Therapeutic implications of the pathophysiology of COPD.

This review examines 18 studies published > or =30 yrs ago. They show that the earliest manifestation of chronic obstructive pulmonary disease (COPD) is an increase in residual volume suggesting that the natural history of COPD is a progressive increase in gas trapping with a decreasing vital capacity (VC). The reduction in VC forces the forced expiratory volume in 1 s to decline with it. This is aggravated by rapid shallow breathing leading to dynamic hyperinflation. The earlier studies show that this is energetically opposite to a minimal work or force pattern and is responsible for dyspnoea and exercise limitation. This information, available for >30 yrs leads to three virtually untested hypotheses: 1) training patients to breathe slowly and deeply transiently during exercise should decrease the work of breathing, dynamic hyperinflation and improve exercise performance; 2) rapid shallow breathing is caused by alveolar and bronchial inflammation that stimulates non-myelinated vagal C-fibre afferents, which are known to cause this breathing pattern; and 3) if so, therapeutic efforts to block these afferents might restore a slow-deep pattern and be beneficial, particularly in COPD exacerbations.

The diaphragm: two muscles.

The costal and crural parts of the diaphragm were separately stimulated in anesthetized dogs. Stimulation of the costal part increased the dimensions of the lower rib cage, whereas stimulation of the costal part decreased the dimensions of the lower rib cage. It is concluded that the diaphragm consists of two muscles that act differently on the rib cage.

Bronchodilatation: noncholinergic, nonadrenergic mediation demonstrated in vivo in the cat.

The composite vagus nerve was stimulated during intravenous infusion of 5-hydroxytryptamine in cats subjected to pharmacologic autonomic blockade with atropine, propranolol, and phentolamine. Bronchial caliber, as assessed by changes in pulmonary resistance, demonstrated a marked dilatation, and dilatation could still be demonstrated after preliminary treatment with reserpine. By stimulating the component branches of the vagus nerve, it was determined that the parasympathetic branch is responsible for this phenomenon.

Frequency dependence of compliance as a test for obstruction in the small airways.

We selected five bronchitics and four asthmatics in remission, whose routine lung function tests were not significantly abnormal. Dynamic compliance was measured at different respiratory frequencies and the results compared with those obtained from a normal control group. In all patients compliance was frequency dependent and remained so after the administration of bronchodilator aerosols. Compliance was frequency dependent in only one normal subject, and this was completely reversed by bronchodilators. Because the elastic properties of the patients' lungs were normal, and because pulmonary resistance was normal or only minimally increased, we interpret these results as indicating obstruction in peripheral airways.

The resistance of collateral channels in excised human lungs.

We measured the resistance of collateral channels, R(col), in incomplete interlobar fissures in eight normal and eight emphysematous excised human lungs. Similar measurements were also made from the basal segments to the superior segment of the lower lobe in three normal and five emphysematous lungs. The lobe or segments were inflated through a bronchial cannula; air leaked through collateral channels and out of the other lobe or segment through a pneumotachograph which measured flow. Catheters inserted directly into the lung through the pleural surface on either side of the collateral channels measured the alveolar pressure difference producing collateral flow. R(col) is the ratio of this pressure difference to flow. By also measuring the inflating pressure and the airway pressure at the pneumotachograph, we calculated the lobar or segmental airway resistance, R(aw). In the normal lungs R(col) varied inversely with lung volume and was higher on inflation than on deflation. R(aw) was very small compared to R(col) which ranged from 260 to 3300 cm H(2)O/liter per sec when the distending pressure was 20 cm H(2)O. In the emphysematous lungs on the other hand, R(col) was markedly decreased and ranged from 5 to 20 cm H(2)O/liters per sec at the same distending pressure and was less than R(aw). We conclude that collateral channels are important ventilatory pathways in emphysema. When many units within a lung are ventilated by these pathways there may be disturbances of gas exchange and phase differences between normally and abnormally ventilated areas.

