A Systematic Review of the Therapeutic Role of Gastric Pacemakers in Adults With Gastroparesis

Gastroparesis or gastric stasis is the delayed transit of the ingested contents through the stomach in the absence of mechanical obstruction. It can have multiple etiologies, most commonly idiopathic (ID) and diabetic (DM). Gastroparesis can cause significant distress to patients as it leads to symptoms like intractable nausea and vomiting, weight loss, abdominal bloating, early satiety, etc. The pathogenesis is mainly thought to be due to the dysfunction of the gastric pacemaker cells, i.e., interstitial cells of Cajal (ICC), and their interaction with the other gastric motor function regulatory components. There are several proposed treatment options for gastroparesis. Despite that, most patients remain refractory to medical treatment and require additional interventions for symptomatic relief. One such intervention is gastric electrical stimulation or gastric pacemaker, which aids in improving gastric motility. We have searched PubMed, PubMed Central (PMC), Medline, Science Direct, and Google Scholar for articles pertaining to the use of gastric electrical stimulation in gastroparesis published in the last 10 years. The keywords used include "gastroparesis", "gastric stasis", "gastric pacemaker'', "gastric electrical stimulation", "nausea", "vomiting", "abdominal bloating", "gastric neuromodulation". We have finally included twelve studies that were the most relevant to our research question and met the quality assessment criteria. Exclusion criteria consisted of pediatric population studies, studies conducted on animals, books, and grey literature. Overall, these twelve studies helped evaluate the impact of gastric pacemakers on symptoms of gastroparesis like nausea, vomiting, weight loss, abdominal bloating, and quality of life. We found that most studies favored gastric pacemakers, improving the incidence of nausea and vomiting in patients with gastroparesis. There was a marked improvement in the BMI as well. On the other hand, most open-labeled studies showed improved quality of life and Gastroparesis Cardinal Symptom Index (GCSI) scores, while randomized controlled trials and meta-analyses did not reflect the same result. In addition, some other parameters improved with gastric pacemakers, Inflammatory markers, insulin levels (especially in diabetics), and the number of hospitalizations. In conclusion, gastric pacemaker is a potential treatment option for patients with medically refractory gastroparesis. As noted from the results of our study, nausea/vomiting, weight loss, and overall GCSI scores have shown marked improvement with gastric electrical stimulation (GES). Nevertheless, more extensive research is needed to understand better the full extent of this device’s use as a viable treatment option for patients suffering from gastroparesis.


Introduction And Background
Gastroparesis (GP) is chronic and often disabling neuromuscular disorder of the upper gastrointestinal tract [1]. It is characterized by impaired gastric motility in the absence of mechanical obstruction of the stomach [2]. Symptoms most commonly include nausea, vomiting, early satiety, postprandial fullness, upper abdominal pain, bloating, and weight loss [3]. Aetiologies of gastroparesis can be idiopathic, diabetic, iatrogenic, post-surgical, or post-viral [4]. In the United States, the incidence of hospitalizations related to gastroparesis has increased substantially since 1995 and particularly after 2000. In one only communitybased study, the age-adjusted prevalence of idiopathic gastroparesis per 100,000 persons was higher in women than men. In another study about gastroparesis in diabetes mellitus (DM), the average cumulative incidence of symptoms and delayed gastric emptying over 10 years was higher (up to 5%) in type 1 DM than in type 2 DM (1%) [5].
The underlying pathophysiological mechanisms are complex. Some of the involved mechanisms include abnormal gastric motility (accommodation, emptying), autonomic dysfunction, visceral hypersensitivity, low-grade mucosal inflammation, and cellular changes in enteric nerves, muscle, or interstitial cells of Cajal [6,7]. The current treatment strategies primarily include symptomatic management and dietary measures, fluid therapy, prokinetic drugs, gastric electrical stimulation, and endoscopic or surgical intervention [8].
Gastric pacemaker therapy or gastric electrical stimulation (GES) has been proposed as an alternative effective treatment option for patients with gastroparesis whose symptoms persist despite medical therapy [9]. Recent studies suggest that electrical stimulation improves symptoms and physiology with (a) an early and sustained anti-emetic effect; (b) an early and durable gastric prokinetic effect in delayed emptying patients; (c) an early antiarrhythmic effect that continues over time; (d) a late autonomic effect; (e) a late hormonal effect; (f) an early anti-inflammatory effect that persists; and (g) an early and sustained improvement in health-related quality of life [10]. (Figure 1)

