Comparison of the Effects of Inhaled SCH 1000 and Fenoterol on Exercise-Induced Bronchospasm in Children

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PEDIATRICS Vol. 66 No. 1 July 1980 109

Comparison

of the

Effects

of Inhaled

SCH

1000

and

Fenoterol

on Exercise-Induced

Bronchospasm

in Children

R. Yeung, C. M. Nolan, MB,BCh, and H. Levison, MD

From the Pulmonary Function Laboratory, Hospital for Sick Children, Toronto

ABSTRACT. The effect of4O g ofSCH 1000 (ipratropium bromide, an anticholinergic agent) on bronchodilation and suppression of exercise-induced bronchospasm (EIB) was compared with 400 .tg of fenoterol and a placebo in a single-blind controlled study. Twenty-seven randomly selected asthmatic children performed a standardized treadmill exercise challenge and the 17 children who were shown to have EIB continued in the study. Pulmonary function was evaluated before and after drug administra-tion and exercise. When individual results were analyzed

and grouped according to the responsiveness of EIB to

the drugs, two patterns emerged: (1) the EIB was more severe in those (6/17) children who did not respond to

either drug than in the rest of the children; (2) the resting pulmonary function was significantly better in the

chil-dren (4/17) who responded to both drugs than in those

(7/17) who responded to fenoterol alone. In conclusion

SCH 1000 was shown to be an effective bronchodilator comparable to, but no better than, fenoterol. It had minimal side effects. As an EIB inhibitor it depended on

relatively normal base line pulmonary function and only a moderate deterioration following exercise, whereas

fen-oterol depended on the exercise response alone. Although anticholinergic drugs are not very extensively used, SCH 1000 may be useful in some patients where the $2 adre-nergic drugs cause significant side effects or are

contrain-dicated. Pediatrics 66:109-1 14, 1980; exercise-induced

bronchospasm, bronchodilation, SCH 1000, fenoterol.

and xanthine ri2 Recently, there have

been conflicting reports of the efficacy of anticho-linergic drugs in suppressing EIB.7 This conflict could be due to variations in the standards for the definition of EIB, exercise techniques, drug dosages,

or interindividual differences in the role of the

parasympathetic pathway in EIB.

SCH 1000 (ipratropium bromide), a quarternary

isopropyl derivative of atropine, has been shown to

be an effective anticholinergic drug with minimal

side effects although the occurrence of blurred

vi-sion and thirst have been reported.4’8’9 The most

appropriate route of administration is by

inhala-tion8 with an optimum dose of 40 g.9 Doses greater than 40 provide little improvement in pulmonary

function and increase side effects.4’8 The onset of

maximal bronchodilation action is within 30

mm-utes and the effect persists for three to four hours.’#{176}

The present investigation was undertaken to try

to assess the relative importance of the

parasym-pathetic and sympathetic pathways in the

patho-genesis of EIB and to determine the clinical use of

SCH 1000 in the prevention of EIB and as a

bron-chodilator.

MATERIALS AND METHODS

Airway constriction induced by physical exertion may put severe limitations on the daily activities of

many asthmatic children. Pharmacologic

preven-tion of such exercise-induced bronchospasm (EIB)

has involved the use of diverse agents including

$2-sympathomimetic amines, disodium cromoglycate,

Received for publication Oct 2, 1979; accepted Nov 28, 1979.

Mr Yeung was a Cystic Fibrosis Foundation summer student. Dr Nolan is a Cystic Fibrosis Foundation Research Fellow.

Reprint requests to (H.L.) Pulmonary Function Laboratory,

Hospital for Sick Children, 555 University Aye, Toronto, M5G 1X8 Ontario, Canada.

This single blind controlled study was conducted

to assess the efficacy of SCH 1000 in comparison to

fenoterol, a $2 adrenergic agent known to be

effec-tive in EIB,’ 1.12 and a placebo. Twenty-seven chil-dren (14 boys, 13 girls) with a previous diagnosis of

asthma’3 were randomly selected to participate in

the study. The age range was from 9 to 18 years

(mean 13 years). The spectrum of severity of

asthma in the subjects studied varied from

asth-matic patients who had occasional attacks not

re-quiring

regular medication to those who required

daily maintenance therapy including oral

theophyl-line (short acting), oral and/or inhaled

at Viet Nam:AAP Sponsored on September 7, 2020

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110- 100-9#{216}: 0 80 0 0 70 S 60 50 40 0 - FENOTEROL Schl000

--- PLACEBO -

-PEFR

$ 15 30 45 EXERCISE :

DRUG TIME mm)

Fig 1. Mean PEFR (% predicted) in the total group of 17 patients showing bronchodilation (0 to 45 minutes) and exercise response (3 to 15 minutes) following treat-ment with fenoterol, SCH 1000, and the placebo. Bars indicate SE.

mimetic agents, disodium cromoglycate, and

in-haled beclomethazone diproprionate. All

medica-tions were stopped 12 hours prior to each study.