Site of airway obstruction in asthma as determined by measuring maximal expiratory flow breathing air and a helium-oxygen mixture.

Because maximum expiratory flow-volume rates in normal subjects are dependent on gas density, the resistance between alveoli and the point at which dynamic compression begins (R(us)) is mostly due to convective acceleration and turbulence. We measured maximum expiratory flow-volume (MEFV) curves in asthmatics and chronic bronchitics breathing air and He-O(2). In the latter and in some asthmatics, MEFV curves did not change, indicating that R(us) is mostly due to laminar flow. Therefore, the point at which dynamic compression begins must be further upstream than in normal subjects and the site of obstruction must be in small airways. In other asthmatics, flow increased normally indicating obstruction in larger airways. The response to He-O(2) did not correlate with initial values of pulmonary resistance, the initial MEFV curves or the response to bronchodilators. We conclude that the site of airway obstruction varies among asthmatics and that the site of obstruction is not detectable by measurement of the usual parameters of lung mechanics.

Frequency dependence of flow resistance in patients with obstructive lung disease.

Total respiratory, pulmonary, and chest wall flow resistances were determined by means of forced pressure and flow oscillations (3-9 cps) superimposed upon spontaneous breathing in a group of patients with varying degrees of obstructive lung disease. Increased total respiratory and pulmonary resistances were found, whereas the chest wall resistance was normal or subnormal. The total respiratory and pulmonary resistances decreased with increasing frequencies. Static compliance of the lung was measured during interrupted slow expiration, and dynamic compliance was measured during quiet and rapid spontaneous breathing. Compliance was found to be frequency-dependent. The frequency dependence of resistance and compliance are interpreted as effects of uneven distribution of the mechanical properties in the lungs. The practical application of the oscillatory technique to the measurement of flow resistance in patients with lung disease is discussed. Measurements of total respiratory resistance by the forced oscillatory technique at frequencies less than 5 cps appear to be as useful for assessing abnormalities in airway resistance as either the plethysmographic or esophageal pressure techniques.

Regional distribution of pulmonary ventilation and perfusion in elderly subjects.

Using radioactive xenon, we measured the regional distribution of pulmonary ventilation and blood flow in six normal men, whose ages ranged between 65 and 75 yr. The measurements were made in the standing position. The static volume-pressure relation of the lungs was also measured in five of the subjects. The results indicate that by comparison with normal young men: (a) Blood flow to the upper lung zones was increased, although it still remained predominant in the lower zones. (b) Ventilation distribution during a vital capacity inspiration was similar to that seen in young subjects. (c) In five of the six elderly subjects, however, the distribution of ventilation in the resting tidal volume range was not preferential to the lower zones as it was in young men. This was probably caused by airway closure in the lower lung zones. The elderly subjects thus exhibit during normal tidal volume breathing a ventilation distribution pattern similar to that observed in young subjects when breathing at low lung volumes, i.e., near residual volume. This difference is probably due to the combined effect of the loss in elastic recoil of the lungs observed in the elderly subjects and of a decreased resistance to collapse of the aged airways. These findings suggest that in the elderly subjects there is a significant regional ventilation-perfusion impairment during quiet breathing, which may explain in part the reported increase in alveolar-arterial oxygen difference with advancing age.

The Use of a Helium-Oxygen Mixture during Maximum Expiratory Flow to Demonstrate Obstruction in Small Airways in Smokers.

