Combined forced oscillation and forced expiration measurements in mice for the assessment of airway hyperresponsiveness

Background

Acute exacerbations contribute to the morbidity and mortality associated with chronic obstructive pulmonary disease (COPD). This proof-of-concept study evaluates whether intermittent pulsed moxifloxacin treatment could reduce the frequency of these exacerbations.

Methods

Stable patients with COPD were randomized in a double-blind, placebo-controlled trial to receive moxifloxacin 400 mg PO once daily (N = 573) or placebo (N = 584) once a day for 5 days. Treatment was repeated every 8 weeks for a total of six courses. Patients were repeatedly assessed clinically and microbiologically during the 48-week treatment period, and for a further 24 weeks' follow-up.

Results

At 48 weeks the odds ratio (OR) for suffering an exacerbation favoured moxifloxacin: per-protocol (PP) population (N = 738, OR 0.75, 95% confidence interval (CI) 0.565-0.994, p = 0.046), intent-to-treat (ITT) population (N = 1149, OR 0.81, 95% CI 0.645-1.008, p = 0.059), and a post-hoc analysis of per-protocol (PP) patients with purulent/mucopurulent sputum production at baseline (N = 323, OR 0.55, 95% CI 0.36-0.84, p = 0.006). There were no significant differences between moxifloxacin and placebo in any pre-specified efficacy subgroup analyses or in hospitalization rates, mortality rates, lung function or changes in St George's Respiratory Questionnaire (SGRQ) total scores. There was, however, a significant difference in favour of moxifloxacin in the SGRQ symptom domain (ITT: -8.2 vs -3.8, p = 0.009; PP: -8.8 vs -4.4, p = 0.006). Moxifloxacin treatment was not associated with consistent changes in moxifloxacin susceptibility. There were more treatment-emergent, drug related adverse events with moxifloxacin vs placebo (p < 0.001) largely due to gastrointestinal events (4.7% vs 0.7%).

Conclusions

Intermittent pulsed therapy with moxifloxacin reduced the odds of exacerbation by 20% in the ITT population, by 25% among the PP population and by 45% in PP patients with purulent/mucopurulent sputum at baseline. There were no unexpected adverse events and there was no evidence of resistance development.

Trial registration

ClinicalTrials.gov number, NCT00473460 (ClincalTrials.gov).     

Transverse images of the human thoracic trachea during forced expiration

The thoracic trachea and the proximal portion of the major bronchi were imaged in five normal volunteers during a forced expiration maneuver using a cine-computer-tomography system. Sixteen images of two contiguous slices were obtained in less than 1 is while expiratory flow was recorded at the mouth. The area of the thoracic trachea decreased rapidly as flow rate rose to its maximum and the wave of collapse propagated distally. The compressive narrowing of both the pars membranacea and the ventrolateral wall was asymmetric. A contact area appeared between the posterior and the left lateral walls. In one subject the trachea was imaged during the entire maneuver with a lower scan frequency. By 725 ms after the beginning of the forced expiration, the area had first decreased to 15% of its initial value and then reincreased to 46% of its initial value. It stayed constant for the remainder of the maneuver. The measured maximum air velocity was greater than the estimated local wave velocity.     

A mathematical analysis of mechanical factors in the forced expiration

A one compartment, mechanical model of the human lung-thorax system is presented and mathematically analyzed. The equation relating the thoracic muscular stress to the expired air volume is developed and investigated. Assuming that the pressure drop along the airways is a linear function of air flow rate and that the effective lung-thorax compliance is constant, a form for the muscular stress as a function of time is developed. This is used to predict volume-time and flow-volume curves, which are compared to those measured on a normal individual. It appears that these theoretical results have the essential characteristics of the experimental curves. These results, coupled with the one-to-one correspondence between the parameters of the model and those of the prototype, suggest that this model should have great utility in the study of ventilatory mechanics.     

