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(Chest. 2004;125:2101-2106.)
© 2004 American College of Chest Physicians

Acidification of Distal Esophagus and Sleep-Related Breathing Disturbances*

Soren Berg, MD, PhD; Victor Hoffstein, MD, PhD, FCCP and Thorarinn Gislason, MD, PhD

* From the Lund Sleep Study Group (Dr. Berg), Department of Oto-Rhino-Laryngology, Head and Neck Surgery, University of Lund, Sweden; the Department of Medicine (Dr. Hoffstein), St. Michael’s Hospital, University of Toronto, ON, Canada; and the Department of Respiratory Medicine and Sleep (Dr. Gislason), Landspitali University Hospital, Reykjavik, Iceland.

Correspondence to: Thorarinn Gislason, MD, PhD, Department of Respiratory Medicine and Sleep, Landspitali University Hospital (E7), 105 Reykjavik, Iceland; e-mail: thorarig{at}landspitali.is


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To investigate whether distal esophageal acidification occurs during sleep in patients suspected of sleep-disordered breathing, and whether such acidification is related to respiratory abnormalities.

Design and patients: Fourteen middle-aged, snoring men all complaining of daytime sleepiness and suspected of having obstructive sleep apnea.

Setting: Sleep laboratory, Pulmonary Department, Landspitali University Hospital, Reykjavik, Iceland.

Measurements and results: Each patient underwent full nocturnal polysomnography testing, which included continuous monitoring of esophageal pressure (Pes) and pH. We identified all pH events, which were defined as a reduction in esophageal pH of ≥ 1.0. During each pH event, the respiratory recordings where examined for the presence of apneas or hypopneas, and Pes was recorded. The data were analyzed to determine the possible relationships between pH events and respiratory events, and between changes in pH and changes in Pes. We found that there were more respiratory events than pH events. The mean (± SD) number of apneas and hypopneas per hour of sleep was 33 ± 22, whereas the mean number of pH events per hour of sleep was 7 ± 6. Overall, 81% of all pH events were associated with respiratory events. Correlation analysis did not reveal any significant relationship between pH events and the magnitude of Pes or apnea-hypopnea index.

Conclusions: Episodes of esophageal acidification are common in patients with sleep apnea, and are usually associated with respiratory and pressure events. However, changes in pH were independent of the magnitude of the Pes.

Key Words: esophageal pressure • obstructive sleep apnea • pH • respiratory event


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The association between gastroesophageal reflux (GER) and pulmonary disease was recognized > 30 years ago.1 More recently, there has been an increasing interest in the possible role of GER in such specific respiratory diseases as asthma and sleep apnea.234 The latter association is particularly intriguing since patients with GER and obstructive sleep apnea syndrome (OSAS) share similar contributing factors such as age and obesity, and some common aspects of pathogenesis. Sleep itself can contribute to GER, and can facilitate it by a decrease in the lower esophageal sphincter (LES) tone and other pharmacologic and gastric factors (ie, GER).45 Sleep is associated with a prolongation of acid clearance6 and impaired swallowing.67 In addition, episodes of upper airway obstruction during sleep are associated with large intrathoracic/esophageal negative pressures swings,8 which result in increased a transdiaphragmatic pressure gradient and may, at least in theory, lead to regurgitation of the gastric acid into the esophagus. Such sleep-related GER could potentially cause respiratory dysfunction, bronchoconstriction, coughing, wheezing, laryngospasm, and sleep disturbance.3910111213 There are also reports indicating that patients who snore, independently of whether or not they have sleep apnea, frequently have GER symptoms14 and also episodes of reflux defined as pH ≤ 4.1516

A better understanding of the relationship between GER and OSAS is important,9 and if a significant association between OSAS and GER is found, the traditional evaluation and treatment of patients with reflux may change by adding sleep investigations and considering therapeutic trials of continuous positive airway pressure (CPAP), particularly since the beneficial effects of CPAP in patients with GER already have been reported.16171819

