Journalof Asthma, 33(6), 407-41 5 (1996)

Efficacy and Side Effects of Beta,-Agonists by

Inhaled Route in Acute Asthma in Children:
Comparison of Salbutamol, Terbutaline, and
Fenoterol
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Deolinda M. F. Scalabrin, M.D., Dirceu Solk, M.D., and

Charles K. Naspitz, M.D.
Diuisioii of Allergy, Clinical lmiizunolopj and Rheunzatolopj
Department of Pediatrics
Universidnde Federal de Siio Paul0
Siio Paulo, Brazil
For personal use only.

ABSTRACT
Thirty-seven separate episodes of acute bronchial asthma were studied in 21
asthmatic children. The bronchodilator, cardiovascular, and tremorigenic re-
sponses following administration of salbutamol (SAL), terbutaline (TER) and
fenoterol (FEN) by closed-port intermittent nebulization were compared for a
period of 8 hr. SAL was used at the maximum dose recommended by the
manufacturer and TER and FEN at theaveragedoses commonly used in children.
Eleven acute attacks were treated with SAL, 12 with TER, and 14 with FEN.
Pulmonaryfunction was evaluated by clinical assessment and by the spirometric
indices FEVi and FEF25-75. Tremor was objectively measured, as well as heart
rate (HR), respiratory rate, and blood pressure. The onset of bronchodilating
effect occurred at 5 min for all three drugs and there were no differences in
intensity and duration of bronchodilation between drugs. All three drugs caused
rapid onset of tremor (5 min) and this tended to be more intense with SAL. There
was a slight decrease in HR in the TER group, whereas SAL and FEN caused
increase in HR, with mean values significantly greater than in the TER group
from 5 to 30 min after drug administration. Our results indicate that the three
short-acting beta~agonistsstudied are equally effective in treatment of acute
bronchospasm by the inhaled route in children, in the doses used. Our findings

Address for correspondence: Deolinda M. F. Scalabrin, M.D., Al. Equador, 8, CEP 0630CL000,Carapicuiba, SP, Brazil.

