Eur Aesplr J
1991, 4, 544-550
Plasma levels and effects of salbutamol after inhaled
or i. v. administration in stable asthma
C. Janson
Plasma levels and effects of salbutamol after inhaled or i.v. administration in
stable asthma. C. Janson.
ABSTRACT: The response and plasma levels of inhaled (0.15 mg•kg'1) and
intravenous salbutamol (5 J.tg•kg'1) were studied in 12 patients wbo bad
previously been Included in a study of acute severe asthma and were now
in a stable phase. The maximal value for change (A) In plasma salbutamol
compared with the pretreatment value was higher after i.v. than after
Inhalation treatment (59 vs 30 nmol·t1) but the areas under the curve (AUC)
during 90 mins after treatment were similar for the two administration
routes. The inter-individual differences In peak plasma salbutamol and
AUC for A plasma salbutamol were much greater after inhalation than
after i.v. infusion. Immediately after treatment there was a greater Increase
in pulse rate (mean+17 vs +6 beats·min) and lower serum potassium level
(mean -0.3 mmoH1) after i.v. than after inhalation treatment. The increase
in peak expiratory flow (PEF) measured 90 min after the start of treatment
(85 vs 31 /·mln·•) and as AUC was significantly higher after Inhalation than
after i.v. treatment,
Six patients had received i.v. treatment In the acute asthma study: in
these patients APEF Immediately after i.v. treatment was significantly
lower in the stable situation (+49 vs +115 l·min·1). There was also a significant difference in the effect on the pulse rate immediately after i.v.
treatment, with a decrease In the acute asthma and an increase ln the
stable asthma situation (·5 vs +16 beats·min·1).
Dept of Lung Medicine, Uppsala University,
Akademiska Sjukhuset, Uppsala, and Dept of Clinical
Pharmacology, Sahlgren's University Hospital,
Gothenburg, Sweden.
Correspondence: C. Janson, Department of Lung
Medicine, Akademiska Sjukhuset, S· 751 85 Uppsala,
Sweden.
Keywords: Asthma; inhalation; intravenous; plasma
levels; salbutamol.
Received: March 26 1990, accepted after revision,
January 16, 1991.
This study was supported financially by the Bror
Hjerpstedt Foundation, Uppsala, the Swedish Heart·
Lung Foundation, Stockholm and AB Glaxo
Lllkemedel, M6Indal, Sweden.
Eur Respir J., 1991, 4, 544-550.
~ 2 -agonists are commonly used as first line treatment
in all forms of asthma [1]. The treatment can be
administered either by inhalation or systemically, i.e.
intravenously, subcutaneously or orally. In several studies the effects of inhaled and infused j32-agonists in the
treatment of acute asthma have been compared: in
several studies these alternative routes were found to be
equally effective [2-5] and in others intravenous infusions seemed to be more effective in relieving
bronchoconstriction in severe asthmatic attacks [6, 7].
In a Swedish multicentre study of 176 patients with acute
severe asthma, salbutamol was, however, found to be
more effective when given as a high-dose inhalation than
when infused intravenously [8].
The principal aim of the present study was to compare
the plasma levels, anti-asthmatic effects and systemic
effects of inhaled and intravenous salbutamol treatment
in doses which are used in the emergency treatment of
acute asthma [SJ. A further aim was to compare the
effect of the treatments in acute asthma with that in a
non-acute situation. The study was therefore conducted
on asthmatic patients who had previously taken part in
the acute asthma study and who now were in a stable
phase.
Material and methods
The study lasted from June to September 1988. Twelve
patients (mean age 54 yrs (range 33-71), 6 men and 6
women), were recruited from the Swedish multicentre
study of acute asthma performed two years earlier. These
twelve lived in Uppsala. All the patients had bronchial
asthma as defined in the earlier study [8]. No patient
had severe heart disease or hypertension. The patients
anti-asthmatic maintenance treatment is presented in
table 1. All the patients were now in a stable phase - e.g.
they had no acute asthmatic symptoms for at least two
weeks. They all gave informed consent and the study
was approved by the Ethics Committee of the Medical
Faculty at Uppsala University.
