The Effect of Cromolyn Sodium and Nedocromil Sodium Administered by A pressurized Aerosol with A spacer Device on Exercise-Induced Asthma in Children

To compare the effectiveness of cromolyn sodium (CS) (10 mg) and nedocromil sodium (NS) (4 mg) administered by a metered dose inhaler (MDI) with a spacer device in preventing exercise-induced asthma (EIA), eight asthmatic children with EIA were studied in a randomized double-blind, cross-over, placebo-controlled study, CS and NS provided significant, comparable protection from EIA and both were better than placebo. We conclude that CS and NS administered by a pressurized aerosol with a spacer device provide equal protection against EIA in children.


Introduction
Cromolyn sodium (CS) and nedocromil sodium (NS) are two anti-inflammatory drugs which have been shown to be effective in preventing exerciseinduced asthma (EIA) in both adults and children. [1][2][3][4] Metered dose inhalers provide an aerosolized dose with high particle velocity, necessitating respiratory coordination to obtain optimal drug deposition in the lung. The use of a spacer device attached to the MDI reduces the velocity of aerosol particles and significantly improves drug delivery to the peripheral lung. To compare the effectiveness of CS and NS administered by a MDI with a spacer device in preventing EIA in childhood, a double-blind, crossover, placebo-controlled study was performed.

Subjects and Methods
The study was double-blind, randomized, crossover and placebo-controlled. Eight patients (five males, three females), aged 7 to 11 years (mean 8.7 + 11.2 years) were recruited. All patients attended the Pediatric Asthma Clinic at Perugia General Hospital, and all had asthma as defined by the American Thoracic Society. All subjects previously demonstrated a consistent fall in FEV of at least 15% from baseline after a 6 min standard treadmill exercise screening test. They were being treated with different anti-asthmatic regimens, such as sustained release theophylline, beta-agonists, SCG, NCS, and inhaled steroids; none was under therapy with oral steroids. Sustained release theophylline was withheld for 24 h, and other drugs for 12 h before each exercise test.
None of the subjects had had respiratory infections in the 4 weeks before the trial. Informed consent was obtained from patients and their parents, and the protocol was approved by the Hospital Ethics Committee.
The screening test consisted of steady state running for 6 min on a treadmill at an incline which would produce a heart rate of at least 85% of the maximum predicted for age. After screening in randomized order on 3 separate days, patients were tested on different treatments inhaled from a metered dose inhaler with a spacer device (Aerochamber, Trudell Medical, London, Ontario): SCG (5 mg twice), or NCS (2 mg twice), or placebo (2 puffs). The drugs were administered by a trained physician, and all the patients were skilled in the use of MDI with aerochamber. The patients performed the exercise test 20 min after every drug inhalation. Each patient always performed tests at the same time of the day, and all four tests were completed within 10 days.
Room temperature and relative humidity were monitored. Differences of IC in temperature and 5 mg H,.O/1 of air in water content on the test days of each patient were considered acceptable. 8  The protection percentage was 70.0 + 33.3, 65.8 + 21.7 and 32.8 + 32.9 for CS, NS and placebo, respectively. A protection value greater than 50% (clinical protection) was obtained in 6/8 (75%) patients treated with SC, 7/8 (87.5%) treated with NS, and 1/8 (12.5%) patients who received placebo (Table 2).

Discussion
Both CS and NS have been shown to be effective in protecting against EIA in children. 3,4 The mechanism by which these two drugs exert their action in preventing EIA has yet to be determined, but both drugs exhibit a considerable protective effect on the mucosal mast cells in vivo and in vitro. 1,14 This double-blind, within patient comparative study shows that CS and NS inhaled by a MDI with a spacer device have a significant and comparable effect in preventing EIA in children, and that both drugs are more effective than placebo.
Our data are in agreement with those from other studies, which showed the comparable effectiveness of CS and NS in preventing EIA, both in adults 15a6 and in children. 17,18 A variable protective effect, which is highlighted by the large standard deviation of the mean maximum fall in FEV1, was found between CS and NS in some of our patients. This has been previously reported in other studies 16,19 and may reflect the response variability that exists between asthmatics. 15 Patel and Albazzaz 19 found a significantly higher protection against EIA with NS when compared with CS. In addition, Morton et al. 15 reported that the percentage of adults who were completely protected from EIA was higher after NS (62.5%) than after CS (25%). However, as CS was administered at a low dosage, the results may have been distorted.
The use of a spacer device in adjunct to MDI has been strongly advocated for children who may not be able to perform the inhalation correctly. However, although spacer devices have several potential advantages over MDIs, their use did not modify the effect of both CS and NS in a previous study. 17 This was probably due to the correct technique by which previously skilled children used MDI, allowing optimal drug deposition to peripheral airways.
A statistically significant effect of a drug on EIA does not necessarily indicate the effect is clinically important. Therefore, we also evaluated the protection percentage against EIA, as an index of a good clinical control. This analysis yielded the same results as the analysis of the percentage fall FEV1 itself.
It is concluded that CS and NS provide equal protection against EIA in children when the clinical recommended dose is administered by a pressurized aerosol with an aerochamber. Further studies are needed to compare the duration of action of these two drugs in inhibiting EIA.