Changes In Airway Caliber Research Articles

0164 Evidence Suggesting Early Airway Collapse as Cause of Spontaneous Arousals

Abstract Introduction Spontaneous arousals can occur in response to a number of stimuli like noise, movement, hypoxia, or airway obstruction. Some arousals occur “spontaneously” and in individuals donning a hyper-arousable phenotype, spontaneous arousals can dominate the sleep architecture. While arousal mechanisms for some stimuli have been well described, there is a profound lack of knowledge to explain spontaneous arousals. During clinical testing of a device that was designed by SleepMethods, Inc. to anticipate obstructive sleep apnea events by the ability to sense minute airway caliber changes, it was noted, incidentally that the device would signal impeding airway collapse but a spontaneous arousal followed the signal before an obstructive airway event ever developed. This phenomenon was observed many times within and between subjects, suggesting the possibility that very early airway changes are causing “spontaneous arousals” Methods Ten adults (7M;3F) aged 18-80y/o (avg. 54.7y/o) with a known AHI ≥ 15/hr (avg. AHI = 42.6/hr) underwent 1 overnight PSG recording while wearing the device. Patients were required to forego their usual CPAP therapy on the night of study in efforts to expose the device to an adequate number of total obstructive events (defined as apneas and hypopneas; RERAs and snores were excluded). Standard PSG analysis was performed. Scoring rules were applied to determine whether signals were true/false positives and/or true/false negatives based on pre-clinical data showing anticipation accuracy for up to 45 seconds prior to an obstructive airway event. Signals designed to herald obstructive events were noted, incidentally, appearing prior to spontaneous arousals. Results Preliminary results suggest that early phases of airway collapse, as the airway progresses from patency to clinically significant obstruction, are causing EEG arousals which, by current standards, are considered “spontaneous”. Because these findings were incidental to another primary purpose of the clinical study, data analysis is in early stages but currently suggesting at least an associative relationship. Conclusion If final data analysis shows statistically significant correlation between early airway collapse and “spontaneous arousals”, it may have tremendous implications for patients with hyper-arousability, insomnia, and/or pathologically elevated spontaneous arousal indices by proposing therapies aimed at airway patency maintenance. Support N/A

A new role for the exhaled nitric oxide as a functional marker of peripheral airway caliber changes: a theoretical study.

Although considered as an inflammation marker, exhaled nitric oxide (FENO) was shown to be sensitive to airway caliber changes to such an extent that it might be considered as a marker of them. It is thus important to understand how these changes and their localization mechanically affect the total NO flux penetrating the airway lumen ( JawNO), and hence FENO, independently from any inflammatory status change. In this work, a new model was used. It simulates NO production, consumption, and diffusion inside the airway epithelium, NO excretion from the epithelial wall into the airway lumen and, finally, its axial transport by diffusion and convection in the airway lumen. This model may also consider the possible presence of a fluid layer coating the epithelial wall. Simulations were performed. They show the great sensitivity of JawNO to peripheral airway caliber changes. Moreover, FENO shows distinct behaviors, depending on the location of the caliber change. Considering a bronchodilation, absence of FENO change was associated with dilation of central airways, FENO increase with dilation down to pre-acinar small airways, and FENO decrease with intra-acinar dilation due to the amplification of the back diffusion flux. The presence of a fluid layer was also shown to play a significant role in FENO changes. Altogether, the present work theoretically supports that specific FENO changes in acute situations are linked to specifically located airway caliber changes in the lung periphery. This opens the way for a new role for FENO as a functional marker of peripheral airway caliber change. NEW & NOTEWORTHY Using a new model of nitric oxide production and transport, allowing realistic simulation of airway caliber change, the present work theoretically supports that specific changes of the molar fraction of nitric oxide in the exhaled air, occurring without any change in the inflammatory status, are linked to specifically located airway caliber changes in the lung periphery. This opens the way for a new role for FENO as a functional marker of peripheral airway caliber change.

Histologic and biochemical alterations predict pulmonary mechanical dysfunction in aging mice with chronic lung inflammation.