Mouth pressure curve on abrupt interruption of airflow during forced expiration

An attempt was made to investigate how the mouth pressure curve represents the process of air flowing into the collapsed segment downstream to the choke point when the airflow is abruptly interrupted at the mouth during forced expiration. Immediately after the interruption of airflow, the mouth pressure suddenly increased (phase 1), followed by a slower rise in pressure (phase 2) within approximately 100 ms until the pressure reached the alveolar pressure. The pleural and alveolar pressures remained constant during this process. The first phase of the abrupt rise represented the pressure induced by the instantaneous interruption of the airflow itself. Analysis of the supramaximal flow (Vsupramax) observed after resumption of the airflow suggested that the choke point remained constant during the second phase of the mouth pressure after interruption of maximal flow (Vmax). From these results, examination of the second phase of the mouth pressure curve may provide useful information about the downstream segment of the airway.     

Computer quantification of airway collapse on forced expiration to predict the presence of emphysema

Background

Spirometric parameters are the mainstay for diagnosis of COPD, but cannot distinguish airway obstruction from emphysema. We aimed to develop a computer model that quantifies airway collapse on forced expiratory flow–volume loops. We then explored and validated the relationship of airway collapse with computed tomography (CT) diagnosed emphysema in two large independent cohorts.

Methods

A computer model was developed in 513 Caucasian individuals with ≥15 pack-years who performed spirometry, diffusion capacity and CT scans to quantify emphysema presence. The model computed the two best fitting regression lines on the expiratory phase of the flow-volume loop and calculated the angle between them. The collapse was expressed as an Angle of collapse (AC) which was then correlated with the presence of emphysema. Findings were validated in an independent group of 340 individuals.

Results

AC in emphysema subjects (N = 251) was significantly lower (131° ± 14°) compared to AC in subjects without emphysema (N = 223), (152° ± 10°) (p < 0.0001). Multivariate regression analysis revealed AC as best indicator of visually scored emphysema (R² = 0.505, p < 0.0001) with little significant contribution of K_CO, %predicted and FEV_1, %predicted to the total model (total R² = 0.626, p < 0.0001). Similar associations were obtained when using CT-automated density scores for emphysema assessment. Receiver operating characteristic (ROC) curves pointed to 131° as the best cut-off for emphysema (95.5% positive predictive value, 97% specificity and 51% sensitivity). Validation in a second group confirmed the significant difference in mean AC between emphysema and non-emphysema subjects. When applying the 131° cut-off, a positive predictive value of 95.6%, a specificity of 96% and a sensitivity of 59% were demonstrated.

Conclusions

Airway collapse on forced expiration quantified by a computer model correlates with emphysema. An AC below 131° can be considered as a specific cut-off for predicting the presence of emphysema in heavy smokers.     

Patterns of neural and muscular electrical activity in costal and crural portions of the diaphragm

To determine whether the central respiratory drives to costal and crural portions of the diaphragm differ from each other in response to chemical and mechanical feedbacks, activities of costal and crural branches of the phrenic nerve were recorded in decerebrate paralyzed cats, studied either with vagi intact and servo-ventilated in accordance with their phrenic nerve activity or vagotomized and ventilated conventionally. Costal and crural electromyograms (EMGs) were recorded in decerebrate spontaneously breathing cats. Hypercapnia and hypoxia resulted in significant increases in peak integrated costal, crural, and whole phrenic nerve activities when the vagi were either intact or cut. However, there were no consistent differences between costal and crural neural responses. Left crural EMG activity was increased significantly more than left costal EMG activity in response to hypercapnia and hypoxia. These results indicate that the central neural inputs to costal and crural portions of the diaphragm are similar in eupnea and in response to chemical and mechanical feedback in decerebrate paralyzed cats. The observed differences in EMG activities in spontaneously breathing animals must arise from modulation of central respiratory activity by mechanoreceptor feedback from respiratory muscles, likely the diaphragm itself.     

Surface electromyography activity of the rectus abdominis,internal oblique,and external oblique muscles during forced expiration in healthy adults

We aimed to characterize rectus abdominis, internal oblique, and external oblique muscle activity in healthy adults under expiratory resistance using surface electromyography. We randomly assigned 42 healthy adult subjects to 3 groups: 30%, 20%, and 10% maximal expiratory intraoral pressure (PEmax). After measuring 100% PEmax and muscle activity during 100% PEmax, the activity and maximum voluntary contraction of each muscle during the assigned experimental condition were measured. At 100% PEmax, the external oblique (p < 0.01) and internal oblique (p < 0.01) showed significantly elevated activity compared with the rectus abdominis muscle. Furthermore, at 20% and 30% PEmax, the external oblique (p < 0.05 and < 0.01, respectively) and the internal oblique (p < 0.05 and < 0.01, respectively) showed significantly elevated activity compared with the rectus abdominis muscle. At 10% PEmax, no significant differences were observed in muscle activity.Although we observed no significant difference between 10% and 20% PEmax, activity during 30% PEmax was significantly greater than during 20% PEmax (external oblique: p < 0.05; internal oblique: p < 0.01). The abdominal oblique muscles are the most active during forced expiration. Moreover, 30% PEmax is the minimum intensity required to achieve significant, albeit very slight, muscle activity during expiratory resistance.     

