Introduction
Chronic
Obstructive Pulmonary Disease (COPD) is a disease caused by a chronic
inflammatory response of the airways to different noxious particles or gases,
leading to persistent, progressive airflow limitation.(1) It is ranked as the sixth leading cause of
death worldwide, and is expected to become the fourth leading cause of death in
2030.(2)
The role of
Theophylline in the management of COPD remains controversial. The British
Thoracic Society (BTS) guidelines regarding COPD management recommend the use of
Xanthine derivatives as a last resort, because of modest bronchodilator effects
and narrow therapeutic index.(3)According to the Global
Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, Theophylline
is recommended as a third line option.(1)
However, despite
the current guidelines, interest in the use of Theophylline in patients with
COPD is coming back.(4) Many clinical trials have actually
shown that Theophylline is useful in the management of stable COPD patients.(5,6)
Other studies showed that Theophylline withdrawal causes worsening of
the clinical condition in patients with COPD.(7) An important
effect of Theophylline in COPD patients, is its ability to restore Histone
Deacetylase (HDAC2) activity,(8,9)
which is usually defective in these patients, thus reversing
steroid resistance in alveolar macrophages, which will cause an enhancement in
the anti-inflammatory action of Inhaled Corticosteroids (ICS) in patients with
COPD.
In our study, the
primary endpoint was to investigate the efficacy of adding Slow-Release
Theophylline to the regular treatment of patients with moderate, severe and
very severe COPD, treated in King Hussein Medical Center (KHMC). We assessed
the effect of low dose Theophylline on lung function and oxygenation after 4
weeks of adding it to regular treatment, as well as its effect on disability
caused by COPD. Side effects related to Theophylline were also monitored to
assess its safety, as a secondary endpoint.
Methods
In this prospective observational study, 109 patients
with stable, moderate, severe and very severe COPD, classified according to the
GOLD guidelines regarding the degree of their airflow limitation,(1)who
were treated in KHMC, were enrolled between August 2014 and March 2015.
Approval of the ethical committee was obtained in order to carry out the study.
None of the patients who were included had ever received Theophylline
previously.Inclusion criteria were the following: age >45 years, current or
former smokers, post bronchodilator FEV1 / FVC <70%, moderate to
very severe COPD and a diagnosis of COPD for >2 years. Exclusion criteria
were as follows: history of acute exacerbation of COPD
within the last 3 months;history of use of oral corticosteroids due to an
unstable respiratory condition within the last 4 weeks; history of upper or
lower respiratory tract infection within the last 4 weeks; recent unstable
angina or arrhythmias; epilepsy; concurrent use of medications that might
interact with Theophylline metabolism and excessive alcohol consumption.
During their
initial visit before being enrolled in the study, the patients were informed
about the aim of the study, and a written consent was obtained from all of
them.
After being
enrolled in the study, evaluation of the pulmonary function by spirometry was
done for all the patients in their first visit. FEV1 and FVC, as
percentage of predicted, were measured and recorded. A qualified respiratory nurse
was in charge of performing spirometry.At least three “acceptable” spirograms
were done for each patient, after which “repeatability” criteria were applied.(10) The largest FEV1 and FVC
were reported after examining all of the acceptable curves. Also, oxygenation
of the patients at rest was evaluated by recording oxygen saturation levels at
room air, using 2 different pulse oximeters.Despite our knowledge that
oxygenation status is more accurately assessed by Arterial Blood Gases (ABG’s)
results, because most of the patients refused blood gas analysis, as it was
perceived as invasive, made us settle for the oxygen saturation readings
obtained through the pulse oximeter.
The enrolled patients were asked also to assess their level of
disability using the Medical Research Council (MRC) dyspnoea scale,(11)as
shown in TableI. Patients assessed their disability on a scale from 1 to 5,
with”1” meaning that the patient is breathless only on strenuous exercise, and
“5” meaning that the patient is too breathless to leave the house or breathless
when dressing.
After assessing all the above mentioned parameters, the enrolled
patients had a fixed low dose of Theophylline added to their regular treatment
regimen, in the form of Slow-Release Theophylline (Quibron-T SR) 300 mg
slow-release capsules once daily.
The patients were followed up 4 weeks after their initial visit in the
clinic. During the follow-up visit, lung function was assessed by spirometry,
and oxygen saturation recorded, and level of disability was reassessed using
the MRC dyspnoea scale. The patients were also evaluated for any side effects
related to Theophyllinethrough non-specific questioning, or spontaneous report.
Adverse effects were classified as “non-serious” and “serious” side effects.
Non-serious side effects included headache, nausea and vomiting, abdominal discomfort,
restlessness, gastroesophageal reflux, and diuresis. Serious side effects
referred to convulsions, cardiac arrhythmias, and death.
By the end of the 4 weeks period of the study, the pre and
post-Theophylline data were compared, including FEV1, FVC, Oxygen
saturation and disability level, and statistical significance was calculated
for each. The safety profile of Theophylline was assessed by calculating the
number of patients who developed any side effects, whether or not any serious
side effects took place or if any patients withdrew from the drug because of
side effects.
Student’s paired
t-test was used for the statistical analysis. Continuous variables were
expressed as mean±standard deviation; categorical variables were expressed as
percentages. Level of statistical significance was defined as p<0.05.
Results
Patients
diagnosed with COPD, in whom Theophylline was added to their regular treatment,
were enrolled in this study. Of the 109 patients enrolled in our study, 96
patients (88%) were males and 13 patients (12%) were females. Their ages ranged
between 46-82 years, with a mean age (±SD) of 69.0 years (±7.8).
