Effects of Spontaneous and Simulated Gastroesophageal Reflux on Sleeping Asthmancs':'
WAN
c.
TAN, RICHARD J. MARTIN, R. PANDEY, and ROBERT D. BALLARD Introduction
Revious reports have described an increase in gastroesophageal reflux (GER) in patients with asthma (1-12) and have suggested that the treatment of reflux improves asthma (3, 7, 8). The most widely held theory for this association is that acid reflux may stimulate vagal receptors in the lower esophagus, inducing bronchoconstriction. The results of investigations involving lower esophageal acid perfusion are conflicting. Spaulding and coworkers (9) observed small increases in total respiratory resistance when acid was infused intraesophageally in asthmatics with evidence of esophagitis (13). Davis and coworkers (12) studied nine asthmatic children with GER symptoms during sleep and found indirect evidence of bronchoconstriction (14) after acid perfusion in four patients who also had positive Bernstein tests (13). Other investigators did not find such an association (15-17).
Several studies have suggested that GER is most likely to occur in asthmatic patients with nocturnal wheezing (12, 18, 19). It has also been suggested that patients with esophagitis have more frequent episodes of GER that last longer and occur in the supine position than do normal subjects (20,21). It would be reasonable to assume that an association between GER and asthma would be best studied in patients with nocturnal asthma and reflux esophagitis. Hence, previous studies have been inadequate in one or more ways. They have lacked reliable, objective, and direct indicators of bronchoconstriction such as continuous lower airway resistance measurements (9, 11, 12, 15, 18, 22), reliable documentation of esophageal reflux such as continuous esophageal pH (9, 15), have not included sleeping nocturnal asthmatic subjects (9, 11, 17), or all of the above. (9) In this study simultaneous and continuous measurements of lower airway resistance and esophageal pH were made in patients with nocturnal asthma and 1394
SUMMARY Weexamined the effect of intraesophageal acid (either spontaneous gastroesophageal reflux or infused) on airflow resistance in 15sleeping asthmatic subjects. Weobserved no significant acute or sustained changes in airflow resistance relative to periods of Intraesophageal acid. Overnight changes In spirometry and lower airway resistance also demonstrated similar nocturnal worsening of bronchoconstrlction despite the occurrence of spontaneous or simulated gastroesophageal reflux. The presence or absence of clinical evidence of esophagitis (Bernstein test response) did not alter the observed lack of response to Intraesophageal acid. We conclude that gastroesophageal reflux contributes little to the nocturnal worsening of asthma. AM REV RESPIR DIS 1990; 141:1394-1399
clinical esophagitis during sleep. Our goals were (1) to establish if acid in the esophagus triggered bronchoconstriction, (2) to see if the presence of esophagitis was necessary for such an effect, and (3) to determine if there was a difference between the airway responses to spontaneous reflux and intraesophageal acid infusion. Methods Subjects Fifteen adult patients (three women, 12men), 19 to 46 yr of age, with bronchial asthma as defined by the American Thoracic Society criteria (23) were studied. All had nocturnal asthma defined by greater than 20% fall in FEV I or PEFR from bedtime to morning awakening on three consecutive nights before the study but were clinically stable and had no change in medications for at least 1month before the study. All patients required bronchodilators on a regular basis for the control of symptoms. Twelve patients wereusing twice daily sustained-release oral theophylline; six patients used corticosteroids; none smoked. Inhaled bronchodilators werewithheld for 6 h and antihistamine and H 2 blockers for 72 h before the study. Oral theophylline was not discontinued at the patients' request for fear of acute exacerbation and because significant overnight falls in FEV 1 (> 20010) persisted in the presence of optimal theophylline levels. Because a positive Bernstein test had been widely accepted as a clinical test of esophagitis (13), the patients were further categorized by the Bernstein test into two groups: Bernstein positive (B+) and Bernstein negative (B-). Three B+ patients had frequent heartburn, used antacids regularly and had GER confirmed on a previous occasion by 24-h esophageal pH recordings. A total of 10 B+ and five B- subjects were studied.
