A trial of ranitidine in ... with or without pathological gastro-oesophageal ...

Eur Reaplr J
1992, 6, 201-208
A trial of ranitidine in asthmatic children and adolescents
with or without pathological gastro-oesophageal reflux
P.M. Gustafsson*, N-I.M. Kjellman*, L. Tibbling**
A trial of ranitidine in asthmatic children and adolescents with or without patho·
logical gastro-oesop!Jageal reflux. P.M. Gustafsson, N-l.M. Kjellman, L. Tibbling.
ABSTRACT: In order to study tbe Importance of gastro-oesophageal reflux
(GOR) as a trigger of asthma the effect of lohlblfioo or gastric acid secretion
on asthma was assessed In a double-blind, cross-over, placcbo-cootrollcd
trial over four weeks In 37 children and adolescents (mean age 14 yrs) with
bronchial asthma.
Ranitldlne 300 mg, (ISO mg If B.W, was <40 kg) was given as a single even.lng
dose during four weeks. lo previous Investigations 18 of the 37 patients had
been shown to have pathological GOR by 24 h pH monitoring In the oesophagus. The remaining 19 patients with normal GOR served as controls for
possible effects or ranltidine on asthma, not related to reduction or GOR.
A modest (30%) but statistically significant reduction of nocturnal asthma
symptoms was produced by ranltidlne in the patients with pathological GOR
when compared to those with normal GOR. There was a significant correlation between the improvement In asthma symptoms and the degree of acid
reflux. Side-effects of ranltid.ine were negligible.
Acid reflux appears to be only a weak stimulus for bronchoconstrlction In
children an d adolescents with bronchial asthma and pathological GOR.
Further confirmative trials with more potent inhibitors of gastric acid secretion are, however, warranted.
Eur Respir J., 1992, 5, 201-206.
Pathological gastro-oesophageal reflux (GOR) and
oesophageal dysfunction (OD) are common findings
in children and adults with bronchial asthma [1-9].
There has been much discussion of whether GOR has
a negative influence as an inducer and trigger of
asthma or whether it is merely a eo-finding in asthma
[9-10]. Studies in which asthma symptoms have been
alleviated by medical (11-15] or surgical (16-20] treatment of GOR support the idea of a cause and effect
relationship between GOR and asthma.
The aim of the present investigation was to see
whether reflux of gastric acid was important for
asthma, especially for nocturnal and morning asthma
symptoms, in an unselected group of children and
adolescents with bronchial asthma and pathological
GOR. Therefore, we studied the reduction in gastric
acid reflux by treatment with the H2-blocker ranitidine,
taken as a single dose in the evening during four
weeks, to see whether it could improve asthma symptoms and lung function . We thought that a reduction
of nocturnal or morning asthma symptoms by at least
50% would indicate that acid reflux is of major importance for asthma. Asthmatic subjects with normal
GOR served as controls, should there be a beneficial
or negative effect of ranitidine on asthma not related
to its effect on gastric acid reflux.
Depts of • Paediatrics and
• • Otorhinolaryngology
Faculty of Health Sciences
University Hospital
LinkOping
Sweden.
Correspondence: Dr P.M. Gustafsson
Dept of Paediatrics
University Hospital
S-581 85 LinkOping
Sweden.
Keywords: Adolescents; bronchial
asthma; children; gastro-oesophageal reflux; H 2-receptor antagonists; ranitidine.
Received: June 5, 1990; accepted after
revision August 22, 1991.
This study was supported by a grant from
the Swedish Medical Research Council,
project No. 17X·4260, and by Glaxo
Pharmaceuticals, Sweden Ltd.
Patients and methods
Forty two children and adolescents with bronchial
asthma were asked to take part in a randomized,
double-blind, placebo-controlled, cross-over study of
the effect of ranitidine (150-300 mg) taken orally
once a day in the evening over four weeks. They had
all previously undergone a 24 h two level pH monitoring of the oesophagus 0-14 months (mean 3.3
months) prior to the present ranitidine trial, in another
study aimed at elucidating the prevalence of pathological GOR in children and adolescents with moderate or
severe bronchial asthma [21]. They had also been
investigated with an oesophageal acid perfusion
test (APT) (8] 3.5-20 months (mean 9.9 months)
before the ranitidine trial. Forty of the 42 subjects
agreed to participate and 37 subjects, 22 males and 15
females, completed the study (table 1). All participants
were using regular asthma medication (table 1) and all
of them inhaled beta2-agonists when required.