Each subject was tested on three separate days

within one week at the same time of the day to

minimize variations in EIB.’4 Informed consent was

obtained from subjects and their parents.

Pulmonary

function

tests

were performed using

a Wright peak flow meter (Airmed, Harlow,

Eng-land) to measure peak expiratory flow rate (PEFR)

and a Wedge spirometer with a model 270

x-Y plotter (Med-Science Electronics, mc, St

Louis) to measure forced expiratory volume in one

second (FEy,) and forced midexpiratory flow

(be-tween 25% and 75% of the forced vital capacity)

(FEF2575). Seven sets of tests were performed on

each study day at the following times: 0 minutes

(resting base line), 15 minutes, 30 minutes, and 45

minutes following drug administration and 3

mm-utes, 9 minutes, and 15 minutes postexercise. Each

drug was delivered as two puffs from a metered

aerosol delivering 40 ig of SCH 1000 (20 g/puf,

400 tg of fenoterol (200

tg/puff),

or placebo. The

placebo was given single blind on day 1 to establish

the existence of EIB and the two active drugs were

randomly assigned on the subsequent days. Heart

rate, blood pressure, and tremor were measured and

side effects (dryness of mouth, gastric irritation, blurred vision, flushing, headache, nervousness)

were monitored by direct questioning before each

pulmonary function test during the preexercise

pe-nod.

Exercise provocation performed 45 minutes after

inhalation of the drug involved six minutes of run-ning on a treadmill (Collins treadmifi) at 15-degree

gradient. The speed was adjusted so that the mean

heart rate as monitored by a telemetered ECG

(CDC 70 Cardiac Diagnostic Center, Hittman

Med-craft, Skippack, PA) was between 170 to 180 beats

per minute. The average speed used in this study

was 3.1 mph (range 2.25 to 4.75 mph). The speed

used on the first day for each patient was used on

subsequent days. Patients were encouraged to

breathe through their mouths. To normalize for

differences in height, age, and sex, results were

expressed as percentages of normal predicted

val-ues.’5 The values at 45 minutes postdrug inhalation

were used as base lines for analyzing the EIB

re-sponse to normalize for the degree of basal

bron-choconstriction and the degree of bronchodilation following drug inhalation.

The criteria for EIB with treadmill exercise pre-viously established at this laboratory’6 were used:

namely, a minimal postexercise decrease of 12.5%

in PEFR, 10% in FEy,, and 26% in FEF2575,. If two

or more of these criteria were met the EIB response

was termed positive. As changes in PEFR and FEy,

were shown to detect 99% of those who developed

EIB these parameters were used for the tables and

figures in this paper.

In this study an active drug was regarded as: (1)

a complete EIB blocker when the postexercise

de-crease in PEFR and FEy, was less than 12.5% and

10%, respectively; (2) a partial EIB blocker

(clini-cally effective) when the postexercise decrease in

PEFR and FEy, was greater than 12.5% and 10%,

respectively, but less than half of the magnitude of

the fall seen with the corresponding placebo; (3) a

non-EIB blocker when the postexercise decreases

in PEFR and FEy, were greater than half those

seen with the placebo. Results were expressed as

means ± SE. Statistical analysis was performed

using Student’s paired and unpaired t-tests where

appropriate.

RESULTS

Of the 27 subjects, only 17 demonstrated positive

EIB response on day 1 (placebo run). The negative

response group (ten subjects) showed a mean ± 1

SE postexercise lowering of 1.6 ± 1.7%, 0.5 ± 4.4%,

and 3.7 ± 3.3% in PEFR, FEV1 and FEF2575,

respectively. These patients were excluded from the

study. Four subjects (two negative, two positive

EIB) had repeat placebo studies and similar results

were found on both days.

Total Group

The base line pulmonary function data (Fig 1 and

Table 1) showed no significant differences on

dif-ferent days (P > .05). Bronchodilator response (Table 2) ,as measured by the differences between

0 and 45 minutes, showed significantly better

bron-chodilation with both fenoterol and SCH 1000 than

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ARTICLES I II placebo. Although the results appeared to be better

with fenoterol than with SCH 1000, this difference was not significant (P > .05).

