Minireviews
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Respirol. Mar 28, 2015; 5(1): 28-33
Published online Mar 28, 2015. doi: 10.5320/wjr.v5.i1.28
Respiratory physiotherapy in gastroesophageal reflux disease: A review article
Renata Carvalho de Miranda Chaves, Tomás Navarro-Rodriguez
Renata Carvalho de Miranda Chaves, Tomás Navarro-Rodriguez, Department of Gastroenterology, FMUSP, São Paulo PE 51030-010, Brazil
Author contributions: Chaves RCM and Navarro-Rodriguez T contributed equally to the literature review and writing of this paper.
Conflict-of-interest: Nothing to declare.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Renata Carvalho de Miranda Chaves, MD, Department of Gastroenterology, FMUSP, Rua Setúbal, 812/101 Recife, São Paulo PE 51030-010, Brazil. remicasa@hotmail.com
Telephone: +55-81-94317722 Fax: +55-11-30697560
Received: September 29, 2014
Peer-review started: September 29, 2014
First decision: December 12, 2014
Revised: January 20, 2015
Accepted: February 4, 2015
Article in press: February 5, 2015
Published online: March 28, 2015

Abstract

Gastroesophageal reflux disease (GERD) is a frequent disorder which is expensive to diagnose and treat. Initiating therapy with empiric trial of proton-pump inhibitor is a well established strategy; however, symptoms of GERD do often persist regardless of effective medication. Nowadays, increasing interest concerning the efficacy and safety of chronic acid suppression with proton-pump inhibitors (PPIs), prompts a consideration for GERD treatment strategies related to the basic physiology of the lower esophageal sphincter, including modulation of its tone and ending of spontaneous transient lower esophageal sphincter relaxation, which contributes to reflux. Together, the lower esophageal sphincter and the crural diaphragm represent the major antireflux barrier, protecting the esophagus from reflux of gastric content. In order to prevent the need for enduring PPIs therapy or surgical procedures, substitute therapeutics approaches are being researched. Recently, studies have focused on the response of the respiratory muscles to inspiratory muscle training. As a result, inspiratory muscle training has emerged as a potential alternative for treatment of gastroesophageal reflux. The present report reviews the physiologic factors contributing to GERD, and presents the newly developed therapies that can be applied either alone or in association with available efficient GERD therapy.

Key Words: Gastroesophageal reflux disease, Lower esophageal sphincter, Inspiratory muscular training, Threshold

Core tip: Gastroesophageal reflux disease is a common gastrointestinal condition in the Western world, but remains challenging to treat. Acid suppression with proton-pump inhibitors substantially improves medical therapy, though it is not successful in all patients. Recently, some studies have shown that inspiratory muscle training increases lower esophageal sphincter pressure in patients with gastroesophageal reflux disease. However, other well-controlled studies are needed to establish if there is a substantial gain and maintenance in pressure, as well as clinical improvement, and to access the influence of inspiratory muscle training in particular group of individuals.



INTRODUCTION

Gastroesophageal reflux disease (GERD) is characterized by troublesome symptoms and/or complications, such as heartburn and regurgitation, caused by the reflux of stomach contents. The condition is classified according to the Montreal Group’s Classification[1,2], and represents one of the most common gastrointestinal disorders in the Western world, with a prevalence of 10%-20%[1,3]. A large proportion of the adult population experiences GERD at least once a month, and nearly 10% of patients are affected by symptoms weekly or daily[4], thus affecting their well-being and quality of life[1].

ANATOMIC STRUCTURE

GERD occurs from exposure of the distal esophagus to gastric juice due to failure of the lower esophageal sphincter (LES)[5]. This failure in patients with GERD has largely been considered from a structural perspective[6,7]. The LES is placed where the esophagus joins the top of the stomach; the upper portion is positioned in the diaphragmatic hiatus, and its bottom is intra-abdominal. The LES is retained within the abdominal cavity by the phrenoesophageal ligament, an elastic fascia which attaches the diaphragm to the esophagus, avoiding stomach contents going up into the esophagus. This ligament, the diaphragm, and the LES contribute to the maintenance of gastroesophageal competence[8] (Figure 1).

