Volume 120 Number 4, Part I
Clinical and laboratory observations
64 1
Detrimental effect of hypotonic cromolyn sodium Terry W. Chin, MD, PhD, a n d Eliezer N u s s b a u m , MD From the Department of Pediatrics, University of California, Irvine
In a randomized, double-blind, placebo-controlled, crossover study, inhalation of the commercially available nebulized form of cromolyn sodium resulted in a significant decrease in forced midexpiratory flow rate between the 25th and 75th percentile points, equivalent to that observed for distilled water, in children with chronic asthma. We conclude that inhalation of the current hypotonic concentration of cromolyn sodium may be detrimental. (J PEDIATR1992;120:641-3)
Numerous studies have documented the clinical effectiveness of cromolyn sodium in the treatment of pediatric asthma. Many of these studies used micronized powder or the metered-dose (pressurized) inhaler. Two studies of the commercial 1% nebulizer solution for children have shown improvement in daily symptom scores and significant reductions in emergency department visits, hospitalizations, and the use of additional medications.1, 2 All three preparations, including the 1% nebulizer solution, have been compared. No differences were found in ability to prevent exercise-induced bronchospasm.3 The nebulizer solution is a hypotonic solution, however, and such solutions can cause bronchospasm in persons with reactive airway disease. 4, 5 Indeed, inhalation of distilled water has been advocated as an effective bronchial provocation test for the diagnosis of asthma, especially for children, in whom the diagnosis can be especially difficult. 6 We report our results of a doubleblind, crossover study in patients with asthma that evaluated pulmonary function variables before and after inhalation of aerosolized CS in 0.9% saline solution, compared with the standard 1% solution in distilled water. METHODS
Patient population. We studied 13 pediatric patients aged 6 to 14 years (mean 10.2 _+ 0.2 years) who were followed
Supported by Memorial Medical Center Foundation, Long Beach, Calif. Submitted for publication Aug. 2, 1991; accepted Nov. 15, 1991. Reprint requests: Terry W. Chin, MD, PhD, Director, Allergy/ Immunology, Assistant Director, Pediatric Pulmonary, Memorial Miller Children's Hospital, Long Beach Memorial Medical Center, 2801 Atlantic Ave., Long Beach, CA 90801-1428. 9/26/35028
in the Children's Specialty Center of Memorial Miller Children's Hospital and who had asthma satisfying the criteria of the American Thoracic Society] At entry into the study the subjects' pulmonary function studies showed mild disease, with forced vital capacity 97.6% + 1.0% of the predicted value, forced expiratory volume in 1 second of CS C r o m o l ysodium n FEF25-75 Forcedmidexpiratory flow rate between the 25th and 75th percentile points FEVI Forced expiratory volume in 1 second FVC Forced vital capacity 89.7% _+ 1.2%, and forced midexpiratory flow rate between the 25th and 75th percentile points of 78.9% + 2.2%. Four were receiving inhaled steroids, but no patients had received systemic steroids for 4 weeks before the study. All were receiving inhaled beta-2 agonists, eight were receiving inhaled CS, and eight were receiving theophylline (serum levels between 10 and 15 #g/ml). None had had a recent exacerbation of illness. The study protocol was approved by the human subjects review committee of the Long Beach Memorial Medical Center. Experimental design. In this double-blind, placebo-controlled, crossover study, patients were randomly assigned to treatment in the order in which four solutions were delivered by a compressed-air nebulizer (Pulmo-Aide; De Vilbiss Co., Somerset, Pa.) at an output flow rate of 6 L/rain. The administration of 2 ml of each solution occurred on four consecutive days at the same time of day to minimize possible diurnal variation in pulmonary function. The four solutions were as follows: ( 1) hypotonic CS solution consisting of one vial of the standard Intal Nebulization Solution, which contains 20 mg of CS in 2 ml of distilled water, (2) isotonic
642
Clinical and laboratory observations
9-
The Journal of Pediatrics April 1992
0
t~
IZl
E s
-5
o') -10
9
.c t~ -15 C
o -20 0.. -25
D Hypotonic Cromolyn | Isotonic Cromolyn Water Saline FVO
,k.
