IV. Effect
of
Dexamethasone
Aerosols
in Asthmatic
Children
Sheldon C. Siegel, M.D., Ernest M. Heimlich, M.D., Warren Richards, M.D.,
and Vincent C. Kelley, M.D., Ph.D.
Children’s Medical Group, Los Angeles, Harbor General Hospital, Torrance, California, Department of
Pediatrics, University of Washington, and Department of Pediatrics, University of California at Los Angeles
(Submitted June 3; accepted for publication July 3, 1963.)
This research was supported in part by grants from the Harbor General Hospital Attending Staff
Asso-ciation and the Merck, Sharp, and Dohme Co.
ADDRESS: (S.C.S.) Childrens Medical Group, 5830 Overhill Drive, Los Angeles 43, California.
PEDIVIIHCS, February 1984
ADRENAL
FUNCTION
IN
ALLERGY
245
DRENOCORTICOT1IOPIN (AGTH) and the
glucorticosteroids have become
rec-ognized as potent antiallergic therapeutic agents. However, their use has been limited by the serious untoward effects which
fre-quently result from their prolonged
admin-istration. Attempts to circumvent these un-desirable side-effects through the develop-ment of new steroid compounds or by vary-ing tile regimen of steroid administration
(
such as intermittent therapy) have beenonly partially successful.1 Because compli-cations of steroid therapy are in large part related to the quantity and duration of steroid administration, a means of admin-istenillg steroids which would materially re-duce tile amount of drug necessary to
con-trol symptoms could theoretically obviate them.
In recent years newer steniods have been synthesized which exert greater topical anti-inflammatory activity on a milligram basis than does cortisol. One such steroid is dexa-methasone. Because of its enhanced topical anti-inflamnlatory capacities, it was postu-lated tilat dexamethasone when adminis-tered by aerosol might exert antiasthmatic activity at doses sufficiently low to obviate systemic side-effects. Since it has been dem-onstrated that relatively small quantities administered systemically produce marked adrenal suppression in 24 to 48 hours, the measurement of adrenocortical function in children receiving aerosols of
dexametha-sone was chosen as a sensitive index of whether sufficient quantities of the drug
would be absorbed to produce systemic
side-effects.2
The purpose of the present investigation was, therefore, (1) to determine whether aerosols of dexamethasone were effective in controlling asthma ill children; and (2) to
determine the effects of such aerosol therapy on adnenocortical function.
SUBJECTS AND METHODS
The subjects were severely, chronically, asthmatic children and adolescents ranging in age from 5 to 20 years from the allergy clinics of the Harbor General Hospital and the University of California at Los Angeles and from the private patients of the Ghil-drens Medical Group. Study subjects were selected from two main categories of pa-tients: (1) steroid dependents who were receiving oral steroids prior to the
admin-istration of the dexamethasone aerosols, and
(2) patients who had not received any oral steroids for at least 3 months before institu-tion of aerosol treatment. Adrenal function studies were limited to the patients of this second group.
In the selection of the patients strict ad-herence to criteria previously set forth for steroid administration in asthmatics was maintained.1,3
sus-pended in a fluorchlorohydrocarbon pro-pellant veilicle. Each aerosol container con-tamed tile following formulations :
dexa-methasone phosphate, disodium, 26.0 mg;
ethanol, absolute, 290.0 mg; sorbitan tn-olate (purified Span 85), 29.0 mg; and freon 12/114 (20/80 ration) to 14.5 gm. Approxi-mately 160 to 170 inhalations could be de-livered from each of the containers, which were designed to deliver a uniform quantity of the aerosol spray by a metered valve (approximately 0.084 mg from one spray,
as per information from manufacturer). The
starting dose used throughout the study was 12 inhalatiolls per day (three inhala-tions four times a day). Except for those
periods when the effects of the dexametha-sone on adrenal suppression were being studied (usually the initial 2 weeks) the dosage was lowered to the minimal num-ber of inhalations that would reasonably control the childs symptoms.
Adrenocortical function was assessed (1) by a standard-17-hydroxycorticosteroid re-sponse test which consists of the measure-ment of 17 hydroxycorticosteroid (17-OHGS) plasma levels before and 2 hours after the intramuscular administration of 25 units of ACTH,’ and (2) by measuring the total 24-hour urinary excretion of 17-OHCS
by the method of Glenn and Nelson.5
To determine whether dexamethasone aerosols were effective in alleviating the symptoms of asthma, a double-blind cross-over study was conducted, using a placebo aerosol container which was similar in ap-pearance and contents but contained no dexamethasone. The patients were started on either the active or placebo preparation,
labeled A or B, as determined by a
pre-arranged random code and following a
two-week trial period were given the opposite preparation. Each subject was examined
frequently throughout tile study period and
the parents were requested to keep a daily record listing symptomatology and addi-tional medicament taken (Fig. 1). From these data it was determined whether pre-paration A or B was more efficacious in
con-trolling the asthma.
