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Shan-Ping
Jiang, Rui-Yun Liang, Qi-Liang Liu, Yong-Kang Liang, Jian-Guo Li,
Department of Respiratory Medicine, The Second Affiliated Hospital,
Sun Yat-Sen University, Guangzhou 510120, Guangdong Province, China
Zhi-Yong Zeng, Department of Gastroenterology, The Second Affiliated
Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong
Province, China
Correspondence to: Professor Shan-Ping Jiang, Department of
respiratory Medicine, The Second Affiliated Hospital, Sun Yat-sen
University, 107 Yanjiang West Road, Guangzhou 510120, Guangdong
Province China. zengzhiyong99@hotmail.com
Telephone: +86-20-81332441
Fax: +86-20-81332441
Received: 2002-12-22
Accepted: 2003-01-16
Abstract
AIM: To investigate the effects of antireflux treatment on bronchial
hyper-responsiveness and lung function in asthmatic patients with
gastroesophageal reflux disease (GERD).
METHODS:
Thirty asthmatic patients with GERD were randomly divided into two
groups (group A and group B). Patients in group A (n=15) only
received asthma medication including inhaled salbutamol 200 ?g four
times a day and budesonide 400 ?g twice a day for 6 weeks. Patients
in Group B (n=15) received the same medication as group A, and also
antireflux therapy including oral omeprazole 20 mg once a day and
domperidone 10 mg three times a day for 6 weeks. Pulmonary function
tests and histamine bronchoprovocation test were performed before
and after the study.
RESULTS: There was no significant difference in the baseline values
of pulmonary function and histamine PC20-FEV1 between the
two groups. At the end of the study, the mean values for VC, VC%,
FVC, FVC%, FEV1, FEV1%, PEF, PEF%, PC20-FEV1
were all significantly improved in group B, compared with group A.
CONCLUSION: Antireflux therapy may improve pulmonary function and
inhibit bronchial hyper-responsiveness in asthmatic patients with
GERD.
Jiang SP, Liang RY, Zeng ZY, Liu
QL, Liang YK, Li JG. Effects of antireflux treatment on bronchial
hyper-responsiveness and lung function in asthmatic patients with
gastroesophageal reflux disease. World J Gastroenterol
2003; 9(5): 1123-1125
http://www.wjgnet.com/1007-9327/9/1123.asp
INTRODUCTION
Bronchial asthma is likely to be associated with gastroesophageal
reflux disease (GERD). Bronchial hyper-responsiveness is one of the
characteristics of asthma. Numerous observations have suggested that
GERD may be causally related to the reactive airways condition, and
may at least be a trigger causing airways to react[1-4].
Our study was carried out to determine the effects of antireflux
treatment on bronchial hyper-responsiveness and lung function in
asthmatic patients with GERD.
MATERIALS
AND METHODS
Thirty asthmatic patients with GERD were included in our study. All
patients were recruited in the Second Affiliated Hospital Sun
Yat-Sen University from December 2000 to December 2001. The
diagnosis of asthma was established according to the Global
Initiative for Asthma issued by the National Heart, Lung, and Blood
Institute. The presence of GERD was determined in accordance with
below standards[5]: typical clinical symptom of GERD such
as postprandial chest pain and sour regurgitation, signs of erosive
esophagitis shown by barium esophagogram and/or lower esophageal
erosions shown by endoscopic examination and mucosal biopsy.
The patients were
randomly divided into two groups. Group A included 15 patients (7
men, 8 women; range of age 23-60 years, mean 34.9�19.2 years), with
duration of asthma ranging from 1-19 years (mean 8.2�6.3 years).
Group B included 15 patients (6 men, 9 women; range of age 20-65
years, mean 35.6�17.4 years), with duration of asthma ranging from
1-25 years (mean 7.8�6.1 years). There was no significant
difference in age, sex, and duration of asthma between these two
groups.
Patients in group A only
received asthma medication which included inhaled salbutamol 200 mg
four times a day and budesonide 400 mg
twice a day for 6 weeks. Patients in Group B received the same
medication as group A, and also antireflux therapy which included
oral omeprazole 20 mg once a day and domperidone 10 mg three times a
day for 6 weeks. Pulmonary function tests and histamine
bronchoprovocation test were performed before and at the end of the
medications.