Figure 1
Figure 1 Sphincter mechanisms at the lower end of the esophagus[9]. This figure is reprinted with permission through the Massachusetts Medical Society, Copyright © 1997.

The LES concedes coordinated passage of food into the stomach and venting of gas after meals, and reflux of acidic liquid contents back up into the esophagus is a common event in healthy adults, happening mainly during episodes of transient lower esophageal sphincter relaxation (TLESR), defined as LES relaxation in the absence of a swallow. The frequency of TLESR is similar between healthy individuals and those with GERD, but the refluxate tends to be more acidic in GERD patients[8,10].

The LES is comprised of both intrinsic and extrinsic musculature. Endoscopic ultrasonography shows that the wall of the distal esophagus is thicker than the wall of the body of the esophagus, indicative of an intrinsic sphincter[11]. This intrinsic muscle is originated from a semicircular arrangement of esophageal smooth muscle. The extrinsic striated musculature is compounded of the crural diaphragm (CD), which involves the upper 2-4 cm of the LES and increases its tone in the course of inspiration. The highest radial pressures occur where the intrinsic and extrinsic fibers combine, normally at or near the diaphragm[8]. Together, the CD and the LES play an essential role protecting the esophagus from the acidic gastric content. Klein et al[12] described that subsequently removal of the LES, a pressure zone is identified as consequence of the CD contraction.

Vegesna et al[13] and McGray et al[14] demonstrated that the lower esophageal circular sphincter and CD are two distinct structural entities. Vegesna et al[13] performed a study using an endoscopic ultrasound/manometry catheter pulled through the proximal stomach and distal esophagus and found that in 10/20 subjects, the right CD was the first to compress the esophagus. In two subjects, the left CD was the first portion to compress the esophagus, and both the left and the right CD compressed the esophagus at the same location in eight subjects. The authors showed that three distinct anatomic structures, the clasp and sling muscle fibers, CD, and lower esophageal circular smooth muscle fibers combine to form the anti-reflux barrier of the proximal stomach and distal esophagus[13].

It is known that when the LES and the diaphragm are detached, more reflux occurs comparing to in reduced hernia state. This disconnection allows reduction of basal LES pressure due to deficit of the intra-abdominal segment[8], and results in isolation of the intrinsic and extrinsic sphincteric components. Reduced pressures, particularly those that are less than half of normal, can promote an early return of symptoms in patients being treated for GERD[15]. However if the intra-abdominal pressure is reduced > 70% of baseline, gastroesophageal reflux disappears, though no changes will be seen in the LES pressure if the abdominal pressure declines quickly, as in paracentesis in ascitic patients[16].

Kahrilas et al[17] found that the peak end-expiratory high pressure zone (HPZ) is 2 cm above the esophageal-cardiac junction, 1 cm above the squamocolumnar junction and 0.5 cm above the hiatus. The HPZ has two discrete segments in individuals with hiatus hernia, each proximal and distal to the squamocolumnar junction, attributable to the extrinsic compression within the hiatal canal. Inspiration and abdominal compression mostly augment the lower segment[17]. McCray et al[14] showed that it is possible to divide the HPZ into its two components (the intrinsic LES and the extrinsic CD) using simultaneous high-resolution endoluminal sonography and esophageal manometry. The HPZ was characterized as the CD distally, and as an overlap of CD and LES proximally. During end inspiration, the CD contributes to the initial distal rise in pressure at the HPZ. In all subjects, peak pressure of the HPZ corresponds to an overlap of the LES with the CD[14].

