Pediatric Pulmonology 13:20S214 (1992)
Clinical Observations of Nebulized Flunisolide in Infants and Young Children With Asthma and Bronchopulmonary Dysplasia Peter Konig, MD, pm,' Miriam Shatley, MD,' Clive Levine, M D , ~and Thomas P. Mawhinney, PhD' Summary. Severe bronchopulmonary dysplasia (BPD) is frequently associated with asthma. The combination is often severe enough to necessitate corticosteroid therapy. There are no commercially available nebulizer solutions of corticosteroids for use in infants and young children. Seven infants and small children with very severe BPD and asthma aged 6-24 months, were treated with flunisolide, 187-250 pg q.i.d. in the form of nasal spray delivered by nebulizer. After treatment for 2.5-20 months, four patients showed clinical improvement, one initially improved but later deteriorated and died of cardiac failure, and two patients showed no improvement and died within 3 months. The number of days of hospitalizationwas significantly reduced from 8.4/month to 23month ( P < 0.05). No side-effects were detected and it was felt that the three patients who died, did so as a consequence of very severe BPD and its cardiac consequences. The suspension remained stable for 80 min when mixed with normal saline, cromolyn sodium, albuterol, or acetylcysteine. It is concluded that nebulized flunisolide is a potentially useful treatment for infants and young children with asthma and BPD. Pediatr Pulmonol. 1992; 13:209-214. D 1992 Wiley-Liss, Inc. Key words: Clinical-radiologic score; mortality; hospitalization; side effects; physicochemical compatibility.
INTRODUCTION As much as 91% of patients with severe bronchopulmonary dysplasia (BPD) have bronchial hyperreactivity . I A long-term follow-up study by Northway and associates2 has shown that even at age 14-23 years, 52% of patients with BPD still have reactive airway disease (asthma). They represent a very difficult group to treat because they have a combination of two obstructive lung diseases. Because of the underlying BPD changes, consequences of even moderately severe asthma can be quite serious. A number of antiasthma medications, such as adrenergic agents,'.' a t r ~ p i n e , ~ theophylline,' .~ cromolyn sod i ~ m , ' ,and ~ systemic corticosteroids8~9have been shown to be beneficial in patients who suffer from a combination of BPD and asthma. Because many of these children have severe asthma, they would be candidates for corticosteroid therapy. However, in addition to the side-effects Of Systemic corticosteroids, in these young children severe infections constitute an additional risk. In older children systemic side-effects of corticosteroids are generally minimized by using the inhaled route through a metered-dose (MD1)' lo Most under 4 years do not possess sufficient coordination to use metered-dose inhalers, although the addition of a
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0 1992 Wiley-Liss, Inc.
spacer device can lower the age to 2-3 years." Some investigators advocate MDIs with spacers in infants as young as 6 months,'* but the methodology is not yet well established. Nebulizer solutions of cromolyn sodium6 and adrenergic agents3 have been used very successfully in infants and young children. Several corticosteroid drugs such as beclomethasone dipropionate'' and budesonide l 4 have been tested as nebulizer suspensions, but none of these is commercially available in the United States. Flunisolide is available in the form of nasal spray (NasalideB) which has been used by clinicians as nebulizer solution for some years. However, the published data on this use are restricted to one sentence in a review article by Robert S. Zeiger,I5 one study showing no ill-effects from a single dose administration, l 6 and two abstracts. 1 7 7 1 x From the Department of Child Health' and Department of Radiology,' University of Missouri-Columbia, Columbia, Missouri. Received November 18, 1991; (revision) acccpted for publication April 20* 19y2. Address correspondcnce and reprint requests to Dr. P. Konig, Department of Child Health, University of Missouri Health Sciences Center, I Hospital Drive, Columbia, MO 65212.
Konig et al.
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TABLE 1-Personal Data of the Patients
Patient number
Sex
F F F F F M M
1 2 3 4 5 6 7
Mean SD
Age at Start of flunisolide treatment (months) I I '/z 6 17 10 6 24
Gestional Age (weeks)
Birth weight
(s)
I252 2010
10
28 32 25 30 31 28 28
12.1 6.4
28.9 2.3
1429.9 460.0
Length of NlCU stay (months)
I600 I620
3 3 4 4 4 v2
19 10
4%
1000
718
Length ol' ventilatory support (months) 7 3
9
I 2 3 '/2 3 55 2% 8
4.6 2.0
3.06 2.45
Previous asthma therapy Cr, Alb, Th, Atr Cr. Alb, Th, Atr Cr, Alb, Th Cr, Alb, Th Cr, Alb, Th Cr. Alb, Th. Atr Cr, Alb, Th
Outcome Improved Improved lmproved No change, death No change, death Improved Initial improvement death later
Cr, Cromolyn sodium: Alb, albuterol: Th, theophylline; Atr, atropine.
The duration of the trial was 21/2-20 months (mean, 7.8 months). Parents gave their informed consent in writing. Flunisolide was given as Nasalide nasal solution 0.025%,in a dose of 0.75mL (187 pg) q.i.d. to patients under one year, and 1 mL (250 p,g) q.i.d. to patients over MATERIALS AND METHODS one year of age. The dose was adopted from that used for Seven patients were treated. There were five females years by R.S. Zeiger (personal communication) and and two males aged 6-24 months (mean, 12.1 -t 6.4 found to be safe (including absence of changes in adrenal SD). All had BPD defined as oxygen dependency for function tests) and effective. The solution was delivered more than 28 days following mechanical ventilation dur- by a jet nebulizer, at a flow rate of 6 Umin and a face ing the first week of life, with persistent increased densi- mask or "blow-by" (held close in front of their face). The ties on chest radiographs, l 9 and asthma as defined by the same nebulizers were consistently used in individual paAmerican Thoracic Society.2" The diagnoses were clini- tients throughout the observation period. cal and no pulmonary function tests were performed. Personal characteristics of the patients are shown in Table 1 . All were premature, had prolonged stay Physicochemical Compatibility of Flunisolide (mean SD, 4.6 2 2.0; range, 3-9 months) in the Neo- With Other Nebulized Medications natal Intensive Care Unit, and needed weeks to months of Because these children were treated at the same time ventilator support (3.06 k 2.45; range, 0.66-8 months). with other nebulized medications, we examined the physAll but one were still on supplemental oxygen therapy. icochemical compatibility of the flunisolide suspension Chest X-rays were scored according to their severity by a with a number of other drugs. Flunisolide 0.025%(Naradiologist who was not aware of treatment status2' All salide), Syntex Laboratories, lot No. 36029; albuterol but one patient (No. 5 , who had moderately severe sulfate 0.5% (ProventiP), Schering Corporation lot No. changes) had severe radiologic changes. They all re- 0-KPJ-23; cromolyn sodium (IntaP) nebulized solution, ceived conventional asthma treatment, including nebu- Fisons Pharmaceuticals, lot No. H N 3720A; acetylcyslized cromolyn sodium and albuterol, theophylline, and teine (Mucosil-lo), Dey Laboratories, lot No. 3258 H; in some cases also nebulized atropine (Table 1). All but and normal saline (sodium chloride 0.9%)lot No. 1E398, one patient at times needed systemic corticosteroids. were studied in amounts used clinically. The mixtures These drugs were continued after the start of flunisolide were continuously rotated on a laboratory shaker and treatment until the patient showed sufficient improve- sampling was performed at 0,20,40,60, and 80 min. At ment to discontinue some of them. Clinical improvement each sampling time the pH was measured and the mixwas assessed based on the symptoms of cough, wheez- tures were examined against a light and dark background ing, and dyspnea, which in some cases were documented in order to detect precipitation or color change.22.23The by symptom diaries, by the need for oxygen, by an oxy- concentrations of the drugs were determined by highgen saturation of at least 9096, by the result of follow-up pressure liquid chromatography. At each sampling time physical examination (respiratory rate, wheezing, retrac- three aliquots were tested and the results presented as tions), and by appetite and weight gain. means of the three. Therefore, we decided to describe our preliminary experience in seven patients with severe asthma and bronchopulmonary dysplasia, treated with nebulized flunisolide.