Measurements Continuous and simultaneous recordings of the polysomnogram, ear oximetry,esophageal and supraglottic pressures, respiratory flow, tidal volume and resistances, and esophageal pH were made for each study using a multichannel chart recorder (Model 78D; Grass Instruments, Quincy, MA). Each study was routinely started at 11:00 P.M. and terminated at 6:00 A.M. Sleep state was monitored and analyzed according to the standard criteria of Rechtshaffen and Kales (24), using standard polysomnographic techniques: electroencephalogram (C 4-A.. C 3-A2 ) , electrooculogram, submental electromyogram, and electrocardiogram were obtained from surface electrodes (Grass Instruments). Arterial O 2 saturation was monitored using an ear oximeter (Biox III; Biox, Boulder, CO). The esophageal pH was monitored using a pH probe (Sandhill, Littleton, CO) that was positioned manometrically 5 em above the gastroesophageal junction. Flow and tidal volume (VT) weremonitored by the use of a tight-fitting mask (Laerdal)
(Received in original form March 3, 1989 and in revised form October 31, 1989) 1 From the Department of Medicine, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado; and the Department of Medicine, National University of Singapore, Republic of Singapore. 2 Supported by a Research Grant from the Clinicaiinvestigation Board of the National Jewish Center for Immunology and Respiratory Medicine and by Grant No. HL-36577 from the National Heart, Lung, and Blood Institute. J Correspondence and requests for reprints should be addressed to Wan C. Tan, M.D., Department of Medicine, National University Hospital,S lower Kent Ridge Road, Singapore 0511.
1395
GASTROESOPHAGEAL REFWX AND SLEEPING ASTHMATICS
with an attached heated pneumotachygraph (No.1; Fleisch, Lausanne, Switzerland) and a differential pressure transducer (MP-45; Validyne, Northridge, CA). A perforated tubing was placed around the outside edge of the face mask adjacent to the skin and connected to a capnograph (Puritan-Bennett, Los Angeles, CA) adjusted to maximal sensitivity to detect air leaks between the mask and the face (25, 26). Both flow and volume were calibrated at the beginning and conclusion of every study and continuously recorded on the chart recorder throughout each study. Esophageal pressure (Pes) was monitored from a lO-cmlatex balloon positioned in the esophagus (27) according to the "occlusion test" technique of Baydur and coworkers (28). Supraglottic pressure (Psg) was monitored from a disposable microtip catheter (MPC5000; Millar Instruments, Galveston, TX) positioned just above the epiglottis. Pulmonary resistance (RL) was calculated on a breath-by-breath basis using Pes, VT, and flow data. RLwas computed continuously by a computer (Model 6; Buxco, Sharon, CT) using the Neergard-Wirtztechnique at inspiratory flow rates of 0.25 Lis, as we routinely observe maximal flow rates in the range of 0.25 to 0.5 Lis in sleeping asthmatic patients. The accuracy of this computer was previously evaluated in studies of sleeping asthmatics and was found to correlate well to hand calculations of RL using both the isovolume (r = 0.99) and the Neergard-Wirtz (r = 0.99) techniques (29). The computer calculations were validated against the hand calculations made from the pressure and flow tracings at l-h intervals in all studies (r = 0.97). Supraglottic resistance (Rsg) was also calculated by a second computer (Model 6; Buxco) on a breathby-breath basis using Psg and flow data. Oneminute means of Rsg were subtracted from I-min means of RL to yield l-min means of lower airway resistance (RIa). Spirometry (Eagle II; Warren B. CoIlins, Braintree, MA) was performed at bedtime, at the time of awakening in the morning, and at any other awakenings caused by symptoms of increasing bronchoconstriction. Each reported measurement consisted of the best (highest FEV I) of three consecutive efforts.
Bernstein Test The Bernstein test (13) used for categorizing the patients was performed in the seated subject on the morning of the study. A nasogastric tube was placed 30 cm from the nares. Normal saline wasinfused for 15min followed by O.1N HCI for 15min. The rate of infusion was 6 ml/min. The test was considered positive only if symptoms of heartburn occurred within 10 min of acid perfusion (30) and was twice reproduced during acid perfusion and relieved by saline. Lower Esophageal Acid Perfusion This was performed in the sleeping patient in the supine position (13). A nasogastric tube (4 mm diameter) wasinserted through the nostril so that the tip was 2 to 3 ern proximal
to the tip of the pH probe. Normal saline or 0.1 N hydrochloric acid at room temperature was instilled at a rate of 3 mllmin. The aim was to maintain the esophageal pH at < 4 for about 30 min.
