Treatment of asthma in children with triamcinolone acetonide aerosol R. Michael Sly, M.D., Manuel Imseis, M.D., Marilyn Frazer, and Fred Joseph, B.S. New Orleans, La.
Triamcinolone acetonide aerosol, 100 pg qid, was administered for 8 wk to 5 steroid-dependent asthmatic children and IO who had not previously required continual corticosteroid treatment. Symptomatic control and pulmonary function improved in all 15 children despite discontinuation of oral corticosteroids in 3 of the steroid-dependent children. Determination of morning plasma cortisol concentrations disclosed no evidence of substantial adrenal suppression. Satisfactory symptomatic control has subsequently been maintained for 6 to 32 mo with doses of 100 pg bid to 300 pg qid without more extreme changes in plasma cortisol concentrations than were observed during the jrst 8 wk.
Systemic adrenal corticosteroids are very effective in the treatment of asthma, but their use has been limited by numerous side effects, including suppression of the hypothalamic-pituitary-adrenal axis. l The extent and frequency of adrenal suppression and other side effects of continual treatment with corticosteroids can be reduced by oral administration of a steroid with intermediate duration of activity, such as prednisone, prednisolone, or methyl prednisolone, as a single morning dose on alternate days, but some adrenal suppression can occur in some patients despite this precaution.2, 3 Administration of steroids by inhalation has been investigated as a possible method of reducing the dosage necessary for control of asthmatic symptoms to one which would not cause adrenal suppression. Inhalation of dexamethasone four times each day at doses which usually have achieved symptomatic control has been found also to cause significant adrenal suppression. 4 More recently, inhalation of beclomethasone dipropionate5, 6 or triamcinolone acetonide’-l2 has been found often to afford adequate control of asthma at doses which cause no significant adrenal suppression. Triamcinolone acetonide, 9o-fluoro-1 l/3, 21-dihydroxy- 16a, 17o+isopropylidenedioxy- 1, 4-pregnadiene-3, 20-dione, is a nonpolar compound insoluble in From the Department
of Pediatrics,
Louisiana
State University
Medical Center. Received for publication Dec. 14, 1977. Accepted for publication March 6, 1978. Reprint requests to: Dr. R. Michael Sly, Director of Allergy Immunology, Childrens Hospital National Medical Center, Michigan Ave., N. W., Washington, D. C. 20010.
Vol. 62, No. 2, pp. 76-82
and 111
water. It is micronized and aerosolized as a fine suspension with dichlorodifluoromethane (Freon 12) as propellant and 1% alcohol USP. Particle size is estimated to be 1 to 5 p in diameter. The drug is delivered from a collapsible aerosol unit designed to minimize deposition in the mouth by reducing the momentum of the aerosol, directing it away from the roof and sides of the mouth, and by favoring complete vehicle volatilization to assure delivery of dry particles (Fig. 1). Each actuation is estimated by the manufacturer to deliver 200 pg triamcinolone acetonide from the cartridge and 100 pg to the patient. PILOT STUDY Five asthmatic children, aged 8 to 12 yr, including 4 boys and 1 girl, were selected for a preliminary 4wk study because of the presence of severe chronic asthma necessitating continual treatment with oral prednisone or prednisolone, 10 to 30 mg, as a single morning dose on alternate days. After informed consent, each received triamcinolone acetonide aerosol, 100 s qid, in addition to the oral corticosteroid and usual bronchodilators for the first week. Oral steroid dosage was then gradually decreased and discontinued after 6 to 20 days while administration of triamcinolone acetonide aerosol was continued. It was possible to decrease the dosage of triamcinolone acetonide aerosol to 50 @ qid* in one child but it was necessary to increase it in another to 200 e qid *Possible because of an earlier cannister from which each actuation released 100 ccg of which an estimated 50 pg was delivered to the patients.
0091-6749/78/0262-0076$00.70/O 0 1978 The C. V. Mosby Co.
VOLUME NUMBER
62 2
Triamcinolone
ACTUATOR
acetonide
in children
77
CHANNEL
COVER -CARTRIDGE ACiUATOR
BAR’REL
u ACTUATOR 3
BARREL
II
MOUTHPIECE OVER ON
WITH
(Remove
Cover)
FIG. 1. Collapsible actuator-adaptor for delivery of triamcinolone acetonide aerosol. After shaking well the cartridge is inserted into the actuator, 1. The barrel is then fully extended,2, and the actuator is bent upward at a right angle to the barrel, 3. After removal of the mouthpiece cover the unit is ready for use.
in adjusting the dose to the minimal amount which maintained adequate clinical control during the 4 wk. Fasting plasma cortisol concentrations were measured at 9:00 A. M. and 30 min after the intramuscular injection of cosyntropin, 0.25 mg, both before treatment with triamcinolone acetonide and after 4 wk of treatment. Throat cultures for Cundida albicuns were obtained before treatment and after 4 wk of treatment. Measurement of forced vital capacity, forced expiratory volume in one second, and flow rates at 25% and 50% vital capacity after all medications had been withheld for 8 hr before treatment with triamcinolone acetonide aerosol and at weekly intervals disclosed no significant changes (one-way analysis of variance). Peak expiratory flow rate was measured 3 times each day, and there was no significant change in mean daily readings during the 4 wk (one-way analysis of variance). Comparison of 9:00 A.M. plasma cortisol concentrations before and after 4 wk of treatment with triamcinolone acetonide aerosol disclosed substantial increases to normal in two children whose initial values indicated adrenal suppression and a decrease in another, whose response to stimulation with intramuscular injection of cosyntropin improved (Table I). Throat cultures obtained for Cundidu were positive in 2 patients before treatment with triamcinolone acetonide aerosol but negative after 4 wk of treatment. A positive culture was found after treatment in another patient whose initial culture had been negative. Cultures were negative both before and after treatment in the other two children. There was no clinical
evidence of candidiasis at any time in any of the children. Thus, treatment with triamcinolone acetonide aerosol made it possible to discontinue oral corticosteroids in all five children without significant changes in pulmonary function or evidence of consequent adrenal suppression. Because of these encouraging results another study was designed to investigate further the safety and efficacy of triamcinolone acetonide aerosol in asthmatic children.
MATERIALS AND METHODS Patients Fifteen asthmatic children, aged 6 to 13 yr, including 10 boys and 5 girls, were selected for study because of the presence of severe, chronic asthma requiring continual treatment with oral bronchodilators, 5 having required continual treatment with oral prednisone or prednisolone for 6 to 92 mo at doses of 10 to 30 mg on alternate days. These steroid-dependent children had been examined at l4-wk intervals and had been receiving the lowest dose of steroids which afforded satisfactory symptomatic control as determined by frequent attempts to reduce the dosage. Some of the children who were not receiving corticosteroids had received them intermittently for a few days at a time in the past, but they had received none during the previous month. Four of the children were also receiving cromolyn; the others had failed to respond to cromolyn in the past. None of those receiving cromolyn had received it for less than 4 months. Reversibility of bronchospasm was demonstrated in all children by increases of at least 15% in forced expiratory
78 Sly et al.
J. ALLERGY
TABLE I. Plasma cortisol
concentrations (pgldl) at 9:00 A.M. in 5 steroid-dependent asthmatic children before and after 4 wk of treatment with triamcinolone acetonide aerosol and 30 min after injection of cosyntropin Before treatment
Patient
After treatment
Baseline
After stimulation
Baseline
After stimulation
15.8 16.2 5.2 4.2 0 8.3
29.3 20.9 27.0 20.8 20.0 23.6
13.4 9.2 7.3 9.5 9.5 9.3
27.0 30.3 30.1 29.1 27.3 28.8
1 2 3 4 5 Mean
volume in one second (FEV,) following inhalation of isoproterenol or subcutaneousinjection of 1: 1,000 aqueous epinephrine. All children had peripheral eosinophilia and most had nasal eosinophilia. All had positive immediate wheal-andflare reactions to several inhalant allergens following scratch or intradermal testing. All had positive immediate family histories for atopic diseases.The only one with a history of aspirin intolerance was a 6-yr-old boy who had had generalizedurticaria following administration of aspirin as an infant. None of the children was known to have tuberculosis, diabetes mellitus, or cardiovascular, renal, or hepatic disease.