FE'V1
FEF25-75
Pulmonary Function Tests Figure. Mean percentage of change from baseline (_+ SEM, indicated by error bars) for lowest values in FVC, FEV1, and FEF25_75observed in 13 subjects 10, 10, or 30 minutes after aerosol treatment with 0.9% saline solution, distilled water, hypotonic CS, and isotonic CS (prepared and administered as described in the text). Asterisks show significant decrease in FEF25_75after aerosol treatment with hypotonic CS, as compared with 0.9% saline solution (p
Clinical and laboratory observations
64 1
Detrimental effect of hypotonic cromolyn sodium Terry W. Chin, MD, PhD, a n d Eliezer N u s s b a u m , MD From the Department of Pediatrics, University of California, Irvine
In a randomized, double-blind, placebo-controlled, crossover study, inhalation of the commercially available nebulized form of cromolyn sodium resulted in a significant decrease in forced midexpiratory flow rate between the 25th and 75th percentile points, equivalent to that observed for distilled water, in children with chronic asthma. We conclude that inhalation of the current hypotonic concentration of cromolyn sodium may be detrimental. (J PEDIATR1992;120:641-3)
Numerous studies have documented the clinical effectiveness of cromolyn sodium in the treatment of pediatric asthma. Many of these studies used micronized powder or the metered-dose (pressurized) inhaler. Two studies of the commercial 1% nebulizer solution for children have shown improvement in daily symptom scores and significant reductions in emergency department visits, hospitalizations, and the use of additional medications.1, 2 All three preparations, including the 1% nebulizer solution, have been compared. No differences were found in ability to prevent exercise-induced bronchospasm.3 The nebulizer solution is a hypotonic solution, however, and such solutions can cause bronchospasm in persons with reactive airway disease. 4, 5 Indeed, inhalation of distilled water has been advocated as an effective bronchial provocation test for the diagnosis of asthma, especially for children, in whom the diagnosis can be especially difficult. 6 We report our results of a doubleblind, crossover study in patients with asthma that evaluated pulmonary function variables before and after inhalation of aerosolized CS in 0.9% saline solution, compared with the standard 1% solution in distilled water. METHODS
Patient population. We studied 13 pediatric patients aged 6 to 14 years (mean 10.2 _+ 0.2 years) who were followed
Supported by Memorial Medical Center Foundation, Long Beach, Calif. Submitted for publication Aug. 2, 1991; accepted Nov. 15, 1991. Reprint requests: Terry W. Chin, MD, PhD, Director, Allergy/ Immunology, Assistant Director, Pediatric Pulmonary, Memorial Miller Children's Hospital, Long Beach Memorial Medical Center, 2801 Atlantic Ave., Long Beach, CA 90801-1428. 9/26/35028
in the Children's Specialty Center of Memorial Miller Children's Hospital and who had asthma satisfying the criteria of the American Thoracic Society] At entry into the study the subjects' pulmonary function studies showed mild disease, with forced vital capacity 97.6% + 1.0% of the predicted value, forced expiratory volume in 1 second of CS C r o m o l ysodium n FEF25-75 Forcedmidexpiratory flow rate between the 25th and 75th percentile points FEVI Forced expiratory volume in 1 second FVC Forced vital capacity 89.7% _+ 1.2%, and forced midexpiratory flow rate between the 25th and 75th percentile points of 78.9% + 2.2%. Four were receiving inhaled steroids, but no patients had received systemic steroids for 4 weeks before the study. All were receiving inhaled beta-2 agonists, eight were receiving inhaled CS, and eight were receiving theophylline (serum levels between 10 and 15 #g/ml). None had had a recent exacerbation of illness. The study protocol was approved by the human subjects review committee of the Long Beach Memorial Medical Center. Experimental design. In this double-blind, placebo-controlled, crossover study, patients were randomly assigned to treatment in the order in which four solutions were delivered by a compressed-air nebulizer (Pulmo-Aide; De Vilbiss Co., Somerset, Pa.) at an output flow rate of 6 L/rain. The administration of 2 ml of each solution occurred on four consecutive days at the same time of day to minimize possible diurnal variation in pulmonary function. The four solutions were as follows: ( 1) hypotonic CS solution consisting of one vial of the standard Intal Nebulization Solution, which contains 20 mg of CS in 2 ml of distilled water, (2) isotonic
642
Clinical and laboratory observations
9-
The Journal of Pediatrics April 1992
0
t~
IZl
E s
-5
o') -10
9
.c t~ -15 C
o -20 0.. -25
D Hypotonic Cromolyn | Isotonic Cromolyn Water Saline FVO
,k.
FE'V1
FEF25-75
Pulmonary Function Tests Figure. Mean percentage of change from baseline (_+ SEM, indicated by error bars) for lowest values in FVC, FEV1, and FEF25_75observed in 13 subjects 10, 10, or 30 minutes after aerosol treatment with 0.9% saline solution, distilled water, hypotonic CS, and isotonic CS (prepared and administered as described in the text). Asterisks show significant decrease in FEF25_75after aerosol treatment with hypotonic CS, as compared with 0.9% saline solution (p
