Symptomatic Gastroesophageal Reflux in Subjects With a Breathing Sleep Disorder

Symptomatic Gastroesophageal Reflux in Subjects With a Breathing Sleep Disorder* Arschang Valipour, MD; Himender K. Makker, MD; Rebecca Hardy, PhD; Stephen Emegbo, MSc; Tudor Toma, MD; and Stephen G. Spiro, MD

Study objectives: A link between gastroesophageal reflux (GER) and obstructive sleep apnea (OSA) has been suggested; however, the prevalence and frequency of symptomatic GER and the influence of OSA severity on GER are not known. Design and patients: Two hundred seventy-one subjects referred for overnight sleep studies were investigated for subjects with a breathing sleep disorder, occurrence of symptomatic GER, potential risk factors for both conditions, and comorbidity using a validated questionnaire. Results: Overall, 160 of the 228 respondents (73%; 135 subjects with OSA and 93 subjects who snore) reported GER-related symptoms, with heartburn and/or acid regurgitation being the leading symptoms. No evidence of a difference in the occurrence of symptomatic GER between subjects who snore and subjects with OSA was observed (odds ratio [OR], 1.21; 95% confidence interval [CI], 0.7 to 2.1). Furthermore, the occurrence of reflux symptoms was not influenced by the severity of OSA (OR per 10 4% arterial oxygen saturation [SaO2] dips per hour, 0.98; 95% CI, 0.8 to 1.1). Self-reported comorbidity was higher in subjects with OSA compared with subjects who snore (p ⴝ 0.02), but none of the potential risks produced an association with the presence of reflux symptoms in this sample of patients with a breathing sleep disorder. Conclusion: We conclude that symptomatic GER is common in subjects with a breathing sleep disorder, but there was no difference between those with OSA and subjects who snore. (CHEST 2002; 121:1748 –1753) Key words: gastroesophageal reflux; obstructive sleep apnea; questionnaire-based survey; subjects with a breathing sleep disorder; subjects who snore Abbreviations: CI ⫽ confidence interval; GER ⫽ gastroesophageal reflux; GERQ ⫽ gastroesophageal reflux questionnaire; NSAID ⫽ nonsteroidal anti-inflammatory drug; OR ⫽ odds ratio; OSA ⫽ obstructive sleep apnea; PSC ⫽ psychosomatic symptom score; Sao2 ⫽ arterial oxygen saturation

sleep apnea (OSA) is a condition O bstructive characterized by repetitive, sleep-related obstruction of the upper airway resulting in oxygen desaturation and arousals from sleep.1 The minimum prevalence of this condition among middle-aged subjects is 5.7% for men and 1.2% for women.2 Gastroesophageal reflux (GER) is a chronic condition in which gastric contents enter and remain in the lower esophagus, which if left untreated can lead to esophagitis, Barrett’s esophagus, bleeding, and *From the Department of Thoracic Medicine (Drs. Valipour, Makker, Toma, and Spiro, and Mr. Emegbo), The Middlesex Hospital, University College London Hospitals; and MRC National Survey of Health and Development (Dr. Hardy), Department of Epidemiology and Public Health, Royal Free and University College Medical School, London, UK. Manuscript received March 9, 2001; revision accepted January 15, 2002. Correspondence to: Stephen G. Spiro, MD; Department of Thoracic Medicine, Middlesex Hospital, Mortimer St, London W1N 8AA, United Kingdom; e-mail: [email protected] 1748

cancer.3 A number of epidemiologic studies4 –9 have examined the prevalence of reflux symptoms, such as heartburn, acid regurgitation, and dysphagia, in the For editorial comment see page 1730 general population. In a population survey in Minnesota, Locke et al,9 using a validated GER questionnaire (GERQ), identified a prevalence rate of 59% for occasional episodes of GER-related symptoms, of which 20% reported weekly symptoms. A link between GER and OSA has been suggested,10 –13 with patients being predisposed to both conditions, with similar etiologic risk factors such as obesity and alcohol use. GER may also precipitate symptoms suggestive of OSA, including awakening, nocturnal choking, and reduced sleep efficiency. Kerr et al11 noted that five of six patients with severe OSA had significant esophageal reflux on overnight sleep and Clinical Investigations

esophageal pH monitoring. Others13 demonstrated that subjects with OSA had more frequent and prolonged reflux episodes than matched control subjects. Furthermore, the treatment of OSA with nasal continuous positive airway pressure also reduced frequency and duration of nocturnal GER episodes.11,13 However, the prevalence of symptomatic GER in subjects with OSA is not known. It is also not known whether the severity of OSA has any influence on GER. In this prospective study, we used a validated GERQ14 to investigate the prevalence of symptomatic GER and to identify potential risk factors for GER in subjects with OSA compared with simple snorers.