Pulmonary function tests
included vital capacity (VC), forced vital capacity (FVC), forced
expiratory volume at the first second (FEV1), and the
peak expiratory flow rate (PEF), and the percentage of the above
parameters over the predicted values (i.e. VC%; FVC%; FEV1%
and PEF%). Bronchial hyper-responsiveness was detected by histamine
bronchoprovocation test (HIT). Briefly, the patients were asked to
orderly inhale a series of histamine solutions with increasing
concentrations ranging from 0.03, 0.06, 0.12, 0.24, 0.48, 1, 2, 4 to
8 g/L for two minutes with an interval of 5 minutes. Every 30
seconds and 90 seconds after each inhalation, FEV1 was
detected. The test was stopped when FEV1 fell by 20 % from baseline
value. Histamine-PC20-FEV1, the concentration of
histamine required to produce a 20 % fall from baseline in FEV1,
calculated from Cockcroft formula[6], represented the
degree of bronchial responsiveness. Pulmonary function tests and
inhaled histamine bronchoprovocation test were performed with the
Spiroanalyzer ST-300, Fukuda Sangyo, Japan.
Statistical
analysis
The differences of mean values �SD were determined by t test. The
distribution of frequency of histamine PC20-FEV1 was
skewed distribution. When the values were expressed as geometric
mean, it became a normal distribution. A P value of < 0.05 was
considered statistically significant.
RESULTS
There was no significant difference in the baseline values of
pulmonary function and histamine PC20-FEV1 between the
two groups. At the end of the study, the mean values for VC, VC%,
FVC, FVC%, FEV1, FEV1%, PEF, PEF%, PC20-FEV1
did not change significantly in group A, while in group B the mean
values for VC, VC%, FVC, FVC%, FEV1, FEV1%,
PEF, PEF%, PC20-FEV1 all significantly increased. Also,
at the end of the study, the mean values for above indices were all
significantly higher in group B than in group A. The changes in
pulmonary function and bronchial responsiveness were showed in Table
1.
Table 1
Changes in pulmonary function and bronchial responsiveness in
asthmatic patients with GERD (mean values �SD)
| Index |
Group
A n=15 |
Group
B n=15 |
| Before
therapy |
After
therapy |
Before
therapy |
After
therapy |
| VC(L) |
2.9�0.4 |
2.7�0.9 |
2.8�0.7 |
3.7�0.7ab |
| VC% |
86.3�14.6 |
85.9�1.9 |
84.9�18.9 |
111.2�13.6ab |
| FVC(L) |
2.9�0.6 |
2.7�0.8 |
2.8�0.4 |
3.6�0.9ab |
| FVC% |
88.4�19.2 |
85.1�23.6 |
86.3�21.7 |
102.6�16.1ab |
| FEV1(L) |
2.3�0.9 |
2.4�0.6 |
2.2�0.8 |
2.8�0.5ab |
| FEV1% |
76.8�11.6 |
77.5�16.3 |
75.6�14.5 |
84.6�12.7ab |
| PEF(L/S) |
4.4�1.5 |
4.8�1.7 |
4.6�1.2 |
5.9�1.6ab |
| PEF% |
74.8�19.6 |
75.�16.3 |
70.5�20.4 |
85.1�23.1ab |
| PC20-FEV1(g/L) |
0.31�0.11 |
0.28�0.16 |
0.33�0.14 |
0.84�0.22ab |
aP<0.05
vs. group A after therapy, the t values were 2.34, 2.59, 2.31, 2.55,
2.49, 2.26, 2.63, 2.22, and 2.68, respectively. bP<0.01
vs. group B before therapy, the t values were 3.93, 4.16, 3.87,
4.04, 3.95, 3.62, 4.46, 3.98, and 4.33, respectively.
DISCUSSION
It has been indicated that there is a causal relationship between
asthma and GERD: asthma may cause or precipitate GERD and vice
versa, and so much as a vicious cycle[11-13]. On one
hand, asthma may be the cause of GERD in some patients. Prolonged
period of cough, wheezing and greater respiratory muscle effort in
asthma increase abdominal pressure, and facilitate the movement of
gastric secretions towards the lower esophageal sphincter (LES).
Moreover, the diaphragm's contribution to sphincter tone is
decreased in asthma. Furthermore, bronchodilator therapies (both
beta-agonists and theophylline) appear to reduce LES pressure[7].
It has become clear that the pressure gradient across the LES is
increased in asthma, which promotes the development of GERD.
On the other hand, GERD
may cause or facilitate asthma. Mechanisms of bronchospasm inspired
by reflux include[8,9]: (1) acid in the inflamed
esophagus may stimulate exposed acid sensitive receptors which act
through vagal afferents to the airways to cause an increase in
bronchial hyper-responsiveness which leads to bronchoconstriction;
(2) microaspiration, with stimulation of upper-airway vagal
receptor, causes bronchoconstriction; and (3) microaspiration of
gastric contents into the lung results into exudative mucosal
reaction.
