Increase in gastroesophageal reflux during methacholine-induced bronchospasm

Increase in gastroesophageal reflux during methacholine-induced bronchospasm D. William Moote, M.D., F.R.C.P.(C), David A. Lloyd, M.D., F.R.C.P.(C), David R. McCourtie, M.D., F.R.C.P.(CI, and George A. Wells, Ph.D. London,

Ontario,

Canada

‘There is an increased incidence in gastroesophageal rejlu.x (GER) in subjects with asthma. The cause-effect relationship remains controversial. We compared I5 subjects with mild asthma to 15 control subjects (nonasthmatic) to ascertain if GER might be induced by bronchospasm. Continuous monitoring of lower esophageal sphincter pre.isure and pH at 5 cm above the lower esophageal sphincter was per$ormed in seated subjects for 3 hours in total: I hour oj baseline measurements, 1 hour of methacholine inhalation with a dosimeter, and I hour after the inhalation of 200 pg of salbutamol (albuterol). During bronchospasm, subjects with asthma had more episodes of GER (3.9 k 1.5) and dropped their pH to lower levels (pH 2.23 2 0.3) than did the control subjects (0.8 2 0.3 episodes, pH 3.22 + 0.3) p < 0.05. We conclude that in these subjects with mild asthma, methacholine-ina’uced bronchospasm produced GER episodes of greater frequency and severity. (J ALLERGY CLINIMMUNOL78.619-23, 1986.)

The association of GER and pulmonary symptoms was first documented in 1887 in patients with achalasia,’ and the first documentation of GER associated bronchospasm was during obstetrical anesthesia in 1946.’ There is agreement among authors that GER is increased in subjects with asthma. Estimates vary from 45% up to 89% of the subjects.3.4 GER has been associated with a wide variety of pulmonary diseases and has been recently reviewed in this JOURNAL.’ Study of the LES is complicated by the many extrinsic factors that influence it. Some of these are presented in Table I. Earlier studies did not control for bronchodilators and premeditations, and many of these can decrease LESP, thereby increasing GER.6 More recent studies have controlled for this and still have demonstrated an increase in GER in subjects with asthma. This can occur even without symptoms of heartburn and is especially common in subjects with asthma with perennial or nocturnal symptoms. Although it is accepted that there is an increased frequency of GER in subjects with asthma, there remains some controversy about the cause. Most studies

From the Sectionsof Allergy and Clinical Immunology and Gastroenterology, Department of Medicine, University of Western Ontario, London, Ontario, Canada. Sponsoredby a grant from the Ontario Thoracic Society. Received for publication Oct. 11, 1985. Accepted for publication March 18, 1986. Reprint requests:D. William Moote, M.D., Victoria Hospital, London. Ontario, CanadaN6A 4G5.

Abbreviations used

GER: Gastroesophagealreflux

I

LESP: LES:

Lower esophageal sphincter pressure Lower esophageal sphincter

MeCh: Methacholine

have suggested that asthma is caused by GER. Two mechanisms are proposed for this: (1) microaspiration of gastric contents’, ’ and (2) an increase in vagal tone caused by acid stimulation of the lower esophagus.“, ” Other studies have noted a subgroup with asthma with what has been called a primary respiratory disorder in which the wheezing or coughing occurs before the GER. “-F The association of asthma and GER has resulted in aggressive anti-GER management, including surgery, in the hope of improving asthma. Such improvement may not occur if the GER was in fact caused by the asthma. The purpose of the present study was to document the frequency of GER during acute bronchospasm induced by methacholine. MATEiRlAL AND METHODS Subjects Sixteen subjects with mild asthma and 16 control subjects without asthma were recruited. All were volunteers. Subjects were excluded if they had a history of daily heartburn or if they were pregnant. Their asthma had to be mild enough 619

620 Moote et al.

TABLE I. Factors affecting --

J. ALLERGY

LESP

Decrease

Fatty foods Acid Alcohol Cigarette smoking* Chocolate (theobromine)* Coffee (caffeine)* Theophylline* P-Adrenergic drugs* PGE,, PCA, Dopamine Atropine* Morphine, meperidine, diazepam* Secretin Glucagon CCK

Increase

TABLE II. Comparison of subjects baseline pulmonary function Subjects with asthma

Protein foods Alkali

5-HT, a-adrenergic drugs P-Blockers PGF,,, indomethacin Metoclopramide Cholinergics* Histamine* Gastrin Motilin

GIP, VIP

CCK = cholecystokinin; GIP = gastric inhibitory peptide; VIP = vasoactive intestinal peptide: 5-HT = 5-hydroxytryptamine; PG = prostaglandin. *Factors that may have affected other studies becauseof patient population, drugs, or premeditation and illustrate the effects of agentsused for bronchial challenge.

in order to withhold all medications for 12 hours without causing an exacerbation of their disease.

