pii: jc- 00069-16
http://dx.doi.org/10.5664/jcsm.6126
S CI E NT IF IC IN VES TIGATIONS
Effect of CPAP Therapy on Symptoms of Nocturnal Gastroesophageal Reflux among Patients with Obstructive Sleep Apnea Sadeka Tamanna, MD, MPH1; Douglas Campbell, MD1; Richard Warren, MD1; Mohammad I. Ullah, MD, MPH2 G. V. (Sonny) Montgomery VA Medical Center, Jackson, MS; 2University of Mississippi Medical Center, Jackson, MS
1
Study Objectives: Nocturnal gastroesophageal reflux (nGER) is common among patients with obstructive sleep apnea (OSA). Previous studies demonstrated that continuous positive airway pressure (CPAP) reduces symptoms of nGER. However, improvement in nGER symptoms based on objective CPAP compliance has not been documented. We have examined the polysomnographic characteristics of patients with nGER and OSA and looked for association of OSA severity and CPAP compliance with improvement in nGER symptoms. Methods: We interviewed 85 veterans with OSA to assess their daytime sleepiness (Epworth Sleepiness scale [ESS]) and nGER symptom frequency after their polysomnography and polysomnographic data were reviewed. At 6 months’ follow-up, ESS score, nGER score, and CPAP machine compliance data were reassessed. Data from 6 subjects were dropped from final analysis due to their initiation of new medication for nGER symptom since the initial evaluation. Results: Sixty-two of 79 (78%) patients complained of nGER symptoms during initial visit. At baseline, nGER score was correlated with sleep efficiency (r = 0.43), and BMI correlated with the severity of OSA (r = 0.41). ESS and nGER improved (p < 0.0001) in all patients after 6 months, but more significantly in CPAP compliant patients. A minimum CPAP compliance of 25% was needed to achieve any benefit in nGER improvement. Conclusions: Nocturnal gastroesophageal reflux is common among patients with OSA which increases sleep disruption and worsens the symptoms of daytime sleepiness. CPAP therapy may help improve the symptoms of both nocturnal acid reflux and daytime sleepiness, but adherence to CPAP is crucial to achieve this benefit. Keywords: OSA, obstructive sleep apnea, GERD, nocturnal reflux, CPAP Citation: Tamanna S, Campbell D, Warren R, Ullah MI. Effect of CPAP therapy on symptoms of nocturnal gastroesophageal reflux among patients with obstructive sleep apnea. J Clin Sleep Med 2016;12(9):1257–1261.
I N T RO D U C T I O N
BRIEF SUMMARY
Obstructive sleep apnea (OSA) is characterized by repeated collapse of the upper airway, leading to complete (apnea) or partial cessation (hypopnea) of breathing during sleep. Approximately 4% of men and 2% of women suffer from this condition in USA.1 Nocturnal gastroesophageal reflux (nGER) is also a common condition. In a population based survey, about 79% of general population have reported to suffer from it, and 63% of them felt that their sleep is disturbed due to their reflux symptom.2 nGER is also diagnosed frequently among patients with OSA.3,4 It has been postulated that OSA may predispose to nGER by lowering intrathoracic pressure and causing leakage of lower esophageal sphincter.5 A few studies have reported that continuous positive airway pressure therapy (CPAP) reduces the frequency and duration of nGER during sleep.6,7 Self-reported CPAP compliance has been reported to be a strong predictor of nGER improvement, but objective measurement would be crucial to examine its effect on nGER symptoms. Polysomnographic characteristics of these patients have not been studied in the past. In our study, we compared the polysomnographic characteristics of OSA patients with and without nGER. We investigated the effects of OSA severity, rapid eye movement (REM) sleep, and supine position on nGER symptoms. We 1257
Current Knowledge/Study Rationale: Nocturnal gastroesophageal reflux (nGER) frequently coexists in patients with obstructive sleep apnea (OSA). Previous studies reported some improvement in nGER symptoms with CPAP therapy but no objective measurement of CPAP compliance was documented. Study Impact: Our study revealed that CPAP therapy with adequate compliance (as documented by the downloaded machine data) helps improve the symptoms of both nocturnal acid reflux and daytime sleepiness. Clinicians should encourage all patients with OSA and nGER to maintain a good CPAP compliance to achieve this benefit.
also examined the effect of CPAP therapy and CPAP compliance on improvement of nGER. METHODS We prospectively evaluated 101 patients who had been diagnosed with OSA by nocturnal polysomnography (PSG) in the G.V (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, between May 2011 and December 2014. The research proposal has been reviewed and approved by the IRB of the same institution. The patients were approached for the study when they came to a clinic appointment to discuss the sleep Journal of Clinical Sleep Medicine, Vol. 12, No. 9, 2016
S Tamanna, D Campbell, R Warren et al. Effect of CPAP on Symptoms of GERD among Patients with Sleep Apnea
study result and receive the CPAP equipment after their nocturnal PSG. The patients who were already on a proton pump inhibitors (PPI) or an H2 blocker were excluded from the study. After exclusion, 85 patients were enrolled in the study, and their written informed consents were obtained. OSA was diagnosed if a patient had an apnea hypopnea index (AHI) ≥ 15 events/h, or AHI ≥ 5 but < 15 events/h with any of the following: excessive daytime sleepiness, impaired cognition, mood disorder, insomnia, hypertension, ischemic heart disease, or history of stroke. All of these patients were prescribed CPAP therapy for treatment of their OSA. Polysomnography reports of these patients were reviewed and information about the following variables were collected: total AHI, supine and non-supine AHI, REM sleep and NREM sleep AHI, sleep efficiency (SE), and total sleep time (TST). During the initial visit, patients were asked to fill out a questionnaire to assess their heartburn, which is widely used to assess nGER in population based research.8–10 They were asked if they had a specific set of symptoms suggestive of nGER and at what frequency. The instruction in the questionnaire asked the respondent to “consider the question as applying to the previous 6 months of their life.” The question stated, “My sleep is disturbed by severe heartburn and choking (regurgitation/ bringing up bitter stomach fluid).” The answer to this question was recorded by asking the respondent to agree to the
Figure 1—Flow diagram of study design and distribution of patients.
