In asthma, the involvement of airways from the glottis to the alveolar ducts is likely, and the site of this involvement determines the resulting pathophysiology. The small airways of less than 2 mm in diameter are pathways of low resistance and normally contribute about 10% of the total resistance to flow (1, 2). They are reportedly more resistant in the first few years of life (3), but experiments showing this have not been repeated, so that idea has neither been confirmed nor denied. Confirmation of these results would be an important advance, because if the small airways are high-resistance pathways in infancy, then bronchiolitis would be a much more serious condition in infants than in adults. Hogg and colleagues claimed that this was the reason that acute bronchiolitis was a serious disease in infants but apparently not in adults (3). If one-half of all small airways became completely obstructed, their combined resistance would double. However, the large airways would remain unobstructed and their resistance would not change. If small-airway resistance is only 10% of the total, doubling it would only increase total resistance by 10%. Thus it is difficult to detect small airway obstruction by the usual lung function tests.
Brown and colleagues confirmed this theory of small-airway resistance almost 20 years ago by blowing small beads into the periphery of the lung to block the small airways and by blocking the large airways with larger beads (4). Small-airway obstruction had no measurable effect on the pressure–volume curves of dog lungs. Although many airways were occluded, air entered the air spaces beyond the occluded airways via collateral channels, leaving the vital capacity unimpaired. However, in pig lungs, which lack collateral channels, the vital capacity was reduced by 50%; airways to 50% of the lung were occluded, and 50% of the alveoli received no ventilation. In both species, pulmonary resistance increased by approximately 10%. However, different results were obtained with large beads. In dogs, the blockage had no effect on vital capacity (as with the small beads); one could still get as much air in the lung after the beads as before, but because the obstruction was in the high-resistance pathways, total pulmonary resistance was double that after small airway obstruction. In pigs, the vital capacity was again decreased by 50%, resulting in half of the alveoli being unventilated after obstruction. As in dogs, resistance doubled.
These experiments show that small-airway obstruction has very little effect on the mechanical properties of the lung, particularly if there is collateral ventilation, but it does affect the distribution of inspired gas if air is displaced from one set of air spaces across collateral channels to alveoli beyond the obstructed airways. Fresh air will enter the unobstructed alveoli, whereas the collaterally ventilated spaces will receive alveolar gas. Thus one would predict that with small-airway obstruction there would be little effect on the mechanical properties of the lungs, but there would be a major effect on ventilation distribution. This was demonstrated by Hogg and colleagues using a single-breath nitrogen washout curve following an inflation with 100% oxygen (5). Before the beads were blown in, the nitrogen concentration on the alveolar plateau of these curves was flat; that is, the alveolar gas composition from various air spaces was almost uniform and ventilation was evenly distributed. But after the beads caused small-airway obstruction, alveolar gas composition became nonuniform, with a rising nitrogen concentration on the alveolar plateau. The early expired alveolar gas had low nitrogen and high oxygen concentrations, showing that it was derived from well-ventilated alveoli. The later gas, with higher nitrogen and lower oxygen concentrations, came from collaterally ventilated spaces. Thus, in species with collateral ventilation (such as humans) small-airway obstruction has little effect on lung mechanics, but it does affect ventilation distribution.
An important structural difference between large and small airways is that the total cross-sectional area of a given generation of small airways can be several orders of magnitude greater than the total cross-sectional area of the large airways. The flow is the same for both cross-sections, but because the linear velocity of the gas is the flow divided by the cross-sectional area, gas velocity is much less in the small airways. As a result, small airways have fully developed laminar flow. In the large airways, the linear velocities of the gas are considerably greater and gas flow becomes more turbulent. Fully developed laminar flow is the only flow regimen independent of gas density, so that changes in gas density have little or no effect on small-airway resistance. Gas density does affect large-airway resistance. Wood and colleagues (6) showed that the resistance of airways smaller than approximately 2 mm in diameter was the same for air as for sulfur hexafluoride, which is a very dense gas. However, the resistance in the large airways with sulfur hexafluoride was systematically larger than with air. Therefore, the effect of gas density on airway resistance or maximum expiratory flow can provide evidence of where the obstruction lies.
Another physiologic difference between small and large airways is that the liquid lining small airways has the characteristics of a surfactant with a low surface tension, particularly on expiration (7). This low surface tension protects the small airways from closing at low lung volumes. One would therefore predict that if the normal surfactant, which has a minimum surface tension of approximately 5 dynes/cm, were replaced by serum with a surface tension of approximately 40 dynes/cm or mucus, which has a surface tension of approximately 25 dynes/cm, these airways might become unstable and collapse. If this collapse were extensive, it would lead to gas trapping and an increase in residual volume. It is known that it is the small airways that close at residual volume in normal lungs (8). Residual volume rises with age, caused by closure of the terminal bronchioles. Thus, it is possible that the terminal bronchioles are responsible for most of the gas trapping characterizing asthma.
These physiologic differences between small and large airways enable criteria to be developed for detecting small-airway obstruction. These criteria are abnormal ventilation distribution, combined with the normal elastic and flow-resistive properties of lungs; independence of maximal expiratory flow or flow resistance to gas density; and gas trapping. With the final criterion there is a caveat: it is clear that gas trapping in the normal lung occurs due to closure of small airways, but it is not so clear that this mechanism is responsible for gas trapping in disease.