Therefore, the purpose of this study was to investigate further the characteristics of distal esophageal acidification during sleep in patients suspected of sleep-disordered breathing, and whether such acidification was related to obstructive respiratory events during sleep, such as apneas, hypopneas, or changes in pleural pressure.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
We studied 20 consecutive patients who, over a period of 2 weeks, were referred to the Department of Pulmonary Medicine, Landspitali University Hospital (Reykjavik, Iceland), for the investigation of suspected sleep apnea. All patients reported habitual snoring and complained of excessive daytime sleepiness. None had sought or received medical attention for GER. All patients answered a questionnaire dealing with their symptoms of GER, comprising six questions answered on a 4-point scale (1, no symptoms; 2, occasional symptoms; 3, daily symptoms; 4, continuous symptoms). In addition to this, the patient was evaluated for consumption of alcohol and coffee, smoking habits, medications, and the history or presence of other diseases. Daytime sleepiness was evaluated with Epworth sleepiness scale. No specific dietary restrictions were instituted prior to measurements. All patients underwent nocturnal polysomnography with measurements of esophageal pressure (Pes) and pH.

Polysomnography
All polysomnographs where recorded online and were monitored continuously using a 16-channel system (EMBLA; Medcare-Flaga; Reykjavik, Iceland). For each patient, we recorded oronasal airflow using thermistors (Pro-Tech Services; Mukilteo, WA), and measured excursions of the chest wall and abdomen using inductance plethysmography (Respitrace; NIMS, Inc; North Bay Village, FL). In addition, we monitored sleep position (Protech Systems Inc), EEGs, submental and tibial electromyograms, ECG, oxygen saturation, Pes, and pH. Signal acquisition, processing, storage, display, and retrieval were accomplished using appropriate software (Somnologica; Medcare-Flaga).

Two types of respiratory events (ie, apneas and hypopneas) were defined based on a reduction in the oronasal flow lasting at least 10 s (Table 1 ). Apneas were defined as occurring when oronasal flow was reduced by > 80%. Hypopneas were defined as occurring when the reduction exceeded 50% and was accompanied by oxygen desaturation of at least 4% from baseline. Neither the EEG nor Pes changes were used to define hypopneas, only changes in airflow and oxygen saturation. The apnea-hypopnea index (AHI) was defined as the number of apneas and hypopneas occurring per hour of sleep.


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  		Table 1.. Definitions of pH, GER, Pressure, and Respiratory Events

 
Measurement of Pes
The measurement of Pes was accomplished using a microchip-catheter (Reditech; Copenhagen, Denmark). Prior to each measurement, the Pes sensor was calibrated against a water manometer at pressures of 10 and 20 cm H2O. One nostril and the oropharynx of each patient were anesthetized using a local anesthetic (ie, xylocaine spray). The catheter was introduced through the nostril into the esophagus and the stomach. The gastroesophageal junction was identified as the region where inspiratory pressure changed from negative to positive. The catheter then was retracted 10 cm proximally, thus positioning it in the middle third of the esophagus.

Baseline Pes was calculated as the difference between inspiratory and expiratory Pes averaged from five typical breath-to-breath changes in Pes amplitudes during awake, unobstructed breathing at rest. A pressure event (Table 1) was defined as an episode of change in Pes amplitude of > 50% from the baseline, averaged over five continuous breaths.

Measurement of pH
We used a glass electrode esophageal pH catheter (model 91-9011; Medtronic; Minneapolis, MN), which was accurate to within ± 0.2 pH units. Before each measurement, the pH sensor was inspected and calibrated against buffer solutions at pH 1 and pH 7. The pH catheter was positioned 5 cm proximally to the gastroesophageal junction. The baseline pH at that location during stable unobstructed breathing was 7. The sampling rate was 10 Hz. We used the following criteria for establishing an acidification event: An acidification event (ie, a pH event) was defined as an period of > 30 s that was characterized by a fall in esophageal pH of ≥ 1. The number of such drops in pH per hour of sleep was termed the pH index (pHI) [Table 1]. The percentage of all pH events associated with pH ≤ 4 was termed a GER event.