CLIN. IMMUNOL. AUGUST 1978
this was done 48 hr after the last dose of oral steroids. Venous blood was drawn at 8:00 A.M. and immediately immersedin an ice bath. Plasma was separatedwithin 30 min, and cortisol was then determinedin duplicate samples by the tluorometric method of Silber and co-workers with somemodifications.r3-i4 Plasma,0.1 to 1.Oml, was diluted to 2.0 ml with distilled water before extraction. Two cortisol standard solutions were used through the entire procedure. Individual readings were taken at I-min intervals 40 min after the addition of methylene chloride extract to the fluorescent reagent. Maximum fluorescence was obtained on the Aminco-Bowman spectrophotofluorometer with metermultiplier, 0.3, primary filter, 480 rnp, secondary filter, 530 rnp. Blood counts with differentials, urinalyses, and determinations of fasting blood sugar, blood urea nitrogen, alkaline phosphatase, serum glutamic oxaloacetic transaminase @GOT), serum calcium, phosphorus, sodium, potassium, and chloride were obtained before treatment and at 4 and 8 wk. Chest roentgenogramswere obtained before treatment. Continued
treatment
Following the initial 8 wk of treatment with triamcinolone acetonideaerosol, therapy was continued with variations in dosageas indicated by responsebut not exceeding 1,200 pg/day. Children were re-examined and pulmonary function retested at 1 to 2-mo intervals. Plasma cortisol was measuredat 2-mo intervals during the first year and 4mo intervals after that. Other laboratory testswere repeated at 6-mo intervals. Chest roentgenogramswere obtained again at 1 yr. RESULTS
Methods One week before treatment was startedparents began a daily diary of symptoms and medications. After informed consent, each child received triamcinolone acetonide aerosol,* 100 M qid for 8 wk. Bronchodilators and cromolyn were continued. After the first week, prednisoneor prednisolone dosagewas decreasedby 5 mg every other day each week if tolerated. Daily symptom and medication diaries were continued. Medical histories, physical examinations, and pulmonary function testing, including determination of forced vital capacity (FVC), FEVi, and forced expiratory flow at 25%-75% vital capacity (FEFZ5%-,&, were repeatedat weekly intervals. All medications were withheld for at least 6 hr before pulmonary function testing and physical examination ( 12 hr for sustained-release theophylline preparations). Oral corticosteroids were withheld for 24 or 48 hr before assessments. Laboratory
studies
Plasma cortisol concentrations were determined before treatment with triamcinolone acetonideaerosol and after 4 and 8 wk of treatment. In the steroid-dependentchildren *Supplied as Aristocort Aerosol by Dr. Paul A. Kennedy, Jr., Lederle Laboratories, Pearl River, N. Y.
Symptomatic control improved in all 15 children despite a decrease in the use of bronchodilators in 7. Brochodilator usage increased slightly in 3 children and remained unchanged in 5 during the eight weeks. The severity of wheezing reported by patients and parents tended to decrease during the eight WC&S (Fig. 2). None was free of wheezing during the we& before treatment was started, but 7 reported no whcczing during the eighth week. The total number of nights that the children were awakened by wheezing decreased from 25 during the week before treatnmt to 1 during the eighth week (Fig. 3). Pulmonary function after medications had been withheld at least 6 hr improved at some time in all 15 children, but was not improved in every child at each week (Figs. 4 and 5). Paired t tests disclosed that differences from the week before treatment were significant for weeks 2 (FVC, FEVr), 3 (FVC), and 8 (FVC, FEV1, FEFzs%-r5%), as well as 4 months (FVC, FEVr) and 6 months (FVC). Treatment with ttiamcinolone acetonide aerosd permitted discontinuation of oral corticosteroids in 3 of the 5 steroid-dependent children. These three had
VOLUME 62 NUMBER 2
Triamcinolone
acetonide
in children
79
8
NMiMSVS
NMiMS
NMiMS
NMiMS
0
I
2
3
Vs
NMiMSVS
4 N Mi M S VS
= None = Mild = Moderate = Severe = Very Severe
N=15 NMiM
5
S
6
7
8
012345678 WEEK
WEEK FIG. 2. Severity of wheezing in 15 asthmatic children the week before treatment and during and after 8 wk of treatment with triamcinolone acetonide aerosol.
FIG. 3. Total number of nights 15 asthmatic children were awakened by wheezing the week before treatment and during and after 8 wk of treatment with triamcinolone acetonide aerosol.
been receiving prednisone continually for 6,9, and 29 mo and were receiving 10, 25, and 20 mg qod, respectively, when admitted to the study t.T. W., A. J., N. C. ). The two other steroid-dependent children had received prednisolone or prednisone for 5% to 7% yr and were receiving 20 to 30 mg qod before treatment with triamcinolone acetonide. by 8 wk it was possible to reduce their oral steroid dosage to 15 and 20 mg qod, respectively. A slight decrease in mean plasma cortisol concentration was found after 4 wk of treatment in the steroid-dependent children, but this was not statistically significant. This was partly due to an extreme decrease in one boy from 22.2 pg% to 2.7 pg%, but his cortisol concentration was 20 pg% at 8 wk and it was suspected that the specimen obtained at 4 wk might have been drawn 24 hr rather than 48 hr after his dose of 22.5 mg prednisone. Mean plasma cortisol concentration at 8 wk was unchanged from the pretreatment value for the steroid-dependent children (Table II). By 8 wk, plasma cortisol concentrations had increased in 2 steroid-dependent children, including one who was still receiving oral prednisolone, and decreased to 6.4 pg% in one in whom prednisone had been discontinued (Table II). The mean plasma cortisol concentration in the 10 steroid-independent children decreased slightly at 4 wk and at 8 wk (Table II). By 8 wk, the plasma cortisol concentration had decreased in 7 children who had not previously received continual treatment with steroids. Satisfactory symptomatic control has subsequently been maintained for 8 to 32 mo with doses ranging from 100 pg bid in one child to 300 pg qid in 5 children at least for a few weeks at a time. Plasma cortisol
concentrations determined at 2-mo intervals during the first year and 4-mo intervals after that have continued to show variations from time to time, but have been less than 5 pg% only twice in patients who might have received oral prednisone 24 hr earlier and in whom values of 2.0 and 4.9 pg% increased to 12.8 and 16.3 pg% 4 days later (D. P. and A. R. ). Mean plasma cortisol concentration was not less than 9 pg% after the first 2 mo of treatment except at 28 mo, where data are limited (Table II). Administration of oral prednisone for a few days at a time has been necessary in 2 children, including 1 of the 3 in whom prednisone had been discontinued during the first 8 wk of treatment with triamcinolone acetonide aerosol. The other 2 steroid-dependent children in whom prednisone was discontinued during treatment with triamcinolone acetonide aerosol have received no prednisone for 28 and 30 mo. Continual treatment with oral prednisone at doses of 10 to 40 mg qod became necessary at 5 mo and 3 mo in 2 other children (D. W., D. P.) who were not initially steroiddependent. Triamcinolone acetonide aerosol has been discontinued in 2 patients after treatment for 12 and 27 mo. No side effects have been observed or reported by the patients with the possible exception of two episodes of hoarseness for a few days. Symptoms subsided without treatment. No evidence of candidiasis has been found by physical examination, but no cultures have been obtained in these 15 children. No drug-related changes in blood counts, urinalyses, or blood chemistries have been recognized. Initial chest roentgenograms disclosed only hyperinflation and a generalized slight increase in bronchovascular markings in some children, and subsequent
80 Sly et
al.
