Upsala J Med Sci 97: 149-155 

Intravenous Theophylline After Beta2-Agonist 
Treatment in Severe Acute Asthma. Effect on Patients 

Who Are Not Pre-treated with Theophylline 
Christer Janson and Gunnar Boman 

Department of Lung Medicine, Uppsala University, Akademiska sjukhuset, Uppsala, Sweden 

ABSTRACT 
The effect of i.v. theophylline after high-dose 02-agonist treatment in severe acute 
asthma was studied in 30 patients from a multicentre study who reported not having 
taken theophylline during the last 24 hours. One hour after the start of inhaled or i.v. 
salbutamol treatment, all patients received 6 mg/kg of i.v. theophylline. The plasma 
concentration 30 minutes after the start of the theophylline infusion was 78 _+ 13 
ymolll (mean f SD). The mean change (A) in peak expiratory flow (PEF) was 8 f 6% 
of the predicted 30 minutes after the theophylline infusion and 7 f 5% 60 minutes 
after it. The increase in PEF was greater in this patient group than in a group of 101 
patients from the same multicentre study who were on theophylline medication and 
were therefore given a reduced dose (3 mg/kg) (7 f 5 vs. 4 f 6% of the predicted 
value, pc0.01). The proportion of patients with an increase in PEF of 2 10% of the 
predicted at discharge was 27% (8/30) in the patient group in this investigation and 
14% (14/101) in the group who was on theophylline treatment. 

I NTR 0 D U CTf ON 
Inhaled 02-agonists and systemically administered corticosteroids are recognized 
as the cornerstones of the modern treatment of acute asthma (2,16). Theophylline 
has subsequently been degraded to the position of a third-line drug in the current 
guidelines on the management of acute asthma (2,16). In fact, there are several 
studies in which no additional bronchodilatory effect has been found when theo- 
phylline has been administered with inhaled 0-agonists (1,6,15). A further 
disadvantage of theophylline is the risk of potential serious side-effects owing to the 
narrow therapeutic interval of the drug (4). 

In a Swedish multicentre study, i.v. theophylline was given 60 minutes after inhaled 
and i.v. 02-agonist treatment (1 7). Most of the patients in the study were taking theo- 
phylline as maintenance treatment and were therefore given a reduced theophylline 
dose. In a subanalysis we found that only a small proportion of these patients had a 
clinically significant additional improvement after theophylline (9). Since the time of 
the multicentre study there has, however, been a change in therapy practice. As a 
result, most patients admitted because of acute asthma today are not on 
theophylline. The aim of this investigation was therefore to study the effect of i.v. 

149 



theophylline after 02-agonist treatment in acute asthma on the subgroup of patients 
who had not taken theophylline during the last 24 hours before admission to the 
emergency room. 

MATERIAL AND METHODS 
Between September 1985 and January 1987 the Swedish Society of Chest 
Medicine conducted a multicentre study on the effect of i.v. versus inhaled salbuta- 
mol treatment in severe acute asthma (17). One hour after the start of salbutamol 
treatment (Ventoline, Glaxo), i.v. theophylline was given to both patient groups. An 
infusion of aminophylline (Teofyllamin, ACO) in a dose corresponding to 6 mg/kg of 
theophylline was given to patients who had not taken theophylline during the last 24 
hours. The dose was reduced to 3 mglkg in those patients who had taken oral 
theophylline. 

In this analysis we have only included those patients who were not taking oral theo- 
phylline before treatment and were thus given a dose corresponding to 6 mg/kg of 
theophylline. We have excluded the patients who reported having taken broncho- 
dilatory drugs for which no method of determining the plasma level was available; 
they included fenoterol, orciprenaline, isoprenaline and ipratropium bromide. This 
analysis thus comprised 30 adult patients (13 men and 17 women, mean age 54 
years, range 18-73) who attended the emergency room with a severe acute attack of 
asthma (peak expiratory flow rate (PEF) of 2 5 0 %  of the patient's predicted normal 
value ( 7 ) ,  pulse rate of 2 100 beatslmin.). A s  initial treatment 15 patients received 
inhaled salbutarnol (0.15 mglkg x 2) and 15 received i.v. salbutamol (5 pglkg). The 
infusion time for the i.v. aminophylline was 20-30 minutes. 