statement by circling a number from 1 to 5, with the following keys: “1 = never; 2 = rarely; 3 = sometimes; 4 = usually; and 5 = always.” These symptoms of heartburn and acid regurgitation are considered to be specific for gastroesophageal reflux (GERD). Patients with initial response ≥ 2 were considered to have nGER. The Epworth Sleepiness Scale (ESS) questionnaire, which is widely used in the literature for assessing daytime sleepiness, was also given to the patients on the same visit. Demographic data including age, gender, BMI, and race were also obtained. All patients were re-evaluated in the sleep clinic during follow-up visits after 6 months of initial enrollment. Six patients reported to have started on either a PPI or an H2 blocker since their initial evaluation for their worsening heartburn symptoms and they were excluded from the study, reducing our total sample size to 79. Data from the CPAP machines were downloaded by the sleep technicians for accurate compliance documentation. We have used standard Medicare criteria to define CPAP compliance. The patients who demonstrated CPAP use ≥ 4 h/ night for ≥ 70% of the nights were considered compliant. The nGER questionnaire and ESS questionnaire were given again to everyone to assess the change in nGER symptoms and daytime sleepiness. The study design has been described in the flow diagram in Figure 1. Data were analyzed with statistical analysis system (Stata 14.1). Chi-square was used for categorical variables and t-test for continuous variables. Regression analysis was performed to show effect of different variables on outcome data. A p value of less than 0.05 was considered significant. R ES U LT S Sixty-two of 79 patients (78%) with OSA had symptoms of nGER at baseline. Patients with OSA with and without nGER were fairly similar in demographic and polysomnographic characteristics, which are summarized in Table 1. There was no significant difference in mean age, AHI, BMI, total sleep time (TST), or sleep efficiency (SE) between CPAP compliant and noncompliant groups. BMI had a positive correlation with total AHI (r = 0.41), which means that the degree of obesity
Table 1—Baseline characteristics of patients with OSA with and without nGER.
Age (year) BMI (kg/m2) Total AHI (events/h) Supine AHI (events/h) REM AHI (events/h) ESS score TST (min) SE (%)
With nGER (n = 62) Mean SD 54.24 11.84 32.22 4.70 30.82 23.9 32.45 27.03 22.76 22.54 13.06 5.82 310.20 69.11 75.60 14.3
Without nGER (n = 17) Mean SD 57.88 10.64 33.95 5.34 30.52 9.71 30.75 14.49 19.52 24.26 10.10 5.90 325.23 66.55 78.1 14.20
p value 0.25 0.19 0.99 0.81 0.66 0.04 0.43 0.48
Values in bold are statistically significant. AHI, apnea-hypopnea index; BMI, body mass index; ESS, Epworth Sleepiness Scale; nGER, nocturnal gastroesophageal reflux; OSA, obstructive sleep apnea; SD, standard devation; SE, sleep efficiency; TST, total sleep time.
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was associated with the severity of OSA (Figure 2). The BMI was much lower (mean = 28.98 kg/m2, n = 24) in patients with mild OSA (AHI < 15, p < 0.001) than those with moderate to severe OSA (mean = 34.17 kg/m2, n = 55). In multiple linear regression, sleep efficiency (R 2 = 0.14, p = 0.001) was found to be negatively associated with nGER severity, after adjusting for total AHI, supine AHI, age, and BMI (Figure 3). The daytime sleepiness (ESS) was higher (p = 0.04) in patients with nGER (13.06) than those without nGER (10.1) before CPAP therapy. Even though supine position generally worsens the nocturnal reflux symptoms,11 supine AHI (p = 0.81) in our study was not statistically significant in predicting severity of nGER. On the other hand, we found an interesting observation about the relationship of OSA severity (total AHI) in predicting baseline nGER in simple linear regression model. When we used the total AHI of all subjects (n = 79) to predict nGER, it failed to show any statistically significant relationship (R 2 = 0.002, p = 0.186). But when we analyzed the data in 2 separate groups (mild OSA with AHI < 15, and moderate-severe OSA with AHI ≥ 15), the findings were slightly different. It revealed a
weak, yet statistically significant positive linear association between AHI and nGER score among patients who had moderate-severe OSA (R 2 = 0.11, p = 0.011). Among the patients with nGER, 49% (n = 39) were compliant with the use of CPAP for ≥ 4 h/night for ≥ 70% of the nights. Characteristics of patients by compliance of CPAP have been summarized in Table 2. There was no difference in mean age, BMI, CPAP pressure requirement, total AHI, supine AHI, or REM AHI between compliant and noncompliant groups except for mean ESS score and nGER which were higher in the noncompliant group (p < 0.01). Both of these scores decreased after CPAP therapy in both groups, but these improvements were much more prominent in the CPAP compliant group (Figures 4 and 5). The mean ESS decreased by 43% (from 12.05 to 6.95, p = 0.0001) in the CPAP compliant group, and by 23% (from 12.75 to 9.85, p = 0.001) in the noncompliant group. The mean heartburn score decreased by 62% (from 3.69 to 1.38, p = 0.0001) in the CPAP compliant group, and by 29% (from 3.75 to 2.65, p = 0.01) in the noncompliant group. CPAP compliance was also the only significant predictor for nGER score reduction in the multiple regression analysis
Figure 2—Plot of BMI by total AHI (severity of OSA) before CPAP use.