FIGURE 1: The possible beneficial effects of a gastric pacemaker
Gastric electrical stimulation offers a variety of potential benefits, including synchronization of intrinsic gastric electrical activity, evoking propagating contractions, and alleviating symptomatology in individuals with gastroparesis, depending on stimulus settings and stimulation locations. Extra-intestinal effects of gastric stimulation parameters include alterations in systemic hormonal and autonomic neural activity, as well as modification of afferent nerve pathways projecting to the central nervous system, which might be significant mechanisms of action [11].
Currently, pathophysiological research continues to focus on the cause of disordered motility and visceral hypersensitivity in the pathogenesis of GP symptoms. Studies show that patients with gastroparesis had different clinical outcomes after GES therapy based on underlying etiology [12].
A better understanding of the targeted neural circuits and their physiological and pathophysiological roles, as well as improving stimulation regimens and discovering which patients benefit the most from this therapy, could improve the clinical success of the GES [13]. In this review, we aim to understand some of the alterations leading to disorders such as gastroparesis and the effectiveness of gastric electrical stimulation as a potential therapeutic option for relieving the symptoms of gastroparesis in various patient populations.

Data Extraction
Two reviewers went through a total of 1924 articles and identified them to be relevant to either gastroparesis and its symptoms or the gastric electrical stimulation therapy in all the databases after exclusion of duplicates. Two investigators had screened the titles of the publications identified independently. After careful screening of titles, if all the inclusion criteria were met and the article suited the research question, the full text was obtained. Of all these articles, 124 met initial inclusion and exclusion criteria, 41 articles were found to be most relevant, and were available with abstracts. Out of which, we included 12 studies with full text in the results. The data extraction has been presented in the form of Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow chart below ( Figure 2) [14]. The review has been carefully drafted following the PRISMA guidelines for systematic review [14].

Inclusion Criteria
The following inclusion criteria were used: studies published in the last 10 years; studies conducted on humans and published in English; studies including data on adults with medically refractory gastroparesis that required gastric electrical stimulation therapy; and peer review papers. We included review articles, observational studies, and clinical trials. The following exclusion criteria were applied: studies involving the pediatric population, studies conducted on animals, books, and grey literature.

Quality Appraisal
The quality of all 12 studies was assessed based on different tools for each type of study: 1) Cochrane risk bias assessment tool for randomized clinical trials; 2) Newcastle Ottawa scale for observational studies; 3) AMSTAR2 was used to assess the quality of systematic reviews; 4) JB checklist for case series; 5) Sanra checklist to assess the quality of reviews.

Results
Of all the relevant articles found, 12 articles have been analyzed, and the results are presented below. These studies helped evaluate gastric pacemaker's impact on symptoms of gastroparesis like nausea, vomiting, weight loss, abdominal bloating, and quality of life.

Discussion
Gastroparesis is a clinical illness characterized by symptoms suggestive of altered digestive function of the proximal gastrointestinal tract and objective evidence of abnormally prolonged retention of stomach contents in the absence of apparent mechanical obstruction [27]. Most gastroparesis cases can be divided into three categories: idiopathic gastroparesis (ID, 36%), diabetic gastroparesis (DG, 29%), and postsurgical gastroparesis (PSG, 13%). Idiopathic Gastroparesis refers to a symptomatic patient with delayed stomach emptying with no identifiable fundamental underlying problem. ID is the most common form of gastroparesis. Most patients with ID are typically young or middle-aged women [28]. One significant cohort of ID is post-viral; these patients present with rapid onset of GP symptoms after a phase of viral prodrome. Typically, patients have a rapid onset of GP symptoms with intractable nausea and vomiting, and they improve over a year. In comparison, the most identified cause of gastroparesis is diabetes [29]. In the NIH consortium cohort, type 1 DM patients had more delayed gastric emptying [4]. The 10-year incidence of gastroparesis has been recorded as 5.2 % in type 1 diabetes, 1 % in type 2 diabetes, and 0.2 % in non-diabetic controls in a US community [28]. Other less common causes of gastroparesis are Parkinsonism, amyloidosis, paraneoplastic, scleroderma, and mesenteric ischemia [29] (shown in Figure 3).

