With the growing awareness of GERD and its dangers, the concept of GERD disease itself and its treatment have been revolutionized. The application of proton pump inhibitors was a milestone in the medical treatment of GERD, while the invention and application of laparoscopic fundoplication and gastroscopic radiofrequency of the lower esophageal sphincter brought the treatment of GERD into the era of comprehensive treatment. This technique has been successfully applied to extraesophageal symptoms caused by high level reflux after entering China, and it is more simple and minimally invasive than anti-reflux surgery, which has a broad application prospect.
Gastroesophageal reflux disease; gastroesophageal laryngotracheal syndrome; radiofrequency lower esophageal sphincter
The dangers of gastroesophageal reflux disease (GERD) are gaining attention from multiple disciplines. Anti-reflux medications such as proton pump inhibitor (PPI) can meet the needs of many patients, but there are limitations. Gastroscopic radiofrequency of the lower esophageal sphincter is simple and minimally invasive, and similar to laparoscopic fundoplication, it can partially compensate for the lack of pharmacological treatment and has its own unique application prospects. In this paper, we review the development of radiofrequency lower esophageal sphincter in China and discuss its safety, efficacy, therapeutic significance, therapeutic indications and application prospects in the context of our 8-year experience in applying radiofrequency for the treatment of GERD, especially extraesophageal symptoms.
1.GERD overview, definition and diagnosis
GERD has a high prevalence worldwide but with some regional differences. In terms of typical symptoms of GERD (such as reflux and heartburn), the prevalence ranges from 18.1% to 27.8% in North America, 23.0% in South America, 8.8% to 25.9% in Europe, 8.7% to 33.1% in the Middle East, 11.6% in Australia[1] , and 6% to 10% in Asia[2] . . GERD symptoms can cause significant discomfort, and conservative treatment may require lifelong lifestyle changes and medications for some patients, reducing quality of life and imposing a significant financial burden[3] . A study in Shanghai showed that GERD affected the diet of 47% of patients, the sleep of 32% of patients, and the ability to work of 32% of patients, negatively affecting both their health status and mood [4].
The 2006 evidence-based Global Consensus on GERD defines GERD as a condition in which reflux of gastric contents causes uncomfortable symptoms and/or complications. When symptoms associated with GERD affect a person’s health they are called uncomfortable symptoms (GERD should not be diagnosed if the reflux symptoms do not cause discomfort and there are no associated complications). Non-erosive reflux disease (NERD) is defined as the presence of uncomfortable reflux-related symptoms but lack of evidence of endoscopic mucosal damage. This definition has been the most accepted and widely used since 2006. Therefore, patients with milder symptoms present for 2 or more d per week, and moderate or severe symptoms present for more than 1 d per week. GERD is diagnosed when gastroscopy shows clear complications of GERD (reflux esophagitis, Barrett’s esophagus, peptic stricture, etc.), and/or positive monitoring of intraesophageal reflux, and/or effective diagnostic treatment with proton pump inhibitors [5].
As the research and understanding of GERD has increased, the extraesophageal symptoms of GERD have been increasingly emphasized. Since it is not yet completely clear whether extraesophageal symptoms are due to direct extraesophageal invasion by reflux, vagally mediated reflexes, or other possible mechanisms, and there is still a lack of extraesophageal symptom screening with high sensitivity and reliability, extraesophageal symptoms often do not have the manifestations of typical GERD (acid reflux, heartburn, or esophagitis, etc.) and the diagnostic criteria differ from those of typical GERD (for the esophagus, 1 d the presence of 50 refluxes can make normal. However, in the pharynx, the presence of 3 refluxes in 1 week can produce meaningful pathological changes; refluxes with pH <5 may also be significant), so there is still no clearer definition of extraesophageal symptoms. LPR is usually diagnosed on the basis of symptoms, laryngoscopy (with low specificity), and responsiveness to experimental PPI therapy (with high predictive value for positive PPI tests and low predictive value for negative tests), while intraesophageal multichannel reflux is usually diagnosed on the basis of symptoms, laryngoscopy (with low specificity), and responsiveness to experimental PPI therapy (with high predictive value for positive PPI tests and low predictive value for negative PPI tests). ), while intraesophageal multichannel reflux monitoring or pharyngeal reflux monitoring can be an important reference. In addition, histopathological examination of airway pathology and secretion testing are expected to enter clinical applications [6].