gti
J. ALLERGY
CLIN. IMMUNOL. AUGUST 1978
012345678 WEEK
FIG. 4. Mean FEV, in 15 asthmatic children before, during, and after 8 wk of treatment with triamcinolone acetonide aerosol.
films have shown only changesconsistentwith asthma with a single exception. One steroid-dependent15yrold boy developeda right perihilar infiltrate associated with fever and tachypnea and ascribedto pneumonia after he had been receiving treatment with triamcinolone acetonide aerosol for 26 mo and while receiving prednisone, 25 mg qod. He was treated with erythromycin, and the infiltrate cleared within 1 wk. DISCUSSION
Our results agree with many other reports that symptomsof asthmausually can be well controlled by inhalation of certain adrenalcorticosteroids, including beclomethasonedipropionate5* 6 and triamcinolone acetonide.‘-‘“3 15-18It was possible to maintain adequate symptomatic control despite discontinuation of oral prednisoneduring the first 8 wk of therapy with triamcinolone acetonide aerosol in 3 of the 5 steroiddependentchildren, although only modest reductions of dosagewere possible in the other two. Addition of oral prednisone on alternate days did become necessary in 2 of the children who had not initially required continual oral steroid therapy after 3 to 5 mo of treatment with triamcinolone acetonideaerosol. Twelve of the 15 children have required increasesin dosageto 300 pg tid to qid at least once for a few weeks, while adequatecontrol has been maintained at other times with as little as 100 pg bid. It is also known, however, that inhalation of excessive doses of beclomethasonecan cause adrenal suppressionlgor maintain suppressionpreviously induced by oral steroids.2o Inhalation of modest but effective doses of triamcinolone acetonidehas been reported to have no significant effect upon adrenal function as measuredby changesin plasma cortisol concentrations.8-‘2Treatment of steroid-dependent asthmatic patients with triamcinolone acetonide aerosol has usually been found to permit discontinuation of oral steroids or at least a reduction in their dosageoften but not always
I 3 , I 1 012345678 WEEK
,
,
I
FIG. 5. Mean forced expiratory flow at 25%-75% vital capacity in 15 asthmatic children before, during, and after 8 wk of treatment with triamcinolone acetonide aerosol.
associatedwith increasesin plasma cortisol concentrations and increasedadrenal responsivenessto stimulation with cosyntropin.‘3 8, l8 Treatment of patients who had not previously received continual steroid therapy, however, has been reported to cause a decreasedresponseto metyrapone stimulation.8 Morning plasma cortisol concentrationshave been found to correlate well with plasmacortisol responses to hypoglycemia induced by intravenous insulin,“’ and cortisol responsesto induced hypoglycemia have been reported to correlate well with responsesto surgical stress.% The metyraponetest, on the other hand, has sometimes been found to be abnormal even in subjects who can respond normally to stress,“‘, 23 and responsesto metyraponevary, dependingupon how the test is done.24,25Consequently, morning plasma cortisol concentrations probably indicate ability to respond to stressmore accurately. Lower limits of normal for morning plasma cortisol concentrations determined by various methods from different laboratories have usually ranged from 5 pg% to 10 pg%. 3, ‘9 26The mean plasma cortisol concentrationwhich we found in the 10 children who had not previously received continual steroid therapy decreasedslightly from 14.9 pg% to 10 pg% after 8 wk of treatmentwith triamcinolone acetonideaerosol, and this was a statistically significant change (paired t test, p = 0.05), but there was no significant decreasefrom the mean pretreatmentcortisol after 4 and 6 mo of therapy with triamcinolone acetonide aerosol. In a single child (D. C.) plasmacortisol concentrations have remained less than the pretreatment value although they have not been less than 5 pg/dl. Pharyngealand laryngeal candidiaseshave beenreported as complications of inhalation of beclometha-
VOLUME NUMBER
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Triamcinolone
TABLE II. Plasma cortisol concentrations triamcinolone
acetonide
(pgldl)
at 8:00 A.M. in 15 asthmatic
children
acetonide
in children
81
treated with
aerosol Month
Patient
C. D. R. T. D. D. C.
Age (yr)
H. C. J. R. G. P.
D. K. H.
D. W. P. c.
9 6 9 13 10 9 9
II 13 IO
Mean Steroid-dependent 10 N. C. D.A. II 10 A. J. 13 A. R. T. W.
7
0
1
2
4
6
8
10
12
16
20
24
28
32
11.0
34.2 10.6 15.3 13.9 10.7 12.3 9.3 14.9 13.3
8.9 8.7 21.5 8.6 12.0 8.6 10.1 9.1 12.4 16.5
7.2 6.6 14.8 7.6 8.7 12.8 14.9 23.9 9.0 6.9
15.5 7.2 13.9 7.8 14.3 14.2
8.1 11.9 25.2 15.6 8.4 9.1
10.0 7.4 19.7 22.4 8.5 7.7
11.0 5.2 20.9 11.9 18.8 12.6
17.4 5.9 17.0 7.7 14.3
11.9 5.9 24.6 13.3
7.3 6.7 12.8
24.5 15.2
10.0
8.8 7.2 18.0 9.0 10.7 8.6 8.4 11.3 11.8 6.6
10.7 7.6 12.9
14.9
14.5
10.0
11.6
11.2
11.6
13.1
12.6
13.4
12.5
13.9
8.9
19.8
16.7 4.4 15.2 22.2 5.4
7.6 10.5 9.6 2.7 9.4
6.4 13.0 15.4 20.0 8.0
11.2 8.3 12.0 14.2 6.1
13.4 9.3 5.0 18.0 9.6
7.9 8.2 11.6 18.4 14.0
11.9 7.3 16.0 22.6 9.0
5.6 16.8 17.8 11.3 13.9
7.3 8.1 14.7 7.1
7.0 11.8 8.0 16.3
13.3 7.9 12.1 5.1
7.0 9.1 7.9 9.7
12.4
12.8
8.0
12.6
10.4
11.1
12.0
13.4
13.1
9.3
10.8
9.6
8.4
13.1
16.0 29.8 11.8 8.2 5.6 27.4 17.8 10.5 10.9
sone dipropionate, but this has usually occurred in patients who have also been receiving oral corticosteroids.27 This complication has rarely been found in patients treated with triamcinolone acetonide aerosol and was not detected among our patients by physical examination. It is concluded that triamcinolone acetonide aerosol is effective in the treatment of asthmatic children at doses which do not cause substantial adrenal suppression. SUMMARY Triamcinolone acetonide aerosol, 100 pg qid, was administered for 8 wk to 15 asthmatic children, including 5 who had previously required continual treatment with oral prednisone or prednisolone, 10 to 30 mg qod for 6 to 92 mo. Symptomatic control and pulmonary function improved in all 15 children despite gradual reduction in dosage of oral corticosteroids and their discontinuation in 3 children. Morning plasma cortisol concentrations increased in 2 steroid-dependent children and decreased in 1 steroid-dependent child and in 5 children who were not steroid-dependent, but the lowest plasma cortisol concentration at 8 wk was 6.4 pg%. Satisfactory symptomatic control has subsequently been maintained for 8 to 32 mo with doses of 100 lug bid to 300 pg qid without more extreme changes in plasma cortisol concentrations.
