Inhalation corticosteroid (dexamethasone PO4) management of chronically asthmatic children

cvch

MANAGEMENT Seymowr

T

B. Crepea,

OF CHRONICALLY M.D.,

F.A.C.P.,

AST%MATIC

CEILDlU!iN

Tucson, Ariz.

F.A.A.A.,”

applied corticosteroid drugs in the symptomatic management of chronic asthma would be valid only if such a method presented distinct advantages over the oral route of administration without new or significant disadvantages. Although there are no exact criteria for the use of corticosteroids in the symptomatic control of asthma, one might say they are used when the disability incurred or the probability of deterioration due to asthma outweighs, in the estimation of the physician, the potential adverse effects. The adverse effects of corticosteroids are, in general, dependent upon systemic distribution and activity, whereas, in asthma, the desired effect is local. The objective of the current study was to determine the potential of ohtaining localized corticosteroid activity while minimizing systemic effects. PART

HE use of topically

I:

CLINICAL

STUDIES

Proce&re.-Children, all residential patients at the Sahuaro School, and ranging from 6 to 13 years of age, were selected for study. Each child was referred to the School as a disabled, intractable asthmatic who had not responded to conventional medical therapy in the home community. Following admission to the School, each child was followed until the asthma pattern stabilized. Only those children in whom maintenance oral corticosteroids were necessary for control of asthma, or those in whom the asthma was of sufficient magnitude for oral corticosteroid therapy were used in the study. The topical corticosteroid used was dexamethasone PO, dust, with a fluorocarbon propel1ant.t This product, as furnished in the appropriate device, was presumed to deliver 0.084 mg. of dexamethasone per metered delivery with supplied particle sizes ranging from 0.5 to 4 microns.+ The total formulation and used contained per 14.5 grams: 26.0 mg. Dexamethasone phosphate, disodium 290.0 mg. Ethanol, absolute 29.0 mg. Sorbitan trioleate (20/80 ratio) to 14.5 Gni. Freon 12/114 Received for publication Oct. 4. 1962. Sahuaro School *Medical and Research Director. Tucson, Ariz. tDrug supplied by Marck and Co., West Point, Pa. SD&a supplied by manufacturer. 119

for

Asthmatic

Children,

BOX

12096,

120

CREPEA

March-April.

1963 J. Allergy

For the study, each child exhaled maximally and then took a sharp deep inhalation, simultaneously releasing the metered dose of dexamethasone and maintaining deep inspiration for a few seconds. Two such inhalations four times a day, delivering a maximum of 0.67 mg. of dexamethasone, was the dose used in this study unless otherwise noted. Of the School population of 62 children, 30 were selected as suitable for study. One child, with a previous lobectomy for bronchiectasis complicating severe asthma and emphysema who required 20 to 30 mg. of prednisolone per day for partial control of asthma, had a severe coughing spell after the first inhalation treatment. Because of the general clinical status and lack of experience with the method she was deleted from the group. The remainder of the group of 29 children were observed for 6 to 9 months. When the child became completely asthma-free on inhalation therapy by verbal report, clinical observation, and repeated physical examination, oral corticosteroids were withdrawn gradually. When the child was maintained asthma-free for 2 weeks without oral corticosteroids or other medication, the inhalation therapy was abruptly withdrawn. Inhalations were reinstituted only when the progressive recurrence of asthma indicated the need for reinstituting corticosteroid therapy. Placebos, identical with the inhalation formula except for the dexamethasone content, were employed in four instances. After the disease was controlled by the inhalation program, oral corticosteroid was used only when it was apparent that 8 inhalations in divided dosages over a 12 hour period would not control the asthma and that aminophylline or Adrenalin injections were necessary for symptomatic control. For purposes of convenience the following classification code was used to record the status of each child: 0 - Asymptomatic; no bronchodilator; lungs clear on examination. 1+ - Slight wheezing or oral bronchodilator as needed. 2t - Moderate symptoms not interfering with routine; maintenance oral bronchodilators. 3t - Moderate to severe symptoms interfering with routine, requiring injections of epinephrine or aminophylline. Clinical Results.-Of the 29 children, 15 required maintenance oral corticosteroid prior to inhalation therapy, without which rapid deterioration of the asthmatic state occurred (Table I). For a period of 4 to 7 days prior to initiation of inhalation therapy, 12 had asthma Class 2t and 3 children Class 3+. Each child was then given two inhalation treatments four times a day until an end point of freedom from asthma without oral corticosteroids and other forms of medication was reached. This also reflects the time for gradual withdrawal of the oral corticoids. Of the remaining group of 14 children, all had had courses of corticosteroid therapy prior to this study. Six children (Table II) had required no oral corticosteroid for approximately 3 months. However, the progressive increase in asthma severity was such that oral corticosteroid would ordinarily be employed. The remaining group of 8 children (Table III) had all been on oral

Volume 34 &umber 2

INHALATION

TABLE

I.

