Non-acid reflux and sleep apnea: the importance of drug induced sleep endoscopy

Abstract

Background

We present the first case of a patient with obstructive sleep apnea syndrome (OSA), where drug induced sleep endoscopy was helpful to suspect a non-acid reflux disease and showed an improvement in a swollen epiglottis after treatment. Patient ameliorated significantly his disease only with medical therapy.

Case presentation

A 54-year-old man without significant anatomical findings with obstructive sleep apnea syndrome and non-acid gastroesophageal reflux disease (GERD) disease whose Apnea- hypopnea index (AHI) was significantly reduced with the intake of 500 mg of sodium alginate twice a day for 6 months. Conventional digestive tests such as esophagoscopy and simple- and double-channel 24-h pH-metry suggested mild GERD. Conventional proton-pump inhibitor treatment with pantoprazole (40 mg daily) was started without any improvement in his sleep. Multichannel intraluminal 24-h impedanciometry indicated the presence of severe pathological GER of gaseous origin. The patient’s AHI decreased from 25.3 at baseline to 8 after treatment with sodium alginate. A drug-induced sleep endoscopy study showed the changes before and after this treatment and was helpful for the diagnosis.

Conclusions

Thus, medical treatment can be a therapeutic option in some patients with OSA. Multichannel 24-h impedanciometry should be performed when nonacid GERD is suspected.

Background

Gastroesophageal reflux disease (GERD) can be categorized as acid and non-acid types. Non-acid reflux is defined as GERD episodes resulting in an esophageal pH drop to ~ 4.0. It is associated with refractory reflux symptoms in GERD with proton-pump inhibitor (PPI) failure and other extraesophageal symptoms, including coughing [1]. A laryngopharyngeal reflux (LPR) is defined as GERD reaching the laryngopharynx. It is supposed to cause inflammation in the airway and lead to respiratory symptoms. The exact role of reflux in the pathogenesis of obstructive sleep apnea syndrome (OSA) is still unclear, especially for non-acid reflux and LPR [2]. We present the first documented case of a patient with OSA where the epiglottis inflammatory changes after using gastric mucosal protector have been documented with a drug-induced sleep endoscopy (DISE) and correlated with a significant improvement in his apnea-hypopnea index (AHI).

Case presentation

A 54-year-old man was referred from our Department of Pulmonology to our Department of Otorhinolaryngology complaining of continuous positive airway pressure (CPAP) device intolerance. He was not able to use it more than 3 h per night, despite changing masks and improving humidity. He only takes tadalafil 20 mg for erectile dysfunction and showed no other comorbidities. His wife did not complain about his snoring. His main concern was a sensation of suffocation during the night, as well as when lying on his back. His body mass index (BMI) was 23.1 m/kg2. Laboratory polysomnography (PSG) showed 299 snore events per hour, an AHI of 25.3, a saturated oxygen level (Sat O2) minimum of 74%, and an oxygen desaturation index (ODI) of 20.2. Awake rhinofibrolaryngoscopy did not show any anatomical findings that explained the CPAP intolerance showing an epiglottis with normal shape and appearance. In this case, our clinical protocol established the recommendation to perform a DISE. It was done following the European position paper protocol using the VOTE classification in the operating room, starting with the patient in supine position. For sedation, 2% propofol syringe infusion pump with target-controlled infusion (TCI) was used, with a target concentration of 2 ng/ml if progressive increases were requiered: 0.2–0.5 ng / ml. Sedation level was monitored using bispectral index (BIS) (BIS Quatro®. Covidien ILc. MA. USA). When the patient was asleep and actively snoring (BIS between 70 and 50), video-flexible endoscopy (TGH Endoscopia. MACHIDA ENT-30PIII. Spain) was used to assess the upper airway to visualize the site of collapse in real time and recording equipment. During DISE, the head was first turned to the right, then to the left and, finally, the mandibular advance maneuver was performed. The findings were observed for a minimum of two cycles in each segment and for each maneuver.

DISE was done without adverse incident and revealed significant swelling of the epiglottis (Supplementary Video 1). A severely obstructed airway surrounded by fluid compatible with LPR was found (Fig. 1A). The VOTE classification [3] was V1O1T1E2AP, which improved with the Esmarch maneuver.

[IMAGE OMITTED: SEE PDF]

Additional file 1: Video S1. Drug-induced sleep endoscopy showing active GER with a swelling epiglottis blocking the airway.