Technique Subjects were studied in a sitting position after an overnight fast. All medications, caffeine, and cigarettes were withheld for at least 12 hours. Serum theophylline concentrations were measured in all subjects. A standard continuously perfused 6-lumen nasoesophageal manometry tube was inserted with a pH microelectrode in one of the channels (Microelectrodes Inc., Londonderry, N. H.). Baseline LESP was performed with standard methods.14The tube was then positioned to measure the pH at 5 cm above the LES and was taped in that position. LESP and pH were then continuously recorded on a polygraph (Grass Instrument Co., Quincy, Mass. 1. FEV, was measured at the onset of the study before and after the nasoesophageal tube placement with a Vitalograph (Vitalograph Medical Instrumentation, Kansas City, Kan.) wedge spirometer. The study was divided into three l-hour segments. Hour I consisted of resting baseline measurements. After the completion of hour I, MeCh was inhaled by use of a DeVilbiss 646 (DeVilbiss Co.. Somerset, Pa.) nebulizer with a Rosenthal-French dosimeter (John Hopkins University, Baltimore, Md.) and a standard challenge protocol.15 All subjects began with five inhalations of a dilute solution of MeCh (0.15 mg/ml), a total of 0.75 breath units (1 breath unit = 1 inhalation of 1 mg/ml of MeCh). FEV, was repeated at 1 and 5 minutes after each inhalation challenge. Challenges

Age W SEX M:F FEV, FVC FEV,/FVC

27.6 ? 8:7 3.95 2 4.94 k 80.6 2

2.4 0.25 0.34 2.0

and

Control subjects (nonasthmatic)

27.2 t 9:6 4.6 t 5.46 4 85.5 t

CLIN. IMMUNOL. OCTOBER 1986

p Value

2.1

NS NS

0.20 0.26 1.2

p < 0.05

NS p < 0.05

NS = not significant were repeated every 5 minutes until either the FEV, was reduced to 60% to 80% of baseline (the group with asthma), or the maximum dose of five inhalations of 25 mg/ml of MeCh was inhaled without causing wheezing or reducing the FEV, below 90% of baseline. Two subjects were excluded at this point: one with asthma whose FEV, did not fall below 114%on the study day and one control subject who was unable to reproducibly perform an FEV, with the nasoesophageal tube in place. This challenge protocol took approximately 10 to 30 minutes, depending on the sensitivity of the individual subject to methacholine. Because of the variable time involved, LESP and pH data from this segment were not included in the final analysis. Hour I1 commenced at the time of inhalation of the highest tolerated concentration of MeCh. During this second hour, MeCn inhalations at the highest tolerated concentration and FEV, measurements were repeated every 10 minutes. This was performed in both subjects with asthma and control subjects and served to maintain ongoing mild bronchospasm in the subjects with asthma without affecting the control subjects. At the clnset of hour III, both groups inhaled 200 kg of salbutamol (albuterol) by metered-dose inhaler, and FEV, was repeated to demonstrate return to baseline values. LESP and pH data were collected for the remainder of this final hour.

Statistical

methods

Analysis of the frequency of GER was determined by a blinded observer from episodes of esophageal, pH c4.0, that lasted for 5 seconds or longer. Statistical analysis was performed for GER data by use of analysis of variance for a two-factor design with one repeated factor, the first factor being the groups (subjects with asthma and nonasthmatic control subjects) and the repeated second factor being the three segments of 1 hour each. In addition, examination of all pair-wise differences between groups and within groups was achieved by use of Tukey’s honestly significant difference. This rigorous test incorporates a penalty for performing mult lple comparisons. The age, sex. and baseline pulmonary function tests of the two subject groups were compared by Student’s two-tailed t test. All data are expressed as mean plus or minus the standard error of the mean.