CORTICOSTEROII~

TI~!CE TO ACHIEVE

TOTAL

CONTROL

MANAGEMENT OF AsTH~~A

121

ON INHALATION

TREATMENT --

STATUS

PRIOR

AVERAGE DAILY DEXAMETHASONE

CASE

TO INHAI,ATIONS

ORAL LEVEL

CLINICAL

STATl:S*

DAYS

TO CLASS

1

1.5

2+

2 4 5 6 7 :

1.5 0.75 0.75 1.5 0.75 2.25 0.75

2+ 2+ 2+ 2+ %+ 2+ 3+ 2+

10

2.25

2+

63

11 12

1.50

2+

14

2.25 00:75 75

a+ 2+ 4+

28 287

3

:: 15

2.25

*Clinical tTime,

inhalation

status in days,

corticosteroid.

tDesDite TABLE

II.

3+

for several days prior to necessary for maintenance

inhalation

therapy,

CLINICAL

RESPONSE

CASE

0.75

mg.

16

CLINICAL

STATUS*

was No

ORAL

/

corticosteroid.

medications needed

CORTIC'OSTEROII)

DAYS

18 19 20 21 Table

I for

explanation

of column

other

than

throughout

-___-.. TO CLASS

2+ 2+ 2-k 3+ 3+ 3+

17

*See

dexamethasone

OF CHILDREN REQUIRING 3 MONTHS INITIAL

114

institution OP inhalation free of asthma without

oral

Ot

56$ 35 2 10 7 49 28 146

study. FOR ---OH

11 6 3

titles.

corticosteroids in the past. In this group, withdrawal of oral corticosteroids had been accomplished no more than 4 weeks prior to the study. Here, the withdrawal of corticosteroids resulted in a recurrence of asthma of a progressively increasing nature which appeared to warrant the reinstitution of corticosteroid therapy. In all children, once total control of asthma was obtained and the patient maintained without medication other than inhalation corticosteroid. withdrawal TABLE

III.

CLINICAL

RESPONSE

OF CHILDREN REQIJIRING 1 MONTH

No

ORAL

CORTICOSTEROW

FOR __-.

INITIAL

CASE

STATUS*

1

TIME

TO 0"

22 23 24 2

2+ 2+ 2+ 2+ 2+

7 6 4 316

27 28

3+ 2c 2+

21 14 13.----_

29 *See

CLINICAL

Table

I for

explanation

of column

titles.

122

CREPEA

March-April.