The 2013 guidelines for the diagnosis and management of GERD in The American journal of gastroenterology define GERD as a disease in which reflux of gastric contents into the esophagus, oral cavity, larynx, and/or lungs causes corresponding symptoms and complications, and this definition indicates the organs involved in gastroesophageal reflux, further emphasizing extraesophageal reflux in GERD [ 7]. As the diagnosis of extra-esophageal symptoms remains controversial, the epidemiological features remain unclear, and the prevalence of extra-esophageal symptoms in GERD is evident from the co-morbidity of GERD and asthma. 59.2%, 50.9%, 37.3% and 51.2% of GERD patients had GERD symptoms, abnormal pH tests, esophagitis and esophageal hiatal hernia, respectively, and the prevalence of asthma among GERD patients was 4.6% higher than that of 3.9% in the control population [8], and it has also been estimated that 21% to 41% of chronic cough is associated with GERD [9].
GERD has a variety of clinical manifestations, especially extraesophageal symptoms, and can be considered as a syndrome involving multiple disciplines, but it is often undiagnosed, thus missing the opportunity for causal treatment. The concept of “gastroesophago-laryngotracheal syndrome (GELTS)” is a series of clinical manifestations involving respiratory and digestive systems and the ear, nose and mouth caused by GERD with the pharynx as the core and the respiratory manifestations, especially asthma and laryngotracheal spasm, as the salient points, or with the gastroesophageal junction as the initiator and the pharynx as the reactor. A new clinical syndrome with the pharynx as the reactor, the mouth and nose as the effector, and the laryngeal airway as the wheezing generator, and the syndrome was divided into four phases, namely, the gastroesophageal phase (phase A), the pharyngeal phase (phase B), the oronasal cavity phase (phase C), and the laryngotracheal phase (phase D) [10]. phase A contains the typical symptoms of GERD, while phases B, C, and D refine the sites of occurrence and clinical features of extraesophageal symptoms. Thereafter, further in-depth studies were conducted based on the accumulation of cases treated with radiofrequency and gastric fundoplication [11].
2. Limitations of pharmacological treatment
Most patients with GERD have been treated mainly with medication, but some of them have difficulty in stopping medication permanently, and most of them are treated with maintenance therapy or on-demand therapy, while others have difficulty in controlling symptoms with only partial relief, and patients with extraesophageal symptoms have even more difficulty in achieving satisfactory results with medication.
Most of the esophageal symptoms of GERD can be effectively controlled through psychological and lifestyle management, acid suppression, protection of the upper gastrointestinal mucosa and improvement of the gastrointestinal tract dynamics and other medical treatments. Commonly used acid suppressants such as the proton pump inhibitor PPI can effectively control heartburn and other phase A symptoms [12], but because PPI works mainly by reducing reflux acidity, it cannot yet improve the functional defects of the anti-reflux barrier at the gastroesophageal junction, such as relaxation or transient relaxation of the lower esophageal sphincter, esophageal hiatal hernia and other etiologies that lead to the occurrence of GERD, combined with patient compliance, drug resistance, hypersensitivity to symptoms, drug PPI has its inherent limitations due to the problems of patient compliance, drug resistance, high sensitivity to symptoms, adverse drug reactions, and cost.