Both aging and chronic inflammation produce complex structural and biochemical alterations to the lung known to impact work of breathing. Mice deficient in surfactant protein D (Sftpd) develop progressive age-related lung pathology characterized by tissue destruction/remodeling, accumulation of foamy macrophages and alteration in surfactant composition. This study proposes to relate changes in tissue structure seen in normal aging and in chronic inflammation to altered lung mechanics using a computational model. Alterations in lung function in aging and Sftpd -/- mice have been inferred from fitting simple mechanical models to respiratory impedance data (Zrs), however interpretation has been confounded by the simultaneous presence of multiple coexisting pathophysiologic processes. In contrast to the inverse modeling approach, this study uses simulation from experimental measurements to recapitulate how aging and inflammation alter Zrs. Histologic and mechanical measurements were made in C57BL6/J mice and congenic Sftpd-/- mice at 8, 27 and 80 weeks of age (n = 8/group). An anatomic computational model based on published airway morphometry was developed and Zrs was simulated between 0.5 and 20 Hz. End expiratory pressure dependent changes in airway caliber and recruitment were estimated from mechanical measurements. Tissue elements were simulated using the constant phase model of viscoelasticity. Baseline elastance distribution was estimated in 8-week-old wild type mice, and stochastically varied for each condition based on experimentally measured alteration in elastic fiber composition, alveolar geometry and surfactant composition. Weighing reduction in model error against increasing model complexity allowed for identification of essential features underlying mechanical pathology and their contribution to Zrs. Using a maximum likelihood approach, alteration in lung recruitment and diminished elastic fiber density were shown predictive of mechanical alteration at airway opening, to a greater extent than overt acinar wall destruction. Model-predicted deficits in PEEP-dependent lung recruitment correlate with altered lung lining fluid composition independent of age or genotype.

Airway calibre variation is a major determinant of exhaled nitric oxide's ability to capture asthma control.

Changes in airway calibre have the potential to modify exhaled nitric oxide fraction (FENO) values and could hamper how FENO captures changes in asthma control. Here, our objective was to assess whether forced expiratory volume in 1 s (FEV1) variations alter the ability of FENO to reflect asthma control.FENO, asthma control (Asthma Control Questionnaire (ACQ)) and FEV1 were measured at least two times in 527 patients during 1819 pairs of visits. Determinants of FENO-ACQ discordance probability were evaluated through a logistic regression analysis. The effectiveness of FENO at capturing either asthma control worsening or improvement between two visits was then assessed by undertaking a stratified receiver operating characteristic curves analysis.When FEV1 and FENO change in the same direction, the odds of FENO-ACQ being discordant are multiplied by 3 (p<0.001). The area under the curve values were 0.765 (95% CI 0.713-0.805) (improvement; p<0.001) and 0.769 (95% 0.706-0.810) (worsening; p<0.001) or 0.590 (95% 0.531-0.653) (improvement; p=0.001) and 0.498 (95% 0.416-0.567) (worsening; p=0.482) when FEV1 and FENO changed in the opposite or same direction, respectively.The manner in which FENO and FEV1 vary concomitantly when asthma control changes determines the ability of FENO to capture this change: parallel or opposite changes in FEV1 and FENO either decrease or increase this ability to capture asthma control changes.

Diagnosing occupational asthma.

Making an accurate diagnosis of occupational asthma (OA) is, generally, important. The condition has not only significant health consequences for affected workers, but also substantial socio-economic impacts for workers, their employers and wider society. Missing a diagnosis of OA may lead to continued exposure to a causative agent and progressive worsening of disease; conversely, diagnosing OA when it is not present may lead to inappropriate removal from exposure and unnecessary financial and social consequences. While the most accurate investigation is specific inhalation challenge in an experienced centre, this is a scarce resource, and in many cases, reliance is on other tests. This review provides a technical dossier of the diagnostic value of the available methods which include an appropriate clinical history, the use of specific immunology and measurement of inflammatory markers, and various methods of relating functional changes in airway calibre to periods at work. It is recommended that these approaches are used iteratively and in judicious combination, in cognizance of the individual patient's circumstances and requirements. Based on available evidence, a working diagnostic algorithm is proposed that can be adapted to the suspected agent, purpose of diagnosis and available resources. For better or worse, many of the techniques - and their interpretation - are available only in specialized centres and where there is room for doubt, referral to such a centre is probably wise. Accordingly, the implementation or development of such specialized centres with appropriate equipment and expertise should greatly improve the diagnostic evaluation of work-related asthma.