In a questionnaire, which was filled in before the
trial commenced, symptoms of acid regurgitation,
heartburn or dysphagia were graded from 0 to Ill.
Grade 0 indicated no symptoms; grade I infrequent and
mild symptoms; grade II symptoms quite frequently,
often requiring some kind of relief, e.g. drinking milk
202
P.M. OUSTAFSSON, N·I.M. KJELLMAN, L. TIBBLINO
or taking antacids; and grade III disabling symptoms
(table 1). Nocturnal and morning asthma was graded
I-IV. Grade I denoted no asthma attacks in the night
or in the morning; grade II denoted asthma attacks
1-9 nights or mornings; grade Ill denoted asthma
attacks 10-99 nights or mornings, and grade IV
denoted asthma attacks during ll!:100 nights or mornings over the previous year.
tablets before each treatment period, each containing
150 mg ranitidine or placebo, respectively. These patients were instructed to take two tablets in the
evening, one hour before going to bed, during the
treatment periods.
The patients with a B.W. <40 kg were given 4.30
mg (mean; range 3.85-5.00 mg) ranitidine·kg·1 B.W.
per day and the heavier subjects were given 5.63 mg
Table 1. - Demographic data, percentage total reflux time, number of patients with
positive acid perfuslon test (APT), oesophageal symptoms, asthma history, and asthma
medication in the patients with normal and those with pathological GOR
Normal GOR
n=19
Male/female
Age yrs, mean (range)
Asthma duration yrs, mean (range)
Reflux time %, mean:tSEM
Positive APT n
Heartburn grade n
0
I
II
Regurgitation grade n
Ill
0
I
II
Ill
Dysphagia grade n
0
I
II
Ill
NoctumaVmorning
asthma grade n
I
11
Ill
IV
Medication n
Sodiul)l cromoglycate
Inhaled steroids
Oral beta2-agonists
Oral theophylline
Oral steroids
9/10
14.2 (10.0-20.8)
12.5 (3.2-19.8)
0.5:t0.1
13/5
13.9 (9.5-17.5)
11.3 (3.Cr16.7)
2.7:t0.3
6
7
9
3
0
6
10
3
0
7
4
12
2
0
16
2
1
0
11
6
1
0
1
2
8
8
0
1
8
9
9
7
9
13
1
GOR: gastro-oesopbageal reflux; n: number of patients.
Eighteen of the 37 subjects (49%) had pathological
reflux according to the 24 h pH test, i.e. reflux to the
distal oesophagus during more than 1% of the recording period (22], and 13 subjects (35%) had a positive
APT, i.e. heartburn Jr chest pain during acid infusion,
at the pretrial oesophageal investigation [8].
Th~ study was arranged as a randomized, doubleblind, cross-over trial with a two week run-in period
before the first four week treatment period and a two
week wash-out period before the second treatment period. Patients with a body weight (B.W.) <40 kg were
supplied with 28 tablets before each treatment period,
containing either 150 mg ranitidine per tablet, or a placebo of identical appearance. The patients were instructed to take one tablet one hour before going to
bed every evening during the treatment periods. Patients with a B.W. of ll!:40 kg were supplied with 56
Pathological GOR
n=18
5
11
2
0
14
5
10
12
1
(mean; range 3.61-7.32 mg) ranitidine·kg·1 B.W. per
day.
The main evaluation of the trial was based on daily
record cards. The patients were instructed to record
asthma symptoms and peak expiratory flow rate
(PEFR), using a Wright mini peak flow meter twice
daily. Each morning the patients made separate notes
on any asthma symptoms, which had appeared during
the previous night and the morning hours, and
performed three PEFR recordings before medication,
the highest of these three values being registered. In
the evening they made a note of the degree of wheezing, coughing, and restriction in acitivities that
had occurred during the day. They were also instructed
to perform three PEFR recordings and to note the
highest of the three. All symptoms were graded from
0 to 3 points. Zero denoted no symptoms at all and
RANITIDINE, REFLUX AND ASTIIMA
3 points indicated very severe symptoms. The maximum daily asthma symptom score was 15.
All medication taken during the day was recorded.