Despite the increasing use of PPIs, approximately 10% ~ 40% of patients still respond poorly to PPI therapy [13, 14]. PPI therapy tends to control reflux symptoms worse than heartburn symptoms [15] and provides poorer relief of non-erosive reflux disease symptoms than reflux esophagitis [16]. A satisfaction survey study of 460 cases of GERD treated with PPI in six Asian countries in the Asia-Pacific region showed that 45% of patients had limited improvement in nocturnal symptoms and 49% still required other adjuvant therapy; despite improvements in patient health scales, 76% of patients with partially relieved GERD symptoms still had negative health effects after medication [17]. The results of our study [18] showed that patients with extraesophageal symptoms of GERD often had diverse symptoms, had been bounced around to multiple hospitals or physicians before being suspected of extraesophageal reflux, and were often poorly treated as respiratory medicine diseases. A study of the cost of medical consultations for patients with suspected extraesophageal reflux showed that patients with extraesophageal reflux went through an average of 10.1 (9.4 to 10.9) physicians, underwent 6.4 (3 to 9) tests, and had a total cost in year 1 (52% for proton pump inhibitors) that was 6.6 times higher than that of typical GERD patients, with only 54% of patients showing improvement in symptoms with medication[19] . . Other studies have shown improvement in gastroesophageal reflux-related asthma symptoms in some patients after PPI application and improvement in some indicators of lung function in a small number of patients, however, controlled studies with placebo showed limited control of asthma and chronic cough with PPI [9, 20].
It is evident that there are still a large number of patients, especially those with GELTS stages B, C, and D, who are difficult to obtain satisfactory results by simple lifestyle modification and pharmacological treatment, so laparoscopic fundoplication or endoscopic treatment becomes an option for further treatment.
3 .The principle, safety, effectiveness and development of radiofrequency treatment overview
Reconstruction of the anti-reflux barrier at the gastroesophageal junction by safe and minimally invasive endoscopic treatment is an ingenious idea based on modern technology and has been developed into endoscopic radiofrequency of the lower esophageal sphincter (Stretta RF and MER-200G RF), folding sutures (Endo- Cinch method, Sew- Right method and Plicator method, non-full or full), injections or implantation (Enteryx method, Roll method and Endotonics method), endoscopic folding system (Endoscopic plication system and Esophyx), and other 4 main endoscopic treatment methods. There are a few successful reports of gastroscopic endoluminal folding sutures at home and abroad, and the method needs to be improved and the long-term efficacy needs to be observed due to the problem of suture loosening or detachment [21]. The main mechanism of radiofrequency treatment is the inactivation of some nerve endings of the lower esophageal sphincter, contraction of collagen molecules, and reconstruction of collagen and microstructure through the thermal coagulation effect, which eventually leads to shortening and narrowing and thickening of the gastroesophageal junction, thereby decreasing compliance, reducing the number of occurrences of transient lower esophageal sphincter relaxation, and decreasing hypersensitivity at the treatment site [22]. Intravenous administration of midazolam-isoproterenol-fentanyl for deep sedation anesthesia can be performed on an outpatient basis and is minimally invasive and safe, with minimal complications and repeatable treatment. Each case takes about 45 min, with a liquid diet 6 h after surgery, followed by a semi-liquid diet the next day and a transition to a general diet in 1 week [23-25].