study requiring a 4% Sao2 dip rate of ⬎ 5/h. Subjects with a 4% SaO2 dip rate ⱕ 5/h, without a typical history or symptoms of sleep apnea, but audible snoring on the analysis, were defined as simple snorers. Statistical Analysis Anthropometric data and results of the sleep investigations were compared for the two diagnostic groups (OSA and subjects who snore) using unpaired t tests and ␹2 tests. ␹2 tests were then used to assess the frequency of GER symptoms between the two groups and also to compare the distribution of risk factors for GER between the two groups. The association between each potential risk factor and reflux symptoms was assessed separately. The outcome was defined as either the presence or absence of reflux symptoms and hence odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated. The effect of diagnosis of breathing with a sleep disorder on reflux symptoms was also investigated.

Materials and Methods The reflux questionnaire was administered to 271 consecutive and previously untreated patients with a suspected breathing sleep disorder, referred for sleep studies between October 1998 and April 2000 just before their initial sleep study. The GERQ was a self-reported instrument designed to measure symptoms experienced during the last year, and was comprised of 80 questions as well as a psychosomatic symptom checklist for a measure of somatization. The first section (30 questions) inquired into the symptoms of heartburn and acid regurgitation, which are considered highly specific for GER,6,15 as well as atypical symptoms of GER, including noncardiac chest pain, dysphagia, epigastric pain, vomiting, and nausea associated with food intake.16 Symptom frequency and symptom severity were also recorded. The remaining questions measured other symptoms relating to the upper digestive tract; respiratory complaints; history of esophageal, gastric, cardiac, or pulmonary disease; as well as potential risk factors for GER, including nonsteroidal antiinflammatory drug (NSAID) intake, nicotine, alcohol, and coffee consumption, and the use of antacids. The psychosomatic symptom score (PSC), as part of the GERQ, asked the subjects to rate (from 0 to 4) how often each of 16 common, non-GI symptoms occurred and how troublesome they were.17 The ratings were summed to give a total score (range, 0 to 128). The GERQ has been tested for its reproducibility and understanding, it identifies accurately the presence of heartburn and acid regurgitation as compared with a physician interview, and it appears to be a valid measure of GER symptoms.14 Written permission was obtained for the use of the questionnaire from the authors of the questionnaire. Investigation for subjects suspected of a breathing sleep disorder was performed overnight automated system (Visi-lab; Stowood Scientific Instruments; Oxford, UK) that measured arterial oxygen saturation (Sao2) via peripheral pulse oximetry (Pulsox-7; Minolta; Tokyo, Japan), heart rate, body-movement, respiratory sounds, and also included an 8-h video recording of the subject.18 The analysis function of the system scored the number of 4% falls in Sao2 per hour (dip rate), the lowest Sao2 value observed, cumulative noise distribution, as well as trend evaluations of the four assessed parameters. A chest physician analyzed and reported all of the sleep studies, without knowledge of the results from the reflux questionnaire. A second sleep study was performed if there were technical difficulties in interpreting the indeterminate results of the sleep study or if the patient slept badly. Diagnosis of OSA was made on the clinical findings, sleep apnea-related symptoms, spouse’s history of loud snoring and apneas,1 and analysis of the sleep www.chestjournal.org

Results Of 271 eligible participants, 228 subjects (84%) were included in the analysis. Of the other 43 participants, 24 subjects did not complete the questionnaire, 12 subjects were unable to speak or read English, 6 subjects refused to participate, and 1 subject was mentally handicapped. Anthropometric data and results of the sleep investigations for the 228 eligible participants with complete information are shown in Table 1. The 4% Sao2 dip rate, body mass index, Epworth sleepiness scale score, and male/female ratio for patients with OSA were significantly higher than for subjects who snore. Prevalence of GER-Related Symptoms Table 2 shows the prevalence and distribution of all GER-related symptoms for the whole sample and for the two diagnostic groups. Overall, 168 of 228 subjects (73.7%; 95% CI, 68.0 to 79.4%) reported symptoms consistent with GER experienced at least once at any time in the last year. One hundred