Figure 3—Effect of nocturnal heartburn on sleep efficiency.
Table 2—Characteristics of patients with OSA by compliance with CPAP.
Age (year) BMI (kg/m2) TST (min) SE (%) CPAP pressure (cm) Total AHI (events/h) Supine AHI (events/h) REM AHI (events/h) ESS after CPAP nGER after CPAP
CPAP Compliant (n = 39) Mean SD 55.82 11.32 32.69 4.79 306.71 71.50 73.33 16.38 12.02 4.07 32.11 21.61 30.60 22.84 21.53 27.59 6.94 3.97 1.38 0.63
CPAP Noncompliant (n = 40) Mean SD 54.25 12.01 32.50 4.99 320.11 66.32 78.86 12.06 11.50 3.90 28.46 24.52 33.63 27.56 22.59 26.26 9.85 5.24 2.65 0.89
p value 0.72 0.57 0.39 0.09 0.71 0.48 0.60 0.86 0.001 0.01
Values in bold are statistically significant. AHI, apnea-hypopnea index; BMI, body mass index; CPAP, continuous positive airway pressure; ESS, Epworth Sleepiness Scale; nGER, nocturnal gastroesophageal reflux; OSA, obstructive sleep apnea; SD, standard deviation; SE, sleep efficiency; TST, total sleep time.
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Figure 4—Effect of CPAP compliance on nocturnal gastroesophageal reflux symptoms (nGER) improvement.
Figure 5—Effect of CPAP compliance on ESS after CPAP therapy.
Figure 6—Improvement of nGER by CPAP compliance quartiles.
Y axis indicates nGER score; Q = quartile of CPAP compliance percentage.
(p = 0.001). There was a progressive reduction in nGER score with increase in CPAP compliance (Figure 4). We stratified the CPAP compliance at 4 quartiles (Q1 = compliance ≤ 25%, Q2 = compliance 26% to 50%, Q3 = compliance 51% to 75% and Q4 = compliance > 75%) to see the effect of different levels CPAP compliance on nGER improvement. Patients who had ≤ 25% of CPAP compliance (Q1) did not show any significant improvement in their nGER score (Figure 6) despite CPAP treatment (p = 0.07). D I SCUS S I O N Our study confirms that CPAP therapy improves the symptoms of nocturnal esophageal reflux in patients with coexisting OSA. This is consistent with previous studies that reported that symptoms of nGER improves with CPAP therapy regardless of the presence or absence of OSA.7,10,12,13 Respiratory disturbance and thoraco-abdominal paradoxical movements during sleep in OSA cause arousals and stimulate swallowing, which leads to vagally mediated esophageal peristalsis and reflex opening of the LES.5,6 The CPAP therapy prevents apnea/hypopnea by Journal of Clinical Sleep Medicine, Vol. 12, No. 9, 2016
creating a continuous flow of air which acts like a pneumatic stent to keep the pharyngeal airway patent preventing recurrent arousals and swallowing reflexes. Our study is possibly the first assessing the effect of objective CPAP compliance on nocturnal gastroesophageal reflux symptoms. Previous studies showing improvement of nGER by CPAP therapy were primarily based on subjective reports of patients on their nightly use of CPAP. This self-reported compliance of CPAP use is not a reliable tool compared to measured compliance from CPAP device, as majority of patients often overestimate their CPAP use.14,15 This study shows that improvement of nGER score from better CPAP compliance is not linear. While higher CPAP compliance leads to better improvement in nGER score, low CPAP compliance (< 25%) does not result in any improvement (Figure 5) There was no statistically significant association between OSA severity (total AHI) and baseline nGER score when all patients were analyzed together. This is consistent with findings of multiple studies in the past which showed lack of association between overall AHI and nGER severity.16–18 The most recent study by Shepherd and Orr reported such finding by documenting the nGER by esophageal pH monitoring during polysomnography and suggested that obesity rather than AHI may have a greater role in the relationship between OSA and nGER.17 This prompted us to perform further subgroup analyses, which revealed that the BMI of our patients with moderate-severe OSA (mean = 34.17 kg/m 2) was much higher than those with mild OSA (mean = 28.98 kg/m2). The total AHI revealed a linear positive association with nGER score among patients with moderate to severe OSA (AHI ≥ 15), but not among those with mild OSA (AHI < 15). This observation is similar to the findings by Rodrigues et al., who reported that obese patients with moderate to severe OSA had more severe nGER symptoms than non-obese patients.19 Obesity is a common risk factor for both OSA and nGER and BMI has been found to be positively associated with postprandial transient lower esophageal sphincter relaxation.20 But there are other numerous risk factors that contribute to these two conditions.