GERD has been found to
occur in 30-80 % of asthmatic patients. Kiljander et al found that
the prevalence of GERD in asthmatic patients is 53 %[11].
Dal Negro et al reported that GERD was found in 78.9 % of atopic
asthmatic patients[12]. Sontag et al demonstrated that
more than 80 % of asthmatic patients had abnormal GERD[13].
A number of authors have suggested that some factors may be
associated with an increased risk for the development of GERD in
asthmatic patients, and thus further diagnostic tests should be
proposed to evaluate the presence of GERD in such patients. These
factors include[10]: (1) asthma of adult onset; (2)
asthmatic symptoms that are largely or predominantly nocturnal; (3)
large meals, which might cause or worsen cough and wheezing;
(4)asthma of non-smokers; (5) sour dietary and drinks that can cause
cough and wheezing; (6) non-allergic (it may be changed to no
allergen identified); (7) responders to antacid therapy; and (8)
steroid resistant asthma.
Many diagnostic tests
have been used to prove the presence of GERD, including barium
esophagogram, endoscopic examination and mucosal biopsy, measurement
of the LES pressure, esophageal acid perfusion tests,
gastroesophageal scintiscan, and twenty-four-hour esophageal PH
monitoring.
In 1985, Barish et al
established a series of procedures to determine the prevalence of
GERD in asthmatic patients[5] including barium
esophagogram, endoscopic examination, mucosal biopsy and measurement
of the LES pressure. It was suggested that GERD be definitely
diagnosed if there are two positive results from above examinations.
Otherwise, ambulatory 24-hour esophageal PH monitoring can be used
as the gold standard to determine the prevalence of GERD[14,15].
However, Barish et al emphasized that this test should only be used
in cases with diagnostic difficulties because of long time of
catheter inserting or shortage of equipment[5]. David et
al established that in patients with predominant reflux symptoms and
supportive evidence from endoscopy, the diagnosis of GERD was
straightforward[10]. Allescher et al suggested that in
patients with persistent reflux problems and erosive reflux
esophagitis indicated by endoscopy, the diagnosis of GERD was
certain[17]. Hollenz et al also proposed that
gastroesophageal reflux was diagnosed when endoscopy revealed
typical esophageal lesions[16]. In some uncertain cases,
24-hour pH monitoring can be used to verify and objectify an acid
gastroesophageal reflux[17].
All the thirty cases in
our study had classic symptoms of GERD and positive signs by both
barium esophagogram and endoscopic examination. Therefore, the
presence of GERD is certain.
A
variety of different treatments aiming at the improvement of reflux
symptoms have been used in adult asthmatic patients with GERD. Most
investigators[10,18] have suggested the three-step
procedures. The first step includes elevation of the head of the
beds 15-20 cm, no eating or drinking for three hours before
sleeping, avoidance of large meals, weight loss, restricted
consumption of caffeine, alcohol, spicy foods and chocolate and no
smoking. The second step consists of medical management including
antacids, H2-receptor antagonists, proton pump
inhibitors, pro-kinetic agents and cytoprotective agents. The third
step consists of surgical management. In asthmatic patients with
GERD, many studies have indicated that medical antireflux therapy
can improve the symptoms of asthma. Harding et al reported
improvements in both symptoms and pulmonary function in asthmatic
patients with GERD after antireflux therapy[19]. Levin et
al demonstrated that omeprazole improved PEF and quality of life in
asthmatic patients with GERD[20]. Teichtahl et al found
that omeprazole therapy significantly increased evening PEF in
asthmatic patients with GERD[21]. Meier et al indicated
that medical antireflux therapy by omeprazole might predispose to
improve respiratory function in asthmatics with GERD[22].
Our observation also demonstrated that antireflux medications could
make an obvious favor in the improvement of pulmonary function and
inhibition of bronchial hyper-responsiveness in asthmatic patients
with GERD. These results provide strong evidence that GERD can
precipitate asthma. Therefore, in such subset of patients,
elimination of GERD may be proven to be especially beneficial.
In patients with GERD,
esophageal acid exposure is reduced by up to 80 % with H2-receptor
antagonists and up to 95 % with proton pump inhibitors[10].
So, proton pump inhibitors are superior to H2-receptor
antagonists. In addition, pro-kinetic agents also decrease GERD by
improving gastric emptying.
In conclusion, our
observations indicate that antireflux therapy by proton pump
inhibitors and pro-kinetic agents is beneficial to asthmatic
patients with GERD.
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