 4% CO2. Respiratory mechanics were measured by a forced oscillation technique at 5 Hz during tidal breathing. At baseline, respiratory resistance (R5) was significantly higher in subjects with asthma (2.53 ± 0.38 cmH2O·L-1·s) than healthy subjects (2.11 ± 0.42 cmH2O·L-1·s) (P = 0.008) with room air. Similar values were observed with CO2 2% or 4% in the two groups. V̇e, tidal volume (VT), and breathing frequency (BF) significantly increased with CO2-containing mixtures (P < 0.001) with insignificant differences between groups. After methacholine, the increase in R5 and the decrease in respiratory reactance (X5) were significantly attenuated up to about 50% with CO2-containing mixtures instead of room air in both asthmatic (P < 0.001) and controls (P < 0.001). Mediation analysis showed that the attenuation of methacholine-induced changes in respiratory mechanics by CO2 was due to the increase in V̇e (P = 0.006 for R5 and P = 0.014 for X5) independently of the increase in VT or BF, rather than a direct effect of CO2. These findings suggest that the increased stretching of airway smooth muscle by the CO2-induced increase in V̇e is a mechanism through which hypercapnia can attenuate bronchoconstrictor responses in healthy subjects and subjects with mild asthma.NEW & NOTEWORTHY The main results of the present study are as follows: 1) breathing gas mixtures containing 2% or 4% CO2 significantly attenuated bronchoconstrictor responses to methacholine, not differently in healthy subjects and subjects with mild asthma, and 2) the causal inhibitory effect of CO2 was significantly mediated via an indirect effect of the increment of V̇e in response to intrapulmonary hypercapnia.

Distinct Mechanical Properties of the Respiratory System Evaluated by Forced Oscillation Technique in Acute Exacerbation of COPD and Acute Decompensated Heart Failure.

Discriminating between cardiac and pulmonary dyspnea is essential for patients' management. We investigated the feasibility and ability of forced oscillation techniques (FOT) in distinguishing between acute exacerbation of COPD (AECOPD), and acute decompensated heart failure (ADHF) in a clinical emergency setting. We enrolled 49 patients admitted to the emergency department (ED) for dyspnea and acute respiratory failure for AECOPD, or ADHF, and 11 healthy subjects. All patients were able to perform bedside FOT measurement. Patients with AECOPD showed a significantly higher inspiratory resistance at 5 Hz, Xrs5 (179% of predicted, interquartile range, IQR 94-224 vs. 100 IQR 67-149; p = 0.019), and a higher inspiratory reactance at 5 Hz (151%, IQR 74-231 vs. 57 IQR 49-99; p = 0.005) than patients with ADHF. Moreover, AECOPD showed higher heterogeneity of ventilation (respiratory system resistance difference at 5 and 19 Hz, Rrs5-19: 1.49 cmH2O/(L/s), IQR 1.03-2.16 vs. 0.44 IQR 0.22-0.76; p = 0.030), and a higher percentage of flow limited breaths compared to ADHF (10%, IQR 0-100 vs. 0 IQR 0-12; p = 0.030). FOT, which resulted in a suitable tool to be used in the ED setting, has the ability to identify distinct mechanical properties of the respiratory system in AECOPD and ADHF.

Mechanical effects of obesity on airway responsiveness in otherwise healthy humans.

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.

Tobacco Smoke Exposure, Urban and Environmental Factors as Respiratory Disease Predictors in Italian Adolescents.

Risk monitoring in childhood is useful to estimate harmful health effects at later stages of life. Thus, here we have assessed the effects of tobacco smoke exposure and environmental pollution on the respiratory health of Italian children and adolescents using spirometry and the forced oscillation technique (FOT). For this purpose, we recruited 188 students aged 6-19 years living in Chivasso, Italy, and collected from them the following data: (1) one filled out questionnaire; (2) two respiratory measurements (i.e., spirometry and FOT); and (3) two urine tests for Cotinine (Cot) and 15-F2t-Isoprostane (15-F2t-IsoP) levels. We found a V-shape distribution for both Cotinine and 15-F2t-IsoP values, according to age groups, as well as a direct correlation (p = 0.000) between Cotinine and tobacco smoke exposure. These models demonstrate that tobacco smoke exposure, traffic, and the living environment play a fundamental role in the modulation of asthma-like symptoms (p = 0.020) and respiratory function (p = 0.007). Furthermore, the results from the 11-15-year group indicate that the growth process is a protective factor against the risk of respiratory disease later in life. Lastly, the FOT findings highlight the detrimental effects of tobacco smoke exposure and urbanization and traffic on respiratory health and asthma-like symptoms, respectively. Overall, monitoring environmental and behavioral factors in childhood can provide valuable information for preventing respiratory diseases in adulthood.

