Spontaneous Gastroesophageal Reflux and Airway Patency during the Night in Adult Asthmatics GIUSEPPINA CUTTITTA, FABIO CIBELLA, ALFREDO VISCONTI, NICOLA SCICHILONE, VINCENZO BELLIA, and GIOVANNI BONSIGNORE Istituto di Fisiopatologia Respiratoria del Consiglio Nazionale delle Ricerche, and Istituto di Pneumologia dell’Università, Palermo, Italy
Controversies still exist on the role of nighttime gastroesophageal reflux (GER) in precipitating nocturnal asthma. We tested the relationship between GER and nocturnal bronchoconstriction by continuously and simultaneously monitoring both respiratory resistances and esophageal pH in seven asthmatics with moderate to severe GER disease. Twenty-nine GER episodes were found during the study night lasting more than 5 min (LGER) and 72 not longer than 5 min (SGER). Both long (LGER) and short (SGER) gastroesophageal refluxes were able to maintain significantly higher lower respiratory resistances (RLR) at the resolution of each GER episode (RLRe) with respect to baseline values. RLR, expressed as the area under the RLR curve along each GER episode (AUCRLR) and as RLRe, showed significant correlations with GER duration. Moreover, a significant correlation was found between RLR measured 10 min after GER resolution and GER duration during each episode. We conclude that GER itself is able to elicit nocturnal bronchoconstriction in asthmatics with moderate to severe GER disease and that bronchoconstriction severity and duration are related to GER duration. Cuttitta G, Cibella F, Visconti A, Scichilone N, Bellia V, Bonsignore G. Spontaneous gastroesophageal reflux and airway patency during the night in adult asthmatics. AM J RESPIR CRIT CARE MED 2000;161:177–181.
Previous studies have reported a high incidence of gastroesophageal reflux (GER) among asthmatics (1, 2) and have also suggested that the treatment of reflux may result in marked improvement of asthma symptoms and pulmonary function (3– 6). In awake adult asthmatics with a positive Bernstein test, intraesophageal acid infusion has been reported to trigger bronchoconstriction with subsequent return toward baseline function when these symptoms were relieved with antacid treatment (7). Nighttime GER has been advocated as a possible causative and precipitating factor of nocturnal worsening of asthma: it can trigger changes in respiratory pattern in asthmatic children when asthma is complicated by the presence of esophagitis (8). Converserly, other reports present conflicting data. In fact, in a study based on the use of noninvasive methods, Hughes and coworkers reported that reflux did not play any role in the production of nighttime asthma symptoms (9). Similarly, Ekstrom and coworkers reported that GER does not play any important role as an immediate trigger factor in nocturnal asthma (10). Therefore, the relationship between GER and nocturnal asthma is still controversial: the heterogeneity of results may be partly due to methodological limitations in previous studies, in particular the need of waking up the patient to perform the functional measures. In addition, the selection of the samples in terms of severity of GER disease may have influenced the possibility of detecting any relationship with airway reactivity: in fact, the only study based on
(Received in original form August 6, 1998 and in revised form July 20, 1999 ) Correspondence and requests for reprints should be addressed to Giuseppina Cuttitta, M.D., Istituto di Fisiopatologia Respiratoria del CNR, Via Trabucco, 180, I 90146 Palermo, Italy. E-mail:
[email protected] Am J Respir Crit Care Med Vol 161. pp 177–181, 2000 Internet address: www.atsjournals.org
a reliable method (i.e., continuous and simultaneous measurement of airflow resistance and esophageal pH monitoring in nocturnal asthmatics) and reporting negative results was carried out on patients with mild GER disease (11). The aim of the present study was to test this hypothesis by applying proper techniques to the evaluation of the relationship between GER and nocturnal bronchoconstriction in asthmatics with moderate to severe GER disease.