Blood samples for the determination of plasma theophylline levels were taken 
before the start of treatment and 30 minutes after the start of the aminophylline 
infusion. Plasma theophylline levels were determined at the Department of Clinical 
Pharmacology at Sahlgren's University Hospital, Gothenburg, using a high-pressure 
liquid chromatographic method (5). Using this method, the lowest detectable level is 
1 ymolll. The coefficient of variation is 4% for a plasma level of 3 ymolll and 3% at 55 
pmolll. Plasma levels of salbutamol and terbutaline were determined 55 minutes 
after the start of the salbutamol treatment. From the result of the salbutamol and 
terbutaline assay an estimation of the total l32-agonist plasma concentration was 
made. The methods for this drug concentration assay and for the estimation of the 
total 02-agonist plasma level have been described in detail elsewhere (8). 

Peak expiratory flow (PEF), pulse rate and blood pressure were followed from arrival 
at the emergency room until 60 minutes after the start of the theophylline treatment. 

The informed consent of all patients was obtained and the study was approved by all 
the relevant local ethics committees. 

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Statistics 
Differences between subgroups of the population were analysed using the Mann- 
Whitney U test. Spearman's rank correlation test was used to analyse the correlation 
of the change (A) in PEF after the theophylline treatment with the other variables. A 
p-value of < 0.05 was regarded as statistically significant.The results are expressed 
as mean f SD. 

R E S U L T S  
Measurable plasma levels of theophylline before treatment were found in 20 of the 
30 patients (3f2 pmolll, range 1-9). The mean P-Theophylline concentration 30 
minutes after the start of the theophylline infusion was 78 f 13 pmol/l (range 52-102) 
(Fig. 1). 

n 
I 

E 
5. 
Y 

Q) 
c 
* 
c 
a 

.I 
I 
I 

0 
Q) 
c 
I- 

I 

n 

2v 

0 I 

Figure 1 .P-theophylline concentration 30 minutes after the start of i.v theophylline 
treatment (6 mg/kg) in 30 patients with severe acute asthma (individual 
values, median, inter-quartile range (2575%) and range). 

Following the theophylline infusion, A PEF was 8 f 6% of the predicted value (40 f 
33 Vmin) after 30 minutes and 7 f 5% of the predicted (37 f 30 I/min) after 60 
minutes (Table 1). 

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Table 1.Peak expiratory flow, pulse rate and blood pressure before and 30 and 60 
minutes after treatment with 6 mg/kg of i.v. theophylline (n=30). 
(Mean + SD) (* p<0.05, ** p<O.Ol, *** p<O.OOl, compared with before treatment.) 

Before 30 min 60 min 

Peak expiratory flow (% of predicted) 45+16 53+15*** 53+15*** 

Pulse rate (beatshin) 99+21 104+21** 1 0 3 f l 9 *  
Systolic blood pressure (mm Hg) 137+25 133+21 131f19 
Diastolic blood pressure (mm Hg) 85+15 82+14 84+14 

(Vmin) 229f82 269+86*** 266f82*** 

Patients treated with inhaled salbutamol displayed a significantly greater increase in 
PEF before the theophylline infusion than those treated with i.v. salbutamol (pc0.05). 
There was, however, no significant difference in A PEF after the theophylline treat- 
ment between the inhalation and i.v. salbutamol group (Fig. 2). At discharge (60 
minutes), 8 patients had an increase of 2 10% of the predicted value. Four of these 
patients had received inhaled salbutamol and 4 i.v. salbutamol. 

APEF 
(“A of pred.) 

T 

20 

15 

10 

5 

-I I 

inhalation intravenous 
(n=15) (n=15) 

Figure 2.Change in PEF (mean and SE) 55 minutes after inhaled or intravenous 
salbutamol (open bars) and 60 minutes after the addition of intravenous 
theophylline (cross-hatched bars). 

152 



No significant correlations were found between the post-theophylline increase in 
PEF and age, sex, PEF before treatment, A PEF before theophylline, P-02-agonist 
concentration or A P-theophylline after treatment. 

The increase in PEF after theophyline treatment was significantly greater in the study 
group in this investigation than in a group of 101 patients from the same multicentre 
study who were on theophylline medication and were therefore given a reduced 
theophylline dose (3 mg/kg) (8 f 6 vs. 4 f 6% after 30 minutes and 7 f 5 vs. 4 * 6% 
of the predicted after 60 minutes, pc0.01). The number of patients with an increase 
in PEF of 2 10% of the predicted at discharge was 8 (27%) in this investigation and 
14 (14%) in the group who were on theophylline treatment. The average increase in 
PEF before the theophylline infusion was 13% of the predicted in both groups. 