Orthopnea and tidal expiratory flow limitation in chronic heart failure.

BACKGROUND: Tidal expiratory flow limitation (FL) is common in patients with acute left heart failure and contributes significantly to orthopnea. Whether tidal FL exists in patients with chronic heart failure (CHF) remains to be determined. PURPOSES: To measure tidal FL and respiratory function in CHF patients and their relationships to orthopnea. METHODS: In 20 CHF patients (mean [+/- SD] ejection fraction, 23 +/- 8%; mean systolic pulmonary artery pressure [sPAP], 46 +/- 18 mm Hg; mean age, 59 +/- 11 years) and 20 control subjects who were matched for age and gender, we assessed FL, Borg score, spirometry, maximal inspiratory pressure (Pimax), mouth occlusion pressure 100 ms after the onset of inspiratory effort (P(0.1)), and breathing pattern in both the sitting and supine positions. The Medical Research Council score and orthopnea score were also determined. RESULTS: In the sitting position, tidal FL was absent in all patients and healthy subjects. In CHF patients, Pimax was reduced, and ventilation and P(0.1)/Pimax ratio was increased relative to those of control subjects. In the supine position, 12 CHF patients had FL and 18 CHF patients claimed orthopnea with a mean Borg score increasing from 0.5 +/- 0.7 in the sitting position to 2.7 +/- 1.5 in the supine position in CHF patients. In contrast, orthopnea was absent in all control subjects. The FL patients were older than the non-FL patients (mean age, 63 +/- 8 vs 53 +/- 12 years, respectively; p < 0.03). In shifting from the seated to the supine position, the P(0.1)/Pimax ratio and the effective inspiratory impedance increased more in CHF patients than in control subjects. The best predictors of orthopnea in CHF patients were sPAP, supine Pimax, and the percentage change in inspiratory capacity (IC) from the seated to the supine position (r(2) = 0.64; p < 0.001). CONCLUSIONS: In sitting CHF patients, tidal FL is absent but is common supine. Supine FL, together with increased respiratory impedance and decreased inspiratory muscle force, can elicit orthopnea, whom independent indicators are sPAP, supine Pimax and change in IC percentage.

Closing capacity and gas exchange in chronic heart failure.

BACKGROUND: Although it is commonly assumed that pulmonary congestion and edema in patients with chronic heart failure (CHF) promotes peripheral airway closure, closing capacity (CC) has not been measured in CHF patients. PURPOSES: To measure CC and the presence or absence of airway closure and expiratory flow limitation (FL) during resting breathing in CHF patients. METHODS: In 20 CHF patients and 20 control subjects, we assessed CC, FL, spirometry, blood gas levels, control of breathing, breathing pattern, and dyspnea. RESULTS: The patients exhibited a mild restrictive pattern, but the CC was not significantly different from that in control subjects. Nevertheless, airway closure during tidal breathing (ie, CC greater than functional residual capacity [FRC]) was present in most patients but was absent in all control subjects. As a result of the maldistribution of ventilation and the concurrent impairment of gas exchange, the mean (+/- SD) alveolar-arterial oxygen pressure difference increased significantly in CHF patients (4.3 +/- 1.2 vs 2.7 +/- 0.5 kPa, respectively; p < 0.001) and correlated with systolic pulmonary artery pressure (r = 0.49; p < 0.03). Tidal FL is absent in CHF patients. Mouth occlusion pressure 100 ms after onset of inspiratory effort (P0.1) as a percentage of maximal inspiratory pressure (Pimax) together with ventilation were increased in CHF patients (p < 0.01 and p < 0.005, respectively). The increase in ventilation was due entirely to increased respiratory frequency (fR) with a concurrent decrease in Paco2. Chronic dyspnea (scored with the Medical Research Council [MRC] scale) correlated (r2= 0.61; p < 0.001) with fR and P0.1/Pimax. CONCLUSIONS: In CHF patients at rest, CC is not increased, but, as a result of decreased FRC, airway closure during tidal breathing is present, promoting the maldistribution of ventilation, ventilation-perfusion mismatch, and impaired gas exchange. The ventilation is increased as result of increased fR, and Pimax is decreased with a concurrent increase in P0.1, implying that there is a proportionately greater inspiratory effort per breath (P0.1/Pimax). These, together with the increased fR, are the only significant contributors to increases in the MRC dyspnea score.