407
Copyright 01996 by Marcel Dtkker, Inc.
 408
imply that a dose of SAL twice as great as that commonly used by nebulization
in children is equipotent to those usually employed for TER and FEN, as far as
therapeutic effect is concerned, but it could generate more intense tremorigenic
and tachycardic side effects.
INTRODUCTION
Asthma prevalence, morbidity, and mortal-
ity had shown a worldwide rising trend in the
last two to three decades, and only very re-
cently are decreasing or tending to plateau in
J Asthma Downloaded from informahealthcare.com by University of Newcastle on 12/28/14
some countries (12).The beta-adrenergic ago-
nists have been implicated in this trend and
remain the focus of intense controversy (14).
The safety of long-term use of these drugs has
been especially debated, so the current guide-
lines in the management of asthma had cau-
tiously recommended use of beta2-agonists
only on an "as needed" basis (5).
Tremor is the most common side effect of
beta2drugs, but the cardiovascular effects raise
For personal use only.
the most concern. It has been suggested that
fenoterol (FEN)has more adverse cardiovascu-
lar effects than salbutamol (SAL)or terbutaline
(TER) (6), but it is not clear whether this differ-
ence is due to a lesser selectivity of fenoterol for
beta2-receptorsor because it has been marketed
at a higher equivalent dose than other beta2-
agonists (3,7).When risk per 100 pg was calcu-
lated to compare SAL microgram for micro-
gram with FEN, the risks of death and near-
death seemed to be similar (3).
In view of these conflicting reports, we car-
ried out the present study comparing therapeu-
tic efficacy and side effects of three short-acting
beta2-agonist drugs available to treat acute
bronchospasm: SAL, TER,and FEN. We treated
children in acute asthma attack by nebulizing
FEN and TER in single average doses currently
recommended by the manufacturers and SAL
in a dose (5 mg) that corresponds to the upper-
limit dose recommended by the manufacturer.
This dose was established because, in a prelimi-
nary comparative study, a smaller dose (2.5
mg) administered by open continuous nebuli-
zation in children seemed to be insufficient to
give maximum bronchodilator response. There-
fore, we intended to determine if that previous
Scalabrin, Sole, and Naspitz
impression about SAL dosage held true when
the drugs were nebulized via a closed intermit-
tent system, in order to add data to the issue of
equipotent dosing of these drugs.
METHODS
Study Design
The study was designed as a parallel, single-
blind trial. Thirty-seven different episodes of
acute bronchial asthma were studied in 21 asth-
matic children, 12 boys and 9 girls. Their ages
ranged from 7 to 14 years (mean 10.41),and the
mean weight was 33.84 k 10.58. Children had
to demonstrate an FEV, lower than 80% of
normal predicted value and should not have
taken long-acting theophylline, antihista-
mines, or corticosteroids for 24 hr and beta-ad-
renergic agents or other bronchodilator medi-
cation for 12 hr before the study. Subjects were
randomly assigned to receive one of three treat-
ment drugs by closed-port intermittent nebuli-
zation: SAL, TER, or FEN. Some subjects en-
tered the study more than once, in different
acute episodes of asthma; in those patients,
each episode was treated with a different drug.
The number of acute attacks treated by each
drug was: 11 with SAL, 12 with TER, and 14
with FEN. Parental informed consent was ob-
tained.
The dose of SAL used was 5 mg, irrespective
of body weight. The dose of TER was 0.1 mg/
kg (maximum 4.0 mg), and FEN was used in a
dose of 0.083 mg/kg (maximum 2.5 mg).
Procedures
Clinical assessment of the patients was
made according to a clinical scoring system
(Table 1) (8). Spirometry was performed in a
Vitatrace model 130dry spirometer (Sociedade
Comercial Pr6 Medico, R.J.). The best of three
 Inhaled SAL, TER, and FEN in Acute Asthma
Table 1. Clinical Score of Patients with Acute Asthma
CLINICAL
CRITERIA SCORE 0 1
Wheezing None Terminal
expiratory
Retract ions None Mild
Clinical score is the sum of wheezing plus retractions score.
maneuvers for each studied spirometirc pa-
J Asthma Downloaded from informahealthcare.com by University of Newcastle on 12/28/14
rameter (FEV, and FEF2575)was recorded at
each time point.
Tremor was objectively measured accord-
ing to a previously employed procedure (9),
using a movement sensor (n. 230, Siemens-
Elema AB) that was taped to the extensor sur-
face of the right index finger with the tip over
the proximal phalanx. The patient had the
right arm resting in a sling bandage and the
hand dangling from the sling mechanism.
For personal use only.
Tracings were quantitated in an electromag-
netic table (Summagraphics Summasketch
MM1201), using a graphic software (Sigmas-
can, version 3.0, Jandel Scientific). Measure-
ments are expressed in centimeters and repre-
sent changes in amplitude and frequency of
tremor, during a period of 10 sec. Irregular
tracings were not included, so the number of
tracings of tremor in each treatment group was
reduced to 10.
Heart rate (HR) was measured by precordial
auscultation, over a full minute. Blood pressure
(BP) was measured with the same sphygmo-
manometer (Perfect-Aneroid ERKA) on the left
arm.
Before beginning drug therapy, all subjects
received a nebulization with 2 ml of saline. We
considered pulmonary f'unction tests (PFTs)
obtained 10 min after this as baseline values.
PFTs, measurements of tremor, HR, and respi-
ratory rate (RR) were recorded before and at 5,
15/30! 60,120,180,240,300,360, and 480 min
after drug administration. Owing to the need
for temporal coordination with the other meas-
ures, BP was measured before and at 30,60,120,
180, 240, 300, 360, and 480 min after drug ad-
ministration. After 180 min, the study was con-
409
2 3 4
Entire Ins and exp No aeration
expiratory wheezing
heard without
stethoscope
Moderate Severe
tinued only in those children whose FEVl value
remained above 15% from baseline with clini-
cal score less than 3.
Drugs were diluted in 2 ml of saline, and
oxygen in a flow rate of 7 L/min was used to
generate the aerosol, which was inhaled via a
mouthpiece of a closed intermittent nebulizer
(De Vilbiss nebulizer model 645), with the pa-
tient using noseclips. The average time spent to
complete treatment was 15 min.
The three treatment groups were compared
regarding all studied variables, as well as the
duration of bronchodilator effect, by the analy-
sis of varianace (ANOVA) test of Kruskal-Wal-
lis. When these ANOVA results were signifi-
cant, the Dunn test was used. The level of
significance for all tests was p < 0.05.
R ES ULTS
There were no significant differences on se-
verity of presentation of the patients, as as-
sessed by the analysis of percentage of pre-
dicted FEVl (Table 2). Similarly, the analysis of
absolute values of FEVl and FEF25=15in the
baseline time (after inhalation with oxygen and
saline), as well as the percentage values of these
variables in relation to initial values, showed
no difference between groups. There was only
one difference between treatment groups: in-
itial absolute values of HR of the TER group
were statistically significantly greater than
those of the FEN group. After drug administra-
tion, all studied variables were compared as
percentage changes from baseline (for spiro-
metric indices) or from initial values (for the
other variables) at each examination time.
 410 Scalabrin, Sole, and Naspitz