METHODS Sample Seven adult lifelong nonsmokers affected by nonseasonal asthma (4 male, 3 female), as defined according to American Thoracic Society (ATS) criteria (12), age 20 to 52 yr, were studied; all reported a personal history of heartburn, pain, and regurgitation suggesting GER disease. The severity and the frequency of these symptoms were classified according to Vigneri and coworkers (13). Only subjects showing a symptom score > 12 were considered for the study. Their main anthropometric and functional characteristics are presented in Table 1. All the subjects were affected by nocturnal asthma as demonstrated by a fall in peak expiratory flow (PEF) values > 15% from bedtime to morning awakening and had not required changes in medications during the last month before the study. All the subjects reported awakenings associated with nocturnal asthma symptoms and, frequently, with GER-related symptoms. All of them were receiving regular inhaled corticosteroids and short-acting b2-agonists on an “as needed” basis. None of them received theophylline or antacid, protonic pump inhibitors, H2-blockers, or prokinetics. All patients gave written, informed consent, and approval for this study was granted by the institutional ethic committee.
Protocol Each subject slept in the sleep laboratory and was submitted to a polysomnographic assessment. The following signals were continuously recorded both on paper (Hewlett-Packard 7758B; Hewlett-Packard
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TABLE 1
TABLE 3
GENDER, AGE, BASELINE FEV1, AND RLR VALUE AT THE BEGINNING OF THE STUDY (RLRst, PATIENTS IN SUPINE POSITION) MEASURED DURING WAKEFULNESS OF EACH SUBJECT
TOTAL EXPERIMENTAL AND SLEEP TIME FOR ALL THE SUBJECTS, WITH MEDIAN SLEEP STAGE DURATION AND RANGE
Subjects
Sex
Age
FEV1 (% pred )
RLRst (cm H2O ? L21 ? s)
BON CAR CUS GOV IMB NOL PRE
M F F M M F M
52 47 43 37 20 42 38
40 85 55 52 76 68 67
13.5 8 19 11 9 12 10
Mean SD
— —
39.9 10.2
67.6 20.2
11.8 3.7
Co., Waltham, MA) and on tape recorder (Hewlett-Packard 3968A) for further playback and analysis: electroencephalogram, electro-oculogram and chin electromyogram, for conventional sleep staging (14); · bidirectional oronasal airflow (V ) by a light tight-fitting face mask with a calibrated heated pneumotachograph (Fleisch no. 1) connected to a differential pressure transducer (MP-45 Validyne, range 6 5 cm H2O; Validyne, Northridge, CA); volume by electronic integration of · V signal; transpulmonary pressure (PL) by a balloon-tipped catheter placed in the lower third of the esophagus connected to a calibrated differential pressure transducer (MP-45 Validyne, range 6 80 cm H2O) referenced to the mask. The position of the esophageal catheter was adjusted following the occlusion technique proposed by Baydur and coworkers (15); supraglottic pressure (Psg) at supraglottic level by a second balloon-tipped catheter positioned at a distance of 15 to 17 cm from the nares and connected to a calibrated differential pressure transducer (MP-45 Validyne, range 6 5 cm H2O) referenced to the mask; esophageal pH by intraesophageal glass electrode (ProximaLight; SensorMedics, Milano, Italy) placed 5 cm above the esophagogastric junction. The electrode was previously calibrated using a neutral buffer and an acid buffer of pH 4. The data of a pH meter were recorded at a rate of 12 samples/min.
Analysis Total lung resistance (RL) was computed breath-by-breath by the isovolume method using computer-based routines on a Digital Alpha Station (Digital Equipment Co., Maynard, MA): PL was referred to different flows at equal lung volumes (200 ml) (16); in this way, the elastic component is made constant, and any pressure change can be referred to flow-resistive properties. Supraglottic resistance (Rsg) was com· puted as the ratio between Psg and V . Lower respiratory resistance (RLR) was derived breath-by-breath as the difference between RL and Rsg and expressed as cm H2O ? L21 ? s. GER episodes were evaluated in terms of decreases in esophageal pH below 4. They were separately evaluated on the basis of duration: short GERs < 5 min (SGER) and long GERs . 5 min (LGER). Because of its skewed distribution, the GER duration was expressed as natural log (lnGER duration).