RESULTS
Double-blind Cross-over Placebo
Controlled Study
Thirty-two subjects were included in the
double-blind cross-over controlled investi-gation. The results of this study are tabu-lated here.
Active Placebo Neither Both
Best Best Effective Effective
24 (75%) 4 (12.5%) 3 (9sf) 1 (3.1%)
In 24 of the patients the active material
was found to be superior to the placebo. The
results of physical examinations corrobo-rated the patient report data. In only four of the children was the placebo seemingly
bet-ten. In three of tile subjects neither the active
drug nor the placebo were effective. In one patient both preparations were apparently beneficial (placebo reactor).
Effects of Dexamethasone Spray on
Systemic Use of Steroids
In addition to the double-blind cross-over
study, seven patients who required systemic
steroids in established maintenance doses were given the dexamethasone aerosol to determine whether the oral dose of hormone could be reduced. In three of these sub-jects the oral hormones could be completely eliminated. During stressful episodes sup-plementary oral hormones were neverthe-less administered. In one subject the dose could be reduced and in three the results were equivocal.
Adrenal Function Studies
AGTh response tests, including 24-hour urinary, excretion for 17-OHGS, were per-formed in 24 children. These results, in-cluding the clinical data (the patients’ ages, number of inhalations at the time the tests were performed, and the duration of therapy) are summarized in Table I.
ASTHMA WHEEZING
Once a day
On and off
Continuous
COUGHING
Once a day
On and off
Continuous
SHORTNESS OF BREATH Exercise
SCHOOL ABSENCE OTHER ILLNESS
‘COLDS
Sore throat
Fever
MEDICATI ONS
Fic. 1. Form used by parents in keeping daily record during the study period.
NAk4F
ARTICLES
PATIENT’S PROGRESS REPORT
CASE NO. _________________
DATE
____
DI AGNOSIS
At rest
ECZEMA
ITCHING Infrequently
On and off
Continuous
NOSE ALLERGY
SNEEZING
All day
Occasionally
ITCHING OF NOSE All day
Occasionally
NOSE STUFFINESS
All day
Occasionally
APPETITE
Good
Fair
Poor
SLEEP Good
Poor
Plasma 17 OJICS (mg/lOO ml) Urinary 17 OIICS (mg/14 hr) Patient R.A. MB.’ D.C. 111). J. F. aG. P.11. 1)11. N.J. P.K. N.K. D.M. N.M. T.R. s.N. TN. TN. I).V. 1).\. Na. 3 4 5 6 7 8 9 10 Ii Id 13 14 16 17 18 19 dO dl dl Mean SEM Age 11 8 11 8 94 19 134 13 11 9 13 8 11 11 134 13 Id 154 Id 10 .Vun, bar of Puffs 9 Id Id 6 Id Id ld Id Id 8 Id dl Id Id Id ld Id Id Id ld Id id Id TABLE I
EFFE-r OF 1)EXAMETIIASONE AEuosoL ON ACTH-17 HYDIIOXYC0RTIcOSTEIIOIuS (1 7-OIICS) HEsPoxsF:
TESTS AND UIIINAaY 17 IIYDROXYC0RTICOSTEROID ExeltETlox
2hr Change Before After
9.0 d8.0 0.7 if)
14.4 7.4 0.3 0.4
17.0 15.8 d.0 3.7
dI.d 16.5 1.4 3.9
18.9 11.9 . . .
17.5 14.9 0.3 0.9
0.5 0.3
.
..I6.d i4.8 0.7
0.d 0.2 0.1 0.d
11.1 7.1 .. ..
11.8 d.1 0.1 0.9
d4.6 dl.9 d.l
0.0 -2.0 0.1 0.5
3.1 3.1 0.4 1.4
dS.8 d3.0 0.4 d.9
d.I 1.0 0.1 0.3
0.0 0.0 0.0 0.0
0.3 -0.1 0.1 0.6
9.d 9.d 0.0 1.0
14.1 14.1 0.0 0.4
9.7 4.9 0.5 1.5
10.0 5.4 .
.