Experimental Protocol Fifteen subjects were studied after Bernstein tests in the sleep laboratory on three nights (one familiarization night and two study nights) within 1 wk. On each of the study nights, the last meal and bronchodilator were taken 6 h before the study, and serum theophylline was measured just before bedtime. Simultaneous monitoring of the polysomnogram, pulmonary mechanics, and esophageal pH was done on the two study (control and intervention) nights. The presence or absence of spontaneous reflux during sleep was determined on the control night. An episode of spontaneous esophageal reflux was defined as a decrease in pH to less than 4.0 for at least 5 s (31). For defining significant spontaneous reflux (SpGER) for the whole night in our experimental protocol, we chose the criteria of total time esophageal pH < 4 to be greater than 2.4010 of the total study time. This choice was based on the study by Dent and coworkers (32) who reported that in normal supine subjects the total time esophageal pH < 4 was less than 2.4% of the total study time. No such data existed for supine asthmatic subjects. On the intervention night, those subjects who had SpGER during sleepon the control night were pretreated 2 hourly with antacid throughout the day and 300 mg of an H2 antagonist (ranitidine) at bedtime. Those patients who did not haveSpGER on the control night weregiven intraesophageal acid perfusion for 30 min twice (at midnight and at 4:00 A.M.) during sleep on the intervention night. Our goal was to select 10 patients we felt likely to reflux (10 B + patients), but if they failed to reflux we wereprepared to simulate reflux with an HCL infusion (SmGER). We could therefore (1) compare direct measurements of RIa between two nocturnal sleep periods, one with the presence of acid in the esophagus, the other with the absence of acid in the esophagus, and (2)determine any differences between the effects on RIa of spontaneous reflux and intraesophageal acid infusion. We could also compare the airway responses of two different groups, one with evidence of esophagitis (B +) and one without evidence of esophagitis (B- ). This study protocol was approved by the hospital's Institutional Review Board, and informed consent was obtained from all subjects prior to their participation. Data Analysis The data were grouped in several ways in order to obtain the following information. (1) The effect of intraesophageal acid on nocturnal bronchoconstriction. Here the data were separated into two groups according to the presence or the absence of intraesophageal acid, which comprised both SpGER and SmGER. (2) The effect of Bernstein status
on the response to intraesophageal acid was examined by comparing the data of the two groups (B + and B- ) as previous studies had indicated that patients with esophagitis (with positive Bernstein tests) responded to intraesophageal acid by bronchoconstriction, whereas patients without esophagitis (negative Bernstein tests) did not (9, 12). (3) Differences between the effects of SpGER and SmGER on nocturnal bronchoconstriction. Data from the two groups, SpGER and SmGER, were analyzed separately and compared. For each of the above sections we examined both the progressive overnight and the acute airway responses to esophageal acidity. The acute effects on airway caliber wereevaluated by comparing the regression slopes of RIa changes over time (Rla/T) during the period of esophageal acidity with: (1) slope of RIa changes 30 min before and 30 min after intraesophageal acid, and (2) RIa increases throughout the night. This interval of 30 min was chosen because it was felt that this was of sufficient duration to include both acute and sustained changes to acid events. Wewere also able to select this interval because there was no overlapping of the postreflux interval of one reflux episode with the prereflux period of the next episode in individual subjects. However, the duration of intraesophageal acidity was variable in both SpGER and SmGER. The acid period varied for two reasons: (1) Although the aim was to infuse acid for 30 min, we had to terminate the infusion prematurely in some subjects if the procedure caused awakening. (2) The duration of spontaneous reflux could not be strictly controlled. Data are expressed as mean ± 1SEM. The data between groups were compared using Student's t test, two-factor analysis of variance (ANOVA), and linear regression analysis. Differences were considered significant at p < 0.05. Results
The two groups (B + and B- ) of asthmatic subjects did not differ in age, sex distribution, or baseline FVC, though B- subjects had lower baseline FEV 1 than did B+ subjects (table 1).There was also no difference in the sleep architecture and serum theophylline concentrations between the two study nights (table 2).