Airway and Parenchymal Strains during Bronchoconstriction in the Precision Cut Lung Slice.

The precision-cut lung slice (PCLS) is a powerful tool for studying airway reactivity, but biomechanical measurements to date have largely focused on changes in airway caliber. Here we describe an image processing tool that reveals the associated spatio-temporal changes in airway and parenchymal strains. Displacements of sub-regions within the PCLS are tracked in phase-contrast movies acquired after addition of contractile and relaxing drugs. From displacement maps, strains are determined across the entire PCLS or along user-specified directions. In a representative mouse PCLS challenged with 10−4M methacholine, as lumen area decreased, compressive circumferential strains were highest in the 50 μm closest to the airway lumen while expansive radial strains were highest in the region 50–100 μm from the lumen. However, at any given distance from the airway the strain distribution varied substantially in the vicinity of neighboring small airways and blood vessels. Upon challenge with the relaxant agonist chloroquine, although most strains disappeared, residual positive strains remained a long time after addition of chloroquine, predominantly in the radial direction. Taken together, these findings establish strain mapping as a new tool to elucidate local dynamic mechanical events within the constricting airway and its supporting parenchyma.

Self-reported Symptoms after Induced and Inhibited Bronchoconstriction in Athletes.

ABSTRACTPurposeA change in the perception of respiratory symptoms after treatment with inhaled beta2 agonists is often used to aid diagnosis of exercise-induced bronchoconstriction (EIB). Our aim was to test the association between subjective ratings of respiratory symptoms and changes in airway caliber after induced and inhibited bronchoconstriction in athletes with EIB.MethodsEighty-five athletes with diagnosed or suspected EIB performed a eucapnic voluntary hyperpnea (EVH) challenge with dry air. Of the 45 athletes with hyperpnea-induced bronchoconstriction [i.e., post-EVH fall in forced expiratory volume in 1 s (FEV1) ≥10%, EVH−], 36 were randomized in a double-blind, placebo-controlled, crossover study. Terbutaline (0.5 mg) or placebo was administered by inhalation 15 min before EVH. Spirometry (for FEV1) was performed before and after EVH, and respiratory symptoms were recorded 15 min after EVH on visual analog scales.ResultsTerbutaline inhibited bronchoconstriction (i.e., maximal fall in FEV1 <10% after EVH) in 83% of the EVH-positive athletes, with an average degree of bronchoprotection of 53% (95% confidence interval [CI], 45% to 62%). Terbutaline reduced group mean symptom scores (P < 0.01), but the degree of bronchoprotection did not correlate with individual differences in symptom scores between terbutaline and placebo. Of the 29 athletes who had less than 10% FEV1 fall after EVH in the terbutaline condition, almost half (48%) rated at least one respiratory symptom higher under terbutaline, and more than one quarter (28%) had a higher total symptom score under terbutaline.ConclusionSelf-reports of respiratory symptoms in conditions of induced and inhibited bronchoconstriction do not correlate with changes in airway caliber in athletes with EIB. Therefore, subjective ratings of respiratory symptoms after treatment with inhaled beta2 agonists should not be used as the sole diagnostic tool for EIB in athletes.

