INTRODUCTION — Gastroparesis is defined as a delay in gastric emptying that produces nausea, vomiting, bloating, early satiety, and discomfort [1]. In severe cases, nausea and vomiting may cause weight loss, dehydration, electrolyte disturbances, and malnutrition due to inadequate caloric and fluid intake.
Management of gastroparesis consists of supportive measures (eg, hydration and nutrition), optimizing glycemic control in patients with diabetes mellitus, medications, and occasionally surgical therapy. The limited efficacy of these options for severe gastroparesis has provided a rationale for development of novel approaches for treatment. Electrical stimuli can be delivered to the stomach as low-energy, high-frequency gastric electrical neurostimulation or high-energy, low frequency gastric pacing. The former has limited evidence of efficacy and is available for humanitarian treatment of gastroparesis that is refractory to other therapies, while the latter is at present too bulky for implantation.
This topic review will provide an overview of the methods of electrical stimulation of and their efficacy in treating gastroparesis. The pathophysiology, etiology, diagnosis, and treatment of gastroparesis are discussed separately. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis" and "Pathogenesis of delayed gastric emptying" and "Treatment of gastroparesis".)
PATHOPHYSIOLOGY — The emptying of gastric contents after a meal is controlled by specific motor and myoelectric activities of different gastric regions.
●The proximal stomach exhibits changes in tone in response to eating, which serve initially to accommodate the ingested bolus and then, as digestion progresses, to regulate delivery of food particles into the distal stomach [2].
●The distal stomach exhibits a fed motor pattern consisting of phasic contractions that propagate from the gastric body to the pylorus at a maximal frequency of three cycles per minute (cpm). These grind and mix the food into a fine particulate suspension [3].
Impairment of normal phasic motor activity in the distal stomach produces the clinical condition of gastroparesis. The frequency and direction of this activity is regulated by the gastric slow wave, a rhythmic electrical oscillation, which is generated by interstitial cells of Cajal in the proximal gastric body, the "pacemaker" zone of the stomach [4]. The slow wave is ubiquitously present at a frequency of 3 cpm, regardless of the contractile state of the stomach. During motor quiescence, the slow wave exhibits a plateau potential of low amplitude. Phasic contractions are generated when the slow wave plateau potential increases in amplitude or when action potentials are stimulated by meal-induced neurohumoral activators [5].
CANDIDATES FOR GASTRIC ELECTRICAL STIMULATION
Indications
Refractory idiopathic and diabetic gastroparesis — The gastric electrical neurostimulator (Enterra Therapy system) is not approved by the United States Food and Drug Administration for unrestricted marketing for treatment of gastroparesis, but is approved as a humanitarian use device. In addition, because of probable benefit rather than established effectiveness, the device has also received humanitarian device exemption approval for treatment of refractory diabetic and idiopathic gastroparesis, documented by objective measures of delayed gastric emptying. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis", section on 'Scintigraphic gastric emptying'.)
Other — Other potential compassionate use applications of gastric electrical stimulation that have been evaluated in small series of patients with refractory nausea and vomiting include:
●Gastroparesis due to other causes – Patients with refractory gastroparesis from other causes, including delayed gastric emptying secondary to a malignancy, after fundoplication for gastroesophageal reflux disease, esophagectomy for esophageal carcinoma, Roux-en-Y gastric bypass for morbid obesity, chronic intestinal pseudo-obstruction, and transplantation.
●Refractory cyclic vomiting syndrome – In one study that included 11 patients with refractory cyclic vomiting syndrome, patients who underwent gastric electrical stimulation had a reduction in nausea and vomiting of 62 percent and 83 percent, respectively as compared with baseline [6]. Placement of permanent gastric electrical stimulation was associated with a decrease in nausea and vomiting of 46 and 69 percent, respectively.
Relative contraindications — There are no absolute contraindications to gastric neurostimulation. However, due to the risk of infection after surgery, patients on immunosuppressive therapy may not be optimal candidates. Chronic opiate use may also adversely impact the therapeutic response to gastric stimulation and should be considered when referring opioid medication-dependent patients for gastric stimulation. Gastric neurostimulation should be avoided during pregnancy as the effects of stimulation on the developing fetus are unknown.