Duration of Spontaneous Reflux and Intraesophageal Acid Infusion Six subjects (all B +) had a total of 11 episodes of SpGER during sleep. The mean duration of these episodes was 10.4 ± 2.3 min (range, 1.1 to 24 min). The mean total reflux time for the study night was 19.1 ± 5.7 min or 5.4 ± 1.4070 of 346 ± 10 min of the total study time. The distribution of time with pH < 4 expressed as percent of study time in all the patients is shown in figure 1.
1396
TAN, MARTIN, PANDEY, AND BALLARD TABLE 1 SUBJECT CHARACTERISTICS' Age (yr)
Sex
29 ± 2 32 ± 4
8M/2F 4M/1F
Sub jects Bernstein-positive Bernstein-negative
FEV,
FVC
(% pred)
(% prod)
76.62 ± 3.13t 62.53 ± 4.19t
84.17 ± 2.44 79.85 ± 5.89
• Values are mean :i: SEM.
t p < 0.02.
TABLE 2
Spontaneous Reflux and Sleep Stages
THE SLEEP EFFICIENCY, DISTRIBUTION, AND SERUM THEOPHYLUNE CONCENTRATIONS ON THE TWO NIGHTS (ACID AND NO-ACID) ' Acidt
262.37 70.58 23.62 61.35 3.47 3.57 7.99 17.01
Sleep time, min Sleep efficiency, % Stage 1, % Stage 2, % Stage 3, % Stage 4, % REM ,% Theophylline, 1l9/ml
No-ac id:j:
± 16.50
242.13 69 .80 22.60 56.70 5.47 5.84 8.73 14.39
4.20 3.58 2.93 0.69 ± 0.99 ± 2.40 ± 1.66 ± ± ± ±
± 19.23
4.56 5.22 4.82 1.38 1.84 ± 2.51 ± 2.80
± ± ± ± ±
NS NS NS NS NS NS NS NS
4
II)
C CD
;:
3
IV
-... Q.
0
Fig . 1. The dist ribution of time pH < 4 expressed as a percentage of total study time in six asthmatic SUbjects who had spontaneous reflux.
2
CD ,g
E
:::J
Z
2
to % study time (pH 0.2) (figure 3).
Effect of Bernstein Status on Response to Intraesophageal Acid
0
-
The onset of six episodes of spontaneous reflux occurred during transient arousals, four in Stage II and one in Stage III sleep. None occurred in Stage I or REM sleep. The majority of reflux occurred during wakefulness and in Stage II sleep, 41.7 ± 13.2% and 36.5 ± 11.4070, respectively, of the total study time (figure 2).
Effect of Intraesophageal Acid on Nocturnal Bronchoconstriction
, Values are expressed as mean :i: SEM. Acid constnutes spontaneoud reflux and acid infusion. j No-acid constitutes no spontanous reflux and acid suppression.
t
-
The remaining four B+ and all five B - subjects did not have significant SpGER on the control night and therefore had intraesophageal acid perfusion or SmGER on the intervention night. There were 10episodes of SmGER, which lasted 32.1 ± 4.2 min in four B + patients, and 10 such episodes, which averaged 24.3 ± 6.6 min in five B - patients. These were not significantly different (p > 0.3).
40
Fig. 2. The distribution of reflux time and the relationship to sleep stages duro ing the whole night in six asthmatic subjects who had spontaneous reflux (solid column = time in reflux as a percent- . age of study time ; hatched column = time in sleep as a percentage of study time) . Values are mean ± 1 SEM.
>-
'tl :::J
30
'0
20
Ui
::e 0
10
0 Awake
2
Sleep stages
3
4
REM
The presence of esophagitis (Bernstein test positive) did not influence the response to intraesophageal acid . The overnight falls in FEV 1 (expressed as a percentage of baseline FEV 1) in B + and in B- subjects during the acid and the noacid nights were 28.9 ± 6.2% and 30.4 ± 5.7%, respectively, in B+ subjects and 31.5 ± 7.1% and 30.6 ± 8.7%, respectively, in B- subjects (p > 0.7) (figure 4). No difference was noted in the progressive overnight rise in Ria between the B + and the B - subjects on either night. The regression slopes (R1a/T) for the B + subjects for the acid night and the noacid night were 0.025 ± 0.004 and 0.035 ± 0.005, respectively, and for the B subjects it was 0.024 ± 0.006 and 0.034 ± 0.006, respectively (p > 0.1). Similarly, no difference existed between the B+ and the B- subjects in
1397
GASTROESOPHAGEAL REFLUX AND SLEEPING ASTHMATICS
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WAN
c.