13.8
Triamcinolone acetonide aerosol is effective in the treatment of asthmatic children at doses which do not cause substantial adrenal suppression. We wish to express our appreciation to Mr. William Johnson, Assistant Professor of Biometry, LSU Medical Center, for assistance with the statistical analyses. REFERENCES 1. Siegel, S. C.: ACTH and the corticosteroids in the management of allergic disorders in children, J. Pediatr. 66:927, 1965. 2. Easton, J. G., Busser, R. J., and Heimlich, E. M.: Effect of alternate-day steroid administration on adrenal function in allergic children, J. ALLERGY CLIN. IMMUNOL. 48:355, 1971. 3. Morris, H. G., Neuman, I., and Ellis, E. F.: Plasma steroid concentrations during alternate-day treatment with prednisone, J. ALLERGY CLIN. IMMUNOL. 54:350, 1974. 4. Siegel, S. C., Heimlich, E. M., Richards, W., and Kelley, V. C.: Adrenal function in allergy. IV. Effect of dexamethasone aerosols in asthmatic children, Pediatrics 33:245, 1964. 5. Brown, H. M., Storey, G., and George, W. H. S.: Beclomethasone dipropionate: A new steroid aerosol for the treatment of allergic asthma, Br. Med. J. 1:585, 1972. 6. Klein, R., Waldman, D., Kershnar, H., Berger, W., Co&on, A., Katz, R. M., Rachelefsky, G. S., and Siegel, S. C.: Treatment of chronic childhood asthma with beclomethasonedipropionate aerosol. I. A double-Und crossover trial in nonsteroid-dependent patients, Pediatrics 60~7, 1977. 7. Falliers, C. J.: Triamcinolone acetonide aerosols for asthma. I. Effective replacement of systemic corticosteroid therapy, J. ALLERGY CLIN. IMMUNOL. 57:I. 1976. 8. Webb, D. R.: Triamcinolone acetonide by aerosol for chronic
82
Sly et al.
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bronchial asthma: Effects on adrenal function, J. ALLERGY CLIN. IMMLJNOL. 57~257, 1976. 9. Chervinsky, P.: A double-blind evaluation of triamcinolone acetonide aerosol in steroid independent patients with bronchial asthma, Ann. Allergy 39~7 1, 1977. 10. Falliers, C. J., Kennedy, P. A., Petraco, A. J., and Vrchota, J. A.: Triamcinolone acetonide aerosols for asthma. Ill. A double-blind confirmation of long-term efficacy, Ann. Allergy 39:71, 1977. 11. Boldon, D. P., Rodriguez, G. E., Megathlin, K. N., Massie, F. S., and Mollen, E. L.: Long-term treatment of severe childhood asthma with triamcinolone acetonide aerosol, Ann. Allergy 3971, 1977. 12. Chervinsky, P.: Treatment of steroid-dependent asthma with triamcinolone acetonide aerosol, Ann. Allergy 38: 192, 1977. 13. Silber, R. H., Busch, R. D., and Oslapas, R.: Practical procedure for estimation of corticosterone or hydrocortisone, Clin. Chem. 4~278, 1958. 14. Mattingly, D., Dennis, P. M., Pearson, J., and Cope, C. L.: Rapid screening test for adrenal cortical function, Lancet 2: 1046,1964. 1.5. Williams, M. H., Jr., Kane, C., and Shim, C. S.: Treatment of asthma with triamcinolone acetonide delivered by aerosol, Am. Rev. Respir. Dis. 109r538, 1974. 16. Williams, M. H., Jr.: Treatment of asthma with triamcinolone acetonide aerosol, Chest 68~765, 1975. 17. Kriz, R. J., Chmelik, F., doPico, G., and Reed, C. E.: A short-term double-blind trial of aerosol triamcinolone acetonide in steroid-dependent patients with severe asthma, Chest 69:455, 1976. 18. Kriz, R. J., Chmelik, F., doPico, G., and Reed, C. E.: A oneyear trial of mamcinolone acetonide aerosol in severe steroiddependent asthma, Chest 72:36, 1977.
Information
CLIN. IMMUNOL. AUGUST 1978
19. Choo-Kang, Y. F. J., Cooper, E. J., Tribe, A. E., and Grant, I. W. B.: Beclomethasone dipropionate by inhalation in the treatment of airways obstruction, Br. J. Dis. Chest f&101, 1972. 20. Toogood, J., Lefcoe, N., Haines, D. S. M., Jennings, B., Errington, N., and Chuang, L.: Prolonged high-dose beclomethasone aerosol therapy of asthma, Ann. Allergy 3970, 1977. 21. Morris, H. G., and Jorgensen, J. R.: Recovery of endogenous pituitary-adrenal function in corticosteroid-treated children, Pediatrics 79:480, 197 1. 22. Plumpton, F. S., and Besser, G. M.: The adrenocortical response to surgery and insulin induced hypoglycemia in corticosteroid-treated and normal subjects, Br. J. Surg. 56:216, 1969. 23. Liddle, G. W., Estep, H. L., Kendall, J. W., Jr., Williams, W. C., Jr., and Townes, A. W.: Clinical application of a new test of pituitary reserve, J. Clin. Endocrinol. Metab. 19~875, 1959. 24. Spark, R. F.: Simplified assessment of pituitary-adrenal reserve, Ann. Intern. Med. 75:717, 1971. 25. Meikle, A. W., West, S. C., Weed, J. A., and Tyler, F. H.: Single dose metyrapone test. I lp-hydroxylase inhibition by metyrapone and reduced metyrapone assayed by radioimmunoassay, J. Clin. Endocrinol. Metab. 40:290, 1975. 26. Champion, P., MacLean, L., and Chan-Yeung, M.: Beclomethasone dipropionate in asthma, Can. Med. Assoc. J. 113:213, 1975. 27. Cayton, R. M., Sontar, C. A., Stanford, C. F., Turner, G. C., and Nun”, A. J.: Double-blind trial comparing two dosage schedules of beclomethasone dipropionate aerosol in the treatment of chronic bronchial asthma, Lancet 2~303, 1974.
for authors
Most of the provisions of the Copyright Act of 1976 became effective on January 1, 1978. Therefore, all manuscripts must be accompanied by the following statement, signed by each author: “The undersigned author(s) transfers all copyright ownership of the manuscript entitled (title of article) to The C. V. Mosby Company in the event the work is published. The author(s) warrants that the article is original, is not under consideration by another journal, and has not been previously published. ” Authors will be consulted, when possible, regarding republication of their material.