Using these criteria we can review the investigations already performed in this area. In all normal lungs the flow–volume curve is density-dependent (9, 10). There is an increase in maximum expiratory flow on breathing 80% helium with 20% oxygen, and a concomitant decrease in pulmonary resistance (10). In patients with irreversible airway obstructions, breathing 80% helium and 20% oxygen can lead to an increase in resistance because this mixture has a greater viscosity than air. Laminar flow resistance is viscosity-dependent, so in the presence of fully developed laminar flow there is a small increase in resistance. In children with asthma, Wood and Bryan demonstrated that all subjects increased maximum expiratory flow when gas density decreased (9); therefore, it appears that in childhood asthma the flow-limiting segments are in larger airways where flow is density-dependent. Despas and colleagues showed that adults with asthma fall into two groups: responders to the helium/oxygen mixture and nonresponders (10). Subsequently Antic (11) showed that nonsmoking subjects who had asthma uncomplicated by respiratory infections or chronic cough were the responders. But in nonsmokers with recurrent infections, there was approximately a 50% chance of being a nonresponder. The greatest prevalence of nonresponders was in smokers with asthma who had recurrent infections with chronic cough and sputum production (11). Therefore, smoking appears to be a major factor in converting asthma patients from being responders with flow limitation in large airways to being nonresponders with small-airway obstruction.
A problem with this line of reasoning is the poor correlation between patients' response in terms of maximum expiratory flow and the response in terms of pulmonary resistance (10, 12). One of the reasons is that different factors are being measured with the two tests: maximum expiratory flow measures only the resistance of airways between alveoli and flow-limiting segments and is unaffected by downstream structures such as the glottis and upper airway. If the flow-limiting segments are out in the periphery, the effects of the large airways will not be detected, even if there is considerable obstruction in them. However, measurement of total pulmonary resistance includes the whole airway from the mouth to the alveolar ducts and it also includes tissue viscance. These differences in what is being measured may explain why the effects of gas density on maximum expiratory flow do not correlate with its effects on pulmonary resistance.
Examination of the effects of small-airway obstruction on ventilation distribution in the presence of normal elastic and flow-resistive properties has been carried out by measuring frequency dependence of dynamic lung compliance (13). This is very difficult because the precise measurement of dynamic compliance requires a great deal of attention to detail. Nevertheless, Woolcock and colleagues successfully used this methodology to show that smokers did have small-airway obstruction (13), and it is now well established that the obstruction is found in these airways in smokers.
In the past few years, King and colleagues have developed a method of assessing airway closure using Technegas (14), which is a gas with some remarkable properties. It has properties between those of a gas and those of an aerosol and it has a tendency to adhere to lung tissue. It can be tagged with 99mTc so that its distribution in the lung can be measured by single photon emission computed tomography, which then determines where in the lung the inspired gas resides. From a transmission scan, the outlines and volume of the lung can be obtained. By superimposing an emission scan on the transmission scan, one can measure where a bolus of Technegas goes when inhaled from residual volume. In the normal lung, Technegas is inhaled into superior lung regions because, as shown in earlier experiments, the airways at the base of the lung are closed at residual volume (15). Furthermore, Technegas has demonstrated that the degree of basal airway closure increases with age, again confirming earlier studies (16). In patients with asthma, in contrast, wedge-shaped areas of nonventilated lung indicate closure of a number of large airways compared to normal subjects. In other patients with asthma, many of the nonventilated regions appear nonsegmental in distribution, suggesting that airway closure occurs in small airways. After administration of methacholine, King and colleagues found large wedge-shaped areas of airway closure (17). So unquestionably the large airways can close in asthma. Furthermore, two studies conducted weeks apart in the same patient with asthma indicated that the same airways closed both times. Large airway closure can be induced in patients with asthma, and it tends to recur in the same airway. Nevertheless, in the absence of bronchoprovocation it is a strong possibility that pathologic gas trapping in asthma may be the result of small, not large, airway closure.
Why do the airways close excessively in asthma? This is an interesting question. The obvious answer is smooth-muscle contraction. But Woolcock and colleagues failed to induce gas trapping in dogs even with marked increases in small-airway resistance following vagal stimulation (18, 19). It was only when vagal stimulation was combined with beta-sympathetic blockade that there was any gas trapping. Large airway constriction alone did not induce gas trapping under any circumstances. Thus, gas trapping in asthma could be due to surfactant abnormalities resulting from inflammatory exudate or excess mucus production; because of the small radius of curvature of small airways, this would almost certainly lead to closure of bronchioles in asthma.
Does gas trapping indicate small-airway closure in asthma? This is an important question and one that needs to be answered, because gas trapping induced by smooth-muscle agonists can be quite different from the changes in FEV1 in patients with asthma. In some patients the FEV1 falls because the FVC falls, whereas in others FEV1 decreases with little change in FVC (20). The degree of gas trapping induced, as measured by the decrease in FVC, is highly variable among patients with asthma, and it is much more than the small amount of gas trapping induced in normal lungs.
There is no correlation between the concentration of an agonist producing a 20% fall in FEV1 (PC20) and the reduction in FVC at the PC20 (20). The conclusion is inescapable: the PC20 and the reduction in FVC are measuring two entirely different, uncorrelated parameters. To the extent that the reduction in FVC is measuring airway closure and airway closure is the maximum amount of airway narrowing that can possibly occur, the reduction in FVC measures excessive airway narrowing. Because excessive airway narrowing is arguably the most serious of the pathophysiologic abnormalities in asthma, it may be advisable to measure FVC instead of FEV1 in response to smooth-muscle agonists. The decrease of FVC at the PC20 is a direct measure of excessive airway narrowing and might prove to be the best and easiest test of small-airway function in asthma.
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