TAN, RICHARD J. MARTIN, R. PANDEY, and ROBERT D. BALLARD Introduction
Revious reports have described an increase in gastroesophageal reflux (GER) in patients with asthma (1-12) and have suggested that the treatment of reflux improves asthma (3, 7, 8). The most widely held theory for this association is that acid reflux may stimulate vagal receptors in the lower esophagus, inducing bronchoconstriction. The results of investigations involving lower esophageal acid perfusion are conflicting. Spaulding and coworkers (9) observed small increases in total respiratory resistance when acid was infused intraesophageally in asthmatics with evidence of esophagitis (13). Davis and coworkers (12) studied nine asthmatic children with GER symptoms during sleep and found indirect evidence of bronchoconstriction (14) after acid perfusion in four patients who also had positive Bernstein tests (13). Other investigators did not find such an association (15-17).
Several studies have suggested that GER is most likely to occur in asthmatic patients with nocturnal wheezing (12, 18, 19). It has also been suggested that patients with esophagitis have more frequent episodes of GER that last longer and occur in the supine position than do normal subjects (20,21). It would be reasonable to assume that an association between GER and asthma would be best studied in patients with nocturnal asthma and reflux esophagitis. Hence, previous studies have been inadequate in one or more ways. They have lacked reliable, objective, and direct indicators of bronchoconstriction such as continuous lower airway resistance measurements (9, 11, 12, 15, 18, 22), reliable documentation of esophageal reflux such as continuous esophageal pH (9, 15), have not included sleeping nocturnal asthmatic subjects (9, 11, 17), or all of the above. (9) In this study simultaneous and continuous measurements of lower airway resistance and esophageal pH were made in patients with nocturnal asthma and 1394
SUMMARY Weexamined the effect of intraesophageal acid (either spontaneous gastroesophageal reflux or infused) on airflow resistance in 15sleeping asthmatic subjects. Weobserved no significant acute or sustained changes in airflow resistance relative to periods of Intraesophageal acid. Overnight changes In spirometry and lower airway resistance also demonstrated similar nocturnal worsening of bronchoconstrlction despite the occurrence of spontaneous or simulated gastroesophageal reflux. The presence or absence of clinical evidence of esophagitis (Bernstein test response) did not alter the observed lack of response to Intraesophageal acid. We conclude that gastroesophageal reflux contributes little to the nocturnal worsening of asthma. AM REV RESPIR DIS 1990; 141:1394-1399
clinical esophagitis during sleep. Our goals were (1) to establish if acid in the esophagus triggered bronchoconstriction, (2) to see if the presence of esophagitis was necessary for such an effect, and (3) to determine if there was a difference between the airway responses to spontaneous reflux and intraesophageal acid infusion. Methods Subjects Fifteen adult patients (three women, 12men), 19 to 46 yr of age, with bronchial asthma as defined by the American Thoracic Society criteria (23) were studied. All had nocturnal asthma defined by greater than 20% fall in FEV I or PEFR from bedtime to morning awakening on three consecutive nights before the study but were clinically stable and had no change in medications for at least 1month before the study. All patients required bronchodilators on a regular basis for the control of symptoms. Twelve patients wereusing twice daily sustained-release oral theophylline; six patients used corticosteroids; none smoked. Inhaled bronchodilators werewithheld for 6 h and antihistamine and H 2 blockers for 72 h before the study. Oral theophylline was not discontinued at the patients' request for fear of acute exacerbation and because significant overnight falls in FEV 1 (> 20010) persisted in the presence of optimal theophylline levels. Because a positive Bernstein test had been widely accepted as a clinical test of esophagitis (13), the patients were further categorized by the Bernstein test into two groups: Bernstein positive (B+) and Bernstein negative (B-). Three B+ patients had frequent heartburn, used antacids regularly and had GER confirmed on a previous occasion by 24-h esophageal pH recordings. A total of 10 B+ and five B- subjects were studied.