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In fact, Ing et al. reported that less than half of all apneas were temporally related to acid reflux, and only 43.8% of arousals were related to nGER events in their study.12 Therefore, AHI may have not correlated with nGER in patients with lower BMI in our study because of the complex interactions of other variables. Future studies may be done to look at the association of AHI and nGER by varying degrees of OSA and BMI to further verify our observation. CO N CLUS I O N S Nocturnal gastroesophageal acid reflux is common among patients with OSA which increases sleep disruption and worsens the symptoms of daytime sleepiness. CPAP therapy may help improve the symptoms of both nocturnal acid reflux and daytime sleepiness. Adherence to CPAP is crucial to achieve this benefit. The patients with nGER may benefit from being screened for symptoms of obstructive sleep apnea as treating this condition will also help control nGER symptoms. A B B R E V I AT I O N S AHI, apnea-hypopnea index BMI, body mass index CPAP, continuous positive airway pressure ESS, Epworth Sleepiness scale nGER, nocturnal gastroesophageal reflux PPI, proton pump inhibitors PSG, polysomnography REM, rapid eye movement SE, sleep efficiency TST, total sleep time R E FE R E N CES 1. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;328:1230–5. 2. Shaker R, Castell DO, Schoenfeld PS, Spechler SJ. Nighttime heartburn is an under-appreciated clinical problem that impacts sleep and daytime function: the results of a Gallup survey conducted on behalf of the American Gastroenterological Association. Am J Gastroenterol 2003;98:1487–93. 3. Graf KI, Karaus M, Heinemann S, Körber S, Dorow P, Hampel KE. Gastroesophageal reflux in patients with sleep apnea syndrome. Z Gastroenterol 1995;33:689–93. 4. Morse CA, Quan SF, Mays MZ, Green C, Stephen G, Fass R. Is there a relationship between obstructive sleep apnea and gastroesophageal reflux disease? Clin Gastroenterol Hepatol 2004;2:761–8. 5. Mittal RK, Balaban DH. The esophagogastric junction. N Engl J Med 1997;336:924–32.
6. Kerr P, Shoenut JP, Millar T, Buckle P, Kryger MH. Nasal CPAP reduces gastroesophageal reflux in obstructive sleep apnea syndrome. Chest 1992;101:1539–44. 7. Green BT, Broughton WA, O’Connor JB. Marked improvement in nocturnal gastroesophageal reflux in a large cohort of patients with obstructive sleep apnea treated with continuous positive airway pressure. Arch Intern Med 2003;163:41–5. 8. Klinkenberg-Knol E, Castell DO. Clinical spectrum and diagnosis of gastroesophageal reflux disease. In: The Esophagus, 3rd ed. Philadelphia, PA: Lippincott Williams and Wilkins, 1999:375–80. 9. Klauser AG, Schindlbeck NE, Müller-Lissner SA. Symptoms in gastrooesophageal reflux disease. Lancet 1990;335:205–8. 10. Shoenut JP, Kerr P, Micflikier AB, Yamashiro Y, Kryger MH. The effect of nasal CPAP on nocturnal reflux in patients with aperistaltic esophagus. Chest 1994;106:738–41. 11. Scott DR, Simon RA. Supraesophageal reflux: correlation of position and occurrence of acid reflux-effect of head-of-bed elevation on supine reflux. J Allergy Clin Immunol Pract 2015;3:356–61. 12. Ing AJ, Ngu MC, Breslin AB. Obstructive sleep apnea and gastroesophageal reflux. Am J Med 2000;108:120–5. 13. Bernard F, Dupont C, Viala P. Gastroesophageal reflux and upper airway diseases. Clin Rev Allergy 1990;8:403–25. 14. Rauscher H, Formanek D, Popp W, Zwick H. Self-reported vs measured compliance with nasal CPAP for obstructive sleep apnea. Chest 1993;103:1675–80. 15. Kribbs NB, Pack AI, Kline LR, et al. Objective measurement of patterns of nasal CPAP use by patients with obstructive sleep apnea. Am Rev Respir Dis 1993;147:887–95. 16. Kim H-N, Vorona RD, Winn MP, Doviak M, Johnson DA, Ware JC. Symptoms of gastro-oesophageal reflux disease and the severity of obstructive sleep apnoea syndrome are not related in sleep disorders center patients. Aliment Pharmacol Ther 2005;21:1127–33. 17. Shepherd K, Orr W. Mechanism of gastroesophageal reflux in obstructive sleep apnea: airway obstruction or obesity? J Clin Sleep Med 2016;12:87–94. 18. Sabaté JM, Jouët P, Merrouche M, et al. Gastroesophageal reflux in patients with morbid obesity: a role of obstructive sleep apnea syndrome? Obes Surg 2008;18:1479–84. 19. Rodrigues MM, Dibbern RS, Santos VJB, Passeri LA. Influence of obesity on the correlation between laryngopharyngeal reflux and obstructive sleep apnea. Braz J Otorhinolaryngol 2014;80:5–10. 20. Wu JC, Mui LM, Cheung CM, Chan Y, Sung JJ. Obesity is associated with increased transient lower esophageal sphincter relaxation. Gastroenterology 2007;132:883–9.
SUBM I SSI O N & CO R R ESPO NDENCE I NFO R M ATI O N Submitted for publication February, 2016 Submitted in final revised form April, 2016 Accepted for publication May, 2016 Address correspondence to: M. I. Ullah, MD, MPH, Associate professor of Medicine, 2500 N State St, Jackson, MS, 39216; Tel: (601) 984-5660; Fax: (601) 984-6870; Email: [email protected]
D I SCLO S U R E S TAT E M E N T This was not an industry supported study. The authors have indicated no financial conflicts of interest. This study was conducted at the G.V. (Sonny) Montgomery VA Medical Center, Jackson, MS.