Alternative functional criteria to assess airflow-limitation reversibility in asthma

IntroductionInternational guidelines define significant bronchodilator response as absolute and percentage change from baseline in forced expiratory volume (FEV1) in the first second and/or forced vital capacity (FVC) ≥12% and 200mL. However, bronchodilator effects on other lung function parameters have also been correlated to some degree of reversible airflow limitation. ObjectivesTo determine whether changes in other lung function parameters apart from FEV1 and FVC detect functional responses to bronchodilator in asthmatic patients. Materials and methodsSpirometry and body plethysmography were performed at baseline conditions and after administration of 400μg of salbutamol by metered-dose inhaler through a space chamber device in asthmatic patients. Paired t-tests were used to compare lung function parameters between those with and without criteria for reversibility of airway obstruction according to ATS/ERS criteria. Cut-off values were obtained from the corresponding ROC curves. Measurements evaluated were FEV1, FVC, maximum mid-forced expiratory flow (FEF25–75%), residual volume (RV), inspiratory capacity (IC), airway resistance (Raw) and specific airway conductance (sGaw). ResultsFrom a total of 100 consecutive asthmatics patients (46% of them men; average age 58.7±14.1 years; 76% with mild to moderate obstruction), 50 patients had a significant bronchodilator response. All of these had noteworthy variations (p<0.004) in PEF, FEF25–75%, RV, Raw and sGaw. The most accurate in predicting a significant bronchodilator response were the absolute and percentage improvements in PEF (≥0.4L/s and 8%), FEF25–75% (≥0.087L/s and 27%) and the percentage of sGaw compared with that at baseline (≥25%). Based on these cut-off values, a sizeable number of the patients defined as non-responders had important changes in airway caliber. 17 patients had significant increments in the percentage of PEF and 10 had changes in absolute volume; 6 patients had increments in percentage and 16 in absolute change of FEF25–75%; 22 patients had increments in the percentage change of sGaw. ConclusionsChanges of FEV1 and/or FVC may underestimate significant functional response to bronchodilators in asthmatic patients with airway obstruction when considering the change in other lung function parameters.

Predicting Success of Transoral Robotic Surgery for OSA Using Preoperative Sleep Endoscopy and MRI Analysis

Objectives: Determine the relationship between surgical success and both preoperative drug-induced sleep endoscopy (DISE) airway caliber changes and volumetric magnetic resonance imaging (MRI) in patients with obstructive sleep apnea (OSA) undergoing transoral robotic assisted posterior glossectomy and uvulopalatopharyngoplasty (OSA-TORS). Methods: From 2009 to present, as part of a nonrandomized prospective trial, patients with OSA undergoing OSA-TORS had preoperative DISE and pre- and postoperative volumetric MRI of the upper airway. Quantitative analysis of the endoscopy and MRI were compared with surgical success based upon pre- and postoperative polysomnogram, with success defined as postoperative apnea-hypopnea index (AHI) &lt;20 and AHI decrease ≥50%. Preoperative MRI volumes were also compared against DISE changes. Results: Thirty-five apneics undergoing OSA-TORS underwent DISE, 21 received MRIs. DISE data showed that patients with surgical success had a smaller percentage decrease in overall airway collapse in the retroepiglottic ( P = .045) and retroglottic regions ( P = .08) compared with nonsuccesses. Larger preoperative MRI retroglottic airway volumes correlated with increased retroglottic ( P = .05) and retroepiglottic ( P = .03) lateral airway collapse on DISE, however, differences in pre- and postoperative MRI airway volumes did not correlate with surgical success. Conclusions: Larger retroglottic airway volume on MRI correlated with greater lateral airway collapse during DISE, but not with surgical success. Successes after OSA-TORS had significantly smaller airway collapse in the retroepiglottic regions than nonsuccesses during DISE, possibly due to better baseline muscle tone, allowing for better ability to benefit from the relatively small change in airway volume that OSA-TORS provides. Preoperative quantitative DISE could be used to identify patients more likely to succeed after OSA-TORS.

