High-energy stimulation with a pulse width of 10–600 ms and a frequency similar to the physiologic stomach frequency of 2.5–3.5 cpm was shown to “pace” the stomach through entrainment of the stomach slow waves. Studies showed correction of the gastric dysrhythmias, better control of symptoms, and faster gastric emptying in a dog model as well as in humans [9, 11].

Historically, gastric emptying was not accelerated in pacing experiments on vagotomized dogs done by one of the pioneers, Keith Kelly [12]. Subsequently, the effect of gastric pacing on gastric emptying and gastrointestinal symptoms was studied in nine patients with severe gastroparesis [9]. Four pairs of temporary pacing wires were placed surgically 4 cm apart, and the most distal pair was located 2–4 cm proximal to the pylorus. The proximal pair was used for electrical stimulation, while the three distal pairs recorded the effects. Gastric dysrhythmias were identified in two patients. Using a gastric pacing frequency 10 % higher than the intrinsic slow wave frequency, gastric slow waves were entrained in all patients. In the distal antrum, the amplitude of the gastric slow wave was higher during electrical stimulation compared with the sham stimulation [9]. Some unique points need to be mentioned about this study. All the patients in this study were referred for treatment of severe gastroparesis and had failed standard medical therapy. It was established that entrainment of gastric slow waves was always achieved even when initial dysrhythmia was present by optimizing the pacing parameters. At the end of the 4 weeks of gastric pacing, a gastric emptying study was performed, which confirmed an accelerated rate of emptying and patients were also symptomatically improved.

A clinical trial in patients with severe GP secondary to diabetes compared an external pacing device with high energy and low frequency to an implantable low-energy, high-frequency neurostimulator (Enterra System) [13]. The study investigated primarily the effect of two-channel gastric pacing on the stomach myoelectric activity and energy consumption with the secondary goal of evaluating the patients’ symptoms and monitoring gastric emptying. Four pairs of temporary pacing wires were inserted and secured in the serosa of the stomach at the time of placing the Enterra System (Fig. 10.2). Nineteen patients with severe GP who did not respond to medical therapy were included in the pacing group. Electrical stimulation was provided through two pairs of wires 16 and 8 cm from the pylorus, and the other two pairs 12 and 4 cm from the pylorus were utilized for recording of the slow waves. Serosal recording measured the optimal pacing parameters in each patient for entrainment of gastric slow waves 5 days after the surgery. Gastric pacing was initiated for 6 weeks using an external multichannel pulse generator during the day, while the battery was charged overnight. It was concluded that two-channel, low-frequency gastric electrical stimulation at 1.1 times the intrinsic frequency was able to entrain gastric slow waves, improve symptoms, significantly accelerate the mean 4-h gastric retention rate, normalize gastric dysrhythmia, and decrease tachygastria in fasting and postprandial states in severe diabetic GP patients with an excellent safety profile. These results confirmed earlier studies of multichannel gastric pacing performed in dogs [14, 15]. The advantage of the two-channel gastric pacing system is mainly to improve energy consumption. For a single-channel pacing system, high energy is needed to entrain gastric slow waves and normalize dysrhythmias. The electrode being placed in the proximal stomach to avoid reverse pacing makes it necessary to consume very high energy enough to get the pulses to travel a distance of more than 20 cm to reach the distal antrum. In the two-channel gastric pacing, there is much less energy required to entrain slow waves as each channel is responsible for a smaller distance, approximately 8 cm, thus saving the battery life.

The short-pulse high-frequency stimulation parameters are a pulse width of few hundred microseconds (300 μs) and a frequency of 12 cpm, which is about four times the physiologic gastric slow wave frequency [16]. Studies in humans had initially showed stronger gastric contractions could be induced using these programming parameters as well as accelerated gastric emptying [1, 17]. Based on these principles of high-frequency and low-energy parameters, the implantable device named Enterra therapy (Medtronic, Inc, Minneapolis, MN) was developed (Fig. 10.3). A number of clinical trials ensued and the consistent outcome was that gastric electrical stimulation with the Enterra device showed both sustained and significant improvement in symptoms in most patients with severe gastroparesis refractory to medical therapy [10]. The initial double-blind crossover study using Enterra System was named World Anti-Vomiting Electrical Stimulation Study (WAVESS) [10]. The system was either turned on or shammed after implantation. After 1 month of this therapy, patients were then crossed over to the other arm of treatment for another month utilizing a randomized double-blind approach. This study was positive as far as significant differences observed in symptoms of nausea and vomiting in Enterra versus Sham arm. In the year 2000, Enterra electrical stimulation was approved by the United States Food and Drug Administration for treatment of patients with gastroparesis refractory to other therapies under the umbrella of Humanitarian Device Exemption (HDE) [18].