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http://dx.doi.org/10.5664/jcsm.6126
S CI E NT IF IC IN VES TIGATIONS
Effect of CPAP Therapy on Symptoms of Nocturnal Gastroesophageal Reflux among Patients with Obstructive Sleep Apnea Sadeka Tamanna, MD, MPH1; Douglas Campbell, MD1; Richard Warren, MD1; Mohammad I. Ullah, MD, MPH2 G. V. (Sonny) Montgomery VA Medical Center, Jackson, MS; 2University of Mississippi Medical Center, Jackson, MS
1
Study Objectives: Nocturnal gastroesophageal reflux (nGER) is common among patients with obstructive sleep apnea (OSA). Previous studies demonstrated that continuous positive airway pressure (CPAP) reduces symptoms of nGER. However, improvement in nGER symptoms based on objective CPAP compliance has not been documented. We have examined the polysomnographic characteristics of patients with nGER and OSA and looked for association of OSA severity and CPAP compliance with improvement in nGER symptoms. Methods: We interviewed 85 veterans with OSA to assess their daytime sleepiness (Epworth Sleepiness scale [ESS]) and nGER symptom frequency after their polysomnography and polysomnographic data were reviewed. At 6 months’ follow-up, ESS score, nGER score, and CPAP machine compliance data were reassessed. Data from 6 subjects were dropped from final analysis due to their initiation of new medication for nGER symptom since the initial evaluation. Results: Sixty-two of 79 (78%) patients complained of nGER symptoms during initial visit. At baseline, nGER score was correlated with sleep efficiency (r = 0.43), and BMI correlated with the severity of OSA (r = 0.41). ESS and nGER improved (p < 0.0001) in all patients after 6 months, but more significantly in CPAP compliant patients. A minimum CPAP compliance of 25% was needed to achieve any benefit in nGER improvement. Conclusions: Nocturnal gastroesophageal reflux is common among patients with OSA which increases sleep disruption and worsens the symptoms of daytime sleepiness. CPAP therapy may help improve the symptoms of both nocturnal acid reflux and daytime sleepiness, but adherence to CPAP is crucial to achieve this benefit. Keywords: OSA, obstructive sleep apnea, GERD, nocturnal reflux, CPAP Citation: Tamanna S, Campbell D, Warren R, Ullah MI. Effect of CPAP therapy on symptoms of nocturnal gastroesophageal reflux among patients with obstructive sleep apnea. J Clin Sleep Med 2016;12(9):1257–1261.
I N T RO D U C T I O N
BRIEF SUMMARY
Obstructive sleep apnea (OSA) is characterized by repeated collapse of the upper airway, leading to complete (apnea) or partial cessation (hypopnea) of breathing during sleep. Approximately 4% of men and 2% of women suffer from this condition in USA.1 Nocturnal gastroesophageal reflux (nGER) is also a common condition. In a population based survey, about 79% of general population have reported to suffer from it, and 63% of them felt that their sleep is disturbed due to their reflux symptom.2 nGER is also diagnosed frequently among patients with OSA.3,4 It has been postulated that OSA may predispose to nGER by lowering intrathoracic pressure and causing leakage of lower esophageal sphincter.5 A few studies have reported that continuous positive airway pressure therapy (CPAP) reduces the frequency and duration of nGER during sleep.6,7 Self-reported CPAP compliance has been reported to be a strong predictor of nGER improvement, but objective measurement would be crucial to examine its effect on nGER symptoms. Polysomnographic characteristics of these patients have not been studied in the past. In our study, we compared the polysomnographic characteristics of OSA patients with and without nGER. We investigated the effects of OSA severity, rapid eye movement (REM) sleep, and supine position on nGER symptoms. We 1257
Current Knowledge/Study Rationale: Nocturnal gastroesophageal reflux (nGER) frequently coexists in patients with obstructive sleep apnea (OSA). Previous studies reported some improvement in nGER symptoms with CPAP therapy but no objective measurement of CPAP compliance was documented. Study Impact: Our study revealed that CPAP therapy with adequate compliance (as documented by the downloaded machine data) helps improve the symptoms of both nocturnal acid reflux and daytime sleepiness. Clinicians should encourage all patients with OSA and nGER to maintain a good CPAP compliance to achieve this benefit.
also examined the effect of CPAP therapy and CPAP compliance on improvement of nGER. METHODS We prospectively evaluated 101 patients who had been diagnosed with OSA by nocturnal polysomnography (PSG) in the G.V (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, between May 2011 and December 2014. The research proposal has been reviewed and approved by the IRB of the same institution. The patients were approached for the study when they came to a clinic appointment to discuss the sleep Journal of Clinical Sleep Medicine, Vol. 12, No. 9, 2016
S Tamanna, D Campbell, R Warren et al. Effect of CPAP on Symptoms of GERD among Patients with Sleep Apnea
study result and receive the CPAP equipment after their nocturnal PSG. The patients who were already on a proton pump inhibitors (PPI) or an H2 blocker were excluded from the study. After exclusion, 85 patients were enrolled in the study, and their written informed consents were obtained. OSA was diagnosed if a patient had an apnea hypopnea index (AHI) ≥ 15 events/h, or AHI ≥ 5 but < 15 events/h with any of the following: excessive daytime sleepiness, impaired cognition, mood disorder, insomnia, hypertension, ischemic heart disease, or history of stroke. All of these patients were prescribed CPAP therapy for treatment of their OSA. Polysomnography reports of these patients were reviewed and information about the following variables were collected: total AHI, supine and non-supine AHI, REM sleep and NREM sleep AHI, sleep efficiency (SE), and total sleep time (TST). During the initial visit, patients were asked to fill out a questionnaire to assess their heartburn, which is widely used to assess nGER in population based research.8–10 They were asked if they had a specific set of symptoms suggestive of nGER and at what frequency. The instruction in the questionnaire asked the respondent to “consider the question as applying to the previous 6 months of their life.” The question stated, “My sleep is disturbed by severe heartburn and choking (regurgitation/ bringing up bitter stomach fluid).” The answer to this question was recorded by asking the respondent to agree to the
Figure 1—Flow diagram of study design and distribution of patients.