Exhaled nitric oxide: A biomarker integrating both lung function and airway inflammation changes

The increased fraction of exhaled nitric oxide (Feno) values observed in asthmatic patients are thought to reflect increased airway inflammation. However, Feno values can be affected by airway caliber reduction, representing a bias when using Feno values to assess asthma control. We sought to determine the effect of changes in both airway caliber and inflammation on Feno values using the allergen challenge model. FEV1 and Feno values were measured during early airway responses (EARs) and late airway responses after challenge with house dust mite allergens in 15 patients with mild allergic asthma. Helium and sulfur hexafluoride (SF6) phase III expired concentration slopes (SHe and SSF6, respectively) from single-breath washout tests were measured to identify sites of airway constriction. In EARs, FEV1 and Feno value decreases reached 36.8% and 22%, respectively (P < .001). ΔSHe was greater than ΔSSF6 (+189.4% vs +82.2%, P = .001). In late airway responses FEV1 and Feno value decreases reached 31.7% and 28.7%, respectively (P < .001), with the same ΔSHe and ΔSSF6 pattern (+155.8% vs +76%, P = .001). Eight hours after the EAR, FEV1 was still decreased (P < .001), whereas Feno values had returned to baseline. At 24 hours, FEV1 had returned to baseline, with Feno values increased by 38.7% (P = .04). In patients with mild allergic asthma, airway caliber changes modulate changes in Feno values resulting from airway inflammation. Therefore Feno should no longer be considered solely an inflammation biomarker but rather a biomarker that integrates both airway inflammation and lung function changes. Furthermore, early and late phases resulting from allergen exposure were shown to involve similar lung regions.

Pregnancy is associated with a decrease in pharyngeal but not tracheal or laryngeal cross-sectional area: a pilot study using the acoustic reflection method

BackgroundThe risk of difficult upper airway access is increased during pregnancy, especially in labor. Changes in upper airway calibre have been poorly studied during pregnancy. The acoustic reflection method is a non-invasive technique that allows a longitudinal assessment of the cross-sectional area of the upper airway from the mouth to carina. We used this technique to evaluate upper airway calibre during normal pregnancy. MethodsWe conducted a prospective, single centre, observational study with a clinical and upper airway acoustic reflection method evaluation of healthy women during the first, second and third trimesters of pregnancy, and up to two days and one month after delivery. ResultsFifty women participated to the study. The mean pharyngeal cross-sectional area decreased between the first and third trimesters (P<0.001) with no significant change of the minimal and mean tracheal cross-sectional areas. The Mallampati score increased during pregnancy between the first and third trimesters (P<0.001). ConclusionUsing measurements with the acoustic reflection method, normal pregnancy is associated with a significant reduction in the cross-sectional area of the pharynx and a concomitant increase in the Mallampati score. No change was observed in the minimal and mean tracheal cross-sectional areas.

Mechanisms of Decrease in Fractional Exhaled Nitric Oxide During Acute Bronchoconstriction

Fractional exhaled nitric oxide measured at expiratory flow of 50 mL/s (Feno50), a biomarker of airway inflammation, is affected by changes in airway caliber. Whether a lower Feno50 level during bronchoconstriction is only an artifact due to the strong flow dependence of this parameter is controversial. We aimed to evaluate the dynamics of airway and alveolar nitric oxide (NO) during acute bronchoconstriction induced by methacholine. Exhaled NO was measured at expiratory flows of 10, 50, 100, 150, and 250 mL/s before and after metacholine in 26 responders to methacholine and 37 nonresponders. Flow-independent parameters (airway wall NO flux, airway NO diffusing capacity, airway wall NO concentration, alveolar NO concentration) were calculated using a two-compartment model, and correction for NO axial back diffusion was applied. Bronchoconstriction in responders was associated with a decrease in Feno50 (-28%, P &lt; .0001), in airway wall NO flux (-34%, P &lt; .0001), and in airway NO diffusing capacity (-15%, P &lt; .05). In contrast, alveolar NO concentration was not affected by bronchoconstriction. Postmethacholine changes in Feno50 were more strictly related to the ventilation distribution, assessed by single-breath carbon monoxide uptake, than to larger airways caliber, assessed by FEV1. When bronchoconstriction was reversed by salbutamol, airway wall NO flux and airway NO diffusing capacity returned to values comparable to those measured premethacholine. The changes in airway caliber induced by noninflammatory stimuli alter NO transport in the lung. The changes in NO dynamics are limited to conductive airways and are characterized by a reduction of NO flow to luminal space.

