METHODS

Ten subjects with mild asthma and 11 normal subjects were studied (table 1⇓). None of the asthmatic subjects was taking more than 400 μg of inhaled steroid (beclomethasone) per day. Normal subjects were all hospital employees who reported no symptoms of asthma, had never received a diagnosis of asthma from a physician, and had normal spirometric volumes. All subjects were non-smokers and had had no recent upper respiratory tract infection. Approval was obtained from the local ethics committee and written informed consent was obtained.

All respiratory function tests were performed with the subject seated and breathing via a mouthpiece attached to a flow sensor (Sensormedics), the output of which was integrated to give volume. Lung volume and specific airway conductance (sGaw) were measured by plethysmography.^14,15 sGaw was measured during panting at functional residual capacity (FRC).

Additional resistance for inspiration was provided by the attachment in series to a standard mouthpiece of an orifice 3 mm wide and 3.4 cm long.

RESULTS

All results are expressed as mean (SD) values. Subject groups were of similar mean age and sex distribution (table 1⇑). The asthmatic subjects had mild airways obstruction.

In asthmatic subjects sGaw following forced inspiration against resistance (sGaw_{DI RES}) showed a consistent small decline compared with sGaw measured following the voluntarily controlled deep inspiration against no added resistance (sGaw_DI) and was, on average, 13.5% lower (table 2⇓). This difference was statistically significant (p=0.003). In healthy subjects there was no difference in the sGaw following the two types of inspiratory manoeuvre. The % change from sGaw_DI to sGaw_{DI RES} was significantly different between the two groups. In the asthmatic subjects there was no statistically significant difference between FRC_DI and FRC_{DI RES}, although in healthy subjects a difference of similar average magnitude was statistically significant.

There were no differences in the mean (SD) inspiratory time when measured at the voluntarily controlled rate without added resistance in asthmatic and normal subjects (9.5 (2.3) s v 10.5 (3.1) s) and the calculated time to inspire with maximal force performed against added resistance (9.5 (3.0) s v 10.2 (2.9) s).

DISCUSSION

The different responses of asthmatic and healthy airways to deep inspiration probably reflect a fundamental feature of asthmatic pathophysiology. Studies in healthy subjects consistently show a bronchodilating response to deep inspiration,^{2,5–8,10,11} but in subjects with asthma the response is more variable.^12,13,16–,¹⁹ While milder asthmatics simply display a more limited bronchodilator response, subjects with more severe asthma show bronchoconstriction after deep inspiration. Indeed, some studies have identified an inverse relationship between the bronchodilating effect of deep inspiration and severity.^1,4,12,13 The bronchodilatation after deep inspiration in healthy subjects is largely attributable to a reduction in airway smooth muscle tone. This explanation is consistent with the enhanced bronchodilating effect of deep inspiration seen in the context of methacholine induced bronchoconstriction in both asthmatic^13,17,18 and healthy subjects,^6,20 and with diminution of the bronchodilating effect of deep inspiration following administration of β₂ sympathetic agonists.^12,18,21

The mechanism underlying the bronchoconstriction observed after deep inspiration in some asthmatics is not fully established. A diminution of the bronchodilating effect of deep inspiration can be explained by a reduction in the degree of stretch imposed on smooth muscle by deep inspiration in asthmatic subjects.²² An additional mechanism, however, is required to explain the observed bronchoconstrictor response. Hysteresis within the parenchyma resulting in lower lung recoil pressure following deep inspiration and a diminished retractive force on the airway wall has been proposed as such a mechanism, with the net effect on airways after deep inspiration being a balance of the hysteresis within the airways and parenchyma (the “relative hysteresis hypothesis”).^{5,11,17,21,23} This mechanism explains many reported findings, but it does not account for the increase in isovolumic forced expiratory flow following deep inspiration seen in conjunction with a reduction in sGaw in two studies of asthmatic subjects.^10,17

We therefore propose the following mechanism which, together with the stretching effect of deep inspiration on airway smooth muscle, would account for all the published observations.

A large proportion of the increased thickness of the airway wall in asthma is due to inflammation, which includes increased vascularity, increased mucosal blood flow,²⁴ leaky capillaries, inflammatory exudate, and oedema.²⁵ Even in stable situations the equilibrium of intra/extravascular fluid flux is dynamic and delicately balanced. This equilibrium would be disturbed by a change in hydrostatic pressure. The markedly negative intrathoracic pressure generated during a rapid deep inspiration would lead to a pressure gradient across the capillary wall. In the context of the leaky low pressure capillary bed of a more vascular asthmatic airway, this would cause extravasation of fluid into the airway wall, increasing its thickness and reducing its lumen (and thus reducing sGaw). The increased interstitial fluid would also render the airway wall more turgid, reducing its compliance, and the airway would therefore be less susceptible to compressive forces during the subsequent forced expiration.¹⁰ It has been shown that relatively small changes in airway wall oedema can potentiate the bronchoconstricting effect of smooth muscle constriction^26,27 and lead to significant airway narrowing. Thus, relatively small net movements of fluid could be responsible for the observed changes. In healthy subjects without inflammatory changes such a mechanism would be absent or insignificant.

In the current study we have tested this hypothesis by comparing the bronchoconstricting effect of deep inspiration (reduction in sGaw) in asthmatic and healthy subjects both with and without added resistance. The inspiratory manoeuvres were designed to be identical in their time-volume relationship in order to minimise differences in the behaviour of smooth muscle or any other element in which intrinsic tone varies in response to stretch, including factors contributing to both airway and parenchymal hysteresis. Inspiration against added resistance enhanced the negative intrathoracic pressure during deep inspiration. Thus, the only difference between the two types of inspiratory manoeuvre was the change in intrathoracic pressure. The fluid flux hypothesis predicts enhanced airway narrowing in asthmatic subjects following deep inspiration against resistance compared with resistance free inspiration. In healthy subjects without airway inflammation the hypothesis predicts substantially less sensitivity to changes in intrathoracic pressure and a smaller difference in sGaw following the two types of inspiratory manoeuvre. Our results are entirely consistent with this hypothesis.

This study suggests that the changes in airway function observed after deep inspiration in asthmatic subjects result, not only from changes in airway and parenchymal components of the lung which are subject to the stretch/relaxation phenomenon (already extensively studied), but also from the effects of transient changes in intrathoracic pressure on the inflamed asthmatic airway wall.

Further testing is required to investigate the full implications of this mechanism. The potential to influence airway wall oedema by manipulation of the intrathoracic pressure could have clinical benefits. Positive pressure applied by non-invasive ventilation, for example, could have the effect of reducing airway wall oedema. If effective, such interventions could have a role in clinical management in the acute setting.