*
Nebulized Flunisolide for Asthma and BPD in Early Life
Statistical Analyses The small number of patients and the fact that it was a retrospective study allowed statistical analyses on a very limited scale. The number of hospitalizations and the number of days of hospitalization during equal periods of time before and after the introduction of flunisolide treatment were analyzed by Wilcoxon Signed Rank Test. P values of less than 0.05 were considered statistically significant. RESULTS
TABLE 2-Number of Hospitalizations and Days of Hospitalization Before and After Flunisolide Therapy Number of hospitalizations/rnonth Patient number
I 2 3 4
5" 6 7
One patient could be weaned off oxygen and two more reduced their need from 1 to 0.5 Wmin, while maintaining good saturation (at least 9096). All but two patients showed some clinical improvement. However, patients No. 4 and 5 died about 3 months after the onset of flunisolide therapy without showing any beneficial effect. Patient No. 7 initially had some improvement, but later deteriorated and died of cardiac failure. In the two treatment failures who showed no improvement and eventually died (patients No. 4 and 5) asthma did not seem to be the main problem. Patient No. 4 had severe congestive heart failure and patient No. 5 had severe recurrent episodes of apnea. In patient No. 7, the main problem was cor pulmonale and congestive heart failure which eventually caused his death. One patient could discontinue atropine and another one cromolyn sodium. Of the four patients who improved clinically, in two the number of days on systemic corticosteroids were substantially reduced (from 42 days in 6 months to 21 days in 6 months and from 17 days in 6 months to none, respectively). The other two patients had slightly increased need (from 0 to 10 days and from 31 to 42 days in 6 months, respectively). Two of the three patients who died needed more systemic corticosteroids (from 31 days to 42 days in 6 months and from 0 to 60 days in 2 months, respectively), while one was never on systemic corticosteroids. In some patients improvement was also reflected in better weight gain. For example, patients No. I and 3 moved from below the 3rd percentile to the 5th percentile and patient No. 6 from below the 3rd to the 25th percentile. The number of hospitalizations and days of hospitalization are shown in Table 2. Equal periods of 3-6 months before and after flunisolide treatment were analyzed and the results were averaged per month. Patient No. 5 was eliminated from the statistical analyses because she had a prolonged hospitalization due to apnea and not connected with asthma, that lasted the whole period of flunisolide treatment. There were 0.64 hospitalizations per month before, and 0.28 after start of flunisolide therapy, but the difference was not statistically significant. The number of days of hospitalization
211
Mean SD P
Before flunisolide
After flunisolide
0.17 0.17 0.50 0.50 0.33 0 I .00 0 1.33 0.50 0.50 0.50 0.64 0.28 0.44 0.25 Not significant
Days of hospi talizations/month Before flunisolide
After tlunisolide
I .83 3.83 I .83 7.67
0.67 2.00 0 0 2.00 10.50 2.53 4.00
-
20.83 14.50 8.42 7.74 c0.05
"Patient No. 5 not analyzed because of prolonged hospitalization due to apnca and not asthma.
was 8.4 before and 2.5 after therapy. This diffcrence was statistically significant (P < 0.05). Chest radiographs showed generally little change (Table 3). However, there was a tendency for improvement in hyperinflation, with 3 patients improved, 3 unchanged and one worsening. These changes generally correlated with clinical improvement. Considering the relatively short period of follow-up, components other than hyperinflation could not have been expected to show changes. There were no clinically evident side-effects such as oral candidiasis or Cushingoid appearance, but hypophyso-pituitary-adrenal (HPA) axis tcsts to measure adrenal function were not performed. Physicochemical Compatibility of Flunisolide With Other Nebulized Medications
The mixtures were very stable. There was no precipitation or change in color. The pH varied between 4.95 and 5.26 at the onset and changed very little during 80 min (Table 4). There was no evidence of degradation of flunisolide in any of the mixtures, all changes (plus or minus) being less than 2.5% (Table 4). DISCUSSION
This clinical experience on a small sample has shown that patients who have both BPD and asthma can benefit from treatment with nebulized flunisolide. Even though one of the two criteria submitted to statistical analyses did not show significant difference, probably due to the small number of patients, the number of hospitalizations per month was reduced to less than half by treatment with flunisolide. Although patients with BPD tend to improve with age, the relative shortness of the period of observa-
212
Konig et al.