Predictors of response — Patients with diabetes are more likely than those with idiopathic disease to exhibit clinical improvement following stimulator surgery [7-9]. Opioid dependence has been identified as a negative predictor of response [10]. In a meta-analysis of 49 studies, clinical improvements with gastric stimulation were greater in patients with more severe initial symptoms [11].
Rates of gastric emptying generally do not predict responses to gastric stimulation. However, some studies noted better responses in those with more prolonged retention, while another found that more severe emptying delays predicted the need to perform stimulator implantation in diabetics but not idiopathic patients [8,12-14]. Findings of damage to myenteric ganglia and with loss of interstitial cells of Cajal in the stomach have been reported as gastric histologic predictors of response to gastric stimulation [15,16].
HIGH-FREQUENCY GASTRIC ELECTRICAL STIMULATION
Mechanism of action — The mechanism of action of high-frequency gastric electrical neurostimulation at 12 cpm is uncertain, but probably does not relate to stimulating gastric emptying. Consistent acceleration of solid phase emptying has not been observed in clinical trials. In one retrospective review, gastric stimulation reduced gastric retention at four hours by only 7 percent [17]. High-frequency neurostimulation also has no effect on basal gastric electrical activity or on slow wave dysrhythmias [18,19]. However, it enhances slow-wave amplitude and propagation velocity [19]. Intraoperative techniques to measure high resolution gastric electrical conduction profiles have shown no effects of gastric neurostimulation on slow wave dysrhythmias, conduction blocks, retrograde propagation, ectopic pacemakers, or colliding waveforms [20]. The device does increase maximally tolerated volumes of gastric distention, reflecting blunting of luminal perception [21]. Gastric neurostimulation modifies sympathovagal activity and modulates activity in thoracic spinal neurons that are responsive to gastric distention, however, autonomic benefits only become evident months after implantation, suggesting they are not critical for symptom improvements [22-25]. In animal models, gastric neurostimulation increases ghrelin-positive cells and mRNA and plasma ghrelin levels, suggesting possible mechanistic participation of this neurohumoral agent [26]. Reductions in serum tumor necrosis factor-alpha levels after surgery may indicate additional anti-inflammatory effects of gastric neurostimulation [24].
Technique
Permanent stimulator — The gastric electrical neurostimulator can be implanted via laparotomy or laparoscopic surgery. The device consists of a pair of leads, a pulse generator, and a programming system. The leads are placed in the muscularis propria of greater curvature of the stomach, about 10 cm proximal to the pylorus and connected to a pulse generator. The pulse generator is typically placed subcutaneously in the right or left upper quadrants of the abdomen. An external programming device controls the gastric stimulation parameters. The battery life is typically 5 to 10 years, but this duration can vary depending on the energy level settings.
Temporary stimulator — Use of endoscopically placed temporary stimulating electrodes have been employed by some centers of expertise to help predict who might respond to a permanently implanted device [27,28]. Percutaneous electrodes have been proposed as a means of delivering high-energy pacing stimuli from external current sources.
Benefits
Clinical outcomes — In a systematic review that included 19 studies in which patients with gastroparesis underwent gastric electrical stimulation, symptoms of nausea and vomiting were more likely to improve as compared with abdominal pain [10,29,30]. Symptomatic improvement has been reported as soon as three days after device implantation [6,10,31-42]. However, gastric electrical stimulation has not consistently demonstrated benefits in reducing other gastrointestinal symptoms including fullness, bloating, or acid reflux symptoms [9,10].
Observational studies have reported associated improvements in body mass index, HbA1c, serum albumin, and reduction in the need for prokinetic medication and supplemental nutrition with gastric electrical stimulation [32,35,43,44]. Gastric stimulation has also been associated with improvements in physical and mental quality of life scores and reduction in the need for hospitalization [32,34,43]. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis", section on 'Clinical features'.)
Efficacy — A systematic review of 38 studies reported smaller improvements in nausea and abdominal pain with gastric neurostimulation as compared with pyloromyotomy or pyloroplasty and less effective antiemetic effects than after pyloric surgery or gastrectomy [29].
Although response rates to gastric neurostimulation in larger uncontrolled studies range from 50 to 92 percent with continued improvement in gastroparesis symptoms for up to 15 years [45-49], there is less convincing benefit in four published randomized controlled crossover trials [45,50,51]:
●The first suggested that there was significant benefit with treatment on versus off in a combined group of idiopathic and diabetic gastroparesis patients with the predominant benefit in those with diabetes [50].