TREATMENT
Proton-pump inhibitors

Treatment of GERD is targeted on arising the pH of the stomach’s contents, which has primarily been achieved since the 1990s with proton-pump inhibitors (PPIs)[18]. Currently, when a patient presents with symptoms typical of GERD, the initial pragmatic clinical strategy is two-month therapy with twice-daily PPIs. Once symptoms improve with therapy, patients should be stepped down to single-dose PPI[19,20]. For those whose ongoing symptoms are incompletely controlled with acid suppressants, an additional option is antacids, taken in response to symptoms, usually after meals[20], which act by locally raising the pH[21]. H2 receptor antagonists are reserved in general to control nocturnal acid breakthrough in spite of maximum PPI dose, or for maintenance treatment for GERD on an “as-needed” basis[12]. Nevertheless, treatment failures are inevitable regardless of which therapy is chosen[22].

The clinical effects of long-term maintenance treatment with PPIs have been a concern, including a raised liability of bone fracture, medication interactions, respiratory and enteric infections. Furthermore, once-daily PPI therapy fails to normalize esophageal acid exposure in a considerable percentage of adults who experiences reflux, particularly those with severe or complicated GERD. Patients with non-erosive reflux disease (the most common presentation of GERD), who account for the majority of refractory GERD patients, tend to continue to experience symptoms despite single-dose PPI therapy[8].

Refractory patients with documented data of continuing reflux as the cause of symptoms should be evaluated for further antireflux therapies. However, before moving to the next step, it is fundamental to identify lack of adherence among patients. In a cross-sectional and prospective study, 114/240 patients (47.5%) self-reported a low level of adherence to medication[23]. The factors identified with risk of non-adherence were age < 60 years, marital status, and being symptomatic.

Surgical procedures

Laparoscopic fundoplication substantially improves GERD symptoms, although symptoms return in some individuals, requiring the use of acid-suppressive medication[22,24]. In clinical trials, the risk of PPI use after antireflux surgery is 12%-44% within 1-2 years[25]. There are also some data to suggest that laparoscopic fundoplication is less effective at decreasing symptoms in partial responders to medical therapy than in complete responders[24,26]. Therefore, surgical therapy for GERD requires precisely indication and appropriate patient selection[19,23].

On the other hand, surgical invasiveness, cost, and inherent risks have created an interest in endoscopic therapies for GERD. Some of these endoscopic therapies include the Stretta radiofrequency procedure, in which radiofrequency energy is delivered through an endoscope to tighten the LES, the EndoLinch, in which an endoscopic sewing device is used[4], and the Enteryx, an endoscopic implantation of a bulking polymer into the muscle or deep submucosa of the LES[27]. The long-term efficacy, cost-effectiveness and impact of such procedures and risk for GERD-related complications have not been determined[26]. Currently, endoscopic treatment should be performed only in the context of a clinical trial[27].

Lifestyle modifications

Lifestyle and dietary changes are considered the first-line treatment with the lowest possibility of side effects[16,19]. Treating obesity, stopping smoking, avoiding certain foods and alcohol, and elevating the head of the bed are recommended lifestyle adjustments for GERD. Nevertheless, few robust data have been published (Table 1)[19]. There is some physiologic evidence that exposure to tobacco, alcohol, chocolate, and high-fat meals decreases LES pressure. However, there is no evidence supporting an improvement in GERD measures after cessation of tobacco, alcohol, or other dietary interventions[28]. Observational studies of overweight and obese patients indicate that weight loss improves GERD symptoms, as obesity can alter esophagogastric joint (EGJ) anatomy and physiology by developing a significant spatial dissociation of the LES and the CD[19].