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tion (2-6 months) makes it unlikely that the improvement was a spontaneous one. Eisenberg also found some benefit from nebulized flunisolide (Nasalide), although his patients were a more mixed group, only 4 out of the 9 having both BPD and asthma. In their series the mortality was also high (two out of four with BPD). Chin and NussbaumI8 treated 7 patients with asthma, and reported a reduction in hospitalizations and in systemic corticosteroid use. Their patients were somewhat older (2-7 years) and had no BPD, therefore, these results are not strictly comparable with those in the present group. Inhaled flunisolide by metered-dose inhaler has been shown to be effective and safe in older ~ h i l d r e n ~ and ~.~' adults.26 Piacentini and associates2' treated older children (8-13 years) suffering from asthma alone with nebulized flunisolide, 0.5 mg b.i.d. for 2 months in a double blind study. They showed the drug to be significantly better than placebo and it had no effect on the HPA axis. Ciorgi and colleagues28 gave nebulized flunisolide, 1,600 kg/day for 2 months. to 6-1 I year old children with asthma and found no side-effects on the HPA axis or carbohydrate and lipid metabolism. The literature on the use of other corticosteroids by nebulizer in asthma (with no BPD) is somewhat contradictory. Beclomethasone dipropionate and budesonide are available as nebulizer suspension in Europe and elsewhere. A number of studies have been published with these drugs and although most had positive re13.14,2'&)-33 others showed them to be no better than p l a ~ e b o . ' ~ . ' BCrubC ~ and associates described clinical improvement in infants given budesonide, 2 mg/day , but no significant change in maximal expiratory flow at functional residual capacity (V,,,, FKC) and a significant suppression of the ACTH response.'" Many of these publications are in the form of letters to the Editor, 14.30 abstract^,'^ or open trials,28 only five were controlled trials. 13*3"323433' Of the controlled studies, three were positive'3,'o.32 and two negati~e.'~.~' Therefore, more controlled studies are needed. The safety of nebulized beclomethasone dipropionate and budesonide seemed to be good in these studies, although Clark reported one patient who developed a severe asthma attack from nebulized beclomethasone dipropionate.'7 However, most studies were limited to clinical side-effects. 2')3234*3' Only a few tested the adrenal axis showing either no signs of ~uppression'~ or suppression by some tests.36 One group of investigators commented on no change in growth rate,2' but sensitive modem techniques such as knemometry were not used. Wolthers and Pedersen'8 demonstrated a dose-dependent reduction in growth velocity with budesonide regular doses (200, 400, and 800 pg/day in MDI) in older children. No clinically evident side-effects were noted in our patients. None of the patients who died had evidence of sepsis at the time of their death, however, patient No. 5
Nebulized Flunisolide for Asthma and BPD in Early Life
213
TABLE 4-Physicochemical Compatibility of Flunisolide Mixed With Different Drugs Given by Nebulization Time 0
I . 1 ML flunisolide (0.025%) 2. I mL flunisolide (0.025%) + 2 mL saline (0.9%) 3. I mL flunisolide (0.025%) + 2 mL cromolyn sodium (20 mg/2 mL H,O) 4. 1 mL flunisolide (0.025%) + 0.5 mL albuterol sulfate (0.5%) 5 . 1 mL flunisolide (0.025%) + 2 mL saline (0.9%)+ 0.5 mL albuterol sulfate (0.5%) 6. I mL flunisolide (0.025%) + 2 mL cromolyn sodium 0.5 mL albuterol sulfate (0.5%) 7. I mL flunisolide (0.025%) + I mL Mucosil-10 (acetylcysteine 10%)
+
Concentration” PH Concentration PH Concentration PH
24
20 min
40 min
pg/rnL 5.26 80.9 pg/mL 5.25 8 I . 7 pg/mL 5.18
100.1% 5.28 99.8% 5.21 99.6% 5.10
99.78 5.30 99.4% 5.29 99.4%
Concentration PH Concentration PH
165.0 pg/mL 5.09 70.9 pg/rnL 4.95
10.3% 5. I4 l00.1% 5.04
99.9% 5.10 101.3% 5.01
Concentration PH
70.9 pg/mL 5.15
100.8% 5.13
Concentration PH
8 I .4 pg/mL 5.19
100.6% 5.20
60 min
80 min
98.2% 5.29 9X.6% 5.23 98.5% 5.12
98.2% 5.28 98.4% 5.24 97.6% 5.12
99.9% 5.15
5.04
99.X% 5.15 99.4% 5.07
100.4% 5 . I5
100.6% 5.10
99.98 5.13
99.9% 5. I7
100% 5.19
99.5% 5.18
5.15
100%
“Concentrationsof flunisolide at time 0 are measured by means of three aliquots; at times 2WO min, concentrations are percents of values at time 0.
had several previous episodes of sepsis during the prolonged hospitalization that ended with her death. This patient was a very sick girl with multiple problems (frequent apneic spells, cor pulmonale, pulmonary edema, pneumonia) and it was not at all clear if flunisolide in any way contributed to her sepsis. Three deaths in a series of 7 patients might seem too high, but since only extremely severe patients were treated with flavisolide this death rate must not be considered excessive. In two abstracts published on nebulized Nasalide treatment in young children no side-effects are mentioned, but no details are given.”*18 Even though little is known about systemic side-effects of nebulized Nasalide, it is unlikely that they would be serious enough to counterindicate its use in such severe life-threatening cases of BPD with asthma. Nasalide is in a formulation intended for nasal spray and not for nebulizer solution. It contains preservatives and solvents such as propylene glycol and it has a pH of 5.3. Propylene glycol causes nasal stinging in many patients and could, in theory, cause bronchospasm. However, Wood and associates did not observe any bronchospasm with nebulization of up to 2 mL of Nasalide.I6 Chin and Nussbaum found no bronchospasm in 10 older children with asthma after nebulization of a single dose of 2 ml of Nasalide. In our patients albuterol was always given together with Nasalide because of clinical need and this seems to be a reasonable precaution for future studies. Toxic effects other than bronchospasm from the additives could be encountered, but so far none was detected. It is not known what effect the additives have on particle size and drug delivery. We have shown that the Nasalide
suspension is compatible with nebulized solutions of cromolyn sodium, albuterol, and normal saline, therefore, these can be administered together, saving a lot of time. Conner and associates showed good response to albuterol administered by MDI and a spacer (Aerochamber) in as young as 6-month-old infants.’* Freigang and Ashford in an open trial treated 12 to 26-month-old children with beclomethasone by MDI plus a special AIDAC inhalation all patients improved and the ACTH test showed no change. Another study in 2- to 6-year-old children, using budesonide by MDI with a spacer, showed a reduction in FRC.40 It is possible that this mode of administration is a viable alternative to nebulized corticosteroids, but more studies are needed in infants and young children. I t is concluded that nebulized flunisolide is a potentially beneficial treatment for severe asthma in infants and young children with BPD. Because of the severity of the associated irreversible obstruction resulting from BPD perhaps the decision to start corticosteroids should be made earlier than in patients with asthma only. More studies, preferably of a double-blind placebo controlled design, are needed to confirm the findings of this clinical experience. Nebulized corticosteroids are necessary also for the treatment of severe asthmatics with no BPD, therefore it would be important to have commercially available solutions specially prepared for nebulizer use. As the total patient population that has this need is relatively small but very severely ill, perhaps the agent could be made available as an “orphan drug” and provided by pharmaceutical companies on humanitarian grounds.