●The second controlled study in diabetic gastroparesis showed no difference between on and off treatment periods after an initial six weeks unblinded on treatment phase [45]. Following these blinded on and off treatment periods, all patients had their stimulators turned on and all had clinical improvements after 12 months of follow up compared with baseline.
●A third controlled study in idiopathic gastroparesis patients had a similar trial design as the investigation in diabetics and results paralleled the diabetic study, showing no significant differences in symptoms in the blinded crossover phase regardless of whether the device was on or off [51]. As in the diabetic study, symptoms significantly decreased during the unblinded study phases.
●In preliminary results from a multicenter randomized trial in which 149 patients with diabetic, idiopathic, or postsurgical gastroparesis were assigned to on versus off stimulation for four months with crossover to the other arm for an additional four months, [14] vomiting scores were significantly lower with the device on versus off, but other symptoms were not reported.
Risks — Risks of high-frequency gastric neurostimulation include infection, lead migration or erosion, lead dislodgement, electrode penetration into the gastric mucosa requiring re-operation, seroma, and bowel obstruction.
Reasons for device explantation in one large series included nonresponse to therapy (4 percent), mechanical issues (3 percent), and infection (2 percent) [52]. Battery life has not been well defined, although repeat surgery for battery replacement is often required within 10 years of initial device implantation [46]. Forty-three percent of patients in one longitudinal study required an average of 2.15 additional surgeries over eight years of follow-up, mostly for battery exchange and device relocation [48].
Management of treatment failures — In patients who fail to respond to gastric electrical stimulation but then develop recurrent symptoms, we perform repeat transient gastric neurostimulation and gastric empting.
●Pyloric myotomy – In patients with a poor response and delayed gastric empting, addition of pyloroplasty may improve symptoms. In one study, addition of pyloroplasty to gastric stimulation promoted greater acceleration of gastric emptying compared with stimulator implantation alone with greater symptom improvements in one study [53,54].
●Additional gastric electric stimulator – In patients initially unresponsive to gastric electrical stimulation or a response to repeat transient gastric electrical stimulation and normal gastric empting, implanting a second stimulator with positioning of the new electrodes to alternate locations on the gastric serosa has been associated with reduced symptoms [55].
OTHER MODES OF GASTRIC STIMULATION
High-energy, low- frequency gastric pacing — Gastric pacing aims to reset a regular slow wave rhythm. It involves giving the gastric wall long duration pulse stimuli lasting 30 to 500 ms during a non-refractory period to generate an extra slow wave that propagates along the gastric wall. However, gastric pacing is impractical at the present time, as the external current source needed to generate the energy to entrain the slow wave is too large for implantation.
The benefits of gastric pacing have been suggested in small uncontrolled studies [56]. An early trial of gastric pacing observed entrainment of the intrinsic slow wave in 10 of 16 patients with postoperative gastroparesis [57]. In an open-label trial of gastric pacing, nine patients with prokinetic medication-resistant gastroparesis (five diabetic, three idiopathic, one postvagotomy) received high-energy electrical stimulation at a rate slightly higher than the normal slow wave frequency through surgically implanted electrodes [56]. When delivered just before and after meals, the pacing stimuli entrained the slow wave in all individuals and underlying rhythm disturbances were reversed in the two patients with spontaneous slow wave dysrhythmias. After one month, gastroparetic symptoms were improved, eight patients no longer required jejunal tube feedings, and gastric emptying was enhanced compared with prestimulation values. In a diabetic rat model, application of pacing stimuli to the stomach promoted proliferation of interstitial cells of Cajal suggesting possible additional healing effects of this therapy [58].
Investigational approaches — New approaches to gastric electrical stimulation continue to be developed. Progress in nonoperative methods of electrode insertion, device miniaturization, battery technology, and development of devices that deliver variable stimuli may expand the options available to patients with medication-refractory gastroparesis. Prototype endoscopically-delivered miniaturized stimulators that can be affixed to the gastric mucosa have been developed that enhance slow wave regularity and amplitudes [59,60]. A percutaneous electrode system has been developed to deliver neurostimulating pulses for up to eight weeks in patients with gastroparesis [61,62]. With this technique, a cannula with an internal needle is introduced percutaneously and advanced to the gastric submucosa. A self-anchoring electrode is then placed through the needle. Electrodes that can be placed during percutaneous gastrostomy placement have also been devised [62,63].