With this diagnosis, the patient was offered a mandibular advancement device, but rejected it for economic reasons. He was referred to our Department of Gastroenterology. A PPI, pantoprazole (40 mg daily), was prescribed. Conventional esophagoscopy and single-channel pH-metry confirmed grade A esophagitis with mild GERD. Two-channel 24-h pH-metry indicated excellent suppression of gastric acid production with the PPI. Patient was recommended to avoid heavy meals for dinner and to raise the head of the bed for sleeping. The patient continued taking pantoprazole for 3 months but without improvement in his sleep symptoms, so he stopped the PPI treatment. During this time, he asked us to perform an epiglottectomy, but we rejected this option because non-acid reflux had not been discounted. Multichannel impedanciometry with 24-h pH-metry was performed and indicated severe alkaline GERD, mainly of gaseous origin (Fig. 2). Non-acid reflux therapy was started with sodium alginate (500 mg twice daily), and his sleep symptoms improved. After 6 months, a control PSG was performed. The AHI had decreased to 8, the Sat O2 min had improved to 87%, and the ODI had declined to 7.7 and snore events decline to 48 per hour. There was no change in his BMI. We performed a new DISE to evaluate the anatomical changes and this showed complete normality, with a VOTE classification of V1O1T1EO (Fig. 1B; Supplementary Video 2).

[IMAGE OMITTED: SEE PDF]

Additional file 2: Video S2. After 6 months of therapy with 500 mg sodium alginate daily. The epiglottis had recovered its normal shape.

Treatment with CPAP devices may aggravate airway obstruction in patients with a collapsed epiglottis [4]. Surgery in these cases could be an option [5], but it is always essential to evaluate the reason for collapse. In our case, the initial findings suggested a potential association with GERD, and DISE was mandatory for a complete evaluation [6]. A conventional ENT examination did not show any pathological findings of the epiglottis that were visualized during DISE.

Discussion

There is great controversy on the possible link between GERD and OSA [7,8,9]. Some authors have considered that these diseases lack significant association, especially when non-acid GERD is diagnosed [2],. while other authors have shown such relation, especially after multichannel intraluminal impedance pH testing is done [10,11,12].

However there are few studies published about this matter, because the gold standard procedure to diagnose non-acid reflux, is the multichannel intraluminal impedance ph testing and this is expensive, invasive and not well tolerated in all the patients [13].

A recent metanalysis [14] has shown an overall incidence of 45,2% of LPR positivity in OSA patients. However, up to date, there are two studies [2, 15] published focused only in the association between nonacid reflux and sleep disordered breathing who concluded that there is no association between non-acid reflux and OSA. Both studies were prospective case control studies, and they presented a statistical significant difference between BMI, in the OSA and non OSA group. According to Halum et al., in obese patients, the correlation with GERD is also quite clear, but the association with LPR alone is not [16]. We believe BMI can act as a confounding variable that could affect the results of association and prediction of LPR in OSA. Our patient had a normal BMI.

Multichannel impedance pH monitoring enables the quantification of acid and non-acid GERD episodes and contact time and also allows the investigators to distinguish liquid-, gaseous-, and mixed-type GERD [17, 18]. It should be done when reflux symptoms remain after prolonged PPI treatment [2, 11]. It may help understanding persistent cough in patients having OSA and GERD [2, 19]

There is no established formal therapy for patients with non-acid GERD. Treatment is usually based on weight loss, lifestyle changes, having small meals, tobacco and alcohol withdrawal, avoiding late dinners, and elevation of the head during bed rest. Prokinetics such as metoclopramide and domperidone, or mucoprotective agents have been shown to be helpful [17, 18]. Therapy with baclofen has also been suggested to improve the tone of the lower esophageal sphincter [18]. Our patient is now stable after taking sodium alginate 500 mg twice a day, and he is currently considering a laparoscopic Nissen fundoplication procedure to be done.

Alginate–antacid formulations may protect from both acid and non-acid gastro-oesophageal reflux [19]. They have proven efficacy for reducing symptoms in GERD, both as and as add-on therapy for patients experiencing breakthrough symptoms with PPIs [20]. Alginate–antacids have a unique mode of action, creating a viscous antacid gel matrix that can form a physical barrier in the proximal stomach that suppresses reflux events. Alginate–antacids also bind pepsin and bile, potentially removing them from the refluxate. This may contribute to the mucosal protection provided by alginates because pepsin is known to damage oesophageal and laryngopharyngeal mucosa even in weakly acidic reflux (pH 5–6) [21].