214
Konig et al.
19. Bancalari E, Gerhardt T. Bronchopulmonary dysplasia. Pediatr Clin North Am 1986;33:l-23. The authors wish to thank John E. Hewett, Ph.D., 20. American Thoracic Society. Chronic bronchitis, asthma, and pulmonary emphysema. Am Rev Resp Dis 1962;85:762-768. Professor of Statistics, and Jane C. Johnson, B.A., Computer Programmer/Analyst for help with the statistical 21. Toce SS, Farrell PM, Leavitt LA, Samuels DP, Edwards DK. Clinical and roentgenographic scoring systems for assessing bronanalyses and Mrs. Shirley Haden and Mrs. Joyce chopulmonary dysplasia. AJDC 1984; 138:581-585. Schlemper for typing the manuscript. 22. Lesko LJ, Miller AK. Physical-chcmical compatibility of cromolyn sodium nebulizer solution-bronchodilator inhalant solution admixtures. Ann Allergy 1984:53:236-238. REFERENCES 23. Emin T,Metcalf JE, Lesko LJ, Chai MF. Update on thc physicalchemical compatibility of croinolyn sodium nebulizer solution: I . Motoyama EK, Fort MD, Klesh KW, Mutich RL, Guthrie RD. Bronchodilator inhalant solution admixtures. Ann Allergy 1991: Early onset of airway reactivity in premature infants with bron66:185-189. chopulmonary dysplasia. Am Rcv Respir Dis 1987; 136:SO-S7. 2. Northway WH Jr, Moss RB, Carlisle KB, ct al. Late pulmonary 24. Mcltzcr EO, Kcmp JP. Orgel HA, Izu AE. Flunisolide aerosol for treatment of severe, chronic asthma in steroid-independent chilsequelae of bronchopulnionary dysplasia. N Engl J Med 1990; dren. Pcdiatrics 1982;69:34&345. 32311793-1799. 3. Kao LC, Ourand DJ, Nickerson BG. Effects of inhaled nietaprw 25. Shapiro GG. Isu AE, Furukawa CT, Pierson WE, Bierman CW. Short-term double-blind evaluation of flunisolide aerosol for steterenol and atropine on the pulmonary mcchanics of infants with roid-dependent asthmatic children and adolescents. Chest 198I ; bronchopulnionary dysplasia. Pediatr Pulmonol 1989;6:74-80. 80:67 1-675. 4. Logvinoff MM, Lcmen RJ, Taussig LM. Lamont BA. Bronchodilators and diuretics in children with bronchopulmonary dyspla- 26. Slavin R, Izu AE, Bernstein L. et al. Multicenter study of flunisolide aerosol in adult patients with stcroid-dependent sia. Pediatr Pulmonol 1985; I : 198-203. asthma. J Allergy Clin lmmunol 1980;66:379-385. 5. Rooklin AR. Moomjian AS, Shutack JG, Schwartz JG, Fox WW. Theophylline therapy in bronchopulmonary dysplasia. J Pediatr 27. Piacentini GL, Sette L, Peroni DG, Bonizzato C, Bonetti S, Boner AL. Doublc-blind evaluation of effectiveness and safcty of 1979;95:882-885. flunisolidc aerosol for treatment of bronchial asthma in children. 6. Stenmark KR, Eyzaguirre M, Rcmigio L, Seccombe J, Henson Allergy 1990;45:612-616. PM. Rccovery of platelet activating factor and leukotrienes from infants with severe bronchopulmonary dysplasia: Clinical im- 28. Giorgi PL, Oggiano N, Biraghi M, Kantar A. Effect of high doses of inhaled flunisolide on hypothalamic-pituitary-adrenal axis provement with cromolyn treatment. Am Rev Resp Dis 1985: function in children with asthma. Current Therapeutic Res 1991; 13 1 :A236. 49:778-783. 7. Shook LA, Pauly T 11, Desai NS, Cunningham MD. Improved lung resistance and compliance during cromolyn therapy in infants 29. Pcdcrscn W, Prahl P. Jet-nebulized beclomethasone dipropionate in the management of bronchial asthma. Allergy 1987;42:272with bronchopulmonary dysplasia. Pediatr Res 1988;23:524A. 275. 8. Mammel MC, Green TP, Johnson DE, Thompson TR. Controlled trial of dexamethasone therapy in infants with bronchopulmonary 30. Carlsen KH, Leegaard J, Larsen S. 0rstavik 1. Nebulised bccloincthasone dipropionate in recurrent obstructive episodes after dysplasia. Lancet 1983; 1:1356-1357. acute bronchiolitis. Arch Dis Childh 1988; 63:1428-1433. 9. Avery GB, Fletcher AB, Kaplan M, Brudno DS. Controlled trial of dexaniethasonc in rcspirator-dependent infants with broncho- 31. Godfrey S, Avital A, Rosler A, Mandclberg A. Uwyyed K. Nebuliscd budcsonide in severe infmtile asthma. Lancet 1987;2 8 5 Ipulmonary dysplasia. Pcdiatrics 1985;75:106-I I I . 852. 10. Godfrey S, Kiinig P. Beclomethasone aerosol in childhood 32. Storr J, Lenney CA. Lcnney W. Nebuliscd beclomethasone diproasthma. Arch Dis Childh 1973;48:665-670. pionatc in preschool asthma. Arch Dis Childh 1986;61:27&273. 1 1 . Kiinig P, Gayer D, Kantak A, Kreutz C, Douglass B, Hordvik NL. A trial of metaproterenol by metered-dose inhaler and two 33. Zimmerman B, Treiiiblay D, Naus F. Nebulized inhaled steroid (Budesonide): prolonged high dose therapy in children less than spacers in preschool asthmatics. Pediatr Pulmonol 1988;5247age 5 . J Allergy Clin lnimunol 1990;85( I ) , Part 2258. 251. 