The patients were told to note possible adverse
reactions to the treatment in their record cards.
The patients were seen at the clinic by one doctor
(PMG) on three occasions: i.e. on the day after
completion of the run-in period, and on the day after
completion of each of the two treatment periods. On
these occasions spirometry (forced expiratory volume
in one second (FEV1)) was performed with a dry
sealed spirometer (Vicatest 5•, Mijnhardts, The
Netherlands), as well as a bronchial histamine challenge. Before evaluation of data, FEV1 and PEFR were
transformed into percentage of the predicted values
[23].
The histamine challenge was performed if the
FEV1 was >70% of the predicted FEY values [23].
The same jet nebulizer (Pari Boy•, Paul Ritzau PariWerk GmbH, FRG) was used throughout the trial.
After checking that the FEV1 was stable within 5%,
the patients inhaled saline for 2 min and the FEV1
recorded after saline was used as baseline. Histamine
chloride solutions were then inhaled by 2 min tidal
volume breathing at 5 min intervals, starting with
a concentration of 0.03 mg·mP and increasing by
fourfold increments up to 8 mg·ml·1 or until a fall in
FEV1 by at least 20% was recorded. The provoking
concentration of histamine causing a 20% fall in FEV1
(PC20Hi) was calculated by logarithmic interpolation.
At the three visits to the clinic asthma symptoms
and oesophageal symptoms over the previous week
were evaluated by means of a Visual Analogue Scale
(VAS). Symptoms were scored on a VAS ranging
from 0-10 cm, with 1 cm marks between the endpoints. At the last visit to the clinic the patients were
asked which treatment period they had preferred as
regards their asthma symptoms.
Venous blood samples for blood cell count, serum
concentrations of electrolytes, creatinine, urea, bilirubin, liver transaminases, alkaline phosphatases, and
a urinary dip stick, were taken at each visit to the
clinic.
Statistical analysis
The trial was dimensioned with an aim of obtaining a 90% chance of detecting a 50% reduction of
nocturnal and morning asthma symptoms. The
Wilcoxon's signed rank test was used for comparison
of the placebo and the ranitidine treatment periods
separately in the patients with and in those without
pathological GOR. A comparison between the
two groups of patients, regarding the effect of
ranitidine on asthma, i.e. the difference in asthma
symptom score between the ranitidine and placebo
periods, was further performed and analysed by the
Mann-Whitney U-test. A p-value <0.05 was regarded
as significant. Two-tailed tests were used throughout.
Regression analysis was used to see if the difference
in asthma symptoms between the ranitidine and
203
placebo periods correlated with percentage reflux
time at the previous oesophageal pH monitoring.
Ethics
The study was approved by the Ethics Committee
for Human Research at the University Hospital of
Linkoping and written consent was obtained from all
subjects and their parents.
Results
Comparison between the complete four week
ranitidine and the placebo period showed no significant reduction of asthma symptoms or improvement
of morning or evening PEFR during ranitidine treatment in either the patients with pathological or in
those with normal GOR. The patients with pathological acid reflux had a beneficial effect on nocturnal
asthma symptoms significantly more often (fig. 1)
than those with normal reflux. The regression
analysis showed significant positive correlations
between the total percentage reflux time at pH monitoring and the reduction of nocturnal asthma symptom
score (r=0.46; d.f.=35; p<0.01), nocturnal-morning
asthma symptoms by the VAS (r=0.39; p<0.05) (fig.
2), and total asthma symptom score (r=0.35; p<O.OS)
(fig. 3) during ranitidine treatment.
0.6
~
0
~
0.4
CIS
E
i
eoc
.._
~
z
'-NS....J
' - - - p=0.016 -~
Pathol. GOR
Normal GOR
n=18
n=19
Fig. 1. - Nocturnal asthma symptom score during the placebo
and the ranitidine treatment periods, and the difference in score
between the two periods, in the patients with pathological and in
those with normal gastro-oesophageal reflux (GOR). Mean:tsEM
are given. Statistical comparison between the placebo and the
ranitidine periods was performed separately for the two groups
of patients by the Wilcoxon's signed rank test. The effect of treat·
ment (ranitidine-placebo score) was compared between the two
groups by the Mann-Whitney U-test. c:::J: placebo; rzl: ranitidine;
D : ranitidine-placebo.