Triamcinolone acetonide aerosol, 100 pg qid, was administered for 8 wk to 5 steroid-dependent asthmatic children and IO who had not previously required continual corticosteroid treatment. Symptomatic control and pulmonary function improved in all 15 children despite discontinuation of oral corticosteroids in 3 of the steroid-dependent children. Determination of morning plasma cortisol concentrations disclosed no evidence of substantial adrenal suppression. Satisfactory symptomatic control has subsequently been maintained for 6 to 32 mo with doses of 100 pg bid to 300 pg qid without more extreme changes in plasma cortisol concentrations than were observed during the jrst 8 wk.
Systemic adrenal corticosteroids are very effective in the treatment of asthma, but their use has been limited by numerous side effects, including suppression of the hypothalamic-pituitary-adrenal axis. l The extent and frequency of adrenal suppression and other side effects of continual treatment with corticosteroids can be reduced by oral administration of a steroid with intermediate duration of activity, such as prednisone, prednisolone, or methyl prednisolone, as a single morning dose on alternate days, but some adrenal suppression can occur in some patients despite this precaution.2, 3 Administration of steroids by inhalation has been investigated as a possible method of reducing the dosage necessary for control of asthmatic symptoms to one which would not cause adrenal suppression. Inhalation of dexamethasone four times each day at doses which usually have achieved symptomatic control has been found also to cause significant adrenal suppression. 4 More recently, inhalation of beclomethasone dipropionate5, 6 or triamcinolone acetonide’-l2 has been found often to afford adequate control of asthma at doses which cause no significant adrenal suppression. Triamcinolone acetonide, 9o-fluoro-1 l/3, 21-dihydroxy- 16a, 17o+isopropylidenedioxy- 1, 4-pregnadiene-3, 20-dione, is a nonpolar compound insoluble in From the Department
of Pediatrics,
Louisiana
State University
Medical Center. Received for publication Dec. 14, 1977. Accepted for publication March 6, 1978. Reprint requests to: Dr. R. Michael Sly, Director of Allergy Immunology, Childrens Hospital National Medical Center, Michigan Ave., N. W., Washington, D. C. 20010.
Vol. 62, No. 2, pp. 76-82
and 111
water. It is micronized and aerosolized as a fine suspension with dichlorodifluoromethane (Freon 12) as propellant and 1% alcohol USP. Particle size is estimated to be 1 to 5 p in diameter. The drug is delivered from a collapsible aerosol unit designed to minimize deposition in the mouth by reducing the momentum of the aerosol, directing it away from the roof and sides of the mouth, and by favoring complete vehicle volatilization to assure delivery of dry particles (Fig. 1). Each actuation is estimated by the manufacturer to deliver 200 pg triamcinolone acetonide from the cartridge and 100 pg to the patient. PILOT STUDY Five asthmatic children, aged 8 to 12 yr, including 4 boys and 1 girl, were selected for a preliminary 4wk study because of the presence of severe chronic asthma necessitating continual treatment with oral prednisone or prednisolone, 10 to 30 mg, as a single morning dose on alternate days. After informed consent, each received triamcinolone acetonide aerosol, 100 s qid, in addition to the oral corticosteroid and usual bronchodilators for the first week. Oral steroid dosage was then gradually decreased and discontinued after 6 to 20 days while administration of triamcinolone acetonide aerosol was continued. It was possible to decrease the dosage of triamcinolone acetonide aerosol to 50 @ qid* in one child but it was necessary to increase it in another to 200 e qid *Possible because of an earlier cannister from which each actuation released 100 ccg of which an estimated 50 pg was delivered to the patients.
0091-6749/78/0262-0076$00.70/O 0 1978 The C. V. Mosby Co.
VOLUME NUMBER
62 2
Triamcinolone
ACTUATOR
acetonide
in children
77
CHANNEL
COVER -CARTRIDGE ACiUATOR
BAR’REL
u ACTUATOR 3
BARREL
II
MOUTHPIECE OVER ON
WITH
(Remove
Cover)
FIG. 1. Collapsible actuator-adaptor for delivery of triamcinolone acetonide aerosol. After shaking well the cartridge is inserted into the actuator, 1. The barrel is then fully extended,2, and the actuator is bent upward at a right angle to the barrel, 3. After removal of the mouthpiece cover the unit is ready for use.
in adjusting the dose to the minimal amount which maintained adequate clinical control during the 4 wk. Fasting plasma cortisol concentrations were measured at 9:00 A. M. and 30 min after the intramuscular injection of cosyntropin, 0.25 mg, both before treatment with triamcinolone acetonide and after 4 wk of treatment. Throat cultures for Cundida albicuns were obtained before treatment and after 4 wk of treatment. Measurement of forced vital capacity, forced expiratory volume in one second, and flow rates at 25% and 50% vital capacity after all medications had been withheld for 8 hr before treatment with triamcinolone acetonide aerosol and at weekly intervals disclosed no significant changes (one-way analysis of variance). Peak expiratory flow rate was measured 3 times each day, and there was no significant change in mean daily readings during the 4 wk (one-way analysis of variance). Comparison of 9:00 A.M. plasma cortisol concentrations before and after 4 wk of treatment with triamcinolone acetonide aerosol disclosed substantial increases to normal in two children whose initial values indicated adrenal suppression and a decrease in another, whose response to stimulation with intramuscular injection of cosyntropin improved (Table I). Throat cultures obtained for Cundidu were positive in 2 patients before treatment with triamcinolone acetonide aerosol but negative after 4 wk of treatment. A positive culture was found after treatment in another patient whose initial culture had been negative. Cultures were negative both before and after treatment in the other two children. There was no clinical
evidence of candidiasis at any time in any of the children. Thus, treatment with triamcinolone acetonide aerosol made it possible to discontinue oral corticosteroids in all five children without significant changes in pulmonary function or evidence of consequent adrenal suppression. Because of these encouraging results another study was designed to investigate further the safety and efficacy of triamcinolone acetonide aerosol in asthmatic children.
MATERIALS AND METHODS Patients Fifteen asthmatic children, aged 6 to 13 yr, including 10 boys and 5 girls, were selected for study because of the presence of severe, chronic asthma requiring continual treatment with oral bronchodilators, 5 having required continual treatment with oral prednisone or prednisolone for 6 to 92 mo at doses of 10 to 30 mg on alternate days. These steroid-dependent children had been examined at l4-wk intervals and had been receiving the lowest dose of steroids which afforded satisfactory symptomatic control as determined by frequent attempts to reduce the dosage. Some of the children who were not receiving corticosteroids had received them intermittently for a few days at a time in the past, but they had received none during the previous month. Four of the children were also receiving cromolyn; the others had failed to respond to cromolyn in the past. None of those receiving cromolyn had received it for less than 4 months. Reversibility of bronchospasm was demonstrated in all children by increases of at least 15% in forced expiratory
78 Sly et al.
J. ALLERGY
TABLE I. Plasma cortisol
concentrations (pgldl) at 9:00 A.M. in 5 steroid-dependent asthmatic children before and after 4 wk of treatment with triamcinolone acetonide aerosol and 30 min after injection of cosyntropin Before treatment
Patient
After treatment
Baseline
After stimulation
Baseline
After stimulation
15.8 16.2 5.2 4.2 0 8.3
29.3 20.9 27.0 20.8 20.0 23.6
13.4 9.2 7.3 9.5 9.5 9.3
27.0 30.3 30.1 29.1 27.3 28.8
1 2 3 4 5 Mean
volume in one second (FEV,) following inhalation of isoproterenol or subcutaneousinjection of 1: 1,000 aqueous epinephrine. All children had peripheral eosinophilia and most had nasal eosinophilia. All had positive immediate wheal-andflare reactions to several inhalant allergens following scratch or intradermal testing. All had positive immediate family histories for atopic diseases.The only one with a history of aspirin intolerance was a 6-yr-old boy who had had generalizedurticaria following administration of aspirin as an infant. None of the children was known to have tuberculosis, diabetes mellitus, or cardiovascular, renal, or hepatic disease.