Following traditional scoring of the polysomnographs, data from all patients were reexamined by one of the authors (SB) in two different ways. First, each pH event during sleep was identified and examined, whether it was accompanied by a pressure event or by respiratory apnea. The lowest Pes occurring within a 30-s period preceding each acidification event also was recorded. Second, all respiratory events were identified and examined to see whether they where associated with an acidification event.

Statistical Analysis
Correlation analysis was employed to determine the relationships among acidification events, respiratory events, and pressure events.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Of the 20 patients studied, 6 were excluded from the outset of the study due to malfunctioning of the pH catheter, which continued to show gastric pH despite being placed 5 cm proximally to the gastroesophageal junction. The anthropometric and sleep data of the remaining 14 patients (all men) are shown in Table 2 . We note that as a group they were obese, middle-aged men with moderate sleep apnea, although two of them were nonapneic snorers (AHI, < 10). These two patients also were included because they showed increases in negative intrathoracic pressure associated with snoring. We note considerable variability in their AHI and pHI. Overall, there were many more respiratory events than pH events per hour of sleep (33 ± 22 vs 7 ± 6, respectively).


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  		Table 2.. Anthropometric and Sleep Data for All Patients*

 
Esophageal pH Changes During Sleep
Table 3 shows Pes values, changes in pH, and the number of respiratory events in all patients. We noted wide fluctuations in all variables. In 8 of 14 patients, pH never dropped to < 4, which is the acidity level commonly associated with symptomatic GER. In the remaining six patients, the percentage of GER events ranged between 7% and 57% of all pH events. There was no difference with respect to age, body mass index, AHI, lowest Pes value, or mean Pes value between the groups with a pHI > 5 and those with a pHI < 5. Similarly, there were no differences between patients whose pH dropped to < 4 compared to those whose pH always remained > 4. There was no significant correlation between symptomatic heartburn and episodes of GER.


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  		Table 3.. Pes Values, pH Changes, and No. of pH, Respiratory, and GER Events During Sleep for All Patients*

 
Table 4 shows that most respiratory events (mean [± SD], 81 ± 31%) were associated with pH events. However, correlation analysis did not demonstrate a significant relationship between AHI and pHI (Fig 1 ).


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  		Table 4.. Relationship Between pH Events and Respiratory and Pressure Events*

 


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  		Figure 1.. Scatter plot showing lack of relationship between pH events and respiratory events.

 
We note from Table 4 that most pH events (76%) were associated with respiratory and pressure events, but we could not demonstrate a definite relationship between changes in Pes and the occurrence of acidification episodes. Figure 2 shows a scatter plot of pH vs the percent reduction of Pes from baseline for all subjects. Contrary to what one might expect (ie, larger reductions in inspiratory pressure during episodes of airway obstruction leading to more profound acidification), the correlation analysis did not demonstrate such relationship.



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  		Figure 2.. Relationship between esophageal pH and Pes for all patients.

 
For each subject, the Pes changes were plotted against changes in pH. The plots then were analyzed for possible individual threshold effects between Pes changes and pH changes, but no such pattern could be found.

An examination of individual results revealed that there were four patients in whom there was a correlation between esophageal pH and changes in Pes. Figure 3 shows these individual results, simply to point out that these significant correlations are most likely spurious for the following reasons. In three of the four patients (patients 1, 2, and 3), the analysis was based on only a few points. In fact, in patient 1 the significance seemed to be achieved solely because of one or two strategically placed outliners. Only in patient 4 might there have been a weak, although statistically significant, relationship between pH and Pes.



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  		Figure 3.. Relationship between esophageal pH and lowest Pes in four patients who demonstrated significant correlation between these variables.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The association between sleep apnea and GER already had been noted by Samelson15 > 10 years ago. It seemed natural that both diseases (ie, OSA and GER) might be related, since the majority of patients with these disorders shares a common predisposing factor (ie, obesity). Furthermore, some of the clinical manifestations such as nocturnal choking and gasping are present in both conditions. However, it is uncertain whether sleep-disordered breathing constitutes an additional independent risk factor for GER in addition to obesity, and whether there is a causal relationship, rather than simply an association, between these two conditions.