Table 1—Anthropometric Data and Patient Characteristics* Variables

Total (n ⫽ 228)

OSA (n ⫽ 135)

Snorer (n ⫽ 93)

p Value, t Test

Age, yr Body mass index 4% Sao2 dip rate ESS score† Male gender‡

48.3 (11.7) 32.0 (8.0) 20.4 (22.0) 12.0 (5.5) 78.9 (2.7)

49.3 (11.1) 34.0 (8.7) 31.2 (22.2) 12.7 (5.7) 83.7 (3.2)

46.7 (12.5) 29.0 (6.6) 3.3 (2.0) 10.9 (5.0) 72.0 (4.6)

0.110 0.001 0.001 0.027 0.034§

*Data are presented as mean (SD). †Epworth sleepiness scale (ESS) score available from 177 subjects (105 subjects with OSA and 72 snorers; no data on 51 subjects). ‡Presented as % (SD). §␹2 test. CHEST / 121 / 6 / JUNE, 2002

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Table 2—Prevalence of GER-Related Symptoms in Subjects With OSA and Snorers* Variables Typical symptoms of GER Heartburn Acid regurgitation Heartburn and/or acid regurgitation 95% CI Atypical symptoms of GER Dysphagia Epigastric pain Non-cardiac chest pain Vomiting‡ Nausea‡ More than one atypical symptom 95% CI

Total (n ⫽ 228)

OSA (n ⫽ 135)

Snorer (n ⫽ 93)

p Value (␹2 Test)†

93 (40.8) 112 (49.1) 136 (59.7) 53.2%–66.0%

54 (40.0) 62 (45.9) 78 (57.8) 49.4%–66.0%

39 (41.9) 50 (53.8) 58 (62.4) 52.6%–72.2%

0.77 0.24 0.48

51 (22.4) 45 (19.7) 53 (23.3) 25 (11.0) 19 (8.3) 117 (51.3) 44.8%–57.8%

26 (19.3) 19 (14.1) 23 (17.0) 10 (7.4) 9 (6.7) 68 (50.4) 42.0%–58.8%

25 (26.9) 26 (28.0) 30 (32.3) 15 (16.1) 10 (10.8) 49 (52.7) 42.6%–62.9%

0.17 0.01 0.01 0.04 0.27 0.73

*Data are presented as No. of cases (%) unless otherwise indicated. †␹2 compares OSA and snorers. ‡Symptoms experienced spontaneously and/or with food intake.

thirty-six subjects (59.7%) reported heartburn and/or acid regurgitation, of whom 53 subjects (23.2%) reported that these symptoms occurred at least once a week. One hundred seventeen subjects (51.3%) reported atypical symptoms, and 85 of those subjects (72.6%) reported additional heartburn and/or acid regurgitation. There was a considerable overlap of symptoms because 52% of the subjects experienced more than one atypical symptom. Most subjects with frequent symptoms (75.5%) reported the symptoms to be moderate to severe in intensity. The OR of GER for subjects who snore compared with subjects with OSA was 1.21 (95% CI, 0.7 to 2.1; p ⫽ 0.74), suggesting no evidence of a difference in symptoms between the two groups. The occurrence of reflux symptoms was not significantly influenced by presence or severity of OSA (OR per 10 4% Sao2 dips per hour, 0.98; 95% CI, 0.8 to 1.1; p ⫽ 0.70). The percentage with such symptoms ranged between 50% and 65% for different categories of OSA severity, and there was no trend with increasing severity (Fig 1). There was higher reporting of reflux-induced awakenings in subjects with OSA compared with subjects who snore (62.8% vs 41.4%; p ⫽ 0.013). However, subjects who snore reported the use of antireflux medication more frequently than subjects with OSA (47.3% vs 36.3%; p ⫽ 0.09), with a similar proportion of histamine type-2 antagonists and use of proton pump inhibitors between both groups.

(average, six drinks per week), and 55 subjects reported regular use of NSAID (average, six tablets per week). There was no significant difference in any of the potential risk factors between groups, with the exception of a higher prevalence of coffee consumption (78% vs 64%; p ⫽ 0.02) and higher mean body mass index (34.0 vs 29.0; p ⫽ 0.001) in subjects with OSA. None of these potential risk factors for GER produced a statistically significant association with the occurrence of reflux symptoms (Table 3). Comorbidity The self-reported medical history included hypertension, ischemic heart disease, and asthma in addition to GI diseases, and were reported as common current or previous problems (Table 4). Subjects with OSA had a significantly higher prevalence of overall comorbidity (p ⫽ 0.02), especially heart disease and hypertension, than subjects who snore.