Effect of methacholine on peripheral lung mechanics and ventilation heterogeneity in asthma

The forced oscillation technique (FOT) and multiple-breath nitrogen washout (MBNW) are noninvasive tests that are potentially sensitive to peripheral airways, with MBNW indexes being especially sensitive to heterogeneous changes in ventilation. The objective was to study methacholine-induced changes in the lung periphery of asthmatic patients and determine how changes in FOT variables of respiratory system reactance (Xrs) and resistance (Rrs) and frequency dependence of resistance (Rrs5-Rrs19) can be linked to changes in ventilation heterogeneity. The contributions of air trapping and airway closure, as extreme forms of heterogeneity, were also investigated. Xrs5, Rrs5, Rrs19, Rrs5-Rrs19, and inspiratory capacity (IC) were calculated from the FOT. Ventilation heterogeneity in acinar and conducting airways, and trapped gas (percent volume of trapped gas at functional residual capacity/vital capacity), were calculated from the MBNW. Measurements were repeated following methacholine. Methacholine-induced airway closure (percent change in forced vital capacity) and hyperinflation (change in IC) were also recorded. In 40 mild to moderate asthmatic patients, increase in Xrs5 after methacholine was predicted by increases in ventilation heterogeneity in acinar airways and forced vital capacity (r(2) = 0.37, P < 0.001), but had no correlation with ventilation heterogeneity in conducting airway increase or IC decrease. Increases in Rrs5 and Rrs5-Rrs19 after methacholine were not correlated with increases in ventilation heterogeneity, trapped gas, hyperinflation, or airway closure. Increased reactance in asthmatic patients after methacholine was indicative of heterogeneous changes in the lung periphery and airway closure. By contrast, increases in resistance and frequency dependence of resistance were not related to ventilation heterogeneity or airway closure and were more indicative of changes in central airway caliber than of heterogeneity.

Quantitative airway analysis during drug‐induced sleep endoscopy for evaluation of sleep apnea

To quantitatively measure changes in airway caliber at multiple anatomical levels during drug-induced sleep endoscopy (DISE) for evaluation of sleep apnea. We hypothesize that patients undergoing DISE will show: 1) collapse at multiple upper airway regions (retropalatal, retroglossal, and retroepiglottic), with greater collapse in the retropalatal region; and 2) greater anterior-posterior dimensional narrowing than the lateral. Case series. Patients underwent DISE employing propofol as part of a nonrandomized prospective trial assessing candidacy for transoral robotic surgery intervention for sleep apnea. Images of the retropalatal, retroglossal, and retroepiglottic regions were captured during an initial period of light sedation and again in a period of deep sedation. Images were analyzed using software to measure the percent change in regional airway measurements as a result of DISE. Thirty-seven sleep endoscopy videos were analyzed from patients with obstructive sleep apnea (apnea-hypopnea index: 42.9 ± 27.0 events/hour). Analyzable images were in the retropalatal (n = 24), retroglossal (n = 27), and retroepiglottic (n = 29) regions. The patients demonstrated mean reductions in airway area in the retropalatal (84.1 ± 18.7%), retroglossal (39.3 ± 37.5%), and retroepiglottic region (44.6 ± 42.8%). No statistically significant differences were found between lateral and anterior-posterior airway dimensional changes. Patients undergoing DISE had significant reductions in airway area at multiple regions under deep sedation with propofol. We conclude that collapse in the retropalatal region is greater than the hypopharyngeal region. This method can be used to quantitatively measure DISE upper airway changes, which could potentially be used as a means for understanding surgical outcomes in patients with sleep apnea.

Evaluation of upper airway patency during Cheyne–Stokes breathing in heart failure patients