The response to exercise (Table 3) as measured

by the maximum percent of decrease from the 45

minute base line showed significant differences in

the EIB responses between the three treatments

(placebo, SCH 1000, and fenoterol). The mean

val-ues for the total group indicated that SCH 1000 did

not block EIB and that fenoterol was an effective EIB blocker. This did not take into account individ-ual differences in patterns of response; therefore,

when the group was rearranged according to the

EIB response to the drugs, three groups emerged:

(1) F group-those who were completely blocked

by fenoterol alone (seven subjects); (2) F + S

group-those who were completely blocked by

fen-oterol and SCH 1000 (four subjects); and (3) N

TABLE 1. Base Line Pulmonary Function and Group Comparison (% Predicted)*

Group PEFR FEy,

Placebo Fenoterol SCH 1000 Placebo Fenoterol SCH 1000

Total (n = 17) 90.3 ± 6.3 88.4 ± 5.2

Nt

85.0 ± 5.1 77.1 ± 5.3

I

72.7 ± 3.7

N

71.3 ± 4.5

F group (n = 7) 83.1 ± 4.5 79.3 ± 7.9 . 76.9 ± 3.9 72.5 ± 5.1 71.3 ± 4.9 71.5 ± 4.4

F + S group (n = 4) 109.6 ± 4.6 104.0 ± 3.5 105.5 ± 2.6 93.3 ± 10.4 85.9 ± 5.0 89.7 ± 4.0

N group (n = 6) 85.9 ± 15.9 88.7 ± 10.0 80.9 ± 11.8 71.6 ± 11.2 65.5 ± 6.9 58.9 ± 8.8

Group comparison

F/F + S P < .001 P < .05 P < .001 P < .05 P < .05 P < .05

F/N NS NS NS NS NS NS

N/F + S NS NS NS NS P < .05 P < .05

A Abbreviations used: F group, EIB completely blocked by fenoterol; F + S group, EIB completely blocked by fenoterol and SCH 1000; N group, EIB completely blocked by neither drug; PEFR, peak expiratory flow rate; FEy,, forced expiratory volume in one second. Values are means ± SE.

t

NS P > .05.

TABLE 2. Bronchodilator Response and Group Comparison: Change in % Predicted from 0 to 45 Minutes*

Group PEFR FEV

Placebo Fenoterol SCH 1000 Placebo Fenoterol SCH 1000

Total -1.9±2.6 +18.1±3.4 +12.5±2.3 -1.1±1.7 +17.0±1.7 +10.2±2.7

-P<.001 LNS I t-P<.001 I 1-P<.05

F group -3.3±2.4

P<xxfl

+19.8±5.4 +16.8±3.2

I

+0.8±2.1 +17.5±3.0

I

+9.7±3.9

-P<.001 LNS -NS

F + S

I

-1.1±2.0

P.cz.0O1 I

+13.9±2.4 +12.5±2.0

___________

-1.2±4.9

NS

+19.7±3.3

I

+10.6±4.4

group

I P<.05 ILNSJ 1-P<.05 -NS

N group

I

-0.9±7.2

P<.05 I

+19.0±7.6 +7.6±4.8

I

NS

-3.2+2.8 +14.7±2.4 + 10.4±6.2

P<05 LNS I L_ Pz.005

LNS

I

L

_NS _I _I _NS

_I

6 Values are means ± SE. Group comparison among all groups was not significant. NS P > .05. See Table 1 for definition of

abbreviations.

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group-those who were not completely blocked by

CO either drug (six subjects).

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Cl I C I iS shown in Fig 2. The base line values (Table 1) in

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the F + S group were significantly higher than the

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F group. Because the range of the base line in the

N group was so great, there was no significant

difference between it and the other two groups.

Bronchodilation (Table 2) was observed in all

groups after fenoterol and SCH 1000 inhalation. In

- 6 cz N each group (Fig 2) fenoterol gave better results than

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ARTICLES 113

were small, the differences between them are such

that we feel the groupings are valid. The differences in the groups could not be explained by the degree

of bronchodilation of a drug. The severity of the

exercise response and the base line pulmonary func-tion were the two significant differences.

The nonresponsive (N) group had greater

de-creases in pulmonary function after exercise than

either of the other two groups (F and F + 5). The

base line pulmonary function in this

group

covered

such a large range that it was difficult to separate

it from the other groups. Those patients who had a

less severe exercise response could be separated

according to the base line values; those with a

relatively normal base line responded to both SCH

1000 and fenoterol (F + S group); while those with

40

0 20 LU

I,)

LU

Fig 2. Mean PEFR (upper three graphs) and mean

FEV1 (lower three graphs) in the three groups (F + S, F, and N), showing bronchodilation (0 to 45 minutes) and

exercise response (3 to 15 minutes) following treatment with placebo, fenoterol, and SCH 1000. Bars indicate SE.