Table 2 . Mean Initial dnd Baseline” Values of Measured Variables for Each Treatment Group
VARIABLE SA L TER FEN
Number of treated Crises 11 12 14
Mean initial FEVi (L) 0.90 f 0.36 0.86 f 0.48 1 . 1 3 f 0.50
Mean of OO/ predicted FEVi 42.45 42.92 53.1 1
Range of YOpredicted FEVi 24.00-6 2.90 14.30-73.80 18.90-79.80
Mean baseline FEVi (L) 1 . 0 4 f 0.53 0.94 f 0.44 1.18 f 0.50
Mean baseline FEF25-7s (L/s) 0 . 7 9 f 0.41 0.71 f 0.44 1.01 f 0.65
b
Mean initial tremor (cm) 20.65 f 6.04 18.62 f 3.54 20.96 f 5.32
Mean initial HR 100.00 f 12.77 *106.67 f 15.38 92.71 f 11.30
Mean initial SBP 105.45 f 14.57 109.58f15.44 105.36 f 10.09
Mean initial DBP 70.91 f 9.17 7 4 . 1 7 f 9.73 73.21 f 7.99
%seline PFTs correspond to the values measured 10 min after inhalation with oxygen and saline.
bThe number of treated crises in which tremor was measured was 10 for all treatment groups.
J Asthma Downloaded from informahealthcare.com by University of Newcastle on 12/28/14

‘Significantly greater than the FEN group ( p < 0.05).

SAL = salbutamol; TER = ter1)utaline; FEN = fenoterol.

For assessment of response to bronchodila- statistically significant differences in RR fol-

tor therapy, emphasis was on FEVl as the criti- lowing administration of each of the three
cal variable. The onset of bronchodilating effect drugs.
was defined as the first time point at which the Time of peak was defined as the time point
For personal use only.

mean of percentage change of FEVl from base- at which the mean of percentage change was
line reached 15%. It occurred at 5 min for all maximum, for FEV, and tremor (peak re-
three drugs (Fig. 1). The increases in FEVl were sponse).Time of peak of bronchodilating effect,
not significantly different between groups. In- assessed by FEV1, was 15 min for FEN and 60
creases in FEF25-75in the three treatment groups min for SAL and TER.
were parallel to those in FEVl. There were no Duration of bronchodilation was defined
for each crisis as the length of time during
which the FEV, was increased by 15% or more
over the baseline with clinical score less than
3. Mean duration of bronchodilator effect was
365 min for the group treated with SAL, 285
min for the group treated with TER, and 287
min for the group treated with FEN. Statistical
analysis of the duration of bronchodilation
showed no significant differences between
treatment groups. The numbers of treated cri-
ses with FEVl greater than 15%from baseline
N
T 40{
and clinical score less than 3, from 180 min on,
therefore remaining in the study, are shown in
fi$ ,5. ........... -
Table 3.
R
Tremorigenic effect or “pharmacological
011 I 1 tremor,” meaning tremor caused by the drug
6 15 30 60 120 180
TIME (MINUTES) and not physiological resting tremor, was con-
sidered as a mean of percentage change from
Figrrc I. Mean percent change in FEVi from baseline,
predrug readings of 50% or more. Onset of
during the first 180 min after administration of salbutamol
(SAL), terbutaline (TER), or fenoterol (FEN)by closed-port tremorigenic effect was registered at 5 min for
intermittent nebuli7i1tion. all three drugs; peak of tremorigenic effect was
 Inhaled SAL, TER, and FEN in Acute Asthma 41 1