The patients were instructed not to take oral ~ 2 -agonist
drugs for 24 h or inhaled ~2 -agonists for 6 hours prior
to the two treatments described below. Each patient received both of the following treatments: A: Inhalation of
0.15 mg·kg·1 of nebulised salbutamol (Ventoline, Glaxo)
in an undiluted solution (5 mg·/·1) from a Pari-lnhalier
Boy. This nebuliser, which is driven by compressed air,
is reported to produce a mass median particle diameter
of 9.7 mm, with an intrapulmonary deposition of 35% of
545
INHALED AND INTRAVENOUS SALBUTAMOL
Table 1. - Sex, age, maintenance treatment and peak expiratory flow rate (PEF), prior to
inhaled and intravenous salbutamol treatment
Patient
Sex
Age yrs
Maintenance treatment
PEF /·min· 1
in h.
i.v
!3
145
380
420
445
140
220
205
230
480
400
340
430
No
1
2
3
4
5
6
7
8
F
F
M
F
M
M
F
M
9
F
10
M
M
F
11
12
62
33
47
55
53
70
67
62
34
42
71
52
inh.!3
inh.B
inh.B
inh.B
inh.B
inh.B
inh.B
inh.B
inh.B
inh.6
inh.B
inh.B
oral
oral
oral
oral
oral
oral
oral
oral
oral
oral
oral
oral
B
B
B
B
B
B
B
B
B
T
T
oral T
oral T
oral T
inh.C
oral T
oral T
oral T
oral T
oral T
inh.l
inh.C
inh.C
inh.C.
inh.C.
inh.C.
inh.C.
inh.C.
inh.C
inh.C
inh.C
oral T
oral c
oral C.
oral C
oral C
oral C
inh.C
oral C
135
380
430
415
170
220
190
210
490
375
265
445
B = B2·agonists, T = theophylline, I = ipratropium, C = corticosteroids
the particles [9]. B: Intravenous infusion of 5 1.1.g·kg·1
salbutamol (Ventoline, Glaxo) (50 1.1.g·ml·1) for 10
minutes.
The treatments were given on separate days with an
interval of 2 days to 3 weeks. The order of the treatments was randomized so that half of the patients received
the inhalation treatment first and the other half the i. v.
treatment first. Both treatments were given at approximately the same time of day in ten of the 12 patients.
One patient received the infusion 3 hours later than the
inhalation (11 a.m. and 8 a.m respectively), while another patient was given inhaled treatment 4 hours later
than the infusion (1 p.m. and 9 a.m respectively).
Blood samples for salbutamol and potassium assay were
drawn before, immediately after, and 15, 30, 45, 60 and
90 min after treatment. After centrifugation the plasma
was removed, frozen and stored in a freezer (-20°C) until
analysed. Salbutamol was assayed by a gas chromatographic mass spectrometric method (10). Potassium in
serum was analysed by flame photometry.
The following measures of the effect of the salbutamol
treatment were recorded before, immediately after treatment and 30, 60 and 90 min after the start of the
treatment: Peak expiratory flow rate (PEF), using a Wright
peak flow meter. The PEF value was also compared
with the patient's predicted value (%PEF) (11 ]. Pulse
rate by palpitation of the radial artery. Diastolic and
systolic blood pressures, measured with a sphygmomanometer. Side-effect score: the patients were actively
asked about the following symptoms, which they rated
from 0 (none) to 3 (severe): headache, nausea, abdominal
symptoms, palpitations, tremor, and any other symptoms.
The area under the curve (AUC) for change (~) in
plasma (p) salbutamol, PEF and pulse rate from 0 to 90
min was calculated by the trapezoidal rule from a plot of
the measured values versus time on linear co-ordinates
(12).
The results were compared with those obtained in the
same patients in the acute asthma study 2 years earlier
(8).
Statistics
A non-parametric paired test (Wilcoxon test) was used
for analysing the significance of differences between the
effects of the two modes of therapy and between those
of the therapy given in the acute and stable situations.
To test the correlation between the plasma level of
salbutamol measured as change from baseline (~
p-salbutamol) and the effect variables 6 PEF, ~ pulse
rate, 6 blood pressure and 6 potassium, the following
procedure was carried out: the correlation coefficient was
calculated for each patient and the Wilcoxon test was
applied to the coefficients. The correlation between the
peak 6 plasma salbutamol level and the effect of the
treatment was tested with Spearman's rank correlation
test.