We measured the response to breathing a mixture of 80% helium and 20% oxygen (He) during a maximum expiratory flow-volume (MEFV) maneuver in 66 nonsmokers and 48 smokers, aged 17-67. All of the subjects studied had (forced expiratory volume in 1 s/forced vital capacity [FEV(1.0)/FVC]) x 100 of greater than 70%. While the flow rates of the smokers were within +/-2 SD of those of the nonsmokers at 50% VC (Vmax(50)), both groups showed a reduction in flow with age (nonsmokers: r=-0.34, P<0.01; smokers r=-0.52, P<0.001). Nonsmokers showed no significant reduction with age in response to breathing He, while smokers showed a marked reduction with age (r=-0.63, P<0.001 at Vmax(50)). We also measured the lung volume at which maximum expiratory flow (Vmax) while the subject was breathing He became equal to Vmax while he was breathing air, and expressed it as a percent of the VC. This was the most sensitive method of separating smokers from nonsmokers. These results indicate that the use of He during an MEFV maneuver affords sufficient sensitivity to enable detection of functional abnormalities in smokers at a stage when Vmax while they are breathing air is normal.

Mechanics of intercostal space and actions of external and internal intercostal muscles.

It is conventionally considered that because of their fiber orientations, the external intercostal muscles elevate the ribs, whereas the internal interosseous intercostals lower the ribs. The mechanical action of the intercostal muscles, however, has never been studied directly, and the electromyographic observations supporting this conventional thinking must be interpreted with caution. In the present studies, the external and internal interosseous intercostal muscles have been separately stimulated in different interspaces at, above, and below end-expiratory rib cage volume in anesthetized dogs. The axial (cephalo-caudal) displacements of the ribs were measured using linear displacement transducers. The results indicate that when contracting in a single interspace and other muscles are relaxed, both the external and internal intercostals have a net rib elevating action at end-expiratory rib cage volume. This action increases as rib cage volume decreases, but it progressively decreases as rib cage volume increases such that at high rib cage volumes, both the external and internal intercostals lower the ribs. Stimulating the intercostal muscles in three adjacent intercostal spaces simultaneously produced similar directional rib motion results. We conclude that (a) in contrast with the conventional thinking, the external and internal interosseous intercostals acting alone have by and large a similar effect on the ribs into which they insert; (b) this effect is very much dependent on rib cage (lung) volume; and (c) intercostal muscle action is primarily determined by the resistance of the upper ribs to caudad displacement relative to the resistance of the lower ribs to cephalad displacement. The lateral intercostals, however, might be more involved in postural movements than in respiration. Their primary involvement in rotations of the trunk might account for the presence of two differently oriented muscle layers between the ribs.

Elastic properties of the centrilobular emphysematous space.

Bronchograms were performed using finely particulate lead on emphysematous lungs obtained at necropsy. X-ray films were taken of these lungs at distending pressures of 0, 5, 10, and 20 cm H(2)O. The volumes of individual centrilobular emphysematous spaces were calculated at each distending pressure from measurements made on these bronchograms and pressure-volume curves were constructed for each space. The pressure-volume characteristics of seven normal lungs and one lung with centrilobular emphysema was also measured. The normal lungs, the lung with centrilobular emphysema, and the centrilobular emphysematous spaces were compared by expressing the volume of air contained in them at each distending pressure as a per cent of the volume contained at 20 cm H(2)O distending pressure. We conclude that centrilobular emphysematous spaces have a high residual volume, are less compliant than normal lung tissue, and are much less compliant than the emphysematous lungs which contain them. Furthermore, these spaces undergo little volume change in the tidal breathing range and probably add a relatively nondistensible series dead space to the surrounding lung parenchyma.

The mechanism of increase in total lung capacity during acute asthma.

In order to investigate the mechanism underlying the increased total lung capacity (TLC) observed during an acute asthmatic attack, we measured respiratory mechanics in a specially trained, exercise-induced, asthmatic. During the acute attack his TLC (determined plethysmographically) increased from 7.8 to 9.2 liters. The static pressure-volume curve of the lung shifted to the left and expiratory compliance increased from 0.24 to 0.55 liter/cm H2O. There was a parallel shift of the static pressure-volume curve of the chest wall resulting in an increase in the outward recoil of this structure. The maximum inspiratory pressure-volume curve of the total respiratory system was shifted so that the inspiratory muscles were able to generate greater pressures at any given lung volume during the attack. The findings indicate that the increase in TLC during acute bronchospasm results from the combination of loss of lung recoil, increased outward recoil of the chest wall and increased strength of contraction of the inspiratory muscles.