Little is known about the changes in upper airway calibre in Cheyne-Stokes respiration (CSR) during sleep in patients with congestive heart failure. This study aimed to test the hypothesis that upper airway closure occurs during central CSR events, by assessing upper airway calibre during sleep using the forced oscillation technique (FOT). Nine males with compensated heart failure (left ventricular ejection fraction mean ± sem 27.9 ± 5.1%) and predominant central CSR (apnoea/hypopnoea index 43.9 ± 4.2 events · h(-1)) were studied during overnight polysomnography, which included pneumotachography, inductance plethysmography or oesophageal pressure and FOT-derived impedance signal (|Z|). Baseline |Z| values during stable breathing in stage 2 sleep were 11.0 ± 1.3 cmH(2)O · s · L(-1). Mean |Z| increased to 31.9 ± 6.7 cmH(2)O · s · L(-1) during obstructive apnoeas (7% of events, n = 46). Increases in |Z| consistent with upper airway narrowing (more than two-fold baseline) were common during central apnoeas (50 ± 12% of events) occurring in the middle or end of apnoeas and occurred during some central hypopnoeas (16 ± 10% of events), typically in the expiratory phase. These findings indicate that in heart failure patients, reductions in upper airway calibre are common during CSR apnoeas, and may also occur during central hypopnoeas.

Association Between Airway Caliber Changes With Lung Inflation and Emphysema Assessed by Volumetric CT Scan in Subjects With COPD

An increase in airway caliber (airway distensibility) with lung inflation is attenuated in COPD. Furthermore, some subjects have a decrease in airway caliber with lung inflation. We aimed to test the hypothesis that airway caliber increases are lower in subjects with emphysema-predominant (EP) compared with airway-predominant (AP) CT scan subtypes. Additionally, we compared clinical and CT scan features of subjects with (airway constrictors) and without a decrease in airway caliber. Based on GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages and CT scan subtypes, we created a control group (n = 46) and the following matched COPD groups (n = 23 each): GOLD-2-AP, GOLD-2-EP, GOLD-4-AP, and GOLD-4-EP. From the CT scans of all 138 subjects, we measured emphysema, lung volumes, and caliber changes in the third and fourth airway generations of two bronchi. We expressed airway distensibility (ratio of airway lumen diameter change to lung volume change from end tidal breathing to full inspiration) as a global or lobar measure based on normalization by whole-lung or lobar volume changes. Global distensibility in the third and fourth airway generations was significantly lower in the GOLD-2-EP and GOLD-4-EP groups than in control subjects. In GOLD-2 subjects, lobar distensibility of the right-upper-lobe fourth airway generation was significantly lower in those with EP than in those with AP. In multivariate analysis, emphysema was an independent determinant of global and lobar airway distensibility. Compared with nonconstrictors, airway constrictors experienced more dyspnea, were more hyperinflated, and had a higher percentage of emphysema. Distensibility of large- to medium-sized airways is reduced in subjects with an EP CT scan subtype. Emphysema seems to alter airway-parenchyma interdependence. ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov.

Effects of respiratory mechanics on the capnogram phases: importance of dynamic compliance of the respiratory system

IntroductionThe slope of phase III of the capnogram (SIII) relates to progressive emptying of the alveoli, a ventilation/perfusion mismatch, and ventilation inhomogeneity. SIII depends not only on the airway geometry, but also on the dynamic respiratory compliance (Crs); this latter effect has not been evaluated. Accordingly, we established the value of SIII for monitoring airway resistance during mechanical ventilation.MethodsSidestream capnography was performed during mechanical ventilation in patients undergoing elective cardiac surgery (n = 144). The airway resistance (Raw), total respiratory resistance and Crs displayed by the ventilator, the partial pressure of arterial oxygen (PaO2) and SIII were measured in time domain (ST-III) and in a smaller cohort (n = 68) by volumetry (SV-III) with and without normalization to the average CO2 phase III concentration. Measurements were performed at positive end-expiratory pressure (PEEP) levels of 3, 6 and 9 cmH2O in patients with healthy lungs (Group HL), and in patients with respiratory symptoms involving low (Group LC), medium (Group MC) or high Crs (Group HC).ResultsST-III and SV-III exhibited similar PEEP dependencies and distribution between the protocol groups formed on the basis of Crs. A wide interindividual scatter was observed in the overall Raw-ST-III relationship, which was primarily affected by Crs. Decreases in Raw with increasing PEEP were reflected in sharp falls in SIII in Group HC, and in moderate decreases in SIII in Group MC, whereas ST-III was insensitive to changes in airway caliber in Groups LC and HL.ConclusionsSIII assessed in the time domain and by volumetry provide meaningful information about alterations in airway caliber, but only within an individual patient. Although ST-III may be of value for bedside monitoring of the airway properties, its sensitivity depends on Crs. Thus, assessment of the capnogram shape should always be coupled with Crs when the airway resistance or oxygenation are evaluated.