..0.5 0.3 0.1 0.4
Ql.5 15.4 0.7
8.9 0.5 1.4
I.7d I 0.14 0.d7
Duration of Aerosol Therapy d4 mo S wk 10 da dOda 4mo Imo 6mo Smo .5 mo 7mo dmo 9 mo 10 da 15 da 7 mo 15 mo dl da 14 mo 10 da 10da 10 da 14da 10da 0hr I .0 7.0 1.2 6.7 7.0 2.6 0.d II 0.0 4.0 9.7 d.7 2.0 0.0 2.8 1.1 0.0 0.4 0.0 0.0 4.8 4.6 0.d 6.1 Change 1.2 0. 1 I .7 d.5 0.6 1.6 0.1 0#{149}.7 0.8 0.4 I .0 2.5 0.2 0.0 0.5 1.0 0.4 1.0 0.3 2.0 0.9 0.17 2.7 0.58 11.6 1.89
* On previotis systemic steroid therapy.
100 ml. respectively).1 As can be seen in Table I, the majority of the plasma 17-OHCS responses fell below the expected “normal” response. As indicated by the sign test, there was a depression of the response observed during dexamethasone inhalation
treatment statistically significant at the 5%
level. Thus, it appears that the use of dexa-methasone aerosols leads to significant sup-pnession of adrenocortical function.
In confirmation of the plasma 17-OHCS response tests were the urinary findings. In previous studies, a mean of 1.8 mg/24 hr. of 17-OHGS was found to be excreted in the urine of 16 asthmatic children.1 Com-parable basal values were also found in seven children in the present investigation (Table II) (mean, 2.2 mg/24 hr). In con-trast to the control levels observed in chil-dren not on steroids, the excretion of 17-OHCS in those receiving dexamethasone aerosols was statistically significantly re-duced (T = 4.48, p < 0.01). In only three
of the subjects did the amount of 17-OHCS excreted per 24 hour exceed 1 mg/24 hr.
The pattern of suppression of adneno-cortical function can be observed graphi-cally in Figure 2 and also in Table II,
which summarizes the excretion findings in
seven subjects over a period of several days. It is rather striking that almost immediately after therapy with the dexamethasone aero-sols were instituted, the levels of 17-OHCS excreted in the urine were decreased. By the second day the levels of 17-OHGS were suppressed to a mean level of 0.5 mg/ 24 hr and remained at approximately this low level until the AGTH response test was
UltixtISY 17 IIYI)It()XY(OIITICOSTEISOID ExcRETIoN (MG./’24 un.) ix 7 SUBJECTS RECEIVING 1 INIIALATIONS
oi’ DExASInTI1As0NE Pnrt D.ky
Days
(ntru!
-1.6 0.8
0.7 0.5 0.3
:1.6 0.d 0.0
2.3 0.8 0.3
1.4 1.3 0.3
3.1 2.7 1.5
Mean d.d 1.1 0.5
NEM 0.48 0.40 0.17
*23 mg AUTh I.M.
.5 #{149}1 .5 6 7
0.7
0.3 1.0 .. 0.7
0.d 0.1 0.0 0.0
0.6 0.2 0.d 0.2
Ott 1.5 1.5 0.8
ARTICLES
-o 25giM
111h
1!
8 9 0TIME IN DAYS
FIG. 2. Pattern of 17-hvdroxycorticosteroid
excre-tion in the urine (mg/24 hr) following 12
in-IIISIIItiOflS of dexametliasone (seven patients).
in \\7l10111 24-ilour urines were ol)tained on
tile SecoIld day after the ACTH response
tests were performed, tile levels of
17-OHCS excreted in the urine again fell to
low values indicating rapid return to
sub-normal adrenal function despite the ACTH
stimulation.
COMMENT
From the results of the double-blind
cross-over study, it is apparent that tile
administration of dexametllasone aerosols
to chronic “intractable” asthmatic cllildren
is highly effective in alleviating tilein
asth-ma. It is also equally clear from the results
of the ACTH response tests and urinary
excretion findings that amounts of dexa-methasone sufficient to cause considerable
suppression of adrenocortical function are absorbed systemically from either the ne-spiratory or gastrointestinal tract. Thus, it
is evident that the use of steroid aerosols
in the doses employed cannot be relied
upon to avoid the untoward effects noted with systemic oral steroids. The important question of whether fewer complications may arise from aerosols versus oral admin-istration has not, however, been answered by the present study. This certainly de-serves further investigation.
The matter of dose of steroids has
sig-nificant bearing on suppression of adreno-cortical function and on other potential complications. Liddle et al. demonstrated
tilat as little as 0.5 mg of dexamethasone
every 6 hours for S doses regularly induced almost complete suppression of 17-OHCS excretion in 54 endocrinologically normal subjects.2 Slater et a!. measured urinary excretion of 17 ketogenic steroids as well
as 17 ketostenoids, and confirmed the
marked suppressive effects of minimal doses of dexamethasone taken systemically.a In the present study an arbitrary dose of 12 inhalations daily was used. Subsequent clinical experience and the results of others have indicated that most intractable asth-matics can be maintained on a lower num-ber of inhalations per day (6-9). The es-timated dose of dexametilasone received by a subject on such a lowered schedule would
TABLE II
0.3 0.5 f).3 0.7 1.8
0.7 0.5 0)1
0.19 0.13 0.26
5 9
0.5
0.d 1 0.1
1.2 1.!