statement by circling a number from 1 to 5, with the following keys: “1 = never; 2 = rarely; 3 = sometimes; 4 = usually; and 5 = always.” These symptoms of heartburn and acid regurgitation are considered to be specific for gastroesophageal reflux (GERD). Patients with initial response ≥ 2 were considered to have nGER. The Epworth Sleepiness Scale (ESS) questionnaire, which is widely used in the literature for assessing daytime sleepiness, was also given to the patients on the same visit. Demographic data including age, gender, BMI, and race were also obtained. All patients were re-evaluated in the sleep clinic during follow-up visits after 6 months of initial enrollment. Six patients reported to have started on either a PPI or an H2 blocker since their initial evaluation for their worsening heartburn symptoms and they were excluded from the study, reducing our total sample size to 79. Data from the CPAP machines were downloaded by the sleep technicians for accurate compliance documentation. We have used standard Medicare criteria to define CPAP compliance. The patients who demonstrated CPAP use ≥ 4 h/ night for ≥ 70% of the nights were considered compliant. The nGER questionnaire and ESS questionnaire were given again to everyone to assess the change in nGER symptoms and daytime sleepiness. The study design has been described in the flow diagram in Figure 1. Data were analyzed with statistical analysis system (Stata 14.1). Chi-square was used for categorical variables and t-test for continuous variables. Regression analysis was performed to show effect of different variables on outcome data. A p value of less than 0.05 was considered significant. R ES U LT S Sixty-two of 79 patients (78%) with OSA had symptoms of nGER at baseline. Patients with OSA with and without nGER were fairly similar in demographic and polysomnographic characteristics, which are summarized in Table 1. There was no significant difference in mean age, AHI, BMI, total sleep time (TST), or sleep efficiency (SE) between CPAP compliant and noncompliant groups. BMI had a positive correlation with total AHI (r = 0.41), which means that the degree of obesity
Table 1—Baseline characteristics of patients with OSA with and without nGER.
Age (year) BMI (kg/m2) Total AHI (events/h) Supine AHI (events/h) REM AHI (events/h) ESS score TST (min) SE (%)
With nGER (n = 62) Mean SD 54.24 11.84 32.22 4.70 30.82 23.9 32.45 27.03 22.76 22.54 13.06 5.82 310.20 69.11 75.60 14.3
Without nGER (n = 17) Mean SD 57.88 10.64 33.95 5.34 30.52 9.71 30.75 14.49 19.52 24.26 10.10 5.90 325.23 66.55 78.1 14.20
p value 0.25 0.19 0.99 0.81 0.66 0.04 0.43 0.48
Values in bold are statistically significant. AHI, apnea-hypopnea index; BMI, body mass index; ESS, Epworth Sleepiness Scale; nGER, nocturnal gastroesophageal reflux; OSA, obstructive sleep apnea; SD, standard devation; SE, sleep efficiency; TST, total sleep time.
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was associated with the severity of OSA (Figure 2). The BMI was much lower (mean = 28.98 kg/m2, n = 24) in patients with mild OSA (AHI < 15, p < 0.001) than those with moderate to severe OSA (mean = 34.17 kg/m2, n = 55). In multiple linear regression, sleep efficiency (R 2 = 0.14, p = 0.001) was found to be negatively associated with nGER severity, after adjusting for total AHI, supine AHI, age, and BMI (Figure 3). The daytime sleepiness (ESS) was higher (p = 0.04) in patients with nGER (13.06) than those without nGER (10.1) before CPAP therapy. Even though supine position generally worsens the nocturnal reflux symptoms,11 supine AHI (p = 0.81) in our study was not statistically significant in predicting severity of nGER. On the other hand, we found an interesting observation about the relationship of OSA severity (total AHI) in predicting baseline nGER in simple linear regression model. When we used the total AHI of all subjects (n = 79) to predict nGER, it failed to show any statistically significant relationship (R 2 = 0.002, p = 0.186). But when we analyzed the data in 2 separate groups (mild OSA with AHI < 15, and moderate-severe OSA with AHI ≥ 15), the findings were slightly different. It revealed a
weak, yet statistically significant positive linear association between AHI and nGER score among patients who had moderate-severe OSA (R 2 = 0.11, p = 0.011). Among the patients with nGER, 49% (n = 39) were compliant with the use of CPAP for ≥ 4 h/night for ≥ 70% of the nights. Characteristics of patients by compliance of CPAP have been summarized in Table 2. There was no difference in mean age, BMI, CPAP pressure requirement, total AHI, supine AHI, or REM AHI between compliant and noncompliant groups except for mean ESS score and nGER which were higher in the noncompliant group (p < 0.01). Both of these scores decreased after CPAP therapy in both groups, but these improvements were much more prominent in the CPAP compliant group (Figures 4 and 5). The mean ESS decreased by 43% (from 12.05 to 6.95, p = 0.0001) in the CPAP compliant group, and by 23% (from 12.75 to 9.85, p = 0.001) in the noncompliant group. The mean heartburn score decreased by 62% (from 3.69 to 1.38, p = 0.0001) in the CPAP compliant group, and by 29% (from 3.75 to 2.65, p = 0.01) in the noncompliant group. CPAP compliance was also the only significant predictor for nGER score reduction in the multiple regression analysis
Figure 2—Plot of BMI by total AHI (severity of OSA) before CPAP use.