Risk Factors for GER One hundred twenty-two subjects had a history of smoking (average, 24.7 pack/years); 166 subjects reported regular coffee consumption (average, 2.9 cups per day), 129 subjects reported alcohol consumption 1750

Figure 1. Relationship between OSA severity and occurrence of GER. Clinical Investigations

Table 3—Unadjusted ORs for Potential Risk Factors of GER Risk Factors Age, yr ⱕ 50 ⬎ 50 Sex Male Female Body mass index ⱕ 30 ⬎ 30 Smoking No Yes Alcohol No Yes ⱕ 6 drinks/wk ⬎ 6 drinks/wk Coffee No Yes ⱕ 3 cups/d ⬎ 3 cups/d NSAID No Yes

Cases/Total Subjects, No.

OR

95% CI

p Value*

75/120 61/108

1 0.78

0.64–1.32

0.36

103/180 33/48

1 1.64

0.84–3.24

0.15

69/109 67/119

1 0.75

0.44–1.27

0.28

63/107 73/121

1 1.06

0.63–1.81

0.82

62/100 74/128 103/170 33/58

1 0.84 1 0.86

0.49–1.43

0.52

0.47–1.57

0.62

41/62 95/166 109/179 27/49

1 0.69 1 0.79

0.37–1.26

0.22

0.42–1.49

0.47

102/173 34/55

1 1.13

0.61–2.06

0.71

*Wald test.

There was no difference in self-reported PSC between subjects with OSA and subjects who snore; however, the mean PSC score was significantly higher in subjects with symptomatic GER than in those without (23.4 vs 32.4; p ⬍ 0.001). Discussion We have shown that GER is common in subjects with a breathing sleep disorder. Typical symptoms Table 4 —Self-Reported Comorbidity in Subjects With OSA and Snorers* Variables

Total (n ⫽ 228)

OSA (n ⫽ 135)

Snorer (n ⫽ 93)

p Value, ␹2 Test

Hypertension Heart disease† GI‡ Asthma Diabetes Others Total

44 (19.3) 33 (14.5) 37 (16.2) 44 (19.3) 12 (5.3) 12 (5.3) 120 (52.6)

32 (23.7) 26 (19.2) 26 (19.2) 24 (17.7) 8 (6.0) 10 (7.0) 80 (59.3)

12 (13.0) 9 (9.6) 13 (14.0) 19 (20.4) 3 (3.2) 5 (5.4) 40 (43.0)

0.04 0.04 0.29 0.61 0.35 0.54 0.016

*Data are presented as No. of cases (%). Overall, reported comorbidity in subjects with OSA was significantly greater than in snorers. †Heart disease: ischemic heart disease (80%), atrial flutter, and cardiomyopathy. ‡GI: hiatal hernia (55%), gastritis, stomach ulcer, and esophagus surgery. www.chestjournal.org

include heartburn and acid regurgitation, which were intermittently noted by almost 60% of the respondents, of which 23% reported frequent (at least weekly) episodes of GER. A subset of patients presented with atypical symptoms, and we observed a high prevalence of potential risk factors for GER and self-reported comorbidity, with hypertension and cardiovascular disease reported more frequently in subjects with OSA. However, there was no statistically significant difference in the prevalence of typical GER symptoms between subjects with OSA and subjects who snore. Furthermore, there was no relationship between the severity of OSA and the occurrence of symptomatic GER. A general population survey in Minnesota,9 using the same formal reflux questionnaire used in this study, reported a surprisingly similar prevalence rate for reflux symptoms, with 59% of the population experiencing occasional heartburn and/or acid regurgitation and 20% of the population reporting frequent episodes of GER. We anticipated that the prevalence of GER in our sample may have been higher. It has been proposed that apneic episodes result in significant transdiaphragmatic pressure swings, which could promote reflux of gastric contents by temporarily increasing the pressure gradient across the lower esophageal sphincter.11 Attempts to confirm this hypothesis in OSA using esophageal pH monitoring have produced conflicting results. Whereas some investigators suggested a causal association between GER and OSA,11,13 others did not observe any relation between respiratory and reflux events.12,19 Ing et al13 performed a controlled study with overnight pH monitoring, showing that subjects with OSA (mean apnea-hypopnea index of 42.5) had a significantly higher esophageal clearance time and more frequent esophageal pH drops compared with those without OSA (mean apnea-hypopnea index of 3.2). However, there was still a significant incidence of reflux in those without OSA, which was expected given the control group profile of overweight, late middle-aged men with significant alcohol intake. We did not observe a higher prevalence of GER in subjects with OSA compared with subjects who snore, and the prevalence in subjects with OSA was also similar to that found in a general population estimate from the Minnesota study. Several factors may have contributed to this: a different approach has been used to diagnose GER. In the present study we did not perform pH monitoring. The diagnosis of GER was based on the GERQ of the Mayo Clinic,14 and the information obtained relies on self-reported and retrospective information. Furthermore, the GERQ has been validated in the general American Midwest population, and its performance in an CHEST / 121 / 6 / JUNE, 2002