Clinical implications
Nausea, vomiting, early satiety, postprandial fullness, bloating, belching, and upper abdominal discomfort are all signs of Gastroparesis, which may overlap with symptoms of functional dyspepsia and rapid gastric emptying. The Gastroparesis Symptom Severity Scale is one of several symptom severity ratings used as patient-reported symptom assessments in gastroparesis, including the Gastroparesis Symptom Index (GCSI, shown in Table 2   Symptom profiling of patients recruited in the Gastroparesis Clinical Research Consortium (GpCRC) revealed that 50-60% of gastroparesis patients felt severe early satiety and postprandial fullness, with DG and ID having similar severity levels. Nausea was noted by 95% of the patients (predominant symptom in 29 percent). It was linked to meals in three-quarters of the patients, and it lasted most of the day in more than 40% of them. Nausea/vomiting sub-score of the Patient's Assessment of Upper Gastrointestinal Disorders-Symptoms (PAGI-SYM) was more significant in DG patients, with vomiting lasting several hours or most of the day in more than half of the DG patients compared to 24% in ID. Patients with DG have also reported vomiting before eating in the morning. Forty percent of gastroparetics experienced severe bloating (GCSI 4 of 5), and it was linked to the female sex, overweight status, changed bowel function, and probiotic use [27].

Physiopathogenesis
A succession of complex and well-coordinated muscular and secretory processes culminates in emptying a meal from the stomach into the small bowel. The fundus, antrum, and pylorus are all implicated in gastroesophageal (GE) from a neuromuscular viewpoint (components of gastric motility have been demonstrated in Figure 4). Swallowing causes the gastric fundus to relax actively, allowing it to take vast amounts of food without causing intragastric pressure to rise. Following that, a continuous increase in fundal tone drives stomach contents toward a fast-closing pylorus, where digestible solids are mashed along with gastric secretions and bounced back into the proximal stomach. The interstitial cells of Cajal (ICC) that are situated in the upper portion of the greater curvature and generate a slow-wave basal electrical rhythm (pacesetter potential) with a frequency of three depolarizations per minute control the maximal frequency of antral contractions. This process continues until all digestible solids are reduced to particles of 2 mm or less, and tiny quantities of fluids and homogenized food (chyme) escape the stomach shortly before pyloric contractions. Normal small bowel function is also required for GE, not only because antro-pyloro coordination is needed to empty the stomach, but also because neuro-endocrine inhibitory signals arise from both the proximal and distal small bowels, based on the composition of the chyme, to modulate emptying rates, ensuring that delivery to the absorbent mucosa matches liver and pancreas secretory activities [27].

FIGURE 4: Gastric motor control apparatus
This figure represents the motor control apparatus of the gut and its components.
The connection between delayed stomach emptying and symptom pattern in Gastroparesis and the distinction between functional dyspepsia and gastroparesis is still a source of debate and ambiguity. The function of pyloric resistance and duodenal motility in developing symptoms has been studied in pathophysiological investigations. Glycemic management did not influence short-term changes in stomach emptying rate in diabetic patients with type 2 diabetes. Still, it was a key risk factor for the long-term development of gastroparesis in type 1 diabetes patients. Diabetic gastroparesis is characterized by a loss of ICCs at the cellular level, which is negatively associated with the amount of CD206+ macrophages, which are considered to protect ICCs. The SIP syncytium (Smooth muscle cells are electrically coupled to ICC and PDGFRα(+) cells, forming an integrated unit called the SIP syncytium), rather than the ICC alone, is now recognized as the pace making unit in the pathophysiology of GP, and GP may be part of a pan-enteric autoimmune and/or autonomic disease with macrophage imbalance [30,31].