F + S group, EIB completely blocked by both fenoterol and SCH 1000 (N = 4); F group, EIB completely blocked

by fenoterol only (N = 7); N group, EIB completely

blocked by neither fenoterol nor SCH 1000 (N = 6).

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lower base line pulmonary function responsed to fenoterol alone (F group).

The groups could not be clearly separated

clini-cally but the main differences between them tended

to be that the N group was obviously more

dis-tressed following the exercise, and these patients

were more labile asthmatics with more frequent

attacks than those in the other groups. The F + S

group

tended to have less severe asthma and

re-quired less regular medication. The F group was

intermediate between the other groups. There was

no difference in the types of medication between

the groups. We feel that it is possible that these

groups were not static and that a patient’s respon-siveness to a drug may alter depending on base line

pulmonary function and exercise response at the

time of the study. Clinically, asthmatic patients do have different responses to exercise at different

times and reproducibility of EIB has been shown to

diminish as time elapses between studies.’4

In summary, the participation of the vagal path-way in the pathogenesis of EIB was demonstrated

in those patients who were protected by SCH 1000,

but it appears to play a minor role and suggests

multifactorial involvement in EIB. SCH 1000 was

shown to be an effective bronchodilator with

mini-mal side effects. The bronchodilation was

compa-rable to but not better than that of fenoterol. As an

EIB inhibitor, it depended on a relatively normal

base line and only a moderate deterioration

follow-ing exercise, whereas fenoterol depended on the

exercise response alone. Although anticholinergic

drugs are not very extensively used, SCH 1000 may

be useful in some patients in whom the $2

adrener-gic drugs cause significant side effects or are

con-traindicated.

REFERENCES

1. Anderson SD, Silverman M, K#{246}nigP, et al: Exercise-induced

asthma. Br J Dis Chest 69:1, 1975

2. Godfrey S, K#{246}nigP: Inhibition of exercise-induced asthma

by different pharmacological pathways. Thorax 31:137, 1976 3. Poppius H, Salorinne Y: Comparative trial of salbutamol

and an anticholinergic drug, SCH 1000, in prevention of exercise induced asthma. Scand J Respir Dis 54:142, 1973 4. Borut TC, Tashkin DP, Fischer TJ, et al: Comparison of

aerosolized atropine sulfate and SCH 1000 on

exercise-in-duced bronchospasm in children. J Allergy Clin Immunol

60:127, 1977

5. Kivioog J: The effect of pretreatment with atropine in exercise-induced bronchoconstriction. Pediatrics 56(suppl): 940, 1975

6. Chan-Yeung M: The effect of SCH 1000 and disodium

crom-oglycate on exercise-induced asthma. Chest 71:320, 1977 7. Tinkelman DG, Cavanaugh MJ, Cooper DM: Inhibition of

exercise-induced bronchospasm by atropine. Am Rev Respir

Di.s 114:87, 1976

8. Engelhardt A: Pharmacology and toxicology of Atrovent.

Scandinavian Symposium on Chronic Obstructive Airway Disease 1978. Stockholm, A Lingren & S#{246}ner,M#{246}lndal, 1979,

p 110

9. Ahonen A, Alanko K, Mattson K: Bronchodilator action of

two different doses of ipratropium bromide (SCH 1000)

compared with fenoterol and placebo. Curr Ther Res 24:65, 1978

10. Gross NJ: SCH 1000: A new anticholinergic bronchodilator. Am Rev Respir Dis 1 12:823, 1975

11. Weinberg EG, Shore SC, Marshall S, et al: The effect of

fenoterol (berotec) on exercise-induced asthma in children.

Med Proc 18:73, 1972

12. Eggleston PA, McMahan SA: The effects of fenoterol, epheclrine, and placebo on exercise-induced asthma. Chest 73:1006, 1978

13. Pulmonary terms and symbols: A report of the ACCP-ATS

Joint Committee on Pulmonary Nomenclature: Chest 68:

583, 1975

14. Silverman M, Anderson SD: Standardization of exercise

tests in asthmatic children. Arch Dis Child 47:882, 1972 15. Weng T-R, Levison H: Standards of pulmonary function in

children. Am Rev Respir Dis 99:879, 1969

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1980;66;109

Pediatrics

R. Yeung, G. M. Nolan and H. Levison

Bronchospasm in Children

Comparison of the Effects of Inhaled SCH 1000 and Fenoterol on Exercise-Induced

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