CLIN. IMMUNOL. AUGUST 1978
this was done 48 hr after the last dose of oral steroids. Venous blood was drawn at 8:00 A.M. and immediately immersedin an ice bath. Plasma was separatedwithin 30 min, and cortisol was then determinedin duplicate samples by the tluorometric method of Silber and co-workers with somemodifications.r3-i4 Plasma,0.1 to 1.Oml, was diluted to 2.0 ml with distilled water before extraction. Two cortisol standard solutions were used through the entire procedure. Individual readings were taken at I-min intervals 40 min after the addition of methylene chloride extract to the fluorescent reagent. Maximum fluorescence was obtained on the Aminco-Bowman spectrophotofluorometer with metermultiplier, 0.3, primary filter, 480 rnp, secondary filter, 530 rnp. Blood counts with differentials, urinalyses, and determinations of fasting blood sugar, blood urea nitrogen, alkaline phosphatase, serum glutamic oxaloacetic transaminase @GOT), serum calcium, phosphorus, sodium, potassium, and chloride were obtained before treatment and at 4 and 8 wk. Chest roentgenogramswere obtained before treatment. Continued
treatment
Following the initial 8 wk of treatment with triamcinolone acetonideaerosol, therapy was continued with variations in dosageas indicated by responsebut not exceeding 1,200 pg/day. Children were re-examined and pulmonary function retested at 1 to 2-mo intervals. Plasma cortisol was measuredat 2-mo intervals during the first year and 4mo intervals after that. Other laboratory testswere repeated at 6-mo intervals. Chest roentgenogramswere obtained again at 1 yr. RESULTS
Methods One week before treatment was startedparents began a daily diary of symptoms and medications. After informed consent, each child received triamcinolone acetonide aerosol,* 100 M qid for 8 wk. Bronchodilators and cromolyn were continued. After the first week, prednisoneor prednisolone dosagewas decreasedby 5 mg every other day each week if tolerated. Daily symptom and medication diaries were continued. Medical histories, physical examinations, and pulmonary function testing, including determination of forced vital capacity (FVC), FEVi, and forced expiratory flow at 25%-75% vital capacity (FEFZ5%-,&, were repeatedat weekly intervals. All medications were withheld for at least 6 hr before pulmonary function testing and physical examination ( 12 hr for sustained-release theophylline preparations). Oral corticosteroids were withheld for 24 or 48 hr before assessments. Laboratory
studies
Plasma cortisol concentrations were determined before treatment with triamcinolone acetonideaerosol and after 4 and 8 wk of treatment. In the steroid-dependentchildren *Supplied as Aristocort Aerosol by Dr. Paul A. Kennedy, Jr., Lederle Laboratories, Pearl River, N. Y.
Symptomatic control improved in all 15 children despite a decrease in the use of bronchodilators in 7. Brochodilator usage increased slightly in 3 children and remained unchanged in 5 during the eight weeks. The severity of wheezing reported by patients and parents tended to decrease during the eight WC&S (Fig. 2). None was free of wheezing during the we& before treatment was started, but 7 reported no whcczing during the eighth week. The total number of nights that the children were awakened by wheezing decreased from 25 during the week before treatnmt to 1 during the eighth week (Fig. 3). Pulmonary function after medications had been withheld at least 6 hr improved at some time in all 15 children, but was not improved in every child at each week (Figs. 4 and 5). Paired t tests disclosed that differences from the week before treatment were significant for weeks 2 (FVC, FEVr), 3 (FVC), and 8 (FVC, FEV1, FEFzs%-r5%), as well as 4 months (FVC, FEVr) and 6 months (FVC). Treatment with ttiamcinolone acetonide aerosd permitted discontinuation of oral corticosteroids in 3 of the 5 steroid-dependent children. These three had
VOLUME 62 NUMBER 2
Triamcinolone
acetonide
in children
79
8
NMiMSVS
NMiMS
NMiMS
NMiMS
0
I
2
3
Vs
NMiMSVS
4 N Mi M S VS
= None = Mild = Moderate = Severe = Very Severe
N=15 NMiM
5
S
6
7
8
012345678 WEEK
WEEK FIG. 2. Severity of wheezing in 15 asthmatic children the week before treatment and during and after 8 wk of treatment with triamcinolone acetonide aerosol.
FIG. 3. Total number of nights 15 asthmatic children were awakened by wheezing the week before treatment and during and after 8 wk of treatment with triamcinolone acetonide aerosol.
been receiving prednisone continually for 6,9, and 29 mo and were receiving 10, 25, and 20 mg qod, respectively, when admitted to the study t.T. W., A. J., N. C. ). The two other steroid-dependent children had received prednisolone or prednisone for 5% to 7% yr and were receiving 20 to 30 mg qod before treatment with triamcinolone acetonide. by 8 wk it was possible to reduce their oral steroid dosage to 15 and 20 mg qod, respectively. A slight decrease in mean plasma cortisol concentration was found after 4 wk of treatment in the steroid-dependent children, but this was not statistically significant. This was partly due to an extreme decrease in one boy from 22.2 pg% to 2.7 pg%, but his cortisol concentration was 20 pg% at 8 wk and it was suspected that the specimen obtained at 4 wk might have been drawn 24 hr rather than 48 hr after his dose of 22.5 mg prednisone. Mean plasma cortisol concentration at 8 wk was unchanged from the pretreatment value for the steroid-dependent children (Table II). By 8 wk, plasma cortisol concentrations had increased in 2 steroid-dependent children, including one who was still receiving oral prednisolone, and decreased to 6.4 pg% in one in whom prednisone had been discontinued (Table II). The mean plasma cortisol concentration in the 10 steroid-independent children decreased slightly at 4 wk and at 8 wk (Table II). By 8 wk, the plasma cortisol concentration had decreased in 7 children who had not previously received continual treatment with steroids. Satisfactory symptomatic control has subsequently been maintained for 8 to 32 mo with doses ranging from 100 pg bid in one child to 300 pg qid in 5 children at least for a few weeks at a time. Plasma cortisol
concentrations determined at 2-mo intervals during the first year and 4-mo intervals after that have continued to show variations from time to time, but have been less than 5 pg% only twice in patients who might have received oral prednisone 24 hr earlier and in whom values of 2.0 and 4.9 pg% increased to 12.8 and 16.3 pg% 4 days later (D. P. and A. R. ). Mean plasma cortisol concentration was not less than 9 pg% after the first 2 mo of treatment except at 28 mo, where data are limited (Table II). Administration of oral prednisone for a few days at a time has been necessary in 2 children, including 1 of the 3 in whom prednisone had been discontinued during the first 8 wk of treatment with triamcinolone acetonide aerosol. The other 2 steroid-dependent children in whom prednisone was discontinued during treatment with triamcinolone acetonide aerosol have received no prednisone for 28 and 30 mo. Continual treatment with oral prednisone at doses of 10 to 40 mg qod became necessary at 5 mo and 3 mo in 2 other children (D. W., D. P.) who were not initially steroiddependent. Triamcinolone acetonide aerosol has been discontinued in 2 patients after treatment for 12 and 27 mo. No side effects have been observed or reported by the patients with the possible exception of two episodes of hoarseness for a few days. Symptoms subsided without treatment. No evidence of candidiasis has been found by physical examination, but no cultures have been obtained in these 15 children. No drug-related changes in blood counts, urinalyses, or blood chemistries have been recognized. Initial chest roentgenograms disclosed only hyperinflation and a generalized slight increase in bronchovascular markings in some children, and subsequent
80 Sly et
al.