Research into newer gastric pacing methods is focusing on developing implantable devices that do not require permanent externally-wired connections. Multichannel stimulation protocols have been devised to deliver high-energy pulses in sequential fashion that evoke propagating contractions and enhance gastric emptying [64,65]. Some groups use stimulus protocols that entrain intrinsic slow-wave activity, while others advocate stimuli that stimulate gastric neural activity independently of intrinsic electrical oscillations. In one study, stimulation energies for four-channel pacing were only 1 percent of the levels needed for single-channel pacing, suggesting that implantable pacemakers might be feasible [65]. Two-channel pacing with reduced current requirements has also shown efficacy in stimulating gastric emptying and reducing symptoms in patients with severe diabetic gastroparesis [66]. An impedance-based, feedback-controlled mechanism that can turn the pacer on or off depending on the intrinsic contractile state of the stomach has been developed [67]. Such devices that are activated only when triggered may reduce current requirements and prolong battery life. An investigational battery-powered gastric pacing device combined with high-resolution electrical mapping which is activated in wireless fashion by a mobile phone or computer was shown to entrain slow waves in a porcine model [68].
Another area of investigation relates to developing devices that deliver variable stimuli, which elicit beneficial effects both on symptoms and gastric emptying. In canine studies, stimulation with low-energy pulses of short duration alternating with high-energy pulses of long duration exerted antiemetic effects and reversed slow wave dysrhythmias caused by the emetic stimulus vasopressin [69]. Such dual stimulation protocols combine the effective features of both neurostimulation and pacing.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gastroparesis".)
SUMMARY AND RECOMMENDATIONS
●Electrical stimuli can be delivered to the stomach as low-energy, high-frequency gastric electrical neurostimulation or high-energy, low frequency gastric pacing. (See 'Introduction' above.)
●High-frequency gastric electrical stimulation has no effect on basal gastric electrical activity or slow wave dysrhythmias but modifies sympathovagal activity and perception of gastric distention. While uncontrolled studies suggest clinically important benefits of gastric neurostimulation, including improvements in nausea and vomiting associated with gastroparesis, there is inconsistent evidence of benefit in randomized controlled crossover trials. (See 'Mechanism of action' above and 'Benefits' above.)
●Patients with severe nausea and vomiting (occurring on average at least once daily) that are refractory to aggressive antiemetic and prokinetic drug therapy for at least one year may be candidates for gastric electrical stimulation. In the United States, the gastric electrical neurostimulator (Enterra Therapy system) has been approved as a humanitarian exemption device only for diabetic and idiopathic gastroparesis. (See 'Indications' above.)
●The benefits of gastric neurostimulation in patients with predominant symptoms other than nausea and vomiting are uncertain. Patients with nausea and vomiting and those without narcotic dependence have a more favorable clinical response than those with predominant abdominal pain, bloating, or fullness. Patients with diabetic gastroparesis have greater symptom reductions with gastric electrical stimulation compared with individuals with idiopathic or postsurgical disease. (See 'Predictors of response' above.)
●Risks of high-frequency gastric neurostimulation include infection, lead migration or erosion, lead dislodgement, electrode penetration into the gastric mucosa requiring re-operation, seroma, and bowel obstruction. (See 'Risks' above.)
●Gastric pacing involves giving the gastric wall current pulse durations lasting 30 to 500 ms during a non-refractory period to generate an extra slow wave which propagates along the gastric wall. The benefits of gastric pacing have been suggested in small uncontrolled studies. However, this method of stimulation is impractical presently, as the external current source is too large for implantation. (See 'High-energy, low- frequency gastric pacing' above.)
●Progress in nonoperative methods of electrode insertion (including endoscopically-placed stimulators or percutaneously-inserted stimulator wires), device miniaturization, battery technology, and development of devices that deliver variable stimuli may extend the range of options available to patients with severe medication-refractory gastroparesis. (See 'Other modes of gastric stimulation' above.)