The US FDA approved the clinical application of Stretta radiofrequency therapy for GERD treatment in phases in 2000 and 2001, operated by Curon Medical, which declared bankruptcy in 2006. the program was acquired by Mederi Therapeutics in 2008 and Stretta re-entered the market in 2010. Since the introduction of Stretta into clinical use more than 30 studies have demonstrated the safety and efficacy of Stretta RF, including four adequately robust randomized controlled studies, a comprehensive meta-analysis, and several prospective clinical trials [26] [Journal of Minimally Invasive 2]. meta-analysis showed that Stretta RF significantly improved typical symptoms of GERD patients such as reflux, heartburn In 2013, the American College of Gastrointestinal Endoscopic Surgeons actively recommended the use of Stretta radiofrequency for the treatment of GERD as a safe and effective method for the treatment of GERD. minimally invasive approach for the treatment of GERD [26, 27]. Recently, Noar et al [28] reported the results of a 10-year study of the safety, efficacy, and durability of a single-center Stretta radiofrequency treatment for GERD typical symptoms: a total of 217 cases of drug-refractory GERD were included, and 10 years after radiofrequency 72% of patients had normalized their GERD-related quality of life scores (GERD-HRQL), 64% had reduced their PPI by half or (41% of patients completely discontinued PPI), 54% of patients had a satisfaction rate of more than 60%, and 85% of patients who had biopsy-proven Barret’s esophagus had reversed esophageal mucosa and no esophageal tumors occurred. This study further confirms the long-term effectiveness of radiofrequency therapy for typical symptoms of GERD.
Table 1 Meta-analysis of the Stretta radiofrequency treatment for GERD efficacy study
Efficacy parameters
Studies (items)
Patients (cases)
Mean follow-up time
(months)
Before radiofrequency (mean)
After radiofrequency (mean)
P-value
Subjective indicators
GERD-HRQL score
9
433
19.8
26.11
9.25
0.0001
QOLRAD score
4
250
25.2
3.30
9.25
0.0010
SF-36 physiological score
6
299
9.5
36.45
46.12
0.0001
SF-36 psychological score
5
264
10.0
46.79
55.15
0.0015
Heartburn score
9
525
24.1
3.55
1.19
0.0001
Satisfaction rating
5
366
21.9
1.43
4.07
0.0006
Objective indicators
Esophageal acid exposure (%, pH <4)
11
364
11.9
10.29
6.51
0.0003
DeMeester Rating
7
267
13.1
44.37
28.53
0.0074
LES pressure (mm Hg)
7
263
8.7
16.54
20.24
0.0302
GERD-HRQL: gastroesophageal reflux disease-related quality of life scale; QOLRA: reflux and dysphagia quality of life score; SF-36: SF-36 quality of life questionnaire; LES: lower esophageal sphincter
Stretta radiofrequency was introduced into China in 2006 for the treatment of respiratory symptoms caused by gastroesophageal reflux, and 17 cases were reported in the same year with good results [22].In 2007, Wang Zhonghao et al [10] reported the efficacy of Stretta radiofrequency in treating 200 cases of gastroesophageal laryngotracheal syndrome with immediate postoperative results: 190 cases (95%) were seen on review with the gastroscopic cardia port wrapped around the endoscope In 198 cases (99%), symptoms disappeared or were significantly relieved within 2 d after treatment, and 188 cases were followed up for 1-11 months, and 180 cases (90%) showed disappearance or significant improvement of symptoms, especially in those with predominantly respiratory symptoms. 2011 Gao Xiang et al [25] reported the efficacy of 505 cases at 12 months after surgery, and the reflux and heartburn symptom scores decreased from 5.02 and 5.31, respectively, to 1.64 and 1.79, and cough, wheezing and hoarseness symptom scores decreased from 6.77, 7.83 and 5.13 to 2.85, 3.07 and 1.81, respectively (p<0.01). Another pediatric asthma patient was treated with a similar cure [29].In 2014 Liang et al [30] reported the outcome of 138 patients with gastroesophageal laryngotracheal syndrome 5 years after Stretta radiofrequency, with a significant decrease in both typical and respiratory symptom scores, with 23.9% of patients able to reduce their medication and 57.2% able to stop, although patients' extraesophageal symptom Although patients' extraesophageal symptom scores rebounded over time, the combined use of PPI drugs could lead to long-term symptom relief; 75.4% of patients felt completely or partially satisfied with this treatment, and 68.1% of patients indicated that they would still choose radiofrequency treatment if they needed to be treated again. The endoscopic radiofrequency treatment technique has fewer complications, as well as higher patient satisfaction. Comparing the long-term efficacy of radiofrequency therapy with laparoscopic fundoplication for gastroesophageal laryngotracheal syndrome, both are effective in controlling gastroesophageal laryngotracheal syndrome, with laparoscopic fundoplication being more effective and radiofrequency being more minimally invasive [31-33].