In the WAVESS trial, 33 patients (17 diabetic GP; 16 idiopathic GP) were randomized to a double-blind crossover study, initially, followed by 10 months open label phase when all patients had their devices activated. The weekly vomiting frequency (WVF) is a monitoring parameter set as a primary objective in many studies. After the total 12-month follow-up, 80 % of patients had more than 50 % improvement in symptoms [10]. A subsequent trial studied 55 diabetic patients with GP utilizing a different study design [19]. All patients had their devices activated after surgery for 6 weeks. Then they were randomized in a double-blind fashion to two groups, ON or OFF, for 3 months followed by crossing over to the other treatment for a further 3 months. The devices then were activated in all patients and they were followed for up to 1 year. After the initial 6 weeks, the WVF showed a median reduction of 57 % compared to baseline. Interestingly enough, during the 3-month randomization period to sham or active stimulation, the WVF was similar for the two arms. At 1-year follow-up, when all patients had the devices turned ON, there was a median reduction of 67 % in WVF in all patients, associated with improvement in total symptom scores, gastric emptying, and their overall quality of life.

Subsequently, a similar multicenter, randomized, crossover study evaluated the efficacy of GES in 32 idiopathic GP patients using the same study design as in the diabetic GP trial. For 6 weeks after surgery, all devices were activated. This was followed by a double-blinded randomized crossover phase, each of 3 months’ duration with the device either ON or OFF. A total of 25 patients completed the crossover periods and 21 patients continued a 1-year follow-up with the device activated. During the first 6-week period, there was a significant reduction in WVF of 61 %. Again, during the crossover period, the improvement was not significant in the treatment phase versus sham (17 % median reduction of WVF). At 1 year, there was a median reduction of 87 % in WVF from the initial baseline with improvement of GP symptoms, gastric emptying, and with reduction in days of hospitalization [20]. Collectively, these two studies showed that at 12 months of continuing stimulation, there was a significant improvement of symptoms, reduction in hospitalization days, and better quality of life in patients with severe refractory GP unresponsive to medical therapy (Fig. 10.4) [19, 20].

The reason why these two trials did not meet the primary goal still needs to be investigated since there was no difference between Enterra therapy and sham during the crossover period. One possibility is that the initial 6 weeks of GES preceding the crossover phase induced a sustained symptom response resembling a memory or “imprinting” effect that continued despite the device being deactivated. The lesson for future trials is to randomize GES patients at the time of surgery to stimulation versus sham arm, without introducing a crossover phase.

The largest series with long-term follow-up of Enterra treatment describes 221 patients: diabetic (64 %), idiopathic (22 %), and postsurgical (14 %) gastroparetic subjects who were followed for up to 10 years with the GES device being always activated. The total symptom score was improved more than 50 % in 54 % of patients overall, while diabetic GP improved the most (58 %) and the least impressive results were seen in idiopathic GP patients (48 %). The study is considered the largest and longest in the world. It concluded that electrical stimulation achieved significant improvement in patients with severe GP and the efficacy was sustained for up to 10 years. In addition, 89 % of patients who were requiring a jejunostomy tube at time of GES implantation could stop their tube feeding and have the jejunostomy tube removed within 12 months. Most importantly, there was good tolerance and safety profile [21]. An explanation for the idiopathic GP patients to be the least responders is that those patients represent a heterogeneous mixture of patients who have more complaints of abdominal pain than other groups [22, 23]. Unfortunately, abdominal pain is the least likely symptom to improve with electrical stimulation [1].

Although several studies have showed clinical improvement in symptoms and quality of life in patients with severe GP not responding to medical therapy, it is also established that there is no consistent improvement in gastric emptying and no reduction in gastric dysrhythmias. Three main mechanisms are identified to explain symptomatic improvement with GES [24]:

Both laparotomy and laparoscopic approaches are utilized as implantation techniques of the GES depending on the expertise and training of the surgeon (Fig. 10.3) [9]. The laparoscopic technique has the benefit of less need for postoperative pain medication and briefer hospital stay. In both approaches, two leads are inserted in the muscularis propria. They are sutured on the greater curvature 9 and 10 cm from the pylorus and connected by 35 cm long leads to the pulse generator implanted subcutaneously in the abdominal wall, mostly in the right upper quadrant. Using an external programmer, the device is interrogated to standardized parameters termed the “default setting” (5 mA, 14 Hz, 330 μs, cycle on and cycle off 0.1 and 5 s, respectively).