A p value of less than 0.05 (two-tailed test) was considered significant. The results are presented as
mean:t:(so).
Results
There were no significant differences as regards any of
the measured variables before the two treatments.
The mean duration of inhalation was 13 min (range 1015 min), whereas all i. v. infusions were given during 10
min.
Salbutamol plasma levels
All patients claimed to have refrained from taking oral
for 24 hand inhaled ~ 2-agonists for 6 h prior
to the study. In one patient (patient 9), however, the
salbutamol level was 31.8 nmoH1 before the inhalation
but was not measurable before the i. v. treatment. This
patient was th~refore excluded whenever the two modes
of therapy were compared. In addition measurable
salbutamollevels were found in three patients before the
~2 -agonists
C. JANSON
546
inhalation treatment (4.6, 6.3 and 9.2 nmol-1'1), and in two
before the i. v. treatment (4.6 and 9.2 nmoH1).
The individual changes in the plasma salbutamol level
after treatment are presented in table 2 and fig. 1. The
peak increase in the plasma level was greater after the
i.v. treatment than after the inhalation in all patients (58.8
(16.2) vs 30.2 (21.0) nmol·f'l p<0.001). The mean ~
p-salbutamol level was significantly higher 15 min after
and significantly lower 60 and 90 min after the start of
the i. v. treatment compared with the inhalation treatment
(fig. 2).
After i. v treatment there was a significant positive intraindividual correlation between I!. p-salbutamol and I!. pulse
rate (p<0.01) and between I!. p-salbutamol and I!. systolic
blood pressure (p<0.05). A significant negative correlation was found between I!. p-salbutamol and I!. diastolic
blood pressure (p<O.OS) after i. v. treatment. After
inhalation treatment there was no significant correlation
between plasma salbutamol and cardiovascular effects.
For the group as a whole no significant correlation was
found in either treatment alternative between the maximal increase in the plasma level and the effect of the
treatment (~ PEF, ~ pulse rate, ~ blood pressure or ~
serum potassium) at any time point.
There was a ten-fold inter-individual variation in AUC
for a ~ p-salbutamol after the inhalation, while the variation was much lower after i. v. treatment (table 2).
Four patients had a higher AUC value for I!. p-salbutamol
after the inhalation than after i.v. treatment. All of these
patients had a higher AUC for I!. pulse rate and three
of them had a lower AUC for I!. PEF after inhalation
than after i. v. treatment. Of the seven patients who had
Table 2. - Maximal increase in plasma salbutamol concentration, time of maximal
concentration and area under the curve (AUC) for !J.. p-salbutamol from before
treatment to 90 min after its start
Patient
Max. level nmoH1
i.v
No
inhal.
1
2
3
4
12
17.0
37.3
22.7
75.6
13.0
10.7
58.5
15.1
11.8
41.7
20.0
21.2
range
11 - 77
5
6
7
8
9
10
11
AUC nmoH1·h
Time of max. (min)
inhal
i.v
inhal
38.7
38.0
83.2
84.9
72.1
66.0
66.8
51.1
43.5
55.2
45.7
60.2
30
30
15
90
45
45
45
90
12
45
30
90
10
10
10
10
10
10
10
10
10
10
10
10
14.7
35.6
17.4
82.1
14.3
10.5
63.8
15.4
8.4
45.3
23.2
24.5
26.3
19.4
31.4
40.2
28.4
28.7
30.6
20.0
19.1
27.6
26.6
43.9
38- 85
12- 90
10
8- 82
19- 44
Intravenous salbutamol (5!Ag·kg-1)
~
100
...~
-+-+-
......
80
~
0
E
E 60
.....
0
E
ea 40
_.,_
--o__.,_
-o-
s
---
iii
tl} 20
.....,._
--+-
.Q
--*-"
D.
0
i.v.
Inhaled salbutamol (0.15 mg·kg-1)
Petlent1
Patlent2
Patlent3
Patlant4
PatientS
Patient 6
Pal lent 1
Patient 8
Patient 9
Patient 10
Patient 11
Patient 12
100
......
...~
80
0
E
E 60
.....
0
E
40
~
.Q
~
20
A.