Measurements Continuous and simultaneous recordings of the polysomnogram, ear oximetry,esophageal and supraglottic pressures, respiratory flow, tidal volume and resistances, and esophageal pH were made for each study using a multichannel chart recorder (Model 78D; Grass Instruments, Quincy, MA). Each study was routinely started at 11:00 P.M. and terminated at 6:00 A.M. Sleep state was monitored and analyzed according to the standard criteria of Rechtshaffen and Kales (24), using standard polysomnographic techniques: electroencephalogram (C 4-A.. C 3-A2 ) , electrooculogram, submental electromyogram, and electrocardiogram were obtained from surface electrodes (Grass Instruments). Arterial O 2 saturation was monitored using an ear oximeter (Biox III; Biox, Boulder, CO). The esophageal pH was monitored using a pH probe (Sandhill, Littleton, CO) that was positioned manometrically 5 em above the gastroesophageal junction. Flow and tidal volume (VT) weremonitored by the use of a tight-fitting mask (Laerdal)
(Received in original form March 3, 1989 and in revised form October 31, 1989) 1 From the Department of Medicine, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado; and the Department of Medicine, National University of Singapore, Republic of Singapore. 2 Supported by a Research Grant from the Clinicaiinvestigation Board of the National Jewish Center for Immunology and Respiratory Medicine and by Grant No. HL-36577 from the National Heart, Lung, and Blood Institute. J Correspondence and requests for reprints should be addressed to Wan C. Tan, M.D., Department of Medicine, National University Hospital,S lower Kent Ridge Road, Singapore 0511.
1395
GASTROESOPHAGEAL REFWX AND SLEEPING ASTHMATICS
with an attached heated pneumotachygraph (No.1; Fleisch, Lausanne, Switzerland) and a differential pressure transducer (MP-45; Validyne, Northridge, CA). A perforated tubing was placed around the outside edge of the face mask adjacent to the skin and connected to a capnograph (Puritan-Bennett, Los Angeles, CA) adjusted to maximal sensitivity to detect air leaks between the mask and the face (25, 26). Both flow and volume were calibrated at the beginning and conclusion of every study and continuously recorded on the chart recorder throughout each study. Esophageal pressure (Pes) was monitored from a lO-cmlatex balloon positioned in the esophagus (27) according to the "occlusion test" technique of Baydur and coworkers (28). Supraglottic pressure (Psg) was monitored from a disposable microtip catheter (MPC5000; Millar Instruments, Galveston, TX) positioned just above the epiglottis. Pulmonary resistance (RL) was calculated on a breath-by-breath basis using Pes, VT, and flow data. RLwas computed continuously by a computer (Model 6; Buxco, Sharon, CT) using the Neergard-Wirtztechnique at inspiratory flow rates of 0.25 Lis, as we routinely observe maximal flow rates in the range of 0.25 to 0.5 Lis in sleeping asthmatic patients. The accuracy of this computer was previously evaluated in studies of sleeping asthmatics and was found to correlate well to hand calculations of RL using both the isovolume (r = 0.99) and the Neergard-Wirtz (r = 0.99) techniques (29). The computer calculations were validated against the hand calculations made from the pressure and flow tracings at l-h intervals in all studies (r = 0.97). Supraglottic resistance (Rsg) was also calculated by a second computer (Model 6; Buxco) on a breathby-breath basis using Psg and flow data. Oneminute means of Rsg were subtracted from I-min means of RL to yield l-min means of lower airway resistance (RIa). Spirometry (Eagle II; Warren B. CoIlins, Braintree, MA) was performed at bedtime, at the time of awakening in the morning, and at any other awakenings caused by symptoms of increasing bronchoconstriction. Each reported measurement consisted of the best (highest FEV I) of three consecutive efforts.
Bernstein Test The Bernstein test (13) used for categorizing the patients was performed in the seated subject on the morning of the study. A nasogastric tube was placed 30 cm from the nares. Normal saline wasinfused for 15min followed by O.1N HCI for 15min. The rate of infusion was 6 ml/min. The test was considered positive only if symptoms of heartburn occurred within 10 min of acid perfusion (30) and was twice reproduced during acid perfusion and relieved by saline. Lower Esophageal Acid Perfusion This was performed in the sleeping patient in the supine position (13). A nasogastric tube (4 mm diameter) wasinserted through the nostril so that the tip was 2 to 3 ern proximal
to the tip of the pH probe. Normal saline or 0.1 N hydrochloric acid at room temperature was instilled at a rate of 3 mllmin. The aim was to maintain the esophageal pH at < 4 for about 30 min.