TET TST 1–2* 3–4† REM sleep‡
Median (min)
Range (min)
423 194 160 13 —
301–502 60–296 60–269 0–51 27
Definition of abbreviations: TET 5 total experimental time; TST 5 total sleep time. * Non-REM sleep stage 1 and 2. † Non-REM sleep stage 3 and 4. ‡ Only one subject (BON) showed REM sleep.
RLR at the start of the study night were measured while the patients were awake and in supine position. RLR were then analyzed as means per minute along the whole study night. For each GER episode we calculated: RLR value during the minute immediately preceding the GER onset (RLRb); the area under the RLR curve (AUCRLR) computed as the area under the RLR values in each GER episode; end RLR at the resolution of GER episode (RLRe); DRLRe as the difference between RLRe and RLRb. AUCRLR was treated as natural log (lnAUCRLR) after transforming all negative values into positive ones by adding 3.5 since the minimum raw AUC value was 22.5. Because it has been suggested that GER effects on airway resistances may last until 10 min after the resolution of GER episode (17), we also computed RLR 10 min after the resolution of episodes (RLR109). For the latter analysis, when the time interval between GER episodes was shorter than 10 min, more GER were pooled together: in this case, RLRb was the RLR value immediately preceding the first GER; the DRLR109 was again calculated as the difference between RLR at 10 min after GER resolution and RLRb. The GER duration was assumed as the sum of the durations of all pooled GER episodes within such an event. Differences between means were evaluated by two-way analysis of variance (two-way ANOVA), to take into account both differences between variables and between subjects. In order to know whether each GER episode was associated with RLR increases within the individual, we removed the differences between subjects looking only at changes within. Accordingly, correlations between lnAUCRLR, DRLRe, and DRLR109 as outcome variables and lnGER as predictor one were evaluated by analysis of covariance, introducing our data in a multiple
TABLE 2 CUTOFF VALUES USED TO DICHOTOMIZE VARIABLES IN STEPWISE LOGISTIC MULTIPLE REGRESSION MODEL Variable AUCRLR DRLRe GERdur RLRb Wake–sleep state Subject
Cutoff Level 50th percentile 50th percentile < 5 min . 5 min 50th percentile Wake–sleep state Subject number
Figure 1. Trend of RLR over the nighttime for two representative subjects. RLR are shown as means per minute of time. Shaded vertical areas represents the duration of each GER episode.
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Cuttitta, Cibella, Visconti, et al.: Gastroesophageal Reflux in Nocturnal Asthma TABLE 4 GER DURATION FOR EACH SUBJECT WITH RESPECT TO WAKE–SLEEP PHASE IN ABSOLUTE MINUTES AND AS PERCENT OF RELEVANT WAKE–SLEEP PHASE
Subject
Total* (min)
Wakefulness (min)
1–2† (min)
3–4‡ (min)
REM Sleep (min)
Total* (%TET)
Wakefulness (%)
1–2† (%)
3–4‡ (%)
REM Sleep (%)
GOV IMB BON PRE NOL CUS CAR Median
84 43 96 42 168 23 86 84
58 43 34 9 139 9 76 43
22 0 57 33 29 6 10 22
4 0 0 0 0 8 0 —
0 0 5 0 0 0 0 —
19.5 14.3 22.6 11.2 39.7 7.1 17.1 17.1
43.0 17.8 25.2 4.9 39.6 8.0 20.5 20.5
8.2 0 24.7 17.0 40.3 3.8 8.4 8.4
14.8 0 0 0 0 15.7 0 —
0 0 18.5 0 0 0 0 —
* Total time spent in GER. † Non-REM sleep stage 1 and 2. ‡ Non-REM sleep stage 3 and 4.
linear regression model. Each subject was treated as a categorical factor using dummy variables (18). Moreover, to investigate the relationships between AUCRLR and DRLRe as outcome variables and subject number, GER duration, wake–sleep state, and RLRb as predictor ones we used a stepwise logistic multiple regression model. The AUCRLR and DRLRe were dichotomized using a threshold corresponding to the 50th percentile of each variable distribution, whereas the independent variables were transformed in dummy variables as in Table 2. For each of the two outcomes (AUCRLR and DRLRe), all correlates at univariate analysis were entered into a stepwise logistic regression analysis. Variables were considered to be independent predictors of the outcome if the odds ratio differed from 1 and the 95% confidence limits did not include 1. All the statistical procedures were performed by Systat (Systat Inc., Evanston, IL) and Stata (Stata Corporation, College Station, TX) software packages.