Table 1 Lifestyle modifications for treatment of gastroesophageal reflux disease[19].
SuggestedUncertain
Treating obesity (reduce daily caloric intake, increase aerobic physical activity)Reducing weight in patients with a normal body mass index
Changing alimentary habits (increase intake of fiber, fruits, and vegetables, and reduce intake of spicy and sweet foods and carbohydrate beverages)Reducing acid beverage intake (orange or apple juice)
Reducing alcohol and coffee intakeReducing tomato, tomato sauce, mint, and garlic intake
Elevating the head of the bed
Avoiding strenuous exercises

A national inquiry enrolling 13959 adults was conducted in 22 Brazilian cities. Individuals with GERD (defined as those with heartburn more than once a week) related their symptoms to food intake (55.0%), and fatty (25.9%) and spicy (11.7%) foods. Stress and health issues were associated to symptoms in 24.2 and 22.3%, respectively. In women, fatty foods prevailed, an expected finding as fat relaxes the LES and slows gastric emptying. Anxiety, tension, stress, and sadness were observed in 24.1% of GERD patients, once again with a marked prevalence of women[29].

Inspiratory muscle training

As morphologic and functional skeletal muscles, the diaphragm and other inspiratory muscles should react to exercise similarly to any locomotor muscle if a suitable physiologic load is administered. Indeed, structural measurements by ultrasonography and anthropometric calipers have also evidenced that after increasing loading exercise there was an improvement in diaphragmatic thickness[30].

The CD is an essential component of the esophagogastric junction, the contraction of which can increase LES pressure[31]. CD function can be modified by inspiratory training[32], such as speech therapy and relaxation techniques, including diaphragm breathing exercises[19]. Da Silva et al[33] demonstrated a 9%-27% increase in LES pressure in patients who performed osteopathic manipulation techniques.

Initial studies by Carvalho de Miranda Chaves et al[34] indicated a positive result of inspiratory muscle training (IMT) on LES pressure. Using esophageal manometry they showed significantly higher LES pressure in adults with reflux after an eight-week IMT program; there was an increase in mid-respiratory pressure in 15/20 (75%) patients, with an average gain of 46.6%. The eight-week IMT program increased the maximal inspiratory pressure by 40%, as reported in previous studies[35]. Maximal inspiratory pressure is an index to calculate inspiratory muscle strength as it is highly correlated with diaphragmatic thickness[36,37]. Another study showed that four-week IMT results in a 10% gain in the diaphragmatic measurement during contraction[36].

The threshold IMT is utilized to evaluate inspiratory muscular strength. It an accessible, lightweight, portable and handy tool[38]. Progressive threshold loading is frequently applied to develop inspiratory muscle strength, without the necessity of special requirements or adaptation period[39]. As IMT has no recognized side effects, it would be appropriate for patients who commonly undergo extensive treatment[2].

In a randomized controlled study, Eherer et al[40] showed that actively training the CD as part of the LES using breathing exercises can diminish GERD as assessed by quality-of-life instrument, pH study, and on-demand PPI therapy. However, testing response of basal LES pressure augmentation post-treatment according to clinical improvement and patient well-being is mandatory, not only in patients with non-erosive GERD and healed esophagitis, but also in those with non-acidic reflux or extraesophageal symptoms[41].

A recent study evaluated the therapeutic mechanism of diaphragm training in 30 GERD patients using esophageal manometry with a Dentsleeve catheter and simultaneous esophageal pH monitoring, as well as ultrasonic imaging of proximal gastric volume[42]. The conclusion of the study was that diaphragm training the first hour after a meal might reduce postprandial esophageal acid exposure due to enhancement of antireflux barrier function by the EGJ. Therefore postprandial diaphragm training provides a new approach to conservative treatment of GERD. In another research, IMT increased average EGJ pressure in GERD patients and reduced the number and duration of TLESRs[32], and thus may prove beneficial as a GERD add-on treatment.