After 4 weeks of
adding oral Theophylline to their treatment regimens, patients showed a
statistically significant improvement in their FEV1, FVC and MRC
score. There was also a slight increase in the Oxygen saturation, which did not
reach statistical significance as shown in Table II.
Overall,67patients
(61%) showed an improvement in disability, as assessed by the MRC score.A
comparison between the characteristics of patients who showed an improvement in
MRC score, and those who did not, is shown in Table III.
5 patients (5%)
had side effects related to Theophylline. However, none of the patients had
serious side effects.The most encountered side effect was nausea (60%), as shown
in Fig.1. None of the patients who developed side effects stopped using
Theophylline during the study.
Discussion
Our study showed that after 4 weeks of oral
Theophylline, in the form of Slow-Release Theophylline (Quibron-T SR) 300 mg
once daily, added to regular treatment of patients with moderate to very severe
COPD, there was a significant improvement in the pulmonary function. Both mean
FEV1 and mean FVC showed a statistically significant increase (p values 0.0266 and 0.0453
respectively).
FEV1,
which is expressed in some studies in Litres and in other studies as percent of
predicted, is the most common lung function variable assessed in clinical
trials.(12) Many studies have shown that Theophylline causes
a significant increase in the FEV1 of COPD patients.(13-16) Giesselet
al,(17) have actually shown in that Theophylline, in
combination with Salmeterol, causes greater improvement in FEV1 than either
alone. However, some other studies have shown that Theophylline does not
produce a significant increase in the FEV1 in COPD patients.(18)
We also assessed
the effect of Theophylline on the oxygenation of the patients with COPD. Oxygen
saturation, as measured by pulse oximetry, before and after Theophylline
addition, showed an increase after 4 weeks.Although, it did not reach
statistical significance(p value 0.490).However, measuring the Oxygen
saturation by a pulse oximeter is not the best way to assess changes in
oxygenation, as it is insensitive to minor changes in arterial Oxygen partial
pressure (PaO2). Better assessment of oxygenation, by measuring the Arterial
Blood Gases (ABG’s), is needed to interpret the effects of Theophylline on
oxygenation of COPD patients more accurately.
Another variable
that has been assessed in our study was the change in disability related to
dyspnea after introduction of Theophylline. In our study, we adopted the MRC
dyspnea scale as a method to evaluate the change in dyspnea. There was a
significant improvement in the mean dyspnea score after 4 weeks of adding
Theophylline (p value <0.0001). 61% of the patients enrolled in our study
showed an improvement of their dyspnea score, while the remaining 39% did not
notice any change. Patients who showed a significant change in their MRC score
were younger than those who showed no significant response (67.7±8.0 Vs
71.1±7.0years±SD in non-responders).
Many other studies
have also shown the significant effects that Theophylline addition has on
improving the symptoms of patients with COPD.(16, 19, 20)
including dyspnea and cough.
It is essential
to emphasize, that even in some studies that did not show a significant improvement
in the lung function after addition of Theophylline, significant improvement in
the symptoms was observed.(21-23)There have been many
proposed mechanisms to explain how Theophylline can improve the symptoms.
Chrystynet al,(24)studied the effect of oral
Theophylline on patients with COPD. In their study, therapeutic levels of
Theophylline led to a small increase in FEV1 (13%), but a
significant decrease in the trapped gas volume (64%).
A fall in trapped
gas volume, which will lead to a similar fall in the functional residual
capacity, is likely to have a beneficial effect on the mechanics of the
diaphragm and chest wall muscles. An increase in diaphragmatic strength, (25)
and an increase in the respiratory drive independent of the effect on lung
function,(26)have been also shown to be important mechanisms
through which Theophylline improves dyspnea in COPD patients.
In our study, we
evaluated the safety of Theophylline use in COPD patients. We assessed the
occurrence of any side effects caused by Theophyllineafter the 4 weeks, and
whether or not any serious side effects took place. In our study, 5 patients
out of the 109 patients enrolled in the study, (5%) developed side effects
related to Theophylline administration. The most common side effect was nausea
(60%), followed by headache (20%) and restlessness (20%). None of the patients
developed any serious side effects. The low dose of theophylline used is a
likely reason why there were no serious side effects. We used 300 mg compared
to the standard dose of 400 mg/day, or more, for use as a controller.(27)
None of the patients who developed the side effects, related to
Theophyllineuse,stopped taking Theophylline during our study.
As the primary
endpoint of this study was to assess the efficacy of Theophylline in COPD
patients, safety of Theophylline was not surveyed thoroughly. We rather
concentrated on the occurrence of serious side effects related to Theophylline,
and whether or not the serious and non-serious side effects were severe enough
to cause drug withdrawal by the patients.
Limitations of
the study
Larger controlled
studies need to be done in the future, in which two groups of patients, one
receiving a placebo and the other receiving Theophylline, are compared. These
studies will improve our interpretation of the results, and provide more
accurate data regarding the effects of Theophylline in COPD patients.
In assessing
oxygenation of the patients enrolled in our study, we depended on the oxygen
saturation measured by 2 different pulse oximeters.Better assessment of
oxygenation, by measuring the PaO2 in arterial blood sample, is
needed to accurately interpret the effects of Theophylline on oxygenation of
COPD patients.
Another
limitation in our study is not measuring the Theophylline blood concentration
levels. Future studies need to do so, in order to correlate the obtained
results regarding the efficacy and safety of Theophylline, with its blood
levels.
Conclusion
In our study,
Theophylline was shown to cause a significant increase in the lung function of
COPD patients, and to significantly improve their disability caused by dyspnea,
without causing any serious side effects. Use of Theophylline in stable COPD
patients should be weighed however against the risk of possible non-serious
side effects, mainly nausea.
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