Figure 3—Effect of nocturnal heartburn on sleep efficiency.
Table 2—Characteristics of patients with OSA by compliance with CPAP.
Age (year) BMI (kg/m2) TST (min) SE (%) CPAP pressure (cm) Total AHI (events/h) Supine AHI (events/h) REM AHI (events/h) ESS after CPAP nGER after CPAP
CPAP Compliant (n = 39) Mean SD 55.82 11.32 32.69 4.79 306.71 71.50 73.33 16.38 12.02 4.07 32.11 21.61 30.60 22.84 21.53 27.59 6.94 3.97 1.38 0.63
CPAP Noncompliant (n = 40) Mean SD 54.25 12.01 32.50 4.99 320.11 66.32 78.86 12.06 11.50 3.90 28.46 24.52 33.63 27.56 22.59 26.26 9.85 5.24 2.65 0.89
p value 0.72 0.57 0.39 0.09 0.71 0.48 0.60 0.86 0.001 0.01
Values in bold are statistically significant. AHI, apnea-hypopnea index; BMI, body mass index; CPAP, continuous positive airway pressure; ESS, Epworth Sleepiness Scale; nGER, nocturnal gastroesophageal reflux; OSA, obstructive sleep apnea; SD, standard deviation; SE, sleep efficiency; TST, total sleep time.
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Figure 4—Effect of CPAP compliance on nocturnal gastroesophageal reflux symptoms (nGER) improvement.
Figure 5—Effect of CPAP compliance on ESS after CPAP therapy.
Figure 6—Improvement of nGER by CPAP compliance quartiles.
Y axis indicates nGER score; Q = quartile of CPAP compliance percentage.
(p = 0.001). There was a progressive reduction in nGER score with increase in CPAP compliance (Figure 4). We stratified the CPAP compliance at 4 quartiles (Q1 = compliance ≤ 25%, Q2 = compliance 26% to 50%, Q3 = compliance 51% to 75% and Q4 = compliance > 75%) to see the effect of different levels CPAP compliance on nGER improvement. Patients who had ≤ 25% of CPAP compliance (Q1) did not show any significant improvement in their nGER score (Figure 6) despite CPAP treatment (p = 0.07). D I SCUS S I O N Our study confirms that CPAP therapy improves the symptoms of nocturnal esophageal reflux in patients with coexisting OSA. This is consistent with previous studies that reported that symptoms of nGER improves with CPAP therapy regardless of the presence or absence of OSA.7,10,12,13 Respiratory disturbance and thoraco-abdominal paradoxical movements during sleep in OSA cause arousals and stimulate swallowing, which leads to vagally mediated esophageal peristalsis and reflex opening of the LES.5,6 The CPAP therapy prevents apnea/hypopnea by Journal of Clinical Sleep Medicine, Vol. 12, No. 9, 2016
creating a continuous flow of air which acts like a pneumatic stent to keep the pharyngeal airway patent preventing recurrent arousals and swallowing reflexes. Our study is possibly the first assessing the effect of objective CPAP compliance on nocturnal gastroesophageal reflux symptoms. Previous studies showing improvement of nGER by CPAP therapy were primarily based on subjective reports of patients on their nightly use of CPAP. This self-reported compliance of CPAP use is not a reliable tool compared to measured compliance from CPAP device, as majority of patients often overestimate their CPAP use.14,15 This study shows that improvement of nGER score from better CPAP compliance is not linear. While higher CPAP compliance leads to better improvement in nGER score, low CPAP compliance (< 25%) does not result in any improvement (Figure 5) There was no statistically significant association between OSA severity (total AHI) and baseline nGER score when all patients were analyzed together. This is consistent with findings of multiple studies in the past which showed lack of association between overall AHI and nGER severity.16–18 The most recent study by Shepherd and Orr reported such finding by documenting the nGER by esophageal pH monitoring during polysomnography and suggested that obesity rather than AHI may have a greater role in the relationship between OSA and nGER.17 This prompted us to perform further subgroup analyses, which revealed that the BMI of our patients with moderate-severe OSA (mean = 34.17 kg/m 2) was much higher than those with mild OSA (mean = 28.98 kg/m2). The total AHI revealed a linear positive association with nGER score among patients with moderate to severe OSA (AHI ≥ 15), but not among those with mild OSA (AHI < 15). This observation is similar to the findings by Rodrigues et al., who reported that obese patients with moderate to severe OSA had more severe nGER symptoms than non-obese patients.19 Obesity is a common risk factor for both OSA and nGER and BMI has been found to be positively associated with postprandial transient lower esophageal sphincter relaxation.20 But there are other numerous risk factors that contribute to these two conditions.