Asthma diagnosis and treatment: Filling in the information gaps

Current approaches to the diagnosis and management of asthma are based on guideline recommendations, which have provided a framework for the efforts. Asthma, however, is emerging as a heterogeneous disease, and these features need to be considered in both the diagnosis and management of this disease in individual patients. These diverse or phenotypic features add complexity to the diagnosis of asthma, as well as attempts to achieve control with treatment. Although the diagnosis of asthma is often based on clinical information, it is important to pursue objective criteria as well, including an evaluation for reversibility of airflow obstruction and bronchial hyperresponsiveness, an area with new diagnostic approaches. Furthermore, there exist a number of treatment gaps (ie, exacerbations, step-down care, use of antibiotics, and severe disease) in which new direction is needed to improve care. Amajor morbidity in asthmatic patients occurs with exacerbations and in patients with severe disease. Novel approaches to treatment for these conditions will be an important advance to reduce the morbidity associated with asthma.

Effects of Bronchoconstriction, Minute Ventilation, and Deep Inspiration on the Composition of Exhaled Breath Condensate

Exhaled breath condensate (EBC) is composed of droplets of airway surface liquid (ASL) diluted by water vapor. The goal of this study was to determine if the composition of EBC is affected by changes in airway caliber, minute ventilation, or forceful exhalation, factors that may differ among subjects with asthma in cross-sectional studies. In a group of subjects with asthma, we measured the effects of the following: (1) a series of three deep-inspiration and forceful-exhalation maneuvers; (2) a doubling of minute ventilation; and (3) acute bronchoconstriction induced by methacholine on EBC volume, dilution of ASL, and concentration of cysteinyl leukotrienes (CysLTs). With the exception of an increase in EBC volume with increased minute ventilation, there were no significant changes in the volume, dilution, or levels of CysLTs in EBC introduced by each of these factors. The CIs surrounding the differences introduced by each factor showed that the maximum systematic errors due to these factors were modest. These results indicate that changes in airway caliber, minute ventilation, or breathing pattern among subjects with asthma do not significantly alter the measurements of mediator concentrations in EBC.

Electronic nose breathprints are independent of acute changes in airway caliber in asthma.

Molecular profiling of exhaled volatile organic compounds (VOC) by electronic nose technology provides breathprints that discriminate between patients with different inflammatory airway diseases, such as asthma and COPD. However, it is unknown whether this is determined by differences in airway caliber. We hypothesized that breathprints obtained by electronic nose are independent of acute changes in airway caliber in asthma. Ten patients with stable asthma underwent methacholine provocation (Visit 1) and sham challenge with isotonic saline (Visit 2). At Visit 1, exhaled air was repetitively collected pre-challenge, after reaching the provocative concentration (PC20) causing 20% fall in forced expiratory volume in 1 second (FEV1) and after subsequent salbutamol inhalation. At Visit 2, breath was collected pre-challenge, post-saline and post-salbutamol. At each occasion, an expiratory vital capacity was collected after 5 min of tidal breathing through an inspiratory VOC-filter in a Tedlar bag and sampled by electronic nose (Cyranose 320). Breathprints were analyzed with principal component analysis and individual factors were compared with mixed model analysis followed by pairwise comparisons. Inhalation of methacholine led to a 30.8 ± 3.3% fall in FEV1 and was followed by a significant change in breathprint (p = 0.04). Saline inhalation did not induce a significant change in FEV1, but altered the breathprint (p = 0.01). However, the breathprint obtained after the methacholine provocation was not significantly different from that after saline challenge (p = 0.27). The molecular profile of exhaled air in patients with asthma is altered by nebulized aerosols, but is not affected by acute changes in airway caliber. Our data demonstrate that breathprints by electronic nose are not confounded by the level of airway obstruction.