Effects of chest wall strapping on mechanical response to methacholine in humans.

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.

Severity grading of chronic obstructive pulmonary disease: the confounding effect of phenotype and thoracic gas compression.

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.

Orthopnea and tidal expiratory flow limitation in patients with euthyroid goiter.

BACKGROUND: Nontoxic goiters can cause extrathoracic upper airway obstruction and, if large, may extend into the thorax, causing intrathoracic airway obstruction. Although patients with goiter often report orthopnea, there are few studies on postural changes in respiratory function in these subjects. PURPOSE: The aim of this study was to investigate the postural changes in respiratory function and the presence of flow limitation (FL) and orthopnea in patients with nontoxic goiter. METHODS: In 32 patients with nontoxic goiter, respiratory function was studied in seated and supine position. Expiratory FL was assessed with the negative expiratory pressure method. Goiter-trachea radiologic relationships were arbitrarily classified as follows: grade 1, no evidence of tracheal deviation; grade 2, tracheal deviation present in lateral and/or anteroposterior plane but with tracheal compression < 20%; and grade 3, tracheal deviation present with compression > 20%. Subgroups were considered according to this classification and occurrence of orthopnea and FL. RESULTS: In all three groups of patients, the average maximal expiratory flow at 50% of FVC/maximal inspiratory flow at 50% of FVC ratios were > 1.1, suggesting the presence of upper airway obstruction. Grade 3 patients had a significantly lower expiratory reserve volume and maximal expiratory flow at 25% of FVC and higher airway resistance and 3-point FL score than patients with grade 1 and grade 2. The prevalence of orthopnea was highest in patients with grade 3 (75%, as compared to 18% in the grade 1 group). In patients with orthopnea, the prevalence of intrathoracic goiter was also higher (78%, vs 21% in patients without orthopnea). CONCLUSION: There is a high prevalence of orthopnea in patients with goiter, especially when the location is intrathoracic and causes a reduction of end-expiratory lung volume and flow reserve in the tidal volume range, promoting FL especially in supine position. Obesity is a factor that increases the risk of orthopnea in patients with goiter.

Ventilation heterogeneity in obesity.

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/m(2). 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_IQR against FRC % predicted and expiratory reserve volume (ERV) yielded significantly higher correlation coefficients by nonlinear than linear fitting models (r(2) = 0.40 vs. 0.30 for FRC % predicted and r(2) = 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.

Role of alveolar ß2-adrenergic receptors on lung fluid clearance and exercise ventilation in healthy humans.

BACKGROUND: In experimental conditions alveolar fluid clearance is controlled by alveolar ß2-adrenergic receptors. We hypothesized that if this occurs in humans, then non-selective ß-blockers should reduce the membrane diffusing capacity (DM), an index of lung interstitial fluid homeostasis. Moreover, we wondered whether this effect is potentiated by saline solution infusion, an intervention expected to cause interstitial lung edema. Since fluid retention within the lungs might trigger excessive ventilation during exercise, we also hypothesized that after the ß2-blockade ventilation increased in excess to CO2 output and this was further enhanced by interstitial edema. METHODS AND RESULTS: 22 healthy males took part in the study. On day 1, spirometry, lung diffusion for carbon monoxide (DLCO) including its subcomponents DM and capillary volume (VCap), and cardiopulmonary exercise test were performed. On day 2, these tests were repeated after rapid 25 ml/kg saline infusion. Then, in random order 11 subjects were assigned to oral treatment with Carvedilol (CARV) and 11 to Bisoprolol (BISOPR). When heart rate fell at least by 10 beats·min(-1), the tests were repeated before (day 3) and after saline infusion (day 4). CARV but not BISOPR, decreased DM (-13 ± 7%, p = 0.001) and increased VCap (+20 ± 22%, p = 0.016) and VE/VCO2 slope (+12 ± 8%, p<0.01). These changes further increased after saline: -18 ± 13% for DM (p<0.01), +44 ± 28% for VCap (p<0.001), and +20 ± 10% for VE/VCO2 slope (p<0.001). CONCLUSIONS: These findings support the hypothesis that in humans in vivo the ß2-alveolar receptors contribute to control alveolar fluid clearance and that interstitial lung fluid may trigger exercise hyperventilation.

Short-term variability in respiratory impedance and effect of deep breath in asthmatic and healthy subjects with airway smooth muscle activation and unloading.

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.

Mechanical correlates of dyspnea in bronchial asthma.