Due to operational problems of Curon Medical, lack of sufficient evidence-based medical evidence, certain deficiencies of the first generation products, high prices, medical policies, and insufficient domestic experience with this treatment, only four hospitals in China (Second Artillery General Hospital, PLA Hospital 251, the Fourth Affiliated Hospital of Zhengzhou University, and Guangzhou Armed Police General Hospital) have carried out Stretta RF treatment Therefore, there is an urgent need for the localization of esophageal radiofrequency instruments. Since 2007, this device has been researched and improved and gradually obtained domestic patents: anti-reflux radiofrequency treatment tube (ZL 200720149566.6) and a device using micro radiofrequency electrodes to treat sphincter relaxation (ZL 200920135308.1). 2013, the domestic radiofrequency temperature-controlled thermal coagulator [State Food and Drug Administration Machinery (approved) No. 2013 3252035] was applied to clinical practice. In 2014, Wang Feng et al [34] reported the 1-year efficacy of 56 cases of applying domestic radiofrequency to treat gastroesophageal laryngotracheal syndrome, and the esophageal manometry was (13.1±6.7) mm Hg before treatment and (21.8±6.7) mm Hg 3 months after treatment, which was significantly higher than that before surgery (P<0.001); the impedance was (52.4±24.2) The impedance was (52.4±24.2) times/24 h before treatment and (33.9±16.4) times/d 3 months after treatment, which was significantly lower than before (P<0.001); the symptom score was (3.0±1.1) before treatment and (1.8±0.7) and (1.3±0.6) at 3 and 12 months after treatment, respectively, which was significantly better than before (P<0.001); there were no intraoperative adverse events and serious There were no intraoperative adverse events or serious adverse events; there were no long-term complications, and the efficacy was similar to that of Stretta radiofrequency.
Thirty-two overseas clinical studies have demonstrated that patients tolerate Stretta radiofrequency treatment well and have a high safety profile. These studies involved a total of 2774 cases with a very low and mild complication rate that was transient. less than 1% of complications were recorded on the FDA MAUDE website. By 2012, approximately 15,000 patients worldwide had received this treatment without serious complications [27]. According to our center’s study of 505 patients presenting primarily with extraesophageal symptoms, early transient complications after RF included retrosternal discomfort or pain (21.0%), low-grade fever (17.0%), nausea and/or vomiting (19.2%), and mild dysphagia (8.3%), without serious complications such as perforation, mucosal tears, and hemorrhage or death [25]. However, a total of three cases of perforation and two cases of death by misaspiration have been reported abroad due to improper case selection and operative errors [35]. Therefore, proper case selection, preoperative treatment to optimize the patient for RF treatment, timely intraoperative suction (flushing fluid, secretions, and regurgitant), proper anesthetic depth to make the treatment process smooth, and skilled and standardized operation are the keys to ensure the efficacy and avoid complications.
In summary, clinical studies of esophageal radiofrequency therapy have demonstrated that the treatment is free of esophageal damage and fibrotic strictures, with almost non-invasive long-term effects; has stable and long-lasting efficacy in patients who are drug-dependent or refractory to PPI; improves distal esophageal compliance, reduces acid exposure and sensitivity; is very safe and can be repeated if necessary to enhance the efficacy; and does not interfere with other treatment modalities (e.g. PPI treatment and folding surgery, etc.); can also be used to enhance the efficacy of other treatment modalities; can even be used as diagnostic treatment.