Currently available treatment modalities
As discussed in the previous section, there are several complex mechanisms in the gut that cause gastroparesis. Scintigraphy and 13 C breath testing are the best assessment tools for GE. Newer diagnostic modalities like wireless motility capsules and pyloric distensibility (EndoFLIP) are aiding in better characterization of this disease. The only effective medical treatment for gastroparesis has been the use of metoclopramide. Antiemetics (aprepitant), prokinetics (relamorelin, prucalopride), and fundic relaxants are some of the more recent therapeutic options (acotiamide, buspirone). In addition to pharmaceutical compounds in the pipeline, neuromodulation and endosurgical techniques, such as gastric peroral endoscopic myotomy (G-POEM), may help address refractory. Endoscopic pyloromyotomy appears to be effective in the short term, especially for nausea and vomiting, but further study is needed to accurately identify the subset of gastroparesis patients who have pyloric dysfunction, and long-term results must be assessed [15,4] (Figure 5).

Gastric pacemaker/ gastric electrical stimulator
The FDA has approved the use of gastric electrical stimulators (GES) for drug-resistant IG and DG. The device is placed directly into the stomach. GES has been recommended as a treatment option for people who are resistant to medicines.
The device is made up of electrodes surgically implanted in the stomach's anterior wall and coupled to a pulse generator [29]. The Enterra stomach electrical stimulator is implanted by surgery. A laparotomy or a less invasive laparoscopy may be used by the surgeon. The complete device is made up of two leads, a pulse generator, and a programming system, all produced by Medtronic (Medtronic, Dublin, Ireland). At a distance of ten centimeters proximal to the pylorus, the two neuromuscular leads are inserted 1 cm apart within the muscularis propria of the stomach's greater curvature. The stimulation settings for the Medtronic Model 4351 pulse generator are as follows: amplitude: 5 mA, pulse width: 330 s, and cycle: 12 cpm (on time: 0.1 s-14 Hz; off time: 5.0 s). The pulse generator is generally located in the upper right or left quadrant of the abdomen wall. Different stimulation parameters can be programmed using an external device. Highfrequency and low-energy settings are used in Enterra treatment stimulation. The battery lasts about 5 to 10 years in most cases. If a battery must be replaced, the electrodes do not have to be replaced [32] (Figure 6).

Gastrointestinal symptoms
Nausea and vomiting are the most frequent and bothersome symptoms experienced by patients with gastroparesis. The gastric pacemaker has been shown to help alleviate these symptoms, as described in the studies in our review [18]. A study conducted between 1998 to 2009 on 50 patients revealed that there was an improvement in nausea (2.46 vs. 1.35, P =.001) and vomiting (3.35 vs. 1.49, P<0.001) [15]. In another study conducted on 13 patients by Laine et al. showed that before implantation, 13 had severe nausea, 11 had severe vomiting. After the pacemaker implantation procedure, eight patients reported significant relief of these symptoms, and three said partial replacement. One patient did not report any improvement in nausea/vomiting but had substantial weight gain [21].
In a randomized crossover study conducted by Ducrotte et al., GES reduced the frequency of refractory vomiting in a total of 172 patients with and without diabetes [17]. GCSI scale was used to analyze the improvement of nausea and vomiting scores, showing that nausea scores dropped from 3.5 at baseline to 1.7 and 2.6 and six weeks and six months, respectively. Similarly, vomiting scores had dropped from 2.4 to 0.6 and 1.8 as published in a review made by Shine et al. [18].
Another randomized controlled trial published by McCullum et al. presents reduced vomiting scores immediately after induction of GES therapy and after a year of continuous usage whereas, there was no improvement seen when analyzed at three months after the start of GES therapy [24]. In contrast, a randomized controlled trial comprising of 58 patients, conducted by Abell et al., demonstrated no significant reduction in vomiting scores with GES therapy [25].
Abdominal bloating, early satiety, and slow gastric emptying symptoms-Impact of GES on these symptoms was evaluated in a study published by Hedjoudje et al. In 2020 with a total of 50 patients who were implanted with Gastric pacemakers from January 1998 to December 2009 demonstrated that beyond ten years, there is an improvement in early satiety (3.05 vs. 1.76, p <0.001), bloating (2.51 in comparison to 1.70, P =.012) [15]. According to a review published by Shine et al. in 2019, compared to baseline gastric emptying delay, total liquid emptying delay significantly decreased, from 94% at baseline to 52% and 58%, using a temporary and permanent GES, respectively. In addition, baseline total solid emptying delay decreased from 152% to 105% and 100% at six days and six months [18]. About abdominal pain, in a clinical trial conducted by Lahr et al., patients suffering from severe abdominal pain had improved significantly with both temporary and permanent placement of gastric pacemakers [23].