CONCLUSION

Evidence-based reports concerning alternative GERD therapy are scarce. The fact that the LES together with the CD represent the major antireflux barrier, the response of the respiratory muscles to IMT has been an area of recent interest. IMT increases inspiratory muscle strength and diaphragm thickness. Rehabilitation therapy that acts on the CD is therefore a promising supplementary approach to treat reflux, decreasing the need for PPIs therapy or surgery. However, these findings have been based mainly on symptoms, and do not widely demonstrate a reduction of acid reflux events. Additionally, most studies have a small sample size and have been conducted for a short duration only. Quality of life scores, multichannel intraluminal impedance, and pH monitoring should be applied to these researches. As a result, further studies are necessary to ensure the clinical effect on pressure increment, whether these pressures can be sustained, and to validate the use of new methodologies in particular set of patients, such as those with non-acidic reflux, extraesophageal symptoms, or high-surgical risk.

Continual investigation of IMT will also elucidate the impact of various exercising protocols (frequency, intensity and duration of IMT, supervision) on results. Moreover, it is crucial to establish the extent to which changes in outcomes associated with IMT translate into clinically relevant progresses. We feel strongly that promising therapies will emerge in view of the large burden of GERD.

Footnotes

P- Reviewer: Araya J, Chou YJ, Savarino V, Tsuburaya A S- Editor: Ji FF L- Editor: A E- Editor: Lu YJ