This is the first reported case documented with DISE where non-acid-type GERD was demonstrated as the primary cause of airway obstruction. We have shown that the epiglottis has reduced its swelling and the AHI has improved significantly after 6 months of medical therapy with alginate. There are countless other potential explanations for the differences between the two sleep studies and the two DISE studies [22, 23]. However, all of them were exhaustively excluded although retrospectively these factors could be confounding ones: there were no concurrent URTI, the patient does not smoke nor is vaping nor in alcohol use. Environmental exposures, allergies, non-allergic rhinitis, fatigue status, hydration level, and other possible confounding factors were carefully excluded [24]. Finally, positional OSA was also excluded, and tongue weakness or glosoptopsis were also excluded.

This novel case presents an interesting theory that deserves attention and may warrant the design of future studies on the association of OSA and GERD, especially when PPI are not effective and non-acid reflux is suspected.

We understand the limited level of evidence of a case report, but this case can orientate the diagnosis in those patients where, despite proper use of PPIs, symptoms remained.

Conclusions

Thus, non-acid GERD can be a potential cause of OSA in some patients. Medical treatment should be considered before surgery and DISE should be performed in cases where CPAP adaption has failed.

Availability of data and materials

Not applicable.

Abbreviations

AHI: Apnea-hypopnea index

BMI: Body mass index

CPAP: Continuous positive airway pressure

DISE: Drug-induced sleep endoscopy

ENT: Ear, nose, and throat

GERD: Gastroesophageal reflux

LPR: Laryngopharyngeal reflux

ODI: Oxygen desaturation index

OSA: Obstructive sleep apnea syndrome

PPI: Proton-pump inhibitor

References

1. Sifrim D, Dupont L, Blondeau K, Zhang X, Tack J, Janssens J. Weakly acidic reflux in patients with chronic unexplained cough during 24 hour pressure, pH, and impedance monitoring. Gut. 2005;54(4):229–54. https://doi.org/10.1136/gut.2004.055418.

2. Xiao YL, Liu FQ, Li J, Lv JT, Lin JK, Wen WP, et al. Gastroesophageal and laryngopharyngeal reflux profiles in patients with obstructive sleep apnea/hypopnea syndrome as determined by combined multichannel intraluminal impedance-pH monitoring. Neurogastroenterol Motil. 2012;24(6):e258–65. https://doi.org/10.1111/j.1365-2982.2012.01920.x.

3. Kezirian EJ, Hohenhorst W, de Vries N. Drug-induced sleep endoscopy: the VOTE classification. Eur Arch Otorhinolaryngol. 2011;268(8):1233–6. https://doi.org/10.1007/s00405-011-1633-8.

4. Kim H-Y, Sung C-M, Jang H-Y, et al. Patients with epiglottic collapse showed less severe obstructive sleep apnea and good response to treatment other than continuous positive airway pressure: a case-control study of 224 patients. J Clin Sleep Med. 2020;17(3):413–9. https://doi.org/10.5664/jcsm.8904.

5. Jeong S-H, Sung CM, Lim SC, Yang HC. Partial epiglottectomy improves residual apnea-hypopnea index in patients with epiglottis collapse. J Clin Sleep Med. 2020;16(9):1607–10. https://doi.org/10.5664/jcsm.8640.

6. Lee JS, Heo SJ, Kim JS, Ahn D, Sohn JH, Kim H. Relationship between the severity of laryngopharyngeal reflux and sleep apnea: using drug-induced sleep endoscopy (DISE). Eur Arch Otorhinolaryngol. 2018;275(1):219–24. https://doi.org/10.1007/s00405-017-4812-4.

7. Berg S, Hoffstein V, Gislason T. Acidification of distal esophagus and sleep-related breathing disturbances. Chest. 2004;125(6):2101–6. https://doi.org/10.1378/chest.125.6.2101.

8. Caparroz F, Campanholo M, Stefanini R, Vidigal T, Haddad L, Bittencourt LR, et al. Laryngopharyngeal reflux and dysphagia in patients with obstructive sleep apnea: is there an association? Sleep Breath. 2019;23(2):619–26. https://doi.org/10.1007/s11325-019-01844-0.

9. Novakovic D, MacKay S. Adult obstructive sleep apnoea and the larynx. Curr Opin Otolaryngol Head Neck Surg. 2015;23(6):464–9. https://doi.org/10.1097/MOO.0000000000000209.