We hypothesized that dyspnea and its descriptors, that is, chest tightness, inspiratory effort, unrewarded inspiration, and expiratory difficulty in asthma reflect different mechanisms of airflow obstruction and their perception varies with the severity of bronchoconstriction. Eighty-three asthmatics were studied before and after inhalation of methacholine doses decreasing the 1-sec forced expiratory volume by ~15% (mild bronchoconstriction) and ~25% (moderate bronchoconstriction). Symptoms were examined as a function of changes in lung mechanics. Dyspnea increased with the severity of obstruction, mostly because of inspiratory effort and chest tightness. At mild bronchoconstriction, multivariate analysis showed that dyspnea was related to the increase in inspiratory resistance at 5 Hz (R 5) (r (2) = 0.10, P = 0.004), chest tightness to the decrease in maximal flow at 40% of control forced vital capacity, and the increase in R 5 at full lung inflation (r (2) = 0.15, P = 0.006), inspiratory effort to the temporal variability in R 5-19 (r (2) = 0.13, P = 0.003), and unrewarded inspiration to the recovery of R 5 after deep breath (r (2) = 0.07, P = 0.01). At moderate bronchoconstriction, multivariate analysis showed that dyspnea and inspiratory effort were related to the increase in temporal variability in inspiratory reactance at 5 Hz (X 5) (r (2) = 0.12, P = 0.04 and r (2) = 0.18, P < 0.001, respectively), and unrewarded inspiration to the decrease in X 5 at maximum lung inflation (r (2) = 0.07, P = 0.04). We conclude that symptom perception is partly explained by indexes of airway narrowing and loss of bronchodilatation with deep breath at low levels of bronchoconstriction, but by markers of ventilation heterogeneity and lung volume recruitment when bronchoconstriction becomes more severe.

Acute effects of indacaterol on lung hyperinflation in moderate COPD: a comparison with tiotropium.

BACKGROUND: Evidence has been provided that high-dose indacaterol (300 µg) can reduce lung hyperinflation in moderate-to-severe chronic obstructive pulmonary disease (COPD). AIM: To study whether low-dose indacaterol (150 µg) also reduces lung hyperinflation in comparison with the recommended dose of tiotropium (18 µg) in moderate COPD. METHODS: This was a multicenter, randomized, blinded, 3-period cross-over, placebo-controlled study. Spirometry and lung volumes were measured before and 30, 60, 120, 180 and 240 min after the administration of single-doses of indacaterol, tiotropium, or placebo. The primary end-point was the change in peak inspiratory capacity (IC). The area under the 4-h curve (AUC(0-4)) for IC, 1-s forced expiratory volume (FEV(1)) and forced vital capacity (FVC) were secondary variables. RESULTS: 49 patients completed the study. On average, peak IC and AUC(0-4) for IC were significantly greater after indacaterol than placebo by 177 mL (p = 0.007) and 142 mL (p = 0.001), respectively. Differences in peak IC and AUC(0-4) for IC between tiotropium and placebo were 120 mL (p = 0.07) and 85 mL (p = 0.052), respectively. Differences between indacaterol and tiotropium were statistically insignificant. Peak IC increased by >20% in 12 patients with indacaterol and 9 with tiotropium (p = 0.001), and by >30% in 8 patients with indacaterol and 3 with tiotropium (p = 0.001). The effects of indacaterol and tiotropium on FEV(1) and FVC were statistically significant vs placebo. CONCLUSIONS: Low-dose indacaterol has a bronchodilator effect that is similar to the recommended dose of tiotropium, but it is slightly superior in reducing lung hyperinflation. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT00999908.

Contribution of ß-adrenergic receptors to exercise-induced bronchodilatation in healthy humans.

Exercise in healthy subjects is usually associated with progressive bronchodilatation. Though the decrease in vagal tone is deemed to be the main underlying mechanism, activation of bronchial ß(2)-receptors may constitute an additional cause. To examine the contribution of ß(2)-adrenergic receptors to bronchodilatation during exercise in healthy humans, we studied 15 healthy male volunteers during maximum exercise test at control conditions and after a non-selective ß-adrenergic blocker (carvedilol 12.5mg twice a day until heart rate decreased at least by 10beats/min) and inhaled ß(2)-agonist (albuterol 400µg). Airway caliber was estimated from the partial flow at 40% of control forced vital capacity (V˙(part40)) and its changes during exercise from the slope of linear regression analysis of V˙(part40) values against the corresponding minute ventilation during maximal exercise until exhaustion. At control, V˙(part40) increased progressively and significantly with exercise. After albuterol, resting V˙(part40) was significantly larger than at control increased but did not further increase during exercise. After carvedilol, V˙(part40) was similar to control but its increase with exercise was significantly attenuated. These findings suggest that ß(2)-adrenergic system plays a major role in exercise-induced bronchodilation in healthy subjects.