0.5 0.3
0.6 0.5 0.5 0.3
0.34 0.14 0.15 0.d:f
Y
II) 11 1;!
2.0 8.7 0.4
0.4 1.4 0.7
0.5 1.5 0.3
0.6 1.4 0.6
be 0.5 to 0.8 mg rather than to 1.0 mg per
day.
The efficiency of the aerosol unit and the technique of administering tile aerosol are
both important in determining the amount of steroid actually delivered to the bron-cilial mucosa. Pilot studies in adults using tnitiated dexamethasone aerosols have in-dicated that a considerable portion of the radioactive dexamethasone is deposited in
tile fllOuth and subsequently swallowed.8
In children it seems likely that there would be less efficient use of the aerosols than in adults and that eitiler a better method of delivering the aerosol should be devised
(
such an apparatus is being investigated by Merck, Sharp & Dohme Laboratories) or that more stress be given to the technique in administering present available aerosols.In considering the use of aerosols in asth-matic children the authors would like to emphasize tile following facts. (1) The in-dications for the use of aerosols of
dexa-methasone are the same as those for the
systemic use of steroids. Only those patients
who have failed to respond to orthodox nlethods of allergic management should be selected for this treatment. (2) Since our findings have demonstrated that there is sufficient absorption of dexamethasone to suppress adrenocortical function, it is im-portant to taper the dose of the aerosol in discontinuing the medication and to sup-plement tilis form of therapy with oral steroids in tile event of any stressful illness
or injury. (3) Aerosols should not be
em-ployed in the treatment of status asthmati-cus.
SUMMARY
Dexametilasone aerosols were studied in astilmatic children to determine their effec-tiveness and whether they produced sup-pression of adrenocortical function. In a double-blind cross-over study of 32 sub-jects, 24 children were definitely improved by the active material, 4 subjects did better on the placebo, and in 4 asthmatics no
difference between the active and placebo
aerosol could be detected. Adrenocortical function was measured by an
ACTH-17-hydroxycorticosteroid response test and by
measuring total 24-hour urinary excretion
of 17 hydnoxycorticosteroids. Both methods
demonstrated statistically significant sup-pression of adrenocontical function. Thus, tilough aerosols of dexamethasone are
effec-tive in controlling asthma in cilildren they
do not avoid the side-effect of adrenocorti-cal suppression.
REFERENCES
1. Siegel, S. C., et a!.: Adrenal function in
allergy: III. Effect of prolonged intermittent
steroid therapy in allergic children.
PEDI-ATRICS, 24:434, 1959.
2. Liddle, G. W. : Tests of pituitary-adrenal
suppressibility in the diagnosis of Cushing’s
syndrome. J. Clin. Endocrinol. Metab., 20:
1539, 1960.
.3. Siegel, S. C., Birnberg, V., and Kelley, V. C.:
Prednisone in the treatment of allergic
dis-orders in children. Amer. J. Dis. Child., 91:
454, 1956.
4. Ely, R. S., sst al.: Studies of
17-hydroxycorti-costeroids: IV. Evaluation of standard
ACTH-17-hydroxycorticosteroid response test in
children. PEDIATRICS, 13:403, 1954.
. Glenn, E. M., and Nelson, D. H. : Chemical
method for the determination of
17-hydroxy-corticosteroids and 17-ketosteroids in urine
following hydrolysis with B-glucuronidase.
J. Clin. Endocrinol., 13:911, 1953.
6. Slater, J. D. H., et al.: Dexamethasone
sup-pression test irk diagnosis in Cushing’s
syn-drome. Brit. Med. J., 2:1584, 1962.
7. Crepea, S. B., ci a!.: Inhalation corticosteroid
therapy for seventy asthmatic children.
Ex-hibit at the Academy of Pediatrics, Chicago, Illinois, October, 1962.
8. Melby, J. C.: Unpublished data. Personal
com-munication.
Acknowledgment
The dexamethasone aerosols (Respihaler) used
in this study were kindly supplied through Dr.
Robert Feld and Dr. C. J. Donovan of Merck,
Sharpe, & Dohme, New Jersey. The ACTH
(Acthar) used for the response tests was supplied
through the courtesy of John P. Dailey of Armour