Reversibility of pulmonary function abnormalities in smokers. A prospective study of early diagnostic tests of small airways disease.

A prospective study of the reversibility of pulmonary function abnormalities in cigarette smokers was performed. Base line studies of 50 otherwise healthy cigarett smokers included lung volumes, static volume-pressure curves, closing volume, slope of phase III and maximum expiratory flow-volume curves while the subjects breathed air and while they breathed an 80 per cent helium-20 per cent oxygen mixture (He). Ten subjects, seven women and three men, ages 29 to 61, were restudied 6 to 14 weeks after they had stopped smoking. Two of these people had an abnormal closing volume, four had an abnormal slope of phase III and five had an abnormal response to helium. Static volume-pressure curves, slope of phase III and airflow rates were not improved on the repeat studies. There was increases in maximum expiratory flow rates with He at 50 and 25 per cent of vital capacity, reductions in the lung volume at which the maximum expiratory flow rate of air and He became identical, and decreases in closing volume. These reversible functional changes in smokers are thought to indicate improvement of peripheral airways obstruction.

The effect of training on strength and endurance of the diaphragm in quadriplegia.

The diaphragmatic electromyogram was used to detect fatigue of the diaphragm in six chronic quadriplegics while they breathed for 10 minutes against a variety of inspiratory resistances. The maximum static inspiratory mouth pressure was measured at functional residual capacity (Pmmax) and from the electromyogram the critical inspiratory mouth pressure that developed in each inspiration (Pmcrit) below which electromyographic changes of diaphragmatic fatigue do not develop was estimated. The measurements were repeated after 8, 12 and 16 weeks of inspiratory muscle training consisting of inspiring for a period of 30 minutes daily, six days a week, against a resistance just sufficient to produce the electromyographic changes of fatigue. A significant and progressive increase in Pmmax and Pmcrit was found during the training. It was concluded that (1) quadriplegics are predisposed to the development of inspiratory muscle fatigue due to reduced muscle strength and reduction in endurance, and (2) in these patients inspiratory muscle training increases both strength and endurance, and protects against fatigue.

Clinical manifestations of inspiratory muscle fatigue.

Twelve patients exhibiting difficulties during discontinuation of artificial ventilation permitted us to investigate physical examination techniques used in diagnosing inspiratory muscle fatigue. Diaphragmatic and intercostal electromyographic tracings, arterial blood gases, rate and depth of ventilation, and thoracoabdominal motion were monitored during spontaneous breathing. Six patients showed electromyographic evidence of inspiratory muscle fatigue. A sequence of events leading to respiratory acidemia emerged--namely electromyographic evidence of fatigue, accompanied or followed by an increased respiratory rate, in turn followed by alternation between abdominal and rib cage breathing (respiratory alternans), paradoxical inward abdominal motion during inspiration (abdominal paradox), and finally an increase in PaCO2 associated with a fall in minute ventilation and respiratory rate, and worsening of respiratory acidemia. The abnormalities of respiratory movements may be reliable clinical signs of inspiratory muscle fatigue, particularly when accompanied by tachypnea and hypercapnia.

A randomized clinical trial of negative pressure ventilation in severe chronic obstructive pulmonary disease: design and methods.

This report documents the design and methods of a randomized clinical trial designed to test the effectiveness of home negative pressure ventilation in patients with severe chronic obstructive pulmonary disease. Active negative pressure ventilation was compared with a sham version of the treatment after a pre-trial assessment had indicated the feasibility of the latter. Over 1200 patients in the metropolitan Montreal area were screened. Of these, 348 patients were recruited to enter a 4-week stabilization period, and 184 were subsequently randomized to receive either active or sham negative pressure ventilation. A 5-day in-hospital period was used to train patients in ventilator use and obtain baseline measures of exercise capacity, lung function, respiratory symptoms, and quality of life. Home ventilation treatment took place during a following 12-week period. Respirator use was recorded both from patient logs and from concealed meters installed in the units. Patients received four home visits by physiotherapists during the 12-week period and returned for follow-up to the hospital 4 and 12 weeks post-discharge for reassessment.