The patients with pathological APT (n=13) did not
improve during ranitidine treatment significantly
more than those with a negative APT.
FEV1 did not change between visits. As a result
of the low FEY 1 values, histamine threshold
P.M. GUSTAFSSON, N-I.M. KJELLMAN, L. TIBBLING
204
measurements after both treatment periods were restricted to 12 of the 19 patients with normal GOR, and
to 10 of the 18 patients with pathological reflux. No
significant change in bronchial histamine reactivity was
seen between the two test occasions in either patient
group (table 2). The .ranitidine period was not preferred
significantly more often than the placebo period in
either group (table 2).
3
L-Ns .....J
-1
NS
Pathol. GOR
Normal GOR
n=18
n=19
Fig 2. - Nocturnal/morning asthma symptom score according
to visual analogue scale (VAS) over the last week of the placebo
period and of the last week of the ranitidine period, and the difference in score between the two periods, in the patients with
pathological and in those with normal gastro-ocsophageal reflux
(GOR). MeausEM are given. Statistical comparison between the
placebo and the ranitid ine periods was performed separately for
the two groups of patients by the Wllcoxon's signed rank test.
The effect of treatment (ranitidine-placcbo score) was compared
between the two groups by the Mann-Whitney U-test. Ns:
nonsignificant; D : placebo; IZZI : ranitidine; : ranitidineplacebo.
The V AS disclosed only mild and infrequent
oesophageal symptoms in both groups during the
placebo period and there was no significant difference
between the two periods in either group of patients.
Three subjects reported mild side-effects during
the ranitidine period, one with irregular and loose
stools, the second one had abdominal pain twice during the first days of treatment, and the third complained of morning fatigue more than usual. Five
subjects reported possible side-effects during the placebo period: one complained of hoarseness, the second one had slight tremor initially, the third one
developed urticaria, the fourth had epigastric pain on
a few occasions and the fifth patient had a slight headache during the first days of treatment.
No systematic or individual changes in the blood
biochemistry or urinary tests were seen between
the three test occasions. One patient had high serum
creatinine (110 J.Lmol-1· 1 ; reference value: 40-100
J.Lmol-/' 1), on all three occasions. She had normal
urinary dip stick findings and a normal blood pressure.
At follow-up, a radiological examination of the
kidneys was performed showing small kidneys,
possibly due to previous pyelonephritis.
~------Ns------_j
Pathol. GOR
Normal GOR
n=18
n=19
Fig. 3. - Total asthma symptom score during the placebo and
the ranitidine treatment periods, and the difference in score between
the two periods, in the patients with pathological and in those
with normal gastro-oesophageal reflux (GOR). Mean:tSllM ate
given. Statistical comparison between the placebo and the ranitidine
periods was performed separately for the two groups of patients
by the Wilcoxon's signed rank test. The effect of treatment
(ranitidine-placebo score) was compared between the two aroups
by the Mann-Whitney U-test. Ns: nonsignificant.CJ: placebo; I22J:
ranitidine; : ranitidine-placebo.
Table 2. - Bronchial histamine reactivity after the
ranitidine and the placebo periods and the preference
of treatment periods In the patients with pathological
(n=18} and those with normal GOR (n=19)
Pathological GOR
Normal GOR
PC20Hi mg·ml·'
After ranitidine period
0.54:0.17
After placebo period
0.67:0.10
0.99:0.27
4
5
5
2
12
Preferred period
Placebo
Ranitidine
Neither
J
NS
9
0.58::t:0.10
J
NS
NS
Bronchial histamine challenge was performed after both
periods in 10 patients with pathological and in 12 patients
with normal GOR. GOR: gastro-oesophageal reflux; PC20Hi:
provoking dose of histamine causing a 20% fall in forced
expiratory volume in one second.
Discussion
This study in children and adolescents with bron·
chial asthma shows that an oral dose of ranitidine
taken in the evening, in addition to ordinary asthma
medication, produced a statistically significant, but
very modest reduction (30%) of nocturnal asthma
symptoms in patients with pathological GOR when
compared to those with normal GOR. Regression
analysis disclosed significant positive correlations
205
RANITIDINE, REFLUX AND ASTIIMA
between the improvement of nocturnal, morning and
total asthma symptoms and the degree of pathological
GOR at oesophageal pH monitoring. No beneficial
effect of ranitidine was seen on morning or evening
PEFR, FEV1 or bronchial histamine reactivity.