J. Allergy

1963

of inhalation therapy was performed in all cases, and, when asthma recurred, further control with inhalation therapy was again attempted with various doses of inhalation, ranging from 4 breaths once daily through 2 breaths four times a day. Early in the course of the study, clinical impression suggested 2 breaths four times a day was the most satisfactory and, for purposes of this report, is the basis for discussion. Of the group, all had recurrence of asthma of significant intensity to warrant reinstatement of inhalation corticosteroid therapy. Typically, the pattern was that of gradual recurrence of asthma in 2 to 3 days with gradual intensification in the next week. Individual variance from this pattern was wide, ranging from 1 to 14 days, but all suffered relapse. In each instance, reinstitution of inhalation of corticosteroid 2 breaths four times a day resulted in control, usually, within a few days. In all cases there were at least four such withdrawal patterns. In 4 cases, substitution of placebo for inhalation therapy for one week showed no alteration in the course of asthma. Reintroduction of the inhalation corticosteroid resulted in rapid control. Results.--In 14 of 15 cases, replacement of oral corticosteroids by inhalation corticosteroids therapy was accomplished. In the one child in whom total substitution was not possible, the oral maintenance dosage of dexamethasone was decreased from a usual requirement of 1.5 to 0.75 mg. In the remainder of the group, control of asthma was readily obtained by use of inhalation therapy. Although 28 of 29 children were brought to a point where no therapy other than inhalation corticosteroid was needed, maintaining this position was not as general. During two separate influenza-like epidemics in the School population, 16 of the group had exacerbations of asthma which required daily dosages of ephedrine compounds interspersed with injections of epinephrine. During these periods, 10 of the children required supplemental oral corticosteroid. Of those requiring oral corticosteroid supplementation, 7 were from the group in Table I, the most severe cases. In addition, mild attacks of asthma responding promptly to single doses of ephedrine SO, occurred occasionally in all but 6 children while on maintenance inhalation corticosteroid. Some children, not used in the current study, similarly were afflicted with the influenza-like pattern and, also, had exacerbation of asthma. The author did not feel that he could, with validity, assess the relative incidence or reaction to the epidemics in the study group and those not under study. The study group, coincidentally, included 2 children with clinical eczema and asthma. While on 1.5 mg. of dexamethasone equivalent, both the eczema and asthma were controlled. Lesser doses were associated with increases of asthma and eczema. As dexamethasone inhalations, 2 breaths 4 times a day, were used and the oral dexamethasone was gradually decreased, flare of eczema ensued while the asthma remained under control. In 4 cases, coincidental allergic rhinitis manifestations increased, despite continued control of asthma, as inhalation therapy replaced oral corticosteroid. One child, JH, 7 years of age, showed a pattern worthy of individual attention. She received a minimum of 1.5 mg. of dexamethasone equivalent daily for intractable asthma continuously for 18 months and, sporadically, a lesser

Volume 34 number 2

INHALATION

CORTICOBTEROII)

MANAGEMENT

12:i

amount

for some years prior to coming to the School. Cushing-type pat,tern had resulted with moon face, buffalo hump, and marked stria. At. the start of the study, her blood pressure was 100/E% mm. Hg; cholesterol, 29-l mg. per cent; fasting blood sugar, 110 mg. per cent; and a 2 hour post-prandial blood sugar, 140 mg. per cent. Her height was 44 inches and weight was 64 pounds. Her skeletal age, by x-ray examination, was 5 years. Response to inhalation therapy, 2 breaths four times a day, was good and oral corticoids were discoittinued for 4 weeks. Upon completion of 7 months of inhalation therapy, the blood pressure was 90/‘72 mm. Hg; fasting blood sugar, 85 mg. per cent,; 2 hour post-prandial blood sugar, 92 mg. per cent; and cholesterol, 268 mg. per cent. Bone age studies showed a new area of ossification and a calculated age of 6 years, 10 months. Her height was 461/4 inches and weight was 661/, pounds. The general Cushingoid appearance had receded. The stria were no lotqyr red. The child then showed recession of Cushinpoid changes while on inholution therapy. No child in the study group developed any facial swelling or clinical cvidence of Cushing syndrome. PBRT

II:

EFFECTS

ON

24

HOUR

II-OH

CORTICOSTEROID

EXCRETION

Twenty-four hour urinary excretion of ll-OH corticosteroid stud& wcrc performed.* Four children, not included in the clinical study, who had no asthma at the School and had not had any corticosteroid therapy for at least 6 months, and 2 children not included in the clinical study who had been without corticosteroids for one month, were studied. Twenty-four hour urine was collected for 2 days. Inhalation therapy (Table IV) was started on the morning of completion of the second collection and continued throughout the 8 days of study. Urine collection was continued through the first day of treatment and again on the seventh and eighth days. Suppression of 24 hour urinary ll-OH corticosteroid was evident in each case. During the course of the clinical study, 15 of the 29 children had 24 hour urinary 1 l-OH corticosteroid excretion studies while on inhalation treatment TABLE

CASE

I

-1

IV.

24 HOUR

D-4;

-2

URINARY

ll-OH

CORTICOSTEROID

p%gfLq

+1

EXCRETION

/_

‘::’

,

+;

_JB AC AN El*

5.0 r2:; 3.2 7.4

4.1 4.7 3.3 6.8 4.8

2Br. 4Br. 2Br. 2 Br. 4Br.

7.2 10.3 4 Br. RM” X = Specimens damaged in transit. *No steroid one month prior to study.