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In fact, Ing et al. reported that less than half of all apneas were temporally related to acid reflux, and only 43.8% of arousals were related to nGER events in their study.12 Therefore, AHI may have not correlated with nGER in patients with lower BMI in our study because of the complex interactions of other variables. Future studies may be done to look at the association of AHI and nGER by varying degrees of OSA and BMI to further verify our observation. CO N CLUS I O N S Nocturnal gastroesophageal acid reflux is common among patients with OSA which increases sleep disruption and worsens the symptoms of daytime sleepiness. CPAP therapy may help improve the symptoms of both nocturnal acid reflux and daytime sleepiness. Adherence to CPAP is crucial to achieve this benefit. The patients with nGER may benefit from being screened for symptoms of obstructive sleep apnea as treating this condition will also help control nGER symptoms. A B B R E V I AT I O N S AHI, apnea-hypopnea index BMI, body mass index CPAP, continuous positive airway pressure ESS, Epworth Sleepiness scale nGER, nocturnal gastroesophageal reflux PPI, proton pump inhibitors PSG, polysomnography REM, rapid eye movement SE, sleep efficiency TST, total sleep time R E FE R E N CES 1. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;328:1230–5. 2. Shaker R, Castell DO, Schoenfeld PS, Spechler SJ. Nighttime heartburn is an under-appreciated clinical problem that impacts sleep and daytime function: the results of a Gallup survey conducted on behalf of the American Gastroenterological Association. Am J Gastroenterol 2003;98:1487–93. 3. Graf KI, Karaus M, Heinemann S, Körber S, Dorow P, Hampel KE. Gastroesophageal reflux in patients with sleep apnea syndrome. Z Gastroenterol 1995;33:689–93. 4. Morse CA, Quan SF, Mays MZ, Green C, Stephen G, Fass R. Is there a relationship between obstructive sleep apnea and gastroesophageal reflux disease? Clin Gastroenterol Hepatol 2004;2:761–8. 5. Mittal RK, Balaban DH. The esophagogastric junction. N Engl J Med 1997;336:924–32.
6. Kerr P, Shoenut JP, Millar T, Buckle P, Kryger MH. Nasal CPAP reduces gastroesophageal reflux in obstructive sleep apnea syndrome. Chest 1992;101:1539–44. 7. Green BT, Broughton WA, O’Connor JB. Marked improvement in nocturnal gastroesophageal reflux in a large cohort of patients with obstructive sleep apnea treated with continuous positive airway pressure. Arch Intern Med 2003;163:41–5. 8. Klinkenberg-Knol E, Castell DO. Clinical spectrum and diagnosis of gastroesophageal reflux disease. In: The Esophagus, 3rd ed. Philadelphia, PA: Lippincott Williams and Wilkins, 1999:375–80. 9. Klauser AG, Schindlbeck NE, Müller-Lissner SA. Symptoms in gastrooesophageal reflux disease. Lancet 1990;335:205–8. 10. Shoenut JP, Kerr P, Micflikier AB, Yamashiro Y, Kryger MH. The effect of nasal CPAP on nocturnal reflux in patients with aperistaltic esophagus. Chest 1994;106:738–41. 11. Scott DR, Simon RA. Supraesophageal reflux: correlation of position and occurrence of acid reflux-effect of head-of-bed elevation on supine reflux. J Allergy Clin Immunol Pract 2015;3:356–61. 12. Ing AJ, Ngu MC, Breslin AB. Obstructive sleep apnea and gastroesophageal reflux. Am J Med 2000;108:120–5. 13. Bernard F, Dupont C, Viala P. Gastroesophageal reflux and upper airway diseases. Clin Rev Allergy 1990;8:403–25. 14. Rauscher H, Formanek D, Popp W, Zwick H. Self-reported vs measured compliance with nasal CPAP for obstructive sleep apnea. Chest 1993;103:1675–80. 15. Kribbs NB, Pack AI, Kline LR, et al. Objective measurement of patterns of nasal CPAP use by patients with obstructive sleep apnea. Am Rev Respir Dis 1993;147:887–95. 16. Kim H-N, Vorona RD, Winn MP, Doviak M, Johnson DA, Ware JC. Symptoms of gastro-oesophageal reflux disease and the severity of obstructive sleep apnoea syndrome are not related in sleep disorders center patients. Aliment Pharmacol Ther 2005;21:1127–33. 17. Shepherd K, Orr W. Mechanism of gastroesophageal reflux in obstructive sleep apnea: airway obstruction or obesity? J Clin Sleep Med 2016;12:87–94. 18. Sabaté JM, Jouët P, Merrouche M, et al. Gastroesophageal reflux in patients with morbid obesity: a role of obstructive sleep apnea syndrome? Obes Surg 2008;18:1479–84. 19. Rodrigues MM, Dibbern RS, Santos VJB, Passeri LA. Influence of obesity on the correlation between laryngopharyngeal reflux and obstructive sleep apnea. Braz J Otorhinolaryngol 2014;80:5–10. 20. Wu JC, Mui LM, Cheung CM, Chan Y, Sung JJ. Obesity is associated with increased transient lower esophageal sphincter relaxation. Gastroenterology 2007;132:883–9.
SUBM I SSI O N & CO R R ESPO NDENCE I NFO R M ATI O N Submitted for publication February, 2016 Submitted in final revised form April, 2016 Accepted for publication May, 2016 Address correspondence to: M. I. Ullah, MD, MPH, Associate professor of Medicine, 2500 N State St, Jackson, MS, 39216; Tel: (601) 984-5660; Fax: (601) 984-6870; Email: [email protected]
D I SCLO S U R E S TAT E M E N T This was not an industry supported study. The authors have indicated no financial conflicts of interest. This study was conducted at the G.V. (Sonny) Montgomery VA Medical Center, Jackson, MS.
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