12. Conncr WT. Dolovich MB, Frame RA, Newhouse MT. Reliable 34. Webb MSC, Milner AD, Hiller El, Henry RL. Nebulised beclornethasone dipropionate suspension. Arch Dis Childh 1986: 6 I : salbutamol administration in 6- to 36-month-old children hy 1108-1 110. means of a inctcred dose inhaler and Aerochamber with mask. 35. VanBever HP, Schuddinck L. Wojciechowski M, Stevens WJ. Pediatr Pulnionol 1989;6263-267. Acrosolized budesonide in asthmatic infants: A double blind 13. Maayan C, ltzhaki T. Bar-Yishay E, Gross S, Tal A, Godfrey S. study. Pediatr Pulmonol 1990;9:177-180. The functional response of infants with persistent wheezing to nebulized beclomethasone dipropionate. Pediatr Pulmonol 1986: 36. BdrubC D. Spier S, Lapierre G. Marcotte JE, Lamarre A. Effects of budesonide in infantile asthma. Am Rev Resp Dis 1990; 2:9-14. I41:A90S. 14. DeJongste JC, Duiverman EJ. Nebulised budesonide in severe 37. Clark RJ. Exacerbation of asthma after ncbulised beclomethasone childhood asthma. Lancet 1989; I :1388. dipropionate. Lancet 1986;2574-575. IS. Zeiger RS. Special considerations in the approach to asthma in 38. Wolthers OD, Pedersen S. Growth of asthmatic children during infancy and early childhood. J Asthma 1983;20:341-359. treatment with budesonide: A double blind trial. Br Med J 1991; 16. Wood BR, Baldwin JN, Kobayashi RH. An evaluation of the risk 303:163-1 65. of bronchospasm with intrapulmonary acrosolization of fluniso39. Freigang B, Ashford DR. Adrenal cortical function after longlide. Pediatr Asthma, Allergy lmmunol 1987: I : I 11-1 14. term beclomethasone aerosol therapy in early childhood. Ann 17. Eisenkrg J. Use ol' nebulized flunisolide in infants and children Allergy 1990;64:342-344. with asthma and bronchopulnionary dysplasia (BPD). Am Rev 40. Grccnough A, Pool J, Glccson JGA, Price JF. Effect of budesResp Dis 1990;141:A899. onide on pulmonary hyperintlation in young asthmatic children. 18. Chin T, Nussbaum E. Usc of nebulized flunisolidc in pediatric Thorax 1988:43:937-938. asthma. Am Rev Resp Dis 1991;143:A624.
ACKNOWLEDGMENTS
Clinical Observations of Nebulized Flunisolide in Infants and Young Children With Asthma and Bronchopulmonary Dysplasia Peter Konig, MD, pm,' Miriam Shatley, MD,' Clive Levine, M D , ~and Thomas P. Mawhinney, PhD' Summary. Severe bronchopulmonary dysplasia (BPD) is frequently associated with asthma. The combination is often severe enough to necessitate corticosteroid therapy. There are no commercially available nebulizer solutions of corticosteroids for use in infants and young children. Seven infants and small children with very severe BPD and asthma aged 6-24 months, were treated with flunisolide, 187-250 pg q.i.d. in the form of nasal spray delivered by nebulizer. After treatment for 2.5-20 months, four patients showed clinical improvement, one initially improved but later deteriorated and died of cardiac failure, and two patients showed no improvement and died within 3 months. The number of days of hospitalizationwas significantly reduced from 8.4/month to 23month ( P < 0.05). No side-effects were detected and it was felt that the three patients who died, did so as a consequence of very severe BPD and its cardiac consequences. The suspension remained stable for 80 min when mixed with normal saline, cromolyn sodium, albuterol, or acetylcysteine. It is concluded that nebulized flunisolide is a potentially useful treatment for infants and young children with asthma and BPD. Pediatr Pulmonol. 1992; 13:209-214. D 1992 Wiley-Liss, Inc. Key words: Clinical-radiologic score; mortality; hospitalization; side effects; physicochemical compatibility.
INTRODUCTION As much as 91% of patients with severe bronchopulmonary dysplasia (BPD) have bronchial hyperreactivity . I A long-term follow-up study by Northway and associates2 has shown that even at age 14-23 years, 52% of patients with BPD still have reactive airway disease (asthma). They represent a very difficult group to treat because they have a combination of two obstructive lung diseases. Because of the underlying BPD changes, consequences of even moderately severe asthma can be quite serious. A number of antiasthma medications, such as adrenergic agents,'.' a t r ~ p i n e , ~ theophylline,' .~ cromolyn sod i ~ m , ' ,and ~ systemic corticosteroids8~9have been shown to be beneficial in patients who suffer from a combination of BPD and asthma. Because many of these children have severe asthma, they would be candidates for corticosteroid therapy. However, in addition to the side-effects Of Systemic corticosteroids, in these young children severe infections constitute an additional risk. In older children systemic side-effects of corticosteroids are generally minimized by using the inhaled route through a metered-dose (MD1)' lo Most under 4 years do not possess sufficient coordination to use metered-dose inhalers, although the addition of a
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0 1992 Wiley-Liss, Inc.
spacer device can lower the age to 2-3 years." Some investigators advocate MDIs with spacers in infants as young as 6 months,'* but the methodology is not yet well established. Nebulizer solutions of cromolyn sodium6 and adrenergic agents3 have been used very successfully in infants and young children. Several corticosteroid drugs such as beclomethasone dipropionate'' and budesonide l 4 have been tested as nebulizer suspensions, but none of these is commercially available in the United States. Flunisolide is available in the form of nasal spray (NasalideB) which has been used by clinicians as nebulizer solution for some years. However, the published data on this use are restricted to one sentence in a review article by Robert S. Zeiger,I5 one study showing no ill-effects from a single dose administration, l 6 and two abstracts. 1 7 7 1 x From the Department of Child Health' and Department of Radiology,' University of Missouri-Columbia, Columbia, Missouri. Received November 18, 1991; (revision) acccpted for publication April 20* 19y2. Address correspondcnce and reprint requests to Dr. P. Konig, Department of Child Health, University of Missouri Health Sciences Center, I Hospital Drive, Columbia, MO 65212.
Konig et al.