Table 3. Number of Treated Crises with tremor greater than 50% from initial
Remaining in the Study in Each Group from value, from 5 to 180 min following administra-
180 min on After Drug Administration tion of drugs (Fig. 3). After 180min the calcula-
TIME^ SAL TER FEN tion of this incidence becomes inaccurate be-
cause the total number of patients remaining in
240 9/1 1 7/12 8/14 the study starts to diminish in the studied
300 711 1 511 2 711 4 groups (Table 3).
360 7/11 4/12 7/14 Mean percent changes in HR, systolic blood
420 611 1 411 2 611 4
pressure (SBP), and diastolic blood pressure
480 611 1 411 2 311 4
(DBP) from initial values, following adminis-
aMinutes after drug administration. tration of the three drugs, are shown in Figures
From 180 min forward, o n l y crises with FEVl > 15% 4,5, and 6. TER caused mean percent decreases
from baseline and clinical score <3 remained in the
study.
in HR; these values were significantly lower
SAL = salbutamol; TER = terbutaline; FEN = fenoterol. than those of SAL and FEN from 5 to 30 min
J Asthma Downloaded from informahealthcare.com by University of Newcastle on 12/28/14

after drug administration. BPchanges were mi-

registered at 5 min for FEN and TER and at 15
min for SAL. SAL tended to cause more intense
tremor than the other two drugs, achieving
significantly greater values than ITR, at 30 min,
and than FEN, at 180 min after drug admini-
stration (Fig. 2).
Duration of tremor was considered for each
For personal use only.
nor and no significant differences between
drugs were found at any examination time.
We observed individual susceptibility to the
tachycardic effect of SAL and FEN. At 5 min, 3
of the 11 patients receiving SAL had increases
in HR of 36,60, and 70 beats/min, and 2 of the
14 patients of the FEN group had increases of
38 and 60 beats/min. These values brought the
mean for their respective groups to the high

treatment group as the last examination time

values shown in Figure 4 and fell gradually
point at which the mean of percentage changes
during the next examination times.
of tremor from initial values remained 50% or
Individual variation in the sensitivity to tre-
more. For the group treated with FEN, duration
morigenic effect was also present. There were
of tremor was 60 min, whereas for the groups
at least 3 patients in each treatment group
treated with SAL and TER it was 180 min.
whose increases in tremor at 5 min after drug
Incidence of tremorigenic effect was as-
administration were 3-7 times greater than in-
sessed by calculating the percentage of patients
itial values.

; 180
DISCUSSION
E
150
R Homogeneity of severity of crisis validated
p 120 the comparison of pulmonary effects between
E the groups. The establishment of values post
R
c 90 inhalation with saline and oxygen as baseline
E for spirometric indices gives an additional
N
T 60 rigor to this study because it is evaluating the
C ”therapeutic effect” without the bronchodila-
H 30
A tion that could be due to the use of saline and
N
0 0 1
oxygen. It is assumed that oxygen can interfere
with bronchoconstriction, as it can increase the
threshold to bronchoconstriction in metha-
choline challenges in asthmatic patients (10).
A dose of SAL higher than the standard dose
butamol (SAIL), terbutaline (TER), or fenoterol (FEN) by
closed-port intermittent nebulization.*Significantly smaller recommended for children in acute asthma was
than SAL ( p < 0.05). also used in a study by Schuh et al. (ll),who
 412 Scalabrin, Sole, and Naspitz

% of patients with tremor >SO% from initial value

A 1

5 15 30 60 120 180
TIME (MINUTES)
Figure 3. Incidence of "pharmacological tremor," expressed as percentage of patients with tremor greater than 50% from
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initial value, from 5 to 180 mi11after administration of salbutainol (SAL), terbutahe (TER),or fenoterol (FEN)by closed-port
hitermittent nebuliwtioii.