Exercise ventilatory inefficiency and mortality in patients with chronic obstructive pulmonary disease undergoing surgery for non-small-cell lung cancer.

OBJECTIVE: Surgical resection is the treatment of choice to cure patients with non-small-cell lung cancer (NSCLC); nevertheless, the assessment of the lower limit of surgical tolerance remains difficult. Ventilatory inefficiency (measured as the ventilation to CO(2) production ratio (V'(E)/V'(CO2) slope) is a survival predictor in pulmonary hypertension (PH) and chronic heart failure (CHF) and is considered a marker of PH in chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the role of V'(E)/V'(CO2) slope as preoperative mortality and morbidity predictor in COPD patients submitted to lung resection for NSCLC and considered operable according to current standards. METHODS: A retrospective analysis was performed in 145 consecutive COPD patients with lung cancer (128 males and 17 females), with a mean age of 64 years (range: 41-82 years) who were referred for preoperatory evaluation. Because of bronchial obstruction or reduced pulmonary diffusion capacity for carbon monoxide (D(L,CO)), all these patients were considered operable only after a cardiopulmonary exercise test showed a preserved cardiopulmonary function. RESULTS: A total of 98 lobectomies, eight bilobectomies and 39 pneumonectomies (13 left and 26 right) were performed. Twenty-one patients (14.5%) suffered severe cardio-respiratory complications; 15/106 patients (14.2%) after lobectomy/bilobectomy and 6/39 (15.4%) after pneumonectomy. Five patients (3.4%) died within 30 days after surgery (3/106 after lobectomy/bilobectomy (2.8%) and 2/39 after pneumonectomy (5.1%)). Considering all functional parameters before surgery and the postoperative predicted values, a logistic regression analysis individuated the V'(E)/V'(CO2) slope as the only independent mortality predictor (odds ratio (OR): 1.24 z=2.77; p<0.007). The V'(O2 peak) was instead the best predictor for the occurrence of severe cardiopulmonary postoperative complications (OR: 0.05, z=-2.39, p<0.02). CONCLUSIONS: In COPD patients, a high V'(E)/V'(CO2) slope before lung resection is an independent mortality predictor even in the presence of an acceptable cardiopulmonary performance. COPD patients with high V'(E)/V'(CO2) slope before surgery must be carefully screened to exclude pulmonary hypertension, especially before surgical procedures with large parenchymal exeresis.

Airway distensibility and volume recruitment with lung inflation in COPD.

The effects of full lung inflation on respiratory conductance (Grs) and reactance (Xrs) were measured in 15 subjects with moderate to severe chronic obstructive pulmonary disease (COPD) and 11 matched healthy control subjects. Airway distensibility was estimated from the ratio of the difference of Grs between functional residual capacity and total lung capacity to the relevant changes in lung volume (ΔGrs/ΔVl) or transpulmonary pressure (ΔGrs/ΔPtp). Similar analysis was applied to Xrs to estimate lung volume recruitment (ΔXrs/ΔVl or ΔXrs/ΔPtp). The extent of emphysema in COPD subjects was estimated from the percentage of low attenuation area (LAA) at high-resolution computed tomography. At baseline, ΔGrs/ΔVl and ΔXrs/ΔVl were significantly less in COPD than control subjects, indicating less distensibility and volume recruitment in the former. In COPD, ΔGrs/ΔPtp and ΔXrs/ΔPtp were uncorrelated with LAA but correlated with 1-s forced expiratory volume and with each other. After albuterol, both ΔGrs/ΔPtp and ΔGrs/ΔVl became significantly and negatively correlated with LAA, while ΔXrs/ΔPtp and ΔXrs/ΔVl decreased significantly independently of LAA. Moreover, ΔGrs/ΔPtp and ΔXrs/ΔPtp with lung inflation were no longer correlated with each other, suggesting that airway distensibility and volume recruitment were affected differently by airway smooth muscle tone. Assuming that Grs mainly reflects airway caliber and Xrs the number of ventilated lung units, we conclude that airway smooth muscle contributes to airway stiffness and ventilation inhomogeneities in COPD subjects with prevailing bronchitis but only to the latter in those with more emphysema. We suggest that changes of airway distensibility and volume recruitment with a bronchodilator may be useful for disease phenotyping.