gti
J. ALLERGY
CLIN. IMMUNOL. AUGUST 1978
012345678 WEEK
FIG. 4. Mean FEV, in 15 asthmatic children before, during, and after 8 wk of treatment with triamcinolone acetonide aerosol.
films have shown only changesconsistentwith asthma with a single exception. One steroid-dependent15yrold boy developeda right perihilar infiltrate associated with fever and tachypnea and ascribedto pneumonia after he had been receiving treatment with triamcinolone acetonide aerosol for 26 mo and while receiving prednisone, 25 mg qod. He was treated with erythromycin, and the infiltrate cleared within 1 wk. DISCUSSION
Our results agree with many other reports that symptomsof asthmausually can be well controlled by inhalation of certain adrenalcorticosteroids, including beclomethasonedipropionate5* 6 and triamcinolone acetonide.‘-‘“3 15-18It was possible to maintain adequate symptomatic control despite discontinuation of oral prednisoneduring the first 8 wk of therapy with triamcinolone acetonide aerosol in 3 of the 5 steroiddependentchildren, although only modest reductions of dosagewere possible in the other two. Addition of oral prednisone on alternate days did become necessary in 2 of the children who had not initially required continual oral steroid therapy after 3 to 5 mo of treatment with triamcinolone acetonideaerosol. Twelve of the 15 children have required increasesin dosageto 300 pg tid to qid at least once for a few weeks, while adequatecontrol has been maintained at other times with as little as 100 pg bid. It is also known, however, that inhalation of excessive doses of beclomethasonecan cause adrenal suppressionlgor maintain suppressionpreviously induced by oral steroids.2o Inhalation of modest but effective doses of triamcinolone acetonidehas been reported to have no significant effect upon adrenal function as measuredby changesin plasma cortisol concentrations.8-‘2Treatment of steroid-dependent asthmatic patients with triamcinolone acetonide aerosol has usually been found to permit discontinuation of oral steroids or at least a reduction in their dosageoften but not always
I 3 , I 1 012345678 WEEK
,
,
I
FIG. 5. Mean forced expiratory flow at 25%-75% vital capacity in 15 asthmatic children before, during, and after 8 wk of treatment with triamcinolone acetonide aerosol.
associatedwith increasesin plasma cortisol concentrations and increasedadrenal responsivenessto stimulation with cosyntropin.‘3 8, l8 Treatment of patients who had not previously received continual steroid therapy, however, has been reported to cause a decreasedresponseto metyrapone stimulation.8 Morning plasma cortisol concentrationshave been found to correlate well with plasmacortisol responses to hypoglycemia induced by intravenous insulin,“’ and cortisol responsesto induced hypoglycemia have been reported to correlate well with responsesto surgical stress.% The metyraponetest, on the other hand, has sometimes been found to be abnormal even in subjects who can respond normally to stress,“‘, 23 and responsesto metyraponevary, dependingupon how the test is done.24,25Consequently, morning plasma cortisol concentrations probably indicate ability to respond to stressmore accurately. Lower limits of normal for morning plasma cortisol concentrations determined by various methods from different laboratories have usually ranged from 5 pg% to 10 pg%. 3, ‘9 26The mean plasma cortisol concentrationwhich we found in the 10 children who had not previously received continual steroid therapy decreasedslightly from 14.9 pg% to 10 pg% after 8 wk of treatmentwith triamcinolone acetonideaerosol, and this was a statistically significant change (paired t test, p = 0.05), but there was no significant decreasefrom the mean pretreatmentcortisol after 4 and 6 mo of therapy with triamcinolone acetonide aerosol. In a single child (D. C.) plasmacortisol concentrations have remained less than the pretreatment value although they have not been less than 5 pg/dl. Pharyngealand laryngeal candidiaseshave beenreported as complications of inhalation of beclometha-
VOLUME NUMBER
62 2
Triamcinolone
TABLE II. Plasma cortisol concentrations triamcinolone
acetonide
(pgldl)
at 8:00 A.M. in 15 asthmatic
children
acetonide
in children
81
treated with
aerosol Month
Patient
C. D. R. T. D. D. C.
Age (yr)
H. C. J. R. G. P.
D. K. H.
D. W. P. c.
9 6 9 13 10 9 9
II 13 IO
Mean Steroid-dependent 10 N. C. D.A. II 10 A. J. 13 A. R. T. W.
7
0
1
2
4
6
8
10
12
16
20
24
28
32
11.0
34.2 10.6 15.3 13.9 10.7 12.3 9.3 14.9 13.3
8.9 8.7 21.5 8.6 12.0 8.6 10.1 9.1 12.4 16.5
7.2 6.6 14.8 7.6 8.7 12.8 14.9 23.9 9.0 6.9
15.5 7.2 13.9 7.8 14.3 14.2
8.1 11.9 25.2 15.6 8.4 9.1
10.0 7.4 19.7 22.4 8.5 7.7
11.0 5.2 20.9 11.9 18.8 12.6
17.4 5.9 17.0 7.7 14.3
11.9 5.9 24.6 13.3
7.3 6.7 12.8
24.5 15.2
10.0
8.8 7.2 18.0 9.0 10.7 8.6 8.4 11.3 11.8 6.6
10.7 7.6 12.9
14.9
14.5
10.0
11.6
11.2
11.6
13.1
12.6
13.4
12.5
13.9
8.9
19.8
16.7 4.4 15.2 22.2 5.4
7.6 10.5 9.6 2.7 9.4
6.4 13.0 15.4 20.0 8.0
11.2 8.3 12.0 14.2 6.1
13.4 9.3 5.0 18.0 9.6
7.9 8.2 11.6 18.4 14.0
11.9 7.3 16.0 22.6 9.0
5.6 16.8 17.8 11.3 13.9
7.3 8.1 14.7 7.1
7.0 11.8 8.0 16.3
13.3 7.9 12.1 5.1
7.0 9.1 7.9 9.7
12.4
12.8
8.0
12.6
10.4
11.1
12.0
13.4
13.1
9.3
10.8
9.6
8.4
13.1
16.0 29.8 11.8 8.2 5.6 27.4 17.8 10.5 10.9
sone dipropionate, but this has usually occurred in patients who have also been receiving oral corticosteroids.27 This complication has rarely been found in patients treated with triamcinolone acetonide aerosol and was not detected among our patients by physical examination. It is concluded that triamcinolone acetonide aerosol is effective in the treatment of asthmatic children at doses which do not cause substantial adrenal suppression. SUMMARY Triamcinolone acetonide aerosol, 100 pg qid, was administered for 8 wk to 15 asthmatic children, including 5 who had previously required continual treatment with oral prednisone or prednisolone, 10 to 30 mg qod for 6 to 92 mo. Symptomatic control and pulmonary function improved in all 15 children despite gradual reduction in dosage of oral corticosteroids and their discontinuation in 3 children. Morning plasma cortisol concentrations increased in 2 steroid-dependent children and decreased in 1 steroid-dependent child and in 5 children who were not steroid-dependent, but the lowest plasma cortisol concentration at 8 wk was 6.4 pg%. Satisfactory symptomatic control has subsequently been maintained for 8 to 32 mo with doses of 100 lug bid to 300 pg qid without more extreme changes in plasma cortisol concentrations.