0
0
15
30
45
Tlmemln
60
75
90
0
15
30
45
Time mln
Fig. 1. - Plasma salbutamol concentrations after intravenous and inhaled salbutamol treatment.
60
75
90
547
INHALED AND INTRAVENOUS SALBUTAMOL
80
80
o lntravenoua
... Inhalation
60
40
20
15
30
45
60
90
0
15
30
90
60
0,2
0,0
.0,4
.0.6 .____.__.......__......_____.__ _
15 30 45 60
0
~
90
Tlmemln
Tlmt mln
Fig. 2. - Changes in plasma salbutamol, serum potassium, peak expiratory flow rate and pulse rate (me.aJU:sE) after
intravenous aod inhaled salbutamol (•p<O.OS, ..p<O.Ol).
-l
Patie nt 1
Patient 1 0
'c
l
j
l
A.
~~ ~~
0
"';"
·ec
j•
..J~
16
30
46
eo
76
eo
30
30
20
20
10
10
0
0
· 10
· 10
::I
16
A.
<I
30
46
eo
78
eo
0
18
30
46
eo
78
eo
0
16
30
46
eo
76
eo
16
30
48
eo
78
eo
0
240
2 40
c
180
1eo
&L
120
120
eo
eo
"';"
e
"'
A.
~
16
30
48
eo
T ime m ln
78
eo
T ime mln
Flg. 3. - Patterns of response to intravenous and inhaled salbutamol treatment in two patients
l.v .
lnh•l.
548
C. JANSON
a lower AUC for !l salbutamol after the inhalation than
after i. v. administration, 6 had a higher AUC for !l PEF.
These two patterns of response to the treatment are presented in fig. 3. For the group as a whole there was no
significant difference in mean AUC for !l p-salbutamol
between the inhalation and the i. v. treatment (31.5 (23.2)
1
VS 28.5 (7.6) nmoH ·h).
Systemic effects
There was a significantly larger increase in pulse rate
immediately after the i. v. treatment than immediately after
the inhalation treatment (17 (9) vs 6 (9) beats per min,
p<O.OS) (fig. 2). There was no significant difference
in the mean AUC values for !l pulse rate obtained after
the i. v. and inhalation treatments.
A decrease in serum potassium was noted in all the
patients after the i. v. salbutamol infusions at all
observations. There was no decrease 15 min after inhalation, but 8 patients showed a decrease between 30 and
90 min after this treatment. The mean maximum decrease
in potassium was -0.3 mmoH1 after both treatments (range
-0.2 to -0.6 after i. v. and +0.1 to -0.7 after inhalation
treatment). There was a significant difference in the
change in serum potassium 15 min after treatment
(-0.2 (0.2) after i.v. and +0.1 (0.3) after inhalation
treatment, p<O.OS) (fig. 2). No significant correlation
between ll p-salbutamol and !l potassium was found after
either treatment.
The main side-effects of the treatment were heart
palpitations and tremor. Two patients reported moderate
palpitations immediately after the i. v. treatment and one
patient reported moderate palpitations 30 min after
both the inhaled and i. v. treatment. Five patients reported moderate or severe tremor immediately after i. v.
treatment, while the number had decreased to two, 30
min after the start of this treatment. Two patients had
moderate or severe tremor immediately after the inhalation
and four patients 30 min after the start of this treatment.
No significant differences in side-effect scores were found
between the treatments at any point in time.
same patients in the acute asthma study. The baseline
pulse rates before the intravenous and inhalation treatments in this study were significantly lower (86 (13) and
86 (15) vs 114 (14) beats per min, p<O.Ol) and PEF higher
(310 (124) and 320 (124) vs 202 (36) l·min· 1• p<O.Ol) than
in the acute asthma situation. In the six patients who had
received i. v. treatment in the acute asthma study the
increase in PEF immediately after i. v. treatment was
significantly less pronounced in the stable situation (49
(61 ) vs 115 (63) l·min" 1) The individual responses to the
treatment are presented in fig. 4. There was also a
significant difference in the effect on the pulse rate
immediately after i. v. treatment, with a decrease in the
acute situation and an increase in the stable situation (5 (17) vs + 16 (7) l·min·1) (fig. 5). In the group of six
patients who had been treated with inhaled salbutamol in
the acute asthma study no significant differences in the
effects of inhalation treatment on PEF and pulse rate
were found.