10. Herdman C, Marzio DH, Shah P, Denuna-Rivera S, Doghramji K, Cohen S, et al. Sleep disorders and the prevalence of asymptomatic nocturnal acid and non-acid reflux. Ann Gastroenterol. 2013;26(3):220–5. 24714269.

11. Hoshino M, Omura N, Yano F, Tsuboi K, Yamamoto SR, Akimoto S, et al. The evaluation of recumbent reflux by multichannel intraluminal impedance pH testing for patients with gastroesophageal reflux disease and sleep disturbance. Esophagus. 2020;17(3):348–54. https://doi.org/10.1007/s10388-020-00717-w.

12. Orr WC, Craddock A, Goodrich S. Acidic and non-acidic reflux during sleep under conditions of powerful acid suppression. Chest. 2007;131(2):460–5. https://doi.org/10.1378/chest.06-1312.

13. Elhennawi DM, Ahmed MR, Abou-Halawa AS. Correlation of obstructive sleep apnoea reflux: phmetry study. Clin Otolaryngol. 2016;41:758–61.

14. Magliulo G, Iannella G, Polimeni A, De Vincentiis M, Meccariello G, Gulotta G, et al. Laryngopharyngeal reflux in obstructive sleep apnoea patients: literature review and meta-analysis. Am J Otolaryngol. 2018;39(6):776–80. https://doi.org/10.1016/j.amjoto.2018.09.006 Epub 2018 Sep 12. PMID: 30224217.

15. Bobin F, Auregan G, Muls V, Cammaroto G, Hans S, Saussez S, et al. Impedance-pH monitoring profile of patients with reflux and obstructive sleep apnea syndrome: a controlled study. Clin Otolaryngol. 2021;46(4):816–22. https://doi.org/10.1111/coa.13745 Epub ahead of print. PMID: 33621406.

16. Halum SL, Postma GN, Johnston C, Belafsky PC, Koufman JA. Patients with isolated laryngopharyngeal reflux are not obese. Laryngoscope. 2005;115(6):1042–5. https://doi.org/10.1097/01.MLG.0000162656.05715.57.

17. Storr M. What is non-acid reflux disease? Can J Gastroenterol. 2011;25(1):35–8. https://doi.org/10.1155/2011/626752.

18. Lechien JR, Akst LM, Hamdan AL, Schindler A, Karkos PD, Barillari MR, et al. Evaluation and management of laryngopharyngeal reflux disease: state of the art review. Otolaryngol Head Neck Surg. 2019;160(5):762–82. https://doi.org/10.1177/0194599819827488.

19. Sweis R, Kaufman E, Anggiansah A, Wong T, Dettmar P, Fried M, et al. Post-prandial reflux suppression by a raft-forming alginate (Gaviscon advance) compared to a simple antacid documented by magnetic resonance imaging and pH-impedance monitoring: mechanistic assessment in healthy volunteers and randomised, controlled, double-blind study in reflux patients. Aliment Pharmacol Ther. 2013;37(11):1093–102. https://doi.org/10.1111/apt.12318 Epub 2013 Apr 18.

20. Manabe N, Haruma K, Ito M, Takahashi N, Takasugi H, Wada Y, et al. Efficacy of adding sodium alginate to omeprazole in patients with nonerosive reflux disease: a randomized clinical trial. Dis Esophagus. 2012;25(5):373–80. https://doi.org/10.1111/j.1442-2050.2011.01276.x.

21. Bardhan KD, Strugala V, Dettmar PW. Reflux revisited: advancing the role of pepsin. Int J Otolaryngol. 2012;2012:646901–13. https://doi.org/10.1155/2012/646901.

22. Lan MC, Liu SY, Lan MY, et al. Role of drug-induced sleep endoscopy in evaluation of positional vs non-positional OSA. J Otolaryngol Head Neck Surg. 2020;49(1):83. https://doi.org/10.1186/s40463-020-00478-7.

23. Ha JG, Lee Y, Nam JS, Park JJ, Yoon JH, Kim CH, et al. Can drug-induced sleep endoscopy improve the success rates of tongue base surgery? J Otolaryngol Head Neck Surg. 2020;49(1):8. https://doi.org/10.1186/s40463-020-00405-w.

24. Molyneux ID, Morice AH. Airway reflux, cough and respiratory disease. Ther Adv Chronic Dis. 2011;2(4):237–48. https://doi.org/10.1177/2040622311406464.