References
1.  Sawaya RA, Macgill A, Parkman HP, Friedenberg FK. Use of the Montreal global definition as an assessment of quality of life in reflux disease. Dis Esophagus. 2012;25:477-483.  [PubMed]  [DOI]
2.  Iovino P, Ciacci C. Respiratory physiotherapy in gerd: a proof-of-concept study on the increment of LES pressure. Respir Med. 2013;107:476-477.  [PubMed]  [DOI]
3.  Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol. 2006;101:1900-1920; quiz 1943.  [PubMed]  [DOI]
4.  Gaude GS. Pulmonary manifestations of gastroesophageal reflux disease. Ann Thorac Med. 2009;4:115-123.  [PubMed]  [DOI]
5.  Zaninotto G, DeMeester TR, Schwizer W, Johansson KE, Cheng SC. The lower esophageal sphincter in health and disease. Am J Surg. 1988;155:104-111.  [PubMed]  [DOI]
6.  Fisher RS, Malmud LS, Roberts GS, Lobis IF. The lower esophageal sphincter as a barrier to gastroesophageal reflux. Gastroenterology. 1977;72:19-22.  [PubMed]  [DOI]
7.  Johnsson F, Joelsson B, Gudmundsson K. Determinants of gastro-oesophageal reflux and their inter-relationships. Br J Surg. 1989;76:241-244.  [PubMed]  [DOI]
8.  Hershcovici T, Mashimo H, Fass R. The lower esophageal sphincter. Neurogastroenterol Motil. 2011;23:819-830.  [PubMed]  [DOI]
9.  Mittal RK, Balaban DH. The esophagogastric junction. N Engl J Med. 1997;336:924-932.  [PubMed]  [DOI]
10.  Han SH, Hong SJ. [Transient lower esophageal sphincter relaxation and the related esophageal motor activities]. Korean J Gastroenterol. 2012;59:205-210.  [PubMed]  [DOI]
11.  Liu JB, Miller LS, Goldberg BB, Feld RI, Alexander AA, Needleman L, Castell DO, Klenn PJ, Millward CL. Transnasal US of the esophagus: preliminary morphologic and function studies. Radiology. 1992;184:721-727.  [PubMed]  [DOI]
12.  Klein WA, Parkman HP, Dempsey DT, Fisher RS. Sphincterlike thoracoabdominal high pressure zone after esophagogastrectomy. Gastroenterology. 1993;105:1362-1369.  [PubMed]  [DOI]
13.  Vegesna AK, Sloan JA, Singh B, Phillips SJ, Braverman AS, Barbe MF, Ruggieri MR, Miller LS. Characterization of the distal esophagus high-pressure zone with manometry, ultrasound and micro-computed tomography. Neurogastroenterol Motil. 2013;25:53-60.e6.  [PubMed]  [DOI]
14.  McCray WH, Chung C, Parkman HP, Miller LS. Use of simultaneous high-resolution endoluminal sonography (HRES) and manometry to characterize high pressure zone of distal esophagus. Dig Dis Sci. 2000;45:1660-1666.  [PubMed]  [DOI]
15.  Lieberman DA. Medical therapy for chronic reflux esophagitis. Long-term follow-up. Arch Intern Med. 1987;147:1717-1720.  [PubMed]  [DOI]
16.  Navarro-Rodriguez T, Hashimoto CL, Carrilho FJ, Strauss E, Laudanna AA, Moraes-Filho JP. Reduction of abdominal pressure in patients with ascites reduces gastroesophageal reflux. Dis Esophagus. 2003;16:77-82.  [PubMed]  [DOI]
17.  Kahrilas PJ, Lin S, Chen J, Manka M. The effect of hiatus hernia on gastro-oesophageal junction pressure. Gut. 1999;44:476-482.  [PubMed]  [DOI]
18.  Ren LH, Chen WX, Qian LJ, Li S, Gu M, Shi RH. Addition of prokinetics to PPI therapy in gastroesophageal reflux disease: a meta-analysis. World J Gastroenterol. 2014;20:2412-2419.  [PubMed]  [DOI]
19.  Martinucci I, de Bortoli N, Savarino E, Nacci A, Romeo SO, Bellini M, Savarino V, Fattori B, Marchi S. Optimal treatment of laryngopharyngeal reflux disease. Ther Adv Chronic Dis. 2013;4:287-301.  [PubMed]  [DOI]
20.  Tytgat GN, McColl K, Tack J, Holtmann G, Hunt RH, Malfertheiner P, Hungin AP, Batchelor HK. New algorithm for the treatment of gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2008;27:249-256.  [PubMed]  [DOI]
21.  Sinclair A. Remedies for common family ailments: 1. Indigestion and heartburn. Prof Care Mother Child. 1994;4:23-24.  [PubMed]  [DOI]
22.  Lundell L. Borderline indications and selection of gastroesophageal reflux disease patients: ‘Is surgery better than medical therapy’? Dig Dis. 2014;32:152-155.  [PubMed]  [DOI]
23.  Dal-Paz K, Moraes-Filho JP, Navarro-Rodriguez T, Eisig JN, Barbuti R, Quigley EM. Low levels of adherence with proton pump inhibitor therapy contribute to therapeutic failure in gastroesophageal reflux disease. Dis Esophagus. 2012;25:107-113.  [PubMed]  [DOI]