Voltage and current parameters are then reevaluated at varying times postoperatively. There are no controlled trials regarding the best stimulation parameters to be adopted [21]. In the 10-year trial data that were published [21], the voltage was increased in increments of approximately 20–30 % during follow-up visits if the clinician and the patient felt that symptoms were still not well controlled and more energy was required.

Infection of the generator site is the most common complication with incidence of about 6 %. It occurs more in diabetic patients or due to trauma or falls [1]. Other complications include dislodgement of the electrodes or their penetration through the gastric mucosa, lead insulation damage, erosion or migration of the device and bowel obstruction, or discomfort at the site of the pulse generator.

Removal of the Enterra System may be necessary in some cases of infection (6 %), persistence of symptoms (2 %), lead dislodgement, skin penetration, bowel obstruction, and when gastrectomy is performed due to failure of treatment (4 %). Repositioning and/or replacement of the lead(s) due to dislodgment from trauma or twisted wires (2 %) and device migration (1 %) may also necessary if these complications were radiologically documented.

Batteries can be changed if depleted without changing the electrodes. The life expectancy of the battery is 8–10 years but may be shortened if high parameters (voltage, rate, pulse width) are sustained.

Studies have attempted to identify factors that predict the response to GES. It is very well established that patients with diabetic GP represent a homogenous group in terms of pathophysiology and are the ones who benefit the most from GES [21]. Making the right diagnosis is a very important outcome predictor. GES will not improve nausea and vomiting caused by rumination syndrome, dumping syndrome, cyclic vomiting syndrome, or bulimic/anorexic vomiting.

Other factors that will reduce the response to GES and impair the outcome are concomitant migraine headaches, endometriosis, and the menstrual cycle. When abdominal pain is the major presenting symptom, this is a red flag. GES controls nausea that may lead to less abdominal pain because of reduced vomiting episodes. However, controlling abdominal pain by GES is not the primary goal. Idiopathic GP is less responsive than diabetic group of GP patients, and one reason could be the very strong component of abdominal pain in their clinical presentation. Narcotic use to control abdominal pain or for other reasons like fibromyalgia, back pain, or migraine is more common in idiopathic patients. Narcotic use inhibits gastric motility and increases nausea and vomiting. Finally, the presence of dysrhythmias found by performing an electrogastrogram as a marker for the loss of interstitial cells of Cajal (ICC) has been reported to be associated with less long-term symptom improvement [1]. Recent data now indicate that up to 50 % of patients have depleted ICC population based on smooth muscle biopsies obtained at the surgery [7].

The implantation of the gastric electrical stimulator alone has no positive effects on improving gastric motility and gastric emptying or correcting electrical dysrhythmias [25]. This therapeutic deficiency of continued slow gastric emptying can be overcome by performing the Heineke-Mikulicz pyloroplasty as a supplementary surgery in severe GP patients undergoing implantation of the gastric electrical stimulation system. In a recent abstract submitted to Digestive Disease Week 2016, the mean retention of isotope during gastric emptying was decreased after GES combined with pyloroplasty and 62 % of patients actually normalized their emptying. There were also significantly reduced days of subsequent postoperative hospitalization from 78 to 10 days per patient/year. No postsurgical complications were observed during the long-term follow-up, indicating the addition of pyloroplasty was safe. At Texas Tech University Health and Science Center in El Paso, simultaneous placement of GES and pyloroplasty began in 2012, and our experience now exceeds 40 patients. Currently, the laparoscopic robotic approach (Fig. 10.5) further reduces the risks of postsurgical complications, due to the improved wrist-like articulation that facilitates suturing and electrode placement. The incidence of wound infections and abscess or enteric fistulas did not increase with this procedure. An intraoperative EGD exam is performed in all cases to confirm placement of GES stimulator leads and examine the effect of pyloroplasty on the pylorus. This series demonstrated the safety and efficacy of combining pyloroplasty with implantation of the gastric electrical stimulator, achieving a 50 % improvement in overall gastroparesis score in 71 % of patients during long-term follow-up (Table 10.1) [25]. This compares to only 50 % achieving this response by GES alone.