4.Application scope of radiofrequency treatment
Esophageal radiofrequency and laparoscopic fundoplication are similar in principle, both by reconstructing the anti-reflux anatomical structure and function of the esophagus, and controlling the invasion and reflexes caused by reflux in terms of reducing the time, frequency, volume and height of reflux. The scope of application of both is also similar, so esophageal radiofrequency therapy is also indicated for: 1 failure of medical therapy: unsatisfactory symptom control, severe typical symptoms that cannot be controlled by acid-suppressive drugs or the presence of drug side effects; 2 effective drug therapy but the patient requires further aggressive treatment: including those who require improved quality of life, do not want to take drugs for life or consider drug therapy more costly; 3 with significant gastroesophageal laryngotracheal syndrome stages B, C and D symptoms: including asthma, laryngospasm, cough, nasopharyngeal symptoms and aspiration [36, 37]. It is more appropriate for patients who meet the above criteria and are young patients (<60 years old) with fear of surgery, gastroscopy and esophageal dynamics showing relatively intact esophageal structure and function, and relatively low intraesophageal reflux monitoring scores.
A specialist evaluation for GERD should be performed prior to radiofrequency treatment. Gastroscopy can visualize complications due to reflux such as esophagitis and Barrett’s esophagus, and can also observe the relaxation of the cardia and anatomical abnormalities causing reflux such as esophageal hiatal hernia, excluding peptic ulcers and tumors, and can biopsy for pathological diagnosis; relatively inexpensive upper gastrointestinal imaging can also provide information about GERD and exclude ulcer disease and tumors, especially in the prone head-down position and 24-h dynamic pH or pH+impedance monitoring of pathological reflux and the nature of the refluxed material. High-resolution esophageal manometry provides further esophageal kinetic parameters and allows visual evaluation of esophageal contouring capacity, upper and lower esophageal sphincter function. In contrast, anti-reflux drugs (especially PPIs and others) can be used for diagnostic treatment with high specificity, and responsiveness to drugs is an important predictor of surgical efficacy. In contrast, radiofrequency treatment is not indicated if 1 esophageal hiatal hernia >2 cm, 2 severe esophagitis (esophagitis Los Angeles classification of grade C and D), 3 peptic esophageal stricture, 4 combined with autoimmune diseases (e.g., scleroderma, etc.), 5 combined with collagen vascular disease, 6 severe dysfunction of important organs, such as cardiopulmonary insufficiency, etc., 7 combined with coagulation dysfunction, 8 pregnant women, etc. [37]. For esophageal hiatal hernia >2 cm, laparoscopic fundoplication is indicated, with satisfactory long-term results for both typical and extraesophageal symptoms [38].
Life psychological conditioning, pharmacological treatment, gastroscopic radiofrequency treatment of the esophageal sphincter and laparoscopic fundoplication are complementary, supplementary or alternative to each other in the treatment of GERD, constituting a relatively complete anti-reflux treatment system at present. In addition, for patients with persistent GERD after gastroesophageal surgery, Roux-en-Y jejunostomy can be performed laparoscopically, which can achieve good results [39]. Gastric fundoplication plus highly selective vagotomy in patients with GERD combined with severe acid reflux and reflux-associated asthma can significantly improve the relief of respiratory symptoms [40].
5. Summary
Gastroscopic radiofrequency treatment of the lower esophageal sphincter is a minimally invasive therapy to achieve anti-reflux effects by reconstructing the anti-reflux mechanism at the gastroesophageal junction. It has good near- and long-term efficacy for the treatment of gastroesophageal laryngotracheal syndrome, and is especially unique for the treatment of patients with esophageal laryngotracheal syndrome stages B, C, and D caused by high reflux. Radiofrequency treatment of the esophagus, together with psychological life conditioning, pharmacological treatment, and laparoscopic fundoplication, constitutes a stepwise and complementary anti-reflux treatment system, thus bringing new and effective means for patients who cannot stop medication, whose remission by pharmacological treatment is unsatisfactory, and whose pharmacological treatment is ineffective. The mechanism of radiofrequency therapy needs to be further investigated, and the instrumentation itself needs to be continuously improved.