Bronchial hyporesponsiveness.

It is argued that the dose-response curve for asthmatic patients is of a form that would be expected from the in vitro active force length relationship of bronchial smooth muscle if shortening at maximal isometric tension is quasi-isotonic. If this is the case, it may be more important to attempt to explain normal bronchial hyporesponsiveness, in particular whether bronchoconstriction is quasi-isotonic. In vivo response to inhalation depends on change in length of bronchial smooth muscle cells. Further studies should focus on factors influencing change in length rather than change in force.

Negative pressure ventilation. Effects on ventilation during sleep in normal subjects.

Negative pressure ventilation (NPV) is used for ventilatory support of patients with respiratory failure due to neuromuscular disorders and thoracic deformities, and to provide ventilatory muscle rest for patients with severe chronic airflow limitation. To determine whether NPV would result in episodes of upper airway obstruction during sleep, we studied five normal subjects on two consecutive nights with the first night serving as a control and NPV being administered on the second night. Ventilators were adjusted so as to reduce the peak phasic diaphragm electromyogram signal by at least 50 percent. All subjects demonstrated an increase in the total number of apneas + hypopneas per hour on NPV control nights. Although differences were not significant, there was a tendency to develop decreased sleep efficiency, sleep fragmentation and altered sleep architecture with NPV. We conclude that nocturnal NPV can induce sleep apneas and impair sleep quality in normal subjects.

Radiology of the diaphragm as two muscles.

In order to investigate the postulate that the diaphragm consists of two muscles, cineradiographic studies and plain roentgenograms were taken of the diaphragmatic movement in eight dogs. A characteristic pattern of contraction was seen following direct electric stimulation of each of the sections of the diaphragm, namely the costal muscle, mainly anterior to the central tendon, and the smaller, posterior crural muscle. Stimulation of the roots of the phrenic nerves in the neck showed that, with C5 root stimulation, contraction of the costal area occurred, but that with C6 and C7 root stimulation, contraction of the crural area occurred, although the movement was larger with C6 than with C7 root stimulation. Downward displacement of the entire diaphragm followed stimulation of the intrathoracic phrenic nerves. These results support the concept that the canine diaphragm actually consists of two muscles with a different segmental innervation of each part.

Pleural pressure between diaphragm and rib cage during inspiratory muscle activity.

We measured the changes in pleural surface pressure (delta Ppl) in the area of apposition of the rib cage to the diaphragm (Aap) in anesthetized dogs during spontaneous breathing, inspiratory efforts after airway occlusion at functional residual capacity, and phrenic stimulation. Intact dogs were in supine or lateral posture; partially eviscerated dogs were in lateral posture. delta Ppl,ap often differed significantly from changes in abdominal pressure (delta Pab); sometimes they differed in sign (except during phrenic stimulation). Changes in transdiaphragmatic pressure in Aap (delta Pdi,ap) could be positive or negative and were less in eviscerated than in intact dogs. delta Pdi,ap could differ in sign among respiratory maneuvers and over different parts of Aap. Hence average delta Pdi,ap should be closer to zero than delta Pdi,ap at a given site. Since delta Ppl,ap = delta Prc,ap, where Prc,ap represents rib cage pressure in Aap, delta Pdi,ap = delta Pab - delta Prc,ap. Hence, considering that delta Pab and delta Prc depend on different factors, delta Pdi,ap may differ from zero. This pressure difference seems related to the interaction between two semisolid structures (contracted diaphragm and rib cage in Aap) constrained to the same shape and position.