Christine M. Smith

Hyperosmolarity as the stimulus to asthma induced by hyperventilation

Hyperosmolarity of the epithelial fluid of the large airways caused by evaporative water loss (wloss) has been proposed as the stimulus to exercise-induced asthma. The aim of this study was to compare the wloss during hyperpnea with a theoretical wloss from a known hypertonic stimulus in order to determine whether comparable volumes of wloss will induce the same response. Since wloss also occurs during isocapnic hyperventilation (ISH), we decided to compare the airway response to ISH with the response obtained after inhaling 4.5% NaCl aerosol. Changes in FEV1 were measured in 17 subjects with asthma in response to increasing rates of ventilation (ISH) and increasing doses of 4.5% NaCl aerosol. For ISH, wloss was calculated at 29 mg/L of expired air and for 4.5% NaCl, at 4.0 ml/l ml of aerosol inhaled, as this is the volume of water that will bring the periciliary fluid to normal tonicity. Two dose-response curves were drawn for each subject. These curves were similar both in position (PD20) and in shape (i.e., the slope of the curve as estimated by the ratio of wloss for maximum recorded percent fall in FEV1 [PDmax] to PD20). There was no significant difference in the PD20 (ISH, 10.3 ml, 95% confidence limits 7.5 and 13.9; 4.5% NaCl, 12.3 ml, 95% confidence limits 8.9 and 17.1) or between the ratio of log PDmax:log PD20 (ISH, 1.19 +/- 1 SD, 0.14; 4.5% NaCl, 1.17 +/- 1 SD, 1.17; p = not significant). These findings support the concept that airway hyperosmolarity may be the mechanism for ISH and exercise-induced asthma.

Inhalation provocation tests using nonisotonic aerosols

The measurement of bronchial hyperresponsiveness with inhaled aerosols is now accepted as an objective measurement of the severity of asthma. The most commonly used agents administered as aerosols are methacholine and histamine, which are believed to cause airways to narrow by contracting bronchial smooth muscle via specific receptors. Patients with asthma may also have an attack provoked by inhaling aerosols that increase or decrease the osmolarity of the fluid lining the airways. There is evidence to suggest that a change in the osmolarity of the airways causes the release of mediators from inflammatory cells in the airways. Thus, inhalational challenge with nonisotonic aerosols, such as water and hyperosmolar saline, may be useful to assess bronchial hyperresponsiveness to endogenously released mediators. Described in this article are some of the techniques used to challenge with nonisotonic aerosols, and airway responses are discussed in relation to responses obtained with other bronchial provocation tests. The mechanisms whereby these aerosols cause airways to narrow are considered, and the clinical implications of identifying responsiveness to these aerosols are discussed. Specific recommendations are made with respect to equipment, technique, and choice of aerosol.

Methacholine responsiveness increases after ultrasonically nebulized water but not after ultrasonically nebulized hypertonic saline in patients with asthma.

Airway obstruction can be induced in patients with asthma by the inhalation of ultrasonically nebulized aerosols of nonisotonic solutions. It is the change in osmolarity of the periciliary fluid that is believed to be the stimulus for bronchoconstriction. However, it is not known whether hyperosmolar and hypo-osmolar aerosols induce asthma via the same mechanism. We have previously reported that patients with asthma have a reduction in the dose of provoking agent that induces a 20% fall in FEV1 (PD20) for methacholine after challenge with nebulized water. To determine whether hyperosmolar aerosols also increase sensitivity to methacholine, we studied 13 subjects with asthma on 3 days. On day 1, the PD20 to methacholine was determined. On day 2, a challenge with nebulized 4.5% saline was followed by a challenge with methacholine 40 to 60 minutes later. On day 3, a challenge with nebulized water was followed by a methacholine challenge. Sensitivity to methacholine was significantly increased after water (p less than 0.02) but not after 4.5% saline. Furthermore, there was no relationship between the PD20 to water and to 4.5% saline. When the Spearmans correlation coefficient was used to compare sensitivity to the challenges, there was a significant relationship between the PD20 to 4.5% saline and methacholine (p less than 0.01) but not between the PD20 to water and methacholine. These results suggest that the mechanism of asthma induced by hyperosmolar and hypo-osmolar solutions is different.

Cromolyn sodium inhibits the increased responsiveness to methacholine that follows ultrasonically nebulized water challenge in patients with asthma

We have previously reported that airway responsiveness to inhaled methacholine in subjects with asthma is increased 40 to 60 minutes after challenge with ultrasonically nebulized water. This study reveals that increased responsiveness to methacholine is abolished by administration of cromolyn sodium before the water challenge. The mean dose of methacholine (95% confidence limits) inducing a 20% fall in FEV1 (PD20) was 1.10 mumol (0.43 to 2.80). The PD20 after water challenge was 0.42 mumol (0.17 to 1.01) that was significantly lower (p less than 0.005) than that observed for the initial challenge. Administration of cromolyn before the water challenge abolished this increased responsiveness to methacholine. The mean PD20 was 1.32 mumol (0.47 to 3.68) that was not significantly different from that measured for the initial methacholine challenge. Methacholine responsiveness was unchanged when challenge was performed 40 to 60 minutes after cromolyn alone or after methacholine itself. We conclude that cromolyn abolishes the increased responsiveness to methacholine and probably does so by inhibiting the release of mediators.