13.8
Triamcinolone acetonide aerosol is effective in the treatment of asthmatic children at doses which do not cause substantial adrenal suppression. We wish to express our appreciation to Mr. William Johnson, Assistant Professor of Biometry, LSU Medical Center, for assistance with the statistical analyses. REFERENCES 1. Siegel, S. C.: ACTH and the corticosteroids in the management of allergic disorders in children, J. Pediatr. 66:927, 1965. 2. Easton, J. G., Busser, R. J., and Heimlich, E. M.: Effect of alternate-day steroid administration on adrenal function in allergic children, J. ALLERGY CLIN. IMMUNOL. 48:355, 1971. 3. Morris, H. G., Neuman, I., and Ellis, E. F.: Plasma steroid concentrations during alternate-day treatment with prednisone, J. ALLERGY CLIN. IMMUNOL. 54:350, 1974. 4. Siegel, S. C., Heimlich, E. M., Richards, W., and Kelley, V. C.: Adrenal function in allergy. IV. Effect of dexamethasone aerosols in asthmatic children, Pediatrics 33:245, 1964. 5. Brown, H. M., Storey, G., and George, W. H. S.: Beclomethasone dipropionate: A new steroid aerosol for the treatment of allergic asthma, Br. Med. J. 1:585, 1972. 6. Klein, R., Waldman, D., Kershnar, H., Berger, W., Co&on, A., Katz, R. M., Rachelefsky, G. S., and Siegel, S. C.: Treatment of chronic childhood asthma with beclomethasonedipropionate aerosol. I. A double-Und crossover trial in nonsteroid-dependent patients, Pediatrics 60~7, 1977. 7. Falliers, C. J.: Triamcinolone acetonide aerosols for asthma. I. Effective replacement of systemic corticosteroid therapy, J. ALLERGY CLIN. IMMUNOL. 57:I. 1976. 8. Webb, D. R.: Triamcinolone acetonide by aerosol for chronic
82
Sly et al.
J. ALLERGY
bronchial asthma: Effects on adrenal function, J. ALLERGY CLIN. IMMLJNOL. 57~257, 1976. 9. Chervinsky, P.: A double-blind evaluation of triamcinolone acetonide aerosol in steroid independent patients with bronchial asthma, Ann. Allergy 39~7 1, 1977. 10. Falliers, C. J., Kennedy, P. A., Petraco, A. J., and Vrchota, J. A.: Triamcinolone acetonide aerosols for asthma. Ill. A double-blind confirmation of long-term efficacy, Ann. Allergy 39:71, 1977. 11. Boldon, D. P., Rodriguez, G. E., Megathlin, K. N., Massie, F. S., and Mollen, E. L.: Long-term treatment of severe childhood asthma with triamcinolone acetonide aerosol, Ann. Allergy 3971, 1977. 12. Chervinsky, P.: Treatment of steroid-dependent asthma with triamcinolone acetonide aerosol, Ann. Allergy 38: 192, 1977. 13. Silber, R. H., Busch, R. D., and Oslapas, R.: Practical procedure for estimation of corticosterone or hydrocortisone, Clin. Chem. 4~278, 1958. 14. Mattingly, D., Dennis, P. M., Pearson, J., and Cope, C. L.: Rapid screening test for adrenal cortical function, Lancet 2: 1046,1964. 1.5. Williams, M. H., Jr., Kane, C., and Shim, C. S.: Treatment of asthma with triamcinolone acetonide delivered by aerosol, Am. Rev. Respir. Dis. 109r538, 1974. 16. Williams, M. H., Jr.: Treatment of asthma with triamcinolone acetonide aerosol, Chest 68~765, 1975. 17. Kriz, R. J., Chmelik, F., doPico, G., and Reed, C. E.: A short-term double-blind trial of aerosol triamcinolone acetonide in steroid-dependent patients with severe asthma, Chest 69:455, 1976. 18. Kriz, R. J., Chmelik, F., doPico, G., and Reed, C. E.: A oneyear trial of mamcinolone acetonide aerosol in severe steroiddependent asthma, Chest 72:36, 1977.
Information
CLIN. IMMUNOL. AUGUST 1978
19. Choo-Kang, Y. F. J., Cooper, E. J., Tribe, A. E., and Grant, I. W. B.: Beclomethasone dipropionate by inhalation in the treatment of airways obstruction, Br. J. Dis. Chest f&101, 1972. 20. Toogood, J., Lefcoe, N., Haines, D. S. M., Jennings, B., Errington, N., and Chuang, L.: Prolonged high-dose beclomethasone aerosol therapy of asthma, Ann. Allergy 3970, 1977. 21. Morris, H. G., and Jorgensen, J. R.: Recovery of endogenous pituitary-adrenal function in corticosteroid-treated children, Pediatrics 79:480, 197 1. 22. Plumpton, F. S., and Besser, G. M.: The adrenocortical response to surgery and insulin induced hypoglycemia in corticosteroid-treated and normal subjects, Br. J. Surg. 56:216, 1969. 23. Liddle, G. W., Estep, H. L., Kendall, J. W., Jr., Williams, W. C., Jr., and Townes, A. W.: Clinical application of a new test of pituitary reserve, J. Clin. Endocrinol. Metab. 19~875, 1959. 24. Spark, R. F.: Simplified assessment of pituitary-adrenal reserve, Ann. Intern. Med. 75:717, 1971. 25. Meikle, A. W., West, S. C., Weed, J. A., and Tyler, F. H.: Single dose metyrapone test. I lp-hydroxylase inhibition by metyrapone and reduced metyrapone assayed by radioimmunoassay, J. Clin. Endocrinol. Metab. 40:290, 1975. 26. Champion, P., MacLean, L., and Chan-Yeung, M.: Beclomethasone dipropionate in asthma, Can. Med. Assoc. J. 113:213, 1975. 27. Cayton, R. M., Sontar, C. A., Stanford, C. F., Turner, G. C., and Nun”, A. J.: Double-blind trial comparing two dosage schedules of beclomethasone dipropionate aerosol in the treatment of chronic bronchial asthma, Lancet 2~303, 1974.
for authors
Most of the provisions of the Copyright Act of 1976 became effective on January 1, 1978. Therefore, all manuscripts must be accompanied by the following statement, signed by each author: “The undersigned author(s) transfers all copyright ownership of the manuscript entitled (title of article) to The C. V. Mosby Company in the event the work is published. The author(s) warrants that the article is original, is not under consideration by another journal, and has not been previously published. ” Authors will be consulted, when possible, regarding republication of their material.