24.  Fennerty MB. Review article: alternative approaches to the long-term management of GERD. Aliment Pharmacol Ther. 2005;22 Suppl 3:39-44.  [PubMed]  [DOI]
25.  Lødrup A, Pottegård A, Hallas J, Bytzer P. Use of proton pump inhibitors after antireflux surgery: a nationwide register-based follow-up study. Gut. 2014;63:1544-1549.  [PubMed]  [DOI]
26.  Freston JW, Triadafilopoulos G. Review article: approaches to the long-term management of adults with GERD-proton pump inhibitor therapy, laparoscopic fundoplication or endoscopic therapy? Aliment Pharmacol Ther. 2004;19 Suppl 1:35-42.  [PubMed]  [DOI]
27.  Bianco MA, Rotondano G, Garofano ML, Cipolletta L. Endoscopic treatment of gastro-oesophageal reflux disease. Acta Otorhinolaryngol Ital. 2006;26:281-286.  [PubMed]  [DOI]
28.  Kaltenbach T, Crockett S, Gerson LB. Are lifestyle measures effective in patients with gastroesophageal reflux disease? An evidence-based approach. Arch Intern Med. 2006;166:965-971.  [PubMed]  [DOI]
29.  Moraes-Filho JP, Chinzon D, Eisig JN, Hashimoto CL, Zaterka S. Prevalence of heartburn and gastroesophageal reflux disease in the urban Brazilian population. Arq Gastroenterol. 2005;42:122-127.  [PubMed]  [DOI]
30.  Enright SJ, Unnithan VB, Heward C, Withnall L, Davies DH. Effect of high-intensity inspiratory muscle training on lung volumes, diaphragm thickness, and exercise capacity in subjects who are healthy. Phys Ther. 2006;86:345-354.  [PubMed]  [DOI]
31.  Dantas RO, Lôbo CJ. [Diaphragmatic contraction in the lower esophageal sphincter pressure in Chagas disease patients]. Arq Gastroenterol. 1994;31:14-17.  [PubMed]  [DOI]
32.  Nobre e Souza MÂ, Lima MJ, Martins GB, Nobre RA, Souza MH, de Oliveira RB, dos Santos AA. Inspiratory muscle training improves antireflux barrier in GERD patients. Am J Physiol Gastrointest Liver Physiol. 2013;305:G862-G867.  [PubMed]  [DOI]
33.  da Silva RC, de Sá CC, Pascual-Vaca ÁO, de Souza Fontes LH, Herbella Fernandes FA, Dib RA, Blanco CR, Queiroz RA, Navarro-Rodriguez T. Increase of lower esophageal sphincter pressure after osteopathic intervention on the diaphragm in patients with gastroesophageal reflux. Dis Esophagus. 2013;26:451-456.  [PubMed]  [DOI]
34.  Carvalho de Miranda Chaves R, Suesada M, Polisel F, de Sá CC, Navarro-Rodriguez T. Respiratory physiotherapy can increase lower esophageal sphincter pressure in GERD patients. Respir Med. 2012;106:1794-1799.  [PubMed]  [DOI]
35.  Smith K, Cook D, Guyatt GH, Madhavan J, Oxman AD. Respiratory muscle training in chronic airflow limitation: a meta-analysis. Am Rev Respir Dis. 1992;145:533-539.  [PubMed]  [DOI]
36.  Downey AE, Chenoweth LM, Townsend DK, Ranum JD, Ferguson CS, Harms CA. Effects of inspiratory muscle training on exercise responses in normoxia and hypoxia. Respir Physiol Neurobiol. 2007;156:137-146.  [PubMed]  [DOI]
37.  Volianitis S, McConnell AK, Koutedakis Y, McNaughton L, Backx K, Jones DA. Inspiratory muscle training improves rowing performance. Med Sci Sports Exerc. 2001;33:803-809.  [PubMed]  [DOI]
38.  Richter JE. Gastrooesophageal reflux disease. Best Pract Res Clin Gastroenterol. 2007;21:609-631.  [PubMed]  [DOI]
39.  Ali RA, Egan LJ. Gastroesophageal reflux disease in pregnancy. Best Pract Res Clin Gastroenterol. 2007;21:793-806.  [PubMed]  [DOI]
40.  Eherer AJ, Netolitzky F, Högenauer C, Puschnig G, Hinterleitner TA, Scheidl S, Kraxner W, Krejs GJ, Hoffmann KM. Positive effect of abdominal breathing exercise on gastroesophageal reflux disease: a randomized, controlled study. Am J Gastroenterol. 2012;107:372-378.  [PubMed]  [DOI]
41.  de Miranda Chaves RC, Navarro-Rodriguez T. Reply to Iovino and Ciacci: Respiratory physiotherapy in GERD: a proof-of-concept study on the increment of LES pressure. Respir Med. 2013;107:478.  [PubMed]  [DOI]
42.  Ding ZL, Wang ZF, Sun XH, Ke MY. [Therapeutic mechanism of diaphragm training at different periods in patients with gastroesophageal reflux disease]. Zhonghua Yixue Zazhi. 2013;93:3215-3219.  [PubMed]  [DOI]