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78 4. PART 1

Gastroesophageal

total breath units

total breath units

FIW, %original

reflux

621

FEV, %

100%

700

80%

500

60%

300

100

p
p
FIG. 1. Cumulative breath units of inhaled MeCh and mean FEV, during MeCh inhalation of baseline) in subjects with asthma (closed bars) and control subjects (open bars/.

RESULTS Subjects

(percent

30 L m

The groups were of similar age and sex distribution. The significantly lower FEV, and FEV,/FVC ratio was consistent with underlying asthma and was the only apparent difference between the groups (Table II). All the control subjects inhaled 850 cumulative breath units of MeCh during hour II. They did not wheeze, and their FEV, remained at a mean of 96 -+ 0% baseline. The group with asthma inhaled a mean of 157 + 2.39cumulative breath units of MeCh, and all had symptomatic wheezing and reduced the FEV, to 65 :t 1.7% of baseline. These differences were significant by Student’s two-tailed t tests (p < 0.0001; Fig. 1). LESP and GER data LESP at the onset of the study was within the normal range and was similar in both groups. The data for hours II and III continued to demonstrate similarity between the groups. There was a statistically significant trend to decreasing LESP during the 3 hours; however, this was not to a clinically important degree, and values remained within the normal range. The decrease occurred in both the subjects with asthma and control populations (Fig. 2). The number of GER episodes per hour was similar in hours I and III, but during hour II, there were more episodes of wheezing in subjects with asthma than in the control subjects (nonasthmatic) (3.9 ? 1.5 versus 0.8 t 0.3 episodes). No episodes were associated with clinical heartburn. This difference was significant

:

20-

NON-ASTHMATICS

E

FIG. 2. Relationship between LESP in subjects with asthma and control subjects during each of 3 hours of study. Hour I is baseline, hour II is during MeCh inhalation, and hour III is after bronchodilator.

with Tukey’s honestly significant difference and also analysis of variance for two factors comparing the Ashaped pattern of the subjects with asthma with the V-shaped pattern of the control subjects (p < 0.05); (Fig. 3). The subjects with asthma had a greater drop in pH during hour II to a pH of 2.23 + 0.3 versus pH 3.22 ? 0.3 in the control subjects, demonstrating that with each GER episode, their pH fell to lower levels (Fig. 4). This difference was also significant with Tukey’s honestly significant difference (p < 0.05). The total time of GER measured as the number of seconds per hour during which the pH was ~4.0 did not demonstrate a difference between groups sufficient to fulfill the criteria for Tukey’s honestly significant difference (Fig. 5). Serum theophylline concentrations were measured in all subjects at the onset of the study to ensure

622

Moote

et al.

J. ALLERGY

ASTHMATICS

FIG. 3. Number of GER episodes per hour. During hour II, there was a significant difference between the subjects with asthma and control subjects (Tukey’s honestly significant difference and analysis of variance fortwo factors, p < 0.05).

/8I

ASTHMATICS

I .4 pH

, o

NON-ASTHMATICS

0.6

o’t--+--L

II

III

FIG. 4. Magnitude of pH drop below 4.0 during the greatest recorded drop in pH each hour (Tukey’s honestly significant difference, p <: 0.05).

compliance with abstinence from caffeine and theophylline. Levels were undetectable in all subjects.

DISCUSSION The findings described herein indicate that MeChinduced bronchospasm caused an increase in the number and severity of GER episodes in comparison to control subjects who also inhaled MeCh but did not wheeze. The control subjects behaved as might be expected from the pharmacologic effects of MeCh and salbutamol (albuterol). During hour II, control subjects had a reduced number of GER episodes while they were under the influence of MeCh that might be expected due to the increased tone of the LES. I6 Betaadrenergic drugs such as salbutamol have been demonstrated to relax the LES and would cause an increase in GER episodes.” Despite these expected changes in the GER episodes due to MeCh and salbutamol, we did not observe this in the actual LESP data. Although the subjects with asthma inhaled the same medications, they behaved in the opposite fashion, suggesting

,x

FIG. 5. Total time of GER (number pH C4.0). No significant difference

I

CLIN. IMMUNOL. OCTOBER 1986

NON-ASTHMATICS

of secoilds per hour, between groups.