administered doses of 0.30 mg/kg (maxi-
mum10 mg/dose) at 3-hourly intervals, which
resulted in greater pulmonary improvement
with no significant differences in side effects
when compared with a standard-dose group
(0.15mg/kg). Simdarly, doses of 5 mg of nebu-
For personal use only.
struction, there is effective aerosol penetration
and deposition in the lungs causing rapid, po-
tent, and durable bronchodilation, and leading
to plasma concentration similar to that ob-
served after intravenous administration (12).
There are contradictory results regarding

lized SAL repeated twice in adults in acute
severe asthma were highly effective andcaused
no remarkable side effects (12).
In our study, the bronchodilator action was
rapid in onset (5 min), intense, and sustained
for all three drugs, with no significant differ-
ence between them. As has been demonstrated
for nebulized SAL, despite major airway ob-
dose equivalence of SAL, TER, and FEN in
different studies (6,7,13,14).Higher topical ac-
tivity has been reported for FEN by inhaled
route, when compared with TER (13); on the
other hand, FEN demonstrated smaller bron-
chodilating potency when compared micro-
gram per microgram with SAL (14). Our find-
ings indicate that these drugs were equally

HEART RATE
SYSTOLIC BLOOD PRESSURE
50
P 45
E
R p 40
C
E
6 35
N cE 30
T N 25
C T 20
H C 15
A H
N A lo
G N 5
E 0
€ 0
- 10 -'6e i- s 30 60 120 I00
-5
-101
TIME (MINUTES) 30 60 120 180
TIME (MINUTES)
Figure 4. Mean percent change in heart rate from initial
value, durhig the first 180 min after administration of sal- F i p r c 5. Mean percent change in systolic blood pressure
butamol (SAL), terbutalhie (TER), or fenoterol (FEN) by from initial value, durhig the first 180mhi after admhiistra-
closed-port intermittent nebulization. *Significantlygreat- tion of salbutamol (SAL), terbutahie (TER), or fenoterol
er than TER ( p < 0.05). (FEN) by closed-port intermittent nebulization.
 Inhaled SAL, TER, and FEN in Acute Asthma
50 -
45 -
40-
R 35-
cE 30-
N 25-
T 20-
c 15-
; 10-
N 5-
-1OJ
30 60 120 1‘80
TIME (MINUTES)
Figure G. Mean percent change in diastolic blood pres-
sure from initial value, during the first 180 m h after ad-
J Asthma Downloaded from informahealthcare.com by University of Newcastle on 12/28/14
ministration of salbutamol (SAL), terbutaline (TER), or
fenoterol (FEN) by closed-port intermittent nebulization.
effective in treatment of acute bronchospasin
by the inhaled route in children, in tlie chosen
doses. This implies that a dose of SAL twice a s
great as that commonly used by nebulization in
children has the same bronchodilator capabil-
ity of those usuallyemployed for TER andFEN.
For personal use only.
There are still questions regarding the ade-
quacy of peripheral lung deposition of drugs
during an acute attack of asthma. We found
very similar results for FEVl and FEF2L75,
which probably nieans that both large and
small airways were reached by the studied
drugs in our patients.
TER had demonstrated bronchodilator ac-
tion similarly intense but significantly longer
lasting than FEN (13). Ln our study, the iiiean
duration of bronchodilating action was greater
for SAL but did not reach statistical signifi-
cance. Therefore, based on tlie mean duration
of broncliodilating effect found, we can coil-
firm the generally rccommended dosing fre-
quency of 4-6 hr for the studied drugs, when
used by inhalation on an “as needed basis” (5).
According to Konig et al. (15),similar intensity
but different duration of the bronchodilator
effect can be due to different dose equivalences,
a s they showed in a comparative study of FEN
and SAL This could possibly be applied to our
findings of a greater percentage of patients in
the SAL group (%‘%I) with persistence of bron-
chodilator effect at 480 min after drug adminis-
tration, as compared with only 33% and 21% of
the TER and FEN groups, respectively
413
Regarding cardiovascular effects, the sig-
nificant difference detected between initial val-
ues of HR in the TER and FEN groups does not
invalidate the finding of greater tachycardic
effect of FEN, when compared with TER, as all
the comparative statistical analyses were made
considering the percent changes from initial
values. SAL also caused significantly greater
tachycardic effect than TER. We detected no
significant difference between the increases in
HR caused by SAL and FEN; this is in disagree-
ment with the findings of Bellamy and Penketh
(14), who found that, for the same bronchodi-
lator effect, FEN caused a greater increase in
HR tlian SAL, both drugs being administered