Experimental Protocol Fifteen subjects were studied after Bernstein tests in the sleep laboratory on three nights (one familiarization night and two study nights) within 1 wk. On each of the study nights, the last meal and bronchodilator were taken 6 h before the study, and serum theophylline was measured just before bedtime. Simultaneous monitoring of the polysomnogram, pulmonary mechanics, and esophageal pH was done on the two study (control and intervention) nights. The presence or absence of spontaneous reflux during sleep was determined on the control night. An episode of spontaneous esophageal reflux was defined as a decrease in pH to less than 4.0 for at least 5 s (31). For defining significant spontaneous reflux (SpGER) for the whole night in our experimental protocol, we chose the criteria of total time esophageal pH < 4 to be greater than 2.4010 of the total study time. This choice was based on the study by Dent and coworkers (32) who reported that in normal supine subjects the total time esophageal pH < 4 was less than 2.4% of the total study time. No such data existed for supine asthmatic subjects. On the intervention night, those subjects who had SpGER during sleepon the control night were pretreated 2 hourly with antacid throughout the day and 300 mg of an H2 antagonist (ranitidine) at bedtime. Those patients who did not haveSpGER on the control night weregiven intraesophageal acid perfusion for 30 min twice (at midnight and at 4:00 A.M.) during sleep on the intervention night. Our goal was to select 10 patients we felt likely to reflux (10 B + patients), but if they failed to reflux we wereprepared to simulate reflux with an HCL infusion (SmGER). We could therefore (1) compare direct measurements of RIa between two nocturnal sleep periods, one with the presence of acid in the esophagus, the other with the absence of acid in the esophagus, and (2)determine any differences between the effects on RIa of spontaneous reflux and intraesophageal acid infusion. We could also compare the airway responses of two different groups, one with evidence of esophagitis (B +) and one without evidence of esophagitis (B- ). This study protocol was approved by the hospital's Institutional Review Board, and informed consent was obtained from all subjects prior to their participation. Data Analysis The data were grouped in several ways in order to obtain the following information. (1) The effect of intraesophageal acid on nocturnal bronchoconstriction. Here the data were separated into two groups according to the presence or the absence of intraesophageal acid, which comprised both SpGER and SmGER. (2) The effect of Bernstein status
on the response to intraesophageal acid was examined by comparing the data of the two groups (B + and B- ) as previous studies had indicated that patients with esophagitis (with positive Bernstein tests) responded to intraesophageal acid by bronchoconstriction, whereas patients without esophagitis (negative Bernstein tests) did not (9, 12). (3) Differences between the effects of SpGER and SmGER on nocturnal bronchoconstriction. Data from the two groups, SpGER and SmGER, were analyzed separately and compared. For each of the above sections we examined both the progressive overnight and the acute airway responses to esophageal acidity. The acute effects on airway caliber wereevaluated by comparing the regression slopes of RIa changes over time (Rla/T) during the period of esophageal acidity with: (1) slope of RIa changes 30 min before and 30 min after intraesophageal acid, and (2) RIa increases throughout the night. This interval of 30 min was chosen because it was felt that this was of sufficient duration to include both acute and sustained changes to acid events. Wewere also able to select this interval because there was no overlapping of the postreflux interval of one reflux episode with the prereflux period of the next episode in individual subjects. However, the duration of intraesophageal acidity was variable in both SpGER and SmGER. The acid period varied for two reasons: (1) Although the aim was to infuse acid for 30 min, we had to terminate the infusion prematurely in some subjects if the procedure caused awakening. (2) The duration of spontaneous reflux could not be strictly controlled. Data are expressed as mean ± 1SEM. The data between groups were compared using Student's t test, two-factor analysis of variance (ANOVA), and linear regression analysis. Differences were considered significant at p < 0.05. Results
The two groups (B + and B- ) of asthmatic subjects did not differ in age, sex distribution, or baseline FVC, though B- subjects had lower baseline FEV 1 than did B+ subjects (table 1).There was also no difference in the sleep architecture and serum theophylline concentrations between the two study nights (table 2).