The plasma salbutamol levels 55 and 90 min after i. v.
treatment in the acute asthma study (n=6) were
compared with those found at 60 and 90 min in the present
study. These values were 9.3 (4.8) vs 10.9 (3.1) and 1.4
(4.9) vs 7.3 (2.7) nmolP at the earlier and later time
points respectively. The differences were statistically
non significant.
Intravenous salbutamol Sltg·kg-1
PEF (% of predicted)
100
~
I'
~
50
I'
~
~
~
I'
:'Patient
1
I'
I'
I'
I'
I'
I'
~
I'
I'
~
3
5
7
9
10
mun
Inhaled salbutamol 0.15 mg·kg-1
PEF (% of predicted)
Effect on PEF
There was a tendency towards a greater increase
in PEF after inhalation than after i. v. infusion throughout
the study period, but the difference was only statistically
significant 90 min after treatment (fig. 2). The mean AUC
for !::. PEF was higher after inhalation than after i. v.
treatment (6840 (5760) vs 3130 (3360) l, p<O.OS);
this difference was greater in the patients with
the lowest pre-treatment PEF-values (r=0.7, p<O.OS)
100
-
50
~
I'
~
~
Patient
~
Effect in comparison with the acute asthma situation
A comparison was made between the effect of the
salbutamol treatment in this study and the effect for the
2
~
~
~
~
r"'
~ ~
I'
I'
4
acute uthma
~
~
6
8
G
I'
I'
I'
~
~
~
~
12
11
atable ulhma
~
~
0
mean
effect of treatment
Fig. 4. - Peak expiratory flow (% of the predicted) before and imme·
diately after intravenous and inhaled salbutamol treatment of acute and
stable asthma.
549
INHALED AND INTRAVENOUS SALBUTAMOL
..
'1:
120
ei
i
.c 100
•
--+-acute
....
---e-- stable
41
ID
•
.!
:1
D.
80
0
15
30
45
60
Time mln
Fig. 5. - Pulse rate (mean:sE) before and after intravenous salbutamol
treatment of acute and stable asthma.
Discussion
~ 2-agonists are considered to be the treatment of choice
in acute asthma, but the optimal route of administration
has been discussed for many years (13]. In the Swedish
multicentre study of acute severe asthma 0.15 mg·kg·1 of
inhaled salbutamol produced a greater degree of
bronchodilation than 5 ~-tg·kg· 1 of i. v. salbutamol, but the
systemic effects (change in pulse rate and blood pressure) of the two treatments were similar (8]. In order to
study the plasma levels after inhaled and i. v. salbutamol
treatment and correlate these to the effects of the treatment a follow-up study was made.
In the present study i. v. infusions of 5 ~-tg·kg· 1 of
salbutamol produced a high peak and a rapid decline in
the plasma salbutamol concentration in all patients. The
inhalation treatment was followed by a slow increase in
plasma salbutamol with a lower peak value in all patients.
The i. v. infusion had more pronounced haemodynamic
effects (tachycardia, higher systolic blood pressure and
hypokalaemia) immediately after the treatment than the
inhalation therapy, corresponding to the higher initial
plasma salbutamol value. When the plasma salbutamol
increase was measured as AUC from the start of to 90
min after treatment, however, there was no significant
difference between the treatments, and correspondingly
there was no difference in systemic effects measured as
AUC for !!. pulse rate or as maximum decrease in serum
potassium. Thus, although the inhaled dose was approximately 30 times greater than the intravenous, the
systemic availability from the start to 90 min after treatment seems to have been approximately equal in the two
modes of treatment.
As in our acute asthma study (8] the inhalation treatment had a better anti-asthmatic effect than the i. v.
treatment in most patients. In the present study it was
especially the patients with a high degree of bronchial
obstruction before treatment that fared better on inhalation than on i. v. infusion.