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English population with respiratory disorders remains unknown. A recent survey20 using the GERQ to establish reflux symptoms in subjects with COPD and a clinical control cohort has shown that subjects with COPD have a similar prevalence of weekly GER symptoms (19%) as that reported for the general population but higher than that of control subjects. The authors suggested that the perception of sensing reflux events might be different in subjects with COPD compared with age-matched control subjects. Many subjects may have silent episodes of GER, resulting in discrepancy between objective measurements via pH monitoring and subjectively perceived reflux symptoms.21,22 Harding and coworkers21 undertook 24-h esophageal pH tests in 26 subjects with asthma without reflux symptoms and reported that 62% of the subjects had abnormal pH testing. Penzel et al19 studied 15 subjects with OSA who underwent an overnight sleep study with simultaneous pH monitoring. All of the subjects that they investigated had daytime reflux events on pH monitoring; however, only five subjects experienced reflux symptoms and only four subjects experienced a pathologically prolonged percentage of time with pH ⬍ 4. The lack of a difference in the prevalence of GER between subjects who snore and subjects with sleep apnea in our study may therefore be caused by more episodes of silent reflux in subjects with OSA than in subjects who snore, which we would not have detected using a questionnaire. However, the GERQ provides evidence of patient perceived reflux symptoms, and some authors6,16,23 suggest that the diagnosis of GER should rest primarily on the recognition of symptom patterns. In daily practice, a response of reflux symptoms to empirical treatment is considered diagnostic, with a sensitivity for and specificity comparable with pH monitoring.24 Tests such as invasive pH monitoring are only recommended for the differential diagnosis of atypical symptoms such as chest pain or nausea of unknown etiology.25,26 The diagnosis of OSA in the current study was made on the basis of typical symptoms and a screening sleep study, which gives a diagnosis on diprate not the apnea-hypopnea index. We therefore may have missed subjects with pure hypopnea or the upper airway resistance syndrome. However, similar systems using an off-line automated analysis for the oxygen saturation signal provided an accurate estimate of the apnea-hypopnea index with an excellent diagnostic sensitivity and specificity for sleep apnea.27 Because our results suggest that the severity of OSA had no effect on the incidence of GER, we believe that our data are representative for a wide range of subjects with a breathing sleep disorder, from simple snorers to severe OSA. 1752

It seems more likely that the similarity of prevalence of GER in subjects with and without OSA was caused by a similar risk factor profile in both groups. Potential risk factors for GER include smoking,28 alcohol,29 hiatal hernia,30 and use of NSAIDs.31 There was a high prevalence of these in our study population with no difference in prevalence between the two subject groups. There were no significant relationships between these potential risk factors for GER and its occurrence in this study. However, our sample size was relatively small, and the analyses may not have been able to detect associations because of a lack of power. The importance of the recognition of refluxrelated symptoms and their impact on the quality of life have been reported previously.32,33 Our results confirm that subjects with GER had a higher tendency toward psychosomatic symptoms, irrespective of the severity of breathing with a sleep disorder. Nocturnal symptoms of GER are common,22 and because almost 60% of the subjects with GER and OSA reported reflux-induced awakening, recognition and treatment of GER should help improve the quality of sleep and quality of life in subjects having both conditions. ACKNOWLEDGMENT: We thank K.Y. Wong and A.D. McGown for their help in data collection.

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