RESULTS The median total experimental time (TET) for all the subjects was 423 min (range 301 to 502); the median total sleep time was 194 (range 60 to 296). Table 3 shows total experimental and sleep time for all the subjects, with median sleep stage duration. Rapid eye movement (REM) sleep was observed only in one subject (BON). During the study night, a total of 101 GER episodes were found and analyzed in the overall sample: 72 were SGER (median 1.0 min) and 29 LGER (median 9.0 min, range 6 to 41). Median time spent in GER was 17.1% of TET (range 7.1 to 39.7). The mean RLR at the beginning of study night (patients awake and in supine position) was 11.8 6 3.7 cm H2O ? L21 ? s
(Table 1). The overall trend of RLR over the time in these patients showed instantaneous increases when GER episodes occurred and a subsequent decrease after the resolution of GER episodes. Conversely, not all the increases in RLR occurred after a GER episode. Figures 1A and 1B present the RLR trend during the night for two representative subjects (BON and PRE). Table 4 shows individual GER duration in absolute time and as percent of relevant sleep stages. By the two-way ANOVA we found significant differences between RLRe and RLRb both in SGER and LGER (Table 5); moreover, both AUCRLR and DRLR109 values were found to be significantly higher in LGER with respect to SGER (p , 0.0001 for both). The analysis of covariance showed highly significant correlations between lnAUCRLR, DRLRe, and DRLR109 as outcome variables versus lnGER duration as predictor one (Table 6, and Figures 2–4). A weak subject effect was noted only for the DRLRe versus lnGER duration relationship. The stepwise logistic regression analysis showed that no effect was produced by subjects’ GER duration, wake–sleep state, and RLRb on AUCRLR and on DRLRe, the GER duration being the only significant predictor for RLR increase.
DISCUSSION The present study, based on the direct, continuous, and simultaneous evaluation of both respiratory resistances and intraesophageal pH during nighttime, demonstrates a significant role of spontaneous GER episodes in provoking and sustaining nocturnal bronchoconstriction in adult asthmatics with
TABLE 5 MEAN VALUES (6 SD) FOR LOWER RESPIRATORY RESISTANCES AT THE BEGINNING (RLRb) AND AT THE END (RLRe) OF EACH GER EPISODE, FOR EACH SUBJECT* RLRb
RLRe
No. of Recorded GER Episodes
BON CAR CUS GOV IMB NOL PRE
23.4 6 8.3 15.0 6 4.3 26.5 6 5.6 27.9 6 6.8 19.2 6 8.1 24.9 6 5.6 24.8 6 7.4
26.8 6 8.0 18.1 6 4.8 31.1 6 4.6 32.1 6 6.6 27.0 6 11.5 29.3 6 4.6 29.8 6 3.3
14 22 12 16 9 19 9
Total
22.7 6 7.7
26.9 6 7.9
101
Subject
Values in cm H2O ? L21 ? s. The two-way ANOVA showed a significant difference between RLRe and RLRb. This was true both for SGER (p , 0.01) and for LGER (p , 0.0001).