210
TABLE 1-Personal Data of the Patients
Patient number
Sex
F F F F F M M
1 2 3 4 5 6 7
Mean SD
Age at Start of flunisolide treatment (months) I I '/z 6 17 10 6 24
Gestional Age (weeks)
Birth weight
(s)
I252 2010
10
28 32 25 30 31 28 28
12.1 6.4
28.9 2.3
1429.9 460.0
Length of NlCU stay (months)
I600 I620
3 3 4 4 4 v2
19 10
4%
1000
718
Length ol' ventilatory support (months) 7 3
9
I 2 3 '/2 3 55 2% 8
4.6 2.0
3.06 2.45
Previous asthma therapy Cr, Alb, Th, Atr Cr. Alb, Th, Atr Cr, Alb, Th Cr, Alb, Th Cr, Alb, Th Cr. Alb, Th. Atr Cr, Alb, Th
Outcome Improved Improved lmproved No change, death No change, death Improved Initial improvement death later
Cr, Cromolyn sodium: Alb, albuterol: Th, theophylline; Atr, atropine.
The duration of the trial was 21/2-20 months (mean, 7.8 months). Parents gave their informed consent in writing. Flunisolide was given as Nasalide nasal solution 0.025%,in a dose of 0.75mL (187 pg) q.i.d. to patients under one year, and 1 mL (250 p,g) q.i.d. to patients over MATERIALS AND METHODS one year of age. The dose was adopted from that used for Seven patients were treated. There were five females years by R.S. Zeiger (personal communication) and and two males aged 6-24 months (mean, 12.1 -t 6.4 found to be safe (including absence of changes in adrenal SD). All had BPD defined as oxygen dependency for function tests) and effective. The solution was delivered more than 28 days following mechanical ventilation dur- by a jet nebulizer, at a flow rate of 6 Umin and a face ing the first week of life, with persistent increased densi- mask or "blow-by" (held close in front of their face). The ties on chest radiographs, l 9 and asthma as defined by the same nebulizers were consistently used in individual paAmerican Thoracic Society.2" The diagnoses were clini- tients throughout the observation period. cal and no pulmonary function tests were performed. Personal characteristics of the patients are shown in Table 1 . All were premature, had prolonged stay Physicochemical Compatibility of Flunisolide (mean SD, 4.6 2 2.0; range, 3-9 months) in the Neo- With Other Nebulized Medications natal Intensive Care Unit, and needed weeks to months of Because these children were treated at the same time ventilator support (3.06 k 2.45; range, 0.66-8 months). with other nebulized medications, we examined the physAll but one were still on supplemental oxygen therapy. icochemical compatibility of the flunisolide suspension Chest X-rays were scored according to their severity by a with a number of other drugs. Flunisolide 0.025%(Naradiologist who was not aware of treatment status2' All salide), Syntex Laboratories, lot No. 36029; albuterol but one patient (No. 5 , who had moderately severe sulfate 0.5% (ProventiP), Schering Corporation lot No. changes) had severe radiologic changes. They all re- 0-KPJ-23; cromolyn sodium (IntaP) nebulized solution, ceived conventional asthma treatment, including nebu- Fisons Pharmaceuticals, lot No. H N 3720A; acetylcyslized cromolyn sodium and albuterol, theophylline, and teine (Mucosil-lo), Dey Laboratories, lot No. 3258 H; in some cases also nebulized atropine (Table 1). All but and normal saline (sodium chloride 0.9%)lot No. 1E398, one patient at times needed systemic corticosteroids. were studied in amounts used clinically. The mixtures These drugs were continued after the start of flunisolide were continuously rotated on a laboratory shaker and treatment until the patient showed sufficient improve- sampling was performed at 0,20,40,60, and 80 min. At ment to discontinue some of them. Clinical improvement each sampling time the pH was measured and the mixwas assessed based on the symptoms of cough, wheez- tures were examined against a light and dark background ing, and dyspnea, which in some cases were documented in order to detect precipitation or color change.22.23The by symptom diaries, by the need for oxygen, by an oxy- concentrations of the drugs were determined by highgen saturation of at least 9096, by the result of follow-up pressure liquid chromatography. At each sampling time physical examination (respiratory rate, wheezing, retrac- three aliquots were tested and the results presented as tions), and by appetite and weight gain. means of the three. Therefore, we decided to describe our preliminary experience in seven patients with severe asthma and bronchopulmonary dysplasia, treated with nebulized flunisolide.
*
Nebulized Flunisolide for Asthma and BPD in Early Life
Statistical Analyses The small number of patients and the fact that it was a retrospective study allowed statistical analyses on a very limited scale. The number of hospitalizations and the number of days of hospitalization during equal periods of time before and after the introduction of flunisolide treatment were analyzed by Wilcoxon Signed Rank Test. P values of less than 0.05 were considered statistically significant. RESULTS
TABLE 2-Number of Hospitalizations and Days of Hospitalization Before and After Flunisolide Therapy Number of hospitalizations/rnonth Patient number
I 2 3 4
5" 6 7
One patient could be weaned off oxygen and two more reduced their need from 1 to 0.5 Wmin, while maintaining good saturation (at least 9096). All but two patients showed some clinical improvement. However, patients No. 4 and 5 died about 3 months after the onset of flunisolide therapy without showing any beneficial effect. Patient No. 7 initially had some improvement, but later deteriorated and died of cardiac failure. In the two treatment failures who showed no improvement and eventually died (patients No. 4 and 5) asthma did not seem to be the main problem. Patient No. 4 had severe congestive heart failure and patient No. 5 had severe recurrent episodes of apnea. In patient No. 7, the main problem was cor pulmonale and congestive heart failure which eventually caused his death. One patient could discontinue atropine and another one cromolyn sodium. Of the four patients who improved clinically, in two the number of days on systemic corticosteroids were substantially reduced (from 42 days in 6 months to 21 days in 6 months and from 17 days in 6 months to none, respectively). The other two patients had slightly increased need (from 0 to 10 days and from 31 to 42 days in 6 months, respectively). Two of the three patients who died needed more systemic corticosteroids (from 31 days to 42 days in 6 months and from 0 to 60 days in 2 months, respectively), while one was never on systemic corticosteroids. In some patients improvement was also reflected in better weight gain. For example, patients No. I and 3 moved from below the 3rd percentile to the 5th percentile and patient No. 6 from below the 3rd to the 25th percentile. The number of hospitalizations and days of hospitalization are shown in Table 2. Equal periods of 3-6 months before and after flunisolide treatment were analyzed and the results were averaged per month. Patient No. 5 was eliminated from the statistical analyses because she had a prolonged hospitalization due to apnea and not connected with asthma, that lasted the whole period of flunisolide treatment. There were 0.64 hospitalizations per month before, and 0.28 after start of flunisolide therapy, but the difference was not statistically significant. The number of days of hospitalization
211
Mean SD P
Before flunisolide
After flunisolide
0.17 0.17 0.50 0.50 0.33 0 I .00 0 1.33 0.50 0.50 0.50 0.64 0.28 0.44 0.25 Not significant
Days of hospi talizations/month Before flunisolide
After tlunisolide
I .83 3.83 I .83 7.67
0.67 2.00 0 0 2.00 10.50 2.53 4.00
-
20.83 14.50 8.42 7.74 c0.05
"Patient No. 5 not analyzed because of prolonged hospitalization due to apnca and not asthma.