by metered-dose inhaler (MDI). However, our
findings are in accordance with those of Gray
et al. (13), who found a lower beta*-selectivity
for FEN, a s it caused a greater increase in HR
than TER, in equipotent doses.
Although systemic vascular resistance can
fall in response to beta2-adrenergic vasodila-
tion, actual changes in BP caused by beta2
drugs have been reported to be only minimal
(13), which is in accordance with our findings.
For tremor, we chose a percentage increase
of 50‘%in relation to initial values as repre-
senting “drug effect” (9), according to the defi-
nition by Lipworth et al. (16), who based this
value on the fact that an increase in tremor of
46‘L is required in a n individual subject to rep-
resent a true drug response. Additionally, there
are reports that tremor needs to reach approxi-
mately twice the initial levels to be noticed
subjectively (17).
In the present study, the tachycardic as well
as the tremorigenic effect occurred very soon
after drug administration for all three drugs.
This very rapid onset suggests quick systemic
absorption of the drugs, via bronchial, naso-
pharyngeal, nasal, and/or buccal mucosa. The
inhaled part of the drug could be causing
tremor and tachycardia, a s suggested by Col-
lier et al. (18), who detected significant tachy-
cardia (mean increase in HR of 26%) when SAL
was administered by MDI but not when the
drug was deposited in the buccal cavity. It has
been demonstrated for SAL that systemic ab-
sorption is remarkably fast from lungs, giving
rise to systeiiiic effects as early as 5 inin after
inhalation (19).
 414
In our study, the effects of tremor and HR
changes remained 60-180 min; 60% of the pa-
tients who received SAL still had tremor at 180
min. The rather long duration of side effects
that we found after aerosol administration of
all three drugs was probably due to sustained
removal from the lung into the systemic circu-
lation (20). On the other hand, we think that the
drugs could be acting in part as oral drugs. It
has been shown that, when a drug is inhaled,
about 10% of the dose reaches the peripheral
airways and the rest is partially lost in the
J Asthma Downloaded from informahealthcare.com by University of Newcastle on 12/28/14
apparatus or deposited in the oropharynx and
swallowed (21). Therefore, even though medi-
cations were given by nebulization, there was
a presumed large dose swallowed and ab-
sorbed by the gastrointestinal system.
Pulmonary absorption after inhalation, as
well a s plasma levels, had been demonstrated
to be highly variable among individual patients
(21). This could explain the high interindivid-
ual variability in tremorigenic as well as tacliy-
For personal use only.
cardic effect found in our study.
From our results, it seems that the doses cho-
sen for the three studied drugs were equipotent
in relation to bronchodilating effect but not in
relation to sideeffects. Other studies (13,14)had
also shown that therapeutic equipotency may
not correspond to side effects equipotency. It is
accepted that tachycardia is in part caused by a
compensatory mechanism in response to beta2-
adrenergic vasodilation and in part due to a
positive inotropic beta, effect. Therefore, we
could suggest the presence of different beta2-
adrenergic receptor specificities of these drugs.
Finally, we cannot rule out the existence of dif-
ferences between pulmonary and vascular
betaz-receptors. Structural and/or functional
differences could also be playing a role in the
response of skeletal muscle beta2-receptors to
betaz drugs.
In conclusion, we found no differences re-
garding bronchodilator effect between SAL,
TER, and FEN. As far as broncliodilation effi-
cacy is concerned, this implies that the choice
of one of these three drugs, in the doses used in
the present study, by the inhaledroute, isirrele-
vant. SAL seems to have a slightly greater tre-
morigenic potential than FEN or TER, in the
therapeutic equipotent doses employed; never-
theless, tremor is usually a well-tolera ted side
Scalabrin, Solk, and Naspitz
effect (19) and therefore does not require spe-
cial concern in the clinical practice. SAL and
FEN also have greater tachycardic potency
than TER, suggesting lesser betaz-adrenergic
specificity of the first two drugs. If tachycardic
effect is prominent in a particular individual, a
smaller dose of SAL or FEN should be consid-
ered for treatment in futrure crisis.
ACKNOWLEDGMENTS
We thank Drs. Neil Ferreira Novo and Y6ra
Juliano for the statistical analysis, and Dr. Esper
AbrFio Cavalheiro for helpful discussions.
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