4xday 1 x day 4xday 2 x lxday day 1 x day

*AIiquots of (24 hour) urine samples, preserved in Silber, Rahway, N. J., where the studies were Performed. milligrams of creatinine per 100 C.C.

1.8 x 0.9 2.6 X 2.9

toluene, Urinary

2.1 2.4 X X 1.8 2.6

2.3 3.3 0.9 5.7 2. 1 2.3

were sent to Dr. Robert levels are expressed :is

124

CREPEA

March-April,

J. Allergy 1963

of 2 breaths 4 times a day continuously for 2 to 4 weeks. At least four output studies were done in each case. Values ranged from 0.4 to 3.5 mg., with an average of 1.5 mg. in the group. The output levels for each child were quite consistent, larger amounts of drug generally producing excretion values were well below the range of children not on corticosteroids. As varying doses of inhalation corticosteroids were used for clinical trials, urinary excretion studies were made. The values shown in Table V do not reflect contiguous periods of observation, but represent average levels obtained while each child was on the tabulated dosage. TABLE

24 HOUR URINARY EXCRETION OF ll-OH CORTICOSTEROID IN VARYING PERIODS OF CLINICAL STUDY*

V.

DOSAGE NONE Y-10 DAYS

CASE

OF

INHALED

DESAMETHASONE

4 BREATHS 0i-w~ A 4 BREATHS TWICE 12 BREATHS 4 TIMES DAY FOR 8 DAYS A DAY FOR 8 DAYSIA DAY FOR 8 DAYS

0.3 n.8

JM E SR JP JN KB DG

4.4 4.1

t:: 0:4

0.5 ;.i 1:9 2.0 1.6 1.8 1.4 1.9 0.7

2.2 4.1 5.8

2.9 3.7 2.4 3.5

4.0 3.8 El

1.4 1.2

7.2

2.6

0.5 *Urinary

levels

TABLE

of

VI.

11-OH

corticosteroid

URINARY

EXCRETION

expressed

t: 0:9

as milligrams

ACTH

FOLLOWING

of

CASE

DG JN SR

*Urinary t40 U. $40 U.

FIRST 24 HOURS

0.4 0.4 K

i;

levels OP 11-OH corticosteroid ACTH daily x 2 days. ACTH daily x 4 day&

C.C.

SECOND 24 HOURS

1.8 1.4 3.6 8.8

1.0

3.0t

1.4 expressed

100

ACTH

4:7 3.5 2.0

0:4 0.4 0.8

per

STIMULATION* AFTER

PRIOR TO ACTH (24 HOUR PERIOD)

creatinine

0.6 as milligrams

of

6.6

15.4

creatinine

per

X8$ 100

C.C.

ACTH (Table VI) was administered to 7 children who generally showed the lowest excretory values, all of whom had had inhalation treatment for 4 to 6 months, with oral therapy for several years previously. While on inhalation corticosteroid, 2 breaths four times a day, a 24 hour urine collection was made. As the final specimen was collected, ACTH gel, 40 units intramuscularly, was administered. Continued urine collection was

INHALATTON

Volume 34

Number?

CORTTCOSTERO1D

MANAGEMENT

12.1

made for two 24 hour periods. In ‘2 children the ACTH was repeated daily. with simultaneous urine collection. Attempts were made to equilibrate dcxamethasone by mouth and by inhalation (Table VII). Unfortunately, the chemical determination, to some dcgrcc: reflects the excretion of exogenous corticosteroid and the 2-k hour t,echniquc reflects the static, rather than the periodic, functional status of the adrenal rortrs.

Tasm

VII.

URINARY

EXCRETION

ON

ORAL

ANI)

~KIIALATION

I)EXAMETHASONE

-___PATIENT

ON ORAL DEXAYETHASONE 4 TIslES DAILY (i

RM

MO.