was 8.4 before and 2.5 after therapy. This diffcrence was statistically significant (P < 0.05). Chest radiographs showed generally little change (Table 3). However, there was a tendency for improvement in hyperinflation, with 3 patients improved, 3 unchanged and one worsening. These changes generally correlated with clinical improvement. Considering the relatively short period of follow-up, components other than hyperinflation could not have been expected to show changes. There were no clinically evident side-effects such as oral candidiasis or Cushingoid appearance, but hypophyso-pituitary-adrenal (HPA) axis tcsts to measure adrenal function were not performed. Physicochemical Compatibility of Flunisolide With Other Nebulized Medications
The mixtures were very stable. There was no precipitation or change in color. The pH varied between 4.95 and 5.26 at the onset and changed very little during 80 min (Table 4). There was no evidence of degradation of flunisolide in any of the mixtures, all changes (plus or minus) being less than 2.5% (Table 4). DISCUSSION
This clinical experience on a small sample has shown that patients who have both BPD and asthma can benefit from treatment with nebulized flunisolide. Even though one of the two criteria submitted to statistical analyses did not show significant difference, probably due to the small number of patients, the number of hospitalizations per month was reduced to less than half by treatment with flunisolide. Although patients with BPD tend to improve with age, the relative shortness of the period of observa-
212
Konig et al.
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tion (2-6 months) makes it unlikely that the improvement was a spontaneous one. Eisenberg also found some benefit from nebulized flunisolide (Nasalide), although his patients were a more mixed group, only 4 out of the 9 having both BPD and asthma. In their series the mortality was also high (two out of four with BPD). Chin and NussbaumI8 treated 7 patients with asthma, and reported a reduction in hospitalizations and in systemic corticosteroid use. Their patients were somewhat older (2-7 years) and had no BPD, therefore, these results are not strictly comparable with those in the present group. Inhaled flunisolide by metered-dose inhaler has been shown to be effective and safe in older ~ h i l d r e n ~ and ~.~' adults.26 Piacentini and associates2' treated older children (8-13 years) suffering from asthma alone with nebulized flunisolide, 0.5 mg b.i.d. for 2 months in a double blind study. They showed the drug to be significantly better than placebo and it had no effect on the HPA axis. Ciorgi and colleagues28 gave nebulized flunisolide, 1,600 kg/day for 2 months. to 6-1 I year old children with asthma and found no side-effects on the HPA axis or carbohydrate and lipid metabolism. The literature on the use of other corticosteroids by nebulizer in asthma (with no BPD) is somewhat contradictory. Beclomethasone dipropionate and budesonide are available as nebulizer suspension in Europe and elsewhere. A number of studies have been published with these drugs and although most had positive re13.14,2'&)-33 others showed them to be no better than p l a ~ e b o . ' ~ . ' BCrubC ~ and associates described clinical improvement in infants given budesonide, 2 mg/day , but no significant change in maximal expiratory flow at functional residual capacity (V,,,, FKC) and a significant suppression of the ACTH response.'" Many of these publications are in the form of letters to the Editor, 14.30 abstract^,'^ or open trials,28 only five were controlled trials. 13*3"323433' Of the controlled studies, three were positive'3,'o.32 and two negati~e.'~.~' Therefore, more controlled studies are needed. The safety of nebulized beclomethasone dipropionate and budesonide seemed to be good in these studies, although Clark reported one patient who developed a severe asthma attack from nebulized beclomethasone dipropionate.'7 However, most studies were limited to clinical side-effects. 2')3234*3' Only a few tested the adrenal axis showing either no signs of ~uppression'~ or suppression by some tests.36 One group of investigators commented on no change in growth rate,2' but sensitive modem techniques such as knemometry were not used. Wolthers and Pedersen'8 demonstrated a dose-dependent reduction in growth velocity with budesonide regular doses (200, 400, and 800 pg/day in MDI) in older children. No clinically evident side-effects were noted in our patients. None of the patients who died had evidence of sepsis at the time of their death, however, patient No. 5
Nebulized Flunisolide for Asthma and BPD in Early Life
213
TABLE 4-Physicochemical Compatibility of Flunisolide Mixed With Different Drugs Given by Nebulization Time 0
I . 1 ML flunisolide (0.025%) 2. I mL flunisolide (0.025%) + 2 mL saline (0.9%) 3. I mL flunisolide (0.025%) + 2 mL cromolyn sodium (20 mg/2 mL H,O) 4. 1 mL flunisolide (0.025%) + 0.5 mL albuterol sulfate (0.5%) 5 . 1 mL flunisolide (0.025%) + 2 mL saline (0.9%)+ 0.5 mL albuterol sulfate (0.5%) 6. I mL flunisolide (0.025%) + 2 mL cromolyn sodium 0.5 mL albuterol sulfate (0.5%) 7. I mL flunisolide (0.025%) + I mL Mucosil-10 (acetylcysteine 10%)
+
Concentration” PH Concentration PH Concentration PH
24
20 min
40 min
pg/rnL 5.26 80.9 pg/mL 5.25 8 I . 7 pg/mL 5.18
100.1% 5.28 99.8% 5.21 99.6% 5.10
99.78 5.30 99.4% 5.29 99.4%
Concentration PH Concentration PH
165.0 pg/mL 5.09 70.9 pg/rnL 4.95
10.3% 5. I4 l00.1% 5.04
99.9% 5.10 101.3% 5.01
Concentration PH
70.9 pg/mL 5.15
100.8% 5.13
Concentration PH
8 I .4 pg/mL 5.19
100.6% 5.20
60 min
80 min
98.2% 5.29 9X.6% 5.23 98.5% 5.12
98.2% 5.28 98.4% 5.24 97.6% 5.12
99.9% 5.15
5.04
99.X% 5.15 99.4% 5.07
100.4% 5 . I5
100.6% 5.10
99.98 5.13
99.9% 5. I7
100% 5.19
99.5% 5.18
5.15
100%
“Concentrationsof flunisolide at time 0 are measured by means of three aliquots; at times 2WO min, concentrations are percents of values at time 0.