Overall symptomatic improvement, weight loss, and quality of life
GCSI and total symptom severity (TSS) scores have been used to gauge the impact of GES on a patient's symptoms due to gastroparesis.
Wisconsin's Enterra therapy experience, a clinical study, has demonstrated that GCSI scores improved, and prokinetic and narcotic medication use decreased significantly at ≥ one year. Satisfaction scores were high with the help of gastric pacemakers in 119 patients with gastroparesis, of which 64 had idiopathic gastroparesis, and 45 had diabetic Gastroparesis [19]. Meta-analysis revealed that these baseline differences seemed to have impacted the results of the TSS ratings during treatment [22].
A review published by Chu et al. involving 601 subjects concluded that the beneficial effects of GES were seen more in patients with diabetic Gastroparesis than post-surgical and idiopathic etiologies [26].
A weight loss-A study was conducted with 183 patients who underwent GES from 2005 to 2015. Of the 183 patients with gastroparesis. 50% were diabetic, 42% idiopathic (ID), and 9% post-surgical (PS). The results demonstrate that DM patients saw a greater incidence of weight gain > 4 kg than PS and ID patients (67.6% vs. 8.1% vs. 24.3%, respectively, p < 0.05) [16].
A retrospective multi-center cohort study with 13 patients implanted with GES also supported the benefit of using GES for patients suffering from weight loss due to gastroparesis. According to this study, 11 patients (79%) gained a median of 5.1 kg in weight (P < 0.01) [21]. Another study with positive results is a retrospective single-center study with 50 participants showing improved BMI post gastric pacemaker implantation (23.40 vs. 26.46, p= 0.048) [15].
Quality of life-a large, multi-center, randomized, double-blind trial with a crossover consisting of 172 patients also did not show any significant difference in the quality of life among those with GES therapy [17].  antiarrhythmic action may help restore baseline motility. This study found a significant reduction in hospital days following GES, with annualized median days in the hospital dropping from 2 at baseline to 0 at the end of a year (p = 0.006) [18]. Thus, fewer hospitalizations and shorter stays would result in fewer comorbidities, expenditures, and infections acquired in hospitals.

Limitations
Some of the studies included are open-labeled, which are inherently subject to bias. Therefore, further randomized controlled trials are needed to analyze the impact of gastric pacemakers in the improvement of symptoms in patients with gastroparesis. Some of the studies in this review suggest that symptomatic relief is more pronounced in patients with diabetic gastroparesis rather than Idiopathic and Post-surgical. More research is required to assess the use of gastric pacemakers in idiopathic and post-surgical gastroparesis. We have also only included relevant studies published in the last 10 years, out of which we have excluded the pediatric population, studies conducted on animals, books, and grey literature (Figure 7).

Conclusions
The aim of this study is to see how effective stomach electrical stimulation is at treating gastroparesis symptoms like nausea, vomiting, abdominal bloating, weight loss, and overall quality of life. We found that gastric pacemakers have shown varying effects on each of these symptoms. In this review, most studies support the role of gastric pacemakers in reducing nausea and vomiting experienced by patients suffering from gastroparesis. Similarly, as evidenced by the studies reviewed, there was a significant weight gain noted with this therapy. Although most studies suggest a significant improvement in quality of life and GCSI scores, a few others suggest that there is no substantial change in the quality of life because of GES itself. However, the evidence supporting no difference in the quality of life seems stronger, as shown by the metaanalysis and randomized controlled trials vs. open-label trials that showed positive results for quality of life with gastric pacing. Some of the other parameters that have shown improvement after GES therapy include reduction in inflammatory markers, greater insulin levels (especially in diabetic patients), and reduction in hospitalizations.
We believe that, just as the cardiac pacemaker is extensively studied and used for managing cardiac dysrhythmias, the gastric pacemaker can be potentially used for managing GI dysrhythmias. However, the evidence supporting its use is currently limited; a lot more research is required in this field to harness the full ability of this device to improve the symptoms and, therefore, quality of life of patients with gastroparesis due to any aetiology.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.