The prevalence of GER and the frequency of reflux episodes in patients with OSA is not well-established. On one hand, Penzel et al20 found that only 8 of 15 patients with sleep apnea had nocturnal reflux (approximately five events per hour of sleep), which is similar to the findings of our study. On the other hand, Ing et al16 found a higher frequency of GER (an average of 14 GER events per hour of sleep) in his patients (mean age, 63 years) with sleep apnea. It is not clear from the presented data whether every apneic patient, or only some of them, experienced reflux episodes. Since episodes of esophageal acidification vary with age,21 posture, and sleep stage,22 this may account for the differences in reflux episodes observed by various investigators.

Most, if not all existing studies focused on the occurrence of reflux events, which were defined as episodes of esophageal acidification to pH < 4.15162023 The reasons for focusing on this value of pH are primarily historical. Previous investigations have revealed that symptoms such as chest pain and heartburn develop when esophageal pH drops to < 4. These episodes are generally severe enough to cause complete awakening from sleep.20 However, it is possible that milder episodes of esophageal acidification, associated with a smaller reduction in pH, may interfere with sleep. Our present study was designed to address whether episodes of distal esophageal acidification could be associated with different degrees of upper airway obstruction during sleep, leaving the other part (ie, the association between these episodes with arousals and daytime function assessment) to future investigations.

Nasal CPAP treatment has been reported to reduce nocturnal GER.16171819 These observations appear to be plausible based on the following simple mechanical considerations when breathing against a completely or partially occluded upper airway: pleural pressure becomes progressively more negative; and intra-abdominal pressure becomes progressively more positive. Consequently, the transdiaphragmatic pressure gradient (ie, the difference between intraabdominal and pleural pressure) increases. This creates conditions that are favorable for the regurgitation of gastric contents into the distal esophagus across the LES, causing acidification of esophagus.

Our results indicate that the relationship between minor episodes of esophageal acidification and a reduction in pleural pressure is more complex than might be expected from simple passive mechanical considerations. If the reflux of acid into the distal esophagus was determined solely by the transdiaphragmatic pressure gradient, we would expect that almost every respiratory event would be associated with a pH event. However, we found approximately six times as many respiratory events as pH events. Furthermore, similar to the results of Graf et al,24 we did not find a consistent relationship between AHI and pHI. This suggests that control of the LES tone is active rather than passive. LES is able to constrict and resist mechanical reflux-promoting events.

On the other hand, most of the pH events observed in our study were associated with respiratory and pressure events. This may indicate that when acidification of the lower esophagus occurs in patients with OSA, it is probably caused by a combination of increased transdiaphragmatic pressure gradient and coexisting pathology of LES causing incomplete closure.

The lack of a consistent relationship between episodes of esophageal acidification and apneic events suggests that GER is not caused by OSA but may be facilitated by it, provided that there is already abnormal pathology in the LES. It is possible that frequent episodes of minor esophageal acidification in patients with sleep apnea will eventually result in LES incompetence, leading to established GER. This also may explain why the application of CPAP alone, without any supplemental therapy directed toward improving LES function, does not consistently eliminate GER.1718 If it is true that reflux in patients with sleep apnea occurs only in the presence of abnormal LES function, it is not surprising that the successful treatment of reflux in patients with OSA will require not only treating their OSA (eg, with nasal CPAP) but also pharmacologic therapy directed toward the LES.19

In summary, based on the simultaneous measurements of Pes and pH in patients with sleep-disordered breathing, we concluded that episodes of minor acidification of the distal esophagus are common in patients with sleep-related upper airway obstruction. These episodes often are linked to respiratory and pressure events, but are independent of the magnitude of the transdiaphragmatic gradient and AHI. Our observations suggest that OSA and acidification/reflux are not causally linked, but may be a consequence of coexisting pathology.


   Footnotes
 
Abbreviations: AHI = apnea-hypopnea index; CPAP = continuous positive airway pressure; GER = gastroesophageal reflux; LES = lower esophageal sphincter; OSAS = obstructive sleep apnea syndrome; Pes = esophageal pressure; pHI = pH index

Received for publication October 29, 2003. Accepted for publication December 23, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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