Relationship between axial motion and volume displacement of the diaphragm during VC maneuvers.

During semistatic inspiratory and expiratory vital capacity (VC) maneuvers, axial motion of the diaphragm was measured by lateral fluoroscopy and was compared with diaphragmatic volume displacement. Axial motion was measured at the anterior, middle, and posterior parts of the diaphragm, and the mean of these measurements was used. The volume displacement was calculated in two ways: first, from respiratory inductive plethysmograph-(Respitrace) derived cross-sectional area changes of rib cage and abdomen (Vdi,RIP) by means of a theoretical analysis described by Mead and Loring (J. Appl. Physiol. 53: 750-755, 1982) and, second, from fluoroscopically measured changes in position and anteroposterior surface of the diaphragm (Vdi,F). A very good linear relationship was found between Vdi,RIP and Vdi,F during inspiration as well as expiration (r greater than 0.95), indicating that the analysis of Mead and Loring was valid in the conditions of the present study. The diaphragmatic volume displacement (active or passive) accounted for 50-60% of VC. A very good linear relationship was also found between mean axial motion and volume displacement of the diaphragm measured with both methods during inspiration and expiration (r greater than 0.98). Our data suggest that, over the VC range, diaphragmatic displacement functionally can be represented by a pistonlike model, although topographically and anatomically it does not behave as a piston.     

Comparison between the effectiveness of expiration and abdominal bracing maneuvers in maintaining spinal stability following sudden trunk loading

The purpose of this study was to clarify the effectiveness of expiration and abdominal bracing maneuvers in response to sudden trunk loading in healthy subjects. Fifteen healthy male subjects were anteriorly loaded under different experimental conditions. Tests were conducted at rest and while performing each of the stabilization maneuvers (expiration and abdominal bracing) at 15% of the maximal voluntary isometric contraction of the internal oblique muscle. Subjects had no knowledge of the perturbation timing. An electromyographic biofeedback system was used to control the intensity of internal oblique muscle activation. Muscular pre-activation of three trunk muscles (internal oblique, external oblique, and L3 erector spinae muscles) and lumbar acceleration in response to loading were measured. The expiration and abdominal bracing maneuvers promoted torso co-contraction, reduced the magnitude of lumbar acceleration, and increased spinal stability compared to the resting condition. There were no differences between the expiration and abdominal bracing maneuvers in the pre-activation of the three trunk muscles or in lumbar acceleration in response to loading. It appears that both expiration and abdominal bracing maneuvers are effective in increasing spinal stability in response to sudden anterior loading.     

Effects of bronchoconstriction on respiratory muscle activity during expiration

The effect of methacholine-induced bronchoconstriction on the electrical activity of respiratory muscles during expiration was studied in 12 anesthetized spontaneously breathing dogs. Before and after aerosols of methacholine, diaphragm, parasternal intercostal, internal intercostal, and external oblique electromyograms were recorded during 100% O2 breathing and CO2 rebreathing. While breathing 100% O2, five dogs showed prolonged electrical activity of the diaphragm and parasternal intercostals in early expiration, postinspiratory inspiratory activity (PIIA). Aerosols of methacholine increased pulmonary resistance, decreased tidal volume, and elevated arterial PCO2. During bronchoconstriction, when PCO2 was varied by CO2 rebreathing, PIIA was shorter at low levels of PCO2, and external oblique and internal intercostal were higher at all levels of PCO2. Vagotomy shortened PIIA in dogs with prolonged PIIA. After vagotomy, methacholine had no effects on PIIA but continued to increase external oblique and internal intercostal activity at all levels of PCO2. These findings indicate that bronchoconstriction influences PIIA through a vagal reflex but augments expiratory activity, at least in part, by extravagal mechanisms.