A positive APT did not predict a positive response
to ranitidine, suggesting that the effect of ranitidine
treatment on asthma was more closely related to the
degree of acid reflux, than to the finding of acid
sensitivity of the oesophagus.
Three controlled studies on the effects of H2 blockers on asthma symptoms in adult patients with
bronchial asthma and pathological GOR have previously been published [3, 12, 15], but there is no controlled study of the effect on asthma by reduction of
gastric acid reflux by H2-blocker therapy in asthmatic
children with GOR.
NAGEL et al. [3] treated 15 adult asthmatics with
pathological GOR with ranitidine 300 mg in the morning and 150 mg in the evening for seven days in a
placebo-controlled study. No improvement of asthma
symptoms or PEFR was seen, which might be due to
the very short duration of that trial. In the study by
GOODALL et al. [12] 18 adults with bronchial asthma
and symptoms of pathological GOR were evaluated
in a double-blind, cross-over trial over six weeks with
cimetidine 200 mg three times daily and 400 mg at
night. A significant reduction in reflux symptoms,
and nocturnal asthma symptom scores, and a minor
increase in the last PEFR reading during the day, were
found during the cimetidine period. In the study by
EKSTROM et al. [15], 48 adult asthmatics with symptoms of reflux were given ranitidine 150 mg twice
daily and placebo, respectively, in a double-blind,
cross-over fashion, over a four week period. A significant reduction in reflux symptoms and in nocturnal
asthma scores was seen during the ranitidine period.
However, the positive results were confined to a
subgroup of 27 patients with a history of reflux symptoms preceding episodes of asthma symptoms [15].
One explanation for the limited effect of gastric
acid secretion inhibition on asthma in the present
study could be that ranitidine did not sufficiently
inhibit acid secretion and consequently did not reduce
acid reflux enough. We gave the patients 300/150
mg ranitidine as a single evening dose as it had been
reported that a single dose of 300 mg ranitidine
produces an equivalent inhibition of gastric acid
secretion to 150 mg ranitidine twice daily [24). RUTH
et al. [25] compared the effect on oesophageal acidity of 20 mg omeprazole once daily with that of 150
mg ranitidine twice daily, by 24 h oesophageal pH
monitoring in patients with ulcerative oesophagitis.
The percentage reflux time (pH <4.0) was reduced by
41% during ranitidine treatment and by 82% during
omeprazole treatment [25], indicating that pathological acid reflux is not completely abolished by a single evening dose of ranitidine.
Secondly, there have been some controversies in
the literature as to whether asthma can deteriorate
from H 2 -receptor blockade due to promotion of
histamine release [26, 27] and increase of bronchial
tone [28-30]. Ranitidine may, thus, have a beneficial
effect on asthma symptoms in patients with pathological GOR by reducing acid reflux and a negative
effect on asthma from H 2-receptor blockade on
mediator cells and bronchial smooth muscle.
The present trial indicates that reduction of acid
reflux may improve asthma symptoms, but the study
is not large enough to give a firm understanding of
the size of treatment effects. We have in fact
detected a reduction in nocturnal asthma symptoms
that was supposedly obtained by a reduction in acid
reflux. The size of the reduction in nocturnal
asthma score is estimated to be approximately 30%.
However, judging from a 90% confidence interval,
the true percentage reduction can be practically null
in one extreme and beyond 60% in the other. Thus,
the size of the effect and its clinical significance are
not effectively determined in this study.
In summary, the H2-blocker ranitidine, taken as a
single evening dose over a four week period by
asthmatic children and adolescents, produced a small
reduction in nocturnal asthma symptoms. There was a
significant correlation between the improvement
in asthma symptoms and the degree of acid reflux.
The modest improvement during ranitidine treatment
suggests that mild or moderately severe pathological
acid reflux, which is often seen in children and
adolescents with asthma, is not of major importance
in asthma. The small size of the present study and the
inability of H 2 -blockers to completely abolish acid
reflux, however, preclude conclusive statements on the
importance of pathological GOR for childhood and
adolescent asthma. Therefore, further studies with
more potent inhibitors of gastric acid secretion and
acid reflux, such as omeprazole, are suggested.
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