TABLE 6 MULTIPLE STEPWISE LOGISTIC REGRESSION COEFFICIENTS, IN A MODEL USING AUCRLR AND DRLRe AS OUTCOME VARIABLES Outcome Variables
Predictor Variables
Logistic Coefficient
p Value
AUCRLR
GERdur RLRb Wake–sleep state Subject
4.570 21.484 20.323
, 0.0001 0.138 0.747 0.258
DRLRe
GERdur RLRb Wake–sleep state Subject
3.289 21.814 20.817
0.001 0.070 0.414 0.742
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moderate to severe GER disease. In fact, we found that: (1) GER episodes are associated with significant RLR increase; (2) RLR increases are strongly related with GER duration; (3) RLR increases tend to be maintained for a while after GER episode termination. These results are in agreement with previous studies suggesting that GER may be an important trigger mechanism in asthmatic children with nocturnal wheezing (8, 19). A further indirect evidence of the potential role played by GER in asthma has been provided by Harding and coworkers, who demonstrated the effect of long-term antacid therapy in improving asthma symptoms and pulmonary function (3). Previous studies on the relationship between GER and nocturnal asthma reported controversial results probably owing to different factors. First, complete awakening of the patient is required when a functional index such as PEF is used to monitor nocturnal bronchoconstriction (10); the effect of sleep disruption on airway tone is unpredictable, and a lack of temporal correspondence is produced between acid stimulation on esophageal mucosa and the recorded modification of the functional index. Second, other indexes used to avoid sleep disruption (such as continuous transcutaneous monitoring of oxygen saturation) yield only indirect evidence of bronchoconstriction (8, 19). A third factor is the choice of the population sample: our results seem to demonstrate that the severity of GER disease is an important factor to produce a clear bronchoconstrictive effect, as previously reported (19).
The changes in airway patency found in our study (i.e., significant RLR increase strongly related with GER duration and rapid, even if not immediate, decline after GER termination) may explain the negative results obtained in studies based on measures of respiratory function not simultaneous with GER, and requiring the waking up of the patient (9, 10). These negative results may be further explained on the basis of the low sensitivity of methods used to detect bronchoconstriction. Moreover, the rapid response in terms of RLR changes supports more the hypothesis of a vagal reflex as pathogenetic mechanism originating from irritant esophageal mucosal receptors (20), than that of gastric content aspiration into the airways (21, 22). The time course of changes in resistances with the development of RLR increases when GER episodes occurred (Figure 1) seems to lend some support to the effect of GER duration on the degree (Figures 2–4) of bronchoconstriction. This assumption is founded on the significant correlations between AUCRLR and DRLRe with GER duration. Two-way ANOVA showed significant differences in AUCRLR and DRLR109 values between GER episodes of different length: these results indicate that LGER have a significant effect on RLR increase and on its persistence after GER termination. A significant effect on RLR may also result from GER episodes lasting not more than 5 min, as shown by the significant increase in RLRe in SGER, even if the bronchoconstrictor effect is lower owing to the shorter duration. The importance of duration of GER is confirmed by the fact that the higher the lnGER duration, the more prolonged is the effect on airways 10 min after GER termination, as expressed by higher DRLR109 (Figure 4). This suggests on one hand a slower recovery of pulmonary function after acid is cleared from the esophagus (23), on the other a delayed bronchoconstrictor effect due to bronchial inflammation (latephase reaction) reflecting inflammatory mediator release (21). The wake–sleep status seems to have no impact on the bronchoconstrictor effect of GER episodes as confirmed by the stepwise logistic regression analysis. With regard to the effect of choice of population sample on the results, the only previous nocturnal investigation methodologically comparable to ours found no relationship between spontaneous or simulated GER and nocturnal increase in respiratory resistances, either in presence or in absence of esophagitis; the investigators concluded that GER produces only a poor contribution to nocturnal asthma worsening. However,
Figure 3. Relationship between DRLRe (i.e., the difference between RLR at the resolution of GER episode and R LR value during the minute immediately preceding the GER onset) and ln GER duration, separately for each subject. The analysis of covariance showed a significant effect of ln GER duration (p , 0.0001) and a small subject effect (p 5 0.021). The overall slope was 3.532.
Figure 4. Relationship between DRLR109 (i.e., the difference between RLR 10 min after the resolution of GER episodes and R LR value during the minute immediately preceding the GER onset) and ln GER duration, separately for each subject. The analysis of covariance showed a significant effect of ln GER duration (p 5 0.01) and no subject effect (p 5 0.14). The overall slope was 2.28.
Figure 2. Relationship between ln AUC RLR and ln GER duration, separately for each subject. The analysis of covariance showed a significant effect of ln GER duration (p , 0.0001) and no subject effect (p 5 0.73). The overall slope was 1.105.
Cuttitta, Cibella, Visconti, et al.: Gastroesophageal Reflux in Nocturnal Asthma
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