had several previous episodes of sepsis during the prolonged hospitalization that ended with her death. This patient was a very sick girl with multiple problems (frequent apneic spells, cor pulmonale, pulmonary edema, pneumonia) and it was not at all clear if flunisolide in any way contributed to her sepsis. Three deaths in a series of 7 patients might seem too high, but since only extremely severe patients were treated with flavisolide this death rate must not be considered excessive. In two abstracts published on nebulized Nasalide treatment in young children no side-effects are mentioned, but no details are given.”*18 Even though little is known about systemic side-effects of nebulized Nasalide, it is unlikely that they would be serious enough to counterindicate its use in such severe life-threatening cases of BPD with asthma. Nasalide is in a formulation intended for nasal spray and not for nebulizer solution. It contains preservatives and solvents such as propylene glycol and it has a pH of 5.3. Propylene glycol causes nasal stinging in many patients and could, in theory, cause bronchospasm. However, Wood and associates did not observe any bronchospasm with nebulization of up to 2 mL of Nasalide.I6 Chin and Nussbaum found no bronchospasm in 10 older children with asthma after nebulization of a single dose of 2 ml of Nasalide. In our patients albuterol was always given together with Nasalide because of clinical need and this seems to be a reasonable precaution for future studies. Toxic effects other than bronchospasm from the additives could be encountered, but so far none was detected. It is not known what effect the additives have on particle size and drug delivery. We have shown that the Nasalide
suspension is compatible with nebulized solutions of cromolyn sodium, albuterol, and normal saline, therefore, these can be administered together, saving a lot of time. Conner and associates showed good response to albuterol administered by MDI and a spacer (Aerochamber) in as young as 6-month-old infants.’* Freigang and Ashford in an open trial treated 12 to 26-month-old children with beclomethasone by MDI plus a special AIDAC inhalation all patients improved and the ACTH test showed no change. Another study in 2- to 6-year-old children, using budesonide by MDI with a spacer, showed a reduction in FRC.40 It is possible that this mode of administration is a viable alternative to nebulized corticosteroids, but more studies are needed in infants and young children. I t is concluded that nebulized flunisolide is a potentially beneficial treatment for severe asthma in infants and young children with BPD. Because of the severity of the associated irreversible obstruction resulting from BPD perhaps the decision to start corticosteroids should be made earlier than in patients with asthma only. More studies, preferably of a double-blind placebo controlled design, are needed to confirm the findings of this clinical experience. Nebulized corticosteroids are necessary also for the treatment of severe asthmatics with no BPD, therefore it would be important to have commercially available solutions specially prepared for nebulizer use. As the total patient population that has this need is relatively small but very severely ill, perhaps the agent could be made available as an “orphan drug” and provided by pharmaceutical companies on humanitarian grounds.
214
Konig et al.
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Bronchodilator inhalant solution admixtures. Ann Allergy 1991: Early onset of airway reactivity in premature infants with bron66:185-189. chopulmonary dysplasia. Am Rcv Respir Dis 1987; 136:SO-S7. 2. Northway WH Jr, Moss RB, Carlisle KB, ct al. Late pulmonary 24. Mcltzcr EO, Kcmp JP. Orgel HA, Izu AE. Flunisolide aerosol for treatment of severe, chronic asthma in steroid-independent chilsequelae of bronchopulnionary dysplasia. N Engl J Med 1990; dren. Pcdiatrics 1982;69:34&345. 32311793-1799. 3. Kao LC, Ourand DJ, Nickerson BG. Effects of inhaled nietaprw 25. Shapiro GG. Isu AE, Furukawa CT, Pierson WE, Bierman CW. Short-term double-blind evaluation of flunisolide aerosol for steterenol and atropine on the pulmonary mcchanics of infants with roid-dependent asthmatic children and adolescents. Chest 198I ; bronchopulnionary dysplasia. Pediatr Pulmonol 1989;6:74-80. 80:67 1-675. 4. Logvinoff MM, Lcmen RJ, Taussig LM. Lamont BA. 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Arch Dis Childh 1986: 6 I : salbutamol administration in 6- to 36-month-old children hy 1108-1 110. means of a inctcred dose inhaler and Aerochamber with mask. 35. VanBever HP, Schuddinck L. Wojciechowski M, Stevens WJ. Pediatr Pulnionol 1989;6263-267. Acrosolized budesonide in asthmatic infants: A double blind 13. Maayan C, ltzhaki T. Bar-Yishay E, Gross S, Tal A, Godfrey S. study. Pediatr Pulmonol 1990;9:177-180. The functional response of infants with persistent wheezing to nebulized beclomethasone dipropionate. Pediatr Pulmonol 1986: 36. BdrubC D. Spier S, Lapierre G. Marcotte JE, Lamarre A. Effects of budesonide in infantile asthma. Am Rev Resp Dis 1990; 2:9-14. I41:A90S. 14. DeJongste JC, Duiverman EJ. Nebulised budesonide in severe 37. Clark RJ. Exacerbation of asthma after ncbulised beclomethasone childhood asthma. Lancet 1989; I :1388. dipropionate. Lancet 1986;2574-575. IS. Zeiger RS. Special considerations in the approach to asthma in 38. Wolthers OD, Pedersen S. Growth of asthmatic children during infancy and early childhood. J Asthma 1983;20:341-359. treatment with budesonide: A double blind trial. Br Med J 1991; 16. Wood BR, Baldwin JN, Kobayashi RH. An evaluation of the risk 303:163-1 65. of bronchospasm with intrapulmonary acrosolization of fluniso39. Freigang B, Ashford DR. Adrenal cortical function after longlide. Pediatr Asthma, Allergy lmmunol 1987: I : I 11-1 14. term beclomethasone aerosol therapy in early childhood. Ann 17. Eisenkrg J. Use ol' nebulized flunisolide in infants and children Allergy 1990;64:342-344. with asthma and bronchopulnionary dysplasia (BPD). Am Rev 40. Grccnough A, Pool J, Glccson JGA, Price JF. Effect of budesResp Dis 1990;141:A899. onide on pulmonary hyperintlation in young asthmatic children. 18. Chin T, Nussbaum E. Usc of nebulized flunisolidc in pediatric Thorax 1988:43:937-938. asthma. Am Rev Resp Dis 1991;143:A624.
ACKNOWLEDGMENTS