With the i. v. treatment the effect/side-effect ratio was
more favourable in the acute than in this non-acute situation. Thus the side-effects of the treatment were more
pronounced in the stable situation. The probable reason
for this is that in patients with severe acute asthma there
is a sympathetic drive on arrival which decreases during
treatment and masks adverse cardiovascular effects of
the treatments (14, 15]. The fall in heart rate after treatment of acute asthma is thus due to the improvement of
the asthma and not a direct effect of the drug. The ~ agonist treatment resulted in a higher degree ~f
bronchodilation in the acute than in the stable phase, but
this might partly be explained by the lower pre-treatment
PEF values in the acute situation.
As in earlier studies (16, 17], there were large
interindividual variations in the plasma level pattern
after the inhalation treatment. The time of onset of the
peak salbutamol value also varied. In nine of the 12
patients, however, the peak value was observed within
45 minutes. SHENFIELD et al. have suggested that this early
increase in plasma salbutamol is caused by absorption
into the bronchial circulation and hence reflects the
proportion of the dose that has reached the lung, whereas
the proportion that has been swallowed is absorbed later,
with peak values occurring after 2 to 3 h (18]. It is therefore somewhat surprising that in the patients with a higher
AUC for !J. plasma salbutamol after inhalation the AUC
for !!. PEF was often lower after this treatment than after
i. v. infusion.
It is concluded that there is a large inter-individual
variation in plasma level pattern after inhaled treatment.
The average systemic availability of 0.15 mg·kg· 1 of
inhaled salbutamol is, however, approximately equal to
that of 5~-tg·kg· 1 of i.v. salbutamol. The inhaled salbutamol
dose produces a better anti-asthmatic effect and a lower
maximal pulse decrease than the intravenous one in
stable asthma.
Acknowledgements: I wish to thank Eva Persson R.N.
and Marianne Bylund R.N. at the Dept of Lung Medicine,
Uppsala, for their thorough and skillful work with the pa·
tients. I also wish to thank Professor Nils Svedmyr at the
Department of Clinical Pharmacology, Gothenburg, and
Professor Jacob Boe at the Department of Lung Medicine,
Trondheim, for advising me in the planning and evaluation
of this study and Associate Professor Anders Od~n at the
Department of Mathematics, University of Gothenburg, for
statistical advice and evaluation.
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Niveaux plasmatiques et effets du sa/butamol apres inhalation
ou administration intraveineuse dans l'asthme stable. C. Janson.
RESUME: L'effet et les niveaux plasmatiques de salbutamol
apres inhalation (0.15 mg·kg' 1) ou administration intraveineuse
(5 j.lg•kg'1) ont 6t6 6tudi6s chez 12 patients qui avaient ete
introduits anterieurement dans une etude de l'asthme aigu severe,
et qui etaient en 6tat stable au moment de !'experimentation. La
valeur maximale des modifications du salbutamol plasmatique
(D) comparee avec la valeur avant le traitement, s'avere plus
elevee apres administration intraveineuse qu'apres traitement par
inhalation (59 vs 30 nmoH·1), mais les zones sous la courbe
(AUC) pendant les 90 minutes qui font suite au traitement, sont
similaires pour les deux voies d'administration. Les differences
inter-individuelles du pie de salbutamol plasmatique et de la
zone sous la courbe pour le ~-salbutamol plasmatiqu.e sont bien
plus 61ev6es apres inhalation qu'apres administration intraveineuse.
lmmediatement apres le traitement, l'on a note une augmentation
plus marquee du pouls (moyenne + 17 vs + 6 pulsations par
minute) et des taux de potassium serique plus bas (moyenne •
0.3 mmoH·1) apr~s injection intraveineuse qu'apres inhalation.
L'augmentation du debit expiratoire de pointe mesuree 90 minutes
apr~s le debut du traitement (85 vs 31 /·min· 1) et la zone sous la
courbe, sont significativement plus elevees apr~s inhalation
qu'apres traitement intraveineux.
Six patients avaient reyu un traitement intraveineux au cours de
!'etude sur l'asthme aigu. Chez ces patients, le~ DEP, immediatement
apr~s le traitement intraveineux, est significativement plus faible
en situation stable ( + 49 vs+ 115/·min·1). L'on note egalement une
diff6rence significative dans l'effet sur le pouts immediatement
apres traitement intraveineux, avec une dimminution dans l'asthme
aigu et une augmentation dans l'asthme stable (· 5 vs + 16
pulsations·min' 1).
Eur Respir J., 1991, 4, 544-550.