INHALATION DEXAMETHASONE :! __.~__~-~BR. 4 TIMES DAILY (i DAYSI ~~. ..~

0.5 0.8 3.5

%

JM 0.25

daily

0.9 0.i 1.8

2.0 x 7 days

KH

0.3

4 Rr.

daily

2 Rr.

thrw

2.0 0.125

KR

0.25 DAYS)

3 t,imes

daily 1.4

x 7 days

___-

x 7 days 2.4 times daily 2.0

x 7 days

DISCUSSION

The essential premise that topical corticosteroid control of chronic asthma would be valid only if t,he method had distinct advantages, without new or significant disadvantages, over conventional oral administration warrants discussion. Alt,hough oral corticosteroids are commonly used, their actual and potential adverse effects are such as to be of concern to all. The use of topical corticosteroids in control of chronic asthma is not new and studies have been reported.‘, 2. 3 The clinical data indicate that the current method of propelling dexamethasone PO, dust by Freon in metered doses is quite feasible. Tlw met,hod allows administration on an ambulatory basis with a minimum of equipment and technical supervision. The results given in Table I show that this In the group of chilmet,hod of administration does produce clinical control. dren followed, the total delivered dosage of corticosteroid, necessarily greater than the actual amount remaining in the bronchi, is significantly lower than the oral requirement. However, as evidenced by the patterns seen during the viral-respiratory epidemics, when asthma is increased and the child’s ability to inhale adequately is impaired, the efficiency of this method of inhalation therapy is impaired.” Important,ly, although we found little clinical evidence of acute bronchial irritation, the problem of chronic irritation remains to be answered. The growing literat,ure correlating air pollutants and chronic pulmonary disease is important in this respect4 Any form of inhalation therapy must be considered not only in regard to the actual pharmacological activity of the medication. but also as a “personal iatrogenic air pollutant. ” The second part of the study is quite significant. In all cases a decrease in urinary 11.-OH corticosteroid occurs after inhalation of dexamethasone dust.

126 The attempts to equilibrate reaction to comparable doses of oral with inhalation dexamethasone failed for technical reasons. We could not evaluate the amount of dexamethasone actually deposited and retained by the bronchi. More important, the 24 hour urinary technique of collection and determination does not reflect the periodic fluctuations in adrenal status that would occur with the technique of sporadic oral or inhalation corticosteroid administration. In addition, the determination also measures the presence of exogenous, as well as endogenous, corticosteroid. Regardless of this, the total data do demonstrate the definite adrenal suppressive effects of even the small amounts of dexamethasone given. Although the evidence supports systemic absorption and effect, the patients who showed return of eczematous manifestation with continued control of asthma suggest that greater local activity proportional to systemic metabolic effect can be obtained. The concept is further supported by the observed case of recession of the Cushing state while the patient continued inhalation of dexamethasone. Despite the suppressive adrenal effects, the adrenal cortex remained responsive on withdrawal of the dexamethasone, as well as to ACTH stimulation. Although much more clinical and laboratory experience is necessary in the use of inhalation corticosteroid, the current data suggest that it has certain advantages in minimizing the adverse systemic effects of corticosteroid drugs in chronic asthma. Since adrenal cortical suppression does occur, the criteria for use of inhalation corticosteroids, as well as the principles of medical supervision, remain the same regardless of the the route of administration. CONCLUSION

1. In a group of 29 chronically asthmatic children, dexamethasone PO, dust, Freon propelled, was effective in controlling asthma. 2. The asthma could generally be controlled with less total corticosteroid by the inhaled, than by the oral, route of administration. 3. The reported technique is simple, can be used on ambulatory children, and allows for minimum total dosage of corticosteroid, as well as great flexibility of small dosages. 4. Bronchial insufflation of corticosteroid results in systemic absorption with adrenal suppression comparable to the administered dose. 5. The indications and criteria for clinical observation of children on corticosteroids are the same, regardless of the route of administration. 6. Data on the local effects of long-term therapy are needed. REFERENCES Hydrocortisone W. S., Greaves, D. P., Herxheimer, H., and Kingdom, L. G.: in Treatment of Allergic Conjunctivitis, Rhinitis and Bronchial Asthma, Lancet 1: 234,1955. 2. Segal, M. S., and Attinger, E.: Advances in Inhalation Therapy in the Management of Diseases of the Chest, Am. J. Surg. 89: 387, 1955. 3. Franklin, W., Lowell, F. C., Michelson, A. L., and Schiller, I. W.: Aerosolized Steroids in Bronchial Asthma, J ALLERGY 29: 214, 1958. The Air We Breathe, Springfield, 1961, Charles C 4. Farber, S. M., and Wilson, R. H. L.: Thomas, Publisher. 1. Foul&,