that the bronchospasm itself was responsible for this difference. The greater drop in pH may reflect GER of larger volumes of acid into the esophagus, although the experimental design did not permit actual measurements of these volumes. The results of this study provide an alternative explanation for the increased frequency of GER commonly found in subjects with asthma. Although there have been many publications to support the concept that GEF. is at least sometimes a contributing factor in causing asthma,4. ” the frequency with which this occurs is in question. In an earlier studyI in which symptom scores were used to measure GER, the authors concluded that the treatment of asthma may reduce the incidence of GER. This would agree with evidence demonstrated here that induction of asthma increases GER. We propose that the altered intrathoracic pressures, flattened diaphragm, and coughing that appear during asthma can affect the LESP, thereby causing an increase in GER episodes. We believe that the demonstration of an increased frequency of GER in asthma is not sufficient to prove cause and effect. Before anti-GER surgery is considered in the hope of improving asthma, care should be taken to ensure that GER in that individual is truly an exacetbating cause of the asthma. Twenty-four hour pH monitoring and demonstration of asthma attacks after documented GER episodes would be sufficient for this. If a cause-effect relationship cannot be proven, then it should at least be considered that the increased incidence of GER occurs as a result of the asthma and not vice versa. REFERENCES 1. Mermod E: Dilatation diffuse de I’oesophage. Rev Med Suisse Romande 7422, 1887 2. Merldelsohn CL: The aspiration of stomach contents into the lungs during obstetric anesthesia. Am .I Obstet Gynecol52: 191, 19415

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3. Mays El? Intrinsic asthma in adults: association with gastroesophageal reflurt. JAMA 236(23):2626, 1976 4. Larrain A, Carrasco J, Galleguillos J, Pope CE II: Reflux treatment improves lung function in patients with intrinsic asthma. Gastroenterology 80: 1204, 1981 (absi) 5. Nelson HS: Gastroesophageal reflux and pulmonary disease. J ALLERGYCLANIMMUNOL 73547, 1984 6. Berquist WE, Rachelefsky GS, Kadden M, Siegel SC. Katz RM, Mickey R, Ament ME: Effect of theophylline on gastroesophageal reflux in normal adults. J ALLERGYCLIN IMMUNOL 67:407, I98 1 7. Reich SB, Earle,y WC, Ravin TH, Goodman M, Spector S, Stein MK: Evaluation of gastropulmonary aspiration by a radioactive technique: concise communication J Nucl Med 18:1079. 1977 8. Chemow B. Johnson LF, Janowitz WR, Caste11DO: Pulmonary aspiration as a consequence of gastroesophageal reflux: a diagnostic approach. Dig Dis Sci 24:839, 1979 9. Mansfield LE, Stein MR: Gastroesophageal reflux and asthma: a possible reflex mechanism. Ann Allergy 41:224, 1978 10. Spaulding HS, Mansfield LE, Stein MR. Sellner JC, Gremillion DE: Further investigation of the association between

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gastroesophageal reflex and bronchoconstriction. J ALLERGY CLIN IMMUNOL 69516, 1982 Clernencon GH. Osterman P-O: Hiatal hernia in bronchial asth:na: the importance ofconcomitant pulmonary emphysema. Gastroenterologia (Basel) 9.5:1IO, 1961 Pellegrini CA. DeMeester TR. Johnson LF. Skinner DB. Gastroer.ophageal reflux and pulmonary aspiration: incidence, functional abnormality, and results of original therapy. Surgery 86: 110, 1979 Wolf S, Merrick J, Finch M, Younaszai K, Weinberger M: Relationship between gastroesophageal reflux and obstructive airway disease J ALLERGYCLIN IMMUNOL 75: 171, 1985 (abst) Dodtis WJ: Instrumentation and methods for intraluminal esop lageal manometry. Arch Intern Med 1365 15, 1976 Chai H, Farr RS, Froelich LA, et al: Standardization of bronchial inhalation challenge procedures. J AI LEROY0.1~ IMMU NOL .56:323, 1975 Chri:.tensen J: Effect of drugs on esophageal motility. Arch Intern Med 136:532, 1976 Sing11V, Jain NK: Asthma as a cause for, rather than a result of, gastroesophageal reflux. J Asthma 20:24 I. I983

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