Duration of Spontaneous Reflux and Intraesophageal Acid Infusion Six subjects (all B +) had a total of 11 episodes of SpGER during sleep. The mean duration of these episodes was 10.4 ± 2.3 min (range, 1.1 to 24 min). The mean total reflux time for the study night was 19.1 ± 5.7 min or 5.4 ± 1.4070 of 346 ± 10 min of the total study time. The distribution of time with pH < 4 expressed as percent of study time in all the patients is shown in figure 1.
1396
TAN, MARTIN, PANDEY, AND BALLARD TABLE 1 SUBJECT CHARACTERISTICS' Age (yr)
Sex
29 ± 2 32 ± 4
8M/2F 4M/1F
Sub jects Bernstein-positive Bernstein-negative
FEV,
FVC
(% pred)
(% prod)
76.62 ± 3.13t 62.53 ± 4.19t
84.17 ± 2.44 79.85 ± 5.89
• Values are mean :i: SEM.
t p < 0.02.
TABLE 2
Spontaneous Reflux and Sleep Stages
THE SLEEP EFFICIENCY, DISTRIBUTION, AND SERUM THEOPHYLUNE CONCENTRATIONS ON THE TWO NIGHTS (ACID AND NO-ACID) ' Acidt
262.37 70.58 23.62 61.35 3.47 3.57 7.99 17.01
Sleep time, min Sleep efficiency, % Stage 1, % Stage 2, % Stage 3, % Stage 4, % REM ,% Theophylline, 1l9/ml
No-ac id:j:
± 16.50
242.13 69 .80 22.60 56.70 5.47 5.84 8.73 14.39
4.20 3.58 2.93 0.69 ± 0.99 ± 2.40 ± 1.66 ± ± ± ±
± 19.23
4.56 5.22 4.82 1.38 1.84 ± 2.51 ± 2.80
± ± ± ± ±
NS NS NS NS NS NS NS NS
4
II)
C CD
;:
3
IV
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Fig . 1. The dist ribution of time pH < 4 expressed as a percentage of total study time in six asthmatic SUbjects who had spontaneous reflux.
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Effect of Bernstein Status on Response to Intraesophageal Acid
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The onset of six episodes of spontaneous reflux occurred during transient arousals, four in Stage II and one in Stage III sleep. None occurred in Stage I or REM sleep. The majority of reflux occurred during wakefulness and in Stage II sleep, 41.7 ± 13.2% and 36.5 ± 11.4070, respectively, of the total study time (figure 2).
Effect of Intraesophageal Acid on Nocturnal Bronchoconstriction
, Values are expressed as mean :i: SEM. Acid constnutes spontaneoud reflux and acid infusion. j No-acid constitutes no spontanous reflux and acid suppression.
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The remaining four B+ and all five B - subjects did not have significant SpGER on the control night and therefore had intraesophageal acid perfusion or SmGER on the intervention night. There were 10episodes of SmGER, which lasted 32.1 ± 4.2 min in four B + patients, and 10 such episodes, which averaged 24.3 ± 6.6 min in five B - patients. These were not significantly different (p > 0.3).
40
Fig. 2. The distribution of reflux time and the relationship to sleep stages duro ing the whole night in six asthmatic subjects who had spontaneous reflux (solid column = time in reflux as a percent- . age of study time ; hatched column = time in sleep as a percentage of study time) . Values are mean ± 1 SEM.
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The presence of esophagitis (Bernstein test positive) did not influence the response to intraesophageal acid . The overnight falls in FEV 1 (expressed as a percentage of baseline FEV 1) in B + and in B- subjects during the acid and the noacid nights were 28.9 ± 6.2% and 30.4 ± 5.7%, respectively, in B+ subjects and 31.5 ± 7.1% and 30.6 ± 8.7%, respectively, in B- subjects (p > 0.7) (figure 4). No difference was noted in the progressive overnight rise in Ria between the B + and the B - subjects on either night. The regression slopes (R1a/T) for the B + subjects for the acid night and the noacid night were 0.025 ± 0.004 and 0.035 ± 0.005, respectively, and for the B subjects it was 0.024 ± 0.006 and 0.034 ± 0.006, respectively (p > 0.1). Similarly, no difference existed between the B+ and the B- subjects in
1397
GASTROESOPHAGEAL REFLUX AND SLEEPING ASTHMATICS
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