D I S C U S S I O N  
When designing the Swedish Society of Chest Medicine's multicentre study, the 
main purpose was to compare the effect of inhaled and intravenous 02-agonist 
treatment in severe acute asthma. A further aim was to see whether theophylline 
was of any clinical use after high-dose 02-agonist treatment. In our first report, our 
conclusion was that it was doubtful whether theophylline had any clinical effect after 
high-dose inhaled 82-agonists (1 7). This conclusion was, however, criticized as 
being based on data which was not totally convincing (3). This caused us to make a 
subanalysis of the effect of i.v. theophylline on patients who were taking oral theo- 
phylline as maintenance treatment. In this investigation, there was a small group of 
patients who did improve rather well after i.v. theophylline. This group was 
characterized by having subclinical P4heophylline;concentrations before treatment 
(9). 

The Swedish multicentre study was conducted from 1985 to 1987. Since then 
therapy practice has changed. Maintenance treatment with theophylline has 
markedly declined at least in Sweden (10). A large proportion of patients who 
currently seek emergency treatment are therefore not on theophylline. These 
patients can be given a larger theophylline dose without increasing the risk of toxic 
side-effects. The negative correlation between plasma concentration before 
treatment and the treatment effect reported earlier (9) indicates that patients without 
theophylline pre-treatment might be most suitable for emergency treatment with i.v. 
theophylline. Our results partly support this hypothesis. Consequently the proportion 
of patients whose PEF increased by 10% or more compared with the patients 
predicted value after i.v. theophylline was 27% (8/30) in this patient group compared 
with 14% (14/101) of the patients who had taken theophylline before emergency 
treatment. 

On the basis of previous dose-effect studies, a dose of 5-6 mg/kg theophylline is 
usually recommended in the treatment of acute asthma in patients who are not 
taking theophylline (12,16). In this study nearly all the patients reached a P- 
theophylline concentration of above 55 pmol/l, while none reached a concentration 

153 



above the upper limit of the therapeutic interval (1 10 pmol/l). We can thus confirm 
that a theophylline dose of 6 mg/kg is a suitable loading dose in the emergency 
treatment of patients who are not on theophylline medication. 

As would be the case in a clinical setting, the question of whether the patients had 
taken theophylline before arrival or not was based on their own reports. In several of 
the patients we found small but measurable levels of theophylline. These might have 
been caused by theophylline taken earlier than 24 hours before arrival. In some 
patients the low theophylline levels might also have been caused by drinking tea as 
tea contains small levels of theophylline (1 3). The theophylline concentrations 
measured were below the level at which they could have influenced the clinical out- 
come. 

As in our previous report (9), the effect of theophylline appears to be relatively un- 
related to the 02-agonist treatment. As a result, we found no significant difference 
between the effect in patients treated with inhaled or i.v. salbutamol. There was no 
significant correlation between the estimated P-02-agonist concentration before 
treatment and the effect of the theophylline infusion. In both our investigations the re- 
sponse to theophylline was also unrelated to the patient's age, sex, pre-treatment 
PEF or the level of change in PEF after 02-agonist treatment. There was also no 
difference in PEF response to salbutamol between the patient group with and the 
group without t heophylli ne pre-treatment. 

Lately there has been a discussion as to whether theophylline, apart from being a 
bronchodilator, also has other effects of possible therapeutic value. In one American 
study, theophylline treatment was reported to decrease the need for hospital ad- 
mission despite the fact that there was no difference in the effect on lung function 
between the patients who were given theophylline and the control group (18). The 
author suggests that this might be caused by an anti-inflammatory effect. An editorial 
commenting on the study speculates on a possible future rise for theophylline in 
asthma treatment (11). Our results are a further indication that it is perhaps not 
possible to completely count-out theophylline in the treatment of severe acute 
asthma. We conclude that after high-dose 02-agonist treatment there is a subgroup 
of patients in whom i.v. theophylline produces a further bronchodilation of probable 
clinical value. The factors causing this interindividual difference in theophylline 
response are not known at present. 

ACKNOWLEDGEMENTS 
This investigation was part of a multicentre study conducted by the Swedish Society 
of Chest Medicine. The investigation was supported financially by Bror Hjerpstedt 
Foundation, Uppsala, the Swedish Heart-Lung Foundation, Stockholm, and AB 
Glaxo Lakemedel, Molndal, Sweden. 

154 



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9. 

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Adress for reprints: Dr Christer Janson, Department of Lung Medicine 
Akademiska sjukhuset, S-751 85 Uppsala, Sweden 

I 1  -928572 155